studies in Natural Products Chemistry Volume 20 Structure and Chemistry (Part F)

(Including Cumulative Index Volumes 1-20)

Studies in Natural Products Chemistry edited by Atta-ur-Rahman

Vol. 1 Stereoselective Synthesis (Part A) Vol. 2 Structure Elucidation (Part A) Vol. 3 Stereoselective Synthesis (Part B) Vol. 4 Stereoselective Synthesis (Part C) Vol. 5 Structure Elucidation (Part B) Vol. 6 Stereoselective Synthesis (Part D) Vol. 7 Structure and Chennistry (Part A) Vol. 8 Stereoselective Synthesis (Part E) Vol. 9 Structure and Chemistry (Part B) Vol.10 Stereoselective Synthesis (Part F) Vol.11 Stereoselective Synthesis (Part G) Vol.12 Stereoselective Synthesis (Part H) Vol.13 Bioactive Natural Products (Part A) Vol.14 Stereoselective Synthesis (Part I) Vol.15 Structure and Chemistry (Part C) Vol.16 Stereoselective Synthesis (Part J) Vol.17 Structure and Chemistry (Part D) Vol.18 Stereoselective Synthesis (Part K) Vol.19 Structure and Chemistry (Part E) Vol.20 Structure and Chemistry (Part F)

Studies in Natural Products Chemistry

Volume 20
Structure and Chemistry (Part F)
(IncludingCumulative Index Volumes 1-20)

Edited by

Atta-ur-Rahman

H.E.J. Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan

1998

ELSEVIER
Amsterdam - Lausanne - New York Oxford - Shannon - Singapore - Tokyo

ELSEVIER SCIENCE B.V. Sara Burgerhartstraat 25 P.O. Box 211, 1000 AE Amsterdam, The Netherlands

1998 Elsevier Science B.V. All rights reserved. This work and the individual contributions contained in it are protected under copyright by Elsevier Science B.V., and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier Science Rights & Permissions Department, PO Box 800, Oxford 0X5 IDX, UK; phone: (+44) 1865 843830, fax: (+44) 1865 853333, e-mail: permissions@elsevier.co.uk. You may also contact Rights & Permissions directly through Elsevier's home page (http://www.elsevier.nl), selecting first 'Customer Support', then 'General Information', then 'Permissions Query Form'. In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (978) 7508400, fax: (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London WIP OLP, UK; phone: (+44) 171 436 5931; fax: (+44) 171 436 3986. Other countries may have a local reprographic rights agency for payments. Derivative Works Subscribers may reproduce tables of contents for internal circulation within their institutions. Permission of the publisher is required for resale or distribution of such material outside the institution. Permission of the publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Contact the publisher at the address indicated. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the publisher. Address permissions requests to: Elsevier Science Rights & Permissions Department, at the mail, fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

First edition 1998 Library of Congress Cataloging in Publication Data A catalog record from the Library of Congress has been applied for. ISBN: 0-444-50105-3 The paper used in this pubUcation meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper). Printed in The Netherlands.

FOREWORD

Natural Product Chemistry continues to grow at an increasing pace and this growth is reflected in the present volume of Studies in Natural Product Chemistry which is the 20^^ of this series. The first 20 volumes were largely devoted to structure and synthesis of various classes of natural products, irrespective of their bioactlvity. Subsequent volumes of this series will however be devoted to the chemistry of bioactive natural products and will therefore represent a departure from the earlier volumes. The present volume contains contributions from a number of eminent scientists and covers Interesting reviews on terpenes, alkaloids and other types of natural products reported from terrestrial and marine sources. It is hoped that this volume will be received with the same enthusiasm and Interest as the previous volumes of this series. Comprehensive Indexes covering all the 20 volumes, have been prepared and they include a Cumulative General Subject Index along with more focused Cumulative Indices on Organic Synthesis, Pharmacological Activity and Biological Source. This comprehensive indexing of the volumes should make the entire series much more valuable and user-friendly. I would like to express my thanks to Dr. Farzana Akhtar, Dr. Farhana Noor-e-AIn, Mr. Zaheer-ul-Haq, and Miss Rehana Shah for their assistance in the preparation of the Index. I am also grateful to Mr. Waseem Ahmad for typing and to Mr. Mahmood Alam for secretarial assistance.

Atta-ur-Rahman
July 31. 1998

Ph.D. (Cantab), Sc.D. (Cantab)

This Page Intentionally Left Blank

PREFACE
Volume 20 of this well known series entitled: "Studies in Natural Products Chemistry", continues the high standard of the previous volumes. The 17 Chapters represent a broad spectrum of topics which serve as an excellent overview of the vast array of natural products research continuing on a worldwide basis. The areas covered do not duplicate to any significant extent material covered in previous volumes and indeed present to the interested reader, information which is useful and pertinent to those involved in the highly diverse avenues of natural products. Each of the chapters is well written and brings fonA/ard in review fashion, a particular area of natural products chemistry. The manner of presentation in the majority of chapters allows the linkage of synthetic and structural chemistry with biological applications and relevance. As the area of natural products research continues to expand into these interdisciplinary avenues, the information provided by the authors is particularly useful not only to the specialist but to the scientist wishing to develop a general knowledge of the specific field covered within the Chapter. This Volume, as the previous volumes in this series, is highly recommended as a useful summary of important information which spans the diverse area of biological activity, medicinally Important terpenes, alkaloids, steroidal lactones, carotenoids, natural colourants, peptides and the use of enzymes in the products of chiral synthons.

James P. Kutney

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CONTENTS
Foreword Preface Contributors
Terpenes and their Biological Relevance
G.G. HABERMEHL AND W. FLIEGNER
3
V

vii xi

Crinitol, an Acyclic Diterpene Diol from Marine Algae I. KUBO AND L.R. SMITH Stereoselective Synthesis of Methylcyclopentanoid Monoterpenes
A. BIANCO

25

41

Chemical Constituents of Taxus Species

V.S. PARMAR AND A. JHA
79

Withanolides, Biologically Active Natural Steroidal Lactones : A Review A.S.R. ANJANEYULU, D. S. RAO, P.W. LEQUESNE

135

Natural Products by Oxidative Phenolic Coupling Phytochemistry, Biosynthesis and Synthesis 263 G.M. KESERU AND M. NOGRADI

Narcissus Alkaloids
J. BASTIDA, F. VlLADOMAT AND C. CODINA
323

Total Synthesis of Naphthylisoquinoline Alkaloids

M.A. RIZZACASA
407

DNA - Damaging Natural Products with Potential Anticancer Activity A.A. LESILE GUNATILAKA AND DAVID G.I. KINGSTON

457

In Vitro Models of Human Disease States

J.M. PEZZUTO, C.K. ANGERHOFER AND H. MEHDI
507

Synthesis of Carotenoids H. PFANDER, M. LANZ AND B. TRABER Structure Elucidation of Phenylpropanoid Wood Extractives S. OZAWA, T. SASAYA AND S. NlSHIBE Chemical and Biological Investigations of Salvia Species Growing in Turkey
A. ULUBELEN AND G. TOPCU

561

613

659

The Chemistry of Some Natural Colourants J.H.P. TYMAN Bioactive Natural and Synthetic Acronycine Derivatives Modified at the Pyran Ring S. MICHEL AND F. TILLEQUIN Chiral Synthons by Selective Redox Reactions Catalysed by Hitherto Unknown Enzymes Present in Resting Microbial Cells H. SIMON AND H. GUNTHER Microcystins and Nodularins Hepatotoxic Cyclic Peptides of Cyanobacterial Origin L. MORODER AND S. RUDOLPH-BOHNER Subject Index

719 789

817 887 921

CONTRIBUTORS
A.S.R. Angerhofer Cindy Kay Angerhofer Professor of Organic Chemistry, School of Chemistry, Andhra University, Visakhapatnam-530 003, India Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, U.S.A. School of Chemistry, Andhra University, Visakhapatnan 530 003, India Department of Natural Products, Faculty of Pharmacy, University of Barcelona, Avda., Diagonal 643-08028 Barcelona, Catalonia, Spain Centro di Studio CNR per la Chimica delle Sostanze Organiche, Naturali Dipartimento di Chimica-Universita La Sapienza-Roma, Italy Department of Natural Products, Faculty of Pharmacy, University of Barcelona, Avda., Diagonal 643-08028 Barcelona, Catalonia, Spain Chemisches Institut der Tieraztichen, Hochschule Hannover, Lehrgebiet fur Organische Chemie, Bischofsholer Damm 15, HausNr. 123, 30173 Hannover, Germany Bioresources Research Facility, The University of Arizona, Tucson Arizona, 250 East Valencia Road, Tucson, Arizona 85706, USA Institut fur Organische Chemie und Biochemie, Universitat Munchen, D-8 5 747 Garching, Germany Technische

A.S.R. Anjaneyulu Jaume Bastida

Armandodoriano Bianco

Carles Codina W. Fliegner

Abeysinghe Arachchige Leslie Gunatilaka Helmut Giinther G.G. Habermehl

Chemisches Institut der Tieraztichen, Hochschule Hannover, Lehrgebiet fur Organische Chemie, Bischofsholer Damm 15, HausNr. 123, 30173 Hannover, Germany Department of Chemistry, University of Delhi, Delhi-110 007, India Research Group for Alkaloid, Chemistry of the Hungarian, Academy of Sciences, P.O. Box 91, H-1521 Budapest, Hungary Department of Chemical Information Technology, Technical University of Budapest, POB 91, H-1521 Budapest, Hungary

Amitabh Jha G.M. Keserti

Gyorgy Miklos Keserii

David George Ian Kingston Isao Kubo

Bioresources Research Facility, The University of Arizona, Tucson Arizona, 250 East Valencia Road, Tucson, Arizona 85706, USA Department of Environmental Science, Policy and Management, University of California, 201 Wellman Hall, Berkely California 94720-3112, U.S.A. Department fiir Chemie und Biochemie, University of Berne Freiestr. 3, CH-3012 Berne, Switzerland Department of Chemistry, North Eastern University, Boston, MA 02115, USA Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, U.S.A. Universite Rene Descartes-Paris V, Faculte De Pharmacie, Laboratoire de Pharmacognosie, U.R.A. au C.N.R.S.N. 1310 4, Avenue de I'Observatoire, 75270 Paris Cedex 06, France Max-Plank-Institut far Biochemie, Am Klopferspitz 18a, D-82152, Martinsried, Germany Faculty of Pharmaceutical Sciences, Health Sciences, University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-02, Japan Research Group for Alkaloid, Chemistry of the Hungarian, Academy of Sciences, P.O. Box 91, H-1521 Budapest, Hungary Department of Forest Science, Faculty of Agriculture, Hokkaido University, Sapporo 060, Japan Department of Chemistry, University of Delhi, Delhi-110 007, India Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, U.S.A. Department fiir Chemie und Biochemie, University of Berne Freiestr. 3, CH-3012 Berne, Switzerland

Marc Lanz P.W. LeQuesne Haider Mehdi

Sylvie Michel

Luis Moroder Sansei Nishibe Mihaly Nogradi Shuji Ozawa Virinder Singh Parmar John Michael Pezzuto

Hanspeter Pfander

D. Satyanarayana Rao Mark A. Rizzacasa Sabine Rudolph-Bohner Takashi Sasaya Helmut Simon Leverett R. Smith

School of Chemistry, Andhra University, Visakhapatnan 530 003, India School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia Max-Plank-Institut fur Biochemie, Am Klopferspitz 18a, D-82152, Martinsried, Germany Department of Forest Science, Faculty of Agriculture, Hokkaido University, Sapporo 060, Japan Institut fur Organische Chemie und Biochemie, Universitat Munchen, D-85747 Garching, Germany Technische

Department of Environmental Science, Policy and Management, University of California, 201 Wellman Hall, Berkely California 94720-3112, U.S.A. Universite Rene Descartes-Paris V, Faculte De Pharmacie, Laboratoire de Pharmacognosie, U.R.A. au C.N.R.S.N. 1310 4, Avenue de I'Observatoire, 75270 Paris Cedex 06, France Department of Chemistry, Tubitak, Marmara Research Center, P.O. Box 21, 41470, Gebze-Kocaeli, Turkey Department fur Chemie und Biochemie, University of Berne Freiestr. 3, CH-3012 Berne, Sv^itzerland Department of Chemistry, Brunei University West London, Uxbridge, Middlesex UB8 3PH, U.K. Department of Chemistry, Faculty of Pharmacy, University of Istanbul, 34452 Istanbul, Turkey Department of Natural Products, Faculty of Pharmacy, University of Barcelona, Avda., Diagonal 643-08028 Barcelona, Catalonia, Spain

Francois Tillequin

Giilacti Topcu Bruno Traber John Henry Paul Tyman Ayhan Ulubelen Francese Viladomat

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Structure and Chemistry

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

Terpenes and their Biological Relevance

G.G. Habermehl and W. Fliegner
1. INTRODUCTION Terpenes are a large group of natural products, occurring mainly in higher evolved plants as secondary metabolites. The occurrence in higher evoluted plants only may be understood as a consequence of phylogenesis. Under the pressure of selection from herbivorous animals, the synthesis of substances with repellent properties has been necessary in order to make possible a coexistence of different plant and animal species. The first chemical deterrence mechanisms were of an unspecific kind. The synthesis proceeded via the shikimic acid pathway which was already completely developed in gymnosperms. One example of this is the synthesis of lignin. Lignin is one of the most abundand contents of wood, varying between 18 and 30 %. Although its main property is the formation of the stroma, it possesses some antifungal and insectizide properties. By the shikimic acid pathway phenols and tannins are formed, too, to prevent an attack from microorganisms and animals. During the following evolution this pathway has been left stepwise, until in the angiosperms the acetate-mevalonate pathway dominated. This pathway in angiosperms has opened an immense chemical source to specifically acting poisons and repellents, many of them being terpenes. This invention was followed by intense evolutionary interactions between plants and animals, yielding that high diversity of angiosperms, and at the same time, animal species since about 100 million years ago. About 65 million years ago this development of plants was perfect, and the angiosperms predominant. This evolution of poisonous substances in plants coincides with the extinction of the dinosaurs. If one looks closer to this event, one may observe that there has been no complete extinction; many of the saurians survived in one way or another. For example, our birds come from flying saurians; the close connection between the birds and the reptiles of today can be seen in their closely related physiology, leading to the zoological classification of "Sauropsidae", enclosing both, reptiles and birds. And if you have a look at the saurians of today, nearly all of them are carnivorous. All these facts may lead to the conclusion that the herbivorous saurians only became extinct. This is supported by the fact that the dinosaurs did not disappear within a short period of time, as one should accept if this was due to a cosmic event, or a big vulcanic eruption, but within a million of years or so. All these observations fit together, if one accepts that the complete change in

the plant kingdom, together with the newly developed substances led to the end of the dinosaurs. The new physiology with the new acetate-mevalonate pathway gave the opportunity to the plants to produce a tremendous amount of substances acting as protecting agents. 2. TERPENES AND THEIR ACTIVITIES 2.1 Terpenes as Repellents In a few cases only, the topical situation (spines, thorns) is of protective value against herbivores. The most potent and effective chemical repellents against these animals are those producing pain or discomfort because of a bad taste or smell. Typical examples are the irritating diterpene-esters from Euphorbiaceae or from Thymelaeaceae (1), or the toxic bitter principles from the Cucurbitaceae, e.g. the Cucurbitacines (2). There are also numerous terpenes acting as contact allergens with serious skin irritations, like the sesquiterpenelactones from Asteraceae (3). Sometimes substances may be effective even after consumption, provided that the animal can recognize the connection between feed and result. In many cases this is not true and, therefore, not a protection. It is well known that cattle or horses like to eat outside the fence, even if they are on a good meadow, either for curiosity or instinct of play. Good examples are here andromedotoxin from Rhododendron 2.2 Resistance Formation Microorganisms are able to establish resistances because of their great genetic flexibility, the short generation times, and intraspecific as well as interspecific gen exchange. A generally known example of this capability is the resistance against therapeutically used antibiotics. But insects, too, are able to adapt to chemical repellents, even using such substances for their own defense, as is well known from ants and beetles.In such cases a substance which should protect its producer (allomone) becomes a substance useful for the attacker (kairomone), (4, 9). 2.3 Underground Competition Not only animals but also plants are competing in the struggle for the best conditions of life, and they use chemical defense mechanisms, too. Some plants are able to set free germicides directly from the roots. Another mechanism is to exsude from the surface of the leaves such substances which come into the earth by the rain (5). Typical examples are Salvia leucophylla and Artemisia californica. These shrubs suppress the growth of any plants within a radius of 1 meter completely, by excretion of 1.8-cineol and campher; these substances and Andromeda species, or the terpene-alkaloids from Aconitum, belonging to the most potent plant toxins.

inhibit the growth up to a distance of 9 meters (6). 2.4 Terpenes as Signal Substances Terpenes are also used as signal substances, especially with ants but also with other insects. Farnesol is used as male attractrant (7), Citral, geraniol, nerolic acid, and geranic acid are used to transmit information on feed sources (8). These substances, mostly monoterpenes, and sesquiterpenes are produced by plants and taken up by the insects who store them in special glands from which they are released according to their needs. These mechanisms have been developed in a most sophisticated way by ants, butterflies, and beetles (9). Using mixtures of terpenes in different concentrations, they have established a real "chemical language". 2.5 Activities within the Plants. Some terpenes act as plant hormones, e.g. as growth regulators. Such regulators are the brassinolides, steroids with a seven-membered lacton ring B as well as two vicinal diol functions in ring A, and in the side chain (10). The brassinosteroids show in submicromolar concentrations a complex physiologic activity spectrum, e.g. a raise in resistance against stress factors like heat, cold, drought or phytopathogenic infection. The biochemistry of these effects has been studied in detail (11).

3.

TERPENES AS PLANT POISONS AND REPELLENTS. 3.1 General aspects Among all the activities of terpenes from plants, their toxicity is most

important for several reasons. One aspects is their role in ecology as protection of the plants, the other is the economic aspect and also the health aspect, as terpenes are involved in quite a number of envenomations. Envenomations in humans are not rare; mostly children are involved who eat or suck berries or leaves. However, in an increasing number, also adults are involved. On the "green wave" they collect herbs and roots by themselves, considering them "more healthy" than the commercial ones, but confounding them with dangerous species. In the same way therapeutics from plants are estimated harmless for being "natural remedies", and envenomation occurs, frequently due to an overdose.But in most of the cases animals are involved, not only grazing animals but also small animals at home. In the following section the most important plants with terpenes as toxins will be presented together with their chemistry and the symptoms of poisoning.

3.2 Family: Apicaceae Sium latifoliurriy Water parsnip. The plant is abundand in Central Europe but occurs also in the rest of the continent, and also in parts of Africa. The fruit contains (6-7%) of a mixture of limonen (80 %), perillaaldehyde (6%),oc-, and B-pinene, 6-bisabolon, and c?<.-curcumene. Poisoning has been observed in cattle and in sheep with gastroenteritis which led to sudden death. In humans having eaten roots, vomiting, diarrhea, bradycardia as well as muscle paralysis have been observed (14). 3.3 Family: Aquifoliaceae Ilex aquifolium, Holly. The family includes 440 species distributed all over the world with centres in China (112 species) and Brasil (75 species). Ilex aquifolium is the most abundand species in Central Europe where it may be found in forests, but it is also very popular as ornamental plant in houses and gardens. The poisonous parts are the berries, and to a lesser extent also the leaves; they contain ursolic acid, uvaol, o^-amyrin, and a bisnor-monoterpene, Ilex-lactone (12), as well as 27-p-cumaroxy-ursolic acid (13). The South American Ilex paraguariensis contains also coffein and theobromin, and is therefore used as tea. Symptoms of poisoning have been observed in children after consumption of berries, with vomiting, diarrhea and drowsyness. 3.4 Family: Araliaceae Hedera helixy Ivy Ivy is far distributed in Europe, and in South Africa; it has been introduced to North America. Preferred locations are forests with old trees, bushes, and walls. It is a creeping plant which may go up about 30 meters. It must not be confounded with poison ivy ! The poisonous parts are the leaves, and even more the blue-black pea-size berries. The active terpenes are triterpene saponins, about 2 - 6 % of the weight. The main saponins are oc-hederin which on hydrolysis yields hederagenin, arabinose and rhamnose, and 6-hederin yielding oleanolic acid, arabinose and rhamnose on hydrolysis. Furthermore the sesquiterpenes germacren, 6-elemen, and elixen are found (14). The hederins share with other saponins a strong hemolytic activity (15). Typical symptoms after ingestion are irritation of mucous membranes, vomiting, headache, drowsyness, and irregular pulse. Milk fever like disease has been observed in cattle (16), and poisoning of horses is also described (17). Allergic contact dermatidis in humans has been described extensively (18, 19, 20). The hederosaponins possess antibacterial as well as antifungal activities (20).

Limonen

Perilla aldehyde

Ursolic acid, R=COOH -Amyrin, R=CH3

Ilex lactone

;ooH

Hederagenin, R-j = CH2OH R2= Rhamnose-Arabinose

Oleanolic acid, R-| = CH3

Germacen

B-Elemen

Elixen

3.5 Family: Asteraceae The Asteraceae (Compositae) comprise about 15,000 species, and thus belong to the biggest plant families. They include herbs, shrubs, and trees, and they are divided into two subfamilies: The Asteroideae distributed worldwide, and the Cichorioideae, distributed mainly on the Northern Hemisphere, and characterized by containing a milky juice. Lactuca virosa, Prickleylettuce Prickleylettuce is endemic to the Mediterranean area, but, due to its former use as medicinal plant has been distributed over Europe and Western Asia. It is no more used in medicine due to its toxicity which in humans leads to an increase of the respiration connected with sweating and drowsyness, and eventually exhaustion which explains its former use as narcotic, and as antaphrodisiacum. In animals damage of the heart, and hypotension have been described (14). The toxicity of the main components lactucin, and lactucopicrin is relatively low. The main protection of the plants is due to its bitter taste connected with both of these compounds. Xanthium species, Cocklebur The toxic compounds are atractyloside and carboxyatractyloside (21). The aglycones of these glycosides are of the kauran type (22). These compounds had earlier been isolated from Atractylis gummifera, endemic to the Mediterranean Area (23, 24). The action mechanism of the poisoning is a specific inhibition of the ATP-ADP carrier of the inner mitochondria membranes, thus preventing the transport of the nucleotides to the place of cell respiration within the mitochondria. The result is a deficiency of ADP there, and finally stop of the respiration chain. The toxicity of carboxyatractyloside is 10.7mg/kg body weight (mouse, i.p.) (23). Typical symptoms in animals are faintness, ataxia interrupted by agitation, koma, and finally death. The hematologic examination showed an increase in the neutrophil granulocytes, extreme hypoglycaemia, and a significant rise of the liver enzymes (25). Carboxyatractyloside is a substance inhibiting the growth of other plants; it may be compared in its inhibiting activity with abscissic acid. Wedelia species. Wedelia glauca is a shrub causing losses in cattle in Argentina, Brasil, and Uruguay (26). The toxic substance again is atractyloside (27) and related kauran type acids (26). Wedelia asperrima is responsible for considerable losses in grazing animals, especially of sheep in Australia. The toxin responsible is wedeloside (28) with some unusual features in its structure: The occurrence of an amino sugar is rare in plants; the distribution of the hydroxy groups in the kauran system is quite

Lactucin, R=H Lactucopikrin, R =CO-CH2-C6H4-(p-OH)

HOCH

Atractylosid, R = H Carboxyatractylosid, R = C O O H

PhCH2CH2(:oJ

r-^UO

OOC-^ ^COOH

OH

Wedeiosid

10

unusual. The toxicity is 1 mg/kg body weight (mouse). Death occurs within 24 hours after ingestion of the plant. Experiments showed (28) that this compound has a strong antitumor activity. Helenium species Helenium microcephalum, Smallhead sneezeweed. Helenium microcephalum is a herbal plant distributed in the South of the USA, and in North Mexico, where it is responsible for poisoning of cattle, sheep and goats. The toxic substance is helenalin (29, 30). 2.5 g of fresh plant material per kg body weight lead to the death of the animals. The symptoms occur early, after one hour already and include salivation, colic, diarrhea, vomiting and progressive faintness, and finally death, usually within 24 hours. Post mortem findings include changes in liver, heart, brain, kidney, and mucosa (31). Helenium amarumy Bitter sneezeweed. This plant is endemic to the South and the East of North America. Poisoning in animals is rare because of its low toxicity, and its extreme bitter taste which prevents animals from eating. Occasional uptake of small amounts of leaves, however, are sufficient to give the milk of those animals a bitter taste. The bitter principles are tenulin and isotenulin (32).. Milk with 1 ppm tenulin is undrinkable. The toxicity of tenulin is far lower that that of helenalin; in experiments sheep tolerated up to 700 mg tenulin/kg body weight without showing signs of poisoning (33). Hymenoxis odorata, Western Bitterweed. Western Bitterweed is distributed in the Southwest of the USA, and is the main reason for big losses in sheep and goats (34, 35). The responsible compound is the sesquiterpen lacton hymenovin. Sheep are extremely sensitive: 150 - 200 mg will cause death within 24 hours. Most poisonings do not occur acute but are chronic, as may be seen from the fact that sheep develop the first symptoms after being one or two weeks on grassland with Western Bitterweed. The symptoms start with loss of appetite, followed by mucous flux from the nose, and progressive faintness. Post mortem findings included edema of the mucous membranes as well as necroses in liver and kidneys; the gall bladder shows petechial bleedings. Geigeria species, Vermeerbos. Geigeria species are responsible for losses of sheep and goats, occasionally also cattle in South Africa. The poisoning is known under the name "Vermeersiekte" (Vomiting disease). Just to give one example: In 1954 about 50.000 sheep died from this poisoning in the area close to Kimberley (36). As the name of this disease explains, the prominent symptom is heavy vomiting; muscle tremor is followed by immobility. The toxins are vermeerin and geigerin,

11

Isotenulin

Tenulin

xp:^
Helenalin Hymenovin Vermeerin Gejgerin

12 the first one showing again the exocyclic methylene lacton group, and the second the unsaturated five membered ring keton. Structure-activity relationship. The cytotoxicity of these compounds is due to a very reactive centre in the molecule, the exocyclic oC-methylene-/^lacton group which may easily add to sulfhydryl groups of enzymes or other proteins (32, 34, 35). Therefore, cystein applied immediately has been shown to be a useful antidot in hamsters (34). Tenulin, which is less toxic than the other compounds lacks this methyl en el acton group; it possesses an <>c,6-unsaturated keto group in the cyclopentane ring, as is found in many toxins and carcinogens. Allergic Reactions. Sesquiterpene lactones are a special characteristic of the Asteraceae. In a test of more than 80 of such compounds it has been found that the exocyclic methylene lacton system mentioned above is also responsible for sesitization (37, 38, 39), and allergic reactions. Many Asteraceae have been used as teas or tinctures in traditional medicine. The abundant content of poisonous compounds or allergenes has led to less and less application. 3.6 Family: Brasicaceae Iberis amara, Wild Candytuft, Bitter Candytuft This plant, growing up to 40 cm, is endemic to the Mediterranean Area but may also be found cultivated in gardens. The whole plant is toxic especially the seeds. Poisoning by Candytuft is a synergistic effect from many compounds. As in most other Brassicaceae it contains glucosinolates, but also the cucurbitacines E, I, J, and K (40). The symptoms, therefore, depend on the dominating substances. Glucosinolates possess bacteriostatic properties, the cucurbitacines are cytotoxic. The gastrointestinal form of poisoning is connected with loss of appetite, loss of rumination, thirst, salivation, decrease of milk production, colic, and diarrhea or also constipation. The respiratory form is characterized by edema and emphysema of the lungs resulting in difficulties in breathing. The nervous form of the poisoning shows loss of orientation, and sometimes loss of vision. Hemoglobinuria is frequent (41). 3.7 Family: Chenopodiaceae Chenopodium ambrosioides, Wormseed, Jerusalem oak, Stinking weed. Chenopodium introduced to Chenopodium abrosioides is endemic to South America, but it has been America, to Europe and to Africa. botanical is a variety thereof, and there are a number of in their contents of terpenes. The Central and North

anthelminticum

further varieties, differing

classification has still to be revised. Toxic parts include the fresh blooming

13

leaves, the seeds, and especially the seed oil. "Oleum chenopodii" contains about 70 % Ascaridol, and about 22% of Cymol, limonen, isolimonen, and <?^-terpinen. Ascaridol is a monoterpene with a peroxy group, which is very rare in natural products (7). From a Japanese variety, compounds like pinocarvon and aritason have been isolated (7, 42). In Argentinian plants up to 40% p-Cymol have been found. Envenomations are described in chicken uptaking the seeds. Symptoms were vomiting, gastritis, and faintness (17). Poisoning in humans has not been observed by the plant itself but from improper application of Oleum Chenopodii in pharmacy. Due to its content of ascaridol it is used against intestinal parasites.Even with proper treatment side effects like nausea, vomiting, trembling of hands and feet, as well as deafness (paralysis of the nervus cochlearis) are not rare. After longer application liver, spleen and kidneys are also affected. 3.8 Family: Cucurbitaceae. Bryonia alba, White bryony Bryonia dioica. Red bryony Ecballium elaterium. Squirting cucumber Citrullus colocynthiSy Bitter apple These four plants are endemic to the Mediterranean Area but have been introduced to other parts of Europe; the bitter apple is also found in the savannahs of Africa. All parts of the plants are poisonous, especially roots and fruits. The compounds responsible are the cucurbitacines, a rather big family of tetracyclic triterpenes, occurring either in free form or as glycosides. They have been studied intensively (2, 43, 44, 45, 46). Envenomations in humans occur either by improper use of preparations in traditional medicine; there is a broad spectrum of indications described, so that one can hardly believe the real effectivity. Children are endangered because of the fruits. 15 berries of bryony are considered to be fatal. A general feature of the cucurbitacines is their cytotoxicity, causing irritations of the skin leading to necroses and ulcera. Most of the internal symptoms follow the same way: Diarrhea, vomiting, headache, and in severe cases convulsions and death. There is no difference of symptoms between animals and humans. Most animals would avoid the plants because of their bitter taste. But in cattle it has been observed that they eat again, after having recovered from the first poisoning. Due to the cytotoxicity of the cucurbitacines they have been investigated as potential antitumor agents. In cell cultures they decreased the protein biosynthesis remarkably, but in vivo the side effects are too severe as that there was any practical use.

14

Ascaridol

Pjnocarvon

Acetylandromedol (Andromedotoxin)

Cucurbitacin I: R=OH Cucurbitacin E: R=OAc

15

Cucurbitacin D (Elatericin A), R = =H Cucurbitacin B, R=OAc

^"3 Cucurbitacin K: RrCH(OH)-(j-OH CH3

^"3 Cucurbitacin J: R=lj-OH CH,

Cucurbitacin L

16

3.9 Family: Cupressaceae, Thuja occidentalis American arbor vitae Thuja orientaliSy Oriental arbor vitae Thuja occidentalis is, as its common name says, endemic to North America Thuja orientalis to China. Both plants, however, are widely spread now worldwide as ornamental plants. There is no difference in the composition of their terpenes. The main component, also responsible for the toxicity is thujon with more than 50 per cent of the essential oil from Thuja. Furthermore fenchone, campher, sabinene, and terpineol-4, tannins and bitter principles are found, too. Envenomation in humans was formely due to its use as abortivum. Thujon is a local irritant. Ingestion causes bleedings of the mucous membranes in the gastrointestinal system resulting in diarrhea and vomitus. In more severe cases the temperature is elevated, liver (atrophy), heart (bleeding into the muscle) and kidney (degeneration) are damaged. Tonic-clonic convulsions and finally paralysis of the Central Nervous System preceed death (47). Today Thuja oil is still used in the so-called "natural medicine" as done by non-medical practitioners. Unfortunately people have the idea that "natural medicine" is especially healthy. Poisoning in animals is rather rare as the taste of the tips of the branches is bitter and burning. Juniperus sabina. Savin Juniperns virginiana, Virgin Cedar Juniperus communis, Common Juniper Juniperus spp. are distributed worldwide. The poisonous compounds in the essential oil are sabinen, sabinol, sabinyl acetate as the main substances, and pinen, myrcen, limonen, Cymol and Thujon as byproducts. Envenomation in humans is by improper use of the essential oil in "natural medicine". Besides acute gastroenteritis, central nervous symptoms may be observed as nausea and vomiting, convulsions and respiratory arrest. Other syptoms are arrhythmia of the heart, damage of kidneys and liver, uterine cramps. Juniperus communis is much less toxic and is used as diureticum, diaphoreticum, nervicum, and emenagogum. It is also used against ectoparasites. The fruits are used as aromatics and for the preparation of liquors. Poisoning of animals has not been observed, because of the bad taste of the plant (48).

17

3.10 Family: Ericaceae Rhododendron Rhododendron Rhododendron Rhododendron Rhododendron Rhododendron Rhododendron Rhododendron species ponticum. Common Rhododendron chrysanthum. Yellow Alpine Rose luteum ferrugineum, Alpine Rose hirsutum, Alpine Rose simsii, Azalea

species are far distributed on the Northern hemisphere and in

Australia. Poisoning has been observed in humans and in animals, the most important substance responsible being andromedotoxin (=Acetylandromedol) (48, 49). Usually the whole plant is toxic, including pollen and nectar which is important as honey may be poisonous from andromedotoxin. Andromedotoxin is synonymous with acetylandromedol, asebotoxin, rhodotoxin, and graynatoxin (50); its LD50 is 0.3 mg/kg body weight (dog, orally), and 2-5 mg/kg in rats (orally) (14). Rhododendron ursolic acid, uvaol, and simiarenol. to Rhododendron hirsutum, endemic ponticum also contains the triterpenes Rhododendron Central Europe ferrugineum, does not and possess

andromedotoxin; its toxicity is due to ursolic acid which shows the same symptoms but is much less toxic. Andromedotoxin poisoning leads to a gastroenteritis, connected with burning sensation in the mouth, nausea, vomiting, bradycardia and respiratory distress. Its hypotensive activity in low concentrations is used therapeutically The pharmacology has been studied in detail (51). Poisoning occurs in humans and in animals. The oldest case report in the history of toxicology stems from the Greek author Xenophon: His soldiers during a campaign against Persia had eaten honey and suffered from vomitus and diarrhea; they behaved like drunk, a few of them died. Today we know that this was honey from Rhododendron ponticum (52, 53). Occasionally, one can read in newspapers that such poisonings with honey are still occurring in Turkey. Among animals, mainly sheep are affected; goats and cattle use to vomit immediately, and so get rid of the toxic compounds. This mechanism is also a learning effect. Horses are unable to vomit, and therefore are especially endangered; detailed reports on sheep poisoning have been published (54,55). Ledum palustre, Dutch myrte. Ledum palustre contains two not really toxic but pharmacologically active compounds, ledol, and palustrol, responsible for poisoning (56). They cause local

18

Ledol

Palustrol

P h o r b o l : R-, = R 2 = H TPA, ( 1 2 - 0 - T e t r a d e c a n o y l - p h o r b o l - 1 3 - a c e t a t e ) : R-j = C O - ( C H 2 ) i 2 - C ^ H 3 R2 = C O - C H 3

CH2OH Huratoxin: R = CH=CH-CH=CH-(CH2)6-CH3

19 ecstasy, which has been used to prepare "Porstbeer", beer with addition of a small amount of ledol, producing a "good" intoxication. The use of such herbs in brewing beer, therefore has been forbidden in Germany since 1415, by the so-called "Purity Law for Beer". 3.11 Family: Euphorbiaceae Euphorbia species, Spurge. Euphorbia spp. are distributed worldwide with about 680 species. Their outer appearance may vary considerably, from herbs and shrubs in temperate zones to cactus-like, succulent stems with or without leaves in subtropical or tropical areas. All of them have in common that they contain abundandly milky juice, containing the active compounds. Up to now about 80 species have been investigated for such compounds, and practically all of them contain substances with skin irritating activity followed by formation of blisters and necrosis, the mucosa being damaged severely; in eyes they cause conjunctivitis, sometimes followed by blindness. Taken up orally, they cause vomiting, severe diarrhea, and in rare cases mydriasis, delirium and respiratory distress. Chemically, they are diterpene esters of the tigliane, daphnane, and ingenane type. Many of them possess also cytotoxic or co-carcinogenic activity. Envenomations in humans are limited to improper application in traditional medicine. Poisoning of animals occurs accidentally only, because of the burning taste. Animals usually avoid these plants, but grazing animals sometimes cannot avoid the uptake of such plants. In sheep, cattle and horses poisonings have been described with the signs of hemorrhagic gastroenteritis, liver damage, and central nervous disturbances. The most potent substance is TRA, a diester of phorbol. Croton tigliurriy Croton. Croton is endemic to the tropical parts of Asia; it has been imported to Mauritius and to East Africa. Croton oil was a well-known purgative in human as well as in veterinary medicine (57, 58). The active compounds are esters of phorbol, a tetracyclic, tiglian-type diterpen. Croton oil possesses a burning taste and causes vomiting and diarrhea; applied locally it produces skin irritation followed by formation of blisters and edema. Closely related to phorbol is huratoxin (daphnan-type frame) from Hura crepitans^ a tree endemic to the tropical part of America (59). 3.12 Family: Ranunculaceae. Aconitum napelluSy Monkshood, Wolfsbane. Delphinium species, Larkspur. Both plants are toxic. Poisoning in humans has been reported from the roots as well as from the pollen (honey) (60, 61). Among animals, horses are especially sensitive (51), but due to the bad taste the plant usually is avoided.

20
/0CH3

H3CO

^CH3

Aconitin Aconin

Ri = C O - C Q H S ; R2 = CO-CH3 ; R3 = C2H5 R-| = R2 = H ; R3 = C2H5

J)CH3

Cf^CH2-f-|

Lycoctonin

Taxicin I

21

\^

QH

H
11

OHO
1
li

R-C-NH-ChKH^O-C

Taxol A: R = CgHs Taxol B: R = CH2CH=CHCH3

Daphnetoxin: R-j = CgHs ; R2 = H Mezerein: R-j = CgHs ; R2 = OCO-(CH=CH)2-C6H5 Simplexin: R-j = C9H-19 ; R2 = H

22

The symptoms are more or less identical with those already reported, namely salivation, vomiting, diarrhea, and in severe cases death due to respiratory paralysis. The compounds responsible are aconitin, aconin, lycoctonin and related compounds. 3.13 Family: Taxaceac Taxus species. Common yew, English yew. Taxus species are far distributed in Europe, North Africa, West Asia, and North America (Ground Hemlock). More than 30 compounds have been isolated and investigated chemically, and pharmacologically (62). Poisoning in humans is rare (63, 64) but some fatalities have been reported. Taxus branches, however, are dangerous in animals, especially in horses and pigs. Envenomations in wild living animals are rare. Death occurs very fast from respiratory paralysis (51, 65). Typical compounds are taxicin and the taxols which have been falsely attributed as alkaloids. The taxols have gained interest because of their potential antitumor activity. 3.14 Family: Thymelaceae. Daphne mezereum, Mezereon. Mezereon is endemic to Europe, West Asia, and Canada. Poisoning is due to Daphnetoxin, Mezerein, and Simplexin (66); their toxicity has been determined (51). The structures of the compounds are closely related to huratoxin. The symptoms are identical, but more severe; the kidneys are concerned especially with nephritis, albuminuria, hematuria, and stranguria. Envenomations are observed mainly with children, eating the red berries. In animals poisoning has been reported, but is a rare event because of the burning taste of the plant. This is probably also the reason why poisoning in wild animals is unknown so far. CONCLUSION. This review does not cover all terpenes isolated from plants nor all plants with terpenes as secondary metabolites. This is , however,a selection in respect to their activities. As may be seen, the toxicity is varying,, but what is common in all, is a bad taste, bitter, burning, and causing irritation of mouth lips and tongue. This clearly shows that these compounds have been developed during the evolution as protection, thus establishing an equilibrium between herbivors and plants. Such protection has been especially important in the "early" times of the angiosperms. So it is worth looking for their biological relevance, and it is also interesting that wild animals obviously have learned to deal with the dangers of their feed. And this may explain, too, why many herbivors became extinct some 60 million years ago, while carnivors did not show this break in evolution. 4.

23

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 F.J. Evans and R.J. Schmidt, Planta med., 38 (1980) 289-316. D. Lavie and E. Glotter,Fortschr. Chem. Org. Naturst., 29 (1971) 307-362. H. Schildknecht, Angew. Chem., 93 (1981) 164-183. R.L. Metcalf, R.A. Metcalf and A.M. Rhodes, Proc. Nat. Acad. Sci. USA, 77 (1980) 3767-3772. J. Bonner, Bot. Rev., 16 (1950) 51-65. C.H. Muller, W.H. Muller and B.L. Haines, Science, 143 (1964) 471-473. H. Metzner, Biochemie der Pflanzen, Enke, Stuttgart, 1973. J.G. MacConnell and R.M. Silverstein, Angew. Chem., 85 (1973) 647-657. G. Habermehl, Gifttiere und ihre Waff en. Springer, Berlin, 1994. M.D. Grove, G.F. Spencer, W.K. Rohwedder, N. Mandava, J.F. Worley, J.D. Warthen, G.L. Steffens, J.L. Flippen-Anderson and J.C. Cook, Nature 281 (1979)216. G. Adam and U. Petzold, Naturwissenschaften 81 (1994) 210 ; G. Adam, A. Porzel, J. Schmidt, B. Schneider and B. Voigt in: Atta-ur-Rahman, S.T. (ed) Studies in Natural Products Chemistry: New developments in brassinosteroid research. Elsevier, Amsterdam, 1995. H. Thomas and H. Budzikiewicz, PfanzenphysioL, 99 (1980) 271-276. H. Budzikiewicz and H. Thomas, Z. Naturforsch., 35b (1980) 230-231. H. Liebenow and K. Liebenow, Giftpflanzen, Enke, Stuttgart, 1981. H. Wagner and H. Reger, Dtsch. Apoth. Ztg., 126 (1986) 2613-2617. E. Wiesner, Ernahrungsschaden d. Idw. Nutztiere, Fischer, Jena, 1970. J.W. Hardin and J.M. Area, Human poisoning from native and cultivated plants, Duke University Press, Durham, NC, 1974. L. Goldmann, R.H. Preston and H.R. Muegel, Arch. Derm., 74 (1956) 311-312. J.C. Mitchell, Contact Dermatitis, 7 (1981) 158-159. R. Jaspersen-Schib, Schweiz. Apoth. Ztg., 114 (1976) 265-267; Dtsch. Apoth. Ztg., 124 (1984) 2326. R.J. Cole, B.P. Stuart, J.A. Lansden and R.H. Cox, J. Agr. Food Chem.,28 (1980) 1330. J.A.S. Lewis, J.K. MacLeod and P.B. Oelrichs, Tetrahedron, 37 (1981) 4305-4311. S. Luciani, N. Martini and R. Santi, Life Sci., 10 (1971) 961-968. B. Danieli, E. Bombardelli, A. Bonati and B. Gabetta, Phytochemistry, 11 (1972) 3501-3504. B.P. Stuart, R.J. Cole and H.S. Grosser, Vet. Pathol.,18 (1981) 368-383. J.C. Oberti, A.B. Pomilio and E.G. Gros, Phytochemistry, 19 (1980) 2051. C D . Schteingart and A.B. Pomilio, J. Nat. Prod., 47 (1984) 1046-1047. P.B. Oelrichs, P.J. Vallely, J.K. MacLeod and LA.S. Lewis, J. Nat. Prod., 43 (1980) 414-416. D.A. Witzel, G.W. Ivie and J.W. Dollahite, Am. J. Vet. Res.,37 (1976) 859-861. W. Herz in: R.F. Keeler, K.R. van Kampen and L.F. James (Eds), Effects of Poisonous Plants on Livestock: Sesquiterpene lactones from livestock poisons. Academic Press, New York, San Francisco, London, 1978. J.W. Dollahite, W.T. Hardy and J.B. Henson, J. Am. Med. Vet. Assoc. 145 (1964) 694. G.W. Ivie, D.A. Witzel and D.D. Rushing, J. Agr. Food Chem. 23 (1975) 845-849. J.W. Dollahite, L.D. Rowe, H.L. Kim and B.J. Camp, Southwest. Vet. 26 (1972) 135. G.W. Ivie, D.A. Witzel, W. Herz, R. Kanan, J.O. Norman, D.D. Rushing, J. H. Johnson, L.D. Rowe and J.A. Veech, J. Agr. Food Chem., 23 (1975) 841-845. J.T. MacGregor, Fd. Cosmet. Toxicol., 15 (1977) 225-227.

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

24

36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67

J.PJ. Joubert, J. S.Afr. Vet. Assoc. 54 (1983) 255-258. F. Bohlmann, Naturwissenschaften 67 (1980) 588-594. J.C. Mitchell and G. Dupuis, Brit. J. Derm., 84 (1971) 139-150. B.M. Hausen, Planta med., 50 (1984) 229-234. R. Gmelin, Arzneimittelforschung 13 (1963) 771. G. Rosenberger, Krankheiten des Rindes, Parey, Berlin, Hamburg, 1978. T. Takemoto and N. Nakajima, J. Pharm. Soc. Japan 77 (1957) 1157. P.R. Enslin, F.J. Joubert and S. Rehm, J. Sci. Food Agr., 7 (1956) 646. D. Lavie, D. Willner and Z. Merenlender, Phytochemistry, 3 (1964) 51. M.R. Cooper and A.W. Johnson: Poisonous plants in Britain and their effects on animals and men: Ministry of Agriculture Fisheries and Food, London, 1984. A.A. Forsyth: British Poisonous Plants: Ministry of Agriculture Fisheries and Food. Bulletin 161, pp.73-74, London, 1979. Hagers Handbuch d. pharm. Praxis (P.H. List and L. Horhammer, Eds), Springer, Berlin, Heidelberg, New York, 1980. K. Hiller and G. Bickerich: Giftpflanzen, Enke, Stuttgart, 1988. F. Zymalowski, P. Pachaly and S. Auf dem Keller, Planta med., 17 (1969) 8-13. H. Schindler, Planta med., 10 (1962) 232-237. H.J. Hapke: Toxikologie fiir Veterinarmediziner, Enke, Stuttgart, 1988. E.G.C. Clarke, D.J. Humphreys and T. King: Nachweis von Andromedotoxin, in E.Kaiser (Ed): Tier- und Pflanzengifte, Goldmann, Miinchen, 1973. A.M. Chambers, Scott. Med. J. 29 (1984) 107-108. R.J. Higgins, D.A.R. Hannam, D.J. Humphreys and J.B.J. Stodulsky, Vet. Rec. 116(1985)294-295. L.A.M.G. van Leengoeld and J.J. van Amerongen, Tijdschr. Diergeneesk., 108 (1983) 41-42. D.H.E. Tattje and R. Bos, Planta med., 41 (1981) 303-307. E. Hecker and R. Schmidt: Phorbolesters, the irritants and cocarcinogenes of Croton tiglium L. in: Fortschr. Chem. Org. Naturst. 31 (1974) 377-467. E. Hecker, Dtsch. Apoth. Ztg. 126 (1986) 2599. G. Fiirstenberg and E. Hecker, Planta med., 22 (1972) 241-266. H.H. Kalbfleisch, Arch. Toxicol.,13 (1943/44) 17-20. Y. Saito, A. Midura, K. Sasaki, M. Satake and M. Uchiyama, Bull. Natl. Inst. Hyg. Sci., 9 (1980) 32-35. R.W. Miller, J. Nat. Prod. 43 (1980) 425-437. S. Ritter, Dtsch. Apoth. Ztg. 125 (1985) 1834-1836. S. Ritter and E.G. Krienke: Vergiftungen im Kindesalter. Enke, Stuttgart, 1986. B. von Dach and R. A. Streuli, Schweiz. med. Wschr. 118 (1988) 1113-1116. H. Schildknecht and R. Maurer, Chemiker Ztg. 94 (1970) 849. H. Schildknecht, Angew. Chem. 93 (1981) 164-183.

Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

25

Crinitol, an Acyclic Diterpene Diol from Marine Algae

I. Kubo and L.R. Smith Crinitol, (1), is a diterpene diol whose properties can in some ways be taken as representative of the current challenges in studying and finding uses for secondary plant metabolites. It is readily availability from a natural source and has a relatively uncomplicated structure; despite this, its function in the plant is not fully clarified. As will be discussed below, crinitol shows a modest level of antimicrobial and other biological activity. We can already control many troublesome microorganisms that contaminate food and cosmetics with natural products, including plant secondary metabolites, that are currently available. Nevertheless, discovery
H. OH I I I I ^^Q..M

x'^V^'^v--^^^
9R and 9S Crinitol (1 and 2) of new effective antimicrobial agents continues to be important since microorganisms have developed resistance to many commonly used antimicrobial agents. There is no doubt that plants are still a good source for new antimicrobial agents. However, a typical difficulty with antimicrobial phytochemicals is that they are not usually potent enough to be considered for practical applications. Hence, studies to enhance the total biological activity are needed. In order to proceed with this, understanding the effects on microbial systems on a molecular basis is essential. The moderate activity of crinitol (1) isolated from several marine brown algae is an example of this level of potency, and its chemistry and bioactivity can be taken as a case study of the sort of questions that can arise in current studies of natural products. ISOLATION AND BIOGENESIS Crinitol (1) was first isolated from one of the most studied marine brown algae, Cystoseira crinita Bory (Cystoseiraceae), and its structure was established as 3,7,11,15tetramethylhexadeca-2,6,10,14-tetraene-l,9-diol (1); it was later found in the closely related species Cystoseira baleahca (2). The absolute configuration at C-9 was not determined in the Cystoseira-dQTivQd samples, but was determined as R in crinitol isolated from another brown

26 alga, Sargassum tortile C. Agaedh (Sargassaceae) (3). The Sargassutn identification had been pursued on the basis of assays of insect growth inhibition against the pink bollworm, Pectinophora gossypiella, by an artificial diet feeding assay (4). The larger biosynthetic context of crinitol has been extensively studied in brown algal species, which have yielded a wide variety of related diterpenes (5,6). It has been suggested that in the uncommon cases where plants accumulate geranylgeraniol (3) metabolically, oxidation products of geranylgeraniol "are possibly nothing more than the expression of its catabolism" (6). Such catabolic oxidation products reported have included a number of diols isomeric with crinitol, including 12-(5)-hydroxygeranylgeraniol (12-(5)-3,7,11,15-tetramethylhexadeca-2,6,10,14tetraene-l,12-diol) (4) (7,8); 13-(S)-hydroxygeranylgeraniol (eleganediol, or 13-(5)-3,7,ll,15tetramethylhexadeca-2,6,10,14-tetraene-l,13-diol) (5) (8-12); and bifurcanol (3,7,11,15tetramethylhexadeca-2,6,10,13-tetraene-1,15-diol) (6) (8). In view of the suggested

OH HO H

Geranylgeraniol (3)

12-(S)-Hydroxygeranylgeraniol (4)

OH

Eleganediol (5)

Bifurcanol (6)

^^

16-Hydroxygeranylgeraniol (7)

origin, it perhaps ought to be expected that similar compounds would be present in other plant sources, not just in algae; 16-hydroxygeranylgeraniol (7) has been reported to occur in a Japanese fungus, Boletinus cavipes (13). ABSOLUTE CONFIGURATION AND CONFORMATIONAL CONSIDERATIONS At the time that crinitol was isolated from 5. tortile (3), the absolute configuration at C-9 was not known. To define the absolute configuration of the stereocenter, the circular exciton chirality method (3,14) was applied. Four derivatives (8-11) were made and their CD

27

Ax'0::>^C-^^
(8)
Br

xiv'v.^'^^^
(9)

(10)

(11)

spectra were recorded. Among them, only 10 and 11, whose C-9 hydroxy! group was pbromobenzoylated, showed the predicted benzoate Cotton effects. The absolute value (Ae) of both of these benzoate Cotton effects were almost identical; 10, -5.3 (247 nm) and 11 -5.4 (244 nm). These data clearly indicate that the C-1 benzoate chromophore does not interact with the C-9 benzoate chromophore, unlike dibenzoates of cyclic compounds (15). The observed negative Cotton effect is due to only to the interaction between the benzoate ^La transition and the double bond TT-T* transition. If all possible rotomers were equally present the sum of the Cotton effect should cancel. However, it has been shown for a large number of secondary allylic benzoates the rotomer having the carbinyl hydrogen and double bond eclipsed is favored. The presence of a large /yjc of 9.0 Hz between the olefinic and C-9 carbinyl protons in 10 and 11 is consistent with such a preferred conformer, as the size of the coupling is dependent on the dihedral angle. Thus, the absolute configuration of crinitol was determined to be 9R This was the first actual application of the allylic benzoate method (14) to a natural acyclic allylic alcohol. The configurational assignment did not quite end with this first determination, however. In the course of preparing a sample of the "unnatural" 9S crinitol isomer (2) by racemization, derivatization and recycle HPLC (discussed below), crinitol isolated from S. tortile was later found to contain a small amount (13%) of the 95 isomer (16). Mosher's NMR method (16-18) verified the original assignment of configuration for the dominant natural enantiomer. Given the significant presence of both enantiomers in S. tortile, one might conclude that the biosynthesis of crinitol is not highly stereospecific, and crinitol's optical purity will probably vary from source to source. Before leaving the topic of absolute configuration determination, we should mention a third method applicable to this type of compound, that of Horeau (19), which was used to determine the configuration of eleganediol (12). Horeau's method is based on the differential reactivity of racemic 2-phenylbutyric anhydride with chiral alcohols.

28 Given the size and flexibility of the crinitol molecule, statements about preferred conformations must be regarded as tentative. However, a clue may lie in an interesting concentration effect, found in the 300 MHz ^H NMR spectrum of natural 9R crinitol (15) as shown in Figure 1. The C-9 hydroxy results in a clearly separated C-9 proton (H9) at 6 4.4, whose coupling provide clues to conformational preferences near the center of the molecule. In particular, the observed splitting goes from a quartet (7=7.4 Hz) at ca. 15% in CHCI3, to a triplet (7=8.4 Hz) in ca. 1% solution. Coupling to the C-10 olefinic proton (HJQ, a doublet at 6 5.15) remains almost constant, but a clear differentiation appears in coupling to the diastereotopic methylene protons on C-8. A predominantly anti H9/H10 orientation throughout would be consistent with recent studies reported by Gung et al. (20). The spectra seem to indicate that there is no particular C-8/C-9 conformational preference at high concentration. On dilution, however, the different couplings that emerge would be more consistent with a predominantly extended C-8/C-9 conformation in which H9 is anti to the pro-5 proton (Hg^) on C-8, and therefore gauche to the pro-i? proton (Hg;^; H85 and Hg;^ appear as a partially visible multiplet around 6 3.2. A "hairpin" conformation around C-8/C-9 might also rationalize the observed couplings, but would appear sterically unreasonable and at variance with reported studies on similar analogs (20). Other concentration-related differences appear, for example in the C-1 methylene proton pattern at ca. 6 4.1, but interpretation is not so straightforward. Crinitol may exert its bioactivity by interaction with membranes, and the C-9 proton could perhaps provide an NMR "probe" of the environment in which the center of the crinitol molecule finds itself in such interactions; one might speculate similarly about the related diols 4-7. ANTIBACTERIAL AND OTHER BIOLOGICAL ACTIVITY Crinitol was isolated from 5. tortile by following a bioassay for growth inhibition of P. gossypiella{3). The only active principle isolated in the methanol extract, a viscous colorless liquid, ([]) -5, cO.43, CH3OH) was identified as crinitol (1, [a]D -3), previously isolated from C crinita, by comparison of spectral data (1). The effective dose (ED50) for 50% growth inhibition of P. gossypiella was 500 ppm. In our continuing search for new antimicrobial agents from botanical sources, crinitol was later found to exhibit moderate antibacterial activity against several Gram-positive bacteria (21-23) as shown in Table 1. For comparison. Table 1 also includes results from assays of geranylgeraniol (3), famesol (12) and geraniol (13). Crinitol exhibited weak to moderate activity against all the Gram-positive bacteria tested but not the Gram-negative bacteria up to 800 /xg/ml. It did not show any activity against fungi, except T. mentagrophytes. This dermatologically pathogenic fungus was

29

Figure 1. Downfield Portion of the 300 MHz Proton NMR Spectrum of Crinitol, in Chloroform-d.

30

susceptible to crinitol with the minimum inhibitory concentration (MIC) of 25 figlml (23). Interestingly, T. mentagrophytes was relatively susceptible to many long-chain alcohols (23). Among the Gram-positive bacteria tested, P. acnes was the most sensitive bacterium, with an MIC of 25 jwg/ml. By contrast, S. aureus was the least sensitive, with an MIC of 400 jitg/ml. In addition, crinitol was found to be bactericidal against P. acnes. This was determined as follows: 30 III taken from the medium that was incubated for 2 days with the MIC of crinitol was added into 3 ml of the crinitol-free fresh medium and incubated for 2 days. No recovery of this follicular bacterium was observed.

MIC (fig/ml) 1 Bacillus subtilis Brevibacterium ananoniagenes Streptococcus mutans Staphylococcus aureus Propionibacterium acnes Escherichia coli Pseudomonus aeruginosa Enterobacter aerogenes Saccharomyces cerevisiae Candida utilis Pityrosporum ovale Penicillium crustsum Trichophyton mentagrophytes 50 100 50 400 25 >800 >800 >800 >800 >800 >800 >800 25 3 >800 >800 >800 >800 >800 >800 >800 >800 >800 >800 >800 12 12.5 12.5 12.5 25 6.25 >800 >800 >800 >800 >800 >800 >800 12.5 13 400 400 400 800 400 800 >800 >800 400 400 200 200 200

, the physiological age of the , The rate of activity varied slightly with the seed culture mediaL culture, and the type of culture medium. , Not tested. In addition to crinitol, two structurally related minor acyclic diterpene alcohols, geranylgeraniol (3) and phytol, were also isolated from the active fraction in S. tortile, although neither of them exhibited any activity up to 800 fig/ml as listed in Table 1. In addition, several derivatives of crinitol as well as its two common natural congeners, famesol

31

(12) and geraniol (13) were also assayed. The hydroxy group at C-9 in crinitol seemed to be essential for the antibacterial activity. In fact, the oxidized compound, 9-oxocrinitol, and mono- and diacetyl derivatives, did not exhibit any activity up to 8(X) /ig/ml. Among the three naturally occurring alcohols tested (3,12,13), a sesquiterpene alcohol, famesol (12), exhibited the most potent activity against several Gram-positive bacteria and T. mentagrophytes. In contrast, a diterpene alcohol, geranylgeraniol (3), did not show any activity up to 800 ixglml. Alcohols are among the most versatile of all natural products. Free and esterified alcohols occur widely in nature, e.g. in fruit. The antimicrobial effects of alcohols have been reported. However, studies have been limited to short-chain ( < Cg) alcohols, almost exclusively ethanol. Antimicrobial activity of long-chain ( > C^) alcohols, on the other hand, has been demonstrated only with restricted microorganisms because of their limited solubility in water. To place our results with crinitol in the more general context of antimicrobial activities of alcohols, we investigated a series of simple aliphatic alcohols as a model (23,24). The study was focused towards understanding the role of the hydrophobic portion since all the molecules studied possess the same hydrophilic hydroxyl group. The mechanisms of antibacterial activity of long-chain alcohols are due to a balance between the polar hydrophilic (head) and nonpolar hydrophobic (tail) portions of the molecule. The fluidity of a cell membrane can be disturbed maximally by particular hydrophobic moieties attached to hydroxyl groups. They could enter the molecular structure of the membrane with the polar hydroxyl group oriented into the aqueous phase by hydrogen bonding and nonpolar carbon chain aligned into the lipid phase by dispersion forces. It may not be illogical to suppose that a hydrophobic chain length greater than that for the maximum activity disperses into the lipid layer, resulting in the breaking of the hydrogen bond. Thus, when the balance between hydrophilic and hydrophobic portions of the alcohol was destroyed by the dispersion forces, on the other words when the hydrophobic character, log P, exceeded the maximum value, log PQ, the activity disappeared. The maximum activity depends on the hydrophobic chain length from the hydrophilic hydroxyl group, and also the microorganisms being tested (23,24). This general rule may apply to many other membrane-active antimicrobial agents analogous to crinitol. C-9 CONFIGURATION AND BIOACTIVITY: RACEMIZATION AND RESOLUTION VIA MTPA ESTERS As part of our studies of the antimicrobial activity of crinitol and related compounds (23), it was of interest to test whether the two enantiomers of crinitol exhibit the same or different activities, as a clue to whether the antimicrobial action might be due to some specific interaction beyond the above hypothesized general lipophilic action on cell membranes.

32

However, a source of the non-natural 9S isomer (2) was first required. The ready availability of natural crinitol made a racemization/resolution route, as illustrated in Scheme 1, attractive. Racemization was accomplished by Collins oxidation (16,25) to the dicarbonyl compound (14), followed by lithium aluminum hydride (LAH) reduction to give the racemic mixture (1 -I- 2). Resolution via diastereomeric derivatives seemed plausible. Esterification with enantiomerically pure a-methoxy-a-(trifluoromethyl) phenylacetic acid (MTPA) (17), followed by separation of diastereomers by recycle-HPLC (R-HPLC), had earlier been used to purify enantiomers of ipsenol and ipsdienol (26). A model system, the resolution of ^3-nonen-2-ol, a secondary ally lie alcohol naturally occurring in Rooibos tea (16,27), also worked satisfactorily. Therefore, the route using the te-(MTPA) esters was selected for crinitol. With crinitol, use of MTPA chloride/dimethylaminopyridine (16,28) gave the desired mixed diester (15 + 16) cleanly and in high yield. The mixed diesters were then separated by recycle-HPLC (16). It is of interest that recycle-HPLC of the te-MTPA ester of natural crinitol showed the presence of a small amount (13%) of the 95isomer, as mentioned above. Absolute configurations were checked in the crinitol bis-MTPA esters 15 and 16 by their iH-NMR spectra, using the Mosher method, as extended by Ohtani et al. (16-18). This method presumes a Sj^-periplanar arrangement of the C-H bond at the chiral center, the ester carbonyl bond, and the a-C-trifluoromethyl bond of the ester moiety. In this geometry, the ester's phenyl and methoxy groups, respectively, shield and deshield nearby groups in the alcohol moiety. While the C-9 configurations of the crinitol bis-MTPA esters were already reasonably assignable by comparison with material prepared from the known 9i? natural diol (3), it was nonetheless reassuring that the relative shifts of the clearly identifiable C-8 methylene hydrogens (6 2.37 and 2.17 in 15, vs. 2.42 and 2.21 in 16) were consistent with predictions by the Mosher/Ohtani NMR method. Diastereomeric excesses of the separated MTPA esters 15 and 16 were determined to be >96%, based on NMR measurements. Higher diastereomeric excesses could have been obtained by further chromatography, but the values obtained sufficed for our needs. The "unnatural" 95crinitol was assayed for antimicrobial activity simultaneously with a sample of natural crinitol, against the same battery of Gram-positive microorganisms originally used with the natural material alone (16). Against B. subtilis, B. ammoniagenes, 5. aureus, 5. mutans and P. acnes, the natural and unnatural material showed identical activity, which also matched the results of earlier tests (21) on natural material alone. This indicated that, for these test species at least, the configuration at C-9 is irrelevant to antimicrobial activity. This seems to indicate that antimicrobial activity is not due to interaction with a specific receptor, but rather to the above mentioned more general lipophilic interaction affecting cell membranes (24).

33

Scheme 1

x^>x-v^x^t^^

OH

Collins Oxidation

14 LiAIH/

A > - 0 : v ' 0 ^ > ^ - x ^ ^

+ xW^-vJ^V^^^

MTPA Chloride/DMAP
^ OMTPA

.A>-^\..A>X.^^
15

OMTPA OMTPA

OMTPA 16 1. Recycle HPLC 2. NaOH

Separated

1 + 2

34

ENHANCED ANTIMICROBIAL ACTIVITY BY SYNERGISTIC COMBINATION Although crinitol may play an important role in the defense of living plants, and can easily be obtained in relatively large quantities from S. tortile or other sources (3), its antibacterial activity may not be potent enough to be considered for practical use as a single active ingredient. For this reason, the enhancement of the antibacterial activity of crinitol by combining it with other substances was explored (29), although the rationale for selecting "other substances" remains in a preliminary stage. The initial selection of adjuvants to crinitol was based largely on the above mentioned structure-activity relationship study. Thus, the hydroxy group at C-9 in crinitol seems to be essential to its antibacterial activity. The ally lie C-9 hydroxy group is easily oxidized, a possibility which might detoxify crinitol in bacterial systems. Because crinitol possesses two ally lie alcohol groups in its molecule (at C-1 and C-9), we combined it with several antioxidants which have been used as food and cosmetic additives. Thus two natural antioxidants, vitamins C and E, and two synthetic antioxidants, BHA and BHT, were chosen for the experiment. While the synthetic antioxidants exhibited antimicrobial activity against all the test bacteria (30), natural antioxidants did not show any activity up to 800 jug/ml. In combination with crinitol, neither of the natural antioxidants showed any enhancing activity against the bacteria tested. Neither synthetic antioxidant exhibited any synergistic effect against 5. aureus at all. Table 2 shows the MIC of crinitol in combination with the two synthetic antioxidants at the concentration of each 1/2MIC. The activity of crinitol against 5. mutans was significantly increased by both BHA and BHT. The antibacterial activity of crinitol against this cariogenic bacterium was increased 64-fold by BHT; the MIC was lowered from 50 to 0.78 fjLg/ml. Similarly, BHA also synergized crinitol against S. mutans, but not as much as BHT; the MIC was reduced only from 50 to 12.5 /xg/ml. Interestingly, crinitol also enhanced the antibacterial activity of BHT and BHA against S. mutans 16- and 8-fold, respectively. The data were obtained by the broth checkerboard method (31). By way of comparison, we might consider the famesol/anacardic acid synergism against P. acnes. Its antibacterial activity against this follicular bacterium was significantly increased in combination with ViMlC of anacardic acid isolated from the cashew Anacardium occidentale (Anacardiaceae) apple, nut and nut shell oil (32). More specifically, the MIC of famesol was lowered from 6.25 to 0.78 ^g/ml, in combination with 0.39 figlml of anacardic acid. Interestingly, this synergism was found to be vice versa; the MIC of anacardic acid was reduced from 0.78 to 0.2 /xg/ml when it was combined with 3.13 /xg/ml of famesol (33). The mode of action of the combination, however, remains unclear.

35 Table 2. MICs of crinitol alone and in combination with V2MTC of BHA and BHT MIC (Mg/ml) Microorganisms tested 1 + BHA 1 1 + BHT B. subtilis B. ammoniagenes S. mutans S. aureus P. acnes 50 100 50 400 25 50 100 12.5 400 6.25 12.5 50 0.78 400 6.25

ECOLOGICAL ASPECTS Crinitol was originally reported from C. crinita, "a brown seaweed rather common along the Sicilian coasts" (1); C. baleahca, another species from which crinitol has been reported, also was collected from Sicily for study (2). A wide range of Mediterranean algae have been studied and characterized (5,6); although crinitol itself seems to have been reported from only two species in the region, many related compounds have been described, and there seems to be significant variability in seaweed populations in the region (5,6,8,11,12,34,35). Much less has been reported on congeners of the marine brown alga S. tortile, which is known as "yoremoku" in Japan. This seaweed is commonly found on rocks from below the low-tide level to depths of several meters or more. In order to investigate the biological activity of crinitol, more S. tortile was collected from different geographic locations along coasts of the Pacific Ocean and the Sea of Japan during different seasons. The isolation of crinitol was monitored by an antibacterial activity assay against B. subtilis. As a result of this study, the quantity of crinitol in S. tortile was also analyzed in terms of its geographical and seasonal variation. More specifically, S. tortile was collected from two different geographic location in Japan, one at Kata, Wakayama, which is along the coast of the Pacific Ocean, and the other near Maizuru, Kyoto, which is along the coast of the Sea of Japan. The antibacterial crinitol was isolated as the only active principle based on bioassay-guided fractionation of the CH2CI2 extracts of 5". tortile collected during both spring and fall at Kata. It should be noted that crinitol was not only the antibacterial principle but also it was one of the major compounds (yielding about 1 % of the fresh weight) from 5. tortile collected at Kata. In contrast, it could not be isolated from those S. tortile collected near Maizuru, regardless of the season. Although seasonal variation of crinitol in S. tortile was not observed, the geographical

36 variation was remarkable. This variation could be caused by genotypic and/or by phenotypic factors. These results seem to be interesting from a chemotaxonomic point of view, since species of Sargassum are often difficult to identify. It should, however, be noted that geographical and seasonal variation among marine natural products seems to be common. Morphologically, it is noticeable that S. tortile grows better around Kata (the Pacific Ocean variety) than Maizuru (the Sea of Japan variety); the water temperature around the latter is cooler than the former. Thus, the algae collected from around Kata were larger than those of Maizuru. The observed geographical variation of crinitol in S. tortile may be caused by an environmental difference, if crinitol is hypothesized to be a defense substance. The water temperature around Kata is warmer than Maizuru, and bacteria at the former location may be more active than at the latter. If this hypothesis is true, then the algae growing around Kata may need more antibacterial agent to combat them. Clearly, further study is needed to confirm this. Based on the above findings, we also collected several other species of Sargassum algae along the coast of the Western United States. For example, S, muticum was collected near Trinidad, California. Although its /i-hexane extract exhibited weak antibacterial activity against B. subtilis, its CH2CI2 extract (from which crinitol was isolated from S. tortile) showed no activity. More specifically, crinitol was not identified in S. muticum at all. CONCLUSION Crinitol's natural role in seaweeds remains unclear, but it can be classified as a nonionic surfactant judging from its chemical structure. Its biological activity suggests that it may possibly exert a chemically protective function. The basis of crinitol* s antibacterial activity apparently derives from its properties as a nonionic surfactant that may disrupt cell membranes. The binding of nonionic surfactants can only involve relatively weak head-group interactions, such as hydrogen bonding, so that the predominant interactions will be hydrophobic (36). However, the specific binding site of crinitol still remains to be established. A wider range of bioassays may be appropriate forjudging possibly useful bioactivity; related substances, for example, have shown cytotoxicity in sea urchin egg development (8) and physiological effects on intestinal contractions (37). If crinitol is to find use as an antibacterial agent, this will probably require use of adjuvants to enhance its activity. Combining two or more substances to enhance the total biological activity may not only be a most efficient way to use renewable natural products, but also the microorganisms may take longer to develop their resistance to two or more toxins

37

whose mode of action is diverse. Factors such as potential human toxicity or irritancy (for which there is no current evidence) would also need to be checked. Conceivable uses of crinitol, as with many other natural products, may simply be defined by availability, physical properties, and the relative ease with which possible options might be explored. Acknowledgement This work was supported in part by NOAA, National Sea Grant College Program, Department of Commerce, under grant number NA85AA-D-SG140, project number R/MP-32, through the California Sea Grant Program, and the California State Resources Agency for financial support. The work has involved a number of scientists. We are greatly indebted to the colleagues cited in the references, especially Dr. T. Matsumoto, Dr. N. Ichikawa and Dr. M. Himejima. S. tortile was collected by Dr. N. Ichikawa and identified by Dr. H. Nakahara. We also thank Gretchen Peterson for assisting in the literature search. REFERENCES 1 E. Fattorusso, S. Magno, L. Mayol, C. Santacroce, D. Sica, V. Amico, G. Oriente, M. Piattelli, and C. Tringali, Oxocrinol and crinitol, novel linear terpenoids from the brown alga Cystoseira crinita, Tetrahedron Lett., (1976) 937-940. V. Amico, P. Neri, M. Piattelli and G. Ruberto, Linear diterpenoids from Cystoseira baleahca, Phytochemistry, 26 (1987), 2637-2639. L Kubo, T. Matsumoto and N. Ichikawa, Absolute configuration of crinitol, an acyclic diterpene insect growth inhibitor from the brown algae Sargassum tortile, Chem Lett., (1985) 249-252. I. Kubo, Screening techniques for plant-insect interactions, in Methods in Plant Biochemistry (K. Hostettmann, ed.), Academic Press, London, 1991, Vol. 6, pp 179193. E. Fattorusso, Recent results in the chemistry of mediterranean algae, in Marine Natural Products Chemistry (D. J. Faulkner and W. H. Fenical, eds.), Nato Conference Series, Plenum Press, New York and London, 1977, pp. 165-178. M. Piattelli, Chemistry and taxonomy of Sicilian Cystoseira species. New. J, Chem., 14 (1990) 777-782. R. Vails, B. Banaigs, C. Francisco, L. Codomier and A. Cave, An acyclic diterpene from the brown alga Bihrcaria bifurcata, Phytochemistry, 25 (1986), 751-752. R. Vails, B. Banaigs, L. Piovetti, A. Archavlis and J. Artaud, Linear diterpene with antimitotic activity from the brown alga Biiurcaria biAircata, Phytochemistry, 34 (1993), 1585-1588. J. F. Biard, J. F. Verbist, R. Floch and Y. Letoumeux, Epoxyeleganolone et eleganediol, deux nouveaux diterpenes de BiAircaria biAircata Ross (cystoseiracees). Tetrahedron Lett., 21 (1980), 1849-1852.

2 3

4 5 6 7 8

38

10 11 12

13 14

15 16

17 18

19 20 21 22 23 24

25 26

L. Hougaard, U. Anthoni, C. Christophersen and P. H. Nielsen, Eleganolone derived diterpenes from Bifiircaria blAircata, Phytochemistry, 30 (1991), 3049-3051. R. Vails, V. Mesguiche, M. Pellegrini, L. Pellegrini and B. Banaigs, Variation de la composition en diterpenes de Bifurcaria bifurcata sur les cotes atlantiques frangaises, ActaBot. Gallica, 142 (1995) 119-124. R. Vails, L. Piovetti, B. Banaigs, A. Archavlis and M. Pellegrini, (5)-13Hydroxygeranyl-geraniol-derived furanoditerpenes from Bifurcaria bifurcata, Phytochemistry, 39 (1995), 145-149. T. Wada, K. Kobata, Y. Hayashi and H. Shibata, Two chemotypes of Boletinus cavipes, Biosci. Biotech. Biochejrn., 59 (1995), 1036-1039. N. C. Gonnella, K. Nakanishi, V. S. Martin and K. B. Sharpless, General method for determining absolute configurations of acyclic allylic alcohols, J. Amer. Chem. Soc., 104 (1982) 3775-3776. H. Liu and K. Nakanishi, Additivity relation found in the amplitudes of excitonsplit circular dichroism curves of pyranose benzoates^ J. Amer. Chem. Soc., 103 (1981) 5591-5593. L. R. Smith and I. Kubo, The racemization of crinitol. Resolution of crinitol and of 3nonen-2-ol enantiomers by recycle-HPLC, via MTPA esters, J. Nat. Prod., 58 (1995) 1608-1613. J. A. Dale, D. L. Dull and H. S. Mosher, a-Methoxy-a-trifluoromethylphenylacetic acid, a versatile reagent for the determination of enantiomeric composition of alcohols and amines, J. Org. Chem., 34 (1969) 2543-2549. I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, High-field FT NMR application of Mosher's method. The absolute configurations of marine terpenoids, J. Amer. Chem. Soc., 113 (1991) 4092-4096. A. Horeau and A. Nouaille, Extension et simplification de la methode de determination de la configuration des alcool secondaires par "dedoublement partiel" VIII. Application a la genipine, Tetrahedron Lett., 12 (1971), 1939-1942. B. J. Gung, M. A. Wolf, K. Ohm and A. J. Peat, Conformational preferences of Cloxygenated acyclic chiral alkenes: The effect of vinyl and allyl substituents, Tetrahedron Lett., 34 (1993) 1417-1420. I. Kubo, M. Himejima, K. Tsujimoto, H. Muroi and N. Ichikawa, Antibacterial activity of crinitol and its potentiation, J. Nat. Prod., 55 (1992) 780-785. I. Kubo, H. Muroi and A. Kubo, Antibacterial activity of long-chain alcohols against Streptococcusmutans, J. Agric. Food Chem., 41 (1993), 2447-2450. I. Kubo, H. Muroi and A. Kubo, Structural functions of antimicrobial long-chain alcohols and phenols, Bioorg. Med. Chem., 3 (1995) 873-880. I. Kubo, H. Muroi, M. Himejima and A. Kubo, Antibacterial activity of long-chain alcohols: the role of hydrophobic alkyl groups, Bioorg, Med. Chem. Lett., 3 (1993) 1305-1308. L. F. Fieser and K. L. Williamson, Organic Experiments, D. C. Heath, Lexington, 1979, 4th ed., p. 148. I. Kubo, S. Komatsu, T. Iwagawa and D. L. Wood, Analytical and preparative separation of bark beetle pheromones by high-performance liquid chromatography, J. Chromatogr., 363 (1986) 309-314.

39 27 28 29 30 31 32 33 34 35 36 37 M. Kawakami, A. Kobayashi and K. Katoh, Volatile constituents of Rooibos tea {Aspalathus linearis) as affected by extraction process, J. Agric. Food Chem., 41 (1993) 633-636. H. S. Byun and R. Bittman, Stereospecific synthesis of thioether glycerophospholipids. Catalytic asymmetric epoxidation followed by in situ borohydride-mediated opening of glycidol with hexadecylmercaptan, J. Org. Chem., 59 (1994) 668-671. I. Kubo and M. Taniguchi, Polygodial, an antifungal potentiator, J. Nat. Prod., 51, (1988) 22-29. P. M. Davidson, Phenolic compounds, in Antimicrobials in Foods (A. L. Branen and P. M. Davidson, eds.). Marcel Dekker, New York, 1983, pp. 37-74. C. W. Norden, H. Wenzel and E. Keleti, Comparison of techniques for measurement of in vitro antibiotic synergism, J. Infect. Dis., 140 (1979) 441-443. M. Himejima and I. Kubo, Antimicrobial agents from the Anacardium occidentale (Anacardiaceae) nut shell oil, J. Agric. Food Chem., 39 (1991) 418-421. I. Kubo, H. Muroi and A. Kubo, Naturally occurring antiacne agents, J. Nat. Prod., 57 (1994) 9-17. G. Combaut and L. Piovetti, A novel acyclic diterpene from the brown alga Bifurcaria bifurcata, Phytochemistry, 22 (1983), 1787-1789. L. Semmak, A. Zerzouf, R. Vails, B. Banaigs, G. Jeanty and C. Francisco, Acyclic diterpenes from Bifurcaria biiurcata, Phytochemistry, 27 (1988), 2347-2349. M. N. Jones and D. Chapman, Micelles, Monolayers, and Biomembranes, Wiley-Liss, New York, 1995. F. Delia Pieta, M. C. Breschi, R. Scatizzi and F. Cinelli, Relaxing activity of two linear diterpenes from Cystoseira brachycarpa var. balearica on the contractions of intestinal preparations, Planta Med., 61 (1995), 493-496.

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

41

Stereoselective Synthesis of Methylcyclopentanoid Monoterpenes

A. Bianco

1. Introduction. 2. Structure and biogenesis of methylcyclopentanoid monoterpenes. 3. Synthesis of methylcyclopentanoid monoterpenes. 3.1. 2-Hydroxy-3-oxobicyclo[4.3.0]non-4-ene-type skeleton. 3.1.1. Synthesis via bicycloeptene derivatives. 3.1.2. Synthesis via bicyclooctene derivatives. 3.1.3. Synthesis via bicyclononadiene derivatives. 3.1.4. Diels-Alder reactions. 3.1.4.1. Intramolecular Diels-Alder reactions. 3.1.4.2. Intermolecular Diels-Alder reactions. 3.1.5. Photochemical cycloadditions. 3.1.6. Nitrile oxide cycloaddition. 3.2. 3-Oxobicyclo[4.3.0]nonan-2-one- or 4-one-type skeleton. 3.2.1. 3.2.2. 3.2.3. 3.2.4. Tricyclo[3.3.0.0]octanone degradation. Favorskii rearrangement. Homer-Wadsworth-Emmons reaction. Norrish I type reaction.

1. Introduction

The higher plants routinely, rapidly and efficiently carry out syntheses that offer challenging synthetic targets to the greatest organic chemists. The biogenetic processes, starting from the simplest building bricks, create the asymmetric molecules

42

in a relatively simple manner, being the consequence of specific batteries of enzymes. We have the problem to invent something suitable to take the place of enzymes if we wish to prepare these natural products. Methylcyclopentanoid monoterpenes are a group of isoprenoids characterised by the presence in their skeleton of a cyclopentanoid residue. Both hydrophilic and hydrophobic compounds are known ( ref s 1-3 ), which may be both volatile and non volatile. Products of alkaloidal nature (ref 4 ) are also included in this family.

OOCH3

OOCH3

OOCH3

O 0-glc Loganin CH3 Iridomyrmecin Nepetalacton

Fig.l The principal groups of natural products belonging to this family of monoterpene derivatives are: glycosidic and non-glycosidic iridoids ( see fig 1, ref s 5-7 ), together with related compounds secoiridoids and bisiridoids, and monoterpene alkaloids ( see fig 2).

OOCH3

Gentianine

Fig. 2

43

Methylcyclopentanoid monoterpenes represent key intermediates of monoterpene metabolism of this type; in fact, starting from this skeleton, the typical biotransformation of the cyclopentanoid residue begins, as an oxidative cleavage. In the case of iridoids, they are ring opened to secoiridoids and are incorporated as monoterpenoid part of important groups of alkaloids: indole, ipecacuanha, cinchona, pyrroloquinoline alkaloids and related compounds (ref 8 ). Another aspect of methylcyclopentanoid monoterpenes is their biological role for the organisms which biosynthesise them. They are in fact often involved in the plant/insect and in the plant/plant biochemical interactions; the biochemical role of these compounds has been extensively studied in recent years and the role of methylcyclopentanoid monoterpenes in plant-animal and plant-plant interactions has been demonstrated (ref 9 ). Methylcyclopentanoid monoterpenes and their metabolites also show several biological activities in man and animals (ref 10 ). Therefore there were many reasons which attracted natural products chemists to take up on the total stereoselective synthesis of this class of isoprenoids In this article the stereoselective syntheses of methylcyclopentanoid monoterpenes are reviewed. The chemical procedures performed for the synthesis of glycosidic and non glycosidic iridoids will be presented.

2. Structure and biogenesis of methylcyclopentanoid monoterpenes

Methylcyclopentanoid monoterpenes are structurally characterised by a (1R,6S) 3oxobicyclo[4.3.0]nonane moiety. Two carbons, belonging to the isoprenoid unit, are generally linked to the 9 and 5 positions. So the basic skeleton is that depicted in fig.3.

44

Fig. 3 The biogenesis of this family of compounds constitutes a separate chapter in the metaboHsm of monoterpenes, and does not involve the carbocationic Ruzika's scheme but consists perhaps of an aldolic condensation-type process on an oxidated derivative of geraniol. The biogenesis of methylcyclopentanoid monoterpenes has been carefully studied allowing the key steps of the process to be depicted (ref s 11-13 ). The methylcyclopentanoid monoterpenes arise from geranyl-PP via an intramolecular stereocontroUed Mannich type condensation of a dialdehydic or a trialdehydic intermediate, as shown in fig.4. The resulting cyclopentanaldehydic compound has been named iridodial or iridotrial, depending on the nature of the biosynthesized compound and of its biogenetic pathway.

OPP

.CHO

k
R^^CHO

VCHO /^CHO R

R=CH3 or CHO

R=CH3 or CHO

Fig.4

45

Iridodial and iridotrial intermediates can arise by different biogenetic pathways, giving rise to different groups of methylcyclopentanoid monoterpenes. Intramolecular hemiacetalization between an aldehyde group and the enolic form of a second aldehyde, affords the 2-hydroxy-3oxobicyclo[4.3.0]non-4-ene type structure depicted ( fig.5 ).

OR [^\CHO

R R=CH3 or CHO R=CH3 or CHO R=CH3 or CHO R'=H or sugar

Fig. 5 The hemiacetalic C-2 function can be blocked by a sugar residue, affording the methylcyclopentanoid monoterpenes known as glycosidic iridoids. Otherwise the same function can be esterified giving rise to the non-glycosidic iridoids of plumeria or valeriana-type (fig.6).

CH2OAC

Isovaleroyl-O'

oX^-K^o

Valtrate

Piumericin

Fig. 6

46

Intramolecular redox reaction of iridodial or iridotrial intermediates afford two different skeleton of non-glycosidic iridoids: the iridomirmecin-type and the nepetalactone-type (fig.7).

Fig, 7 Reduction of one or both aldehydic functions of iridodial or iridotrial, responsible for the closure of the pyranoid ring, gives rise to the non-glycosidic iridoids, known as iridodiols, generally having only the methylcyclopentanoid moiety (fig.8 ).

OH OH

Fig.8 The iridodial intermediate can also suffer a well known transamination reaction, followed by intramolecular Schiff base formation, giving rise to the formation of 3azabicyclo[4.3.0]nonane-type skeleton, typical of monoterpene alkaloids.

47

Heterocyclic ring formation can then lead to a piperidine or a pyridine-type ring system, giving rise to tiie two principal groups of monoterpene alkaloids (fig.9 ).

Fig, 9 In the end, it is necessary to cite, in this biogenetic discourse, the secoiridoid group which is derived from methylcyclopentanoid monoterpenes, even if it does not maintain the characteristic methylcyclopentanoid moiety. Secoiridoids arise, in fact, from the oxidative opening of the cyclopentane ring of both glycosidic or nonglycosidic iridoids by cleavage of the C-8/C-9 bond. hifig.10 is depicted the biogenetic transformation of loganin to secologanin.

COOCH3

COOCH3

COOCH3

OHC
^sC o-gic

Loganin

Secologanin

Fig. 10

48

Secologanin is probably one of the best known secoiridoids, being the monoterpenic key intermediate in the biogenesis of indole and related alkaloids.

3. Synthesis of methylcyclopentanoid monoterpenes.

Numerous syntheses of methylcyclopentanoid monoterpenes have been reported, but we will restrict our discussion here to a selected number of the more general and stereoselective syntheses of the basic skeletons, giving particular attention to the stereoselective syntheses of optically active forms of these terpenes. hi view of the very different approaches, we prefer to divide the chapter into two topics. hi the first one ( section 3.1. ) we will consider the syntheses of methylcyclopentanoid monoterpenes having a hydroxyl group at the C-2 carbon and a double bond between the C-4 and C-5 carbons ( essentially glycosidic iridoids and related compounds, having both C-2 and C-4 carbons at the same oxidation level). hi the second one ( section 3.2. ) we will present the syntheses of methylcyclopentanoid monoterpenes having the C-2 and C-4 carbons at different oxidation levels (iridomyrmecin and nepetalactone-type compounds).

3.1.2-Hydroxy-3-oxobicyclo[4.3.0]non-4-ene-type skeleton. This skeleton is typical of iridoid glycosides, but several non-glycosidic iridoids, e.g. plumeria-type and valeriana-type compounds, are also characterised by the same skeleton.

49

It can be synthesised via several methods. Some of these employ bicyclic systems as starting material ( see sections 3.1.1. - 3.1.3. ), while others involve the construction of bicyclic iridoidic skeleton via cycloadditions ( see sections 3.1.4. 3.1.6. ). All the procedures lead only to the aglyconic moiety, the insertion of glucose being accomplished always in the final step.

3.1.1. Synthesis via bicycloeptene derivatives. The strategy, pioneered by Vandewalle, involved a completely stereospecific scheme based on the stereoselective fragmentation of precursors having a norbomane-type skeleton ( ref 14 ). The stereoselective synthesis of the suitable norl)omane-type precursors is shown in scheme 1. The norbomene 1, which is the starting materials for the synthesis of loganin depicted in scheme 2, has been obtained from cyclopentadiene and methyl Ecrotonate in classical Diels-Alder conditions, with a high endo-exo stereoselectivity.

^
COOCH3 COOCH3

Scheme 1

50

After reduction with lithium aluminium hydride and upon treatment with mcMoroperbenzoic acid, exclusively the endo-dXcohoX cyclized to 2, with yields higher than 80%. Swem oxidation followed by reductive cleavage of the ether bond, afforded the desired norbomanone 3 in a stereoselective manner. Fragmentation of norbomanone-precursors like 3 can be performed by two different strategies, depending on the skeleton desired to be obtained. Fragmentation via Norrish I type reaction afforded iridomyrmecin and nepetalactone-type compounds and will therefore be discussed in section 3.2.4. Fragmentation via Baeyer-Villinger oxidation ( ref 15 ) allows access to the 2hydroxy-3-oxobicyclo[4.3.0]non-4-ene-type skeleton and the synthesis of loganin by this approach is reported in scheme 2.

kO^

u
COOCH3 MEMO" COOCH3 XHO HO'" COOCH3

Scheme 2 Norbomanone 3 has been first transformed into the chetal 4 by Swem oxidation and selective transacetalization with 2-methyl-2-ethyl-dioxolane. Oxidation with m-

51

chloro-perbenzoic acid gave the lactone 5 which has been opened to the methylcyclopentanoid derivative 6. The missing carbon has been introduced on the compound 6, after MEM protection of the hydroxyl fiinction, upon metallation with with a 1:1 mixture of tBuOK-LilCA ( compound 7 ). Simple acid work-up afforded the p-methyl acetal of loganin aglucone 8 which is a known intermediate in the synthesis of loganin.

3.1.2. Synthesis via bicyclooctene derivatives This approach has been first used by Sakan and Abe ( ref 16 ) for the total synthesis of the verbenalin aglycon 19 which confirmed the structure and configuration of the corresponding glucoside, verbenalin. The key bicyclooctene derivative 14 has been prepared in stereoselective manner as depicted in the scheme 3.

AcO

11

H3C

COOH

H3C

COOH

O
14

Is,

O13

Scheme 3

52

The dienone 9 has been stereoselectively methylated, from the less hindered endo face of the molecule, to compound 10 having the methyl group in an a configuration. Hydride reduction afforded to the formation of the alcohol in which the hydroxyl function was disposed in anti configuration with respect to the methyl group, again in consequence of the hydride attack from the less hindered face of the molecule. The secondary hydroxyl group has been then protected by acetylation ( compound 11). Permanganate/periodate oxidation of 11 afforded the diacid 12, having the bicyclooctane structure with the correct relative configuration of the chiral centers. The intermediate 12 has been transformed in acid medium to the lactone 13 which on lead tetraacetate oxidation gave the key bicyclooctene derivative 14.

-^

14

COOCH3

COOCH3 CHO "CHO

18

17

Scheme 3 contd Compound 14 has been oxidised with osmium tetroxide to the glycol 15 which has been protected as the acetonide 16. Oxidation in basic medium with ruthenium oxide afforded a ketoacid which has been transformed into the corresponding methyl ester 17.

53

The acetonide protecting group has been then removed in acid conditions and subsequent lead tetraacetate oxidation opened the cyclopentane ring because of the vicinal diolic function, furnishing the hemiacetalic structure 18. The compound 18 gave rise to the more stable hemiacetalic structure of verbenalol 19, corresponding to the methylcyclopentanoid monoterpenic structure of verbenalin. A similar strategy has been employed by Vandewalle et al in the total synthesis of verbenalin aglycone ( ref 17 ), but a different approach has been used for the stereoselective synthesis of the bicyclooctene key synthon.

COOCH3

V^^o
20 R=OH 21R=CI 22 R=0 23R=N2 ^^

Scheme 4 Starting from 2-cyclopentene-l-acetic acid 20, the intermediate 24 has been constructed through a four step sequence as described in scheme 4. Acid 20 has been transformed to the acid chloride 21 which has been condensed with Meldrums acid to give, after solvolysis with metfianol, the p-keto ester 22. Subsequent treatment with/?-tosylazide gave the diazo compound 23 which has been stereoselectively cyclized to 2-carbomethoxy-tricyclo[3.3.0.0]octan-3-one 24 with copper acetylacetonate as catalyst. Tricycloderivative 24 is the starting product for the synthesis of verbenalol 19 reported in Scheme 5. Solvolysis of 24 in acetic acid and subsequent cyanoborohydride reduction has been performed in one pot to afford the alcohol 25 which, after dehydration, gave a,P-unsaturated ester 26 and successively the key compound 27, after methanolysis and Jones oxidation.

54

Selenenylation in the a-position to the carbonyl of 27 with subsequent direct oxidation, gave the enone 28. Double bond migration of the unsaturated ester function of 28 has been performed via allyUc bromination and subsequent reduction with zinc, yielding, in a satisfactory stereocontrolled way, the compound 29. Subsequent conjugate addition with dimethylcopperlithium yielded the desired isomer 30 with good stereoselectivity.

COOCH3 O 24

AcO

COOCH3

AcO

COOCH3

25

26

COOCH3

C00CH3

29

28 \ O COOCH3 COOCH3

27

30

Scheme 5 The double bond of 30 has been cleaved with ozone and successive acid work-up of the reaction mixture afforded in one step the verbenalin aglycone 19.

55

3.1.3. Synthesis via bicyclononadiene derivatives This procedure has been used essentially for the total synthesis of genipin which has been described by Buchi et al ( ref 18 ) and which allowed the confirmation of the structure of this compound as well as the stereochemical assignments. The procedure is depicted in scheme 6 and starts from the bicyclononadiene derivative 31, prepared by thermal decomposition of the ethyldiazoacetate adduct of cyclooctatetraene ( ref 19 ), which has been reduced with lithium in ammonia to the bicyclononadiene derivative whose methylester 32 is the starting product.

COOH

COOCH3

31

32

33

OOOCH3

COOCH3

C00CH3
N

r
36

HO'

OH 35

^N.^

CHO

.^"'^^^-^ HO^

CHO

OH 34

Scheme 6 Osmium tetroxide oxidation of 32 gave a mixture of the isomeric tetraols 33 whose vicinal diolic function on the cyclopentane ring has been regioselectively cleaved with one mole of lead tetraacetate to give the dihaldehydic derivatives 34 which have been isolated as lactols 35. Periodate cleavage of the isomeric lactols 35 afforded the dihaldehyde 36.

56 COOCH3 OHC COOCH3 COOCH3

Scheme 6 contd Regioselective intramolecular aldolic condensation of 36 with piperidinium acetate gave only the compound 37 with the desired 2-hydroxy-3-oxobicyclo[4.3.0]non-4ene-type skeleton. The regioselectivity of this reaction can be explained on the basis of a less hindered transition state which corresponds to the formation of the methylcyclopentanoid derivative 37. (+)-genipin 38 has then been prepared by a regioselective reduction of the free aldehyde function of the intermediate 37 with lithium tri-/-bythoxyaluminium hydride.

3.1.4. Diels-Alder reactions The Diels-Alder reaction has been used for the synthesis of the iridoidic skeleton, starting from both acyclic (described in section 3.1.4.1.) and cyclic (descibed in section 3.1.4.2.) intermediates.. 3.1.4.1. Intramolecular Diels-Alder reactions. This approach has been proposed by Tietze et al which constructed a suitable acycKc intermediate shown in scheme 7. By means of an intramolecular Diels-Alder

57

reaction ( ref. 20 ) the direct preparation of the iridoidic-type skeleton has been described as depicted in scheme 7.

OCH3

Scheme 7 3.1.4.2. Intermolecular Diels-Alder reactions An intermolecular Diels-Alder reaction has been also employed starting from a suitable cyclic diene and the iridoidic skeleton has been prepared in a stereoselective manner (ref 21) as shown in scheme 8.

40

cCf41

H I

H I

39
R=H or COOCH3 R', R"= Alkyl

4r
42 OR"

Hr
OR" 43

Enantiomeric mixture

Scheme 8 The cyclopentene-carbaldehyde 39 reacts with the enol-ether 40 to form the adduct 41, having the skeleton of 3-oxobicyclo[4.3.0]non-l-ene. An alcohol has been then regioselectively and stereoselectively added (compound 42 ) at the double bond from

58

the less hindered p side of the molecule. Finally a regioselective acid catalysed elimination of an alcohol afforded the 2-alkoxy-3-oxobicyclo[4.3.0]non-4-ene moiety ( compound 43), characteristic of methylcyclopentanoid monoterpenes. The reaction can be performed using the enol-ether 40 with both hydrogen or carbon substituents; depending on the employed enol, the 2-alkoxy-3oxobicyclo[4.3.0]non-4-ene-type skeleton may be prepared in substituted or unsubstituted forms at 5 position.

3.1.5. Photochemical cycloadditions The photochemical addition of fimctionalized cyclopentenes and

tricarbonylderivatives has been also used for the preparation of iridoidic skeleton, via a bicylo[3.2.0]heptane intermediate, as shown in the scheme 9.

HsCOOC^

OH

cti
H 44

COOCH3

H I

COOCH3

COOCH3

Scheme 9 This procedure is an adaptation of a photoannulation reaction, originally developed by de Mayo ( ref 22 ) and leads initially to the stereoselective formation of a cyclobutanol ring (intermediate 44 ) which undergoes a spontaneous ring opening to the typical iridoidic dialdehyde ( intermediate 45 ) which is theoretically in equilibrium with the lactol iridoidic moiety ( intermediate 46 ), as depicted in the scheme 9. The first two syntheses of loganin aglycone 58 have been performed in a similar manners by Buchi, Tietze et al ( see scheme 10-13, ref 23 ) and by Partridge et ah.

59

( see scheme 14, ref. 24 ). They differ in the structure of the starting cyclopentene derivative. Buchi started from 3-cyclopentenol 47 which is photochemically added to the enol double bond of 2-formyhnalonaldehyde 48 in a stereoselective way (scheme 10 ).

H3COOC

>=0

COOCH3 THP

THPO-^
47

V ^

OH
48

COOCH3 THPi

50 and 50a

Scheme 10 The hemiacetalic iridoidic intermediate 49 obtained has been successively transformed into the two corresponding enantiomers methylacetals 50 and 50a and the secondary alcoholic function on the cyclopentane ring oxidised to a carbonyl group (enantiomeric mixture 51 and 51a obtained). The missing one carbon unit is introduced at this stage utilising the reactive aposition to the carbonyl and different procedures have been employed, generally in relation to the desired iridoid. In the case of the first synthesis of loganin ( see scheme 11 ) the ketonic intermediate 51 ( as an enantiomeric mixture ) has been formylated in high regioselective way to the aldehyde 52 as the major product, owing to the steric

60 hindrance constituted by the carbomethoxyl group which is more important than the hindrance of methoxyl group in consequence of the structural constitution of the molecule. Aldehyde 52 has been successively derivatized with w-buthyhnercaptan to produce the thiomethylene derivative 53.

COOCH3

o=rtS

COOCH3

COOCH3

OHC^H,
51
Enantiomeric mixture 52 Major products

._ n-BuS"'

. . . /^ ^ H ^^ 3
53

COOCH3 COOCH3

COOCH3

OCH3 55R=H 56 R=Ts ^^sC 54 0CH3

H3C

0CH3 54 and 54a

H T
AcO' H3C 57

COOCH3

COOCH3

H T

COOCH3

AcO'
0CH3

>- AcO--< ^sC 59

I 0-glcAc4

Scheme 11 Desulphurization and reduction of 53 produced a mixture of epimeric ketones 54 and 54a which have been transformed into the thermodynamically more stable ketone 54 via sodium methoxide treatment.

61 As a general rule the substituents on the cyclopentane ring in 3 configuration in this type of molecules suffer a lower steric hindrance with the consequent major thermodynamic stability for compounds having substituents in this absolute configuration. The introduction of a secondary hydroxyl function on the cyclopentane ring in the desired syn configuration with respect to the methyl, has been performed in three steps, firstly by reducing the ketone function with sodium borohydride. The more stable anti hydroxyl ( compound 55 ) has been obtained and, to invert its configuration, it has been esterified with p-toluensulfonate ( compound 56 ), and substituted, in bimolecular nucleofilic substitution conditions, with acetate (compound 57). The classical glucosylation with 2,3,4,6-tetraacetylglucose, afforded the acetate of loganin 59, via the aglycone 58. A simple modification of this procedure has been performed by Tietze (ref 25-28) as shown in scheme 12.
COOCH3

H I
')nr. HOOC

COOCH3 HO-

COOCH3

H i.

OCH3

HOOC

0CH3

60 and 60a
/
COOCH3

61 and 61a

COOCH3

AcO (I
HOH2C

I
OCH3

63 Scheme 12

62

The procedure has been utiUsed to synthesise the hydroxyloganin, the key ring intermediate in the metabolism of iridoids to secoiridoids and subsequently to indole and related alkaloids having this monoterpenic part. The difference in the procedure consists essentially in the different introduction of the missing one carbon unit, at the same stage after the photochemical addition, utilising methyhnagnesium carbonate. The ketone 51, prepared as an enantiomeric mixture as described in scheme 9, is regioselectively carboxylated in the a position to give the p-ketoacid 60 which, without any manipulation, is immediately stereoselectively reduced to the Phydroxyacid 61, with sodium borohydride. Tietze proposed a thermodynamic control in the high regioselectivity of carboxylation of 51 and a steric control, as consequence of convex geometry of molecule, in the stereoselectivity of reduction of 60. Resolution of the enantiomeric mixture can be performed at this step, after acetylation of the secondary hydroxyl, by separation of diastereoisomeric salts 62 and 62a with 1-phenylethylamine. The carboxyl group of the desired enantiomer of 62 is then reduced to a hydroxymethyl group in the intermediate 63 which can afford hydroxyloganin 72 ( ref 25-28 ) or 7-epihydroxyloganin 68 ( ref 25, 28 ) following two different procedures as depicted in scheme 13. Diacetate 64 is transformed into the hemiacetal 66 by a mixture of acetic and perchloric acid in water. Glucosylation of 66 with 2,3,4,6-tetra-O-acetyl-P-D-glucose in the presence of boron trifluoride afforded the hexaacetate of 7-epihydroxyloganin 67 and, after alkaline hydrolysis, the corresponding iridoid 68.

63

RO"'

A\
/
64 R=Ac 65 R=Ms

COOCH3 AcO" ACOH2C " 66

COOCH3 RO' ^^

ROH2C

HT

.rtS
HT
67 R=Ac 68R=H

COOCH3

0CH3

n ROH2C

0-glcR4

COOCH3

COOCH3 AcO-

COOCH3

AcO<
OH^r ACOH2C

RO<

I
0-glcR4 71 R=Ac 72R=H

H i _ . OCH3 69

w.r ACOH2C

Hi..
70

ROH2C

Scheme 13 For the synthesis of hydroxyloganin 72, the same starting intermediate, as dimesylate 65, is treated with tetraethylammonium acetate to invert the configuration at C-7. Hydrolysis of acetal as before allowed to prepare the hemiacetal 70, and successive glucosylation afforded hydroxyloganin hexaacetate 71 and thereafter hydroxyloganin 72. An improvement in the glucosylation procedure has been performed by Tietze ( ref 29 ) which utilized P-trimethylsilyl-2,3,4,6-tetraacetylglucose which reacted with the acetylated hemiacetalic fimction in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate in acetonitrile or liquid sulphur dioxide at -30 or -50 T respectively.

64

Loganin acetate 59 has been rapidly obtained by Partridge et al.X scheme 14, ref. 24 ) starting from enatiomerically pure (-)-(lS,2R)-2-methyl-3-cyclopentenyl acetate 76.

H3COOC H3C-<^ AcO' H3C 73 74R=H 75 R=Ms COOCH3 76 48

COOCH3

AcO-Y
^sC

I
0-glcAc4

AcO<
H3C 58 OH

59

Scheme 14 The optically pure starting material has been prepared from the prochiral 5methylcyclopentadiene 73 by hydroboration with (+)-bis(cis-pinan-trans-3-yl)borane. (-)-(lR,2R)-2-methyl-3-cyclopentenol 74 obtained has been mesylated ( compound 75 ) and the desired (-)-(lS,2R)-2-methyl-3-cyclopentenyl acetate 76 has been prepared by displacement with acetate on heating with tetraethylammonium acetate. This olefin undergoes photoannelation in regioselective and stereoselective manner with methyl-diformyl acetate 48 to produce directly the loganin aglycone derivative 58 in about 20% yield. Classical treatment with 2,3,4,6-tetra-O-acetyl-D-glucose in anhydrous conditions, in the presence of boron trifluoride etherate, afforded loganin pentaacetate 59.

65

A further utilisation of the Patemo-Buchi enone photoannulation reaction has been performed by Chaudhuri et al ( ref 30 ) who, by employing 5-(trimethylsilyl)-l,3cyclopentadiene 77 in acetonitrile at -50 C ( see scheme 15 ), obtained in a regioselective way only the photoadduct 78, by reaction with methyl-diformyl acetate 48.

H3COOC MeaSi

-O
77 48 COOCH3

MeaSi

H ?^"'

78

MeaSi

u 9^^^"3

H 0CH3 L.
79

80 R=CH3C0

Scheme 15 The intermediate 78 is stabilized by acetalization with methanol ( compound 79 ) and the introduction of missing carbon can be easily performed in stereoselective way by allylic displacement of the silyl group with acetyl chloride or other reagents (compound 80).

66

3.1.6. Nitrile oxide cycloaddition The Claisen rearrangement - nitrile oxide cycloaddition sequence has been adapted to the synthesis of methylcyclopentanoid monoterpenes by Curran et al (ref. 31-32 ). This reaction sequence is in fact a useful, stereocontroUed annulation procedure in a carbocyclic ring system which the authors demonstrated to be applicable to the synthesis of heterocyclic systems.

o ^
CHsOOC^ . k . ^O R
82

OEt
83

OMs

OEt
86 85 84

^
87 88

Scheme 16

67

The starting glycal 81 has been prepared by Ferrier rearrangement of D-xylal; the acetalic P-anomer has been employed in the synthetic procedure. As shown in scheme 16, the nature of substituted acetic acid which esterifies the secondary hydroxyl depends on the target structure. freland-Claisen rearrangement of 81, followed by methylation, afforded the intermediate 82 as a single stereoisomer. DIBAL reduction to the aldehyde and successive WoUemberg homologation afforded the key nitro-olefin 83. The nitrile oxide cycloaddition has been performed on 83 under Mukaiyama conditions giving the isoxazoline 84 in about 50% yields with high stereocontrol of the annulation reaction. The 2-hydroxy-3-oxobicyclo[4.3.0]nonane-type skeleton, typical of methylcyclopentanoid monoterpenes, has been then constructed in a stereospecific and regiospecific manner. Successive steps can be designed according to the target molecular moiety. In the case depicted in scheme 16, nickel-Raney reduction of 84 provided the Phydroxyketone 85 which can be easily transformed to the desired skeleton by mesylation (compound 86) and successive treatment with DBU. The 2-hydroxy-3-oxobicyclo[4.3.0]non-5-ene-type structure ( compound 87 ) has been obtained which in turn has been equilibrated in the same conditions to the thermodynamically more stable 2-hydroxy-3-oxobicyclo[4.3.0]non-4-ene-type one ( compound 88). The reported model scheme had shown that Claisen rearrangement-nitrile oxide cycloannulation represented an excellent procedure for the stereoselective synthesis of 2-hydroxy-3-oxobicyclo[4.3.0]non-4-ene-type skeleton differently substituted on the cyclopentane ring.

68

3.2.3-Oxobicyclo[4.3.0]nonan-2-one- or 4-one-type skeleton.

Different approaches have been proposed for the stereoselective synthesis of methylcyclopentanoid monoterpenes with and nepetalactone-type iridomirmecin-type skeleton skeleton (3(3oxobicyclo[4.3.0]nonan-2-one-type)

oxobicyclo[4.3.0]nonan-4-one-type). We will divide the discussion on the basis of the key reactions used in the synthetic strategy.

3.2.1. Tricyclo[3.3.0.0]octanone degradation. 2-Carbomethoxy-tricyclo[3.3.0.0]octan-3-one 24, obtained as described in section 3.1.2., has been utilized as a chiral starting material for the preparation of isoiridomirmecin 92 (ref 17, scheme 17).

COOCH3 O 24

H3C

COOCH3

89

H3C OSi{CH3)3 CH3 91 90

Scheme 17

69

As shown in scheme 17, compound 24 has been methylated in a stereocontroUed way by reaction with methyl iodide in the presence of lithium diisipropylamide, affording the derivative 88. Reaction of 88 with dimethylcopperiithium afforded, again in a stereocontroUed way, the ketoester 89. The hydrolysis of ester function of ketoester 89 led to the decarboxylation, affording a single ketone 90. The kinetic enolate derived from ketone 90 has been trapped as the trimethylsislyl derivative 91. Ozonolysis of 91, followed by reductive work-up with sodium borohydride, afforded directly the isoiridomyrmecin 92.

3.2.2. Favorskii rearrangement. The starting idea of this approach arises from the knowledge that fiinctionalized cyclopentanecarboxylates can be obtained from the Favorskii rearrangement of cyclohexanone derivatives (ref 33 ). (+)-carvone 93 has been chosen as the starting cyclohexanone derivative and it has been transformed into the chlorohydrin derivative 95 via the epoxide intermediate 94, as described in scheme 18.

THPO.

o
93 94 95

Scheme 18

70

The monoepoxide 94 has been obtained by oxidation of (+)-carvone 93 with hydrogen peroxide in alkaline medium (NaOH/MeOH) for 1 h at room temperature. Treatment of 94 with chlorotrimethylsilane in acetonitrile/dimethylsulphoxide opened the epoxide affording, in high regioselective yields, the corresponding chlorohydrin which has been transformed, without isolation, to its tetrahydropyranyl ether 95. When 95 has been treated with sodium methoxide in methanol at room temperature, the Favorskii rearrangement occurred in a stereoselective manner and the cyclopentanecarboxylate 96 has been obtained in high yields as described in scheme 19.

THPO. THPO'

CI "tY
o
95 96

'COOCH3

Scheme 19 In schemes 20 and 21 are depicted the strategies for the stereoselective transformations of the key intermediate 96 in the methylcyclopentanoid monoterpenes with iridomyrmecin- and nepetalactone-type skeleton. For the synthesis of dihydronepetalactone 99, the intermediate 96 has been manipulated as depicted in scheme 20. The key step is represented by the stereoselective hydroboration of 96 with disiamylborane and by the successive oxidation, which led to the formation of the free primary alcoholic function of the intermediate 97. The stereoselectivity of hydroboration is due to the attack of the bulk borane from the less hindered (3-side of

71

the molecule and allowed to have the methyl group in the intermediate 97 in the required a-configuration.

THPO' COOCH3

THPO-

96

97

HO'

n?
98

H \

99

Scheme 20 The hydrolysis of 97 in alkaline conditions, followed by acid treatment, allowed the intramolecular lactonization, affording the hydroxylactone 98. Barton-type deoxygenation of 98 yielded the expected (+)-dihydronepetalactone 99. Alternatively ( see scheme 21 ), the same key intermediate 96 can be transformed into the iridomyrmecin 102. The compound 96 has been transformed into the acetate 100 by reduction with lithium aluminium hydride, followed by acetylation of the free primary hydroxyl and successive deprotection of the secondary hydroxyl. Barton-type deoxygenation of 100, with the same procedure previously described in scheme 20, gave the acetate 101 which is a known intermediate in the synthesis of iridomyrmecin 102.

72

THPO' COOCH3

96

H f

OAc 102 101

Scheme 21

3.2.3. Homer-Wadsworth-Emmons reaction. The Homer-Wadsworth-Emmons reaction is an important methodology used in the synthesis of natural products, but side reactions in many cases do not allow the application of this reaction in stereoselective synthesis. However, Nangia et al ( ref 34 ) recently described, by using the HomerWadsworth-Emmons reaction in a controlled way, the stereoselective synthesis of boschnialactone as depicted in scheme 22. R-pulegone 103 is known to give rise to a rearrangement product 104 as a mixture ofsyn and anti isomers in which (approximately 6:4) the syn one prevails.

73

C00CH3

103

104

105

/
OEt

107

106

Scheme 22 Lithium aluminium hydride reduction of the mixture 104, followed by a chromatographic purification, allowed the preparation of the alcohol 105 as pure stereoisomer. Ozonolysis in buffered conditions, using dichloromethane and sodium hydrogen carbonate, afforded the p-hydroxy alcohol 106 which has been esterified with diethylphosphonoacetic acid in the presence of DCC to the key cyclopentanoid derivative 107. The ester 107 has been submitted to the Homer-Wadsworth-Emmons reaction, using diisopropyl ethyl amine as the base in the presence of lithium chloride. Under these conditions, after 16 h the lactone 108 has been obtained in high yields in a regioselective way, without (3-elimination and a-epimerization.

74

II .OEt
^OEt

^ 0
107

108

109

Scheme 22 contd Highly stereoselective hydrogenation of 108 from the less hindered exo face of the molecule, afforded boschnialactone 109. The authors also showed the possibility, by employing suitable starting products, such as S-pulegone, to obtain iridomyrmecin, isoiridomyrmecin and teucriumlactone with the same Homer-Wadsworth-Emmons reaction.

3.2.4. Norrish I type reaction. Norbomanone-type compounds can be fragmented by a Norrish reaction giving with high stereoselectivity iridomyrmecin-like compounds. Vandewalle et al ( ref 15 ) have demonstrated an alternative route which starts from the norbomanone 3, whose synthesis has been described in scheme 1, and from its epimer 110 which has been prepared in a similar manner as reported in scheme 23. The well known endo adduct 111 of cyclopentadiene and maleic anhydride is the starting material for the preparation of nomomanone 110. The compound 111 has been reduced to the diol 112. Treatment with mchloroperbenzoic acid, in the same conditions previously described in scheme 1 for the preparation of 3, afforded the diol 113.

75

As in the case of the preparation of 3, a cyclization occurred between the two syn primary and secondary alcohoUc fiinctions, with formation of an additional heterocyUc ring.

111

Hcr-^

-f
Scheme 23 the required norbomanone 110. on its epimer 110 (see scheme 24 ).

'

HO

no

113

Regioselective tosylation of the primary free alcohoHc function of 113, followed by reductive removal of the tosylate, Swem oxidation of secondary free alcoholic function and reductive cleavage of the ether bond of the tetrahydrofurane ring, gave Norrish I type reaction has been carried on the norbomanone-type compound 3 and The described procedure allowed to obtain, with satisfactory yields, the lactols 114 and 115, in which the required 4-hydroxy-3-oxobicyclo[4.3.0]nonanane-type skeleton has been prepared in a single step and in a satisfactory stereocontrolled manner. Depending on the required configuration of the methyl group on the cyclopentane ring, the lactols 114 and 115 have been manipulated as depicted in scheme 24.

76

OH

H3C

3 p-methyl llOa-methyl

114 p-methyl 115a-methyl

H3C

9^
116

H3C

ccr
109

Scheme 24 The lactol 115, after oxidation of hemiacetalic fiinction and saturation of the double bond, gave boschnialactone 109. The lactol epimer 114, on introduction of the a-methylene group by means of the Grieco's method, has been transformed into teucriumlactone 116.

References 1. J.M.Bobbitt and K.P.Segebarth, The iridoid glycosides and similar substances in, W.I.Taylor and A.R.Battersby (Ed), Cyclopentanoid terpene derivatives. Marcel Dekker hic. New York, 1969. 2. A.Bianco, The Chemistry oflridoids in, Atta-ur-Rahman (Ed), Studies in Natural Products Chemistry, Elsevier, 1990, vol. 7.

77

3. G.W.K.Cavill Insect terpenoids and nepetalactone, in, W.LTaylor and A.R.Battersby (Ed), Cyclopentanoid terpene derivatives. Marcel Dekker Inc., New York, 1969. 4. G.A.Cordell, Monoterpene alkaloids, in, R.H.Manske (Ed), The alkaloids. Academic Press, New York, 1977, vol. 16. 5. L.J.El Naggar and J.L.Beal, J. Nat Prod., 43, 649 (1980). 6. C.A.Boros and F.R.Stermitz, J. Nat. Prod., 53, 1055 (1990). 7. C.A.Boros and F.R.Stermitz, J. Nat. Prod., 54, 1055 (1991). 8. M.Luckner, Secondary metabolism in microorganism, plants, and animals, Springer-Verlag, Berlin 1990. 9. J.B.Harbome, Introduction to ecological Biochemistry, Academic Press, London, 1989. 10. H.Inouye, Iridoids, in Methods in Plant Biochemistry, Academic Press, London 1991, vol. 7. 11. S.Damtoft, Phytochemistry, 11, 1929 (1983). 12. F.Bellesia, R.grandi, U.M.Pagnoni, A.Pinetti and R.Trave, Phytochemistry, 23, 83 (1984). 13. H.Inouye and S.Uesato, Prog. Chem. Org. Nat. Prod., 50, 169 (1986). 14. P.Callant, H.De Ville and M.Vandewalle, Tetrahedron, 37, 2079 (1981). 15. P.Callant, P.Storme, E.Van der Eycken and M.Vandewalle, Tetrahedron Letters, 24, 5797 (1983). 16. T.Sakan and R.Abe, Tetrahedron Letters, 2471 (1968). 17. P.Callant, R.Ongena and M.Vandewalle, Tetrahedron, 37, 2085 (1981). 18. G.Buchi, B.Gubler, R.S.Schneider and J.Wild, J. Am. Chem. Soc, 89, 2776 (1967). 19. K.F.Bangert and V.Boekelheide, J. Am. Chem. Soc, 86, 905 (1964). 20. L.F.Tietze and T.Eicher, Reaktionen und Synthesen im organisch-chemischen Praktikum, Thieme, Stuttgart 1981, p.364. 21. L.F.Tietze, Chem. Ber., 107, 2491 (1974). 22. P.de Mayo, Ace. Chem. Res., 4, 41 (1971).

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23. G.Buchi, J.A.Carlson, J.E.Powell and L.F.Tietze, J, Am, Chem. Soc, 92, 2165 (1970). 24. J.J.Partridge, N.K.Chadha and M.R.Uskokovic, J, Am. Chem, Soc, 95, 532 (1973). 25. L.F.TiQtzQ.Angew. Chem. Int. Ed Engl., 22, 828 (1983). 26. L..TiQtzQ,Angew. Chem. Int. Ed. Engl., 12, 757 (1973). 27. L.F.Tietze, Chem. Ber., 107, 2499 (1974). 28. A.R.Battersby, N.D.Westcott, K.H.Glusenkamp and L.F.Tietze, Chem. Ber., 114, 3439(1981). 29. L.F.Tietze, R.Fischer and G.Remberg, LiebigsAnn. Chem., 971 (1987). 30. R.K.Chaudhuri, T.Ikeda and C.R.Hutchinson, J. Am. Chem. Soc, 106, 6004 (1984). 31. D.P.Curran, P.B.Jacobs, R.L.Elliot and B.H.Kim, J. Am. Chem. Soc, 109, 5280 (1987). 32. B.H.Kim, P.B.Jacobs, R.L.Elliot D and. P.Curran, Tetrahedron, 44, 3079 (1988). 33. E.Lee and C.H.Yoon, J. Chem. Soc. Chem. Commun., 479 (1994). 34. A.Nangia, G.Prasuma and P.B.Rao, Tetrahedron Letters, 35, 3755 (1994).

Current Address Professor Armandodoriano Bianco Dipartimento di Chimica - Universita La Sapienza Piazzale Aldo More 5,1-00185 Roma (Italy) Fax 39 6 490631 E-mail adbianco@axrma.uniromal.it

Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

79

Chemical Constituents of Taxus Species

V.S. Parmar and A. Jha 1. INTRODUCTION The genus Taxus belongs to the family Taxaceae and consists of much branched trees or shrubs. Taxaceae is a family of five genera: Amentotaxus Pilger, Austrotaxus Compton, Pseudotaxus Cheng, Taxus Linn, and Torreya Am (1). Various species of this genus are also trivially termed as yew and are specified by the region of their occurrence, e.g. Himalayan yew, European yew, Canadian yew, etc. They are evergreen shrubs or trees. The wood of Taxus is one of the heaviest of soft woods. It is also mechanically strong and durable. Its timber is oily and irregular growth rings in the wood provide decorative value. Different Taxus species have proved to be of special significance among phytochemists in recent years because they have been found to possess a number of biological activities. Taxus baccata is a poisonous plant (all parts except the fleshy aril) and has been recorded as a fish poison. Its leaves possess tremendous medicinal properties in Unani system of medicine: they are antispasmodic and emmenagogue and are used for epilepsy and as lithontriptic (2). A tincture made from young shoots has been in use for diarrhoea and severe biliousness. Vohora and Kumar in 1971 reported that the water extract of the leaves oiTaxus baccata possesses good tranquilizing activity (3). The chemical constituents of different Taxus species have been studied for over a hundred years. Taxane alkaloids, diterpenoids with taxane skeleton, lignans, biflavonoids, steroids, sugar derivatives and diterpenes possessing tropone skeleton are commonly found to occur in this genus. The phytochemistry of the genus Taxus has evoked a great deal of interest because of the occurrence of antitumour and antileukemic taxanes, molting hormones, alkaloids, antineoplastic diterpenes and other physiologically important compounds in its various species, in particular because of the importance of taxol/paclitaxel (Taxol is a registered trademark of Bristol-Myers Squibb Co., hence the generic name paclitaxel should be used instead), the world known new antitumour drug. This has made Taxus as one of the most intensely investigated genus of all the plant genera. A few reviews have appeared in the literature (4-7) on this subject while the one that covered maximum information on taxoids, the typical secondary metabolite of the yew tree was published in 1993. Phytochemistry of Taxus species, being a hot topic, a number of reports on the isolation of newer metabolites poured in thereafter. The latest review (5), to our knowledge, covers the literature on the subject from 1987 to mid 1995 and at least fifty new compounds have been reported from the species Taxus after that. There is no updated comprehensive review that enlists all the isolates from various Taxus species. Our present review covers the literature upto June 1996 listing all chemical constituents isolated from different species of Taxus giving due emphasis to the biological activities possessed by them.

80

2. TAXANE DERIVATIVES Taxanes are typical cyclic diterpenoids. A normal taxane (I) contains an eight membered ring sandwiched between two six membered rings, but there are numerous compounds which have rearranged taxane skeleta. 3,11-Cyclotaxanes (11) are tetracyclic systems with an additional bond between C-3 and C-11. Taxanes having ring system III are called 11(15> 1) aZ?eotaxane. They have linearly fused five, seven and six membered rings. A six/ten/six membered ring system (FV) is known as 2(3>20) abeoiaxants. An 11(15>1), 11 (10>9)bisabeoi^x?ine having skeleton V is also known. Compounds with skeleton VI are referred to as pretaxanes as the bond between C-3 and C-8 is not yet formed.

x < \

IV

VI

2.1 Normal Taxanes The naturally occurring diterpenoids with the taxane skeleton are the typical constituents of Taxus. The constituents of the yew became the active subject of phytochemical and synthetic work since the discovery of terpenes belonging to the taxane group (8-10). Roberto and Jelmoni (11) reported a case of poisoning following the ingestion of berries of T. baccata. The alkaloid taxine is the toxic constituent that occurs in the leaves and berries, while the aril is free of alkaloids. Taxine is in fact a mixture of at least 11 compounds, only five of which [taxine A (229) and B (70), 13-deoxo-13a-acetyloxytaxine B (30), 13deoxo-13a-acetyloxy-l-deoxytaxine B (31) and 13-deoxo-13a -acetyloxy-1-deoxy-nor-taxine B (35)] have been structually characterized so far. The action of the alkaloid was only apparent after ingestion of the berries when the latter were chewed. The leaves of T. cuspidata

81

and T. floridana also tested positive for alkaloids (12). The symptoms of taxine poisoning are mainly associated with cardiac and respiratory disturbances and death results from heart failure, accompanied by respiratory paralysis (13). The unusual diterpene, taxol (116) (14) was reported in 1971 by Wani etal. (15) as the major cytotoxic, antineoplastic (16) and antileukemic constituent occurring in yew (1719). It was found to possess confirmed activity in the L-1210, P-388 and P-1534 leukemia, the B-16 melanoma and the Walker 256 carcino-sarcoma m vivo assays. It is speculated that to some extent the activity of taxol may be due to the easily cleaved allylic a -hydroxy ester function at C-13 which may be capable of acting as a leaving group under physiological conditions. Taxol is an interesting drug in that it appears to act by a mechanism that is different from other known anticancer drugs; it has been recognized as a strong antimitotic agent (20). This important biological activity has been related to the in vitro inhibition by taxol and some of its derivatives of the depolymerization process of tubulin. It acts by promoting microtubule formation (21-23) by decreasing the lag time for microtubule assembly and shifting the equilibrium in favour of the microtubule (24). Taxol blocks the processes, essential for prostate tumour cell (PC-3ML) invasion and metastasis (25). The taxol content in various parts of several Taxus species have been determined (26-28). The activity of taxagifine (82) is lesser than that of taxol (ID^^ 5 x lO^M, cf. 10^ for taxol) (29). The taxane esters 10-deacetyltaxol (114), 7-e/7i-10-deacetyltaxol (120), 10deacetylcephalomannine (135) and 7-epr-lO-deacetylcephalomannine (138) have KB activities (ED^Q, g/ml) 2.7X10-2, 3.4x10% 3.1 X 10- and 4.6X10-2, respectively (30). 19Hydroxybaccatin III (104) was inactive in vivo in the PS mouse lymphocytic leukemia system at the doses tested (0.26-4.3 mg/kg). The greater water solubilities of these more polar taxane derivatives {Le. 114 and 135) may help to circumvent in vivo toxicities of the parent compounds and could show some clinical advantages over taxol and cephalomannine (30). The KB and P388 activities of cephalomannine (134) are roughly comparable to those of taxol (116). Cephalomannine gave typical T/C values in the range 152-180 at dose levels of 1-3.3 mg/kg against PS, while taxol showed T/C values of 148-152 in the dosage range 1.4-2.2 mg/kg. Both these compounds showed cytotoxicity (ED^^) against KB cell cultures at 10'^ g/ml, whereas baccatin III (102) had an ED^^ of 2.0 g/ml and 16-hydroxybaccatin I (92) had an ED^^ of 2.9 g/ml (31). Some of the taxoids isolated recently have been demonstrated to be equally or in some cases more potent anti-tumour agents than taxol. Taxol C (129), isolated from the bark of T.media possesses antitumour activity (e.g. IL^^ against L1210 murine leukemia cells of 3.60.3 nM) higher than that of taxol (e.g. 57.03.0 nM) and is also active against adriamycin resistant cells (32). Taxol C possesses selective cytotoxicity in the NCI human cell line screen (33). 10Deacetyltaxol C, A^-methyltaxol C (130) and taxol D (133) also showed activity close to that of taxol in the tubulin assembly assay (32,33). Table 1 lists the different taxanes isolated thus far from different Taxus species.

82

TABLE 1 Normal taxane derivatives isolated from different Taxus species. Compound Species References (34,35) (36,37) (38,39,40) (39) (41,42) (39) (43-46) (47) (38) (43,48,49) (38) (48) (38) (50,51) (52) (53) (40) (54) (53) (55) (56) (55) (55) (38) (43,48,49)

Taxa-4(20),ll-diene-5a,9a,10p,13a-tetraol (1) T. haccata 16,2a,5a,9a,106,13a-Hexaliydroxytaxa4(20),ll-diene (2) Taxusin (3) T. chinensis T. baccata T, hrevifolia T. cuspidata T. floridana T. mairei T. yunnanensis T. haccata T. mairei T. baccata T. mairei T. baccata T. canadensis T. wallichiana T. yunnanensis T. baccata T. brevifolia T. yunnanensis T. baccata T. wallichiana T. baccata T. baccata T. baccata T. mairei

Taxa-4-(20),ll-diene-5a,76,9a,106,13apentaol pentaacetate (4) Taxa-4-(20),ll-diene-2a,5a,9a,106,13apentaol pentaacetate (5) Taxa-4-(20),ll-diene-2a,5a,76,9a,106,13ahexaol hexaacetate (6) 2-Deacetyl-5-decinnamoyltaxinine J (7)

Taxa-4(20),ll-diene-5a-hydroxy16,76,9a,106-tetraacetate (8) 5-Decinnamoyltaxinine J (9) 2-Deacetoxydecinnamoyltaxinine J (10) Decinnamoyl-l-hydroxytaxinine J (11) 2-Deacetyldecinnamoyltaxinine E (12) Taxa-4(20),ll-diene-5a,9a,106,13a-tetraol9a,106-diacetate (13)

83

2a,5a,9a-Trihydroxy-10p,13a-diacetoxytaxa-4(20),ll-diene (14) 16,5a-Dihydroxy-9a, 106,13ot-triacetate2a-benzoate taxa-4(20),ll-diene (15) 16,5a, 13a-Trihydroxy-9a, 106-diacetate-2abenzoate taxa-4(20),ll-diene (16) Taxa-4(20),ll-diene-2a,5a,76,9a,106pentaol 7a,9a, 106-triacetate-2a-amethylbutyrate (17)

T. chinensis T. chinensis T. chinensis T. haccata

(57) (36,37) (36,37) (38)

Taxa-4-(20),ll-diene-2a,5a,76,106-tetraolT. baccata 5a,7p,10p-triacetate-2a-a-methylbutyrate(18) T. mairei Taxa-4(20),ll-diene-lp,2a,5a,19-tetraol9a,10p,13a-triacetate (19) Taxinine E (20) T. chinensis T. cuspidata T. mairei T. yunanensis T. cuspidata T. mairei T. yunanensis T. baccata T. cuspidata T. mairei T. wallichiana T. yunnanensis T. chinensis T. chinensis T. chinensis T. cuspidata T. mairei T. wallichiana T. media

(38) (48,49) (58) (59) (48) (60) (59) (61,62) (47,60) (40) (63) (61) (52,56,64) (47) (58,65) (58,65) (65) (63) (66) (52) (67)

Taxinine J (21)

2a-Deacetoxytaxinine J (22)

2a,13a-Dihydroxy-9a, 106-diacetoxy5a-cinnamate taxa-4(20),ll-diene (23) 106-Hydroxy-2a,9a,13a- triacetoxy5a- ciimamate taxa-4(20),ll-diene (24) 9a,106,13a-Triacetoxy-5a-cinnamoyltaxa-4(20),ll-diene (25) l-Hydroxy-2-deacetyltaxinine J (26) 2a,9a-Dihydroxy-106,13a-diacetoxy5a-cinnamate taxa-4(20),ll-diene (27)

84

2a, lOfi-Dihy droxy-9a, 13a-diacetoxy5a-cinnamate taxa-4(20),ll-diene (28) 16,13a-Dihydroxy-9a, 106-diacetate2a-benzoate-5a-cinnamatetaxa-4(20), 11-diene (29) 13-Deoxo-13a-acetyloxytaxine B (30) 13-Deoxo-13a-acetyloxy-l-deoxytaxine B (31) 2'-Desacetoxyaustrospicatin (32)

T. media T. chinensis

(67) (36,37)

T. haccata T. baccata

(68) (68)

T. baccata T. cuspidata T. wallichiana T. cuspidata T. wallichiana T. yunnanensis T. baccata

(70) (63,71) (72) (32) (72,69) (47) (68)

7,2'-Didesacetoxyaustrospicatin (33) Taxuyunnanine D (34) 13-Deoxo-13a-acetyloxy-l-deoxy-nortaxine B (35) 2a-Acetoxy-2'-deacetyl-l-hydroxyaustrospicatine (36) Taxuspine P (37) Taxuyunnanine C (38) Taxuyunnanine G (39) Taxuyunnanine H (40) Taxuyunnanine I (41) Taxuyunnanine J (42) 2a,5a, lOfi-Triacetoxy- 146-propanoy 1oxy-4(20), 11-taxadiene (43) 2a,5a,106-Triacetoxy-146-(2'-methyl)propanoyloxy-4(20),ll-taxadiene (44) Taiwanxan (45)

T. baccata

(55)

T. cuspidata T. chinensis T. yunnanensis T. yunnanensis T.yunnanensis T. yunnanensis T. yunnanensis T. chinensis

(73) (77) (47) (74,76) (76) (76) (76) (77)

T. chinensis

(77)

T. mairei

(78,79)

85

Taxuyunnanine B (46) 2a,5a,106-Triacetoxy-146-(2'-methyl)butanoyloxy-4(20), 11-taxadiene (47) Taxa-4(20),ll-cliene-106-methoxy2a,5a-diacetoxy- 146-a-methyIbutyrate (48) Yunnanxane (49) Taxinine A (50) 76-Acetoxytaxinine A (51) Taxinine H (52) 2,10-Di-O-acetyl-5-decinnamoyltaxicin I (53) Triacetyl-5-decinnamoyltaxicin I (54) Taxuspine F (55) Taxuspine G (56) 9a,10p-Diacetyltaxicin I (57) 5-Cinnamoyltaxincin I triacetate (58) 10-Deacetyltaxinine B (59) 2-0-Acetyl-5-0-cinnamoyltaxicin I (60) Taxinine (61)

T. yunnanensis T. chinensis T. cuspidata T. haccata T. chinensis T. yunanensis T. chinensis T. cuspidata T. mairei T. cuspidata T. baccata T. baccata T. cuspidata T. cuspidata T. cuspidata T. cuspidata T. cuspidata T. baccata T. T. T. T. canadensis chinensis cuspidata mairei

(47) (77) (42) (40) (77) (60,80) (81) (63,82,83) (48) (84) (55) (55) (32) (32) (85) (63) (83) (86) (87,88) (81) (63,71,75,83,84,89-91) (43) (59,63,71,75,83,89,91) (92) (93) (93) (93)

Taxinine B (62) 5-Cinnamoyl-9,10-diacetyltaxicin I (63) 5-Cinnamoyl-9-acetyltaxicin-I (64) 5-Cinnamoyl- 10-acetyltaxicin-I (65) 5-Cinnamoyl-9-acetyltaxicin-II (66)

T. cuspidata T. baccata T. baccata T. baccata T. baccata

86

5-Cinnamoyl-10-acetyltaxicin-II(67)

T. haccata

(93) (67) (67) (94,95) (96) (63,89) (95,97,98) (99) (99) (99) (99) (50,51) (100) (100) (101) (83) (50) (65) (102) (29,35) (83,103) (83,103) (53) (104) (105,106) (105,106)

l,9a-Dihydroxy-2a,106-diacetoxyT. media 5a-cinnamoyltaxa-4(20),ll-diene-13-one(68) l,106-Dihydroxy-2a,9a-diacetoxyT. media 5a-cinnamoyltaxa-4(20),ll-diene-13-one(69) Taxine B (70) Taxinell (71) Taxine I (72) 2,9-Dideacetyltaxine II (73) 9-Deacetyltaxine I (74) 2,10-Dideacetyltaxine II (75) 10-Deacetyltaxine I (76) 5-Decinnamoyltaxagifine (77) 5-Decinnamoyl-5-acetyltaxagifine(78) Taxinine M (79) 2-Deacetyl-5-decinnamoyltaxagifine (80) 19-Debenzoyl-19-acetyltaxinine M (81) Taxagifine (82) Taxacin (83) 5-Decinnamoyl-ll-acetyl-19-hydroxytaxigifine (84) Taxuspine L (85) TaxchinA (86) Taxchin B (87) T. haccata T. haccata T. cuspidata T. haccata T. haccata T. haccata T. haccata T. haccata T. canadensis T. chinensis T. chinensis T. hrevifolia T. cuspidata T. canadensis T. chinensis T. wallichiana T. haccata T. cuspidata T. cupsidata T. yunnanensis 71 cuspidata T. chienensis T. chienensis

87

5a,76,9a,106,13a-Pentaacetoxy-2abenzoyloxy-4a,20-dihydroxytax-l 1-ene (88) 7B,9a,106,13a,20-Pentaacetoxy-2abenzoyloxy-4a,5a-dihydroxytax-ll-ene (89) Taxumairol A (90) Baccatin I (91) 16-Hydroxybaccatin I (92)

T. mairei T. mairei T. mairei T. baccata T. T. T. T. baccata chinensis mairei wallichiana

(107) (107) (108) (34,109) (109) (110) (48) (31,64) (111) (112,113) (114) (51) (115) (108) (109) (116) (50,117) (58) (108,118) (60) (53) (112) (119) (34,43,111,120-123) (124,125) (19) (60,126) (127,128)

16-Hydroxy-7-deacetylbaccatin I (93)

T. baccata T. brevifolia T. media T. canadensis T. chinensis T. mairei T. baccata T. yunanensis T. canadensis T. chinensis T. mairei T. yunanensis T. yunnanensis T. brevifolia T. media T. baccata T. brevifolia T. cuspidata T. yunanensis T. baccata

ip-Hydroxy-7,9-dideacetylbaccatin I (94)

5-Deacetylbaccatin I (95) 16-Acetoxy-5,7,10-deacetylbaccatin I (96) 16-Hydroxy-2,5,7,10-tetradeacetylbaccatin I (97) l-Acetoxy-5-deacetylbaccatin I (98) l-Hydroxy-2,7,9-trideacetylbaccatin I (99) 16,9a-Dihydroxy-46,20-epoxy-2a,5a,76,106, 13a-pentacetoxy-tax-ll-ene (100) 76-Acetoxy-9-acetylspicataxine(101) Baccatin III (102)

Baccatin V (103)

19-Hydroxybaccatin III (104)

71 haccata T. chinensis T. wallichiana T. yunanensis T. haccata T. brevifolia T. canadensis T. cuspidata T. wallichiana T. yunanensis T. haccata T. canadensis T. yunanensis T. canadensis T. yunnanensis T. chinensis T. haccata T. haccata

(35) (36) (30) (116) (122,129-131) (54,111,125,132,133) (50,51) (83) (52,134) (116,135) (136) (50) (116) (51) (53) (137) (123) (123)

10-Deacetylbaccatin III (105)

9-Hydroxy-lO-deacetylbaccatin III (106) 1-Acetyl-lO-deacetylbaccatin III (107) l-Dehydroxybaccatin III (108) 7-epi-lO-Deacetylbaccatin III (109) 7-Xylosyl-lO-deacetoxybaccatin III (110) 19-Hydroxy-7-e/7i-baccatin III (111) 13-e;?i-10-Deacetylbaccatin III (112) 2-Debenzoyl-2-tigloyl-10-deacetylbaccatin III (113) 10-Deacetyltaxol (114)

T. haccata T. hrevifolia T. canadensis T. cuspidata T. wallichiana T. yunnanensis

(35) (124,125) (51) (83) (30) (135,138) (111) (15,17,26,35,111, 122,130,139,140) (124,125,132,141,142) (50,51) (143,144) (15,17,19,26,63,83,91) (17,26) (31,52,134) (60,126,138,145,146)

106-Hydroxybutyrate-lO-deacetyltaxol A (115^) T. haccata Paclitaxel [Taxol (116)] T. haccata T. hrevifolia T. canadensis T. chinensis T. cuspidata T. media T. wallichiana T, yunnanensis

89 7-Xylosyl-lO-deacetyltaxol A (117) T. baccata T. yunanensis T. baccata T. brevifolia T. canadensis T. yunnanensis T. baccata T. brevifolia T. wallichiana T. yunnanensis T. brevifolia T. yunnanensis T. wallichiana T. brevifolia T. brevifolia T. yunnanensis T. yunnanensis T. yunnanensis T. yunnanenis T. media T. yunnanensis T. media T. baccata T. baccata T. wallichiana (111) (60) (111) (147) (51) (135) (70) (125,132) (52) (60) (132) (53) (52) (54) (54) (145) (138) (138) (138) (148) (149) (148) (111) (70,111) (52) (119) (35,120,122,150) (124,125,132,151,152) (50,51) (19,83)

7"Xylosyltaxol A (118) 7-epi-Taxo\ (119)

7-ep/-10-Deacetyltaxol (120) lO-Deacetyltaxol-7-xyloside (121)

7-Xylosyltaxol (122)

10-Deacetyltaxol-2',7-diacetate(123) Taxol-2',7- diacetate (124) Yunnanxol (125) 7-Epitaxuyannanine A (126) 7-Epi-lO-deacetyltaxuyannanine A (127) 10-Deacetyltaxuyannanine A (128) Taxol C (129)

A^-Methyltaxol C (130) 7-Xylosyltaxol C (131) 7-Xylosyl-lO-deacetyltaxol C (132)

A^-Debenzoyl-A^-butanoyltaxol [Taxol D (133)] T. media Cephalomannine (134) T. T. T. T. baccata brevifolia canadensis cuspidata

90 T. wallichiana T. yunnanensis (31,52,134) (60,126,138,145) (35) (124) (83) (30) (135,138) (111)

10-Deacetylcephalomannine (135)

T. haccata T. brevifolia T. cuspidata T. wallichiana T. yunnanensis T. haccata

lO-ft-Hydroxybutyrate-lO-deacetyltaxol B (136) 7-ep/-Cephalomanine (137) 7-e/7/- 10-Deacetylcephalomannine (138) 7-Xylosyl-lO-deacetyltaxol B (139) 7-Xylosyltaxol B (140) lO-Deacetylcephalomannine-7-xyloside (141) 146-Hydroxy-lO-deacetylbaccatin III (142) 2-Debenzoyl-146-benzoyloxy10-deacetylbaccatin III (143) 10-Deacetyl-lO-oxo-baccatin V(144)

T. media T, yunnanensis T. haccata T.haccata T. hrevifolia T. wallichiana T. wallichiana

(153) (135) (HI) (111) (132) (154) (155)

T. chinensis

(137) (114) (147) (70) (138)

lO-Deacetyl-lO-dehydro-7-acetyltaxol A (145) T. media 10-Deacetyl-10-oxo-7-e;?f-taxol(146) 7 -Xylosyl-10-deacatyltaxol D (147) 10-Deacetyl- 10-oxo-7-e/7/taxuyannanine A (148) Baccatin IV (149)
T. hrevifolia T. haccata T. yunnanensis

T. T. T. T.

haccata hrevifolia mairei wallichiana

(34,121) (113) (61) (64) (111,121) (121) (44,49,61)

Baccatin VI (150) l-Dehydroxybaccatin IV (151)

T. haccata T. haccata T. mairei

91

1-Acetylbaccatin IV (152) 4-Deacetylbaccatin IV (153) l-Dehydroxy-4-deacetylbaccatin IV (154) 7,9-Deacetylbaccatin IV (155)

T. yunanensis T. media T. mairei T. brevifolia T. canadensis T. mairei T. brevifolia T. canadensis T. chinensis T. canadensis T. canadensis T. canadensis T. cuspidata T. baccata

(116) (119) (118) (113) (51) (62) (113) (50,51,156) (115) (51) (51) (51) (32) (86)

1-Dehydroxybaccatin VI (156) 9-Dihydro-13-acetylbaccatin III (157)

lO-Hydroxyacetylbaccatin VI (158) 7,9,10-Trideacetylbaccatin VI (159) 7-e'/7/-9,10-Trideacetylbaccatin VI (160) Taxuspine E (161) 9p-//-9-Dihydro-19-acetoxy-10-deacetylbaccatin III (162) 9,10-Dideacetyl-9,10-dibenzoylbaccatin VI (163) 10-Deacetyl-lO-benzoylbaccatin VI (164) 7-Deacetyl-7-benzoylbaccatin VI (165) Baccatin VII (166) Taxuspine N (167) Yunnanxamine (168) Taxagifine III (169) 4-Deacetyltaxagifine-III (170) Taxuspine K (171)

T. brevifolia

(157)

T. brevifolia T. brevifolia T. baccata T. cuspidata T. yunnanensis T. chinensis T. chinensis T. cuspidata

(157) (157) (121) (73) (145) (65) (65) (104)

92

1 2 3 4 5 6 7 8 9

R-|=R3=R4=R5~OH, R2=R6=R7=H R-|=R3=R4=R5=R6=R7=OH, R2=H Ri=R3=R4=R5=OAc, R2=R6=R7=H Ri=R2=R3=R4=R5=OAc, R6=R7=H R-|=R3=R4=R5=R7=OAc, R2=R6=H Ri=R2=R3=R4=R5=R7=OAc, R6=H Ri=R7=0H, R2=R3=R4=R5=OAc, R6=H Ri=OH, R2=R3=R4=R6=OAc, R5=R7=H Ri=OH, R2=R3=R4=R5=R7=OAc, R6=H

10 Ri=OH, R2=R3=R4=R5=OAc, R6=R7=H 11 R-,=R6=0H, R2=R3=R4=R5=R7=OAc 12 Ri=R7=0H, R2=R6=H, R3=R4=R5=OAc 13 Ri=R5=0H, R2=R6=R7=H, R3=R4=OAc 14 R-,=R3=R7=OH, R2=R6=H, R4=R5=OAc 15 Ri=R6=0H, R2=H, R3=R4=R5=OAc, R7=0Bz 16 Ri=R5=R6=OH, R2=H, R3=:R4=OAc. R7=0Bz 17 Ri=OH, R2=R3=R4=OAc, R5=R6=H, R7=OCOCH(CH3)C2H5 18 Ri=R2=R4=OAc, R3=R5=R6=H, R7=OCOCH(CH3)C2H5

20 21 22 23 25 26

Ri =:R5=H, R2=R3=R4=R6=0AC Ri =:R2=R3=R4=R6=OAc, R5=H Ri =:R2=R3=R4=0AC, R5=R6=H Ri =:R5=H, R2=R3=OAc, R4=R6=OH Ri =:R5=R6=H, R2=R3=R4=OAC

24 Ry- :R5=H, R2=R4=R6=OAc, R3=0H

Ry. :R2=R3=R4=OAc, R5=R6=OH 27 Ry. :R5=H, R2=R6=OH, R3=R4=OAc 28 Ry ;R5=H, R2=R4=OAc, R3=R6=OH 29 Ry :H, R2=R3=OAc, R4=R5=OH, R6=0Bz

93 AcO AcO .OH R3 R2 Ri

AcO\^^^* R5 Re 30 Ri=H, R2=R5=R6=OH. R3=R4=OAc 19 31 Ri=R5=H, R2=R6=OH, R3=R4=OAc 32 Ri=R2=R3=R4=OAc, R5=R6=H 33 Ri=R5=R6=H, R2=R3=R4=OAc

AcO\^^^^

DAc AcO. 34 OH

Aca 35 AcO AcO oAc

O
^ H ^

AcO

AcO

OAc OAc

AcO OAc 37

94
R3 R2

38 Ri :R3P=R4: R5=0Ac, R2=H 39 Ri :R5=0AC, R2=H, R3ft=R4=OH 40 Ri =R3p=0H R2=H, R4=OCOC2H5,R5=OAc 41 Ri =R3p=0H R2=H, R4=OCOCH(CH3)2. R5=0Ac 42 Ri =OAc, R2 R5=H, R3p=R4=OH
OAc, R2=H, R4=OCOC2H5 43 Ri =R3p=R5=| OAc, R2=H, R4=OCOCH(CH3)2 44 Ri =R3p=R5='

45 Ri OH, R2:R3p=R5=OAc, R4=OCOCH(CH3)C2H5 46 Ri R2=R3p= R5=0Ac. R4=OCOCH(CH3)C2H5 47 Ri R3p=R5=OAc, R2=H, R4=OCOCH(CH3)G2H5 48 Ri R5=0AC , R2=H, R3p=OCH3. R4=OCOCH(CH3)C2H5 49 Ri :R3P=R! ' 5 =OAc, R2=H, R4=OCOCH(CH3)CH(OH)CH3 R4 R3 R2

R5

^6

50 51 52 53 54 55 56 57

Ri=OH, R2=R5=H, R3=R4=R6=OAc Ri=OH, R2=R3=R4=R6=OAc, R5=H Ri=R3=R4=R6=OAc, R2=R5=H Ri=R3=R5=OH, R2=H, R4=R6=OAc Ri=R5=0H, R2=H, R3=R4=R6=OAc Ri=OH. R2=R3=R4=R6=OAc, R5=H Ri=R6=0H, R2=R5=H, R3=R4=OAc Ri=R5=R6=OH, R2=H, R3=R4=OAc

95
R3 R2

58 59 60 61 62 63 64 65 66 67 68
69 R2

Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri

H, R2=R3=R5=OAc, R4=0H R2=R5=OAc, R3=0H, R4=H H, R2=R3=R4=OH, R5=0Ac R4=H. R2=R3=R5=OAC R2=R3=R5=OAc, R4=H H, R2=R3=OAc, R4=R5=OH H, R2=0Ac, R3=R4=R5=OH H. R2=R4=R5=OH, R3=0Ac R4=H, R2=0Ac, R3=R5=OH R4=H, R2=R5=OH, R3=0Ac H, R2=R4=OH. R3=R5=OAc

Ri = H, R2=R5=OAc, R3=R4=OH Ri

70 71 72 73 74 75 76

Ri=R2=R3=OH, R4=0Ac Ri=R2=R4=OAc, R3=H Ri=R2=R4=OAc, R3=0H Ri=R4=0H. R2=0Ac, R3=H Ri=R3=0H. R2=R4=OAc Ri=OAc, R2=R4=OH, R3=H Ri=R4=0Ac, R2=R3=OH

77 R i = R 4 = 0 H , R2=H, R3=0Ac 78 Ri=R3=0Ac, R2=H. R4=0H 79 Ri=R4=0H, R2=0Bz, R3=0Ac 80 Ri=R3=R4=OH, R2=H 81 Ri=R4=0H, R2=R3=OAc 82 Ri=OCOCH:CHPh, R2=H, R3=0Ac, R4=0H 83 Ri=OCOCH:CHPh, R2=0Bz, R3=0Ac, R4=0H 84 Ri=R2=0H, R3=R4=OAc

96
85 Ri :R4=0Ac, R2=H, R3=0H 86 Ri O H , R2=H, R3=R4=OAc 8 7 R i =:R4=0Ac. R2=H, R3=0C0CH:CHPh 88 Ri :OBz, R2=R3=OH, R4=0Ac 89 Ri :OBz, R2=R4=OH, R3=0Ac 90 Ri :R2=0H, R3=0Bz, R4=0Ac AcQ OAc OAc

AcO^^^^"

91 92 93 94 95 96 97 98 99

=R2=R3=R4=R5=R7=OAc, R6=H =R2=R3=R4=R5=R7=OAC, R6=0H =R3=R4=R5=R7=0AC, R2=R6=OH =R4=R5=R7=OAC, R2=R3=R6=OH =0H, R2=R3=R4=R5=Fl7=OAc, R6=H
Rs^^^"

=R2=R4=OH, R3=R5=R6=R7=OAC =R2=R4=R6=R7=OH, R3=R5=OAc =0H, R2=R3=R4=R5=R6=R7=OAc =R4=R5=0AC, R2=R3=R6=R7=OH

100 R =R2=R4=R5=R7=OAc, R3=R6=OH 101 R =OCOCH2CH(Ph)NMe2. R2=R3=R4=R5=R7=OAc. R6=H

102 R 103 R 104 R 105 R 106 R 107 R 108 R 109 R 110 R 111 R
112 R

=R4^=R5=OH, R2=H, R3=0AC =R4a=R5=OH. R2=H, R3=0Ac =R2=R4a=R5=OH, R3=0AC =R3=R4^^=R5=OH, R2=H =R2=R3=R4a=R5=OH =R3=R4a=OH, R2=H, R5=0AC =R4=0H, R2=R5=H, R3=0Ac =R3=R4ot=R5=OH, R2=H =axylosyl, R2=R3=H, R4=R5=OH = R2=R4a=R5=OH, R3=0AC =R3=R4p=R5=OH, R2=H R. t)Bz OAc

HO^^^

OH t)

OAc

113

97

114Rip=R2=OH, R3=0Bz 115 Rip=OH. R2=OCOCH2CH(OH)CH3. R3=0Ac 116 Rip=OH, R2=0Ac, R3=0Bz 117 Rip=axylosyl, R2=0H, R3=0Ac 118 Rip=0-xylosyl, R2=R3=0Ac 119 Ri=OH, R2=0Ac, R3=0Bz 120 Ri=R2=0H. R3=0Bz 121 Rip=axylosyl, R2=0H, R3=0Bz 122 Rip=axylosyl, R2=0Ac, R3=0Bz R P OAc

AcO

OH t)Bz OAc

123 R=OH 124R=OAc

OH t)Bz OAc

126 Ria=OH, R2=0Ac, R3=H 127 Ri^=R2=0H, R3=H 128 Rip=R2=0H, R3=H 129 Rip=OH, R2=0Ac, R3=H 130 Rip=OH, R2=0Ac, R3=CH3 132 Rip=0-xylosyl, R2=OH, R3=H Ph131 Rip=0-xylosyl, R2=OAc, R3=H C51

125

OH t)Bz OAc

98 Acq o

OH R3

OAc

134 Rip=OH. R2=0Ac, R3=0Bz 135 Rip=R2=0H, R3=0Bz 136 Rip=OH, R2=OCOCH2CH(OH)CH3, R3=0Ac 137 Ria=OH, R2=0Ac, R3=0Bz 138 Ri=R2=0H. R3=0Bz 139 Rip=0-xylosyl, R2=OH, R3=OAc 140 Rip=0-xylosyl, R2=R3=0Ac 141 Rip=0-xylosyl. R2=OH, R3=OBz

142 Rip=R3=R4=R5=R6=OH. R2=H, R7=0Bz 143 Rip=R3=R4=R6=R7=OH. R2=H, R5=0Bz 144 Rip=R4=R6=OH, R2+R3=0, R5=H 145 Rip=OAc, R2+R3=0, R4=0C0CH(0H)CH(Ph)NHBz, R5=H, R6=0H, R7=0Bz 146 Ria=OH. R2+R3= =0, R4=0C0CH(0H)CH(Ph)NHBz, R5=R6=H, R7=0Bz 147 Rip=0-xylosyl. R2=R5=H, R3=R6=OH. R4=0C0CH(0H)CH(Ph)NHC0C3H7, R7=0Bz 148 Ria=OH. R5=R6=H, R2+R3= =0. R4=OCOCH(OH)CH(Ph)NHCOC5Hii, R7=0Bz

99 R4 Ra

149 150 151 152 153 154 155 156

157

=R2p=R3=R4=R5=R7=OAc, R6=0H, R8=H =R2p=R3=R4=R5=OAc, R6=0H, R7=0Bz. R8=H =R2p=R3=R4=R5=R7=OAC, R6=R8=H =R2p=R3=R4=R5=R6=R7=OAC, R8=H =R6=0H, R2p=R3=R4=R5=R7=OAc, R8=H = 0 H , R2p=R3=R4=R5=R7=OAc, R6=R8=H =R4=R5=R7=0AC, R2p=R3=R6=OH, R8=H =R2p=R3=R4=R5=OAc, R6=R8=H, R7=0Bz R =R4=R5=OAc, R2p=R3=R6=OH, R7=0Bz, R8=H

158 159 160 161 162 163 164 165 166 167 168

R =R2p=R3=R5=OAc, R4=R6=OH, R7=0Bz, R8=H

=R5=0Ac, R2a=R3=R4=R6=OH, R7=0Bz, R8=H =R5=0Ac, R2p=R3=R4=R6=OH, R7=0Bz, R8=H =R2p=0Ac, R3=R4=R5=R6=OH, R7=0Bz, R8=H =R8=0Ac, R2p=R3=R4=R5=R6=OH. R7=0Bz =R2p=R5=OAc, R3=R4=R7=OBz. R6=0H, R8=H

R R R R R

=R2p=R3=R5=OAc, R3=R7=OBz, R6=0H, R8=H =R3=R4=R5=0AC, R2p=R7=OBz, R6=0H, R8=H =R6=0H, R2p=R3=R4=R5=OAc, R7=OCOC5Hii, R8=H =R2p=R3=R7=OAc. R4=0Bz, R5=OCOCH2CH(Ph)NMe2, R6=0H, R8=H =R4=0Ac, R2p=R3=R6=OH, R5=0C0CH(0H)CH(Ph)NHBz, R7=0Bz, R8=H

Acq

g>Ac

oAc

HO^^^"

AcO^^^'
OH O

169 R=OAc 170 R=OH

171

100

2.2 3,11 'Cyclotaxanes 3,11-Cyclotaxanes (Table 2) can be formed upon irradiation of corresponding 13-oxotaxa-11-enes (63,86,158). However, such naturally occurring compounds have^"- geometry in the cinnamoyl side chain, while the irradiated products are a mixture of E- and Zdiastereoisomers. Thus, it is difficult to infer that these compounds are artefacts. TABLE 2 3,11-Cyclotaxanes isolated from different Taxus species. Compound Taxinine K (172) Taxinine L (173) 5-Cinnamoyl-lO-acetylphototaxicin I (174) Taxuspine C (175) Species T. cuspidata T. cuspidata T. baccata T. cuspidata References (82) (82) (158,159) (63) (86) (32)

9-0-Acetyl-5-0-Cinnamoylphototaxicin I (176) T. baccata Taxuspine H (177) T. cuspidata

172 173 174 175 176 177

Ri=OH, R2=R3=R5=OAc, R4=H Ri=R2=R3=R5=OAc, R4=H Ri=OCOCH:CHPh, R2=R4=R5=OH, R3=0Ac Ri=OCOCH:CHPh, R2=R3=R5=OAc, R4=H Ri=OCOCH:CHPh, R2=0Ac, R3=R4=R5=OH Ri=OCOCH2CH(NMe2)Ph, R2=R3=R5=OAc, R4= :H

2.3 11(15>l)-Abeotaxanes A number of taxoids isolated from different Taxus species, on structural reinvestigation were found to contain a rearranged nortaxoid skeleton or 11(15>iyabeo taxoids, as they are more correctly described (133,160,161) and not a taxane skeleton as originally proposed. Brevifoliol (181) was the first natural taxoid with 11(15>iyabeoiaxant skeleton which was initially assigned a normal taxane skeleton (162) but was later corrected to the

101

11(15>l)-a6eotaxane skeleton (57,133,163). In a similar way a number of taxoids whose basic structure, based upon their spectroscopic data were previously reported as derivatives of originally proposed structure of brevifoliol with the normal taxane skeleton or by considering them as baccatin VI derivatives have now been proposed to be rearranged 11(15>l)-abeotaxanes (mainly by HMBC spectrum and X-ray studies). Taxchinin A (189) was the first naturally occurring taxoid to be correctly assigned the 11(15>l)-flbeotaxane skeleton (164) and that with an oxetane ring was taxchinin B (220) (137). However, the fact that the first example of a taxoid with 11(15>l)-afee(9taxane skeleton was a rearrangement product of taxol (19) raises the question as to whether all these compounds are simply artefacts. Although this possibility cannot be completely ruled out, the fact that the rearranged taxoids are being obtained from different species by different research groups, coupled with the fact that rearrangement of taxol requires rather vigorous conditions, suggests that some, if not all of the isolated nortaxoids are genuine natural products. Table 3 contains 11(15>l)-a6eotaxanes isolated so far from various species of yew. TABLE 3 11(15>l)-A/?eotaxanes isolated from different Taxus species. Compound Taxchinin D (178) Taxchinin E (179) Taxchinin G (180) Brevifoliol (181) 13-Acetylbrevifoliol (182) 9-Deacetyl-9-benzoyl-10-debenzoylbrevifoliol (183) 10-Debenzoyl-2a-acetoxybrevifoliol (184) 7-Deacetoxy-lO-debenzoylbrevifoliol (185) 10-Debenzoylbrevifoliol (186) 2a-Acetoxy-7-deacetoxy-10-debenzoylbrevifoliol (187) 9-Deacetyl-9-benzoyl-10-debenzoyltaxichinA(188) Species T. chienensis T. chienensis T. chienensis T. hrevifolia T. wallichiana T. hrevifolia T. wallichiana T. hrevifolia T. wallichiana T. wallichiana T. wallichiana T. haccata T. haccata References (105,106) (106,165) (105,106) (125,133,162) (134) (133) (64) (160) (102) (161,166) (161,166) (86,161) (131)

102 Taxchinin A (189) T. baccata T. chinensis T. wallichiana (98,161,167) (137,164) (64,134) (133)

106-Benzoyloxy-16-hydroxy-5a-(3'-dimethyl- T. brevifolia amino-3'-phenylpropanoyloxy-76,9a,13atriacetoxy-ll(15>l)-fl^eotaxa-4(20),lldiene (190) 106-Benzoyloxy-16-hydroxy-5a-(3'-methylamino-3'-phenyl)-propanoyloxy-76,9a,13atriacetoxy-ll(15>l)-aZ?eotaxa-4(20),lldiene (191) Taxuspine A (192) T. brevifolia

(133)

T. brevifolia T. cuspidata T. chienensis T. wallichiana T. cuspidata T. cuspidata T. cuspidata T. cuspidata

(133) (63) (106,165) (102) (32) (104) (85) (73)

Taxchinin H (193)

Taxuspine J (194) Taxuspine M (195) Taxacustone (196) Taxuspine 0 (197) 5 -0-(6-)-Glucopyranosyl)106-benzoyltaxacustone (198) Taxayuntin G (199) Yunantaxusin A (200) TaxuchinA(201) Taxacustin (202)

T. cuspidata T. yunnanensis T. yunnanensis T. chinensis T. cuspidata T. wallichiana T. baccata T. baccata T. cuspidata T. wallichiana T. yunnanensis

(85) (168) (169) (110) (83) (52) (92) (170) (83) (52) (145,171,172)

7,9,10-TrideacetylflZ7eobaccatin VI (203) Taxayuntin (204)

103

7,13-Dideacetyl-9,10-didebenzoyltaxchinin C (205) 4-Deacetyl-9,10-didebenzoyl-9,10diacetyltaxchinin C (206) 10-Debenzoyltaxchinin C (207) 10-Debenzoyl-lO-acetyltaxchinin C (208) Taxchinin K (209) Taxchinin I (210) Taxuyunnanine F (211) 10,13-Deacetyl a^eobaccatin IV (212) Taxayuntin E (213) Taxayuntin F (214) Taxayuntin A (215) 13-Acetyl-13-decinnamoyltaxchinin B (216) 7, 9-Dideacetyltaxayuntin (217) 10-Benzoyloxy-2,4-diacetoxy-5,20-epoxyl,7,9,13-tetrahydroxy-ll(15>1)abeoiaxsine (218) Taxchinin C (219) Taxchinin B (220) Taxchinin J (221) 13-Deacetoxy-13,15-epoxy-ll(15>1)abeo-13-epi-b^cc2iim VI (222) 10,15-Epoxy-ll(15>l)-fl^^o10-deacetylbaccatin III (223) Taxuyunnanine E (224)

T. brevifolia T. media T. media T. media T. chienensis T. chienensis T. yunnanensis T. wallichiana T. yunnanensis T. yunnanensis T. yunnanensis T. baccata T. yunnanensis T.brevifolia

(160) (72) (72) (72) (106,165) (106,165) (172,173) (174) (175) (175) (176) (177) (178) (113)

T. chinensis T. chinensis T. cuspidata T. chienensis T. media T. wallichiana T. yunnanensis

(137) (137) (16) (106,165) (72) (155) (172,173)

104

178 179 180 181 182 183 184 185 186 187 188 189 190
191

Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri Ri

O H , R2=R3=R5=R6=OAc, R4=0Bz : 0 H . R2=R3=R6=OAc. R4=0Bz, R5=0C0CH:CHPh :R4=0H, R2=R3=R5=R6=OAc :R5=0H, R2=R3=OAc. R4=0Bz, Re^H OH, R2=R3=R5=OAc, R4=0B2, R6=H :R4=R5=OH, R2=0Ac. R3=0Bz, R6=H :R4=R5=OH, R2=R3=R6=OAC :R4=R5=OH, R2=R6=H, R3=0AC :R4=R5=OH, R2=R3=OAc, R Q ^ H
:R4=R5=OH, R 2 = H . R 3 = R 6 = 0 A C :R4=R5=OH, R 2 = R 6 = O A C , R 3 = 0 B Z :R5=0H, R 2 = R 3 = R 6 = O A C , R 4 = 0 B Z

R.^^^^"'

OCOCH2CH(Ph)NMe2, R2=R3=R5=OAc, R4=0Bz, R6=H Ri=< OC0CH2CH(Ph)NHMe, R2=R3=R5=OAc, R4=0Bz, R6=H

192 193 194 195

Ri=R2=R4=OAc, R3=0Bz, R5=H Ri=R2=0Ac, R3=0Bz. R4=0H. R5=H Ri=R2=R3=R4=OAc. R5=H Ri=R2=R4=OAc, R3=0H. R5=H

OAc

PAC R3

196 R i = R 3 = 0 H , R2=H 197 R i = R 2 = 0 H , R3=0Ac 198 Ri=0-D-glucosyl, R2=H, R3=OBz 199 R i = H , R2=R4=OH, R3=R5=OAc 200 Ri=R5=0H. R2=R3=OAc, R4=0Bz

105 QAc OAc AcQ

AcQ

pAc

OAc

Aca
201

t>Ac

222

OH

223
202 R =R2=R3=R6=OAc, R4=R5=OH 203 R =R5=0Ac, R2=R3=R4=OH, R6=0Bz 204 R =R2=R3=R6=OAc, R4=0Bz, R5=0H 205 206 207 208 209 210 211 212 213 214 215 216 =OAc, R2=R3=R4=R5=OH, R6=0Bz = 0 H , R2=R3=R4=R5=OAc, R6=0Bz =R2=R5=OAc, R3=R6=OBz, R4=0H =R2=R4=R5=OAc, R3=R6=OBz =R2=R5=R6=OAc, R3=R4=OBz =R2=R5=OAc, R3=R6=OBz, R4=0H =R2=R3=R5=R6=OAc, R4=0H =R2=R3=R6=OAc, R4=R5=OH =R2=R3=OAc, R4=R5=OH, R6=0Bz =R2=R6=OAc, R3=0Bz, R4=R5=OH =OAc, R2=R6=OBz, R3=R4=R5=OH =R2=R3=R5=R6=OAc, R4=0Bz 224 AcO^^^"' PBz OAc

217 218 219 220 221

R R R R R

=R6=0Ac, R2=R3=R5=OH, R4=0Bz =R6=0Ac, R2=R3=R5=OH, R4=0Bz =R2=R5=OAc, R3=R4=R6=OBz =R2=R3=R6=OAc, R4=0Bz, R5=0C0CH:CHPh =R2=R6=OAc, R3=0Bz, R4=0H, R5=0C0CH:CHPh

106

2.4 2(3>20)-Aheotaxanes These compounds have a distinct biogenetic origin than the other taxoids, resulting from a transannular cyclisation, which is different from that involved in the formation of normal taxanes (92). They are tricyclic systems with a ten membered ring sandwiched between two six membered rings. Isolates of this class from Taxus species are listed in Table 4. TABLE 4 2(3>20) A^eotaxanes isolated from different Taxus species. Compound Taxin B (225) 2-Deacetyltaxin B (226) Deaminoacyltaxine A (227) Taxuspine B (228) Taxine A (229) 7-0-Acetyltaxine A (230) 2-Deacetyltaxine A (231) Species 71 yunnanensis T. yunnanensis T. baccata T. cuspidata T. cuspidata T. baccata T. baccata References (179) (179) (92) (63) (180,181) (55) (55,182)

AcOl'"

225 226 227 228 229 230 231

Ri=OH, R2=R3=R4=OAc Ri=R4=0H, R2=R3=OAc Ri=R2=R3=OH, R4=0Ac Ri=OCOCH:CHPh. R2=R4=OAc, R3=0H Ri=0C0CH(0H)CH(NMe2)Ph, R2=R3=OH, R4=0Ac Ri=0C0CH(0H)CH(NMe2)Ph, R2=R4=OAc, R3=0H Ri=0C0CH(0H)CH(NMe2)Ph, R2=R3=R4=OH

107

2.5 11(15>1), 11(10>9) Bisabeotaxane The only known taxoid with 11(15>1), 11(10>9)bisabeoi?iX?Lnt skeleton is wallifoliol (232) from T. wallichiana (134). A benzil-benzilic acid type rearrangement of 10-dehydro10-deacetyl-11(15>l)-flfeeobaccatin III (A) might be the biosynthetic pathway of this compound.
OH

HO""

AcO

232

2.6 Pretaxoids Paclitaxel, because of its unique mode of action and enormous medicinal potential is under an intensive research effort. The core structure of taxol consists of four rings (six membered A and C rings, eight membered B ring and four membered D ring) and a very little is known about the biosynthesis of this taxane core. Verticillol, a natural product isolated from Scidopitys verticillata, with rings B, C and D not yet formed has been much in the focus of speculation about the biosynthesis of the taxane skeleton (6,183). Verticillol, however differs in the stereochemistry at the C-1 and lacks oxygenation at C-2, C-5, C-7, C-9, C-10 and C-13 and numerous attempts of its cyclisation have failed (184). Very recently a novel pretaxoid, canadensene (233) in which rings B,C and D are not yet formed has been isolated from T. canadensis (185). The isolation of canadensene in the genus Taxus and its structural similarity with the core structure of taxol and related taxanes has considerable importance for biosynthetic studies. Two more such compounds were isolated from T. chinensis (Table 5).

TABLE 5 Pretaxoids isolated from different Taxus species. Compound Canadensene (233) Taxachitriene A (234) Taxachitriene B (235) Species T. canadensis T. chinensis T. chinensis References (185) (186) (186)

Verticillol

108 OAc

OAc

AcO^^^^"'

233 Ri=OAc, R2=R3=OH 234 Ri=R2=0Ac, R3=0H 235 Ri=R2=0H, R3=0Ac

3. LIGNANS Lignans are found in several species of Taxus. Secoisolariciresinol (236), isotaxiresinol (249), isolariciresinol (250) and isotaxiresinol-6-methyl ether (251) are found in several species of Taxus (39,187). Secoisolariciresinol (236), isotaxiresinol (249) and taxiresinol (255) were isolated by Majumdar et a/.(188) from T. haccata, whereas a-conidendrin (252) was isolated from T. marei (43,45). Table 6 lists various lignans isolated from the genus Taxus. TABLE 6 Lignans isolated from different Taxus species. Compound Species References

Secoisolariciresinol (236)

T T. T. T T

baccata brevifolia cuspidata floridana mairei

(39,187,188,190) (39) (39) (39) (43,44,49,191) (187)

(-)-4-0-Methyl-3'-0-demethylsecoisolariciresinol (237) (-)-3-Dimethylsecoisolariciresinol (238) 2-(3,4-Dimethoxybenzyl)-3(3,4-methylenedioxybenzylidene)butane-1, 4-diol (239) (-)-2-(3, 4-Methylenedioxybenzyl)-3(3,4-dimethoxybenzylidene)butane-l,4-diol (240)

T baccata

T. baccata T baccata

(192) (193)

T. baccata

(194)

109

(-)-2-(3,4-Methylenedioxybenzyl)-3(3,4-methy lenedioxybenzy lidene)butane-1, 4-diol (241) Hydroxymatairesinol (242)

T. media T. wallichiana T. haccata T. media T. wallichiana T. haccata T. haccata T. haccata T. haccata T. hrevifolia T. cuspidata T. floridana T. mairei T. haccata T. hrevifolia T. cuspidata T.floridana T. haccata T. hrevifolia T. cuspidata T. floridana T. haccata T. mairei T. wallichiana T. wallichiana T. cuspidata (119) (189) (194) (119) (189) (193) (194) (194) (39,187,188,190) (39) (39,195) (39) (43,44,49,60,191) (39,187) (39) (39,195) (39) (39) (39) (39) (39) (194) (43,45) (189) (189) (39)

(-)-Matairesinol (243) (-)-2-Epinortrachelogenin (244) Isoliovil (245) 4'-0-Demethylsuchilactone (246) (-)-Isohibalactone (247) (-)-Hibalactone (248) Isotaxiresinol (249)

Isolariciresinol (250)

Isotaxiresinol-6-methyl ether (251)

a-Conidendrin (252)

6-Conidendrin (253) Lariciresinol (254)

110

Taxiresinol (255) Z>-Sesamin (256) 4-Hydroxysesamin (257) RiO.

T. baccata T. mairei T. mairei

(188) (44) (44)

OH 236 Ri=R3=Me, R2=H 237 Ri=R2=Me, R3=H 238 R-|=R2=H, R3=CH3 239 Ri+R2=CH2, R3=R4=CH3 240 Ri=R2=CH3, R3+R4=CH2 241 Ri+R2=R3+R4=CH2

H3CO,

OCH3

242 R=OH 243 R=H

H3CO.

246 Ri=OH, R2=0Me 247 Ri+R2=OCH20

Ill
H3CO, CH2OH

RpO'

CH2OH

248

249 Ri=R2=H 250 Ri=CH3; R2=H 251 Ri=H; R2=CH3

H3CO.

H3CO.

H3CO.

254 R=Me 255 R=H

256 R=H 257 R=OH

112

4. FLAVONOIDS Taxus species contain the biflavonoids mainly of the amentoflavone series. A1% emulsion of flavonoidal mixture obtained from T. haccata (196) with tween-80, suitably diluted with normal saline or physiological solution was used by Vohora et al (197). for all studies on pharmacological properties with reference to nervous system. Their observations showed CNS effects by flavonoidal mixture as evidenced by potentiation of pentobarbitone narcosis, hypothermia and delayed reaction of fasted rats in Hebb-William maze. Flavonoidal mixture also showed antipyretic and analgesic effects. Table 7 lists all the flavonoids isolated from the genus Taxus. TABLE 7 Flavonoids isolated from different Taxus species. Compound Ginkgetin (258) Species T haccata T canadensis T cuspidata T. wallichiana T haccata T. hrevifolia T canadensis T. cuspidata T. wallichiana T haccata T wallichiana T haccata T. cuspidata T cuspidata T. haccata T wallichiana T. haccata References (196) (88) (91,198,199) (200,201) (196,202) (75) (88) (91,198,199) (200,201) (196) (200,201) (203,204) (198) (198) (205) (201,205) (206)

Sciadopitysin (259)

Sequoiaflavone (260)

Sotetsulflavone (261)

Kayaflavone (262) Amentoflavone (263)

4',7,7"-Tri-0-methylamentoflavone (264) 4',4",7,7"-Tetra-0-methylamentoflavone (265)

T haccata

(205,206)

113

4',7"-Di-0-methylamentoflavone(266) (+)-Taxifolin (267) Kaempferol (268) Quercetin (269)

T. haccata T. mairei T. hrevifolia T. brevifolia T. cuspidate T. brevifolia T. cuspidata

(205) (49) (75) (75) (91) (75) (91)

Isorhamnetin (270)

RiO,

258 R-i=R2=CH3', R3=R4=H 259 Ri=R2=R4=CH3; R3=H 260 Ri=CH3; R2=R3=R4=H 261 R-j=R2=R4=Hi R3=CH3 262 R-|=R3=R4=CH3; R2=H 263 R-|=R2=R3=R4=H 264 Ri=R2=R3=CH3, R4=H 265 R-|=R2=R3=R4=CH3 266 R-|=R4=H, R2=R3=CH3

268 R=H 269 R=OH 267 270 R=0CH3

114

5. STEROIDS Phytoecdysteroids, the well-known molting hormones are another important class of naturally occurring organic compounds isolated from Taxus species. Insect molt hormone activity associated with extracts of yew leaves has been reported by Takemoto et a/. (207). Table 8 lists phytoecdysteroids alongwith other common steroids isolated from the yew. These consist of a number of closely related active compounds (insect metamorphosis hormones) possessing insect molting activity. The most common of these phytoecdysteroids is ecdysterone (271). TABLE 8 Steroids isolated from different Taxus species. Compound Ecdysterone (271) Species T. baccata T. chinensis T. cuspidata T. cuspidata T. brevifolia T. cuspidata T. cuspidata T. cuspidata T. baccata T. brevifolia T. canadensis T. cuspidata T. floridana T. mairei T. wallichiana T. wallichiana T. cuspidata T. mairei References (208,209) (210) (211,212) (15,213) (113) (211) (214) (89) (39) (39) (88) (39) (39) (39,43,44,49) (52) (52) (89) (191)

Taxisterone (272) Ponasterone A (273)

Makisterone A (274) Campesterol (275) 6-Sitosterol (276)

Daucosterol (277) Stigmasterol (278) p-Sitostenone (279)

115

271 Ri=OH 272 Ri=H

273

276 R=H 277 R=glucosyl

278

279

116

6. SUGAR DERIVATIVES A novel glycoside, taxicatin (280) was isolated from the leaves of T.haccata (215-218). The glycosides of aliphatic and aromatic alcohols, as well as of monoterpene alcohols and eugenol have been detected in Taxaceae (219). Recently we have isolated betuloside (283) from T. haccata, reported its absolute stereochemistry and have found it to possess hepatoprotective activity (220). Table 9 lists various glycosides and other sugar derivatives isolated from the genus Taxus. TABLE 9 Glycosides isolated from different Taxus species.
Compound Taxicatin (280) Species T. baccata T. canadensis T. haccata T. cuspidata T. baccata T. haccata T. canadensis T. haccata T. haccata T. haccata T. haccata T. haccata T. haccata T. haccata T. haccata References (215-218) (88) (221) (222) (221) (130,196,220) (88) (223,224) (225) (187,192) (221) (221) (217,226) (225) (225)

(7?)-Taxiphylline (281)

(5)-Dhurrin (282) Betuloside [Rhododendrin (283)]

L-4-/7-Coumaroyl-m>'o-inositol (284) D-1-O-Methyl-mMco-inositol (285) Taxuside (286) Triglochinine (287) Isotriglochinine (288) Raffinose (289) Z)-Pinitol (290) Sequoitol (291)

117

CN

\
OCHa

-OH

280

281 R=a-0-glucosyl 282 R=p-0-glucosyl

O I
OH

>=<

O HO

287 288

CH2OH OH H

OH

OH

290

291

118

7. MISCELLANEOUS Kojic acid (294), a y-pyrone, isolated from T. mairei is a typical microbial metabolite and fungal contamination of the plant extract might be a reason of its formation (227). The diterpenestaxamairinsA(297)and B (298) possessing tropone skeleton displayed inhibitory activity [IC^^ 30.21 g/ml for taxamairin A and 26.78 g/ml for taxamairin B] against hepatoma cells in vitro (228). (+)-Abscissic acid (317) was extracted from the seeds of T. haccata (229-231). The needles of T. haccata contained 26 carboxylic acids, 80% of which were shikimic (335) and quinic acids (336) (232). Rhodoxanthin (300) has been found to be present in all the species of Taxaceae (87,233). Escholtzxanthone (301) was isolated from T. haccata leaves (234). Various compounds isolated from genus Taxus which are not otherwise classified in the text are listed in Table 10. TABLE 10 Novel compounds of different types isolated from Taxus species. Compound Coniferaldehyde (292) Vanillin (293) Kojic acid (294) 10-Nonacosanol (295) Brevitaxin (296) Taxamairin A (297) Taxamairin B (298) Taxamairin C (299) Rhodoxanthin (300) Escholtzxanthone (301) 3-Phenylpropanol (302) 3-(3',4'-Dihydroxyphenyl)propanol(303) 3-(4'-Hydroxy-3'-methoxyphenyl)propanol (304) Species T. mairei T. mairei T. mairei T. mairei T. brevifolia T. mairei T. mairei T. mairei all species T. haccata T. haccata T. haccata T. haccata References (43,235) (43,191) (227) (227) (236) (228,237) (228,237) (236) (87,233) (234) (187) (187) (187)

119 3-(4-Hydroxyphenyl)propyl tetracosanoate (305) 3-(4-Hydroxyphenyl)propyl pentacosanoate (306) 3-(4-Hydroxyphenyl)propyl hexacosanoate (307) 3-(4-Hydroxyphenyl)propyl dotriacontanoate (308) 3-(4-Hydroxyphenyl)propyl tetratriacontanoate(309) 4-(4'-Hydroxyphenyl)-2/?-butanol [(-)-Rhododend^ol^etuligenol (310)] 4-(4'-Hydroxyphenyl)-25-butanol (311) T. canadensis (88)

T. canadensis

(88)

T.canadensis

(88)

T. canadensis

(88)

T. canadensis

(88)

T. brevifolia T. baccata T. baccata

(133) (187,196,238) (239) (187,238) (187,238)

4-(3',4'-Dihydroxyphenyl)-2/?-butanol (312) T. baccata 4-(3'-Methoxy-4'-hydroxyphenyl)2/?-butanol (313) Deglycosylicariside B^ (314) Dehydrovomifoliol (315) Vomifoliol (316) Abscissic acid (317) d5-5,cis-9-Octdecadienoic acid (318) T. baccata

T. wallichiana T. wallichiana T. wallichiana T. baccata T. baccata T. cuspidata T. baccata T. baccata T. baccata T. baccata

(240) (240) (240) (229-231) (241) (242) (243) (243) (243) (243)

Vanillic acid (319) Pyrocatechuic acid (320) Protocatechuic acid (321) p-Resorcylic acid (322)

120

Gentisic acid (323) Y-Resorcylic acid (324) Pholoroglucinic acid (325) Gallic acid (326) Syringic acid (327) o-Hydroxyphenylacetic acid (328) /7-Hydroxyphenylacetic acid (329) Homoprotocatechuic acid (330) Cinnamic acid (331) /7-Coumaric acid (332) Ferulic acid (333) Caffeic acid (334) Shikimic acid (335) Quinic acid (336) Benzoic acid 2-Hydroxy-, 3-hydroxy- and 4-hydroxybenzoic acids

T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T. baccata T, baccata T. baccata

(243) (243) (243) (243) (243) (243) (243) (243) (243) (243) (243) (243) (232,243) (232,243) (243) (243)

CHO

CHO

OCH3 OH

292

293

294

295

121

296
0CH3

297 R=OH 298 R=0CH3

301

HO'

OH

302 R=H 303 R=OH 304 R=OMe

305 306 307 308 309

n= 22 n= 23 n= 24 n= 30 n= 32

122

HO 310 R 311 S

>^N)H
312 R=H 313 R=Me 314

315

316

COOH 317 318

COOH

COOH 319 Ri=H, R2=OCH3, R3=0H 320 Ri=R2=0H, R3=H 321 Ri=H, R2=R3=OH 322 Ri=R3=0H, R2=H COOH 324 Ri=OH, R2=H 325 Ri=R2=0H

COOH

3 2 8 R i = O H , R2=R3=H 329 Ri=R2=H, R3=0H 330 Ri=H, R2=R3=OH

123 R2 COOH

HO//,,^ ^ C O O H

Ri

COOH

331 332 333 334

Ri=R2=H Ri=H, R2=0H Ri=0CH3, R2=0H Ri=R2=0H

OH

335

336

8. CONCLUSIONS This review of literature covering phytochemical investigations on ten Taxus species have resulted in the isolation of nearly three hundred and fifty compounds belonging to the classes of taxanes, lignans, flavonoids, steroids, sugar derivatives, aromatic acids, etc. Last few years have witnessed a revolution in the phytochemistry of the yew tree; it is evident from the figures that out of the 246 references cited in this review, 151 range in the period 1990-96. Pharmaceutical industries are concentrating too much on this genus to obtain paclitaxel (taxol) and equivalent compounds of paclitaxel. As paclitaxel has become an approved agent to cure cancer, issues regarding its supply have now come to the forefront. The way the yew trees are being cut world-wide to obtain this drug, it is estimated that the source of supply would last for only 5-10 years (244) and it cannot be regarded as an environmentally acceptable source. Of late, four possibilities of supply are being considered: (i) find a better source for the supply of paclitaxel such as a different species or a cultivar of Taxus, or a different plant part or cultivation condition, (ii) semi-synthesis of paclitaxel from a more abundant precursor, (iii) total synthesis of paclitaxel, and (iv) tissue culture production of paclitaxel or its close precursor (245). Thus, we clearly visualise that this area demands still more intensive research to make it fruitful, and this updated and comprehensive review will help fellow scientists in locating information in one source. A cknowledgement We thank the Danish International Development Agency (DANIDA, Denmark) for financial assistance to carry out phytochemical investigations on a few Taxus species.

124

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7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

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27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

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This Page Intentionally Left Blank

Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

135

Withanolides, Biologically Active Natural Steroidal Lactones : A Review

A.S.R. Anjaneyulu, D. S. Rao, P.W. Lequesne

INTRODUCTION Withanolides mainly Solanaceae occur in the SolsLnaceous plants.

is a large family comprising over 2000 species which These are generally Solanaceous (ambergine) plants ( S. The important cash crops among
2

have great economic and medicinal importance. annual shrubs. are potato (Solanum tuberosum) 3 several 8
stramonium ) , Solanum species

brinjal 4

melongena esculentum

) , chili ( Capsicum frutescens ) , ) and tobacco {Nicotiana tobaccum

tomato ( Lycopersium ) . This family

includes
nightshade

medicinally
belladona

{ Atropa

) ,

important 7
the

plants
thorn

like
apple

the deadly
( Batura

9
the poisonous henbane especially s. dulcamara {Hyoscyamus niger , S. indicum )^ and and S .

xanthocarpum

12

These herbs are well known for their alkaloidal In the indigenous Withania Ayurvedic medicinal system the 13 14 and Physalis species have

constituents.

tubers and the leaves great importance. Occurrence of Withanolides

During the last two and a half decades many withanolides and their related compounds have been isolated from Withania other Solanceous physiological species activity. and some of them possess Withanolides have been isolated and remarkable so far

from the following species :~

136 Withania 1. 2. 3. species 15 17 4. 5. (frutescens) W. W. aristata 18 19

W, somnifera I / , coagulins W, arboritus species

obtusifolia

Physalls P.

20 alkekengi . . 21a,b,29 P. minima P. P. angulata 23 viscosa

22

P. ixocarpa P P P. P. iancifolia

25 26a ,b 27 28

7. 8. 9. 10.

peruviana

P. pubescens C. Datura species I. 2. 3. D. D, ;

2^a,b

phyladelphica 28 curasavica

D. stromoniufli

30

quercifolia 32,33 D. metel species

31

4, 5.

D. ferox D.

31,31a 29a

tatura

Nicandra 1.

: physaloides 34

Nicandra

Lycium species ; 1. Lycium chinense 35 : 36 4. 5. 6. J. leucotricha 39,39a, 40

F.

Jaborosa 1. 2. 3.

species

J. integrifolia J. Jbergii^^ J. magellanica

J. odonelliana J. sativa

G.

Acnistus species : 1. 2. 41 A. Jbreveflorus GresiJb 42 A. ramifluoruiD ffeirs 45 3. 4. A. australis A. Griseb 44 arborescens 43

H. I.

Trechonaetes laciniata lochroma 1. species

lochroma cocconeum

46

lochroma

fuchsioides

46a

137 J. K. L. Witharingia Tubocapsicum Dunalis 1. W. JD. species coccoloides 48 anonaium ; 49 2. D. tuJbuiosa

49a

47

australis

Deprea species ; D. orinocensis 50 2. D. procumbens

51

N.

Salpichroa

origan!folia 52

Withanolides : Chemical Classification The withanolides are a group of naturally occurring

steroids built on an ergostane skeleton, in which C-22 and C-26 are The name withanolide was originally proposed by Lavie et al 53 for a group of steroidal lactones of the ergostane series with a six-membered lactone in the nine carbon side chainThe names in acidname appropriately oxidised in order to form a "S-iactone ring*

current use for structure (1) are either withanolide, or according to the Chemical Abstracts system, 22-hydroxyergostan-26-oic 26,22-olide. are catalogued as ergost derivatives. The In the CAS Chemical Substances index the compounds

ergost-26,22-olide based on lUPAC rules, does not seem to be used. 54 The generic 'witha steroids' which has been proposed does not seem to have gained much popularity. carboxylic used, along with the trivial names. For compounds with a modified CA names are being skeleton and or side chain, only

(1)

Withaphysalin B ( 2 )

138 Withaferin known Aswagandha) Subsequently, withaferin A withanolides. was a A first number were (12) the isolated of isolated active by constituent somnifera Lavie and et Dun al. were of the in well 1965. to as by

Indian medicinal plant,

Withania compounds

(Sanskrit : related known elicited

structurally these

(12)

The interesting

biological activities

withaferin A (12) and its congeners augmented the search for this type of compound, and the number of withanolides from different plants has already surpassed two hundred. Withanolides are generally defined as C-28 steroidal lactones built on a skeleton of ergostane intact or rearranged. There exist several interesting review articles on

this group of compounds.

To make a comprehensive account of these

compounds and to depict an overall picture of withanolides, this review was highlighted with some recent developments in the field till the end of August 1996. Withanolides generally contain 28 carbon atoms with

polyoxygenated functionalities. the a, 0-unsaturated-l-oxo-2-ene C-22 and C-26 in the side saturated A 6-lactone system. common feature of

These compounds in general possess in ring A and a 5-lactone between A few, however, contain a

chain.

all

known

withanolides, contain a

including

the related modified ergostane derivatives, is oxidation at C-1, C-22 and C-26. Over 90% of withanolides 1-oxo-group. C-26 is oxidised in most instances.to the carboxylic acid level, thus allowing the formation of a 26,22 lactone. In contrast to the lactone, which in most instances is a , 3 -unsaturated, the precursor a, 0 -unsaturated lactol is never found as such, but found as epoxylactols or the corresponding epoxylactones. In addition to the oxidative processes at the above three centres, one of the characteristic features of the plants producing withanolides side chain. oxidised. Withanolides are classified into two major groups . is their extraordinary ability to introduce oxygen functions at almost every position of the carbocyclic skeleton and Till now, there are only one secondary (C-11) and two tertiary (C-8 and C-9) carbon atoms which have not been found to be

139 A - Withanolides with an unmodified skeleton a) with a regular.: 6-oriented side chain b) with an unusual -oriented side chain.

B - Withanolides with modified carbocyclic skeletons or side chains These withanolides were classified initially on the basis of chemotypes of Withania been initially isolated have species from been depending on the region of the the Withania isolated species.. from other Later species on of plant collected, to the compounds obtained as most of these have several species, withanolides Acnistus

Solanaceae

family, eg. Physalis

species.

species.

Datura species,,

Jaborosa

Chemically, these may be classified as From their structural pattern, these can be

ergostane derivatives-

broadly divided into seven groups. 1. 3. 5B,63-epoxides 5-enes 2. 4. 6a,7a-epoxides Intermediate compounds

5.
7.

5a,6 a-epoxides
Phenolic withanolides

6.

63,73-epoxides

Among these the 53 ,63-epoxides are most common. the compounds possess a 43-hydroxy1 group. which possess an a ,3 -unsaturated-Y-lactone 25 lactone A (61), the rest have ^-lactones. Withanolides 5a-hydroxyl number, eg. originate from having

Most of

Except for four members system, eg. ixocarpa-

6a ,7a -epoxides B

generally are

contain to sizable that

lycium

substance G (107).

(62) and Lavie et

believed

5 3,63 -epoxides.

The 5-enes also form a

eg. withanolide

al. suggested

60,70-epoxides are originated from 5-enes by migration of A -ene to .6-ene with simultaneous hydroxylation at C-5 followed by epoxidation on A . inspection of the intermediates suggests that most of them originate from 53,63-epoxides either by trans-diaxial 181 or diequatorial opening. Sarma et al. suggested that 134 chlorowithanolides are formed by the reaction of chloride ion present in the plant with the 53,63-epoxide system (Tables la-ln) . Hydroxylation Hydroxylation is a common feature in withanolides.

Hydroxyl at C-4 is the most common feature in 53 ,63-epoxides, eg.

TABLE

la
140

53 , 6 8-EPOXIDES U T E 17&

SIDE CEAIN

Compound
Without hydroxyls :

Hydroxyls Epoxide Ene

Other groups

m.p.

("C)

[ UjD

Source

Ref.

Withaphysalin B (2)
Monohydroxy Compounds :

2, 24

18-20 lactol 161-62 (EtOAc) (epimers)

+ +
+

P . minima

64

27-deoxywithaferin A ( 3 ) 48-Hydroxy-5B ,6%-epoxy1-0~0-22R-wltha-2,14,24trienolide (4) 4~-hydrory-l-ox0-58,6%epoxy-wltha (24S,25K)dihydro-2-enolide ( 5 ) Jaboroaalacrone A ( 6 )

48

5%,6%
5%,6%

2,24 2,14,24

--

268-9 (EtOAc)
239-40(~to~c)

101.5

W. somnifera ( S . African variety) W. a r i s t a t a Pauq

65 66

4%

---

122

48

5%.68

252 (CHC13-EtOkc) 215-20 273-4 (EtOAc)

32.5

W. somnifera

65

( s . "African variety)

27

5%,613
58,68

2,24 2,24

-4-0x0

+
+ +

95

LiUll

Jaborosa i n t e g r e f o l i a

67
68

w i tha-2,24-dienolide (7)

58 ,6%-epoxy-ZOR,22R-

~ U E - H Y ~ ~ O X ~ - ~ , ~ - ~ ~ O X 20 O8

113.5

Chemotype 1 1 1 ) 20 B
58,bB

(s. African Vs.

-do-

W. somnifera

2WE-iLydroxy-l, 4-dioxo5 8, bbepoxy-20R,22Rw i :ha-2-enoli de ( 8 ) 2,3-Di.hydro lactone A ( 9 )

&ox0

260-63

49.2

68

27

5%,68

24

--

180-82 (EtOAc)

_-

-do-

69

Compound 2:3, 24:25-Tetrahydro-27deoxywithaferin A (10) 2,3-dihydro-27-deoxywithaferin A (11)

Dthydroq Compounds

Hydroxyls Epoxide Ene

Other groups m.p. ("C) 209-210 236-37 (EtOAc)

[ QID

Source
Acnis tus brevifluorus

Ref.
70

+ 17.4

- 3.0
+ +
114 8.0

-do-

70

Withaferin A (12) 2,3-dihydrowithaferin A

( 13)

4e, 27 56,6e 46,17a 5 6,6% 4e,lk 5 ,6

2,24 24 2,24 2,24

---

243-45 229-30 265-67 195-96 (EtOH) 130-35 (amorphous solid) 256-59

W.somnifera Dun

71 71 72 66

-do-doU. somnifera Dun

27-Deoxy-14C-OHwfthaferin A (14) 17 *Hydroxy-27-deoxywithaferin A -4acetate (15) Withacnistin i16)

----

+ 67
+
175

4~,17a 56,66

(lndian Cfiemotype)

46,18

56,66

2,24

+
+

123

A. aroborescecs

44

4 6,27-Dihydroxy-58,66epoxy-1-0x0-22R-witha2,14,24-trieno1l.de (17)
Jaborosalactone L
(18)

40,27

50,66

2,14,24 --

98

U. frutescens Pauq

17

17427 56,66

2,24

--

214-15

+ 49
141

TABLE la
56,@-EPOXIDES

142

( Ccntd. )

WITH 176- SIDE CHAIN

Compound Withanolide D (19) 24,25-Dihydro-withanolide D ( 2 0 ) 7 a,17a-Dihydroxy-55,65epoxy-1-oxo-22R-witha2,24-dienolide (21)

V i scosalactone A ' (22)

Hydroxyls Epoxide Ene 48,20 8 55,@ 46,20 8 5 8,68 7a,17a 55,68 2,24 2 2,24

Other groups m.p.

("C)

[a ID

Source
W. somnifera

Ref.
73

253-55 275 (EtOAc) 252-54 (MeOH)

+
+

80
14

(Chsmorype 111)
Y. somnifera ( 5 . African variety)
W. somnifera

65
74

-*
-28.0

(Seeds)
P. Viscosa

45,27

55,65

24 24

*
277-80 (Acetone )

23 68

witha-24-enolide (23)

4 8,2Gcl-Dihydroxy-l-oxo5 8,68 -epoxy-ZOR,22R-

45,20 5 58,68

W. s o n n i f e r a

(5. African Vs. Ctmotype 111)

W. o b t u s i f o l i a

A withanolide isomeric to withaferin A (24) 24 q25a-epoxywi thanelide D ( 2 5 ) Jabarosalactone 0 ( 2 6 ) Irrnrcrnclide(Z7) Physagulin A ( 2 8 )

4~,27

5 8,65

2,24 2 24 2,24 2,24

* * *
146-54 (EtOAc) A whi.te powder

(Sudan)

19 75 76 46
77

48,208 58,65 17a,19 5 4 6 8

*
*

P . angulata

4 EJ16cr-OAc5 8,66
14a,l%-OAc 5 3,65

--

Jabarosa l e u c o t r i c h a Leaves Iochroma coccinium

P . angulata

21

TABLE la ( Ccntd. )
:B.;6E-EPOKu)JS WITH 178- SIDE C M I N

Compound Jaborosalactone V @&

)

Hydroxyls Epoxide Ene 17a ,19 193,28 5 46B 5 8,6E 24 24

Other groups m.p. ("C)

[a ID

Source

Ref.

--

287-90 220-22

--

Jaborosa leucotricha 39a

-do-

Jaborosalactone W (26b)
R-Lhydroxy Compounds :

---

--+ 17

39a

27-Hydroxywithanolide D (29) 1 4-Hydroxywithanoltde D (30) 17a-Hydroxywithanoltde D (31) 7~-Hydroxywithanolide D (32) 78- k e toxywithanolide D (33) 17-Isowithanolide E(34) Physapubescin (35) (26-eptmers)

4 E,208,27

5 E,6E

2,24 2,24

202 (4,27dtacetate) 211-13 (EtOAc) (4-acetate)

W. somifera Dun (Chemotype 111)

78
78

@,14 5208 5 B,6B

----

18

-do-

48,17a,20

5E,6E

2,24

196-97 ( Et0 Ac (4-acetate) 260 (Acetone:Hex) 173-75 262 (EtOAc)

+ 2

-do-

78

48,78,208 48,78-OAc 20

5E,6E 5 8,6 8

2,24 2,24 2,24

118.5

A.

australis arborescens

43
79
80

Griseb

--22,26-lactol

-+
21.3

A.

14a,17a,208 58,68 4!3,15a-OAc, 5 E,6 E 26

Y . somnifera (Chemotype LII)

Noncrystalline

--

P . pubescens L

81
143

144

TABLE la ( Ccntd. ) 56,68-EPOXU)ES kTM 17% SIDE CHAIN Compound Hydroxyls Epoxide Ene Other groups m.p. ( C )
[ a ID

Source

Ref.

Viscosalactone B Physapubenolide Substance A

(36)
(37)

38,48,27
OAc

58,68

*
144-45 2,24 2,24 2,24

* +
76

P . viscosa P . pvbescens (Waltair variety)

23 24b
82

48,148 , 1 5 - 58,68 14a,17a,208 55,M 48,14a,

15cl-OAc

(38)

--

*
152-53 148-53

* + +
23.9

W . somnifera (Egyptai.n variety)

Withangulatin A

(39)

5@,68 58,68

---

P . angulata

83

1.8-Acetoxywithanolide D

3 , 18-OAc

71.9

Iochroma f u s c h s i o i d e s 46a

(39a)
Tetrahydroxy Compounds
Substance C (@-OHsubstance A) (40) Withajardin B

45,14a 17a,208

5B,68

2,24

-21,24-cy

* *

W . somnifera (Egyptfan variety)

82 50

(41)

17a ,25

58,68

--

Deprea o r l c e n s i s

methyl

Pentahydroxy Compounds:
Physangultde

(42)

38,48,206 2 4 a , 258

55,63

P . angulata Frli.age

84

145 Fig.la.5p,6p-Epoxides with 17p-side chain

3 R, =OH,R2 = R3=H 4. R, = OH,R2 = R3=H 5. R, =OH,R2=R3=H, 24,25-di-H 6. Ri = R2=H,R3=OH 7 R, = = 0 , R2 = OH, R3 = H 8. R, = = 0 , R2 = OH,R3 = H, 24,25-di H 9. R, = R2 = H,R3 = OH, 2,3-diH 10. R, = OH,R2 = R3 = OH 2,3,24,25-tetra H l l . R , = OH,R2 = R3 = H, 2,3-diH 12. R, = R3 = OH,R2 = H 13. R, = OH,R2=R3=H, 17a-OH,2,3-di H

14. Ri =OH,R2=R3=H, 14a-0H 15 R, = OAc,R2=R3=H, 17a-0H 16 R, = OH, R2 = R3 = H,18-OH 17 R, = OH, R2 = H, R, = OH, 18. R, = R2 = H,R3 = OH, 17a-0H 19. R, = R2 = OH,R3 = H 20. R, = R2 = OH,R3 = H 24,25-di H 21 R, = R2 = R3 = H, 7a-0H, 17a-0H 22. R, = R3 = O H , R 2 = H 2p,3p - epoxy 23. Ri = R2 = OH, R3 =H, 2,3 - di H 24. R, = R3 = OH, R2 - H

146 Fig. l a . 5p,6p- Epoxides with 17p- side chain

25 26

R, = Rz = OH, R3 = H, 24,25 - epoxy Ri R2 ~ R3 ~ H, 17a-0H, 1 9 a - O H , 2 , 3 - d i H

26a. R, =R2 = R3 = H, 17a-0H, 1 9 a - O H , 2 , 3 - d i H 26b. R,=R2 = R 3 = H , 19-OH, 2 8 - O H , 2 , 3 - d i H 27 R, =OH,R2=R3=H, 16a-0Ac 28 Ri = R2 = R3 = H, 14a-0H,15a-0AC 29 . R, = R2 = R3 = OH 30 R, = R2 = OH, R3 - H 14a-0H 31 R, = R2 = OH, R3 = H, 17a-0H 32 Ri = R2 = OH, R3 = H, 33 R, = R2 = OH,R3 = H, 7P-0AC

34 R, = R3 = H, R2 = OH 14a-0H 35 .R, = OH, 1 5 a - 0 A C , R2 = R3 = H, H 26,<o,r 36 Ri = R3 = OH,R2 = H, 3p -OH,2,3- di H 37 Ri = OH, R2 =R3 =H 15a.0Ac, 14P-0H 38 .R, = R3 = H,R2=OH, 14a-OH,17a-OH 39 . R, = OH, R2 =R3 =H, 14a-0H, ISa-OAcA'"* 3 9 a . R , = R 2 = R3=H, 3P-0H, 18-0 Ac 40 . R, = OH, R2 = R3 = H, 14a- OH 41 . R, = 0H, R2 = H , 1 4 a - O H , 1 7 a - O H , 24, 25 - di H,25 - OH, 21, 24 cyclo 42 .Ri = R2=OH,R3 = H, 3P-0H, 24a-OH, 25P-OH, 2,3,24,25 tetra H

TABLE lb
56,6B-EYOXIiIES WITH 17- SIDE CHAIN Compound
Monohydroxy Compounds :

Hydroxyls Epoxide Ene

Other groups m.p. ("C)

[a],

Source

Ref.

Jaboromagellsne (43)
Dthydroxy Compounds :

17

58,68

--

12-OX0

*
--

*
-_-

J. magellanica

38

Jaborosalactone M

(44) 148,178
148,178

2,3-Dehydrojabcrcsalactone M (45).
Rihydroxy Compounds :

58,68, 24a,25a 58,68 24a,25a

-2

---

J. bergii haves
-do-

37 37

--

Withanolide E (46) Withaperuvin E (47) Withaperuvin G

14a,178, 20 8 14a,175, 20 6

58,68 56,68

2,24 24 24
24

-4-ox0

167-68 (Acetone) 248-50 (Acetone) 163 (CHC13) 273-75 (Acetone) 234-36 (EtOAc)

+
-

103.5 72.5

P . peruviana P. peruviana roots

-do-

85a,b

34
26b 26a

( 4 8 )

48,178,208 56,68
20

--22,26-lactol 22,26-laccol

_---

2,3-dihydrowithanolide E (49) Jaborosalactol M (50) 2,3-dehydrojabcrcsalactol M (51)

14a,178,

56,66 58,68 i 4 ~25u , 56,68 24a,25"

P . peruviana
J. bergii

148,176, 26a 148,178, 26a

-2

leaves -do-

37
37

--

_-

147

TABLE

148

l b ( Contd.

% , 6 6-EPOXIDES W I l l I 17a - S D E CHAIN

Compound

Hydroxyls

Epoxi.de

Ene

Other g r o u p s

m.p.

("C)

bID

Source

Ref.

Physagulin C (52)

48,14a, 15a-OAc

56,68 168,176

2,24

--

242.5-243

105.8

P. a n g u l a t a ( L e a v e s & Stems)

86

Tetrahydro-

Compounds:
48,14a 178,208 56,166 2,24

4 -Hydroxywl.thanoll-de E (53)

--

197-98 (EtOAc)

95.8

P . peruviana

26a 87

Pentahydroxy compounds:
Visconolide (54) 48,14a, 178,208, 28
36-OMe, 46 -OH, 14a-OH, 178 -OH, 206-OH

58,66

2,24

---

P. v i s c o s a

88

Physalactone (54a)

58,68

24

P . alkekengi

58

Not a v a i l a b l e

149 Fig. l b . 5 p ,6 p - Epoxides with 17a - side chain

43. R, = R3 = H,R2-CH, 12.0XO,2,3-diH 44. R , - R3-H,R2=OH, 14p-OH,2,3-diH 45 R, -R3-H,R2-OIi 24a, 25a - epoxy 46. R, =H,R2 - R3 - OH, 14a-0H

49 R, = R3 = H, Rz - OH Ma^OH ,2,3-di H 50. Ri = R3 = H,R2^0H, 14p -OH, 22-26, lactd, 24a,25a-epoxy, 2,3-di H 51 R, =R3 = H,R2-OH, 14P-0H, 22-26 lactol, 24a,25a-epoxy 52 R, =0H,R3 = H, 15a-OAc,R2=16p, 17p-q)oxy 53. R, = R2 - R3 = OH, 14a - OH

47. Ri =OXO,R2=R3= OH, 14a-OH,2,3-diH 48. R, = R2 = R3 = OH,

2P, 3p - epoxy

54. R,-R2=R3=OH, 14a - OH, 28-OH 54a. R, - R2 = R3 = OH, 14a - OH, 3p - OMe, 2,3-diH

TABLE l c 5B,6 6-EPOXIDES WITH MODIFIED SIDE CHALN

~

150

Compound
Monohydroxy Compounds :

Hydroxyls Epoxide Ene

Other groups m.p. ("C)

PI,

Source

Ref.

NS 1

Dihydroxy Compounds
(+)

Y-lactone side chain :

vi th

Jabnrnsalactnne M (55)128,178 178,228 176,22,2 175,25

58,66

2,24

12,22-~xidc 22,2641 de 22,26-olide 12 -Me0

*
264 (CH2C12:hex)

Trechonolfde B (56) Trechonnlfde B (57) Acnistin A ( 5 8 )

56,65 2,24 12,22hemiacetal 58,66 2,24 58,66

----

J. mageiianica
Trechonates l a c i n i a t a

a9

45 45

--

-doA . ramifluorum

Meirs

42 215

Jabcrosalactone U (55a) 128.176 Trihydroxy Compounds with Y-lactone in the side

chain :

56 66 2 248 ,258

Leaves
J. sativa

Ixocarpalactnne B (59) Acnistin E

(60)

4 6,200,
22
4 6,178

56,65 56 ,66

2 2 20,24-cyclo methylene

P . ixocarpa Brnt

25 42

--

--

A. ramifluorum

25

Meirs

idth I -lactone

Tetrahydroxy Compounds in the side chain: Ixocarpalactnne A (61) Withajardin E

(61a)

46,166, 205,22a
36,48,

56 ,613

-21,25-cycln

294-95 (Et0Ac:MeOH)

a4

P . ixocarpa

Brot

25 25a

1 7 ,24a ~

58 ,66

Depreaorinocensis

151
Fig, k . 3p,6P- Epoxides with Modified side chain O

OH

55 .

55a . 24P,25P - epoxy OH

5 6 . R = H , R, = OH 5 7 . R = OIVIe,Ri=OH OH

Acnistin A (58) Acnistin (60)4P - OH OH

OHE

HO Ixocarpolactone B (59) HO O

OH 6 1 . Ixocarpolactone

OH

61 ( a )

TABLE

Id

152

6a ,7=-EPOXIDES W I T H 178- SIDE CHAIN

~ ~ ~~

Compound
Monohydroxy Cmpounds :

Hydroxyls Epoxide Ene

Other groups m.p.

("C)

[a ID

Source

Ref.

Lycium substance B (62) Withanicandrin (63) Daturalactone A (64) Daturalactcne D (65) Nicalbin B (66) 5-Dehydroxywithanolide R (67)
Dihydroxy Compounds :

f 3 ,7a

2,24 2,24 2 2 2 2,24

'

--

260-65 267-69 303-05 282 275-76 (EtOAc)

+ 107 + 105

Lycium chinenseleaves 35 Nicandra physaloides Datura guerolfolia 8 D stromoniurn 90 91 31 92 93 94

6a,7Q
6w ,7a 24a,25a
6a ,7a

12-0x0 12-OX0

+ +

63

-16,26-rxidc

-24.2

D . queroifolia

6a ,7a
6a ,7a

Nicandra physaloides var. albiflora

----

--

--

W. somnifera (Pak variety)

Withancne (68) 5-27-dihydrcxy-1-0x06a,7a-epoxy-22R-witha2,24-dienclide (693 Withanolide R (70) Nic-3 (71)

w,ia
@,7a

2,24 2,24

275-76 (CHC13:EtOAc) 230-32 (EtOAc) (27-acetate)

81
73

Gi. somnifera Dun

66 66

(Indian chemctype) -do-

6a ,7a

2,24 2

24 a,25a

6a,7a

- 64 182-83 (23-Acetate) -22,26-lactcl 248

-_

W. somnifera 95 (Chemctype I V s . 111)

Nicandra pysaloides

96a,b

TABLE

Id ( Ccntd.

6a,7a-EWXIDES WITH 178- SIDE CHAIN Compound Nic-7 ( 7 2 ) 5 a, 20aF-dihydrcxy6 a,7 wepoxy-l-cxc-witha2,24-dienclide (73) Daturalactone B (74) Daturalactcne C (75) Nicandrin B (76)* Withaferoxolide (76)* Vamcnolide (77) Ixccarpanclide (78)* Withasomnifercl B (29 Hydroxyls Epoxide Ene 5a,26a 5a,206 m,7a 24a,25a W,7a
2

Other groups m.p. ("C) 12-cxc; 22, 26-lactcl 263 (Benz :CHC13) 282-4

I a ID _-

Source
Nicandra physaloides

Ref.

96a,b 16a

2,24

--

+
0

88

w.

coagulans

5a,12a 5a,12B 5a,12a 5a,12a 5a,14a 5a,206

,7a

2 2

--

260-61 285-86 246-48 278 (mci3)

@,7~ 24a,2Sa 6a,7a

----

I -73

N . Physaloides 8 D. quercifolia D. quercifolia

91 97

2,24 2,24
2

110.7

N . physaloides var.
albiflora

34

6a,7a 6 ,7 6a,7a 6 ,7

116.4

D. ferox aerial parts 31

P. angulata leaves

---

*
*
281-83

98
99 217

*
-123.59

P. ixocarpa aerial parts

>

W,20 6

2
-

W. somnifera r m t s
W. somnifera (Indian chemctype)

Trihydroxy Compounds :

1 a,3 6 , 5 &trihydrcxy6 a, 7 wepcxy-1-cxc-22Rwitha-24-enclide (80) Withanolide T (81)

1~,36,5a ~ , 7 a 24

256-58 (EtOAc) (3-Acetate) 257

+ +

71.5

66

5",14",
20%

6",7a

2,24

--

60.5

W. somnifera (Chemotype I11 Vs. Ind. I)

100
153

154

TABLE Id ( Ccntd. 6a,7oEPOXIDES WITH 178- SIDE CHAIN

~~~~ ~ ~~ ~

Compound Vitastramonolide (82) Nicalbin A (83)

Hydroxyls Epoxlde Ene 5 SlP, 27 5";1@, 26 6a,7'3 2 24a,25a

Other groups m . p . ("C) 269-70 ( MeOH 22,26-lactol 241-43 (EtOAc)

i elD

Source
D . strarnonium

Ref.

101 var.
93

+ 37
i 29.8

N . physaloides

albifl ora

14"-hydrcxywithancne (84) 5 a, 14a, i7a 140 -hydroxywithancne ( 8 5 ) 5 a, 148, 17 148 -hydrexyixccarpanelide 5 a, 146, (86) 20 a
158 -hydroxynicandrin B

W ,7a
W,7" 6a,7a

2,24. 2,24 2

--24,25-dihydr@

250 (CHC13:MeOH) 280 (EtOAc)

w.

s o m n i f e r a (Ind. VS. 102 Chemotype i11)

36.7

doP. a n g u l a t a
D. ferox

102 103

(86a)

5 a, 120,
150

leaves

318
21T

Withascmniferol A (86b)

5 a,208, 27

6a,7a

2,24

--

271-73

74.8

W . somnifera rcots

Nct available

$'*

: May be identical

Identity nct established

155 Fig.Id. 6 a,7 a - Epoxides with 17 P - side chain

OH 62. Lycium substance B 63. 1 2 - 0 X 0 , 64. 12 - 0X0 , 24a,25a - epoxy, 65. 24,25-diH 66. 16,26-oxido,24,25-diH 67. 5 - deoxy, 23 a - OH , 68. 17a -OH 69. 27 - OH 70. 23a-OH 73. 20P-OH 74. 12a -OH , 24a,25a - epoxy 75. 12P-OH, 24a,25a-epoxy 76. 12a-OH 77. 14a - OH , 24,25 - di H * 78. 20p - OH , 24,25 -di H 79. 20p OH, 24,25-diH 72. 1 2 - 0 X 0 , 26 < , 24a,25a-epoxy OH

71. 24a , 25 a - epoxy H 26 < OH * identity not established , appear different by physical constants.

156 iMg. Id. 6a,7a- Epoxides with 17 (]-side chain

80. l a - 0 H , 3 p - 0 H , 2,3 - di H 81. 14a - OH, 20p - OH 82. I2a-OH,27-OH

83. 16a-OH, 26 < 24a,25a - epoxy OH 84. 14a - OH, 17a - OH 85. 14p-OH,17a.OH

86 . 14a-OH,20p-OH, 24,25a - di H 86a. 12a-OH,15p-OH 86b . 20p - OH, 27 - OH

Fig. le. 6 a,7a-Epoxides with 17 a-side chain

87. Withasomniferin A, 4en , 17p - OH H 88. 5a - OH , 17p - OH , 26 < ,24a ,25 a - epoxy, 2 en OH OH 89. 5a - OH, 25 a - OH, 26 < , 17p , 24 p - Oxido , 24,25 - di H H

TABLE

le

6a,7crEPOXIDES WITH 17

SIDE CHAIN
[a],

Ccmpound
Mcnohydrcxy Compounds

Hydroxyls Epoxtde Ene

Other grcups m.p. <"C)

Source

Ref.

Withascmniferin

ZL

(87)

--

W. scmnifera (Pak. variety)

94

Dihydrcxy Compounds

Nil
Trihydrcxy Compounds :

Nic-2 ( 8 8 ) Nic-11 (89)

5a,17B,
26a

6 a , 7a 24a,25a 2

-17i.245 cxidc

224-45 277

-_-

N. physaloidesleaves 104 -do96b

5a,25a, 26 B

6a,7o

m L E

If

6a,7a-EPOXIDES WITH AROMATIC R I N G D (ME0 COHPOUNDS)

Compound

Hydrcxyls Epoxide Ene 5 a,26a 24a,25a 5u, 6 a 24a , 2 P

6Q
6a

Other groups m.p. I ' C )

[%ID

Source

Ref

Nic-1 ( 9 0 ) Nic-1-lactcne (91) Nic-17 ( 9 2 ) Nic-12 (93) Nic-10 ( 9 4 )

5a,26a 50

2 2
2

--

138 230-32 86 174-75

--

N. physaloides
-do-dc-do-do-

105
106 107

-24-rxo 24-cxo
20-ow

34.6

5 a, 22
5a

la
la

-_-

2,22 2

107
1 U7

5a

6a

la

107 (EtOH)

_-

157

158 Fig. If. 6 a,7 a - Epoxides with aromatic ring D

Nic - 10 ( 94 ),

Nic-17(92),

R=

Nic- 1 - lactone ( 9 1 ) , R =

Nic-1 (90),

R=

OH H

TABLE lg
5-ENES WITH 1 7 a SIDE C "

Compound
Mcnchydrcxy Compunds:
No najle ( 9 5 )

Hydroxyls Epox-Lde Ene

Other groups m.p. ( " C )

[a],

Source

Ref.

2,5,8(14) 24

210-11

i 56.5

* *
W. somnifera
P. minima

57

t i c name ( 9 6 )

Withascmifercl Withaphysalin A (97) Withaphysalin D (98) Seccwithametelin ( 9 9 ) Jaturametelin C (100) Daturametelin E (101) Ccagulin (101a) 14,155-epoxywithanclide I 20 (101b) 14,155

2,5,14, -184-85 24 -* 5,24 2,5,24 18-20 lactcne 222-23 3,5,24 18-20 lactcne 2,5,24 27-Me0 5,24 5,24 27-Me0 3 -OS03H

i 7.5

57
5 7.3

*
i 43.6

64 108 109 110 110 126a 16c

(Indian variety)
P . minima var. I n d i c a
D . metel

*
190 199-202 (CHC13:MeOH)
An amcrphcus pcwder

*
i 28.53

i 68.7

-do-dc-

i 25.8

3,5,24 14 ,20 -cxidc 2,5,24

w.

coagdens

--

Withania c o a g u l e o s

159

TABLE

lg ( Ccntd.

160

5 - W S WITH 178- SIDE CHALN

Compound

Hydroxyls Epoxide

Ene

Other groups m.p.

("C)

[a

ID

Source

R2f.

Dihydrcxy Ccmpcunds :

17Q, 27-dihydr~xy-1-cxc 22a-witha-2,5,24trienclide (102) 7,27-dihydrcxy-l-cxc witha-2,5,24-trienclide

(103)

17a,27

--

2,5,24

---

205

(27-acetate) (acetcne:hex)

74

66

78,27

--

2,5,24

208-09 (7,27diacetate) 224-25 201-02 (CHC13:EtOAc)

119

-do-

66

Nc name

(104)

2,5,8(14), 24 2,5,8(14), 24 2,5,8(14) 24 2,5,24 2,5,24 2,5,14,24 17a,205 17a, 20E 14 ,15 2,5,24 3,5,24

----

48 112.5

*
W. somnifera (Chemctype I)
-dc-

57 78 78 111
111

Withanelide 0 (105) Withanclide N (106) Withanclide G (107) Withanclide J (108) Withanclide L (109) Withanclide M (110) Withanclide I (111)

Amcrphous + 31 (27-acetate) 194-95 (EtOAc) 215-16 ( CHCl : EtOAc 213 (EtOAc) 240 (EtOAc) 184 (EtOAc)

----

52.5 32.5
9.6

W. somnifera (Chemctype 111)

-do-do-

+
+

111 111 111

---

+ 44.6

w. somnifera (Chemctype 111)

-do-

--

118

TABLE

lg ( Ccntd.

5-ENES WITH 176- SIDE CHAIN

Compound

Hydroxyls Epoxi.de 4 6,208

Ene

Other groups m.p.

("C)

[ QID

Scurce

Ref. 57 112 113

--

2,5,8(14) 24 5,24

---

230 (4-acetate) 152-55

110.6 48 33.4

*
W. aristata Pauq (aerial parts) P. minima (Indian chemctype)

la -hydrcxywithanclide (113)

la,14a

--

+
+ + +

Withaphysalin C (114)

14 8

13,14 2,5,24 epoxy (13,14-secc)

8-20 lactcl 202-03

J6-Withanclide

(115)

14a,208 4 8,27 46,27 la-OAc,36

---

2,5,16,24 2,5,24 5,24 5,24

------

212-13 (EtOAc) 218-20 (MeOH) 212-13 (EtOAc) Amcrphcus

44 42.5 27.4

W. sornnifera (Chemctype 111)

A.

114

5,6-desoxywithaferin A (116) 2,3-dihydrc-5,6-desrxywithaferin A (117) (20S,20R)-la-acetcxy-3 hydroxyitha-5,24dienclide

breviflorus Gresib
-dr-

70
70

--

+ 58.8

Dunalia australis

rrcts

115

18-acetoxy-4-decxy208,18-OAc 5,6-decxy-5-withanclide D (11W

Trihydroxy Compeunds :

2,5,24

--

--

Iochroma fuchsioides

46a

Withanclide Q

(119)

17a,236,27

--

2,5,24

--

200-02 (EtOAc)

6.6

W. somnifera (Indian chemvtype)

95

161

T&LE

lg ( Ccntd. 1

162

5-ENES WIITH 17 - SIDE CHAIN

~~ ~

Compound

Hydroxyls Epcxide Ene

Other groups Q . P . ("C)

L QID

Source

Ref.

Uithanolide H (120) Withanelide K (121) 17bhydrexywithanclide K (121a)

140,20~, 27 140,170, 20 140,178,

205

2,5,24 2,5,24 2,5,24 2,5,24

141-42 (EtOAc) (27-acetate) 218-19 (CHC13:EtOAc)

35.5

Y. somnifera

111 111 16c

116

9.2

-do-

W . coagulens
234

45,76,20cctrihydrexy-1rxc-witha-2,5,24trienolide (122)
lB-acetoxy-5,6-deoxy5-withenclide D (118b) Withanclide U (123)

46,7B ,208

+ 9.8

Dunalia australis (Griseb) Sleum

45,208,18CH20Ac 45,140,
206

2,5,24
2,5,24 230 (4-acetate)

Iochroma fuchsioides 46a

110.6

W . somifera Chemotype 111 Vs. Ind. I)

100

27-hydroxywithanrlide I
(

124)
~

140,206,27 10,35 ,208

3,5,24 5,24

*
273 (EtOAc)

*
+
19.8

*
W . somnifera
(Chemctype 111)

58
117

3 8,2C 0 -trihydrexyF 20R,22R-witha-5,24dienrlide (125)

i0

Pubescenolide (126) Physalclactcne B (127)

lQ,36,27 la-OAc, 38,206

5,24 5.24

* *

* *

P . pubescens P . peruviana

118 119

TaBLe lg

( Ccntd.

5-ms W I m
Compound Hydrexyls Epoxide Ene

178- SIDE CHAIN

Other groups m.p. ("C)

[.I,
i

Ref.

14a-20a,27-trihydrexy20R-22R-1-cxc-witha3,5,24-trienclide (128) Scminene (129)

Tetrahydrcry Ccmpouuds :

14a,20J, 27 la,36,27

--

3,5,24

-21,24-cycle

184 (EtOAc)

98.7

W. somnifera (Chemctype 111)

W . somnifera

117

--

5,24

*
*
190-92 (EtOAc:MeOH) 135-37
i

* *
64.7 16.7

120

Withajardin (130) 3a-hydrcxy-2,3-dihydrcwithanelide H (131) (ZOR,22R)-3 Eacetcxy-1a, lZB,ZO-trihydrcxy-l-cxewiiha-2,5,24-trienclide (132)

46,14Q, 17Q,25 36,14a, 20aF,27

h ,36-OAC, 126,205

2,5 5,24 5,24

Deprea procumbens

51 121 115

leaves

---

---

W . coagulaos fruits
Dunalia a u s t r a t i s

Nct

available

163

164

Fig.lg . 5 Eiics with 17 p- side chain

95 96 97 98 99

14a - OH, A^ 18,20-lactone 14a-OH, A\18,20-lactone 21-OH,A^27-OMe 100 . 21-OH,27-OMe 101 . 21-OH,3p-0-S03H 27-OH,A\l4a,20a-oxido 20P-OH, 14,15 p-epoxy,A^ 3p - OH, 14a, 15a - epoxy ^ 17a-OH, 27-OH, A 7p - OH, 27 - OH, ^ 17a-OH,27-OH,A^A^^''*^ 4P-0H, 17a-0H,A',A''^'^^
7a - OH,27 -OH, A^A'^'^^

. . . . .

14a-OH, A^A^''^ 20P - OH, A^ , A^^

101a. 101b. 101c. 102 . 103 . 104 . 105 . 106 . 107 . 108 . 109 .

4a - OH,20p - OH, A' 17a- OH,20p-OH,A^

17a -OH, 20p - 0 H , A ' ^

110 . 17a - OH,20P-OH, ^ 14a ,15a - epoxy, A 111 . 17a- OH;20p-OH,A' 8(14) 112 . 4p - OH,20p - OH, A^A' H 113 . 1< , 14a-OH OH

114 . 14P-OH, 13,14, ^ seco - 13,14 - epoxy, A 115 . 14a-OH,20p-OH,A%A'^ 116 . 4p - OH, 27 - OH, A' 117. 4p-OH,27-OH, H 118 . 1< , 3P-0H OAc ^ 118a. 20P-OH, 18-OAc, A 118b. 4p - OH, 20p - 0H,18 - OAc, A ^ 119 . 17a - OH,20p - OH,27 - OH, A ^ 120 . 14a - OH, 20p - OH,27 - 0H,A' 121 . 14a - OH, 17a - OH, 20p - OH, A' 122 . 20p-OH,A^ 123 . 4P-0H, 14a-OH,20p-H,A' 124 . 14a - OH, 20p - OH, 27 - OH,A^ 125 . la - OH, 3P - OH,20p - OH 126 . la - OH, 3P - OH, 27 - OH H 127 . 1>< , 3p - OH, 20p - OH OAc ^ 128 . 14a - OH, 20a - OH,27-OH, A 129 . la - 0H,3p - OH, 27 - OH 130 . 4P-0H, 14a-OH,17a-OH,25-OH, A-,21 - 24 - cyclo, 24,25 - di H 131 . 3P-0H, 14a-OH,27-OH,2,3-diH, 20p - OH H 132. 1>< ,3p-OAc,12p-OH,20p-OH OH

TABLE

lh
SIDE CHAIN
[ 0ID

5-ms WITH 17aCompound Hydroxyls Epoxi.de Ene

Other groups m.p. ("C)

14-20 Oxy

Source
W . somnifera

Ref.

Withanclide withnchydrcxyl k%ydroxy Compounds : Neb? nithznclide (13%) 17 B

Dihydroxj Compounds :

__

- -.

3,5,24 2,5,24

85b 05c

-__ _-

14-20 Oxy

W . somnifera

Withanclide P (133b) New withanclide

Trihydroxy Compounds :

140,176 173,200
1 4 ,176, 205

2,5,24 2,5,24

--4-CXO

216-17 (EtOAc)

51

W. somnifera

85b 85c 85a 122

-dc-

Withanclide F

(134)

2,5,24 5.24

192-93

--

W . somnifera

(Chernctype 111)

Physanclide (135)
Tetrahydroxy Compounds :

P. alkekengi (Turkmenisrhan)

Nil
Pentahydroxy Compounds :

28-hydrcxywithaphysanclide (136)

46,14a, 1)B ,206,28

--

5,24

--

P . viscosa

123

165

Nct available

166

Compound Daturametelin D (137) Wlthametelin (138) Isowlthametelin (139) Daturametelin F (140) Jaborosalactone P (a splranic withanolide) (141) Perulactone B ( 1 4 2 ) Perulactone (143) (176-oriented side chaln)

Hydroxyls Epoxlde Ene

Other groups m.p. 27-Me0

("C)

[al,

Source
D . metel aerial p a r t s D . metel leaves

Ref.

----126,176, 22 14a, 176, 206,22a la-OAc, 36,206, 22a

21,24epoxy 21,24 21,24 21,24 epoxy

2,5 2,5, 25(27) 335, 2 5 ( 2 7 ) 5, 2 5 ( 2 7 )

199.5-201.5
CYCl3-MeOH

- 90.6

110 12 6 126 110 40

--3 -OS03H

210 280 Amorphous pcwder

64.4 77.7

-doD. metel aerial parts

J . odenelliana

i 5.0

---

2,5,24 12,23-cyclo; 23,26-olide 2,5 5 26,28-olide 26,28-olIde

*
217-18 (EtOAc) 239-40 (MeOH) 244-45 (EtOH)

*
i 56.8

P. peruviana leaves (Varanasi variety) P. peruviana (Varanasf. variety)

127 128

--

3.2

167 Fig. Ih , - Enes with 17a - side chain

3,4-diH,A^

I33b R =H,A^ 133c. R = OH, 14-deoxy,A^ 134 . R=OH 135 . R = 0 H , 4 - 0 X 0 136 . R = OH,28-OH,4p-OH Fig.li. 5 Enes with Modifled side chain

137 . A%27-CH20Me 138 . A''"<">

139 .A''25^27)

140 . A ' " ^ ' ' \ 3 p - 0 - S 0 3 H

168

OH

141 Jaborosalactone P. OH 0H =

142 Perulactone B

143 Perulactone

OH 144 With aphysaJian

(145)

TABLE lj
INTEXMDIATE COMPOUNDS WITH 178- SIDE CHAIN

Compound
Hcnchydrcxy Ccmpcunds :

Hydroxyls Epoxide Ene

Ocher gxups m.p. ("C)

[a],

Source

Ref.

Withaphysalin E (144) Withascmidiencne (145)

Dihydrcxy Ccmpcunds :

68

2,4,24 18-20 lactcne 311-12

61.4

P . minima Indica

var.

129 126a

27

W. s o m n i f e r a

Jaborosalactone B (146) Jabcrcsalactone C (147) Jabcrcsalactcne E (148) Withacoagulin (149) 5a,17a-dihydrcxy-l-cxc22R-witha-2,6,24trienolide ( 1 5 0 ) 2,4,6-trien-l-cne (151)

68,27

Jaborosa i n t e g r e f o l i a Lam

67 130 130 131

66

58,27
6 8 , 27

--

2,24 2,24 2,6,24 2,6,24

6 -Cl

218-20 (CHC13:EtOH) 225-28

-dc-

-I

5 -C1

-*
+
75.5

-dcWithania coagiilans

5u 208 5a,17a

--

*
238-39 deccmpcses ( CHC13 : EtOAc ) 220-22 (EtOAc) 180-81

24 ,25

W. SOmnifera Dunal

(Indian chemctype)
W. s o m n i f e r a L (Chemctype I1 Vs. Ind. I)
P . pubescens

14u,206

2,4,6,24

+
+

12.2

132

Pubescencl (152) Scminclide (153)

4u.7a 48,27

2,24

11.4

24a 120

14 ,15

W. s o m n i f e r a

(Panistan variety)

169

TABLE lj
INTEWJDUl"E

170

( Ccntd. )

COIPOUNDS WITH 176- SIDE CHAIN

~

Compound

Hydrcxyls Epaxi.de Ene

Other graups m.p. ("C) 5 a-Me0 5a-ethcxy

200-01

[QID

Source

Ref.

5a-methcxy-4,5-dihydrcJabcrcsalactcne B (154) 5*ethoxy-4,5-dihydrcJabcrcsalactcne B (155)

Trihydrcxy Ccmpeunds :

6 427
68,27

--

2,24
2,24

---

Acnistus b r e v i f l o r u s

69 69

--

203-04

-do-

GO-chlcrc, 5 Ehydrcxywithaferin A ( 1 5 6 )

4Bt5B, 27 48,5B, 16Q

2,24 2,24

6Q-Cl 6a-Cl

281-84 247-49

+ +
+

68

Withania f r u t e s c e n s

133 5a

Pauq
Dunal i a tubul osa

4B,5 B,20 F -trihydrcxyQ

76

6-chlcrc-1-cxc-witha2,24-dienclide (157)

Acnistcferin**(158)

5Q,6B ,27

285-88 227-29 (EtOH)

99.6

Acnistus b r e v i f l o r u s Jaborosa i n t e g r e f o l i a

41

Jabcrcsalactcne D** (159) 5a,68,27 Withametelin C (160) Physagulin B (161) 5a,68,21 6B114Q 15a-OAc

--

130 135 77

Lam D. metel P. angulata L

--

24

*
A white powder

*
159.5

--

2,16,24 5Q-Cl

**

May be identical

Compound

Hydroxyls

Epoxide

Ene

Other groups

m.p. ( " C )

[a],

Source

Ref.

WCthasomnCferol C (162) 5a,14@,205 Tetrahydroxy Compounds: Jaborosalactone F (163) 5a,65,12a, 27 Withamf.nCmin (164)

--

2,7,24

-_

294-95

67.78

U. somnifera

217

2,24

--

268-70 (Acetone: Pet. ether) 208 (Amorphous powder)

Jaborosa i n t e g r e f o l i a 136 Lam

P . minima

5a,66,14a. 15a-OAc

--

2,16,24

--

-.-

21b

Pentahydroxy Compounds: Jaborosalactone X (165)

48, 5a,66,

19,27

24

204-05

Jaborosa l e u c o t r i c h a

3~~

171

172 Fig. IJ , Intermediate Compounds with 17(3- side chain

R,A^'<=

146 . A \ 6p . OH, R, = H, R2 = OH 157. 4P - OH, 5p - OH, R, = OH, R2 =H,6a-Cl 147. 5p - OH, 6a - CI, R, = H, R2 =0H 158. 4p-OH,5p-OH,16a-OH,6a-Cl, 148. 5a - CI, 6p - OH, R, = H, R2 =0H R, = R2 = H 149. 5a - OH, R, = OH, R2 = OH, A' 159. 5a - 0H,6p - OH,R, = H,R2 = OH 150. 5a - OH, 17a - OH, R, = R2 = H,A^ 160. 5a - 0H,6p - 0H,21 - OH,R, = R2 =H, 151. 14a - OH, R, = 0H,R2 = H , A \ A^ 2,3 -di H 152. 4a - 0H,7a - OH,24a ,25a - epoxy, 161. 5a-CI,6p-OH,14a-OH,15a-oAc, R, = R2 =H R, = R2 = H 153. 4p - OH, R2 = OH, R, = H, 162. 5a - OH, 14a - OH, R, = R2 =H 14a, 15a -epoxy 163. 5a - 0H,6p - OH, 12a - OH,R, =H,R2=0H 154. 5a - 0Me,6p-0H,R2 =OH,R, = H 164. 5a.OH,6P-OH,15a-OAc,R, = R2=H 155. 5a - OEt, 6p - OH, R2 = OH,R, = H 165. 4p - OH, 5a - 0H,6P - OH, 19 -OH, 156. 4p - OH, 5p - 0H,R2 = OH, 6a - CI, R2 = 0H,2 ,3 - di H R,=H

TABLE

lk
~~~ ~

INTERMEDIATE COwpouNDS WITH 17a SIDE CHAIN

~~

~ ~ _ _ _ _ _ _
~

Compound
Monohydroxy Compounds :
Ni1

Hydroxyls Epoxide Ene

Other groups m.p. ("C)

I QID

Source

Ref.

Dihydroxy Compounds
N o Name (166)

56.178

-Jaborosalactone T (166a) 58,178 Trihydroxy Compounds : Jaborosalactone R (166b) 66,128,178 -Tetrahydroxy Compounds :
Wi thaperuvi.n C (167)

12.22oxi.do

2.24
2

6a-C1: 12 -Me0 * 23,26101Cde Q-C1; 12-0Me 234-35

J . magelianica
J.
J.

138 219 219 139 140 141 26b 142 37 137

173

* * *

sativa sativa

2,4 2,4,24 24 2,14,24 6a-Cl 2,14,24 2,24

2,4

--

263-64

66,14a 178,206

--

-.-

*
209-11

P . peruviana

Wtthaperuvin D (168)

48,56, 14a, 2a,6a178 ,206 oxido

12

-doP . peruviana

Physalolactone C (169) 46,58, 176,20 8 Withaperuvin F (170) 4-Deoxyphysalolactone (171) 46,56, 176,206 56,14a, 176,208

-3a,6aoxido

*
174-75 (CHC13) 207-208 (Et0Ac) 183-85

-6a-Cl

39.70

-doP . peruviana

-24a,25a

i103

(Varanasi variety)

Jaborosalactol N (172) 68,148, 178,26a Withanolide C (173) 68,14a, 178,206

-5 -C1

--

Jaborosa bergii Y . somnifera

--

2,24

--

--

TABLE lk (Contd.)
IMZRWDIAlZ COMPOUNDS WITH 1 7 ' SIDE CHAIN
~~~

174

Compound Wtthanolide C (17%)

Hydroxyls EpoxCde Ene

Other groups m.p. ("C) 5a-Cl

[a],

Source

Ref.

68,14a,178, 206 Jaborosalactone S (166~) 5a ,613,128,178 Pentahydroxy Compounds: 50,66,14a, 7 6,206 48,56,14a, 176,206 48,58,6a, 176,206 48,58,14a, 178,208 66,14a,i76, 208,28

----

2,24 2 2,24 2,24 2,14,24 2,24

*
265-66 272 227-28

--6a-c1

* *

W. somnifera
3. sativa

137 219 143 144 roots 139 145

WCthanoltde S (174) Physalolactone (175) Wtthaperuvtn B (176) Wtthaperuvtn H (177)

+
-k

97.5 29.4

P. peruviana

---

-doP. peruviana

--

*
+

*
84.3

4,6-mercapto 213-14 acetaldehyde adduct

-do-

28-Hydroxywithaperuvtn C (178)

---

2,4,24 2,24

--

* *

P.peruviana
-do-

leaves

88

Wtthaphysanoltde (179) 46,5",14a, 178,208

Hexahydroxy Compounds:

--

146

23-Hydroxy physalolactone C (180)

48,58,17B, 20 8,23a

--

2,14,24 6GCl.

202-04

-k

60

P. peruviana

leaves 147

TAE4IZ

INTERMEDIATE
Compound Wtthaperuvh (181) 28-Hydroxywithaphysanoltde (182) Physagultn F (183) Hydroxyls
4 8,5 8,6 Q, 14~,178,208 48,5~,14~, 178,206,28 58,68,148,

COMPOUNDS

lk (Contd.) UITB 170- SIDE CIIBLN

m.p. ("C)
225-27

Epoxtde

Ene
2,24

Other groups

Source

Ref.
142

--

--

(MeOH)

156.8

P. peruviana (Varanast vartety)

-16?,178

2,24

*
A white powder

P. viscosa leaves P. angulata L

123
148

2,24

15Q-OAc

--

70.7

Not available

175

176

OH

lAoA^
OH

(166)

OH ( 177) With aperuvinU

166a . 5P - OH , 6a - CI, R = OMe 1 6 6 b . 6 P - O H , R = OH,A4 166c . 5a - OH , 6p - OH, R = OH , 24,25 - di H

177 Fig. 1 k. Intermediate Compounds with 17a - side chain

167 . 6p - OH, 14a - OH, Ri = R2 =0H, A^ 168 . 4p - 0H,5P - OH, 14a - OH, R, = R2 = OH,2,3 - di H,3a -,6a -Oxido 169 . 4p - OH, 5p - OH, Ri = R2 =0H, A^\ 6a - CI 170. 4p - OH, 5p - OH, Ri = Rz = OH, A'\ 2 ,3 - di H,3a , 6a - Oxido 171. 5P - OH, 14a - 0H,6a - C1,R, = Rz =0H 172. 6P - OH, 14P - OH,R, = 0H,R2 =H, H 26 -C < , 24a ,25a - epoxy OH 173. 6p - OH, 14a - OH, R, = R2 ^ OH, 5a - CI.

174. 5a-OH,6p-OH,14a-OH,R, = R2=OH 175 4p-OH,5p-OH,14a-OH,R, = R2 = OH, 6a-CI 176. 4p - OH, 5p - OH, 6a - OH,R, = R2 =0H, 178. 6p - 0H,14a - OH,R, = R2 =OH,28-OH, A^ 179. 4p - 0H,5a -OH, I4a -OH,Ri =R2 K)H 180. 4p - 0H,5P - OH,R, =R2 =0H 23a - 0H,6a - CI 181. 4p -0H,5p-0H, 6a - 0H,14a-0H, R, = R2 = OH 182. 4p - 0H,5a - 0H,14a - 0H,R,=R2 =0H, 28-OH 183. 5p-OH,6p-OH,14p-OH,15a-OAc, 16p,17p-epoxy

TABLE 1L 5 a,6 -Epoxu)ES

178

Compound Wi thanolide Y (184) Salpl.chroli de A (Ring D-arornatlc) (185) Somniferin (184a)

Hydroxyls Epoxide Ene 7Q17Q,205 26

5ah

Other groups m.p. (C)

[a1 ,

Source
Y . somuifera (Chemotype 111 vs. Ind. I)
S. o r i g i n i f o l l a

Ref.
149

2,24

--

270-73 179-80

----

5a,6a

2,13,15,17 22-26 (i3-18) lactol abeo 24

52

58 ,27

5a,6a

4 -0Me
T A B U lm 6 478-EpoXDES

--

W. somoifera

57a

Compound

Hydroxyls 5a,14% 17a

Epoxide Ene
6 6,75 2 9 24

Other Groups m.p. (C)

QI,

Source

Ref. 132

66,7B-Epoxywithanone ( 186)

-TABU

242-44 (CHC13)
In

-47.6

W. somnifera

pI1woLIc UI-LUIES
Compound Jaborol (187) Jaborosalactone Q (188) Hydroxyls Epcxide Ene Other groups m.p. (C)

I I

Source
J. magelienica

Ref. 150a,d 151

-1~,65,27

---

-1,3,5(10) 24

---

135 (MeOH) 176-77

---

J. leucotricha

179 Fig. 1.1. 5a,6a - Epoxides

^"'H

(186)

Fig, l.n. Phenolic Withanoiides O

(187)

OH

(188 )

180 71 withaferin A place at primary, secondary 73 (12), withanolide D (19). Hydroxylation takes A as well as tertiary positions.

primary alcoholic group is generally observed at C-27 in these 44 compounds while that at C-18 as in withacnistin (16) and lochroma withanolides ^ and at C-28 as in visconolide (54) is rare. Even hydroxylation at C-19 has been recently noticed ' Hydroxylation at C-14, C-17, C-20 is very common in withanolides ' ' " ' ^ (46). eq. wi thanolide E " A close observation of the withanolides containing 6 a, 7 of-epoxides suggests the absence of C-4 hydroxyl in them unlike in 5 3 , 6 3-epoxides. Hydroxylation or an oxof unction at C-12 are 97 noticed in some of the compounds eg. daturalactone C (75). 14 3-hydroxy compounds have been isolated from Physalis pubescens 24b eg. physapubenolide (37) and from Withania somnifera eg. 102 (85) and even recently from Jaborosa 143-hydroxywithanone bergii Hydroxylation at C-15 was observed only in five compounds either free or in the form of acetoxy groups eg. Physapubescein (35) and physapubenolide 95 95 Q (119) and R (70) possess 23-hydroxyl. noticed in nicalbin A93 (83). (37). Withanolides C-16 hydroxylation is

Hydroxylation at C-1 and C-3 is mostly noticed in 5-enes. Epoxidation at the C-5 and C-6 positions with Epoxidation . i c j n is 5 0 , 6 3-conf iguration and at 6,7 position with G , 7 -conf i gura l most common in withanolides. The isolation of withanolide Y149 (184), a 5a ,6a-epoxide 132 and 6 3,73-epoxywithanone (186) with 63,7B-configuration provides rare examples. Similarly epoxidation at C--2 and C-3 as in viscosa23 (22) (2 3,3 3-epoxy compound) and at C-14 and C-15, as in lactone A withanolide M (110) are also rare. In the side chain, epoxidation takes place prominently at C-24 and C-25 positions as , m . . ^ . . . 104-107,96b , pubescenol , ,24a , ^ ^ in Nicandra NiCi found steroids , daturac' ,91,97 lactones^ 86 (52) has been ^^ig^ ~^i 7^ " Very recently physagulin C epoxide) isolated by Shingu et al. from Physalis angulata L. The oxirane bridge is noticed between C-12 and C-22

181 positions, eg. Jaborosalactone M (44), trechonolide A (56), datumetelin"^^^ (137) and daturilin"*"^^ (138). The 3o',6a-oxiao (171), the 163,23-oxido bridge in bridge in withaperuvin F 25 ixocarpalactone B (59) and the 16,26-oxirane bridge in nicalbin B 93 (66) are a few other rare examples, 94 have been Two new withnolides of Got, 7 a-epoxide series recently isolated, one without 5ot-hydroxyl 4 A -ene having 2,3-dihydro system. Unsaturation Unsaturation at C-2 and C-24 positions is common in withanolides, while it is present at C-5 in twenty-five compounds. Unsaturation at C-14 and C-16 is rare. The / r compound ' was supposed to be the intermediate in the formation of compounds with 25(27) 17^-oriented side chain. Unsaturation at ^ has been noticed 125 7 in daturilin (138). Withasomniferol (61) with A unsaturation has been reported very recently along with two more new withanolides, withasomniferols A & B from the roots of W. .^ 217 somnifera Dihydro systems A number of 2,3-dihydro derivatives were isolated with saturation of the 2,3-double bond eg. 2,3-dihydrowithaferin A 71 (13). The side chain may also possess saturated lactonic system as in 24,25-dihydro compounds. Incidentally, some tetrahydro derivatives have also been isolated as found in 2,3,24,25-tetra hydro-27-deoxywithaferin A (10). A dihydrosystem at C-5 and C-6 was also noticed in pubescenol (152) which was isolated by Row 4 - al. 1 24a et Aromatisation Aromatisation in expanded ring D is common in steroids 07,96b^ ^^^ nicandrenone (90). Even Nicandra phenolic and the other with

withanolides with B-secosystem were also isolated, eg. (+)-jaborol ' (187). It is observed that aromatisation takes place in ring D in 6 a, 7 o-epoxides and in 5 a, 6 a-epoxides. Nicandra Steroids Nicandra steroids possess a 5^-hydroxy-6 , 7 o-epoxy pattern.

182 Additionally, thoy can bo classified into two types, (a) ring-D aromatic compounds and (b) So^-0H-6a , ? ; 24 a, 25 a-diepoxy lactols. Furthermore, the side chain has been extensively modified to yield such complex structures as in Nic-11 (89) and even with cleaved side chains as in Nic-10''"^^ (94) or Nic-l?-^^^ (92). Several Nicandra steroids are closely related to withanolides (Chart I ) . Among them withanicandrin 90 (63) is the simplest. Their structures were established by X-ray crystallography and by chemical and spectroscopic data. The most important structural modification is the aromatisation of the ring-D in Nic-1 , 10, 12, and 17 . The side chain is also variously modified. The biogenetic relation 107 among these compounds was suggested by Begley et al. (Chart II). The aromatisation of ring-D involves the participation of 18-Me and especially 17 and 14 hydroxyls. found in this group of steroids. A simple and convenient scheme (Chart III) with commonly occurring 17,14-dihydroxy compounds was suggested by L.R. Row for these compounds . The removal of 17-OH gives rise to C-17 carbocation which sets forth a series of rearrangements involving the intermediate 17-18 cyclosteroids giving rise to expansion of ring-D into a benzenoid ring. It is, of course, possible to visualise other schemes, but the scheme suggested has the merit and involves common reactions well known to occur biogenetically. Withanolides - relation with physalins Physalin A^ (89), B " ' ^ ^ (190) and C"^^^ (191) were first reported by Matsuura et al. from Physalis alkekengi in 1969 and they estblished their structures beyond any ambiguity by X-ray analysis and also by chemical and spectroscopic study. Chemically, they are also related to ergostanes and bear resemblance to withanolides. The physalins are 13,14-secowithanolides with a bicyclolactone system in the side chain. (Table 1.0) T ^ al. - 154-156, 22 have ^ - 1 4 . ^ several n new physalins u Row et isolated from P' angulata and P- lancifolia . They are physalins D 154 (192), E 1 5 5 (193), F 1 5 6 (194), G^^ (195), H^^^ ^^^^^ ^ ^22 ^^^^^^ 156 (3^93) ^nd K^^ (199). The structures of the above were Crombie presumed that the aromatisation involves the 16-hydroxyl which is not commonly

183 CilART - i BIOGENETIC RELATION OF NICANDRA STEROIDS TO WITHANOLIDES

6H

Nic -3 (71)

OH

Nic -1 (90)

H Nic-17(92)

O Nic -12 (93)

O Nic -10 (94)

184 Chart -11 Biogenetic Scheme ( Begley ct al) 1^7 ( for aromatisation in ring - D involving C - 18 methyl ) R

185 Chart - HI Biogenetic Scheme (L.R. Row ) 1^1 ( Ring - D aromatisation )

(O)

186

TABLE la
PHYSALINS AND THEIR PHYSICAL CONSTANTS

Compound

m.p.

[a

1 ,

Source

Ref

P h y s a l i n A (189) P h y s a l i n B (190) Physalin C Physalin D Physalin E Physalin F Physalin G

266OC ( A c e t o n e ) 262C (MeOH) 25OOC ( A c e t o n e ) 271C (MeOH) 274-277'C 262-263OC 305-307OC 295-296OC 295-296C 238-240C 305-306
(MeOH)

126

P.alkekeng1

var

franchelli

20 152 153 154

150

-do-doP. minima P. angulata a n d P. (Leaves & Stems) -doP. P. lancifolia angula(Stems1 -doanc fo

191) 192) 193) 194) 19s 1

EtOAc)
EtOAc)

-160

68 83
20

MeOH )

155
156 22
155

17

P h y s a l i n H (196) P h y s a l i n I (197)

(MeOH)

12

22

TABLE lo ( Contd.)

PHYSALINS AND THEIR PHYSICAL CONSTANTS

~

Compound

m.p.

[I,

Source

Re

Physalin J (198) Physalin K (199) Physalin L ( 2 0 0 ) Physalin N (201) Physalin 0 ( 2 0 2 ) Physalin P (203 Epidihydrophysalin C ( 2 0 4 ) Physalin (205)

268-270C 280-282C 248-249OC 252-54C 272-73C

60

P.

angulata 8 P. l a o c i f o l i a

156 22 157 158

-- 118 124 115

P . a n g u l a t a leaves

P. alkekengivar. franchelli

-do-do-

158
159 47
160

* *
270-274C

* *

-doWit h a r i n g i a c o c c u l o l i d e s
P . minima

--

187

188
O Phvsalins

O^ /P

Physalin A ( 1 8 9 ) ; R = OH PhysaliiiC(191);R = H EpidihYdrophYsalin C ( 2 0 4 ) ; PhysaliiiO(202)R = OH, 25 pn - dihydro Physaiin L (200 ) AJ. 2,3-dihydro

-24,25-diVdro

Physalin B ( 190 ) , K> PhvsalinD(192); 5 a - O H , 6 p - O H Phvsalin E (193 ) ; 5 a - O H , 7 a - O H PhysaUn F ( 1 9 4 ) ; 5 p , 6 (5 - cpoxy Physalin G ( 1 9 5 ) ; A*. 6 p - OH PhysalinH( 1 9 6 ) ; 7 P - O H Physalin I (197 ) ; 5 a - OMe , 6 P- OH Physalin J (198 ) ; 5 a , 6 a - epox> Physalin K ( 199 ) ; 4 a 5 a - epoxy - 6 a - OH PhysaUn (205 ) ; A4,6-OH

CH2 Physalin IS ( 2 0 1 ) physalin P ( 2 0 3 )

189 established on the basis of chemical and spectroscopic evidence. Epidihydrophysalin 4 , and a A ,

These are all derivatives of physalin B (190). 47 C (204) from Witharingia cocculolides
1fi0

6-hydroxyphysalin later. Physalin L

(205) from P- minima

have also been reported by Kawai

(200) was isolated from P. alkekengi

1 co

et al. and was shown to be 25-epi~4-dehydro-2,3^25,27-tetrahydrophysalin A. Physalin O (202) (25S) 25,27-dihydrophysalin A and Physalin N (201a) were isolated from P. alkekengi var. franchetti. 159 (203) has been recently isolated from the same Physalin P species. There are several characteristic features of the physalins, A, B and C, in particular. a) b) The lactone between C-18 and C-2 0. The oxido bridge between C-14 and C-17 with a 14 6-hydroxyl and oxido bridge between C-14 and C-27 giving seven membered oxygen heterocyclic system across the ring-C, D to the Y-lactone in physalin B. c) d) 13,14-Seco ring system (C,D rings) with a 13a-hydroxyl. A ketone at C-15. The for biogenesis system of this complex and highly oxygenated These were

steroids (8 rings) containing a minimum of nine oxygen atoms calls an elaborate on the part of the plant. species , not in the other mainly formed in Physalis plants. by Crombie et al. An insight into the biogenetic pathway can be gained from a study Physalis of the structures species. that they of several withanolides cooccurring in They were appropriately named as withaphysalins share the general Solanaceous

A hypothetical biogenetic scheme, (Chart IV) was proposed

characteristics of both 64 64 physalins and withanolides especially withaphysalins A (97), B (114) from P. minima ; 24b pubescens^ physapubenolide (37) from P. {2), C physapubescin (35),

suggesting

The withaphysallins A^"^ (97), B^^ (2) and C"^^"^ (114) share in common with physalins, the lactone (or lactol) between C-18 and C-20 and withaphysalin C is a 13-14 secosteroid with an oxide bridge between C-13 and C-14. It is noteworthy that withaphysalin A 64 (97) carries a 14 oe-hydroxyl while withaphysalin C (114) has

190 Chart - IV

OH OH Withaferin A (12 ) Withanicandrin ( 6 3 )

OH "OH Physlain A ( 189)

191
Q1

143-hydroxyl. Physapubescin (35) has the 24b function whorcas physapubenolide possesses along with 14P-hydroxyl. It has already

rare 15a-acetoxy 15^-acotoxy group remarked

c o

been

that

hydroxyl function is frequently noticed at C-17 and C-20 in several withanolides. corresponding Turkhmenistan. A new withanolide, E occurs physalactone in P. alkekengi (54a) found in

to withanolide

This particular withanolide was shown to possess a (later A structure was

double bond between C-8 and C-14 which might be in fact an artifact from the parent 14a-hydroxywithanolide corrected to 14a-hydroxy compound).
CO

Thus precursor essential formation step

physalactone with to

(54a) start Thus

can the

be

regarded

as

the

ideal an the the the

withanolide prerequisite of physalins.

14a,17a,20B~trihydroxy biogenetic
CO

system, for to

process the key

physalcatone of C-13 and

is C-14

biogenetic process, which is now represented in Chart V. is the oxidative cleavage bond

The key with

formation of 13-methylene, 14-ketone which sets the process to the course as shown in the Chart V Hypothetic biogenetic scheme to withaphysalin C physalin scheme. transient carbocyclic activates C (191) by A E. may Glotter be of the 13,14 (d) Thus is bond shown in 17 o^OH-15-Oxophysalin Odidative precursor which according is (114) to VI. the in a by the 24-25 to

Chart result in of at

cleavage formation from which

should

13a,17a-dihydroxy-14-one (e). frame work

stabilised

14 a,i7 a-hemiketal

rearrangement addition

(d) due by

to the presence

15-one

16-methylene

Michael-type

olefinic bond affords the final product. Withanolide Glycosides Twenty withanolide glycosides have been isolated so far. Adam et al.49 isolated dunawithanine A (206) and dunawithanine B (207), m.p. 213 from the leaves of Dunalis identified (208) al. was on the basis by of A.B. spectroscopic Ray et al. chemical degradation. isolated (Varanasi variety). from P- pubescens australis. evidence from Pas They were well as

Physalolactone B-3-0-3- (D)-glucopyranoside peruviana

Pubescenin (209) was isolated by M. Sahai et 24b (Waltair variety) and it was shown as

la -acetoxy-2 0a -.hydroxy-24 a,25 a-epoxywitha-5-ene-22,26olide-33-0-glucopyranoside.

192 Chart - V Hypothetic biogenetic path of physalins ( L.R. Row ) ^^^

HO^ 5 .R

OH

OAc

OH

OAc

OH

OAc

O
HOL?^R

H^

193 Chart -VI Biogenetic Scheme to 114 & 191 ( E . Glotter^3

Withaphysalin (114)

Physalin C ( 191)

194 Four new withanolide glycosides were isolated australis by Adam et al. very recently. from the 29a Dunalia four

Among

glycosides, three contain physalolactone B as aglycone. Two Very glycosides were isolated from Datura tatura L and

they were named as daturataturin A (210) and daturataturin B recently 28-0-withanolide glycosides

(211). (222)

and G (223) have been isolated from Physalis Withanolide glycosides isolated

eg. physagulins E 1 48

angulata far

so

are

listed

with

their physical constants (Table - Ip) Spectroscopic Studies of Withanolides U.V. Spectra Withanolides containing /N^219-228 nm. 5B,63-epoxides show absorption at

/Nw^ 210-218 nm whereas 5 a-OH-6 a,7 a-epoxides

exhibit absorption at

Withanolides containing 5-enes also absorb similar

to 5a-OH-6ot,7a-epoxides in their U.V. spectra (See Table - 2 ) . I.R. Spectra Withaferin A^ (12), 2,3-dihydrowithaferin A^ (13) and 73 -1 -1 withanolide D (19) exhibit peaks at v 1692 cm , 1695 cm , 1 max 1700 cm respectively due to overlapping of the peaks of two :3-unsaturated six membered ketone in -1 25 ring A is observed at/^'1685 cm . Ixocarpalactones A (61) and
oc 19R 1?7

chromophores.

Generally

B (59), Perulactone (143), Perulactone B (142) contain a saturated-Y-lactone in the side chain which is recorded generally -1 24a at^^-'1770 cm whereas pubescenol (152) exhibits its saturated epoxy- <s-lactone at 1728 cm and its saturated six membered ketone

at 1710 cm""'". (See Table - 3 ) . " * " H NMR Spectra The H NMR spectra (Tables 4a-d) of the polyoxygenated steroids have been diagnostic to derive some basic functionalities present in these molecules. For example an a:3-unsaturated ketone is commonly present in ring A, the others being an a:3-unsaturated< 5 - lactone comprising the side chain, 5 3,6 3-epoxide; 6a ,7a-epoxide etc. The chemical shifts of the 18 & 19-methyls give some specific and C-3 protons of the a : 3-unsaturated carbonyl system information regarding the prsence of 63,73-epoxide or 143-hydroxyl. The C-2

TABLE l p WITHANOLIDE GLYCOSIDES

Compound Dunawithanine A (206) Dunawithanine B (207) Physalolactone B -3 B - 0 D-c,lucopyranoside (208) Pubescenin (209) Duturataturin A (210) Daturataturin B (211) Dunawithanine C (212) Dunawithanine D (213) Dunawithanine E (214) Dunawithanine F (215)

m.p. 208-213'C (Decomposed) 192-195C (Decomposed) Amorphous solid

188-189OC

r a1,
+ o -

Source
Dunalia a u s t r a l i s

Ref.
49

(dried sprouts)
-doP . peruviana P . pubescens 49

+ +

12.5

3.7 38.6 38.1 17.7 15.2 5.7

leaves

162 24b 29 a 29 a 163 163 163 163

195

Amorphous Amorphous Amorphous Amorphous Amorphous Amorphous

Datura t a t u r a L

-doDunalia a u s t r a l i s

-do-

+ 12.3

-do-do-

18

TABLE

I p ( Contd.

196

WITHANOLIDE GLYCOSIDES

Compound Datura metelin A (216) Datura metelin B (217) Datura metelin G-AC ( 2 1 8 ) Sito indoside IX (219 ) Sito indoside X (220) Physagulin D Physagulin E Physagulin G TA TA 221)
222)

r Ol0
Amorphous Amorphous Amorphous

S.ource
Datura m e t e l
L

Ref. llOa 110

llOb
164 164

22.4 1.4 48.4

-do-doY. s o m n i f e r a

* *
A white powder A white powder A white powder
. (

* *

-doP. a o g u l a t a

+ +
+

21.0
56.7

77

leaves

&

stems berries
148 148 48 48

P. a n g u l a t a

223)

31.3

-doT . ano.valum

a (224) b (225)

* *

berries

-do-

Not available

197 Fig. Ip. Withanolide glycosides

OGIc

OH Dunawithanine A ( 206 ) ; Ri=Glc-Glc, R2 = OAc

Daturaturin A (210)

Glc Ri = OH , R4 = H Dunawithanine B ( 2 0 7 ) R, = Glc - Glc , R2 = OAc, R3 = 0H, R4 = H Physalolactone - 3p - 0 Glucopyranoside (208 ) R, = Glc , R2 = OAc, R3 = OH , R4 = H Pubescinin { 20P) R, = Glc , Rz - OH ,
R3 = R4 = H ,

24a , 25a - epoxy Duturataturin A ( 2 1 1 ) R, = Glc , R2 - OH , R3 = R4 = H , 7a - OH

198 Fig. Ip. withanoiide glycosides

R'O Dunawithanine C ( 212) XYI

o-

HO O OH

XYIO

Dunawithanine D (213 )

HO GIcO XYIO OH O

Dunawithanine ( 214 )

GIcO Glc

HO

OH Dunawithanine F (215 ) GIcO GIcO OH 12-OH HO O

199 Fig. Ip. Withanolide glycosides

OH

Daturametelin A ( 216 )

Daturamctclin B ( 217 ) r-0-6'

DaturameteUn G - Ac ( 218 ) Physaguiin D ( 221)

OHoH Physaguiin E(222) Physaguiin G ( 223 ) 16P,17p-epoxy

Sitoindoside IX (219)

Sitoindoside X (220)

200 TABLE 2

U.V. SPECTRAL VALUES OF SOME WITHANOLIDES Compound Withaferin A (12) Withanolide D (19) Bands observed at ( x max 214 nm (e, 17,500) over-lapping of tv70 chromophores 217 n^ (e, 19,500) over-lapping of two chromophores ( :^ unsaturated ketone in ring A, a: 3 -unsaturated- o-lactone in side chain) 210 nm (e, 10,000) 215 nm (^, 17,500) 225 nm (e, 9,600) 216 nm (e, 16,000) over-lapping of two chromophores 214 nm (e, 9,500) 214 nm ( e , 9,500) 71 73 ) Ref.

2,3-Dihydrowithaferin A (13) 27-Deoxywithaferin A (3) 2,3-Dihydro v/ithanolide D (224) acetate 27-Deoxy-14-ot-OHwithaferin A (14) 24,25-dihydrowithanolide D (20) 43~Hydroxy-l-oxo-56,63 epoxywitha-2-enolide (5) Ixocarpalactone A (61)

71 65 73 72 65 65

218 nm ( ^ , 8,200) 218 nm ( e , 8,300) 212 nm 224 nm (log ^4.19) 223 nm {^, 14,000)

25 25 24a 35 16a

Ixocarpalactone B (59) Pubescenol (152) Lycium substa,nce B ( 62) 5a,20a^(R)-dihydroxyr

l-oxowitha-2,24dienolide (73) Withastramonolide (82) 219 nm (log e , 4.28) 101 66

27-Acetoxy-5 a-hydroxy221.5 nm ( ^ , 16,400) l-oxo-6a,7a-epoxy-22Rwitha-2,24-dienolide (69) Nicalbin A (83) 225 nm {^, 9,900)

93

201 TABLE 2 ( Contd. )

U.V. SPECTRAL VALUES OF SOME WITHANOLIDES

Compound Nicabin B (66) Withanolide G (107) Withanolide H (120) Withanolide T (81) Isowithametelin (139)

Bands observed at ( x max 225 nm (e,9,750) 223 nm (e,19,400) 220 nm (G,17,200) 224 nm (e:/18,000) 233, 227 Sh (.13,000) 222 nm (e,7,000) 225 nm (e,8,500) 226 nm
218 nm (G/16,318)

Ref. 93 111 111 100 126 126 127 34 125 150a,b

Withametelin (138) Perulactone B (142) Nicandrin B (76) Daturilin (138) Jabarol (Unusual Phenolic withanolide (187)

(MeOH) 224, 281, 291 nm (log A,29, 3.51, 3.34) (MeOH + OH ) 224, 282, 301 nm (log E' 4.3, 3.51, 3.41)

202 TABLE 3

I.R. SPECTRAL VALUES OF SOME WITHANOLIDES

Compound Withaferin A (12) Withanolide D (19) 2,a-Dihydrowithaferin A (13) 27-Deoxywithaferin A (3) 2,3-Dihydrowithaferin D (224)-4-acetate 24,25--Dihydrowithanolide D (20)

Peaks observed at (cm 1692 1695 1700 1690 1738 1730 1681

Ref. 71 73 71

(a:B-unsaturated six membered ketone) (a:3-unsaturated-6-lactone) (Saturated-6-lactone) (a:3-unsaturated six membered ketone) (Saturated-6-lactone) (a:B-unsaturated six membered ketone) (Saturated-Y~lactone) (a:3-unsaturated ketone)

65 73 65 65 65 65 25 25 25

^ . 0 -Hydroxy--1-OXO-5 B, 63 epoxywitha -2-enolide (5)

1703 1681

Ixocarpalactone

A (61)

1770 1675

Ixocarpalactone B

(59)

1685 1735 1775 (acetate) (Saturated-Y-lactone) (Saturated-Y-lactone) (acetate) (Saturated-Y-lactone) (fit:3-unsaturated six membered ketone) (a:3-unsaturated six membered ketone -do-

Perulactone (143)

1762 1732

128

Perulactone B (142)

1770 1680

127

Nicalbin A (83) Nicalbin B (66)

1685 1685

93 93

203 TABLE 3 ( Contd. )

I.R. SPECTRAL VALUES OF SOME WITHANOLIDES Compound 2,3-dihYdro-27-deoxy withaferin A (11) 2,3,24,25-Tetrahydro-27deoxywithaferin A (10) Lycium substanceB (62) Peaks observed at (cm 3400, 1715, 1697 3420, 1730, 1705 3450 (OH), 1705 (unsaturated-6lactone, 1690 (0:3-unsaturated six membered ketone) ) Ref, 65 70 35

Withaphysalin C (114) Acnistin E (60)

1712, 1685 1675 1730 ( ' :P-unsaturated ketone) (lactone carbonyl)

113 42

Daturalactone A (64)

3590-3500 (-0H), 1730 (Saturated-S -lactone); 1690 (a:3unsaturated six membered ketone) 1655 1730 ( a :3-unsaturated ketone) (lactone carbonyl) (-0H); 1745 (Y-lactone) ( o t : 3-unsaturated-Y-lactone) ( a :3-unsaturated ketone)

91

Acnistin A (58)

42

Withaphysalin E (144)

3460 1690 1655

129

Daturilin (138) (+) Jaborol (Phenolic withanolide) (187)

1650, 1680, 1720, 1125 3400 (-0H); 1700 (12-ketone, six membered saturated ketone) (Lactonic carbonyl) (2,5-di-en-l-one) (Carbonyl)

125 150a,b

1690 Withametelin (138) 1655 1718

126

204 with a 1-keto group are characteristically withaferin A (12) . (46). In a compound with noticed at/xJ6 6.18 the as C-3

doublet and at r ^ 6 6.79 as d/d in compounds having 4-hydroxyl as in no 4-hydroxyl proton appears a little upfield at around withanolide E 6.6-6.9 as d/d/d as in

Of the 5,6-epoxy derivatives, except for two, the rest are 5B,63-epoxides. doublet. epoxy The 6a-H generally appears as a broad peak at around 6 3,20 and the 63-H slightly at lower field at/^'6 3.3 as a The chemical shift difference of this proton in isomeric is too small to distinguish the exact However, using high resolution 500 C-7 was and comparing Altona A them larger with , the the compounds

stereochemistry of 5,6-epoxide. with the methylene constants of protons at

MHz NMR spectra to observe the coupling constants of 6H ( a or 3 ) coupling calculated 5,6-epoxide from equation

stereochemistry,

decided.

coupling

constant 4.5 Hz (calcd. 4.9 Hz) has been noticed for 5a,6a-epoxide for 6 3-H and 7 3-H while a smaller coupling constant 2.7 Hz has been noticed for 5 3,6 3-epoxides for C-6a-H^ and C-7o-H^ coupling. In the case of 6,7-epoxides, except for an isolated

example, all the rest are 6a, 7o'-epoxides. have two protons the 6-H field. The chemical shift of the doublet and the latter as d/d.

The epoxides in general

and 7-H, around/N/ < 5 3.0, the former as a Of these the 7-H, appears at lower

19-methyl

is

subject

to

the

influence of 5,6- or 6,7-epoxides -1-keto system in ring A. In

as well as the presence of the the case of 6 o t , 7a-epoxides the

4 3-hydroxyl and the presence of a:3-unsaturated system or saturated 19-methyl generally comes around 6 1.20 while the same comes around 6 1.30 in 53,63-epoxides because of the deshielding influences of the 63-epoxy oxygen on the 19-methyl in the latter. with 19-methyl moved downfield to 132 63,73-epoxywithanone (186) with 6 3,7 3-epoxy system. The C-6H. configurational of benzene assignments to of this the In agreement 6 1.32 in

53,63-epoxides of

and of

5a,6a-epoxides are decided by solvent induced chemical shifts Addition CDC1-. solution (-5 causes a negative shift on the 19-methyl

5 3,6 3-epoxides

Hz) and a positive

shift (+11 Hz) on the same in the case of isomeric 5a,6a-epoxides. The shift of 19-methyl is more pronounced in pyridine where it moves from 6 1.32 to 1.69 with 53 ,6 3-epoxide as in

205
o|

physapubescin pyridine for from in

(35). Similar strong deshielding was noticed in 132 6 3/70-epoxywithanone where the 19-methyl moved Thus the solvent induced shifts, in particular, of

1.32 to 1.69 but in its 6a,7a-epoxy isomer the shift is just pyridine form diagnostic evidence for the stereochemistry

marginal 0.07 ppm.

the 5,6 and 6,7-epoxy systems. The chemical shift of 18-methyl is also affected to some extent by the presence or absence of hydroxy groups at C-17 and C-14. at In the absence of of both it appears at 6 0.75; with 17a-hydroxyl it comesr^'^O .85 and with 17- and 14 a-dihydroxy system 6 0.95. The presence a 143-hydroxyl lowers its chemical
1 no

shift very much to < 5 1.16 as in 14B-hydroxyl withanone (85). The pyridine induced shift noticed on 18-methyl is much more (-2.4) with 14-hydroxy system. The 21-methyl usually comes around 1.0 without much

deviation even with a hydroxyl at 14 or 17 but the same is very much subjected to solvent induced shifts. The pyridine induced shifts in 14a-0H-withanone 102 (84)

(14a,17a) indicate a significant deshielding effect of 17 a-OH on the signal of 21-methyl but not on that of 18-methyl. been found to with be in agreement to (85) with the relative angle the 18-methyl respect 102 17a-0H (dihedral This has of In of position 150). geometry

143-hydroxywithanone

(143 ,17a-hydroxyls)

the molecule is changed to a cis C/D junction and the effect of the hydroxy groups is clearly felt on both the 18 & 21-methyls with a downfield shift of 0.3 6 ppm and 0.37 ppm respectively in pyridine. The appearance of two methyls on double bond as two

singlets between groups of the around <5i,45.

6 1.85 and 2.0 account for the 27 and 28-methyl system. In the presence around

a : 3-unsaturated-<5-lactone

of an epoxide (24,25) these methyl groups move upfield and appear These two methyls, however, appear upfield ^ 1.2 in the example of having saturated five membered-'^-lactone or a spiro system 25 . In a fair number of examples either of these methyls may be missing to be found as hydroxymethyl which can be diagnosed easily. Another characteristic proton that appears around 6 4.60

generally as d/t is that of C-22 H. a multiplet.

It varies from 6 3.9 to 4.6,

In the case of 5,6-enes, the 6-11 can easily be located at 6 5.6 as

TABLE 4a H ' N M R SPEC'IRBI. DATA OF 5,6-EPOXIDES

Cn-puru

206

2-n

3-ii

4-H

6-ii

22-.2

1u-ri3

19-r13

21-H3

27-33

26-113

Other chsr,ps

58,66-Cpcxides

i;itrefcrin A Withanclide 27-&c:;ywitha-

6.16~ 6 . 9 7 c . d (10) (1O.i) t j . 2 1 d

(1U)

3.75d (6)

3.20~ 4.40dt (Wlw4)

2

0.68s

1.38s

0.97d (7) 1.27s

4.35Lrs 2.03 ( ! . l e t h j r l e n e )
1.91
Trrc

--

6.97dd (lU,6) 7.08dd (10,6)

3.77u 3.25 4.25dd (6; (;Jiy4) 3.76d (6) 3-23 4.37dt ( W j 9 4 ) (12,3.5)

0.85s 0.68s
0.70s

1.41s

aethjrls

ieric A (3165

6.206 (10)

1.39s 0.98d (6)

Twc methyls

1.91

-4.41
4.37 ( 2 7 C & OH)

2,3-dihydrc71 withaferin A (13) 2,3-dihydrc-Jabcrcsalactcne A (9169

Jab? csalactcl M (50157

---

----

3.55t 3.18br 4.40dt (3.5)

1.32s 1.01d 2.09 (6.8) 1.16s 0.97d (6) 1.21s 0.97d 1.25s 1.42s 1.25s 1.29s 1.93s 1.92s 2.03s

----

--

4.42dt 0.67s ( J 2 2 , 2 3 ' 3 H z , (J22,20=12Hz) 1.10s 1.10s 0.98s

(27-CF12 OH)

--

3.22d 0.04d (3) (12,4) 3.20 4.88~1

1.40
1. 88s

3.56d(11),26-OH; 4.99d(11),26-2

Withanclide E (46Iasa

6.03dq 6.87dq
(10)

--_

E 6.03dd 6.86dq -(10,2.7) (10,6, 2.5)

3.20m 4.56dd (Wr6) (12,4)

1.88s

Ccupling ccnstants in parenthesis.

TdBLE

4a ( Ccntd. 1

H ' NMR SPECTRAL DATA OF 5,6EPOXLDES

Ccmpcund Physagulin C (in Bgridine)

(52)

2-H 6.4d (9.8) 6.19d 6.28 6.18d (10)

3-H 7.26dd (9.8,6.2) 6.92dd 7.05 6.95dd (10,5.5) 6.95dt (10,6)

4-H 3.96d
(6.2)

6-H

22-H 4.43m

18-H3 19-H3 21-H3 27-H3 1.26s 1.78s 0.99d (7) 1.38s 1.47
1.02s

28-H3 1.87s

Other charges 2.09~,15-CH CO 5.21s,1 5 1 5 ~ 3.72~,16-E 4.50,16-H; 4.47d,23=& 4.48,16-& 4.97d(4.4), 1% -g; 1.99s ,CH,CO 2.10 (acetate) 4.82dd( 9,2), 7 a -g

--

1.68s

Ixcc2fpalactcne A
(61)

6.73d 3.24 4.66 3.23

3.96s

1.15s 1.06 1.11s 0.88s

1.43s 1.41 1.40s

1.23s 1.18d 1.87s 1.92

1.17s 1.21d 1.94s 2.12

Ixcc palactcne B (59)

If

4.14

Phys3gibenclide ( 3 7 )

3.79d 3.36m 4.32dt (5.5) (W; 4 ) 3.75d (6) 3.33d

(2)

6.20d 7 8 - Acetoxy- 45, 20B-dihydrcxy-56, (10) 6 3 -epcxy-1-cxcwitha2,24-dienclicie (33)79

5 a, 6a-Epcxides

4.18dd (12,4)

1.40s 1.27

Wi thanrlide Y (184)

Salpichrclide A (19515'

5.98dd 6.72ddd 1.93dd 3.36d (10,3) (10,5,2.5) (20,5) (5) ( 4 . & H ) , 3 103t (?0,2.5) ( 4 8-g) 6.0ddd 6.77ddd 3.14ddd 3.24d (10.1, (10.1.5, (19.4, (4.9) 2.8,l) 2.5) 2.5,Z.B) (46-g)

4.51dd (13.5,3.5)

0.83s

1.33s

1.27s

1.87s

1.94s

3.9lddd( 11,5, 5 ) , 7-g 1.98ddd (12,12,5), 8 E axial 6.99d(8),15a -E; 7.12dd(8,1),16-2; 6.90d(1),17-3; 4.99d(9.5),26-Z; 3.40d(9.5),26-%

3.84ddd (11.3,5.6, 2.6)

--

1.38s

1.24d (7)

1.37s

1.35s

207

TABLE 4b H ' NMR SPECTRAL DATA OF 5u-HYDRoxY-6,7-EwxU)Es

Compound 2-H 3-H 6-B 7-H 3.32brs 22-H 18-H3 19-H3 21-H3 1.19s (6.7) 1.18s 1.03d 27-H3 28-H3 Other g r w p s 1.95s 1.89s

208

Lyciun substance B 5.86dd 6.60ddd 3.05d (10.1,2.2) (10.1,5.0, (3.7) (62)35 2.2) 5a,2CilF(R)5.86d d (10,3,1) Dihyarcxv-Fa,70epoxy-i-o::rvi tha2,24-dienclide(73)16a Withastramonclide (82)lo1 12-Oxowithanclide 5.84dd (10,Z.l) 5.85d
(10)

4.39dt 0.77s (13.2,3.4) 4.26dd (1234) 0.95s

---

6.61dd 3.05d (10,4.5,3)

3.33dd (4,l)

1.31s

1.93
Two methyls

6.61ddd (10,4.9, 2.1) 6.6Ad !-d,4.5, 5.2.2.4)

3.04d (4) 3.08d (4) 3.05d (4)

3.32dd 4.44dt 0.78s (3.7,1.8) (13.4,3.3) 3.42d (4.1) 3.28dd (4,l) 4.551~ 1.1s

1.18s

1.10d (6.1) 0.9d (7) 1.31

-1.52s

2.05s 4.04brs(WtN6), 12-H; 4.38d(5.6),27-CH2 1.58s

1.26

---

2,3-Dihydrc-5Q, 20aF(R)-dihydrcxy 6 a,7o-epcxy-l-cxcritha-2,24-dienclide (234)16a Withancne ( 6 8 ) 66 5.81dd (10,2.3)

4.21dd (12,5)

0.95s

1.20

1.91 Two methyls

3.06d 6.60ddd (10,5,2.3) (4.1)

3.34dd 4.64ddd 0.86 (3.8,1.6) (12.3,4.6, 4.0) 3.32dd 4.70ddd 0.97 (3.8,1.6) (10,6.8, 2.6)

1.18

1.03d (6.3)

1.88

1.93

2.69brd(18.7),4-xaxial; 2.53dd(18.7, 5.3), 4-Heq; 2.41111, 20-g 2.68brd(18.7),4-Haxial; Z.Xdd(18.7, 5.3),4-Heq;2.4n,ZO-H

14a-hydrcxy- 102 withancne (84)

5.85dd (10,2.3)

2.98d 6.64ddd (10,5,2,3) (4.1)

1.20

1.08d (6.3)

1.88

1.94

TABLE 4b ( Ccntd. ) H ' NMR SPECTRAL DATA OF 50-HYDROXY-6,7-EF'OXU)ES

Ccmpcund 146-hydrcxywithancne ( 85)lo2 2-H 5.86dd (10.6, 2.6) 3-H 6.61ddd (10.5,5.2 (2.4) 6-H 3.04d (3.8) 7-H 22-H 18-H3 19-H3 21-H3
1.18

27-H3 28-H3 Other grcups 1.89 1.95 2.67brd(19.0).4-Haxial; 2.59dd' (19.2, 5), 4-11dd; 2.67~1, 20-11

3.78dd 4.71ddd 1.16 (3.8,1.6) (12.9,4.4)

1.05d (6.3)

Nicandrin B ( 7 6 ) 3 4 5.83dd (10,2.5) Daturalactcne-3 (75197 Nicalbin A ( 8 3 ) 9 3 5.86dd (10.1,Z) (5.82dd (10,2.5)

6.61ddd 3.04d (10,5,2.3) (4) 6.61ddd (10.1,4.8, 2 ; 4 ) 6.62ddd (10,5,2.5) 3.06d (3.7) 3.04d (3.5)

3.37dd (4,1.7) 3.33d (3.7) 3.26dd (3.5,1) 3.27dd (3.5,l)

4.40~

0.747s 1.17s 1.18s 1.18s

1.09d (6) 1.18d (6.7) 0.93d (7)

1.94s 1.95s 1.42s 1.43s

1.88s 4.02~, 12-02 1.88s 3.55dd (10.4, 4.61, 121.40s 4.18t, 16-11; 5.08s, 26-H 26-11 1.36s 3.98dd-(7.5, 4.5), 16-H; 5.02~,26-g; 1.81dd (10, 7.51, 17-11; 1.59~,2 0 g CH-CO-2.15;5.538 (Zj, 23-11

4.49ddd 0.77s (13.1,3.4, 4.6) 3.97dt 0.76s 3.57t (6.5) 0.82s

Nicalbin B (66lg3 5.83dd (10,2.5)

3.03d 6.59ddd (10,5,2.5) (3.5)

1.17s 1.03d (6.5)

Withanclide R 95 5.85dq (as acetate) ( 7 0 ) (10,5,1)

I a, 36,,50-trihydrcxy-6a ,7aepcxy-witha-24enclide (as 66 acetate) ( 8 0 )

3.05d 6.56dd (10,4.5,3) (4) 5.52 cctet 2.97d (4)

4.73dd (3.5,2) 4.41dt

0.80s 0.75s

1.17s 0.93d (7) 0.85s 1.01d (7)

Twr methyls
Twr

1.97

--

1.92 3.68,1--2;2.05, methyls acetate

66,76-epcxy 132 5.83d withanone (186) (9.4)

6.61m

3.728

3.7910

(4)

4.64m

0.86

1.32

1.07d (6.3)

1.86

1.96

3.19brd(19.5), 4 1 1 6-axial; 2.15dd (19.2, 5.0),4-gdq)

209

210

Ccmpcund

2-H

3-H

4-H

6-H

22-H

18-H3 1.05s

19-H3 1.25s
1.22s

21-H3 1.30s

27-H3 1.91

28-H3

Other grcups

6.76dd -Withanelide G (107)11'5.83dq (10,391) (10,5,2.5)

5.60 4.21dd (Wtw 8 ) (10,6.5)

Two methyls

---

Wlthametelin (138)lZ6 5.88d 6.77dd 3.30dt 5.58t (9.8,2.5) (9.8,5.1, (20,2.5) (5.8) 2.5) 4Pi; 2.80dd (20,5.1), 4 0 1 ! 7a,27-dihydrcxy-l5.99dq cxc-witha-2,5,24trienclide (as acetate) (103)66 Withanelide'U (as acetate) (123) 6.05d (10) 6.83dq

4.65brs 0.71s (Wyd 8.8)

3.95d(12.7)6.76brs 1.44s (12.7) 6.02brs 3.73dd (12.7,3.0) ( 2 l-CZ2) 1.05d (7) 4.90s 2.07 (27-Cl&,)

5.86

4.48dt 0.73 (12, 3.5)

1.26s

2.07 (acetate)

6.75dd (10,4.7) 6.76 (10,5)

5.78d (4.7) 4.62d (5)

6.15 (Wp4) 5.78d (1.5)

4.25dd (10,6.5) 4.22dd (12.5,4)

1.08s 0.91

1.41s

1.30s 1.28

Twc methyls

1.91

2.10 (acetate) 3.85d(6), 7-3

20K, 22R-4 B, 76, 5.92d 20-Trihydrexy-1-cxc- (10) 24-trienclide ( 1 2 2 ) " 6

1.44

1.87

1.93

48,17,27-trihydrcxy- 6.15 l-cxr-22R-witha-2,5, (10) 24-trienclide112

6.70 (10,6)

5.79 (6)

6.10t (2.0)

4.65

0.86

1.47

1.07

--

2.07

4.39, 27-CZ2;

TABLE 4c ( Ccntd. ) H N!lR SPECIRBI, DATA OF 5 =

Ccrnpcund
78 Withanclide N (as acetate) (106)

2-H 5.90dq

3-H 6.83dq

4-H

6-H 5.62t

22-H 4.66dt

18-H3 1.03

19-H3 1.25

21-H3 1.05d

27-H3

28-H3

Other grcups

-6.08dt
(10)

-1.87

2.07 4.93s, 27-CX2; 2.07, acetate; 5.25, 15-11

Withanclied I (111)11 Withanclide K (121)l Iscwithametelin ( 1 3 9 ) l Z 6

---

5.62dt
(10)

5.71t

4.25dd

1.07s

1.40s

1.30s

1.94

----

(11.5,4.5) 5.70 4.66dd (10,5) 1.07s 0.68s 1.3% 1.33s 1.32s 1.88 1.95 1.42s

5.64dt (10)

6.08dt (10) 6.02dd (lo,,?.5)

2.72dd 5.58dt (20,5), 2-H(10,5) 3.28d ( 201 2 J

5.62dd 4.63brs (5,2.5) (Wt@lO)

3.7dd 5.99s (13,2),1-H; 27-H; 3.89d, (13T, 6.73s. 1-I! 27-& 1.25 1.89

36 ,2G0 -dihydrcxyI-cxcwitha-2,24117 dienrlide 10,36,23trihydrcxy-l-cxrwitha-2,24-dienclide (125)7

---

3.87 (Wfrv19.5) 3.99 br.cctet

---

5.62

4.22

0.89

1.29

Twc methyls

1.95

5.58 4.23dd (WfN9.9 ( 13,3.6

0.87

1.03

1.25

1 . 8 ;

Twc methyls

1.96 3.84 (Wd7.2), f 1-26

211

TABLE 4d H ' NMR SPEC'IRAZ. DATA OF 1NTEKi.WJATE

DERIVATIVES

212

Ccnpcund 2,4,6-trien-l-cne (151)~~~ Withaphysalin E ( 144)lZ9 Jabcrcsalactcl Withaminimin (164)

S

2-H 5.97d (9.3) 5.96d (9.7)

3-H 6.99dd (9.4,6.5) 6.9dd (9.7,6)

4-H

6-H

22-H

18-H3 19-H3 1.30s 1.48s 1.49s 1.21s (7)

21-H3 27-H3
1.20s

28-H3
~ ~ ~~

Other grcups 6.30dd,(10,2.9),7-g 2.74brd(12), 8-g

5.97d 5.86dd 4.22dd 1.15s (5.3) (9.4,1.8) (13.2,3.8) 6.14d 4.54t (6) (3) 4.60dd (13.4,3.6)

1.89 1.88s

1.95 1.96 1.40s

-1.18s 1.16s

1.52s 0.96d (7) 1.12d

-5.0d(11),26-H; 3.56d(11),26-g

6.Oldd 6.92dd (9.5,l) (9.5,6) 5.87dd 6.58ddd (10,2.5)(10,5,2)

6.14dd 6.42brs 4.07~ (6,l) 3.19dt 3.60brt 4.34ddd (20,2.5) ( 2 ) (12,7,4) 48-2

Twc methyls

1.87brs

1.98brs 5.33d(2.5),15-H; 5.60brd(2.5),16-g; 2.53m,20-g; 2.31dd ( 17,4), 23%; 2.01s, 1 5 O & 1-97s

2.1) 23-Hydroxy-physalc- 5.90dd 6.55dd lactcne C ( 1 8 0 ) ' 4 7 (10.2,2)(10.2,2.5)

Physalclactcne C (169)141

5.9dd
(10.2,

6.55dd (10.2,2.5)

5.00t 4.391~ 4.76dd (2.4) (12.6,4) 4.99dt 4.3810 (10.3,

2.5)

1.06s

1.22s

1.38

1.85s

-4.34d (8.5), 230g;

4.67d (8.5)

1.04s

1.22s

1.35s 1.85s

i.97~

5a,17a-Dihydrcxy- 5.91 l-rxcwitha-2,6,2466 trienclide (151) Pubescencl (152)24a

6.66

4.2801

5.72~1 4.63dt

0.85s

1.21s

1.04s (7) 0.84d (6)

1.90
Twc methyls

--

--

--

--

4.38m

0.68s

0.91s

1.45s Twc methyls

3.64m,7-11;5.33d, 4a-OH; 4.31111, 7a-OH

TABLE 4d

( Ccntd.

1
DWIVATIVES

H ' NMR SPECTRAL DATA OF DEEiWEDIA'lT

~

Ccmpcund
6a-Chlcrc-4 0,5 6;

2-H

3-H

4-H 5.08m

6-H 4.44dd (12.3, 5.3) 4.53dd

22-H 4.18dd (13.2,3.5)

18-H3 0.81s

19-H3 21-H3 1.22s 1.25s

27-H3 1.87s

28-H3 1.94s

Other grcups

6.OOdd 6.47dd 200 -trihydrrxy-1- (10, (10,2.5) F cxr-22R-witha-2,24- 1.9) 134 dienclide ( 157)

--

Withaperuvin (in pyridine) ( 181)1 4 ' Withaperuvin D ( 168)140

6.28dd 6.89dd

5.77t

5.16dd

1.31s

1.60s

1.78s

1.98s

1.82s

2.37dd 4.46m (18,3*5), 1-11; 2.82d (181, 1 1 !

5.2id (6.5)

4.27d (7.5)

4.48dd (10,4)

1.07s

1.14s

1.40s

1.87s

1.94s

Ccupling ccnstants in parenthesis

213

214
1 f. f.
CDC 1

The

solvent

induced

shifts

on the

25~methyl

in

saturated-6-lactone of lactone system. A fairly chain. 20-hydroxyl withnolide E groups held and in bonding, 18-methyl between (strong on reflected 21-methyl thus has ^'

systems were used

to decide

conformations

large number been

of withanolides According of the to

occur with the

17a-side of

In all these the presence of 14a-hydroxyl, 17B-hydroxyl and noticed. on structure by the E (46) derived by X-ray the a -face the and distances analysis the molecule between 14a,20hydroxy hydrogen and are (46) 1.37, shifts with distance ' to

together

decreasing 17 3-hydroxyl and the

173 -hydroxy1 changes

22-H^ while These of

increasing structural withanolide

20-hydroxyl negative

18-methyl. spectrum shifts and of

pyridine solvent

18-methyl have also

5 1.10

- 61.42 to 1.76 21-methyl

and 22-H; 4.88 to 5 . 1 6 ) . 22-H been

Similar noticed

18-methyl,

40-hydroxy withanolide E ^ ^ ^ ' ^^ (53) (See Tables 4a to 4 d ) .

"*-^C NMR Spectra A followed detailed (Table Kirson by study 5) was and of 13 C by NMR in spectral et 1981. data of various 1 fi8 al. in 1979 ^ ' ^ C NMR data

withanolides

made

Pelletier

Gottlieb-*-^^

The

find useful applications of withanolides. The downfield unambigously and The the two 6132.0 and correspond (13). methyl the lactone chemical to the at

in structural and conformational

analysis

singlets around groups of C-26

6202.0 The

and 6167.0 two

recognise at C-1 around 6 121.0 of A as the lfi8

carbonyl

:3-unsaturated

ketone doublets and C-25

respectively. singlets bond system shifts as to

6 142.0 ppm are of the C-2 and C-3 carbons shift double around in 6149.0 C-24 and carbons

respectively.

: ^-unsaturated the C-24

lactone carbon (12).

2,3-dihydrowithaferin instead of a to 6 153.5 field

The presence of a hydroxymethyl at C-25 lower

simple in

withaferin A Next carbons The C-6 and in C-7

order, to an carbons

the of

carbons

easily a

recognisable or an compounds (62)

are can

the be and

connected

epoxy

oxygen,

hydroxy1

acetate. shift

5oi-hydroxy-6,7-epoxy

easily recognised where both come as doublets with a chemical lower than 660.0 ppm for eg. lycium substance B

(56.2

215 57.3) 1 ^ ( C NMR the data more for the C-6 and C-7 carbons system of can only also one be

isolated example of 66,73-epoxy derivative (186) is not available). Similarly, common 53,66-epoxy recognised by the chemical shifts 664.0 as a singlet for C-5 and (12).

662.0 as a doublet for C6 carbon as in withaferin A

The presence of 5a,6a-epoxide has marked shielding effect 52 on C-6 carbon<\^ 4 ppm as noticed in salpichrolide (185). In the case of Nic-2 lactone (91) v/ith an epoxide at

C-24/ C-25 in the side chain-6--lactone, the two carbons 24 and 25 apper at 659.1 and 63.1 as singlets. In the case of viscosalactone A 29a (22) (having 2B,3 3-epoxy

system) the carbons appear at 6 54.9 and 55.8 as doublets. The C. carbon with 43-hydroxyl as in withaferin A in its acetate. C-10 and C-13 (12)

appears at < 5 69.8 as a doublet which shifts to lower field to 672.I The 2 7-carbon with a primary hydroxyl appears at The 6 42.5 carbons come as singlets at 648.O and ^ 57.0 as a triplet which deshields to "Sss.O on acetylation.

respectively, of which the former is more affected by the presence of a functional group in ring A and B. Of the chemical shifts of methyl carbons C-18, C-19, C-21, C-27 and C-28 the chemical shifts of C-18, C-21 remain more or less constant ( 6 11.5 and 13.5). methyl carbons in particular The chemical shifts of the remaining that of C-19 is affected by the

functionalities as well as their stereochemistries present in rings A and B. The chemical shift of C-2 2 carbon with the 6-lactone oxygen is around 6 78.0 in all the compounds. The presence of 43-hydroxyl produces a deshielding effect on C-3 ir^l ^ ^ ' 2 3 ppm) as well as ppm) and shielding effect on C-2 ( ppm by 1,3-dixial effect on C-5 interaction (r^ 3 ppm) of
1 fift

a shielding effect on C-19 hyf^2 ring A produces ketone has C-4 a deshielding by (r03

The presence of 5 3,6 3-epoxy ring, saturation of 2,3 double bond of C-10 (f^3 ppm), and ppm ). The presence 53 ,63-epoxide A similar

Y -effect not only on C-10 but also on C-S^

Y-effect has been noticed on C-9 by 6a,7a-epoxy systems. In the tives, C-5 commonly is occurring a-axial. 5a-hydroxy-6oi,7a-epoxy With 53-hydroxyl derivais cis

appears

around

73.0 where the ring

junction A/B with A/B

trans and 5-hydroxyl

TABLE

216

13C NMR DATA OF W I m O L I D E S Carbrn

Nr.

2,3-dihydrr Witha- Witha17-1sc Withawithaferin A nclide D ~ ~ A nclide ~ E nclide ~ (12)168 (19)168 202.2 132.5 142.2 69.9 64.0 62.1 31.1 29.1 44.1 47.7 21.7 39.6 42.7 56.3 23.8 21.9 54.6 13.5 17.1 75.1 20.7 80.9 31.4 149.1 121.9 166.2 12.4 20.5 (11)168 211.5 31.6 26.2 72.8 66.7 58.5 29.6 31.4 43.1 50.4 21.3 27.2 42.6 56.2 24.2 39.0 51.9 11.5 15.2 38.8 13.4 78.3 29.4 149.1 121.9 167.0 12.4 20.5
( 4 6 ) 1 6

Ixccarpa ~ lactcne A ? (61)25 202.0 132.6 143.2 73.0 64.1 61.2 31.2 29.0 44.2 48.1 21.3 40.0 43.3 54.5 37.2 70.0 57.6 14.1 16.8 79.5 22.1 73.2 78.9 41.9 40.3 181.6 14.5 13.0

( 3 4 ) 1 6

2,3,24,25Ixrcarpa Physapube- Physapube- Viscrsa Tetrahydrclactrne ~ ~ n nrlide lactcne A 27-derxy (acetate) withaferin A (59)25 (35I8l (37)24b (22)23 201.2 202.5 134.0 132.2 143.2 139.9 72.2 69.7 61.1 63.6 60.1 61.2 31.0 30.4 29.2 28.9 44.3 43.7 48.3 47.6 21.4 20.7 39.4 39.5 42.8 42.9 54.4 58.8 33.7 76.2 37.0 75.2 62.5 5C.2 12.7 14.9 17.0 15.6 74.9 38.4 12.6 27.0 71.9 65.1 107.6 29.5 64.1 49.3 42.4 63.6 177.6 91.7 13.9 16.6 12.2 1 8 . 8 AcO 20.7 AcO 21.4 170.1 171.1 202.6 131.1 143.5 69.6 63.4 62.7 26.1 40.3 36.1 47.9 21.8 41.4 46.1 84.1 80.8 33.6 52.3 15.6 17.2 37.5 17.2 78.5 31.2 149.5 121.9 166.8 12.4 20.5 AcO 21.5 169.8 206.9 54.9 55.8 74.6 64.0 59.6 29.6 31.0 42.7 48.6 20.0 27.3 42.7 56.1 24.3 40.7 51.9 11.5 14.5 38.9 13.3 78.7 29.8 153.8 125.8 167.4 57.2 20.1 211.6 31.6 26.2 72.8 66.7 58.5 29.4 31.4 43.0 50.4 21.2 27.5 42.6 56.1 24.2 38.9 51.9 11.5 15.2 38.2 12.7 80.0 29.2 27.2 38.9 176.2 12.0 18.1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 1 8 19 20 21 22 23 24 25 26 27 28

202.3 132.3 142.5 69.8 63.9 61.7 29.8 31.1 44.0 47.8 21.8 27.2 42.5 56.0 24.2 39.2 51.8 11.6 17.0 38.7 13.3 78.7 29.8 153.5 125.6 167.0 57.0 20.0

203.2 129.8 143.9 32.9 62.2 64.2 26.2 34.1 36.9 48.6 22.9 34.3 54.5 82.3 30.1 37.7 87.8 20.6 14.6 80.0 19.5 80.3 32.5 151.1 121.4 166.6 12.3 20.6

129.7 144.0 33.0 62.1 64.1 25.8 33.3 37.1 48.6 21.9 26.5 50.7 85.3 33.3 32.7 90.9 19.2 14.8 76.2 21.6 81.4 31.6 150.9 120.9 164.8 12.3 20.7

TABLE 5

( Ccntd.

13C NMR DATA OF WITHANOLIDES Carbrn

Nr.

Lycium Withanone substan B ( 6 ~ ) ~ ~ (68)lo2

14wOH 14b-OH Witha- Witha- DaturaNical- Nical- 5a-OH withancne witha- nican- fercxc- lactcne C bin A bin B -6-ene ncne drin lide

Nicandrencne (Nic-1)

( 8 4 ) " '
203.5 127.8 141.1

(85)102 (63l3I (76)31

203.6 127.8 141.2 72.6 53.1a 53.7a 30.8 50.6 21.5 34.3 52.4 83.5 31.6 83.1 16.8 13.8 41.6 10.0 78.4 32.9 151.9 119.9 166.1 12.1 20.1 203.1 202.1 128.8 128.9 139.6 139.8 36.7 36.8 73.2 73.3 56.2 56.2 56.8 57.0 35.7 36.1 37.7 28.7 51.5 50.6 38.4 30.1 212.0 72.5 57.7 47.1 52.9 43.7 23.6 23.1 27.7 26.6 42.8 42.9 11.5* 1 2 . C ' 14.7 14.7 39.5 39.1 13.1* 12.4" 76.3 79.0 29.1 29.7 149.3 149.2 121.8 122.0 166.8 167.0 12.5 12.5 20.5 20.5

(75I3l
202.8 129.0 139.9 36.7 73.2 56.3 57.0 38.6 35.1 50.9 31.3 77.6 48.5 53.4 22.8 26.9 49.6 7.6 14.6 37.7 14.9 79.0 32.7 149.1 122.0 166.9 12.5 20.5

(83Ig3 (66)93 ( 1 5 9 ) 1 6 '

202.5 202.9 129.0 128.9 140.0 139.8 36.8 36.7 73.3 73.3 56.2 56.0 57.0 56.9 35.3 35.4 35.3 35.4 51.0 51.0 21.7 21.1 40.2 38.9 45.1 44.8 48.6 49.5 35.8 35.2 75.2 81.8 64.0 59.4 13.6 13.2 14.7 14.7 38.3 43.2 14.3 19.2 67.2 75.9 32.0b 32.6 65.0 6 0 . 3 ' 9 . 1 ' 63.5b 5 91.9 95.8 16.5 14.4 18.8 21.8 204.8 129.1 141.0 36.5 74.9 132.8 129.5 38.1 40.8 51.4 22.2 32.7 48.9 47.8 23.3 36.5 84.9 15.1 14.6 42.9 9.5 78.9 32.7 150.9 121.3 167.5 12.4 20.6

2 3 4 5 6 7 8 9 10 11 12 13. 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

203.0 129.1 139.5 36.8 73.3 56.2 57.3 35.8 35.6 51.5 21.9 39.9 43.6 52.0 23.6 27.3 51.0 12. i* 14.7 39.2 13.3* 78.3 29.7 149.0 122.1 167.0 12.5 20.4

203.4 128.1 140.9 36.9 72.9 55.1a 55.Za 35.7 34.5 50.4 21.1 32.4 48.2 45.1 22.5 36.3 83.1 14.2 14.7 42.9 9.4 78.5 32.0 150.R 120.1 166.0 12.0 20.1

72.9 52.7a 56. - 6a 25.3 49.8 20.lb 33.5 50.6 84.4 28.1 86.0 18.8 13.8 43.4 9.7 78.7b 33.1 151.3 119.3 166.1 12.4 .19.8

202.8 128.7 140.1 36.9 72.8 56.9 55.7 38.6 31.7 51.7 24.4 29.3 137.0 135.2 124.1 125.4 141.5 128.9 14.1 43.1 17.3 67.4 33.7b 64.7b 63.3 91.7 16.6a 18.7a
217

a,b &

tnterchangeable

218

Carbcn WithaNc. nclide G (107)"~

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Withanclide H

WithaChlcrchydrin Chlcrchydrin 3S-hydrrxy2,3dihydrcwithacf withanclide cf withanrlide nclide-H acetate nclide D ( 1 2 0 ) ~ ~( ~1 2 1 ) ~ ~ (~ 1~)'~~ ( 1 7 4 ) ~( ~1 ~5 7 1 ~ ~ ~ (131)121 Withanclide K Perulactrne B

'-

1~,38,20-trihydrcxy l-cxrwitha-5,24dienclide ( 125)117 72.9 38.3 66.3 41.4 137.6 125.2 31.7
3 1. .?

204.3 128.0 145.3 33.5 135.2 125.0 25.3 35.2a 36.3a 50.8 22.2 32.5 47.5 85.0 32.1 20.6 49.4 17.4 18.9 75.3 21.2 18.4 31.7 149.2 121.9 166.7 12.4 20.5

204.2 128.0 145.5 33.5 135.2 125.0 25.3 35.2a 3 6 . 3 ' 50.9 22.2 32.5 47.4 85.1 31.9 20.7 49.4 17.5 19.0 75.3 21.1 81.7 31.9 153.7 125.6 166.4 57.1 20.1

39.8 127.4 129.4 140.7 121.6 25.2 34.Za 34.ga 52.6 20.7 26.5 51.4 85.9 33.0 33.0 89.2 18.9 20.4b 76.gb 20.2 81.0 32.4 151.6 120.9 12.2 20.7

205.2 127.8 146.1 33.6 135.4 125.2 25.5

35.A

37.2 50.9 23.2 32.3 54.4 83.4 31.7 37.2 88.5 20.5 19.0 78.8 18.8 73.1 30.3 38.4 38.0 181.8 10.5 72.6

204.3 128.6 141.4 35.0 76.3 76.0 25.9 33.5 34.6 52.0 22.8 34.6 54.9 83.5 30.9 37.3 88.2 21.5 15.4 79.0 19.6 81.1 32.6 151.4 121.1 167.2 12.3 20.6 OdC 21.5 170.3

201.1 127.7 143.1 66.6 78.3 66.0 39.1

31.5

206.8 127.0 144.5 34.5 77.6 66.5 31.6

39.1

212.2 52.9 68.7 41.0 134.9 126.0 25.6

35.9

45.7 55.7 22.5 39.2 43.1 57.2 23.5 21.9 54.4 13.7 9.9 74.9 20.6 80.7 31.3 149.3 121.8 165.6 12.5 20.5

37.3 55.7 22.9 34.5 54.9 82.2 30.2 37.6 87.4 20.6 8.6 78.8 19.0 81.0 32.3 152.0 121.3 167.8 12.2 20.6

34.1 51.3 20.9 32.1 47.5 84.9 31.9 20.8 49.4 17.4 19.1 75.2 21.1 82.0 31.9 154.7 125.5 166.9 56.6 20.1

41.5 41.7 20.2 39.8 43.0 56.8 23.9 22.0 54.7 13.6 19.4 75.2 20.8 80.1 31.5 149.1 122.0 166.2 12.5 20.5

a,b interchangeable

TABLE 5 ( Contd. ) 1 3 C NMR DATA OF WITHANOLIDES 150a,b

Carbrn
Nr

Daturilin (138)~~

Withaminimin

23-hydrcxy Physalc- WithaWithaphysalclactrne peruvin peruvin D lactcne (164)~~ (18~1)~~ (175)~~ ( 1 ~ 1 ) ( 168)140 ~ ~ ~

Withaphysalin E

(+) Jabarrl (187)

(144)~
206.1 117.5 140.4 126.0 160.0 72.8 37.1 37.8 44.7 53.8 22.7 36.3 60.0 83.1 34.8 25.7 57.7 177.3 20.0 83.9 26.3 78.4 31.9 148.7 121.9 165.4 12.5 20.7 149.76 114.04; 126.55 116.56a 140.62 7 6 . 1 4 39.57, 43.50, 73.23 121.04b 58.90 212.81 45.5gd 46.96 24.52 34.44 83.35 16.09 11.01 40.85 13.04, 78.29 33.72 153.97 121.67 166.10 12.28 20.52

1 2 3 4 5 6 7 8 9 10

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

11

204.06 204.15 128.0 128.71 145.11 141.33 33.524* 36.03 136.06 77.22 74.26 124.60 33.334* 26.47 33.297 35.43 39.963 35.43 50.544 52.20* 23.678 23.18 39.749 38.82 52.23* 42.662 56.051 82.28 24.124 83.36 26.556 120.37 47.699 161.30 12.751 16.80 18.976 15.10 42.939 36.11 60.574 17.21 75.629 78.47 30.795 32.35 150.25 69.355 139.2 121.44 165.26 167.44 129.74 12.37 25.627 20.64 CH CO 21.36 3 C H - C O 170.63
-3-

203.6 126.8 147.5 65.8 80.0 66.0 35.8 40.0 39.9 58.3 23.7 31.0 55.9 83.7 32.8 37.1 88.2 20.9 9.8 80.4 19.3 85.7 67.5 153.8 122.5 166.9 12.7 16.2

203.8 126.9 147.6 66.0 80.0 66.0 35.7 40.1 39.9 58.3 23.8 35.5 55.8 83.5 31.2 37.8 88.3 21.1 3.7 79.7 19.3 82.5 34.0 153.3 121.8 168.9 12.2 20.5

202.4 127.2 145.2 67.0 79.4 74.5 32.0 37.4 37.8 55.6 22.7 34.5 54.0 82.8 30.7 37.4 87.4 20.7 9.7 78.8 19.1 80.9 32.2 151.1 121.2 166.7 12.2 20.7

214.0 42.3 77.6 74.5 79.8 77.3 26.4 35.8 34.9 55.8 21.6 35.4 55.6 83.9 31.1 37.4 88.7 20.6 15.3 78.3 19.4 83.0 32.8 154.2 121.7 165.7 12.3 20.8

219

a,b,c,d : : Interchangeable

220 ring junction and the hydroxyl being equatorial as noticed in for 134 (171), the C-5 carbon appears 677.6.

eg. chlorohydrin of withanolide E deshielded at

The stereochemical effect of C/D ring junctions can also be noticed, though to a lesser extent, on crbons - 13, 14 and 18 for 102 eg. in 14o-hydroxywithanone (84) with C/D trans stereochemistry, the C-14 appears at 6 84.4 while it appears at 6 83.5 in 143-hydroxy 102 isomer with C/D cis stereochemistry. The 146-hydroxyl has a deshielding effect on C-13 ppm) on C-18 in the isomers. Effect of 14a-0H The presence of 14 0'-axial hydroxyl compared to those with no hydroxyl produces a gauche shielding effect of 5-8 ppm on C-7, C-9 and C-12 in rings B and C. but only C-17 has been found Y-effect. The 17 B-side chain A similar Y-interaction might have shielded. forces This has been explained the 17a-H into an axial also been expected on carbons-16 and 17 in the pentacyclic D ring that in a five-membered ring no more than one carbon experiences a position to receive the Y -effect. since C-17 carbon is non-protonated. Effect of 17a-OH The oxygen atom at C,- shields C-12 and C-14 (but not C-15, also in the pentacyclic, vide supra). 17-OH but not the latter. These In the side chain, C-21 is to the shielded but not C-22; the former carbon is thus gauche conformation such as structure I. was measured from the 270 MHz (12) acetate and withanone However, if a 17^-hydroxyl is (1.8 ppm) and a shielding effect (2.0

present no change is observed in the shifts of either C-16 or C-17

results are explained by a 3 The J(HH) between H-20 and H-22

H NMR spectra of withaferin A (68) and found to be 3 and 3.5 Hz, The gauche relationship between

respectively, in agreement with I.

the lactone ring oxygen and C-2 0, in this conformer explains the quite high field position of the resonance of this methyl group. in the presence of 2 0-OH 169 to or 14 o'-20-(OH)^ functionalities respectively are very similar the case without the additional OH groups, for C-14 in the latter case, where this carbon is nonprotonated and, therefore, does not feel the Y-effect, indicating conformations similar to 1 in the The effects of 17 '-hydroxylation

221 vicinity of C - 1 7 . Effect of 20-OH The relationship presence of a 20-hydroxyl causes a strong Y-effect gauche

r^ 5 ppm on C-16

indicating

the carbon and the oxygen are in

(Structure II) whereas C-23 is unaffected. containing group 17a-oriented which C-12. C-20. causes side-chains a strong the are known

Withanolides to possess is is effect on C-21 group carbon axial

17^-hydroxyl expected almost replaces to the

deshielding of the from this 14 the

(6.1 ppm) (Structure I I I ) . shield one unchanged. may have Probably caused a

The presence of a 14a-0H shift from around Y-effect rotation

Instead, Steric the

Y-alcohol

from

hindrance

oxy-substituent

C,^-Cppj

where a hydrogen bond is possible

(Structure I V ) . does not cause shielding on 20 by

The introduction of 2 0-hydroxyl

C-16 because of formation of a hydrogen bond between the 14 and alcohols (Structure V). The deshielding of C-21 caused

20-hydroxylation is larger than usual. The C-17 epimeric compounds with conformations interesting. where as in V the same Y-effect is noticed from I and V C-20. are C-16 These

In I the 17^-011 experiences Y-effect on C-12 and

interactions are absent in the case of compounds with an side chain such as withanolide E The presence primary double 3.5 ppm. The axial 12o-OH in withaferoxolide axial hydrogens at C C-9, C-14 and C-17 and through shielding by 6.9 in daturalactone C-17 and ( ' S 7.6 ppm) . In withanolides containing 5-enes eg. produces to 8.3 allyl bond of a (46). (ring E) of in the the C-24

-oriented

2 7-hydroxyl

side and

chain this C-25 by

causes deshielding on C-24 and C-25 by 4 ppm. alcohol causes polarisation on C-25 and causing shielding

Acetylation of on

deshielding

C-24

(76) is gauche to the experiences a Y-effect 123 OH

ppm, whereas the equatorial high field C-18 methyl

(75) produces minor shielding effects on C-9, a characteristic signal

withanolide

(107) the C-5 and C-6 carbons appear at<*^<5 135.2 and The C-22 {f^'5 presence of 23-hydroxyl 3 and produces an

125.0 ppm. shift on

upfield

ppm) and produces

Y-effects on C-24 and C-25

as in

222

OH

HO

c^"P
OH
20 ^ 2 1

y
^

H \

H
/23 )^22
ri vi

1 ,/

. ^ ^

1 OH

\y
^0

"^-HO

^21

223 23-hydroxyphysalolactone Mass Spectra Mass spectrometry is a useful tool in diagnosing the (180).

characteristics of a withanolide.

The molecular ion in electron

impact is either weakly present or totally absent in some cases. 65 Cleavage of the side chain at C-20 and C-22 in (3) and 31 91 (62) ' produces m/z 125 whereas in a saturated- <5-lactone it produces m/z 127 by same type of fission. daturalactone B lactone resonance.
the loss of

A fragment m/z 125 may

also be produced by a system containing 5 a--0H-6 a,7a-epoxide as in 31 91 ' (74) or 5,6-glycolic system as in JaborosaF " " " " ^ ^ (163) will be stabilised by The presence of an epoxy- lactone 24a in the side chain,
oxygen 1 fi7 . The same ion m/z 141 which comes from a

(Chart

Vila).

This

revealed by a fragment m/z 141, further disintegrates to m/z 125 by

27-hydroxymethyl disintegrates further by acquiring a hydrogen and

losing water molecule to give m/z 124 (Chart V i l a ) .

Carbonyl group at C-12 in withanicandrin

90

(63) triggers a

fragmentation involving the cleavage of C Q - C, . bond on one side and a McLafferty rearrangement with the participation of 2 0-proton and the 12-ketone leading to a peak m/z 275 (Chart Vila). In 24,25-dihydrowithanolide D (20) fragmentation between C-20 and C-22 produces m/z 127 to confirm the dihydrosystem in the 127 side chain (Chart Vllb). In perulactone B (142) and 125 ixocarpalactone A (61) scission between C-20 and C-22 produces the ion m/z 143. bond producing If the side chain contains a hydroxyl at C-20 or C-20 m/z 169, as in eg. 4 -hydroxywithanolide glycol system at C-20 and C-17 scission occurs at C-17 and E^^^'^"^(Chart Vllb). In the compounds with 5a-0H-6a ,7 a-epoxide in ring a 12 a- or 3-OH the scission system at C-17 containing and C-20

A/B

produces m/z 299 (M-side chain-H^O)

as in withaferoxolide (77). 142 In chlorowithanolides, eg. 4-deoxyphysalolactone the molecular + + ion M could not be located. Under electron impact (M -HCl) is the peak with highest intensity (m/z 486). In B the spectra of 5a-methoxy-4,5-dihydrojaborosalactone B (155); the (154) and 5a-ethoxy-4,5-dihydrojabarosalactone

224 Chart - Vila

m/zHl

m/zl42

m/zl24

m/z275

225 Chart - VII b

Perulactonc B ( 142 )

Ixocarpalactonc A ( 6 1 )

\
OH

O m / z 143

OH e

V o
m/z 113

o^ o
m / z 143

226

m / z 185

227

CHART-Vlld MASS SPECTRAL FRAGMENTATION OF METHANOL ADDUCTOF ISOWITHAMETELIN126 (139)

(139) in/z436 m /z 468 m/zl34 -28 CH2 OMe -OMe in/zl06

-r ^ ^ ' ^
in/zl24 -CO "O^ ^O
iii/zl23

m / z 155

' Q^
m/z95

228 TABLE 6a C D . VALUES OF SOME WITHANOLIDES

Compound

CD values observed at

Ref.

43-Hydroxy withanolide E (53)

400(0) ;340 (+1.42) cis ring junction of A/B; 304(0), 294 (-0.32), 282(0), 22R, 217.5(4-13.91), 252(+4.25), strongly negative at shorter wave-lengths. 370(-0.25), 354(-0.53), 322 (-0.60) due to strong compression. Due to the interaction of substituent and carbons 4,5 and 6. 336(-1.32) 345(-0.71), 245(+7.24) 363(+0.7), 353(+0.1), 348(+0.14), 338(+0.11) cis fusion of A/R, 306(-0.33); 239(+12.35), (22R), 205(-3.53) . 288(-4.55) (cis A / B ) , 251(+5.31) 342(+0.89), 334(+0.85) 336(-0.29), 302 (-0.09), 256(+3.R6) 337(-0.28), 302 (-0.09), 256(+3.86) 339(-2.17), 253(+5.10) 338(-1.95), 250(+3.83), (22R) 338.5(-2.16), 252.3(+5.02), 195(+29.5) 336.5(-1.96), 287 (+0.8), 252(+5.01) 195(+31.0) 302 inflection (+0.35), 253(+4.32), 198(+16)

26a

Withaperuvin (181)

142

Withanolide S (174) Withaperuvin E (47) Physalolactone (175)

143 34 144

Withaperuvin D (168) 4-DeoxyF>hysalolactone (171) Withanolide O (105) Withanolide U (123) Withanolide T (81) Nicandrin B (76) Withanone (68) Withanicandrin (63) 2,3-Dihydroderiv., of 5 a,2 Oa (R)-dihydroxyr

140 142 78 100 100 34 66 90 16a

6a,7a-epoxy-l-oxowitha-2,24-dienolide (234) Nic-1 (90) (Nicandrenone)

338(-1.7), 224(+6.22)

105

229 TABLE 6a ( Contd. )

C D . VALUES OF SOME WITHANOLIDES Compound CD values observed at Ref.

Withanolide Q (acaetate)(119) Withaphysalin C (114) Oxidative product at C-20 of perulactone (234) 18-20 Lactone of withaphysalin B (2) Oxidation product of physapubescin (233) Physapubescin & Nic-2-lactone (232)

340(-3.14), 260.5(+3.85) 346(-3.64), 251(+5.80) 286.8(+3.5), indicative of 17aoriented side chain 345(+1.30) cis A/B, 256(+3.8) (22R) 348,294, 254.5. A positive band 294 nm (e+2.76) is characteristic of 14aH-15-one. 230 nm (Ae_2.9) 22R, 24S, 258, configurations

95 113 128

64 81

81

230 TABLE 6b 2 111 COTTON EFFECTS OF A -EN~l-ONE AND 1-ONE CHROMOPHORES

Compund 226 227 228 229

max

nm

Ae

345 335 294 291

+ 0.96 - 0.76 - 3.32 + 0.67 (shoulder)

TABLE

6c

111 COTTON EFFECTS OF 20-ONE CHROMOPHORE

Compound
X

CD max

36-Hydroxy pregn-5-ene-20-one

(230)

287.5 294.0

+ 3.00 + 3.59 +4.03 +2.83 + 2.29 +3.89

Compound (230a) 3B,17a-Dihydroxy-pregn-5-en-2-one Compound ( 2 3 1 a ) (231)

285.8 298.2 303.0 296.6

231 Table 6a. A positive Cotton effect at r ^ 250 nm suggests 22R configuration in ring E ( a: e-unsaturated-6~lactone) (See Table 6a). Even the stereochemistry of 17~0H ( a or B ) can be decided. A comparison of the CD spectrum of 36 -hydroxypregn-5-ene-20~one (230) with that of 36,17a-dihydroxypregn-5-ene-20-one (231) is shown in Table 6b.
1 oo

An oxidation product of perulactone was confirmed to possess 17a-oriented side chain Ae, 286.8 (+ 3.50). A negatice Cotton effect atro 230 nm ( Ae, - 2.9) in lactone 81 of physapubescin similarly indicates 22R, 24S, 25S configuration as in Nic-2-lactone-'-^^ (232). A positive Cotton effect at 287 (+ 0.80) is indicative of 90 the presence of 12-ketone in withanicandrin (63) as in 5-pregnane-12-one and other ketosteroids. f 2.76) is characteristic of A positive band at 294 nm ( AG, 81 14a-Ii-15-one as in the derivative of physapubescin (233). A very weak triplet of bands at 275.5, 268 and 263 nm are observed for the aromatic ring absorption in Nic-1 (90) due to the dissymmetric environment and 224 nm for side chain epoxy lactone. Even the stereochemistry of ring E (27- and 28-methyls) 1fifi were confirmed from the CD data and from molecular rotation differences (See Table 7 ) . Microbial Transformations and Cell Free Cultures There are several investigations on microbiological transformations of withanolides. Withaferin A (12) is hydroxylated by CuDiiinghamella elegans to give two metabolites , one of them originally identified as 14a-hydroxywithaferin A (236). In a 171 subsequent paper , it was shown that the previous assignment was wrong and that the structure of the above compound is 15 3 -hydroxywithaferin A (237), whereas that of the second compound is 12B-hydroxywithaferin A (238). However, in a patent 172 of 1986, it was claimed that fermenttion of withaferin A with the same microorganism afforded 14a-hydroxywithaferin A (236). 33-Methoxy2,3-dihydrowithaferin A (239) was also transformed by C. elegans

232
TABLE - 7 MOLECULAR ROTATION DIFFERENCES ( A M D ) IN CERTAIN WITHANOLIDES65
Saturated Lactones Unsaturated Lactones AMD

- 425.3

155.3

R MD -412.5

-do-

-342.8

t
OH

Ci ^oK

R MD - 546.0

I
R

OH,

H
- 195.3

-351.6

^ o \

-^S^
AcO

r]^

233 into its 12 3-hydroxy derivatives derivative thus 173 (240). only Biotransformations of 1 74 simplex . Of the 5 a,63-epoxy-2 7-hydroxy-

withaferin A were also induced by Anthrobacter several obtained,

was identified. Anthrobacter l ,4-dioxowitha--2,24-dienolide citreus 175 deacetylated withaferin A (12) 4,27-diacetate t o the free withaferin A"^^^ ( 1 2 ) . From as well extract tissue cultures (242), tissue of W, somnifera stigmasterol cultures. several simple

sterols such as 24-methylene and 24-ethylidenechlesterol (244) were isolated of investigation a s sitosterol 177 these . No withanolides

(247, 241) in the

(243) and campesterol

could be detected

of W. somnifera were isolated

Concomitantly, in an 1 7fi plants , 24-methylcholesterol, sitosterol, along with stigmasterol and small amounts of

24-methylcholesta-5,24-dien-33-ol, 28-isofucosterol 24-methylenecholesterol.

This was the starting point for a study

on the biosynthesis of withanolides, to be discussed. By using labeled physalin B (190) and physalin F (194) in 179 that both were converted only into However, callus derived from the corresponding 5a,6 0-diol (physalin D 180 derived from diploid P. minima plants amounts of physalin P. minima D, in contrast to which synthesized

cell free extracts of P. minima , it was observed rapidly (192)). callus

sysnthesized

small

triploid

physalins B (190), D (192) and F (194). Biosynthesis withaferin 3 A(12) and withanolide D (19), by administering [28-^ H]-24-methylene cholesterol to young leaves of Withania somnifera 3 Similar experiments with [28- H]-24(R,S)-24-methylcholesterol gave negative results, whereas [28H]-24-methylcholesta-5,24-dien-3 -ol gave ambiguous results. Later 184 Whiting et al. found that it was incorporated in Nic-1 (90). r . 4 u w ,24(28) . 24 . ^^ ^ From the above A and A isomers are the precursors of withanolides.
1ftR 1ft7

Goodwin and co-workers

178

isolated radioactive

Investigations of Gros and co-workers by 14 administration of [2- C]-mevalonolactone to seeds and seedlings of A, breviflorus resulted in the isolation of withaferin A (12) and jaborosalactone A (6). The results of the incorporation 185 confirmed the suggestion that jaborosalactone A (6) must be the
1 QC

234

( 226 ) 5P , 6P. ( 227 ) 5a ,6a (228) 2,3.dihydro-5p,6p. (229) 2,3-dihydro-5a,6a-

OH

(90)

(230a)

MeO (232) (233)

235

OH (236); (237): (238); (239); (240); (248);

( 241 ) R = CHCH3 (242) R = CH2CH3

(243) R = CH2CH3,A22 I4a -OH (244) R = C H 3 , A 7 , 5,6-diH ISp -OH ( 244a) R = C2H3 , A25. 24 4oH 12p -OH (247) R= =CH2 3p - McO, 2,3 - di H 3P-lVIeO, I2p - OH, 2,3. diH 3 - (1 - aziridinyl) ,2,3 - di H

OH HO HO

a - ecdysone ( 245 ) ; 22a - OH P - ecdysone ( 246 ) ; 22p - OH

HO

Physalindicanol A,

:x^
(247a)

OH

(246a) and ( 246b) Phsalindicanol B, R = OH

236

(249)

(250)

HO H O Ajugalactone ( 252 )

237 plausible precursor of withaferin a (12) and biosynthesized prior to withaferin A. Whiting and co-workers 18 4 18 8 ' published two papers concerning with the biosynthesis of Nic~l (90) in N.physaloides; 18 8 the first , with the origin of the aromatic D-ring and the 184 second with the elaboration of the epoxylatol side chain (Chart VIII). From the biosynthetic experiments performed by Mulchandani 189 14 et al. with Physalis minima radioactive acetate (1- C and 14 14 2A C) and mevalonic acid (2C ) , were found to efficiently incorporate into physalin D (192). above the authors concluded that Similarly tritiated withanolide withanolides are the possible

(12) was found to incorporate into physalin D (192). From the

precursors of physalins. Ergosta-5,25-diene-3 3 ,24 e-diol (24Aci) isolated from the fruits of W. coagulans and two isomers (246a,b) named 1 90 physalindicanols isolated from P. minima var. indica (whole plant) along with other withanolides, were proposed as potential biogenic precursors. Physalindicanol whereas physalindicanol cholesterol. Biogenesis of Withanolides 24-Methylenecholesterol (247) is the biogenetic precursor A (246a,b) B (247a) is is the 24-epimer of (244a),

25-hydroxy-24-methylene-

of withanolides. The formation of 24-methylenecholesterol from 1 78 cholesterol was explained by Lockley et al. . They synthesised it and also isolated from Withania somnifera cultures. Hydroxylation followed by oxidation at C-1 from the rear side i.e., -side of

produces

1-oxo

compound.

Dehydration

3-hydroxyl produces a: &-unsaturation in ring A. Among withanolides the 4P-hydroxyl is generally noticed in 5-enes and 53 ,6 3-epoxides. 4 3-Hydroxylation is easy as C-4 is allylic to A^'^ system. It is presumed that formation of 4-hydroxyl takes place first and epoxidation at C-5 and C-6 follows later. This explains the formation of more 53,63-epoxides with 43-hydroxywithanolides 7-hydroxyl (Chart IX). and then be with 4d-hydroxyl by the containing 5-enes. of The might formed allylic oxidation 5-enes

238
CHART - Vlll Possible pathways for Ring D > Aromatisation O

II

{Xn^{
(O)

1,7

HQ

itf^-^ixy
R

SAM = S - adenosyl methionine

M
(O)

SAM

Possible pathways to the biosynthesis of the epoxvlactol side chain

OH

(0)

= H

239 CHART-IX BIOGENETIC SCHEME IN RINGS A&B OH

OH

OH

OH

0H

a OH

240 The hydroxylcction at the tertiary positions i.e., 14, 17, 20 is common in both the 173and 17a-side chain derivatives although this system is more dominant in the 17a-oriented system. Lavie et al. isolated a A -withanolide (115) and suggested that side chain. It might have it is the precursor of 17a-oriented

originated due to the dehydration of 17a-hydroxyl and the highly crowded side chain will rearrange to the a-side. Hydroxylation at C-27 is frequent whereas at C-28 is rare. ^-lactone are produced by allylic 95 95 oxidation eg. withanolides Q (119) and R (70) whereas ^-lactone 128 (145). ring is noticed in a few compounds eg. perulactone 25 Ixocarpalactones form C-23 and C-26-olides with 22-free 23-hydroxy compounds with hydroxy1 as in ecdysones ' (245,246). r , a . u u 1- 64,108,129,133 are obtained u^ ^ w 4 - * . Withaphysalms by i lactonisation of 18-methyl and 20-hydroxvl. Hydroxylation at C-18, C-19, C-21 is rare. C-21-hydroxyl C-19-hydroxyl ' and their related derivatives Compounds with , compounds with

and C-18-hydroxyl have been recently reported. steroids is 2,3,24,25-Tetra-

Aromatisation of ring D produces Nicandra Formation of saturated lactones, A dominent in w. somnifera South African variety. breveflorous

24,25-dihydrolactones

hydrolactones were isolated from The explained formation of

5a-hydroxy-6a reason.

,7a -epoxides

can

be are

explained, from 53 ,6 3-epoxides as given in the scheme. from the following less in number.

This was

4-Deoxy-53,63-epoxides

Transdiaxial opening of epoxide forms glycol at Dehydration at C-6 followed by epoxidation

C-5 and C-6 position.

from the rear side produces 5a-hydroxy-6a,7a-epoxides. 5a,63 and 53,6a-dihydroxy systems arise from the scission of 53,6 3-epoxides by the trans Formation of diaxial of and trans diequatorial by the opening respectively. opening chlorowithanolide

diequatorial

53,63-epoxide

bulky nature of chloro group.

ring might be due to the 181 Sarma et al. proved this point by

performing the reaction of NaCl on 53,63-epoxides indicating the presence of NaCl in the plant itself. Hydroxylation at 12, 15, 16 positions is rare. Hydroxyla91 97 tion at C-12 was noticed in daturalactones B (74) and C (75)

241 and Jaborosalactone F (164) whereas a 12-oxo group was found in

Qfl 91 31 withanicandrin^^ (63) and daturalactone A ' (64). Even 12-methoxy group is noticed in (23R)-6a-chloro-5B,17a-dihydroxy-12B 138 ~methoxy-l-oxo-12,22--epoxy-ergosta-2,24-diene-23,26-olide (167). 81 15a-Acetoxy group is noticed in physapubescin (35) and in 24b 152-4 physapubenolide (37) whereas physalins contain 15-oxo group in common. But 15-hydroxy compound as such has been recently , . -,31a isolated q ] 93 25 Nicalbins A'* (83) and B (66), ixocarpalactones A (61) 25 and B (59) possess 16-hydroxyl. Formation of 14B-hydroxyl in 102 146-hydroxywithanone (85) was explained through the formation of carbocation, which produces either 14 3~OH or 14a-OH by (Chart X I ) . Dehydration of 14-hydroxyl gives A by subsequent epoxidation producing a withanolide M (110). at C-14 and C-15. ^ -withanolide of formation 14 -withanolide followed as in The hydration

14,15-epoxide

These compounds are naturally occurring.

frequency of epoxidation is found to be higher at C-5 and C~6 than Similarly, elimination of 17-hydroxyl produces (115) which 17a-oriented is the chain key intermediate for
oc

the by

side

compounds,

followed

epoxidation gives C-16 and C-17 epoxides, eg. physagulin C cholesterol. will give ,

(52).

Hydroxylation at C-22 and C-27 takes place in 24-methylene The oxidation is carried up to the aldehyde stage to The above ' noticed formation , in of epoxy lactol as . in Nicandra Epoxylactone (91). steroids is The form a 6-lactol, which yields a 6-lactone by oxidation. nicalbins pubescenol physapubescin (153),

nic-1-lactone

lactonic ring is found to be stereospecific. Modifications of are shown in Chart X. The formation of the novel side chain of withametelin is considered acnistins to follow a mechanism similar to that proposed for (Chart X I ) . side chain during withanolide formation

Pharmocological Activity Withanolides are polyoxysteroids and several of them

possess significant pharmacological acitivity, eg. Withaferin A(12)

242
Chart-X MODIFICATIONS IN THE SIDE CHAIN

OH H -:

^
CH20H ! 24 - Methylene cholesterol

243

Chart-XI

\ /

r^
OH OH 0 O''^OH

OH R=*-OH X ^ leaving group

Acnistins

Withametelins

244 exhibits activity activity tumor inhibitory in activity, bactereostatic tumors acid-fast in mice and and as cytotoxic well as

experimental against and

immunosuppressive properties. mainly microorganisms 57

Withaferin A possesses antibacterial bacilli grampositive

jergj Aspergillus

antifungal

activity

against

flavus,
Ehrlich

Epidermophyton

floccosum

and Cladosporium

herbarum

.191

and invivo growth inhibitory and radiosensitizing effect on mouse 2 14 ascites carcinoma ' . It showed significant activity in (KB) and in vivo against sarcoma 180 (SA) in mice. It was also a number of secondary was also

vitro against cells derived from human carcinoma of the nasopharynx shown to produce tumour graft significant growth retardation in

systems in mice. (lymphocytes) inhibited.

Withaferin A host

(12) suppressed in chicks

lesions in adjuvant induced arthritis in rats. versus It reaction that strongly seems besides

The locally induced antiproliferative

activity, withaferin A (12) has a complex influence on inflammation 57 and immune response . Withaferin A (12) and its microbial transformation products, 123-hydroxy and 153-hydroxy derivatives, were found to inhibit the growth and biochemical functions of in 171 . The adduct of vitro grown P-388 lymphocytic leukemia cells aziridine withaferin to 2,3 double bond i.e., 2,3-dihydro-3(l-aziridinyl) A (248) possesses antitumor activity against P-388 192 lymphocytic luekemia 27-Deoxywithaferin A is found to be more 193 active than other compounds Withanolide P-388 luekemia and E (46) exhibits cytotoxic activity against L-1210 ,

system, activity against B-16 mouse 57 melanoma and Lewis lung carcinoma , antifeedant property against Shodoptera littorolides antineoplastic activity and immune
o n

suppressive properties.

4 3-Hydroxywithanolide

E (53) possesses a

considerable lifespan increasing activity against L-1210 leukemia and showed less antifeedant property against larvae of 195 Spodoptera littaralis . Even the model compound having resemblance in ring A/B, i.e., (249) , prepared synthetically 53,63-epoxy-l-oxocholest-2-en-43-ol has inhibitory activity against

the growth of sarcoma 180 ascites tumor. Withanolide S (174) and 53,63-epoxy-la,14a,173,20-tetra-

hydroxy-witha-24-enolide (250) possess antifeedant activity against 195 the larvae of 5. littoralis 5 a,20a (R)-DihYdroxy-6 a, 7 a-epoxy-l-oxo-5 oi-witha-2 ,24-dieno-

245 lide (73) exhibits immuno modulating properties 197

33-Hydroxy-2,3-dihydrowithanolide F (251) has a protective effect in the cases of CCl. induced hepatoxicity rats. and has a significant anti-inflammatory . 198 inflammations produced by formalin in adult albino in subacute It also produces a moderate fall of blood pressure in dogs effect

antiinflammatory experimentally

24,25-Et>oxywithanolide D (25) and physangulide (42) have 199 effects when administered mtra-peritioneally induced inflammation. The activity was comparable

to mice and rats (10 mg/kg) in exudative and proliferative types of to that of hydrocortisone. Withangulatin A (39) acts in vitro on induce topo isomerase II mediated DNA damage Several daturalactones show, to some extent, antifertility 201 . Daturalactone B (74) is more (64) and 2,3-dihydrodaturalactone cytotoxic activity B. (180) exhibited (ICcp Topoisomerase II to

effects on albino female rats active than daturalactone A 23~hydroxyphysalolactone

value 40 ug/ml) against L-5178 Y cell in vitro"''^^. The epoxide and quinoid like moiety in AB ring as well as the unsaturated lactone in the side chain have been shown to have tumor-inhibitory
J 202 terpenoids

activity

as

found

in

several

classes

of

Withaferin A (12) and withacinstin

(16) showed cytotoxity

invitro, against KB cell cultures derived human carcinoma of the nasopharynx and invitro against sarcoma 180 in mice and walker 25 6 , . 44,203 intramuscular carcinoma Physalolactone was inactive against 175 , a chlorohydrin lymphycytic of 4P-0H withanolide indicates E P-388 leukemia, the

5,6-epoxide is a requisite for the activity 17P-Hydroxy group along with 5P,63-epoxy system is

essential for the antitumor activity, eg. withanolide E (46), 4P-0H withanolide E (53). Thus 17-isowithanolide (34) possessing 17'-0H be active against a number of potentially pathogenic fungii 16c 204 Even the crude extracts of the leaves of Withania is found to be inactive . 17 3-Hydroxywithanolide K was found to somnifera

Dunal

have been reported in Ayurveda and Unani Medicine (India)

used for the treatment of tumor and tubercular glands and besides

246 being sedative and hypnotic. The glycowithanolides from effective also found findings on Swiss mice in W. somnifera the were shown to be adverse effects of 215 . The same were These ^s in

alleviating

morphine and attendant immunosuppression action

to act on an animal model of Alzheimers disease and taken to support of the effect and of ^' somnifera as used

perturbed central cholinergic markers of cognition in rats. were "medharasayan" (Promoter learning memory)

Ayurvedic medicines A. arborescens and tubercular glands Physalins 44 is also used for the treatment of tumors

which

resemble

closely

in

their

structure species.

to The

withanolides occur mainly in the plants of Physalis to exhibit varied pharmacological activity. P. alkegengi P.angulata^^^ P. angulata was reported are are in Chinese

plants as such as well as the isolated physalins have been reported

medicine .P. PThe and

to

have of

diuretic, anthelmintic andP. peruviana^^^ and P. peruviana

and anticancer activities diuretic. anthelmintic

minima pubescens

leaves

(Puerto Rico) has been used in indigestion. Physalin B (190) and epidihydrophysalin from Witbaringia cocculolides were shown to antitumor activity Physalin B (190) was found to be moderately active in PS. The favourable influence of ' of a 5a,6ot-epoxy was grouping in from the the intensification than physalin B antitumor activity discolsed C (204) isolated promising

possess

observation that 5a,6a-epoxyphysalin B is more cytotoxic in 9 KB

Antitumor activities of physalins A, B, E, F and L were determined Physalin cytotoxic B by using He La cells (IDCQ F cells physalin A (18) exhibited to be (IDc^ moderate in vitro cytotoxicity (190) and physalin tumor against mouse yg/ml) against He La cells. show higher activity

(194), which were known

0.32 -0.35 yg/ml) than physalin A, while physalins E (193) and L (200) were found to be inactive. Physalin X, a compound of unknown modifying physalins of Pbysalis ^ ^.^ . ^54,211 abortifacient minima structure, obtained by

has been reported to be an

247 Nicandra physalolides 104 a South American plant is noticed

for its fly repellent activity. Ecdysones which are yet another closely related group of polyoxy steroids and Nicandra steroids are knwon for their powerful antifeedant properties. These are regarded as insect moulting 212 213 hormones , eg. - and 3 -ecdysones (245,246), ajugalactone (252). Synthesis The methods substitution efforts patterns on synthesis of rings A of withanolides compounds and B with comprise (a) the required for the from starting

for the synthesis

of model

(b) methods

synthesis of the unsaturated 6-lactone side chain

androstane skeleton and (c) attempts involving rings A and B and the side chain finally leading to several natural withanolides, as withaferin A, withanolide D etc. reviewed by E. Glotter These details have been recently and hence no description has been included

in this article on the synthetic aspects. ACKNOWLEDGEMENTS One of the authors (A.S.R. Anjaneyulu) wishes to express

his gratitude to the authorities of Andhra University for granting sabbatical leave from January to June, 1996 and the authorities of Northeastern visiting University, Boston for extending him facilities as rendered Murthy inthe (proof Professor during this period which made it possible to The assistance Krishna

update and finalise V.V.S. Prasada

this review.

preparation of manuscript by Messers D.V. Jagannadha Rao (typing), Rao (drawings) and M.V.R. reading) is gratefully acknowledged.

248
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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

263

Natural Products by Oxidative Phenolic Coupling Phytochemistry, Biosynthesis and Synthesis

G.M. Keseru and M. Nogradi

1. 2.

INTRODUCTION NATURAL PRODUCTS BIOSYNTHESIS OF WHICH MAY INVOLVE OXIDATIVE PHENOLIC COUPLING*

2.2 Curare alkaloids 2.3 Amino acids 2.4 Compounds formed from precursors containing one aromatic ring 2.4.1 Allylphenols, isoprenylphenols and cinnamic acids 2.4.2 Aromatic carboxylic acids 2.4.3 Benzoquinones 2.4.4 Phenols 2.4.5 Lignans 2.4.6 Ellagic acid derivatives (ellagitannins) 2.5 Compounds formed from precursors containing two aromatic rings 2.6 Compounds formed from precursors containing condensed aromatic rings 2.6.1 Naphthols, naphthoquinones 2.6.2 Anthraquinones, anthracenes and reduced derivatives thereof 2.6.3 Phenanthrenes and dihydrophenanthrenes 2.7 Compounds formed from precursors containing four aromatic rings. Bis(bibenzyls) 2.8 Compounds formed by oxidative phenolic coupling of oxygen heterocycles 2.8.1 Benzofurans 2.8.2 Chromenes, chromones, dihydrochromones 2.8.3 Coumarins 2.8.4 Naphthols and naphthoquinones combined with oxygen 2.8.6 Xanthones 2.9 Terpenoids 2.10 Antibiotics 2.11 Marine metabolites

264 3. OXIDATIVE PHENOLIC COUPLING IN THE BIOSYNTHESIS OF SECONDARY METABOLITES. 4. SYNTHETIC METHODS 4.1 Synthetic methods for the formation of biaryls 4.1.1 The Ullmann biaryl synthesis 4.1.2 Nickel- or palladium-catalysed Grignard-type coupling 4.1.3 Pschorr-type diazo-couplings 4.1.4 Photochemical syntheses 4.1.5. Oxidative phenolic coupling 4.1.6 Non-phenolic oxidative coupling 4.1.6.1 Vanadium(V) compounds 4.1.6.2. Thallium(III) compounds 4.1.6.3 Other oxidants 4.2 Synthetic methods for the formation of diarylethers 4.2.1 Ullmann diarylether synthesis 4.2.2 Oxidative coupling 4.2.3 Coupling using arene-metal TT-complexes APPENDIX 1. INTRODUCTION "Oxidative coupling is an important reaction in the biosynthesis of secondary plant metabolites. E.g. it was estimated that the biosynthesis of more than 10% of alkaloids involves one or more oxidative coupling steps [1]. In oxidative coupling more often than not a phenolic hydroxyl group plays an important role role is dual, it may both act active as the and passive. In form of radical attacking agent proper, [la]. This an or, aryloxy as an

electron donating group, activate the aromatic ring in ortho and para positions. Attack of an aryloxy radical leads to compounds of diarylether type, while activation by a phenolic hydroxyl not only facilitates such an attack but may promote the oxidative formation of aryl radicals leading to diaryl type compounds. Considering the vast number of natural products the structures of which suggest that their biosynthesis may involve oxidative phenolic coupling, it is not surprising that rigorous proof of such pathways has only been presented for a few. In the first part of this review we present typical examples of compounds presumably involving oxidative phenolic coupling in their biosynthesis. The compounds are grouped according to structural

265 features rather arbitrarily. A more or less complete list of such compounds compiled from the Dictionary of Natural Products [3] is given as an appendix. It is noteworthy that while with some classes of plant metabolites (e.g. terpenes) oxidative phenolic coupling is exceptional, for others (such as curare alkaloids and ellagic acid derivatives) this reaction produces an amazing variety of products (161 and 164 compounds respectively) listed. In the second part we describe the outline of their biosynthesis, while in the third part some general synthetic methodologies for the formation of aryl-aryl and aryl-0-aryl bonds, the characteristic structural feature of our compounds, are presented. 2. NATURAL PRODUCTS THE BIOSYNTHESIS OF WHICH MAY INVOLVE OXIDATIVE PHENOLIC COUPLING* 2.1 Alkaloids (except curare alkaloids) Although a wide range of alkaloids show structural characteristic from of compounds arising from from oxidative features phenolic

coupling, an overwhelming majority of such compounds are derived isoquinolines, mainly 1-benzyl-l,2,3,4tetrahydroisoquinolines. Some of them are formed from two identical units through C-C bonds (e.g. bisacnadinine) or from two different isoquinolines through an ether bond (e.g. berberidine). In melantolide two identical units are joined both by a C-C and an ether bond, while in medellin two different units were attached to each other by a C-C bond, an ether bond and a methylenedioxy bridge. Isoquinolines may be linked to other structures as well, such as a naphthol (e.g. dioncophylline) or an aromatic ester (e.g. isonoyanine). Intramolecular bridge formation by oxidative coupling is also common, just to mention morphine and the aporphine alkaloids, or as a less well known structure, linaresin. Spermidine alkaloids, such as cadabicin, are essentially macrocyclic cinnamic amides involving a diarylether bond (Schemes 1-4).

*Compounds are mentioned by their trivial names and respective codes of the Dictionary of Natural Products [2] are given in parentheses. When no trivial names were coined, only the codes are given. The bonds which may have been formed by oxidative phenolic coupling are indicated by heavy lines.

266 Scheme 1 MeQ OMe

MeO OH 6 Atalanine (A-2988)

OH (B-562)

Bisjatrorrhizine

iMe

JOQ"^
MeO, (B-287] OMe

Bismurrayafolin (B-584) HN^^O

Berberidine

MeO* MeO Me Cadabicin (C-19) OH Bisacnadinine (B-491)

267

o
12,12'-Bis(11-hydroxycoron a r i d i n e ) .(B-539)
OMe Decaline 9CI

OMe (D-176)

NMe

Dioncophylline (D-3353)

MeO Disazecin (D-3758)

MeO

OH

OMe Heimidine (H-146)

Emestrin B (E-206)

268

Scheme 3
MeN

* 0

MeO MeO Isonoyaine MeO, (1-572) Jolantinine (J-116) MeO.

TTH^
NMe MeO Kreysgenine (K-317) OH MeO

.^'^^^^ Jolantamine (J-113)

MeO Linaresin (L-588)

Lithramine (L-974)

269
Scheme 4 MeO

NMe

MeO.

OMe Medellin (M-368) Melantolide (M-420)

MeO

Me Me-'^'^'^Me Pilocerein (P-1271)

OMe Secolucidine

OH (S-457)

. O H MeN
MeO, MeO'

MeO y-Morphine {M-1697) Speciosin {S-967)

2.2 Curare alkaloids Curare alkaloids are dimers of l-benzyl-1,2,3,4ether

tetrahydroisoquinolines

linked by one, two, or even three

bridges positioned in a most varied manner. Discussing them in a

270 separate section is justified by their impressive number and variety (more than 160 compounds are listed in ref. 3 ) . In some of them, as in baluchristanamine B, oxidative cleavage has severed one of the benzyl groups from the isoquinoline ring. Interestingly compounds derived by C-C coupling do not occur in this group (Scheme 5 ) . Scheme 5

NMe

Me-N

Berbamunine (B-284)

NMe

Me-

o
OH

Me7^r>v.^J^ MeO

CHO istanamine (B-88) Baluchri

Cycleaneonine {C-2215) 2.3 Amino acids Amino acids rarely undergo oxidative coupling, the most important example being thyroxin. Two other examples are shown below (Scheme 6). Bractazonine, B-756, containing a nine membered ring is biosynthetically also related to amino acids. The prerequisite of oxidative phenolic coupling is an aromatic ring and therefore, for want of a more logical ordering principle.

271
nitrogen free compounds will be discussed according to the number of aromatic rings in the precursors.

Scheme 6

CO2H "NHCHO (A-716)

HoNOC

H-4
N=C

/
D-1691

Aldostatin HO OMe

J.

HO
I Bractazonine (B-756)

P^^^"
I Thyroxine

.CO2H

<

NHo

{T-1457)

2.4 Compounds formed from precursors containing one aromatic ring 2.4.1 Allylphenols, isoprenylphenols and cinnamic acids All the examples in this group are products of C-C coupling. In the isoprenyl substituted members the isoprenyl chain often forms, like in tectol, a dihydropyran ring. Isodunnianol is one of the rare trimeric compounds in this group (Schemes 7 and 8 ) .

272 Scheme 7 Me Me

Bisclausarin (B-503)
MeO OH r

Dehydroisopeniclide (D-316)
CO2H OH

>\ ^

loy
v^_/ C02Me

MeO

^ OH

^)

Gr
. I

r^ u ^ ^^ Dehydrodieugenol (D-296)

r.'^ ^' Diferulic a c i d (D-1072)

nCsHii

Magnolol (M-lOO)

Me

MeO OH

"^

OH ^^' ^^ HO OH Mastogophorene D (M-317)

Epiphorellic acid {E-342)

2.4.2 Aromatic carboxylic acids Both diary1 and diarylether type compounds occur in this group. Formally ellagic acid derivatives should also be dicussed here, but due to their large number and high complexity they are treated separately. Two gallic acid molecules are linked by an ether bond in chesnatin, while three such molecules with one ether linkage and one C-C bond occur in valoneanic acid. Canesolide, although formally a furan derivative, also belongs to this group.

273 Scheme 8

Eudesmagnolol (E-18 59)

Hermonionic acid (H-484) Me Me 0'

OH Isodunnialol (1-430) Tectol (T-170) 2.4.3 Benzoquinones Biperezone, B-405, is the only benzoquinone known to exist in a dimeric form (Scheme 10). 2.4.4 Phenols Monocyclic phenols readily form dimers and oligomers involving both C-C and diary 1 ether bonds (Scheme 10) . In the dibenzodioxin M-677 probably two ether bonds are formed by oxidative coupling although it is unclear which ether oxygen is derived from which precursor. Oligomers can be exemplified by pentafuhalol, a homopentamer of pyrogallol (Scheme 11). 2.4.5 Lignans Lignans, themselves products of dimerization of cinnamyl alcohols, can undergo further dimerisation to yield compounds like cerberalignan A (Scheme 12).

274

Scheme 9
HO OH

O
OH HO^ OH Chestnatin -0 . Me OH

OH -OGluc OH MeO95H11 C3H7

CO2H

H02C'''^^

(C-885)

Isodidymic

acid

(1-417)

Me

v\

CH3 (CH2) 6

CO2H

. (CH2) 6CH3 CO2H

MeO

HO ^ Mennegaziac acid (M-467)

HO

MeO

OH Micaric acid (M-1480)

H-1296 CO2H HQ pH HO2'

HO

OH HO2C

HO

OH

CI Canesolide (C-241)

Valoneanic acid (V-46)

275

Me

HO OH D-3060 HO-"^^;^-^ Vi::-X/^^OH

Biperezone M^v^ ^Me

(B-405) M e ^ ^Me

Hematoxylol (H-13)

.OH

OMe

Heyderiol A {H-845)

Leprolomin (L-446)

MeO

Scheme 11

DH

^H

Pentafuhalol (P-413) Scheme 12 HOCH2. OH

OMe Cerberalignan A (C-750)

276 2.4.6 Ellagic acid derivatives (ellagitannins) Oxidative dimerization of two molecules of gallic acid give rise to ellagic acid, which is, in the dicarboxylic acid form, the basic building block of a very large number of highly complex natural products containing at least one but usually two or more molecules of ellagic acid, linked to glucose or some of its transformation products. Sometimes additional gallic acid units and other polyphenols are incorporated into the molecule. These features are well illustrated by acutissimin C and agrimonic acid In the latter the glucose unit is linked as an (Scheme 13) . Copen-chain

glucoside both to a catechin and a gallic acid unit, the latter being attached to ellagic acid by a C-C bond. 2.5 Compounds formed from precursors containing two aromatic rings Often the two aromatic rings involved proceeds in an intramolecular or way. For in oxidative phenolic compounds, acerogenin as A the and

coupling are already linked in some way, in other words coupling some (e.g. diaryIheptanoids dibenzocyclooctanes

binandkatsurin A resp.) this order of events is highly probable, while for others, as in several of the alkaloids discussed above (e.g. lithramine) or in protosappanin B, it is less evident (Scheme 14). 2.6 Compounds formed from precursors containing condensed aromatic rings 2.6.1 Naphthols, naphthoquinones With naphthols and naphthoquinones C-C coupling oxidatively too (Schemes 15 and 16). Both symmetrical seems to be (e.g. 3,3"exclusive, although the ether bond in D-2250 may have been formed bisjuglone) and unsymmetrical homodimers (e.g. bisisodiospyrin) are common. The units can be linked by a double bond, as in diosindigo A, and by a second C-C bond, as in hypocrellin. Naphthoquinones may also form trimers as e.g. in galpinone. Ancistrocongine of a naphthalene ring is an a interesting group. combination with

dihydroisoquinoline. Here the naphthalene moiety

is the acceptor

277

Scheme 13

HOCH

Ellagic acid (dilactone

form)

UO^

OH

Agrimonic acid (A-580) 2.6.2 Anthraquinones, anthracenes and reduced derivatives thereof This group comprises a large variety of types from simple anthraquinone dimers, as chrysotalunin, to combinations of an anthraquinone with an amino acid or a prenylated naphthol (e.g. laccaic acid C and dermocanarin I) , tetrahydroanthracenes and anthraquinones such as setomimycin and julichrome Ql, as well as to compounds with multiple cross-links as, for example, fagopyrin. Biogenetically the tetrahydro derivatives can be rather regarded as substituted naphthols. This is rather obvious e.g. with karviskione. Finally the anthraquinone moiety may combine with other oxygen heterocycles an in the case of euxanmodin A (Schemes 17 and 18).

278

Scheme 14
OH

MeO Acerogenin A (A-144)

HO Q OH

OMe Binandkatsurin A (B-399)

OH HO Caurarinondiol {C-545)

(CH2)i4

Robustol (R-309)

MeO HO OH MeO Diacylkatsulignan C (D-146) Protosappanin B (P-1986)

279

Scheme 15
DMe

OH Ancistrocongine

6 O (A-1666Bisjuglone (B-563) Bisisodiospyrin ; ) H 0

(B-561)

OMe Diosindigo (D-3359)

Me' Diospyrol 0 OH (D-3362)

COMe OMe 0 D-2250 OH 6 OH (H-323 3) Hypocrellin OMe

0 Galpinone

0 (G-88) 0 Toddacoumaquinone (T-1524)

280

Scheme

17 MeO

OH

MeO

OH . 0 A s p e r i n i n e A (A-2902

Dermocanarin I (D-532)

^NH

OH

OH MeO

.NH

OH 0 OH Fagopyrin (F-18)

Karviskione (K-81)

2.6.3 Phenanthrenes and dihydrophenanthrenes The title compounds are much less common than the anthraquinones. An example for a heterodimer, probably formed from a homodimer, is blestrin (Scheme 19) . 2.7 Compounds formed rings. Bis(bibenzyls) from precursors containing four aromatic

It is a reasonable assumption that macrocyclic bis(bibenzyls) such as the marchantins arise by oxidative C-C or ether bond formation from acyclic precursors already containing all four aromatic rings (e.g. perrotetin E). The ether linkage between the second and third rings is probably also established by phenol oxidation. Gnetifolin, though phytochemically unrelated, is structurally rather similar to bis(bibenzyls) (Scheme 20).

281 Scheme 18 Me^ ,iOAc

OH

OH (C-1283)

0 Ql

OH (J-141) CO2H -NH2

Chrysotalunin

Julichrom

QH
HO2C 9 OU HO2C.

Euxanitiodin OH OH

(E-2018) 0

_ OH HO'^ ^^^'^'-^ ^ ^ 1 ^ ^ V ^ ^ O H 0 OH Laccaic acid (L-157)

ir^T

TOT

OH 0 OH OH (S-661) Setomimycin

OH MA 1 4 4 A E 1 (2201)

Antibiotic

Scheme 19
MeOv .OH

Blestrin

(B-653)

0-200

282
Scheme 20

OH Marchantin A (M-258) Perrottetin E (P-845) HO^ . x ^ ^OH

HO

OMe Plagiochin D {P-845) Gnetifolin (G-615)

2.8 Compounds heterocycles

formed

by

oxidative

phenolic

coupling

of

oxygen

2.8.1 Benzofurans From the mulberry tree a large number of 2-arylbenzofurans (e.g. dimoracin), typical products of oxidative phenolic coupling, have been isolated. The sequence of events with dibenzofurans (C-C or OC coupling first) is less clear (Scheme 21). 2.8.2 Chromenes, chromones, dihydrochromones Simple symmetrical homodimers of chromenes with a C-C linkage such as ageratoriparin and non-symmetrical ones with an ether bond, like pterochromene 13 are both known. Chromones can form homodimers, such as compound D-1580, or combine with a flavonoid as in the case of compound D-1419. Ergoxanthine is better considered as a xanthone precursor rather than a proper chromanone. 22) . (Scheme

283

Scheme 21

Dimoracin

(D~3315)

MeO

OMe Candidusin 2.8.3 Coumarins A trimer with both C-C and ether likages is triumbellatin. I-sophysodic acid is an example of an isocoumarin linked to an aromatic acid of very similar structure (Scheme 23). 2.8.4 Naphthols and naphthoquinones combined with oxygen (C-229) Penioflavion (P-308)

heterocycles Naphthols and naphthoquinones anellated with an oxygen

heterocycle like a pyrone or isopyran ring usually form homodimers through C-C bonds (Scheme 24). 2.8.5 Flavonoids Almost diarylether dimeric found. every type of flavonoids form dimers via C-C or than such the

linkages, but dimeric such as

flavones are more two biaryl and of

common

isoflavones. In batramiaflavone Homodimers may

bonds can be

biscyclolobin members

heterodimers group are

abiesin both exist. In the latter even the oxidation level of the monomers differ. Important this

284 oligomeric catechins ranging from dimer to hexamer or probably even to higher polymers (Schemes 2 5 and 26) .

Scheme 22
MeO

OMe

Me AH-11

^^

^Ph

Pterochromene 13 (P-2106)

(D-1580)

D-1419

OH C,H 5^11

Scheme 23
0" ^0

H02C

Triumbellatin

(T-2962) Isophysodic acid

(1-601)

285

Scheme

24

MeO'

MeO" Crisamicin A (C-2000)

T a l a r o d e r x i n e A (T-36) 2.8.6 Xanthones

A few dimeric xanthones and xanthone precursors linked through a C~C bond are known (Scheme 27).

286

HO^

"^ 0 Biscyclolobin (B-50 4

OH (B-109)

Batramiaflavone

2, 3-Dihydrohinokiflavone

(D-1213)

287 Scheme 2 6

Oligomeric catechins

HO' (P-528-532)

^^

0 ^Ph T-589

' M e
Me02C E Eumitrin Al (E-1960) HO 2.9 Terpenoids Terpenoids undergo oxidative coupling only exceptionally. The only examples recorded in ref 1 are shown below. Note that B-538 is not a phenol. Ploiarixanthone (P-1512)

288

Scheme 28

^e-

.CO2H

Me^

Me

Macrophyllic acid 2.10 Antibiotics

(M-530)

Some important groups of antibiotics and antineoplastic agent such as the vancomycins (e.g. vancomycinic acid) and the so called OF peptides (e.g. peptide 49491) are evidently products of oxidative phenolic coupling, while with the tetracylines this process seems to be marginal. In antibiotic A 4103 0 as many as three ether linkages and one C-C bond is formed by oxidative coupling. The dimeric tetracycline A-2201 is shown with the anthraquinones (Scheme 29). 2.11 Marine metabolites Oxidative phenolic coupling giving rise to ether bonds is common with marine metabolites (Scheme 30).

289

Scheme 29

'NHCO

_NHCO " ^ NHCO

NHCO^''NHCO
'NHO

\
HO2C OH

00
OH

A n t i b i o t i c A 41030
^OMe

(A-1923)

CI

JL
H2N^ if

NH I
HO^

^ y
^H CO2H ^C0NH2

HO.^

1^^

HO2C

"NH2

HO2C"" ^NH2

HO2C

''NH2

OF p e p t i d e 49491

(A-2245)

Vancomycinic a c i d

(V-63)

Br Br 0^ I ^ 1 ^ "Br OH Br
HO D-727

Br NH

JU
^OH 4

Br

Bastadin

{B-158)

290
3. OXIDATIVE PHENOLIC COUPLING METABOLITES. Current metabolites has knowledge involving about concerning in the their the biosynthesis of secondary phenolic to the IN THE BIOSYNTHESIS OF SECONDARY

formation

oxidative leading

coupling is rather fragmentary. While a vast body of information accumulated biosynthetic pathways precursors itself. It was Barton and Cohen who first suggested that the biotransformation of benzylisoquinolines to morphine alkaloids may involve phenolic radicals, which by radical pairing form new C-C and C-0 bonds either intraor intermolecularily [4]. This hypothesis was supported, among others, by the finding that in in vivo experiments (R)-reticuline was transformed to salutaridine. Among the enzyme systems performing redox reactions oxidations copper containing oxidases perform the irreversible oxidation of phenols. Two main types of phenol oxidases are known, the catechol oxidases and the laccases of which the latter is supposed to be involved in oxidative phenolic coupling
+

(alkaloids,

flavonoids,

etc.)

undergoing

oxidative

phenolic coupling, much less is known about the coupling process

[5, 6 ] . Laccases contain

2+

four atoms of copper, two Cu and two Cu mechanism of oxidation, generating phenoxide follows: enzyme-Cu " * " + Ar-OH -> enzyme-Cu"*" + Ar-0*

ions. The basic radicals is as

+ H " * "

In a second step the enzyme is reoxidized by molecular oxygen: 2 enzyme-Cu"*" + 1/2 O2 + 2H > enzyme-Cu"*" + H2O.

The phenoxy radicals are subsequently transformed by reactions which are generally not enzymatically mediated and this is the reasons for the usual absence of enantioselectivity in oxidative (e.g. the stable

coupling. For instance no optical activity has been recorded for the macrocyclic bis(bibenzyls) contaning a biaryl bond plagiochins), although we have shown that they chiral conformations at room temperature [7]. Formation of aryl-aryl bond can be explained by an electrophilic attack by the mesomeric form of the phenoxy radical: possess

have

Investigations been very

therefore specific infancy. A

involving

impeded is

on

enzyme

it

short-lived systems was not

by

the

the

details

difficulty that

of

oxidative of in the

surprising

intermediates for

following

phenolic

responsible possible

the

identification reaction of

intact

the

coupling process of and its

plants is

in

the

techniques general on the

breakthrough

biosynthesis relevance.

w h i c h permitted

only

of morphine they Using a

Zenk and his coworkers microsomal P-450 alkaloids.

by

the

use

Their in

to shed new light results of may

tissue

culture

somniferum
NADPH,

transformed hypothesis the of (Scheme

oxygen

capsules to and

of Barton and Cohen A play similar no role, enzyme of

salutaridine

cytochrome

demonstrated [8].

is correct, system and least from in

This

enzyme

that

fraction

Papaver
was of

have

phenol the the

means

(R)-reticuline oxidases, that

the

presence while

such as

the

laccases, 31).

at

above the

Berberis

stolomifera
coupling was

Note that no berbamunin of stereospecificity 32). coclaurin and the

intermolecular

was

regioselectivity biosynthesis

supplied

was formed when only one of the enantiomers to the of the system, enzyme the proving [8a] of

(R)-

involved

(S)-coclaurin

in

microsomal to

transformation stereospecific berbamunin.

fraction

(Scheme

the of

phenoloxidases products.

Of course the above results in

do not exclude of other

classes

intervention

coupling

Scheme

31

MeO~~~/~

~o~~~~_ ~ e ~o- ~ ~
MeO ..... OH OH (R)-Reticuline HO

M e O ~

.....

Meo0
~eO~Ji
0 ~*/~~~_- NMe

M e O ~

______~.

MeO
MeO HO HO MeO H

H NMe

MeO~ Scheme

i~Me

O (+)-Salutaridine

32

MeO~/~~ HO" ~.~.2,. _NMe v __-~H

+

'IH

NMe

H O ~ (R)-Coclaurin MeO~~/~

(S)-Coclaurin NMe

H0~HNMe

'IH

Berbamunine

OH

293 4. SYNTHETIC METHODS 4.1 Synthetic methods for the formation of biaryls General methods for the synthesis of biaryls will be reviewed in this section. Electrochemical processes are outside the scope of this work. Asymmetric syntheses have been excellently reviewed recently by Bringmann [9] and therefore will not be overviewed here. 4.1.1 The Ullmann biaryl synthesis The classical Ullmann reaction has been for long the exclusive method for the formation of aryl-aryl bonds [10]. In a typical procedure two equivalents of an aryl halide react in the presence of copper powder or other copper salts to give biaryls (Scheme 33). Scheme 33 Ar-X + Ar*-X A Ar-Ar + Ar-Ar* + Ar'-Ar'

By the same procedure differently substituted aryl halides can also be coupled to biaryls and heterobiaryls but the method is rather impractical because the desired unsymmetrical product is always accompanied by the symmetrical ones. Yields in the Ullmann reaction are generally low, aryl iodides and bromides are more reactive than the corresponding chlorides, while the fluorides are totally inactive. Introduction of nitro or ester groups in ortho position relative to the halogen atom of the aryl halide may dramatically increase yields. The presence of proton donor substituents such as amino, hydroxy1 and carboxyl groups are, in turn, unfavourable, because these functional groups may also react with the aryl halide [11]. Aldehyde, ester and lactone groups normally remain unchanged [12]. The Ullmann reaction is sensitive to steric effects, large substituents in ortho position may inhibit the reaction completely. The mechanism of the Ullmann reaction has not been fully clarified, however, it should proceed via aryl-copper intermediates [13]. This proposal was supported by an improvement of the method by Koten and Noltes, who reacted an aryl-copper compound with

294
copper(I) trifluoromethane sulphonate and obtained symmetrical

biaryls in high yield [14] (Scheme 34). Scheme 34 Ar + CF3SO3CU

V -cui

V-c^ i
-

CUv

rOaSCFs

it
ArAr +

Cur'

CUO3SCF3

^*CuO which

Ar

^ Ar /
the

IJ.CU :t03SCF3 "Cu n formation synthesis was of of symmetrical unsymmetrical prepared from

This

approach, was [15].

obviates to aryl-copper

products, biaryls

also The

applied

the

compound

corresponding aryl-lithium obtained by direct lithiation of an aryl halide and was coupled with the other aryl halide.

Owing to stabilisation by a nitrogen or sulphur containing ortho substituent stabilisation relatively and high yields effected were by achieved. masking al. [16]. an Both ortho activation,

positioned aldehyde function as an oxazoline ring, were achieved in an elegant synthesis of steganicin by Meyers et

295

Scheme 36

(-)-Steganone 60% de This so-called of "oxazoline" several method was also [17] well applied as for the

synthesis biphenyls

crowded binaphthyls

biaryls, [19], as

tetrasubstituted the highly

[18], and

functionalized cyclic biphenyl moiety of vancomycin [20].

Scheme 37 OTMS OTMS Mg, BrCHoCHoBr THF, 80%

OMe

OMe MeO OMe MeO

obtained by in situ template

OMe OMe
reduction combined of Cu(I) were the

Improved yields in the Ullmann reaction could be realized using activated iodide prepared copper powder potassium a using with [21]. Unsymmetrical alcohol 2,2-biphenyls with

salicylic complexes

catalytic effect of activated copper [22]. Lithium-cuprate iodide applied and in the the obtained by the reaction were also biaryls of Cu(I) [23]. An corresponding synthesis aryllithium of the low successfully oxidative

unsymmetrical

alternative

strategy

involves

temperature

coupling of higher order mixed diarylcuprates

[24]. The classical

Ullmann reaction can be accelerated by using, instead of copper

296

powder, copper(II) oxide, or by ultrasonic irradiation during the reaction [25]. In order to prevent high reaction temperatures a combination of copper(I) triflate and aqueous ammonia in acetone was recommended, which allowed the reaction to be run efficiently at room temperature [26]. The intramolecular version of the Ullmann reaction was useful for the preparation of condensed systems [27] (Scheme 39).

Scheme 39
MeO C02Me OMe C02Me

OMe

MeO Cu,210QC ^ 68% ^ et as al.

The classical methodology of the Ullmann biaryl synthesis was significantly nickel using further improved by Semmelhack using zero-valent Yields were complexes [28]. Aryl iodides were coupled in high yield

bis(1,5-cyclooctadiene)nickel(0)

catalyst.

improved by the application of

tetrakis(triphenylphosphamount of that the

ine)nickel(O) [29] (Scheme 40). While the original methods require stoichiometric nickel complexes, Zembayashi et al. claimed, however,

reaction is also feasible with a catalytic amount of nickel(II) ions and Zn powder [30]. The method was also applied by Colon

297 Scheme 4 0
/^^"2)2X Ni(0)[Ph3P]4 ^

76-83% et al. for the synthesis of unsymmetrical biaryls [31]. Interestingly aryl chlorides afforded a better ratio of coupling to reduction than the corresponding bromides and iodides. A stoichiometric amount of activated nickel powder was also found to be effective [32]. The mechanism of Ni(0)-catalysed coupling was investigated by Tsou and Kochi [33]. Readily available nucleophilic aryl Grignard compounds can be coupled with aryl halide electrophiles to give unsymmetrical biaryls in the presence of Ni, Co, V, Ti, Cu, Cr, Fe, Pd and Tl salts [34] (Scheme 41). Scheme 41 2 Ar-MgX + MX2 [Ar2M] M = N i , Co, V, T i , Cu, C r , Ar-Ar F e , U, Tl

Ni and Pd catalysts were found to be most useful for this purpose [35]. Palladium catalysed reactions show better chemoselectivity, but are restricted to activated aryl bromides while nickelcatalysed processes are more tolerant to steric hindrance of aromatic substituents [36]. These reactions are the best alternative to Ni(0) catalysed high temperature coupling of aryl halides [37]. With stericaly hindered aryl halides generation of a Grignard reagent is recommended. Preferably the component with an ortho substituents should be converted the Grignard compound[38]. Chiral ferrocenyl phosphine nickel complexes are useful for the preparation of optically active biaryls [39]. Ultrasonic irradiation is often applied to accelerate the reaction [40]. Aryllithium reagents are generally inactive, while arylzinc compounds can be efficiently coupled in the presence of nickel catalysts [41]. Compatibility with a wide range of functional groups and easy access to arylzinc compounds from the corresponding aryllithiums is the main advantage of their usage. Effectivity of this approach was demonstrated in the synthesis of steganon by Larson and Raphael [42] (Scheme 42).

298

1) Ni.THF^ 2)HC1 ^ R = -CH=NC8Hi2, 85% R = -COzMe, 0% MeO.

Steganon

MeO MeO MeO

The reaction was exploited very recently in a solid phase synthesis of biaryls. Aryl zinc bromides undergo palladium catalyzed coupling reactions with Ni(0) catalysed aryl bromides bound homocoupling to a polystyrene reagents resin. The also be product can be released from the resin by transesterification [44]. of arylzinc could realised using aryl triflates [45], as well as aryl tosylates and mesylates [46]. As with nickel catalysts, Pd(0) complexes are also effective in the [47]. Aryl triflates are also useful as electrophiles in the reaction of arylzinc compounds [48]. Pd(0) and Ni(0)catalysed cross-coupling and homocoupling reactions of aryl triflates were reviewed recently [49]. Aryl fluorosulfonates gave biaryls in this reaction too. The first application of arylstannanes was presented by Stille who demonstrated of the transferability from of an aryl group and with from aryl aryl aryl the tetraphenyltin [50]. This approach was generalised by the improved preparation halides with arylstannanes by their to give trialkylstannanes catalysed coupling followed Pd(0) coupling of aryl iodides with arylzinc compounds et as al, demonstrated in the synthesis of biphenomycin by Schmidt

halides [51]. Similarly to aryl halides, aryl triflates also react arylstannates are biphenyls suitable [52]. Electron-rich reagents in triflates especially coupling

synthesis of unsymmetrical biaryls [53]. Symmetrical biaryls can be easily obtained by the reaction of an aryl triflate with 0.5 eq. of hexamethyldistannane. Arylcoppers particularly couplings. [54] and mercurials [55] in were found to be from efficient nucleophiles biaryls palladium-catalysed prepared

Symmetrical

can be efficiently

299
arylthalliuin catalyst of coupled fluorine with bis(trifluoroacetate) on treatment could also of a with be Li2PdCl4 as successfully catalyst

[56]. It is interesting that due to the induction effect atoms, arylfluorosilanes aryl halides in the presence Pd(0)

(Scheme 43) [57]. Scheme 4 3

[(n3-G3H3PdCl)2] DMF,KF,lOQOC, 85%

One of the best ways to prepare unsymmetrical biaryls is the Suzuki-coupling utilising aryl bromides and as the nucleophilic partner aryl boronic acids and esters (Scheme 44) [58]. Scheme 4 4 ^B(0H)2 Br + The Suzuki reaction groups and in was

Pd(0)[PPh3]4
1

Na2C03 or NaHC03 to the synthesis of several

applied

unsymmetrical biphenyls [59]. It is compatible with a wide range of functional successful compounds prepared in the aromatic has from been chlorides. ring [60], but up to now no involving a 4 arylborono catalyst of using and Ni(0) coupling aryl situ reported However,

NiCl2(dppf)

equivalents

butyllithium, aryl boronic acids could be successfully coupled with aryl chlorides in the presence of K3PO4 [61]. Ni(0) catalysts were also effective in the coupling of aryl boronic acids such with as the aryl readily available arene sulfonates reactive towards organoboranes [62]. Aryl triflates are also boronates

[63] and

boronic acids [64]. Boronates may be applied more efficiently, but triflates were found to be less reactive than the aryl halides towards organoborono species corresponding that aryl [65]. Note

boronates are more accessible than aryl boranes and can be prepared by transmetallation from the corresponding aryllithium compound and the air-stable boronates require only weak bases for crosscoupling. Base-free couplings can be performed using an equimolar quantity of tetraarylborates [66]. Coupling of aryl boronic acids

300 and aryl halides or triflates is also possible in high yield in the presence of readily available and less expensive heterogeneous palladium catalysts [67], 4.1.3 Pschorr-type diazo-couplings The Pschorr reaction is the intramolecular coupling of arenes involving aryl radicals generated by the reduction of aryl diazonium salts [68]. The reaction was extensively studied during the last 100 years [69]. This Cu(I)-catalysed reaction proceeds via an aryl diazenyl radical intermediate (Scheme 45) [70]. Non-protic solvents from which competitive hydrogen abstraction is impossible, are to be preferred [71]. Scheme 45 +R-H, -R;^^ Ar-Ar' Ar-N2-^.XCu(I)X ^ Ar-N2* "-^2 Ar.+ Ar'-H -H^""^^ Ar-H+Ar'One of the most important fields of application of the Pschorr reaction is the synthesis of isoquinoline alkaloids. The syntheses of_ thalicsimidine [72] (Scheme 46) and aporphine [73] are typical examples. Modifications of the classical method are mainly concerned with the decomposition of the diazonium salt. Thermal [74], photochemical [75], and electrochemical [76] processes were found to be effective for the generation of the radical intermediate. Ti(III)-catalyzed Pschorr reaction of aryl diazonium salts and phenols gave symmetrical biaryls in excellent yield [77]. Scheme 4 6 MeOv ^^^ ^^^ NMe MeO>. NMe

Thalicsimidine The Gomberg-Batchman-Hey reaction is closely related to the Pschorr synthesis and gives unsymmetrical biaryls by treating aryl

301 diazonium salts with bases [78]. Moderate yields may be improved using phase-transfer conditions and crown-ether catalysis [79]. 4.1.4. Photochemical synthesis Since the first photochemical synthesis of phenanthrene from (E)stilbene was realized [80] photochemical methods became a convenient way of aryl-aryl bond formation (Scheme 47). Scheme 47

Dehydrogenation of the dihydrophenanthrene intermediate formed by the cyclization of (Z)stilbene presents can a be general route by to the substituted phenanthrenes [81]. Yields improved

addition of hydrogen abstractors such iodine or [83] and led to application of the synthetically [84] from which aryl radicals can

tetracyanoethene more effective easily

[82]. The method was extended to the preparation of phenanthridones aryl halides be more

generated. Heterolytic cleavage of the carbon-halogen bond effected by irradiation results in the formation of aryl radicals which can then recombine to biaryls by Kihara et al. synthesis of [85]. The catalytic effect of dialkyl anilines was also recognised. This strategy was first demonstrated using an aryl iodide as radical precursor in the [86]. Aporphines and other types of dibenzazocine

isoquinoline alkaloids were prepared by this method [87]. The closure of macrocyclic rings represents a special field of intramolecular chain [89]. aryl-aryl bond formation. Irradiation of an openafforded myricanone (Scheme 48) [88], which diaryIheptanoid dibromide

represented the first synthesis of a macrocyclic

302
Scheme 4

hv
MeO
The accomplished

OMe
of a macrocyclic an intramolecular by

MeO
lactam,

OMe

RO also the of

synthesis

azoninone, was

photocyclization

corresponding open-chain aryl halide precursor [90] (Scheme 49).

MeO
^ ^ IV-'ST hv

-^

HO

MeO'

OMe

4.1.5. Oxidative phenolic coupling As mentioned in Section 3, oxidative phenolic coupling plays an important biomimetic role in the biosynthesis of natural of a wide range of natural in vivo products. This stimulated the application of this reaction to the synthesis biaryls. Unlike the processes, very probably following a radical dimerization pathway [91] yields of in vitro syntheses are generally moderate or low. Classical work in this field has been extensively reviewed [92], and important developments after the 70s will therefore be summarised here. Methodological development was focused on the exploration of various new oxidants in order to replace the traditional but still popular iron(III) chloride and potassium hexacyanoferrate [93]. The non-selective obstacle to give nature of these oxidizing agents is the major in their synthetic application. Note that by-products. The selective could be the products synthesis achieved in of a

themselves are usually phenols too, which can be further oxidized polymeric and hydroxylated methoxylated biaryls

FeCl3/AlCl3 system

[94]. Application of phase transfer conditions [95]. The amount of

might be useful in suppressing overoxidation

303
by-products can be also reduced using silica gel-absorbed oxidizing agents [96]. Although silver(I) oxide is generally more reactive than FeCl3, there are some of as examples biaryls for [97]. its successful application [98], as in the synthesis as well Copper(II) benzoate such be tert-

butylperoxide [99], the more exotic iodosobenzenediacetate [100], traditional were chelates oxidizing in were agents to and potassium First row too. dichromate transition [101] metal used oxidative found [102] couplings.

effective

Manganese(III)

. acetoacetonate

bis(salicylidene)-

ethylenediimino cobalt complex oxidative also be coupling of phenols by the

[103] are typical examples. It is [104] and several of isoquinoline an

interesting to note that molecular oxygen may be also used in the alkaloids were synthesized exemplified isoquinoline alkaloid Cu(I) chloride in this way [105]. This approach can corytuberine,

synthesis

[106]. Intramolecular oxidative coupling of the natural product in moderate yield

reticuline N-oxide effected by molecular oxygen in the presence of afforded (Scheme 50).

Scheme 50
MeOv HO^

^
y J

MeO,

1 ^0"
Me l ) C u ( I ) CI, O2/pyridine
2)NaHS03 HO'

HOv

HO.

MeO

&
MeO"

4.1.6 Non-phenolic oxidative coupling Oxidative electrochemical radical as well coupling as of arenes can be of performed electron by rich

chemical

oxidation

substrates. Application this review, and as

of anodic oxidation sections,

in the synthesis of one will also be

natural [107] and unnatural biaryls [108] are outside the scope of previous this devoted only to chemical syntheses. Non-phenolic aryl-aryl coupling of electron rich aromatics is based on the formation of a radical cation effected by the

304 oxidizing agent via electron transfer [109]. Methods can be classified according to the oxidizing agent generating the radical intermediate. Vanadium, thallium and manganese salts were found to be the most effective reagents. 4.1.6.1 Vanadium(V) compounds The use of vanadium(V) salts in oxidative coupling reactions was prompted by the work of Funk et al. who recognized the ability of vanadium oxytrichloride to form phenoxyvanadium complexes with phenols [110]. As it was shown by Schwartz et al., such complexes can be isolated and used for oxidative couplings [111]. Vanadium oxytrifluoride, a superior reagent [112] was found to be effective not only with free phenols but also with phenol ethers revealing the non-phenolic mechanism of this oxidation [113]. The method was successfully adapted to the oxidative macrocyclisation of a vancomycin subunit [114]. The importance of 3,4-dioxy function was underlined by Halton et al. who observed that the reaction did not proceed in the absence of these substituents [115]. However, the presence of this function is only a necessary, but not a sufficient condition for the success o/ the coupling reaction. Elegant syntheses of lignans and aporphine alkaloids are typical examples demonstrating the synthetic value of this approach [116]. In contrast to benzylic hydroxyls, tertiary or acylated nitrogen atoms do not inhibit the reaction. The formation of macrocyclic rings can be also accomplished in this way [117] (Scheme 51).

4.1.6.2. Thallium(III) compounds The versatile applicability of thallium salts in organic synthesis pioneered by McKillop [118] prompted Schwartz to try them for

305
oxidative coupling [119]. Thalliuin(III) tristrifluoroacetate (TTFA) was found e.g. to be useful for the oxidative intramolecular coupling of phenols to cyclic quinones [120] (Scheme 52). Scheme 52

<IQ
preparation significantly in in classical this way

*<TQ
[121]. This method by-products known was

The use of air-sensitive TTFA was later replaced by its in situ from thallium(III) oxide and TEA represented a new and effective route to biaryls. Conversions were improved, the formation of overoxidized phenolic [123] used couplings (Scheme or in The other TTFA/ could be decreased and in most cases yields were better than those previously TFA system of methods [122]. Phenolic ethers could also be transformed to biaryls 53). occasionally bonds [124]. Scheme 53 for the regioselective formation aryl-aryl

MeO

OMe

T1(02CCF3)3 zTT^

84%

MeO

OMe

MeO

OMe

MeO

OMe

4.1.6.3 Other oxidants Manganese chelates, such as manganese(III) acetonylacetonate

were also tried as oxidants in the coupling of phenols and phenol ethers [125]. In one of the first examples binaphthol was prepared by the oxidative dimerization of 2-naphthol make this method inferior to others. Oxidation by selenium dioxide [128], tellurium(IV) chloride [129], and ruthenium(IV) tetrakis(trifluoroacetate) [130] have also been reported for a limited number of substrates. Notorious toxicity of heavy metal compounds can be avoided using hypervalent iodine(III) reagents [131]. Diaryliodonium salts yield biaryls in the reaction with methylmagnesium bromide in the [126]. Although with this reagent overoxidation can be mostly avoided, low conversions

306 presence of NiCl2 [132]. Moderate conversions in the oxidative coupling of phenols or phenol ethers can be significantly improved using phenyliodine(III) bis(trifluoroacetate) [133]. 4.2 Synthetic methods for the formation of diarylethers 4.2.1 Ullmann diarylether synthesis As shown structural drawbacks, in Section 2 diarylethers are also widely units up to in natural products. recently, Despite its relatively Ullmanns occurring serious was

procedure

almost exclusively the method of choice for preparing diarylethers. According to the original methodology, phenols and aryl halides can be coupled to diarylethers in the presence of activated copper powder and potassium carbonate [134] (Scheme 54). Scheme 54 HO R[CU] -R'

Despite long reaction times and high temperatures, conversions in this nucleophilic aromatic substitution are generally low. As expected, activated aryl halides, such as nitroaromatics however, react faster and give higher yields [135] (Scheme 55).Diarylethers synthesised in this way can be converted to corresponding amines, and the amino group can then be replaced in the usual way either by a hydrogen atom or a hydroxyl group via the Scheme 55 OH OH HOv^^s^OH NO2 C02Me DMF,r.t.,l h C02Me \-^C02Me + COsMe NO2

307 diazonium salts. This approach, which avoids high temperatures, has served well for the preparation of several diarylethers [136]. An aromatic copper compound was postulated as an intermediate and this hypothesis led to the introduction of improved copper catalysts. Activated copper powder, Ullmann's original catalyst, was replaced by Cu(I) salts, such as CuCl [137], Cu(I)Br [138], and Cul [139]. Cu(I)Br was also found to be effective in intramolecular Ullmann macrocyclizations [140]. Cu(II) salts may also have a catalytic effect under similar conditions. CUSO4 [141] Cu(0Ac)2, [142] and CUCO3 [143] were occasionally used. Air sensitive copper(I) salts, such as CuBr, can be stabilised as the dimethyl sulphide complex [144] and we used this catalyst in our laboratory on the multigram scale. In addition to copper(I) halides, copper(II) oxide was found to be an effective catalyst in the Ullmann diarylether synthesis [59, 145, 146] and was used for the preparation of several diarylethers in our laboratory [146]. Cu(I) oxide was first applied by Tomita et al, in the reaction of bromobenzene with 4-hydroxyphenyl acetic acid and they obtained the corresponding diarylether in 60% yield [147]. Organocopper reagents, such as methylcopper prepared from MeLi were also used as catalyst recently [148]. Yields could be further improved by ultrasonic irradiation [149],.as well as under phase transfer conditions [150]. It is surprising that, in contrast to the Ullmann biaryl synthesis, activated aromatic fluoro compounds (e.g. fluoro-esters, -nitrils, -aldehydes and -acetophenones) can couple with phenols in good yield. The reaction does not require any catalysts, but only K2CO3 as a base, [146] (Scheme 56) .

Scheme 56
COoMe

MeO

C02Me
K2C03,DMF

87%

MeO'

MeO

This method and its modified version utilising potassium fluorideon-alumina and 18-crown-6 represents an efficient alternative to the copper catalysed Ullmann synthesis [151]. A combination of the aryl fluoride approach with the activating effect of the aromatic nitro group was useful in intramolecular

308 coupling reactions as for the synthesis of macrocyclic diarylethers [152]. Best results were obtained using K2CO3 and 18-crown-6 in DMF [153] (Scheme 57). Scheme 57

K2CO3, 18-crown-6 DMF, 87% ^ ^OH F

Solvent

effects

in Ullmann

diarylether

synthesis were

also

studied and pyridine was found to be the most suitable [154], but the necessary reaction temperature could also be maintained in DMF [155], [159]. diglim [156], DMSO [157], dioxan [158] and nitrobenzene and solvating Solvents having a high dielectric constant

power such as 1,3-dimethyl~2-imidazolidinone in Scheme 58 is an ambident nucleophile,

(DMI) might be useful but gave only the

in chemoselective nucleophilic substitution. The phenolic component corresponding diarylether with chlorobenzene in DMI [160]. Scheme 58 OH CI

K2C03,Cu(I)Cl

HO'

Scheme 59

CHO KI03,l2 H2S04,KBr

a o
CHO CHO OMe Br" OMe ,C02Me

^C02Me + HO-

OMe CHO NaOMe 50^ OMe

309 A method of limited scope but involving mild conditions, introduced by Doskotch 59). 4.2.2 Oxidative coupling In contrast to the synthesis of biaryls, oxidative coupling has found only limited application in the synthesis of diarylethers. Side-reactions due to the sensitivity of the products toward the oxidising agent, concurrent reactions, such as the formation of biaryls, as well as the fact that several sites at the substrate may be reactive, are all responsible for the lack of interest in this method. Thallium (III) nitrate was used as an oxidant for the synthesis of various diarylethers [163] (Scheme 60) among them the isodityrosin moiety of a number of cyclic peptides [164]. Oxidative macrocyclization of the open-chain precursor of deoxybouvarin was also accomplished by thallium(III) nitrate [165]. VOF3 effected the oxidative cyclization of an open chain precursor of a vancomycin fragment [166]. 4.2.3 Coupling using arene-metal 7C-complexes The use of arene-metal complexes as the halide component is an effective modern alternative of the Ullmann method. Arylhalides can be activated via their metal TT-complexes, and give diarylethers in high yield as was first demonstrated by Pauson and Segal. Although the method was originally developed for the preparation of simple diarylethers, synthesis groups anion in to of [167]. give it A could be extended substituted by Pearson et al.to the diarylethers with sensitive tricarbonyl from functional complex which the the the [161] and used also by us successfully [161] is the reaction of a phenolate anion with a diary1 iodonium salt (Scheme

chloroarene-manganese manganese 61) . Mild

substituted with a chiral side chain was reacted with the phenolate diarylether (Scheme highly of complex diarylether could be liberated without racemization by irradiation acetonitrile of unit conditions diarylethers antibiotics allowed such as construction diarylether functionalized glycopeptide

incorporating

diarylether moieties [168].

310

Scheme 60
OH

Scheme 61

Me02C'^^-'''''^^

NHAc Me02C

-Mn(C0)3 PF,

^^V^^ If 11

^ v

Mn fro) n

hv
MeCN ^ Me02C

NHAc

serious

drawback

of the method

is that

only

few

types of

substituents are compatible with Tl-complex formation

in the aryl

halide component. This problem is eliminated with the use of

Scheme 62
CI
Cl

;
Fe+Cp.PFg

.
Me02C^ NHC02CH2Ph

H [O]
^ ^ 2 C - \HCO2CH2Ph

[VU\
r ' e ^ c p . PFi

IV J\ H
M e 0 2 C ^ ^NHC02CH2Ph

311 Schollkopf^s chiral glycine enolate equivalents, as in the elegant synthesis of the central diarylether unit of ristocetin [169]. It is remarkable that these limitations were partly lifted by using, instead of the manganese tricarbonyl complex the corresponding iron or ruthenium cyclopentadienyl complexes [170] (Scheme 62). 7l-Complex activation was the method of choice complex for the construction of a cyclic peptide model related to the antibiotic teicoplanin, where ring closure of the ruthenium 2,6-di-t-butylphenoxide [171] (Scheme 63). Scheme 63 OMe .Ru+Cp.PFg 2,6-Di-tBuphenoxide H NHBOC MeOoC NHCO NHBOC [ ( OMe ^ ) .0 Ru+Cp.PFg' of the corresponding open-chain hydroxy-chloroarene was effected by sodium

312 APPENDIX Codes in "Dictionary of Natural Products' for Natural Footnote. *Classification Section 1. Alkaloids (aporphins mostly omitted): A-574, 1660-1667, 1669, 2988, 2995, B-490, 491, 497, 539, 562, 584, 586, 587, C-10, 19, 313, 314, 797, 798, 1607, 1727, D-176, 253, 256, D-585, 3352, 3758, E-184, 205, 206, H-146, 490, 1-572, J-113116, K-317, L-200, 201, 347, 585, 588, 974-978, M-368, 420, 701, 1697, N-99, 138, 185, 276, 836, P-47, 48, 271, 323, 1271, 1993, S-457, 967, T-194, 1168, 1169, 1237, 1289, 2963, U-99, 106 , V-215, 218, 228. Curare alkaloids: A-457, 2513, 2537, 2804, 3004, B-88, 89, 282-284, C-106, 107, 481, 741, 882, 900, 1222, 1600, 1602-1604, 2160, 2173, 2174, 2189, 22162218, D-67, 79, 274, 275, 340, 413, 1408, 1429, 3318, 3711, E-57, 351, 1605, F-25, 149, G-357, 762, 925, H-139, 488, 968, 1067, I178, 344, 408, 826, 832, 834, 890, 927, 951, J-103, K-216, 262, L342, 610, M-97, 139, 303, 468, 899, 939, 1341, N-151, 0-1, 5, 83, 546, 589, 661, 683, 825, 826, 836, P-8, 11, 123, 141, 324, 899, 1406, 1651, 1958, 2045, 2057, 2192, 2222, 2223, R-116, 117, 158, 159, 316, S-60, 322, 325, 382, 388, 471, 772, 1214, 1279, 1284, T42, 196, 1149, 1230, 1233, 1236, 1238, 1241, 1250, 1252, 1255, 1258, 1259-1262, 1270, 1272, 1276-1278, 1283, 1292-1297, 1472-1478, 1758, 1914, 2749, 2752, 3029, U-173, V-66, 93, 260, W-11, Y-10, 11. Aminoacids: A-716, B-756, D-2924,D-1691, F-391. Allyl- and isoprenylphenols and naphthols:D-296,297, 2063, 2252, 3430, E-1859), 1925, 1926, 1-430, M-lOO, 317,1673, 0-18, P-1885, R42, T-170 Z-30. Anthracenes: H-1819, K-81, 0-46, P-1050, S-661, 776, 777, T-443, 1562. Antibiotics: A-342, 358, 1925, 1923, 1946, 1953, 1952, 2198, 2223, 2240, 2243, 2244, 2245, 2243, 2728, 3148, C-1038, 1053, 1684, R-72, 299, 0-498, P-205, T-177, V-62, 63. Anthraquinones: 533, 795, E-2018, 2019, F-18, 274, 681, 1-234, 806, J-139, 140-150, in this section may deviate from that followed in Products

Involving in Their Biosynthesis Oxidative Phenolic Coupling*

313 A-1754, 1777, 2902, 2926, 3108, B-609, C-518, 1283, 1417, D-532, 533, 795, E-2018, 2019, F-18, 274, 681, 1-234, 806, J-139, 140-150, 155, K-251, L-155, R-204, 205, 372, S-718, 832, 833, T-656, 668, 669, 1613. Benzoic acids, gallic acids and other bis-acids: C-885, 886, D-298, 1072, E-342, F-542, H-1298, 2023, 1-339, M-467, 1480, 0-545,P-304, 1985, U-97, V-46, 246, 352. Benzofurans: D-3315, M-1746, 1748. Benzopyrans: E-1490, P-2106. Benzoquinones: B-405. Bis-bibenzyls: 1-538, 776, K-217, M-268, 271, 272, N-230, 231, P-845, 846, 1425, R-263, 264, 265, 266. Catehins: P-526-552. Chromenes: A-355, Coumarins: A-574, D-557, 1566, 2080, N-510, 0-489, T-1524, 2962. Diarylethers (oligomeric): B-526, 946, 947. DiaryIheptanoids: A-144-146, 1078, 1087, 2849, C-545, M-1920, P-1677, T-1861. Dibenzodioxins: M-677. Dibenzofurans: P-308. Dibenzocyclooctans: B-399, D-146-148, 513, G-634-642, 1-470, 791, K-8-11, N-212, 215, R-458, S-291-295, 1217, 1218, W-102. Dihydrophenanthrenes: B-647-650, 652, 653. Dityrosines: A-2125, 2245, B-406, 737. Ellagic acid derivatives: A-580-582, 734, 735, 1084, 1086, 2510, B-354, C-108, 183, 184, 536538, 1959, 544, 911, 1777, 1824-1829, D-138, 139, E-114, 1773, 1774, 243, 1978, 1979, 1984, 2016, 2054-2056, F-277, G-194-197,

244, 700, 701, 711, 880, 881, 884, H-170, 171, 511-514, 694-701, 900, 909, 910, 1-530, 779, 780, 790, 827, J-118, L-194-199, 631, M-

314

14-18, 872, 63,

130-133, 266, 377,

143-148, P-272, 378,

154, 1045,

156, 1046,

373,

1650-1655, 285, 286,

N-517-521, R-94-96, 1258-1261,

871, 105, T-57,

0-265, 206,

1117-1120,

1706,

118-120,

467-471,

S-119-125,

207, 211, 212, 1491, 1503, V-45, 232, 1191; B-109, 370, B-504, 619, 984,

W-88-93. D-82-84, 840, 1213,

Flavonoids: A-27, 549, 1419, 1580, M-616, 1147, 0-48, 198, 199, P-534, 1540, 1554, 1667, 2050, R-240, 305, S-523, 524, 1468, 1522, T-589, 1309, 1311, 1564. Lignans: C-750, 751, 752, 756, 757, 759, 760, 761, 762. Marine metabolites: B-156, 157, 158, D-714, 728, 751. Naphthoquinones, naphthols: B-16, 561, 563, D-2083, 2250, 3059, 3359, 3360, 3361, 3362, 3363, E-4, 177, 1794, 1795, G-88, 1248, H-3233, 1-422, 562, M-299, N-186, 272(, P-1055, 1950, 1951, S-1493, T-590. Phenols, polyphenols: D-3060, 1901, 1902, 2931, 2932, 2933, H-845, P-413, 486, T-1161, 2393, 2542. Prenil-allyl-phenols: H-484. Pyranocouinar i n : B-503. Pyranonaphthols: A-2067-2069, Stilbenes: G-615, 616. Terpenes: B-538, C-242, 243, M-53 Xanthones: C-916, E-1960, 1-928, P-1512, S-1579, 1583. 2309, 2310, 3058-3060, C-721, 2000, 1-292, K-81, N411, T-36, U-179.

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

323

Narcissus Alkaloids

Jaume Bastida, F. Viladomat and C. Codina

1.

INTRODUCTION Since the isolation of the first Amaryllidaceae alkaloid lycorlne (1) from Narcissus

pseudonarcissus by Gerrad in 1877, around 200 species belonging to this plant family have been examined for alkaloids. Although this group of alkaloids is of minor pharmaceutical importance, it has aroused increasing interest over the last years. The several reviews in this field are a valuable source of information (1-7) and, likewise, this topic Is regularly reviewed by the journal Natural Products Reports of The Royal Society of Chemistry (8-16). Out of the different genera which make up the Amaryllidaceae family, the genus Narcissus is one of the best known from the horticultural point of view. Due to their phytochemical interest, a chapter about Narcissus alkaloids has been prepared, following the usual general lines. The literature up to August 1996 has been covered. 1.1 Geographical distribution, botanical and taxonomical aspects The Amaryllidaceae are widely distributed. They are richly represented in the tropics and have pronounced centres in South-Africa and in Andean South America. Several genera have their centre in the Mediterranean, e.g. Narcissus. The majority of Narcissus species are found in the Iberian peninsula and North Africa, which substantiates the hypotheses that landmasses of Europe and Africa were once joined taking into consideration the shared distribution of many genera and species. Narcissus can adapt to the different habitats found in this area as well as the different soils, preferring slightly acidic conditions. The genus Narcissus, belonging to the tribe Narcisseae, consists of small to medium-sized herbs with linear leaves and a solid scape bearing an inflorescence of one to several (rarely numerous) flowers. Its spathal bracts are basally fused into a tube. The flowers are actinomorphic and have six equal tepals. Inside this, a corona is

324 generally present. The colours of the tepals usually vary from white to bright yellow and the corona fronn white or light yellow to orange or orange-red. Most are spring-flowering, but a few flower in autumn. The ovary is trilocular and the fruit is a capsule with globose to angular, dry and black seeds. The taxonomy and nomenclature of the genus Narcissus is complex because of its very varied wild populations, its suitability for hybridation and also for historical reasons because many descriptions of taxons have been based on garden specimens, several of which were probably of hybrid origen. The polymorphism of this genus has meant that its taxonomical classification has been constantly changing over the years. 1.2 The Amaryllidaceae family and their alkaloids There has been considerable taxonomical controversy over which genera belong to the Amaryllidaceae family. The revisions of Dahlgren's group (17, 18) have contributed to clarify this aspect. In another direction, one of the best tools for classification of several genera and species of this family has been the type of alkaloids that are exclusively synthezised by Amaryllidaceae species. Thus, e.g. the genus Behria in spite of having been classified as Amaryllidaceae (19), does not have Amaryllidaceae type alkaloids (20) and should therefore be included in another family. Furthermore, it is unusual to find other types of alkaloids in Amaryllidaceae species, but if present, they are always accompanied by true Amaryllidaceae alkaloids. Up to now, only three alkaloids isolated from this family do not belong to this specific type but to the mesembrane {=Sceletium) type -generally found in the family Aizoaceae-, which In spite of having the same aminoacids as precursors has a quite different biosynthesis -for more information about Sceletium alkaloids see Ref. (21, 22)-. These three compounds are amisine (83), mesembrenol (84), and mesembrenone (82) isolated from Hymenocallis arenicola (23), Crinum oliganthum (24) and Narcissus pallidulus (25), respectively (Figure 1). For this reason the Amaryllidaceae alkaloids have a high chemotaxonomical value. The general characteristics of the Amaryllidaceae alkaloids could be summarized by the following points: - a fundamental ring system composed of a Ce-Ci and a N-Ca-Ce building block, derived from L-Phenilalanine respectively. - they are moderately weak bases (pKa 6-9) - each alkaloid contains only one nitrogen atom which is secondary, tertiary or even quaternary, and the carbon content varies from 16 to 20 atoms. (L-Phe) and L-Tyroslne (L-Tyr),

325
NMep

OMe OMe

" ^ - ^

N'

Me 83 82 R,+ R,= = 0

Ri

84 R,= OH, R2 = H Fig. 1. Sceletium alkaloids isolated from Amaryllidaceae species Most of the Amaryllidaceae alkaloids may be classified Into nine principal skeletally homogeneous subgroups although there are several other alkaloids with structures derived from these main molecular frameworks. Representative alkaloids from each of these classes include: norbelladine (85), lycorine (1), homolycorine (23), crinine (86), haemanthamine (49), narciclasine (64), tazettine (59), montanine (87) and galanthamine (70). With the aim of unifying the numbering system of the different types, Ghosal's proposal will be used in this chapter (6) (Figure 2).

2.

NARCISSUS

ALKALOIDS AND THEIR OCCURRENCE

The alkaloids isolated from Narcissus species, classified in relation to the different ring types, are provided in Table 1, and the distribution of the different alkaloids is listed in Table 2.

326

OH

85

23
OH

OH
12

N'
7
6

86

49

OH

0
64

OMe Me0 NMe

59

87

70

Fig. 2. Amaryllidaceae alkaloid types

327

TABLE 1a Narcissus alkaloid structures. Lycorine type.

Alkaloid name 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 lycorine poetaminine pseudolycorine 1 -0-acetylpseudolycorine 2-0-acetylpseudolycorine 9-0-methylpseudolycorine galanthine goleptine jonquilline caranine pluviine norpluviine 9-0-demethylpluviine 1 -O-acetyl-9-O-demethylpluviine 1,9-0-diacetyl-9-0-demethylpluviine

H Ac H Ac H H H H Ac H H H H Ac Ac

Ri

Structure R, R3 OH GH2 OH GH2 OH H OH H OAc H OH Me OMe Me OMe H 0 GH2 H CH2 H Me H Me H H H H H Ac

_3i
Me Me Me Me Me Me

Me H Me Me Me

OMe I

HO..
MeO,

..OH

AcO.

OAc 1

MeO

16 narcissidine

17 nartazine

328

TABLE l a (continued) Narcissus alkaloid structures. Lycorine type.

r^"^
MeO, MeO,

MeO

MeO

18 assoanine 19 oxoassoanine

R^z=R2=H Ri + R2 = 0

20 vasconine 21 tortuosine

R ^=H R ^ = OMe

MeO.

MeO

22 roserine

329

TABLE 1b Narcissus alkaloid structures. Homolycorine type.

Structure 23 24 25 26 27 28 29 30 31 32 33 34 35 Alkaloid name homolycorine 8-0-demethylhomolycorine 8-0-demethyl-8-0-acetylhomolycorine 9-O-demethylhomolycorine masonine normasonine 9-0-demethyl-2a-hydroxyhomolycorine hippeastrine lycorenine O-methyllycorenine oduline 6-0-methyloduline 2a-hydroxy-6-0-methyloduline Me Me Me H
CH2 CH2 Ri R2

Me H Ac Me

R3

H
CH2

Me Me Me

0 0 0 0 0 0 0 0

A_

Me Me
CH2 CH2 CH2

OH OMe OH OMe OMe

H H H H H

H H H H H H OH OH H H H H OH

R5

Re Me Me Me Me Me H Me Me Me Me Me Me Me

Me-CHOH-CHg-COO, OAc MeO

36

dubiusine

330

TABLE 1b (continued) Narcissus alkaloid structures. Homolycorine type.

MeO. OCOEt

37

8-0-demethylhomolycorine-A/-oxide

38

poetinatine

TABLE 1c Narcissus alkaloid structures. Haemanthamine type.

- R 7

Alkaloid name 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 vittatine maritidine 8-O-demethylmaritldine 9-O-demethylmaritidine 0-methylmaritidine papyramine 6-epipapyramine O-methyl-6-epipapyramine 6a-hydroxy-3-0-methylepimaritidine 6p-hydroxy-3-0-methylepimaritidine haemanthamine 11-O-acetylhaemanthamine haemanthidine 6-epihaemanthidine crinamlne narcidine

OH OH OH OH OMe OMe OMe OMe H H OMe OMe OMe OMe H OMe

Ri

Structure R, R4 ~W^ ~^3 H H CH2 H Me Me H H Me H H H H Me H H Me Me H H Me Me H H Me Me OH H Me Me OMe OMe Me Me H OMe Me Me OH H H CH2 H GH2 H H H CH2 H OH CH2 H OMe GH2 H H H Me
1

H H H H H OH H H OH H H H OH H H H

Re

H H H H H H H H H H OH OAc OH OH OH OH

R7

331
TABLE 1c (continued) Narcissus alkaloid structures. Haemanthamine and Crinine types.
.OMe --R4 R.

55 56

cantabricine R^ = H, Rg = Me, R3 = H, R4 = OAc, R5 = H

57 6a-hydroxybuphanisine 58 6p-hydroxybuphanisine

R^ = H, Rg = OH R^ = OH, Rg = H

narcimarkine R^ + Rg = CHg, R3 = OMe, R4 = H, R^= 0CH2CH(0H)Et

TABLE 1d Narcissus alkaloid structures. Tazettine type. OMe

NMe

NMe

59 60

tazettine criwelline

R^ = OMe, Rg = H R^ = H, Rg = OMe

OH 61 pretazettine

OMe

NMe

62

3-epimacronine

63

obesine

332

TABLE 1e Narcissus alkaloid structures. Narciclasine and Montanine types.

OH

r i ^ ^ ^

OH

OH

64

narciclasine

65

narciprinnlne

r^===^

r^^^=^

66 trisphaeridine

67

bicolorine

r ^ ^

OH

<

^^Ij^^^L
OH

NHMe

68

ismine

69

pancracine

333

TABLE I f Narcissus alkaloid structures. Galanthamine type.

MeO

70 71 72 73 74 75 76 77

Alkaloid name galanthamine epigalanthamine 0-acetylgalanthamine norgalanthamine epinorgalanthamine A/-formylnorgalanthamine narcisine narwedine

R, OH H OAc OH H OH OH 0

Structure R, H OH H H OH H H

Me Me Me H H OHO Ac Me

R3

MeO.

Structure Alkaloid name 78 lycoramine 79 norlycoramine 80 epinorlycoramine OH OH H

Ri Rg R3

H H OH

Me H H

334

TABLE 1g Narcissus alkaloid structures. Miscellaneous.

OMe

OMe

81

pallidiflorine (heterodimer)

OMe OMe

k^
Me

82 mesembrenone (Sceletium type)

335 TABLE 2 Occurrence of Narcissus alkaloids.

Alkaloid 18 assoanine Wild species / cultivars A^. assoanus Leon-Duf. A^. jacetanus Fdez. Casas N. pseudonarcissus L. cv. King Alfred A^. assoanus L6on-Duf. A^. jacetanus Fdez. Casas A ^ . bicolor L. A^. obesus Salisb. A ^ . cantabricus DC. A ^ . cantabricus DC. A'; cantabricus DC. N. cv. Livia A^. bujei (Fdez. Casas) Fdez.Casas N. cantabricus DC. A^. cv. Salome A ^ . tazetta L. N. dubius Gouan A'; tortifolius Fdez. Casas N. confusus Pugsley A^. eugeniae Fdez. Casas N. X gracilis Sabine A ^ . X incomparabilis Mill. cv. Daisy Schaffer A ^ . X incomparabilis Mill, cv Flower Record N. X incomparabilis Mill, cv Fortune Helios A ^ . X incomparabilis Mill, cv John Evelyn N. X incomparabilis Mill, cv A ^ . X incomparabilis Mill, cv Marion Cran A ^ . X incomparabilis Mill, cv Nova scotia Pluvius A ^ . X incomparabilis Mill, cv A ^ . X incomparabilis Mill, cv Suda N. jonquilla L. A^. jonquilla L. cv. Golden Sceptre A^. jonquilla L. cv. Trevithian A ^ . kristalli N. lobularis Hort. A^. nivalis Graells A ^ . obesus Salisb. A ^ . X odorus L. var. rugulosus N. papyraceus Ker. Gawl. A ' ^ . poeticus L. A ^ . poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne PN BC TZ DB DB PN PN JC Section JQ PN JQ PN PN BC BC BC BC References (26) (27) (28) (26) (27) (29) (30) (31) (31) (31) (32) (33) (31) (34) (35) (36) (37) (38) (39) (40) (32) (32) (32,41) (32) (32) (32) (32) (32, 42) (32) (43) (40,44, 45) (40) (46) (32) (47) (30) (40) (48) (49, 50) (51,52) (49) (32)

19 oxoassoanine 67 bicolorine 57 6a-hydroxybuphanisine 58 6(3-hy(lroxybuphanisine 55 cantabricine 10 caranine 53 crinamine

60 criwelline 36 dubiusine 70 galanthamine

JQ

PN BC BC JN TZ NC NC

336 TABLE 2 (continued)

Alkaloid 70 galanthamine (cont.) Wild species / cultivars Section References (49) (53, 54) (32, 42) (32) (32) (32) (28, 32, 42, 55) (32, 42) (32) (32) (32) (32) (32, 42) (32) (35, 49 56) (57) (49) (37) (40) (32) (32) (32, 42) (58) TZ PN BC (57, 59) (60) (47) (53, 54) (32, 42) (28, 32, 42) (32, 42) (32) (32) (32) (32, 42) (32) (34) (60) (38) (40) (40) (32) (32,42) (32) (32) (32) (32) (32) (32, 42) (32) (32)

A ^ . poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Carlton N. pseudonarcissus L. cv. Covent Garden A ^ . pseudonarcissus L. cv. Early Glory A ^ . pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator N. pseudonarcissus L. cv. King Alfred A ^ . pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A ^ . pseudonarcissus L. cv. Oliver Cromwell A ^ . pseudonarcissus L. cv. Rembrandt A ^ . pseudonarcissus L. cv. Unsurpassable A ^ . pseudonarcissus L. cv. Van Sion N. pseudonarcissus L. cv. Wrestler N. tazetta L. TZ A ^ . tazetta L. var. chinensis Roem. TZ A'^ tazetta L. cv. Geranium A^. tortifolius Fdez. Casas DB A': triandrus L. cv. Tresamble A ^ . cv. Inglescombe A^. cv. Texas A^. cv. Twink A ^ . pseudonarcissus L. cv. Carlton A ^ . tazetta L. var. chinensis Roem. A^. leonensis Pugsley A ^ . nivalis Graells A ^ . pseudonarcissus L. cv. Carlton A ^ . pseudonarcissus L. cv. Covent Garden N. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Magnificience A ^ . pseudonarcissus L. cv. Rembrandt A ^ . pseudonarcissus L. cv. Rockery Beauty A ^ . pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A'', pseudonarcissus L. cv. Victoria A^. cv. Salome A^. leonensis Pugsley A ^ ' , confusus Pugsley A ^ . cyclamineus DC. cv. Beryl N. cyclamineus DC. cv. Cairhays N. X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill. cv. Deanna Durbin A ^ . X incomparabilis Mill. cv. Flower Record. A^. X incomparabilis Mill. cv. Helios A ^ . X incomparabilis Mill. cv. John Evelyn A ^ . X incomparabilis Mill. cv. Marion Cran A'^. X incomparabilis Mill. cv. Nova scotia A ^ . X incomparabilis Mill. cv. Pluvius A ^ . X incomparabilis Mill. cv. Sempre Avanti 1 A ^ ' , X incomparabilis Mill. cv. Suda

72 O-acetylgalanthamine 71 epigalanthamine 73 norgalanthamine

74 epinorgalanthamine 75 A^-formylnorgalanthamine 7 galanthine

PN PN

337

TABLE 2 (continued)
Alkaloid 7 galanthine (cont.)

Wild species / cultivars

A^. X incomparabilis Mill. cv. Toronto A^. jonquilla L. cv. Golden Sceptre A ^ . panizzianus Pari. N. poeticus L. N. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A'^. pseudonarcissus L. cv. Imperator A'^, pseudonarcissus L. cv. King Alfred A ^ . pseudonarcissus L. cv. Magnet A ^ . pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage N. pseudonarcissus L. cv. Music Hall A'^, pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors N. pseudonarcissus L. cv. Rockery Beauty A^. pseudonarcissus L. cv. Romaine A'^, pseudonarcissus L. cv. Spring Glory A ^ . pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A^. pseudonarcissus L. cv. Wrestler A ^ . tazetta L. A^. tazetta L. cv. Scarlet Gem N. cv. Insulinde A'^. cv. Livia A^. cv. Twink A^. jonquilla L. cv.Golden Sceptre A^. asturiensis (Jordan) Pugsley A^. bujei (Fdez. Casas) Fdez. Casas A ' ^ canaliculatus Guss A^. confusus Pugsley A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Flower Record A^. X incomparabilis Mill. cv. Fortune A^. X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. John Evelyn A^. X incomparabilis Mill. cv. Marion Cran A^. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A'^, X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Suda A^. X incomparabilis Mill. cv. Toronto A^. jonquilla L. cv. Golden Sceptre A ^ . lobularis Hort. A^. obesus Salisb. A ^ . pallidiflorus Pugsley A ^ . poeticus L. var. ornatus Hort. A^. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden A', pseudonarcissus L. cv. Early Glory

Section

References
(32) (45) (61) (49, 50, 62) (51,52) (49) (49) (32, 42) (32) (32) (32) (28, 32,42, 62) (32) (42) (32) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (49) (49) (32) (32) (32, 42) (63, 64)

TZ NC NC

TZ

8 goleptine 49 haemanthamine

PN PN TZ PN

PN BC PN NC PN

(65) (33) (49) (38) (32, 42) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (32) (40, 44, 45) (32) (30) (66) (49,51) (67) (53, 54) (32, 42) (32)

338 TABLE 2 (continued)

Alkaloid 49 haemanthamine (cont.)

Wild species / cultivars

Section

References (32) (32) (28, 32, 42, 55) (32) (32, 42) (32) (32) (32) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (35, 49, 56) (49) (49) (49) (49) (49) (49) (49) (49) (40) (40) (40) (32) (32) (32) (32, 68) (32,42) (33) (65) (40) (46) (57) (65) (40) (46) (57) (32) (40, 44) (40) (53) (55) (35) (49) (34)

A ^ . pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator A ^ . pseudonarcissus L. cv. King Alfred A ^ . pseudonarcissus L. cv. Magnet A ^ . pseudonarcissus L. cv. Magnificience A ^ . pseudonarcissus L. cv. Mrs. Ernst H. Krelage A'^ pseudonarcissus L. cv. Music Hall A^. pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Rockery Beauty N. pseudonarcissus L. cv. Romaine A ^ . pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion N. pseudonarcissus L. cv. Victoria A ^ . pseudonarcissus L. cv. Wrestler A ' ^ , tazetta L. TZ A ^ . tazetta L. cv. Cragford A'^. tazetta L. cv. Early Perfection A^. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee N. tazetta L. cv. Laurens Koster A^. tazetta L. cv. L'innocence N. tazetta L. cv. Scarlet Gem A ^ . tazetta L. cv. St. Agnes N. triandrus L. cv. Silver Chames A'^. triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Inglescombe A^. cv. Insulinde N. cv. Livia A^. cv. Texas A ^ . cv. Twink A^. bujei (Fdez. Casas) Fdez. Casas A^. A^. A ^ . A ^ . A^. A^. A ^ . A ^ . asturiensis (Jordan) Pugsley cyclamineus DC. cv. Cairhays tazetta L. tazetta L. var. chinensis Roem. asturiensis (Jordan) Pugsley cyclamineus DC. cv. Cairhays tazetta L. tazetta L. var. chinensis Roem. PN PN TZ TZ PN TZ TZ

50 11-O-acetylhaemanthamine 51 haemanthidine

52 6-epihaemanthidine

30 hippeastrine

A'^ X incomparabilis Mill. cv. Fortune A ^ . jonquilla L. cv. Golden Sceptre N. X odorus L. var. rugulosus N. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. King Alfred A ^ . tazetta L. A^. tazetta L. cv. Early Perfection 1N. cv. Salome

JN TZ

339 TABLE 2 (continued)

Alkaloid 23 homolycorine

Wild species / cultivars

N. bujei (Fdez. Casas) Fdez. Casas N. confusus Pugsley N. cyclamineus DC. cv. February Gold N. eugeniae Fdez. Casas N. X incomparabilis Mill. cv. Helios A^. jonquilla L. cv. Golden Sceptre N. munozii-garmendiae Fdez. Casas N. X odorus L. var. rugulosus N. pallidiflorus Pugsley N. panizzianus Pari. N. papyraceus Ker. Gawl. N. poeticus L. N. poeticus L. var. ornatus Hort. N. poeticus L. cv. Daphne N. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. N. pseudonarcissus L. cv. Carlton N. pseudonarcissus L. cv. Grand Maitre N. pseudonarcissus L. cv. Imperator N. pseudonarcissus L. cv. King Alfred N. pseudonarcissus L. cv. Van Sion A^. radinganorum Fdez. Casas A ' ^ tazetta L. N. tazetta L. var. chinensis Roem. N. tazetta L. cv. Cragford N. tazetta L. cv. Early Perfection N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A': tazetta L. cv. Laurens Koster A^. tazetta L. cv. L'innocence A^. tazetta L. cv. Scarlet Gem N. tazetta L. cv. St. Agnes A^. tortifolius Fdez. Casas A^. triandrus L. cv. Thalia A^. vasconicus Fdez. Casas N. cv. Inglescombe A^. bujei (Fdez. Casas) Fdez. Casas N. pallidiflorus Pugsley A^. papyraceus Ker. Gawl. A^. primigenius (Lainz) Fdez. Casas & Lainz N. pseudonarcissus L. cv. King Alfred A^. radinganorum Fdez. Casas A ^ . tazetta L. A^. tortifolius Fdez. Casas A^. papyraceus Ker. Gawl. N. vasconicus Fdez. Casas A ^ . bicolor L. A^. confusus Pugsley

Section
PN PN PN PN JN PN TZ TZ NC NC PN PN

References
(33) (69) (40) (39) (32) (44) (70) (40) (66) (61) (71,72) (49) (49,51,73) (32) (67) (74) (53) (32) (32) (28, 55, 62) (32, 42) (75) (76-78) (57) (49) (49) (49) (49) (49) (49) (49) (49) (37) (40) (79) (32) (33) (66) (71,72) (67) (55) (75) (77, 80) (37) (71,72) (79) (29) (69)

PN TZ TZ

DB PN PN PN TZ PN PN TZ DB TZ PN PN PN

24 8-O-demethylhomolycorine

37 8-O-demethylhomolycorine-A^-oxide 25 8-0-demethyl-8-0-acetylhomolycorine 26 9-O-demethylhomolycorine

340

TABLE 2 (continued)
Alkaloid 29 Wild s p e c i e s / cultivars Section DB DB PN PN BC PN References (81) (37) (65) (29) (30) (66) (44) (40) (43) (48) (53, 54) (57) (32, 42) (32, 42) (32, 42) (32) (32) (32) (32,42) (32) PN (60) (54) (33) (40) (40) (39, 82) (32) (32) (44) (40) (70) (62) (49) (49) (32) (49) (53, 54) (32, 42) (32) (28, 32, 42, 55, 62) (32) (32) (32, 42) (57) (40) (40) (32) (33) (70)

9-0-demethyl-2a-hydroxy- A^. dubius Gouan A^. tortifolius Fdez. Casas homolycorine A^. asturiensis (Jordan) Pugsley N. bicolor L. N. obesus Salisb. A^. pallidiflorus Pugsley A^. jonquilla L. cv. Golden Sceptre A^. cyclamineus DC. cv. February Gold A^. jonquilla L. A^. papyraceus Ker. Gawl. A^. pseudonarcissus L. cv. Carlton N. tazetta L. var. chinensis Roem. A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus A^. pseudonarcissus L. cv. Covent Garden L. cv. King Alfred L. cv. Magnificience L. cv. Rembrandt L. cv. Rockery Beauty L. cv. Spring Glory L. cv. Van Sion L. cv. Victoria

68 ismine

9 jonquilline 78 lycoramine

JQ TZ TZ

79 norlycoramine

80 epinorlycoramine

A^. leonensis Pugsley A^. pseudonarcissus L. cv. Carlton A^. bujei (Fdez. Casas) Fdez. Casas A^. cyclamineus DC. cv. February Gold A^. cyclamineus DC. cv. Peeping Tom A^. eugeniae Fdez. Casas A'^, X incomparabilis Mill. cv. Helios A^. X incomparabilis Mill. cv. Suda A^. jonquilla L. cv. Golden Sceptre A^. jonquilla L. cv. Trevithian A'^ munozii-garmendiae Fdez, Casas A^. poeticus L. A^. poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. Carlton A^. pseudonarcissus L. cv. Covent Garden A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A^. pseudonarcissus L. cv. Romaine A^. pseudonarcissus L. cv. Unsurpassable N. pseudonarcissus L. cv. Van Sion A^. tazetta L. var. chinensis Roem. A'^, triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Inglescombe A^. bujei (Fdez. Casas) Fdez. Casas A^. munozii-garmendiae Fdez. Casas

31 lycorenine

PN

PN

PN NC NC

TZ

32

O-methyllycorenine

PN PN

341 TABLE 2 (continued)

Alkaloid

Wild species / cultivars

Section

References
(53, 54) (40) (46) (40) (32, 42) (32) (32) (32) (32) (32, 42) (32) (32) (27) (40) (46) (60) (40) (48,71,72) (49, 50, 83) (49,51,52) (49) (32) (49) (84) (32, 42) (32) (32) (32) (32, 42) (32, 42) (32) (32) (32) (32) (32) (32,42) (32) (35, 46, 49, 56, 7678) (57) (49) (49) (49) (49) (49) (49) (49) (49) (85) (40) (40) (79) (32) (32) (32)

32 0-methyllycorenine (cont.) N. pseudonarcissus L. cv. Carlton 1 lycorine A^. cyclamineus DC. cv. Beryl N.folli N. X gracilis Sabine A^. X incomparabilis Mill. cv. Deanna Durbin N. X incomparabilis Mill. cv. Flower Record N. X incomparabilis Mill. cv. John Evelyn N. X incomparabilis Mill. cv. Marion Cran N. X incomparabilis Mill. cv. Nova scotia A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. X incomparabilis Mill. cv. Toronto A ^ . jacetanus Fdez. Casas A^. jonquilla L. cv. Trevithian A ^ . kristalli N. leonensis Pugsley A ^ . X odor us L. var. rugulosus N. papyraceus Ker. Gawl. A ^ . posticus L. A ^ . poeticus L. var. ornatus Hort. A^. poeticus L. cv. Actaea A^. poeticus L. cv. Daphne A^. poeticus L. cv. Sarchedon N. pseudonarcissus L. A'^ pseudonarcissus L. cv. Covent Garden N. pseudonarcissus L. cv. Early Glory A^. pseudonarcissus L. cv. Grand Maitre A^. pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A'^, pseudonarcissus L. cv. Magnificience A^. pseudonarcissus L. cv. Mrs. Ernst H. Krelage A^. pseudonarcissus L. cv. Music Hall A^. pseudonarcissus L. cv. Queen of Bicolors A^. pseudonarcissus L. cv. Rembrandt A^. pseudonarcissus L. cv. Spring Glory A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A ^ . tazetta L. A ^ . tazetta L. var. chinensis Roem. A^. tazetta L. cv. Cragford A'^. tazetta L. cv. Early Perfection N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A^. tazetta L. cv. Laurens Koster N. tazetta L. cv. L'innocence A^. tazetta L. cv. Scarlet Gem A^. tazetta L. cv. St. Agnes A^. tortuosus Haworth A^. triandrus L. cv. Silver Chames A^. triandrus L. cv. Thalia A^. vasconicus Fdez. Casas A^. cv. Inglescombe A^. cv. Insulinde A^. cv. Irene Copeland

JC

PN PN JN TZ NC NC

PN

TZ TZ

PN PN

342

TABLE 2 (continued)
Alkaloid 1 lycorine (cont.) Wild species / cultivars A ^ . cv. Livia N. cv. Texas A ^ . cv. Twink A^. asturiensis (Jordan) Pugsley A ^ . bicolor L. A ^ . obesus Salisb. N. papyraceus Ker. Gawl. A ^ . tazetta L. var. chinensis Roem. A ^ ' , primigenius (Lainz) Fdez. Casas 8L Lainz A'^. radinganorum Fdez. Casas A ^ . papyraceus Ker. Gawl. A ^ . tazetta L. A ^ . tazetta L. var. chinensis Roem. A ^ . tazetta L. var. chinensis Roem. A ^ . tazetta L. var. chinensis Roem. A'^ bujei (Fdez. Casas) Fdez. Casas A^. jonquilla L. cv. Golden Sceptre A ' ^ , pseudonarcissus L. A^. pseudonarcissus L. cv. Carlton A ^ . tazetta L. A ^ . pseudonarcissus L. cv. Carlton A^. pallidulus Graells A ^ . canaliculatus Guss var. tipica N. cyclamineus DC. var. tipica N. X incomparabilis Mill. cv. Carabinieri A ^ . X incomparabilis Mill. cv. Helios A * " . X incomparabilis Mill. cv. Mercato A^. X incomparabilis Mill. cv. Orange Bruid A'^. X incomparabilis Mill. cv. Mrs. R. O. Backhouse A^. X incomparabilis Mill. cv. Scarlet Elegance A^. X incomparabilis Mill. cv. Sempre Avanti A ^ . X incomparabilis Mill. cv. Tunis A ^ . X incomparabilis Mill. cv. Walt Disney A ^ . jonquilla L. A^. jonquilla L. cv. Trevithian A ^ . X odorus L. var. rugulosus N. poeticus L. cv. Actaea A ^ . poeticus L. cv. Cheerfulness A^. pseudonarcissus L. cv. Carlton A ^ . pseudonarcissus L. cv. Flower Carpet A ^ . pseudonarcissus L. cv. Golden Harvest IA^. pseudonarcissus L. cv. King Alfred CM TZ CM PN FN BC TZ TZ PN PN TZ TZ TZ TZ TZ PN PN TZ Section References (32) (32) (32, 42) (65) (29) (30) (48) (57) (67) (75) (71,72) (77) (57) (57) (57) (33) (44) (74) (53, 54) (35) (53, 54) (25) (86) (86) (86) (86, 87) (86) (86) (86) (86) (86, 87) (86) (86) (43) (86) (86) (86) (86) (86) (86) (86) (62, 86, 87)

62 3-epimacronine

40 maritidine 41 8-O-demethylmaritidine 42 9-0-demethylmaritidine 43 O-methylmaritidine

47 6a-hydroxy3 - 0-methy lepimaritidine 48 6p-hydroxy3 - O-methy lepimaritidine 27 masonine

28 normasonine 82 mesembrenone 64 narciclasine

JQ JN

343

TABLE 2 (continued)
Alkaloid 64 narciclasine (cont.)

Wild species / cultivars

A^. pseudonarcissus L. cv. Mount Hood A^. pseudonarcissus L. cv. President Lebrum A^. pseudonarcissus L. cv. Rembrandt N. serotinus Lofl. ex L. var. tipica N. tazetta L. var. tipica N. tazetta L. cv. Geranium A ^ . triandrus L. cv. Thalia A^. triandrus L. cv. Tresamble A^. cv. Celebrity A^. cv. Clamor A^. cv. Texas A^. cv. Totus Albus N. cv. Verger A^. pseudonarcissus L. cv. King Alfred A^. poeticus L. Narcissus sp N. tazetta L. N. cyclamineus DC. cv. Beryl A^. X incomparabilis Mill. cv. Deanna Durbin A^. X incomparabilis Mill. cv. Pluvius A^. X incomparabilis Mill. cv. Sempre Avanti A^. poeticus L. N. poeticus L. cv. Actaea A^. poeticus L. cv. Sarchedon A^. pseudonarcissus L. cv. King Alfred N. pseudonarcissus L. cv. Rockery Beauty A^. tazetta L. A^. tazetta L. cv. Geranium A^. tazetta L. cv. L'innocence N. poeticus L. N. tazetta L. A ^ . cyclamineus DC. N. kristalli N. pseudonarcissus L. cv. Carlton N. tazetta L. N. cv. Irene Copeland A^. cv. Texas A^. obesus Salisb. A ^ . X incomparabilis Mill. cv. Fortune A ^ . jonquilla L. cv. Golden Sceptre A^. X odorus L. var. rugulosus N. pseudonarcissus L. cv. Carlton A^. bujei (Fdez. Casas) Fdez. Casas N. pseudonarcissus L. cv. Carlton

Section

References
(86) (86) (86) (86) (86-88) (88) (86, 87) (86, 87) (86) (86) (86) (86) (86) (55)

ST TZ

54 narcidine 56 narcimarkine 65 narciprimine 76 narcisine 16 narcissidine

NC

(50, 89) (87)

TZ

(56) (40) (32, 42) (32, 42) (32) (50, 62, 83) (49) (49) (55) (32) (49) (49) (49) (49) (35, 49) (90) (46) (53, 54) (35) (32) (32, 91) (30) (32) (40, 44) (40) (53, 54) (33) (53, 54)

NC

TZ

17 nartazine 77 narwedine

NC TZ CM TZ

63 obesine 33 oduline

BC

JN FN

34 6-(9-methyloduline

344

TABLE 2 (continued)
Alkaloid 35 2a-hydroxy6-0-methyloduline 81 pallidiflorine 69 pancracine 44 papyramine

Wild species / cultivars

A ^ . cv. Salome N. pallidiflorus Pugsley A'', poeticus L. A ^ . panizzianus Pari. A ^ . papyraceus Ker. Gawl. A ^ . tazetta L. var. chinensis Roem. A ^ . panizzianus Pari. A ^ . papyraceus Ker. Gawl. A ^ . tazetta L. var. chinensis Roem. A ^ . papyraceus Ker. Gawl.

Section

References
(34)

PN NC TZ TZ TZ TZ TZ TZ TZ

(66) (92) (61) (48,71,72) (57) (61) (48,71,72) (57) (71,72) (40) (40) (32) (32, 42) (32) (32) (32) (32) (32) (32) (62) (32, 42) (32) (42, 62) (32) (32, 42) (32) (32) (32) (32) (32) (32) (32, 42) (32) (32) (49) (57) (32) (32) (32) (32) (32, 42) (54, 58) (54, 58)

45 6-epipapyramine

46 0-methyl6-epipapyramine 11 pluviine

A^. cyclamineus DC. cv. Cairhays A ^ . cyclamineus DC. cv. Peeping Tom A ^ . X incomparabilis Mill. cv. Daisy Schaffer A^. X incomparabilis Mill. cv. Deamia Durbin A ^ . X incomparabilis Mill. cv. Flower Record A ^ . X incomparabilis Mill. cv. Helios A ^ . X incomparabilis Mill. cv. John Evelyn A ^ ' , X incomparabilis Mill. cv. Pluvius A ^ . X incomparabilis Mill. cv. Sempre Avanti A ^ . X incomparabilis Mill. cv. Suda A ^ . poeticus L. NC A^. pseudonarcissus L. cv. Covent Garden A ^ . pseudonarcissus L. cv. Imperator A^. pseudonarcissus L. cv. King Alfred A ^ . pseudonarcissus L. cv. Magnet A ^ . pseudonarcissus L. cv. Magnificience A ^ . pseudonarcissus L. cv. Mrs. Emst H. Krelage A ^ . pseudonarcissus L. cv. Oliver Cromwell A^. pseudonarcissus L. cv. Queen of Bicolors A ^ . pseudonarcissus L. cv. Romaine A ^ . pseudonarcissus L. cv. Spring Glory A ^ . pseudonarcissus L. cv. Unsurpassable A^. pseudonarcissus L. cv. Van Sion A^. pseudonarcissus L. cv. Victoria A ^ . pseudonarcissus L. cv. Wrestler A ^ . tazetta L. cv. Early Perfection A ^ . tazetta L. var. chinensis Roem. TZ A ^ . cv. Inglescombe A ^ . cv. Insulinde A ^ . cv. Livia A ^ . cv. Texas A ^ . cv. Twink A ^ . pseudonarcissus L. cv. Carlton A ^ . pseudonarcissus L. cv. Carlton

13 9-O-demethylpluviine 14 1-O-acetyl9-O-demethylpluviine

345

TABLE 2 (continued) Alkaloid

15 l,9-(9-diacetyl9-O-demethylpluviine

Wild species / cultivars

N. pseudonarcissus L. cv. Carlton

Section

References
(58)

12 norpluviine 2 poetaminine 38 poetinatine 61 pretazettine

A'^ cv. Texas A^. poeticus L. var. ornatus. Hort. A^. poeticus L. var. ornatus. Hort. A^. bicolor L. A^. confusus Pugsley A^. obesus Salisb. A'^. pallidiflorus Pugsley A^. panizzianus Pari. A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. assoanus Leon-Duf. A^. dubius Gouan A^. jacetanus Fdez. Casas A^. papyraceus Ker. Gawl. A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. cv. Salome A^. assoanus Leon-Duf. A^. assoanus Leon-Duf. A^. nivalis Graells A^. poeticus L. A^. pseudonarcissus L. cv. King Alfred A^. pallidulus Graells A^. asturiensis (Jordan) Pugsley A^. bujei (Fdez. Casas) Fdez. Casas A^. canaliculatus Guss A^. cantabricus DC. A'^. cyclamineus DC. cv. Peeping Tom N.folli N. X gracilis Sabine A^. jonquilla L. cv. Golden Sceptre N. jonquilla L. cv. Trevithian A^. kristalli N. X odorus L. var. rugulosus N. papyraceus Ker. Gawl. A^. poeticus L. var. ornatus Hort. A^. pseudonarcissus L cv. Grand Maitre N. pseudonarcissus L. cv. Van Sion A^. tazetta L. A^. tazetta L. var. chinensis Roem. A^. tazetta L. cv. Cragford A^. tazetta L. cv. Early Perfection NC NC PN PN BC PN TZ TZ TZ JQ DB PN TZ TZ TZ

(93) (51) (52) (29) (38) (30) (66) (61) (56, 76, 77) (57) (94) (81) (27) (48,71,72) (56, 76, 77) (57, 95) (34) (94) (94) (47) (62) (28, 62) (96) (65) (33) (49) (31) (40) (46) (40) (40, 44, 45) (40) (46) (40) (48) (51) (32) (32) (35, 46, 56, 77, 78, 97, 98) (57, 95) (49) (49)

3 pseudolycorine

1-O-acetylpseudolycorine

JQ JQ BC NC

5 2-0-acetylpseudolycorine 6 9-O-methylpseudolycorine

22 roserine 59 tazettine

CM PN PN TZ BC

JC

JN TZ NC

TZ TZ

346

TABLE 2 (continued)
Alkaloid 59 tazettine (cont.)

Wild species / cultlvars

N. tazetta L. cv. Geranium A^. tazetta L. cv. La Fiancee A ^ . tazetta L. cv. Laurens Koster N. tazetta L. cv. L'innocence N. tazetta L. cv. Scarlet Gem N. tazetta L. cv. St. Agnes N. triandrus L. cv. Silver Chames A ^ . tortuosus Haworth A': cv. Salome A'^ asturiensis (Jordan) Pugsley A ^ . bicolor L, A ^ . vasconicus Fdez. Casas A ^ . cv. Salome A ^ . cantabricus DC. A^. pseudonarcissus L. cv. Carlton

Section

References
(49) (49) (49) (49) (49) (49) (40)

21 tortuosine 66 trisphaeridine 20 vasconine

PN FN PN PN BC

(85) (34) (65) (29) (79) (34) (31) (53, 54)

39 vittatine

The taxonomical aspects are based on the works of J. Fernandez Casas (99-105) and other authors (106-110) for wild Narcissus species and hybrids, and those of Jefferson-Brown (111) and Boit and Piozzi (32, 40, 42, 49, 86) for Narcissus cultivars (cv.). Key to sections: BC = Bulbocodii DC; CM = Cyclaminei DC; DB = Dubii Fdez. Casas; JC = x Joncissus Fdez. Casas ( Jonquillae DC x Narcissus L.); JN = x Jonissi Fdez. Casas {Jonquillae DC x Pseudonarcissi DC); JQ = Jonquillae DC; NC = Narcissus L.; PN = Pseudonarcissii DC; ST = Serotini Pari.; and TZ = Tazettae DC

3.

BIOSYNTHETIC

PATHWAYS

The work on the biosynthesis of Amaryllidaceae alkaloids reached a peak in the period 1960-1976 with a great number of studies related with this subject. However, since then, little new work has been produced apart from the isolation of compounds predicted as biosynthetic intermediaries of a certain pathway or, more recently, a new biosynthetic proposal to obtain galanthamine (70), which differs from the initial one. Although L-Phe and L-Tyr are closely related in chemical structure, they are not interchangeable in plants. In the Amaryllidaceae alkaloids, L-Phe serves as a primary precursor of the Ce-C^ fragment, corresponding to ring A and the benzylic position (C-6), and L-Tyr is the precursor of ring C, the two-carbon side chain (C-11 and C-12) and nitrogen, C6-C2-N. The conversion of L-Phe to the Ce-Ci unit requires the loss of two carbon atoms from the side chain as well as the introduction of at least two oxygenated

347

substituents into the aromatic ring, wiiich is performed via cinnamic acids. Tiie presence of the enzyme PAL has been demonstrated in Amaryllidaceae plants (112) and the elimination of ammonia mediated by this enzyme is known to occur in an antiperiplanar manner to give frans-cinnamic acid, with loss of the B-pro-S hydrogen (113). Thus, it may be expected that L-Phe would be incorporated into Amaryllidaceae alkaloids with retention of the B-pro-R hydrogen. However, feeding experiments in Narcissus pseudonarcissus cv. King Alfred showed that tritium originally present at C-3 of L-Phe, whatever the configuration, was lost in the formation of several haemanthamine and homolycorine type alkaloids, which led to the conclusion that fragmentation of the cinnamic acids involves oxidation of C-B to ketone or acid level, the final product being protocatechuic aldehyde or its derivatives (Fig. 3). On the other hand, L-Tyr is degraded no further than tyramine before incorporation into the Amaryllidaceae alkaloids. Thus, tyramine and protocatechuic aldehyde -or derivatives of the latter- are logical components for the biosynthesis of the precursor norbelladine (85). This reaction occupies a pivotal position since it represents the entry of primary metabolites into a secundary metabolic pathway. The junction of the amine and the aldehyde results in a Schiff's base, two of which have been isolated up to now: craugsodine (114) and isocraugsodine (115). The existence of Schiff's bases in nature as well as their easy conversion into the different ring-systems of the Amaryllidaceae alkaloids allow the presumption that the initial postulate about this biosynthetic pathway was correct. Barton and Cohen (116) proposed that norbelladine (85) or related compounds could undergo oxidative coupling of phenols in Amaryllidaceae plants, once ring A had been suitably protected by methylation, resulting in the different skeletons of the Amaryllidaceae alkaloids (Fig. 4). a.- Lycorine and IHomolycorine types. The pyrrolo[de]phenanthridine alkaloids (lycorine type) and the 2-benzopirano[3,4-g]indole alkaloids (homolycorine type) both originate from an orttio-para' phenoloxidative coupling (Fig. 5). The biological conversion of cinnamic acid via hydroxylated cinnamic acids into the Ce-Ci unit of norpluviine (12) has been used in a study of hydroxylation mechanisms In higher plants (117). When [3-3H, P-^^Q] cinnamic acid was fed to Narcissus pseudonarcissus cv. Texas a tritium retention in norpluviine (12) of 28% was observed. This is very near a predicted value of 25%, resulting from para-hydroxylation with

348

L-Phe PAL

COOH

frans-cinnamic add
HO

Tyr-decarboxylase

COOH

para-coumaric acid: R= H caffeic acid: R= OH

HO^

HO"

^CH

protocatechuic aldehyde HO

Sciiiff's base (isomeric structures in solution)

OH

HO

HO

rL3
85

Fig. 3. Biosynthetic pathway to norbelladine (85).

HO O

a NH

Q NH

OH

M e O & q

OH
NR

HO

/
88

HO

/
88

/
88/93

ortho-para

para-para

para-otfho

tvPes
lycorine (1) homolycorine (23)

tVDeS
crinine (86) haemanthamine (49) tazettine (59) narciclasine (64) montanine (87) galanthamine (70)

349

Fig. 4. Oxidative phenyl-phenyl coupling in Amaryllidaceae alkaloids.

OH

M e O & q

NH

M e O &

I t M e O &

350

OMe

M e O &

HO

/
88

Me0
11

Me0

/
6

Me0 7

M e O &

I ) MeO&

Me0

/
OH
31

Me0

0
23

Fig. 5. Alkaloids proceeding from an ortho-para' coupling.

351 hydrogen migration and retention, where half the tritium would be lost In the first hydroxylation and half the remainder in the second. In the conversion of 0-methylnorbelladine (88) into lycorine (1), the labelling position [3-3H] on the aromatic ring of L-Tyr afterwards appears at C-2 of norpluviine (12), which is formed as an intermediate, the configuration of the tritium apparently being p (93). This tritium is retained in subsequently formed lycorine (1), which means that hydroxylation at C-2 proceeds with an inversion of configuration (118) by a mechanism involving an epoxide, with ring opening followed by allylic rearrangement of the resulting alcohol (Fig. 6). Supporting evidence comes from the incorporation of [2p-^H]caranine (10) into lycorine (1) in Zephyranthes Candida (119). However, an hydroxylation of caranine (10) in Clivia miniata occuring with retention of configuration was also observed (120). Further, [2a-^H; ll-^'^Clcaranine (10) was incorporated into lycorine (1) with high retention of tritium at C-2, indicating that no 2-oxo-compound can be implicated as an intermediate. The conversion of the 0-methoxyphenol to the methylenedloxy group may occur late in the biosynthetic pathway. Tritiated norpluviine (12) is converted to tritiated lycorine (1) by Narcissus x incomparabilis cv. Deanna Durbin, which not only demonstrates the previously mentioned conversion but also indicates that the C-2 hydroxyl group of lycorine (1) is derived by allylic oxidation of either norpluviine (12) or caranine (10) (121). Regarding the conversion of [23-^H, S-OMe-^'^Clpluviine (11) into galanthine (7), in Narcissus pseudonarcissus cv. King Alfred, the retention of 79% of the tritium label confirms that hydroxylation of C-2 may occur with inversion of configuration (62). It was considered (122) that another analogous epoxide (89) could give narcissidine (16) in the way shown by loss of the pro-S hydrogen from C-11, galanthine (7) being a suitable substrate for epoxidation. Labelled [a-^'^C, p-^H]-0-methylnorbelladine (88), when fed to Narcissus x incomparabilis cv. Sempre Avanti afforded galanthine (7) (98% of tritium retention) and narcissidine (16) (46% tritium retention). Loss of hydrogen from C-11 of galanthine (7) was therefore stereospecific. Recently, Kihara et al. (123) have isolated a new alkaloid, incartine (89), from flowers of Lycoris incarnata, which could be considered to be the biosynthetic intermediate of this pathway (Fig. 7). The biological conversion of protocatechuic aldehyde into lycorenine (31), which proceeds via 0-methylnorbelladine (88) and norpluviine (12), first involves a reduction of

352

12

Fig. 6 . Biosynthesis of lycorine (1) with inversion of the configuration.

Me0

Me0

HS

Me0

Me0
7

Me0

/
89

Me0
16

Fig. 7. Conversion of galanthine (7) to narcissidine (16) via epoxide (89).

353

the aldehyde carbonyl, and afterwards, in the generation of lycorenine (31), oxidation of this same carbon atom. The absolute stereochemistry of these processes has been elucidated In subsequent experiments (124), and the results show that hydrogen addition and removal take place on the re-face of the molecules concerned (125), the hydrogen initially introduced being the one later removed (126). It is noteworthy that norpluvilne (12), unlike pluviine (11), is converted in Narcissus pseudonarcissus cv. King Alfred primarily to alkaloids of the homolycorine type. Benzylic oxidation of position 6 would afford (90), followed by ring opening to form an amino aldehyde and then a hemiacetal formation and methylation could provide lycorenine (31) (62), oxidation, could give homolycorine (23) as can be seen in Fig. 8. b. Crinine, Haemanthamine, Tazettine, Narciclasine and l\/lontanine types The alkaloids derived from 5,10b-ethanophenanthridine (crinine and haemanthamine types), 2-benzopyrano[3,4c]indole (tazettine type), phenanthridine oxidative phenolic coupling (Fig. 9). Results of experiments with labelled crinine (86), and less conclusively with oxovittatine, indicate that the two naturally occurring enantiomeric series, represented in Figure 9 by crinine (86) and vittatine (39), are not interconvertible in Nerine bowdenii (127). Incorporation of 0-methylnorbelladine (88), labelled in the methoxy carbon and also in positions [3,5-^H], into the alkaloid haemanthamine (49) was without loss of tritium, half of which was sited at C-2 of (49). Consideration of the possible mechanisms involved in relation to tritium retention led to the suggestion that the tritium which is expected at C-4 of (49) might not be stereospecific (128). The conversion of Omethylnorbelladine (88) into haemanthamine (49) involves loss of the pro-R hydrogen from the C-3 of the tyramine moiety, as well as a further entry of a hydroxyl group at this site (129). The subsequent benzylic oxidation results in an epimeric mixture (51/52) which even HPLC can not separate. The epimeric forms were proposed to be interconvertible through (91a). The biosynthetic conversion of the 5,10bethanophenanthridine alkaloids to the 2-benzopyrano[3,4-c]indole was demonstrated by feeding tritium-labeled alkaloids to Sprekeiia formosissima. It was shown that this plant converts haemanthamine (49) to haemanthidlne/ epihaemanthamine subsequently to tazettine (59) in an essentially irreversible manner (51/52) and (130). This (narciclasine type) and 5,11b-methanomorphanthridine (montanine type) originate from a para-para' and, on subsequent

transformation was considered to proceed through (91a) or the related alkoxide anion.

354

M e O &

[ol
/
12

M e O &

/
OH
90

M e O &

HO

HO

HO

CH

II

1
Me0 Me0

rotation

0
23

methylations
Me0 OH 31

n
Me0& HO CH

II 0

Fig. 8 . Conversion of norpluviine (12) to homolycorine type alkaloids.

(&--OH 0

OH
61

OH
51

355

Fig. 9. Alkaloids proceeding from a para-para coupling.

356 although this intermediate (91a) and Its rotational equivalent (91b) have never been detected by spectral methods (131) (Fig. 10). It has also been proved that the alkaloid narciclasine (64) proceeds from the pathway of the biosynthesis of crinine and haemanthamine type alkaloids and not through norpluviine (12) and lycorine (1) derivatives. In fact, in view of its structural affinity to both haemanthamine (49) and lycorine (1), narciclasine (64) could be derived by either pathway. When 0-methylnorbelladine (88) labelled in the methoxy carbon and in both protons of position 3 and 5 of the tyramine aromatic ring, was administered to Narcissus plants, all four alkaloids incorporated activity. The isotopic ratio [^H:^'^C] for norpluviine (12) and lycorine (1) was, as expected, 50% that of the precursor, because of its ortho-para' coupling. On the contrary, in haemanthamine (49) the ratio was unchanged. These results prove that the methoxy group of (88) is completely retained in the alkaloids mentioned, providing a satisfactory internal standard and also, the degree of tritium retention is a reliable guide to the direction of phenol coupling. Narciclasine (64) showed an isotopic ratio (75%) higher than that of lycorine or norpluviine (12) though lower than that of haemanthamine (49). However, the fact that more than 50% of tritium is retained suggests that 0-methylnorbelladine (88) is incorporated into narciclasine (64) via para-para' phenol oxidative coupling. O-methylnorbelladine (88) and vittatine (39) are implicated as intermediates in the biosynthesis of narciclasine (64) (132-134), and the loss of the ethane bridge from the latter could occur by a retro-Prins reaction on 11-hydroxyvittatine (92). Strong support for this pathway was obtained by labelling studies. 11-Hydroxyvittatine (92) has also been proposed as an intermediate in the biosynthesis of haemanthamine (49) and montanine (87) (a 5,11b-methanomorphanthridine alkaloid) following the observed specific incorporation of vittatine (39) into the two alkaloids in Riiodophiala bifida (127) (Fig. 11). Fuganti and Mazza, (133, 134) concluded that in the late stages of narciclasine (64) biosynthesis, the two-carbon bridge is lost from the oxocrinine skeleton, passing through intermediates bearing a pseudoaxial hydroxy-group at C-3 position and further hydrogen removal from this position does not occur. Noroxomaritidine was also implicated in the biosynthesis of narciclasine (64) and further experiments (135) showed that it is also a precursor for ismine (68). The alkaloid ismine (68) has also been shown (136) to be a transformation product of the crinine-haemanthamine series. The precursor, oxocrinine labelled with tritium in the positions 2 and 4, was administered to Sprel<elia formosissima plants and the radiactive ismine (68) isolated was shown to be specifically labelled at the expected positions.

=(
0
51

I
H
52

CH

OH

0
91a

III
OMe
OMe

NH

1 -

methylation

II 0

CH

91b

61

Fig. 10. Biosynthesis of pretazettine (61).

357

358

39

92

87

Fig. 11. Proposed biosynthetic pathways to haemanthamine (49) and montanine (87).

359 c. Galanthamine type. The alkaloids with a dibenzofuran nucleus (galanthamine type) are obtained from a para-ortho' phenyl oxidative coupling. Although norbelladine (85) was shown not to be a precursor of galanthamine (70) in Narcissus pseudonarcissus cv. King Alfred, an incorporation of this labelled compound has been obtained in Leucojum aestivum (128). The initial studies of this pathway suggested that the phenyl oxidative coupling does not proceed from 0-methylnorbelladine (88) but that the order of methylation of the precursors should be norbelladine (85) --> A/-methylnorbelladine -->A/,0-dimethylnorbelladine (93) to finally give galanthamine (70) (137), the conversion of (94) to narwedine (77) either being not reversible or, if so, enzymically controlled (128). The precursor N,0dimethylnorbelladine (93) was first Isolated in 1988 from Pancratium maritimum (138) a species that also contains galanthamine (70) (Fig. 12a). Chlidanthine (95), by analogy with the known conversion of codeine to morphine, might be expected to arise from galanthamine (70) by 0-demethylation. This was shown to be true when both galanthamine (70) and narwedine (77), with tritium labels, were incorporated into chlidanthine (95) (139). However, the most recent studies related to the biosynthesis of galanthamine (70) seem to contradict the evidence set forth here. Experiments carried out in cell suspension cultures of Leucojum vernum have shown that the methylation of the nitrogen atom occurs after the phenolic coupling and is brought about through an acetyl intermediate (140) (Fig. 12b).

360

93

94

77

70

95

Fig. 12a. Biosynthesis of galanthamine (70) proposed by Barton et al., 1963.

0

HO

HO

HO

NH

Me0

Me0

Me0

Me0

00

&NH

/
Me0

&NH

I I )

&NMe

Me0

/
73

Me0

/
70

Fig. 12b. Biosynthesis of galanthamine (70) proposed by Eichhorn and Zenk, 1995.

361 4. SPECTROSCOPY Only ^H NMR, ^^C NMR, and mass spectrometry, the three most important spectroscopic methods for the Amaryllidaceae alkaloids, will be treated here. A list of names of the different Narcissus alkaloids, their physical and spectroscopic properties, as well as literature is given in Table 3. With respect to the spectroscopic results, the most recent data about the mentioned alkaloids are provided, even when isolation was made from species of genera other than Narcissus.

TABLE 3 Narcissus alkaloids data melting Molecular MW point C Formula (Ref) CnHnNO^ CnHisNOs 267 281 238 301 175-176 (141) 247-250 (26) 261-263 (29) [ah'' +37 128-130 MeOH; c 0.25 (31) (31) 128-130 [OC]D'" +37 (31) MeOH; c 0.25 (31) 75-76 (31) 176-178 (144)
M D ' " -7.14 MeOH; c 0.52 (31)

Alkaloid 18 assoanine 19 oxoassoanine 67 bicolorine 57 6a-hydroxybuphanisine 58 6P-hydroxybuphanisine 55 cantabricine

[a]D (Ref.)

Additional data (Ref.) UV(26),IR(26),MS(26), ^H NMR (26), *^C NMR (26)

'H

UV(26),IR(26),MS(26), NMR (26), ^'C NMR (26) IR (29), MS (29), NMR (29), '^C NMR (29)

Ci5H,2N02

'H

C17H19NO4

UV(142),IR(142),MS(142), 'H NMR (142), '^C NMR (143) UV (142), IR (142), MS (142), 'H NMR (142), ^^C NMR (143) IR(31),MS(31),
^ H N M R ( 3 1 ) , *^CNMR(31)

C,7Hi9N04

301

C,8H23N04

317

10 caranine

Ci6HnN03

271

[alo''-196.6 CHCI3; c 2.0 (145)

UV (144), IR (144), MS (144), *H NMR (144), CD (146) UV (148), IR (147), MS (147), ^H NMR (148), ^^C NMR (148), CD (147), X-Ray (149) UV (150), MS (151), ^H NMR (152), '^C NMR (152), CD (153) UV(36),IR(36),MS(36),
'HNMR(36),''CNMR(36)

53 crinamine

CnH,9N04

301

190-192 [a]D''+180 CHCI3; c 0.55 (147) (147) 211-212 (150) 226-228 (36) [a]D''+278 CHCl3;c0.21 (150)

60 criwelline

C18H21NO3

331

36 dubiusine

C23H27NO8

445

362 TABLE 3 (continued)

Alkaloid 70 galanthamine melting Molecular MW point C Formula (Ref.)
C17H21NO3

[a]D (Ref.) [aC-115 EtOH;c0.5 (154)

MD' -61 MeOH;cl.3 (58)

Additional data (Ref.) UV(38),IR(38),MS(38), 'H N M R (38), ''C NMR (154), CD(153),X-Ray(155) UV (58), MS (58), NMR (58), ^C NMR (58)

287

124-126 (38) 129 (58) 199 (156)

72 0-acetylgalanthamine 71 epigalanthamine

C19H23NO4

329

'H

C17H21NO3

287

[ah'' -327A EtOH;c0.27 (155)

UV(156),IR(155),MS(156), 'H NMR (155), CD (153) UV(158),IR(47),MS(47), *H NMR (47), '^C NMR (47), CD(159),X-Ray(160, 161) IR (60), MS (60), ^H NMR (60),^^C NMR (60) UV(38),IR(38),MS(38), 'H NMR (38),'^C NMR (38) UV (162), MS (61), 'H NMR (61),'^C NMR (61) IR(64)

73 norgalanthamine

Cl6H,9N03

273

156-158 [a]D''-74 (47) CHCI3; c 0.28 (157) 150-152 [a]D''-62 (60) CHCI3; c 0.73 (60) 190-192 (38) 160-162 [a]D''-94.7 CHCI3; c 0.69 (61) (162) 141 (64) [aL^^-99 CHCI3; c 0.2 (64)

74 epinorgalanthamine

C16H19N03

273

75 JV-formylnorgalanthamine 7 galanthine

CnH,9N04

301 317

C,8H23N04

8 goleptine

C,7H2,N04

303

49 haemanthamine

CnHi9N04

301

195-198 [a]D''+38.3 CHCI3; c 0.45 (38) (163) amorph. (33) [a]D''-9.1 MeOH; c 0.55 (33)

UV(38),IR(38),MS(38), ^H NMR (164), *^C NMR (143), CD(165),X-Ray(166)

'H

50 11-O-acetylhaemanthamine 51 haemanthidine

C19H21NO5

343

IR (33), MS (33), NMR (33), ^^C NMR (33), CD (33)

C,7H,9N05

317

[a]o''-14 176-179 CHCI3; c 0.28 (167) (167) 176-179 CHCI3; c 0.28 (167) (167) [a]D+138 212-213 CHCI3; c 0.47 (138) (138) 169-171 (69) [a]D''+93.5 CHCl3;cl.2 (28)

UV(168),IR(169),MS(169), 'H NMR (164), '^C NMR (65), CD (153) UV(168),IR(169),MS(169), 'H NMR (164), ^^C NMR (65), CD (153) UV(168),IR(34),MS(34),
' H N M R ( 3 4 ) , *'CNMR(34),

52 6-epihaemanthidine

C,7H.9N05

317

30 hippeastrine

CnH^NOs

315

CD (170) UV(69),IR(69),MS(69), ^H NMR (69), *^C NMR (170), CD (170)

23 homolycorine

C,8H2iN04

315

363
TABLE 3 (continued) Alkaloid melting Molecular MW point C (Ref.) Formula
C17H19NO4

[a]D

Additional data (Ref.)

(Ref.)
[a]D''+89.6 CHCl3;c0.41 (171)
M D ' ' +19 MeOH;c0.1 (72)

24 8-0-demethylhomolycorine

301

138-140 (170)

UV(172),IR(172),MS(75), ^H NMR (172), ^^C NMR (172), CD(172),X-Ray(173) UV (72), IR (72), MS (72), *H NMR (72), *^C NMR (72)

37 8-O-demethylhomolycorineA^-oxide 25 8-O-demethyl8-O-acetylhomolycorine 26 9-0-demethylhomolycorine

CnHi^NOs

317

153-154 (72)

C19H21NO5

343

186-188 (79)

[aJo'' +70.4 EtOH; c 0.54 (79)

IR (79), MS (79), ' H NMR (79),^^C NMR (79)

CnHi9N04

301

270-272 (69)

UV(69),IR(69),MS(69),
^H NMR (69), *^C NMR (69)

29 9-O-demethyl2a-hydroxyhomolycorine 68 ismine

CnHigNOs

317

272-275 (37)

[aJo +98.8 EtOH; c 0.52 (37)

IR (37), MS (37), ^HNMR(37),*^CNMR(37)

CisHisNOs

257

98 (174)

UV(174),IR(174),MS(174), *H NMR (174), " C NMR (65), X-Ray (65)

9 jonquilline

CigHnNOs

327

188-190 (44)

[aC-325
CHCI3; c 0.5 (44) [aJo'' -67.4 CHCI3; c 0.33 (159) [a]D''-39.1 CHCI3; c 0.95 (175) [a]D''+79.1 CHCl3;c0.51 (60)

UV(44),IR(44)

78 lycoramine

C17H23NO3

289

120-121 (159)

IR (159), MS (159), *H NMR (159),^^C NMR (159)

79 norlycoramine

C16H21NO3

275

123-124 (175)

IR (175), MS (175), ^H NMR (175),

80 epinorlycoramine

C,6H2,N03

275

IR (60), MS (60), ' H NMR (60),"C NMR (60)

31 lycorenine

C18H23NO4

317

199-203 (176)

[alo''+172.4 CHCI3; c 0.7 (176) [alo'"+164.1 CHCI3; c 0.53 (70) [ah'' -62 EtOH; c 0.1 (148) [a]D^' +225.6 CHCl3;c0.15 (175)

UV (177), MS (178), *H NMR (82), *^C NMR (82), X-Ray (179) IR (70), MS (70), ' H NMR (70),^^C NMR (70)

32

0-methyllycorenine

C19H25NO4

331

125 (70)

1 lycorine

C,6Hi7N04

287

250 (148)

UV(148),IR(148),MS(148), ^H NMR (148),'^C NMR (148), CD (153), X-Ray (180, 181) IR (29), MS (29), ' H NMR (175),^^C NMR (29)

62 3-epimacronine

C18H19NO5

329

126-128 (29)

364 TABLE 3 (continued)

Alkaloid 40 maritidine melting Molecular MW point C (Ref.) Formula
C,7H2,N03

[a]D (Ref.)

Additional data (Ref.) UV(48),IR(182),MS(163),

'HNMR(163),CD(183),

287

250-252 [ah'' +26.8 (163) MeOH; c 0.78 (163) 139-141 (175) 238-239 (75) 240-242 (72)
W D ' ' +16 MeOH; c 0.1 (72) j

X-Ray(184) IR (175), MS (175),

' H N M R (164),^^C N M R (67)

41 8-(9-demethylmaritidine 42 9-O-demethylmaritidine 43 O-methylmaritidine

C,6H,9N03

273

[ah'' +28 EtOH;c0.53 (67)

C,6H,9N03

273 301

IR (75), MS (75), ' H NMR (75) UV(72),IR(72),MS(72), ^H NMR (72),'^C NMR (72), CD (57) UV(57),IR(57),MS(57), ' H NMR (57), CD (57) UV (57), IR (57), MS (57), ' H NMR (57), CD (57) UV(53),IR(53),MS(53), ^H NMR (53),^^C NMR (53), CD (170) UV(53),IR(53),MS(53),
'HNMR(53),^^CNMR(53)

C,8H23N03

47 6a-hydroxy3-(9-methylepimaritidine 48 6p-hydroxy3-0-methylepimaritidine 27 masonine

C18H23N04

317

[a]D''-10.2 CHCI3; c 0.45 (57) [a]D''-10.2 CHCI3; c 0.45 (57) 180 (185) 229 (picrate) (53) 177-180 (picrate) (25) 231-233 (88) [aJo'' +140 EtOH;c0.1 (88)
M D +16 MeOH; c 0.11 (55)

C18H23N04

317

C,7HnN04

299

[alo'' +55.6 CHCI3; c 0.5 (53) [a]D''+9.1 CHCI3; c 0.4 (53)

28 normasonine

C16H15N04

285

82 mesembrenone

C,7H2iN03

287

IR (25), MS (25), ^H NMR (25), ^^C NMR (186) UV (87), IR (87), MS (88),
'HNMR(88),^^CNMR(88),

64 narciclasine

CuHnNOv

307

X-Ray(187) UV(55),IR(55),MS(55),
*HNMR(55)

54 narcidine

C,7H2,N04

303

56 narcimarkine 65 narciprimine

C2,H27N05

373 271

110 (50) 315-320 (188) 158-160 (56) [aC-18 CHCl3;c0.5 (56)

IR (50), MS (50),

C14H9N05

UV(87),IR(87),MS(188), ' H NMR (87)

76 narcisine

Ci8H2,N04

315

UV(56),IR(56),MS(56),
'HNMR(56),'^CNMR(56)

365 TABLE 3 (continued)

Alkaloid 16 narcissidine Molecular Formula
C18H23NO5

melting MW point C (Ref.) 333 203-205 (189) 185-186 (49) 189-190 (159)

[a]D (Ref.) [a]D''-28.3 CHCI3; c 0.32 (189) [a]D''-120 CHCI3; c 0.25 (49) MD''+112.2 CHCl3;c0.13 (159) [ah'' -5.6 MeOH; c 0.69 (30)

Additional data (Ref.) UV (190), IR (191), MS (192), *H NMR (193), X-Ray (191) IR(49)

17 nartazine

C20H23NO6

373

77 narwedine

CnHi9N03

285

UV(156),IR(159),MS(159), *H NMR (159) MS (30),'H NMR (30), '^C NMR (30) UV(53),IR(53),MS(53),
'HNMR(53),*^CNMR(53)

63 obesine

C,6HnN04

287

33 oduline

Ci7H,9N04

301

165 (53) 164 (picrate) (53) 245-248 (34)

[alo''+149.4 MeOH; c 3.0 (53) [a]D''+148 MeOH; c 0.13 (53) [a]o''+91.1 CHCI3; c 0.34 (34)

34 6-0-methyloduline

C,8H2,N04

315

UV (53), IR (53), MS (53), *HNMR(53),'^CNMR(53) IR (34), MS (34), ^H NMR (34),^^C NMR (34) IR (66), MS (66), 'H NMR (66),'^C NMR (66)

35 2a-hydroxy6-O-methy loduline 81 pallidiflorine 69 pancracine

Ci8H2,N05

331

C34H40N2O7

588 287 272 (194)

C,6Hi7N04

MD^+74

MeOH; c 0.6 (194)

UV (194), MS (194),*H NMR (194), ^'C NMR (194), CD (194) UV(72),IR(61),MS(61),

'HNMR(61),^^CNMR(61)

44 papyramine

C18H23N04

317

110-112 MeOH; c 0.25 (61) (72) 110-112 MeOH; c 0.25 (61) (72) amorph. (72) 220-222 (93) 148 (58) [a]D''-31 MeOH; c 0.1 (72) [a]D-165 CHCI3; c 0.35 (93) [a]D''+61 MeOH; c 2.4 I (58)

45 6-epipapyramine

C18H23N04

317

UV(72),IR(61),MS(61), ^HNMR(61),''CNMR(61) UV(72),IR(72),MS(72), NMR (72), ''C NMR (72) UV (93)

46 O-methyl6-epipapyramine 11 pluviine

C19H25N04

331

'H

C17H21N03

287

13 9-O-demethylpluviine

C16H19N03

273

UV (58), MS (58), ^H NMR (58),'^C NMR (58)

366

TABLE 3 (continued)
Alkaloid melting Molecular MW point C (Ref.) Formula
C.8H21NO4

[a]D (Ref.) [ot]D''+38 MeOH;cl.O (58) [a]D''+8.3 MeOH;cl.l (58)

Additional data (Ref.)

14 1-O-acetyl9-O-demethylpluviine 15 1,9-0-diacetyl9-O-demethylpluviine 12 norpluviine

315

203 (58) 147 (58)

UV (58), MS (58), ^HNMR(58),'^CNMR(58) UV (58), MS (58), (58), '^C NMR (58) UV(93),IR(195)

C20H23NO5

357

'H NMR

C,6H,9N03

273

[a]D-232 239-241 (93) MeOH; c 0.06 (93) 221-223 (196) 212-213 (52) 227-229 (175) [a]D^VlOO EtOH; c 0.2 (196) [a]D''+50 CHCl3;c0.15 (52) [aJo^'+189.9 CHCI3; c 0.64 (197)

2 poetaminine

CisHipNOs

329

UV(196),IR(196)

38 poetinatine

C20H23NO6

373

IR (52), MS (52), 'H NMR (52)

61 pretazettine

C,8H2,N05

331

UV(198),IR(198),MS(198), 'H NMR (198), CD (199) UV (94), IR (94), MS (94), 'H NMR (94),'^C NMR (94) UV(94),IR(94),MS(94), 'H NMR (94) UV(94),IR(94),MS(94), NMR (94), '^C NMR (94)

3 pseudolycorine

C,6H,9N04

289

[a]D''-60 237-240 (94) MeOH; c 0.04 (72) 248-250 (94) 168-170 (94) 222-226 (200) [a]D''-43 EtOH; c 0.4 (200)

4 1-O-acetylpseudolycorine 5 2-O-acetylpseudolycorine 6 9-O-methylpseudolycorine 22 roserine 59 tazettine

C,8H2iN05

331 331 303

C,8H2,N05

'H

C,7H2lN04

UV(200),IR(28),MS(200), 'H NMR (200) MS (96),'H NMR (96), '^C NMR (96)

C,8H22N03

300 331 202-203 (167) 242-243 (85) 132-134 (174) 233-235 (79)

C,8H2lN05

[(X]D''+138

CHCI3; c 0.23 (167)

UV(201),IR(202),MS(198), 'H NMR (198), * ^ C NMR (203), CD (153) IR (85), MS (85), *H NMR (85),'^C NMR (85) UV(174),IR(174),MS(174), 'H NMR (174), '^C NMR (65) IR (79), MS (79),
'HNMR(34),'^CNMR(34)

21 tortuosine 66 trisphaeridine 20 vasconine

Ci8H,8N03

296 223 266

C,4H9N02

CnH,6N02

367

TABLE 3 (continued)
Alkaloid
39 vittatine

melting Molecular MW point C Formula (Ref.)

C,6HnN03 271 206-208 (31)

(Ref.)
[a]D''+26 MeOH; c 0.25 (31)

[a]D

Additional data (Ref.)

UV (138), IR (138), MS (138), ' H N M R (164), ''C NMR (143), CD (204)

The pairs: 6a-hydroxybuphanisine/6p-hydroxybuphanisine (57/58), haemanthidine/6-epihaemanthidme (51/52), 6ahydroxy-3-0-methylepimaritidine/6p-hydroxy-3-0-methylepimaritidine (47/48), and papyramine/6-epipapyramine (44/45), exist in solution as a mixture of C-6 epimers, and their data were obtained from these mixtures. In the case of narwedine (77), a rapid racemisation occurs in the presence of base (89). Narciprimine (65) is considered an artifact produced from narciclasine (64) during acid extraction (89), and tazettine (59) has been shown to be an artifact produced by base-catalysed rearrangement of pretazettine (61) (199, 205). Narcissamine (32, 42) is a quasi-racemic mixture consisting of equimolar amounts of norgalanthamine (73) and norlycoramine (79)

4.1 Proton Nuclear Magnetic Resonance ^H NMR spectroscopy gives important information about the different types of Amaryllidaceae alkaloids. Several early contributions about homolycorine and crinanehaemanthamlne type alkaloids were made by Hawksworth et al. (206) and Haugwitz et al. (207). In the last decade, the routine use of 2D NMR tecniques (COSY, NOESY, ROESY, etc.) has facilitated the structural assignments and the settling of their stereochemistry. A compilation of the different ^H NMR spectra, arranged according to the different skeleton types is shown in Table 4. a." Lycorine type This group has been subject to several ^H NMR studies and lycorine (1) as well as Its main derivatives have been completely assigned. The general characteristics of the ^H NMR spectra are: i ii iii Iv Two singlets for the para-oriented aromatic protons in the range 5 6.5-7.2 ppm. A unique olefinic proton around 5.5 ppm. Two doublets as an AB system corresponding to the benzylic protons of C-6. The deshielding observed in the p protons of positions 6 and 12 In relation to their a-homologues is due to the effect of the c/s-lone pair of the nitrogen atom.

368

Like almost all other lycorine type examples, the alkaloids isolated from Narcissus genus show a trans B/C ring junction, the coupling constant being
^4a.10b~11HZ.

In the plant, the alkaloid lycorine (1) is particularly vulnerable to the oxidation processes giving several ring-C aromatized products. b.- Homolycorine type This group includes lactone, hemiacetal or cyclic ether (unusual) alkaloids. The general traits for this type of compounds could be summarized as follows: i Two singlets for the para-oriented aromatic protons. In lactone alkaloids, differentiation of the H-7 and H-10 signals is readily made by virtue of the deshielding of H-7 by effect of the per/-carbonyl group, ii The hemiacetal alkaloids always show the substituent at C-6 in a-disposition, and the benzylic proton H-6p appears as a singlet between 5-6 ppm, depending on the substituent at C-6. iii The majority of compounds belong to a single enantiomeric series containing a cis B/C ring junction, which is made clear by the small size of the coupling constant J^ ^ob- '" *he Narcissus genus no exception to this rule has been observed, iv V vi The large coupling constant between H-4a and H-10b (J^g^^Q^^~^OHz), is only consistent with a frans-diaxial relationship. In general, the C ring presents a vinylic proton around 5.5 ppm. The singlet corresponding to the A/-methyl group is in the range 6 2.0-2.2 ppm, its non existence being very unusual, vii If position 2 is substituted by an OH, OMe OAc group, it always displays an adisposition. viii The H-12a is more deshielded than H-12P as a consequence of the c/s-lone pair of the nitrogen atom. An interesting study of homolycorine type alkaloids with a saturated ring C has been made by Jeff and coworkers (208). They describe empirical correlations of A/-methyl chemical shifts with stereochemical assignments of the B/C and C/D ring junction.

369 c- Crinine - Haemanthamine types The absolute configuration of these alkaloids, which allows both series to be differentiated, is determined through the circular dichroism spectrum. The alkaloids of the Narcissus genus usually belong to the haemanthamine type, while in genera such as Brunsvigia, Boophane etc., the crinine type alkaloids are predominant. It is also noteworthy that the alkaloids isolated from the Narcissus genus do not show additional substitutions in the aromatic ring apart from those of C-8 and C-9. On the contrary, in the genera where crinine type alkaloids predominate, the presence of compounds with a methoxy substituent at C-7 is quite common. Thus, taking into account the previous considerations, haemanthamine type alkaloids show the following characteristics: i ii Two singlets for the para-oriented aromatic protons In the range 5 6.4-7.0 ppm. Using CDCI3 as the solvent, the magnitude of the coupling constants between each olefinic proton (H-1 and H-2) and H-3 gives information about the configuration of the C-3 substituent. Thus, in those alkaloids in which the twocarbon bridge (C-11 and C-12) was cis to the substituent at C-3, H-1 shows an allylic coupling with H-3 (J^ 3~1-2 Hz) and H-2 a smaller coupling with H-3 (^2,3-0" 1.5 Hz), as occurs in crinamine (53). On the contrary, in the corresponding C-3 epimeric series, e.g. haemanthamine (49), a larger coupling between H-2 and H3 (Ja.sS Hz) is shown, the coupling between H-1 and H-3 not being detectable, iii It is frequently possible to observe an additional coupling of H-2 with the equatorial H-4p, in a W-mechanism. iv V vi The proton H-4a shows a large coupling with H-4a (J4a4a~13 Hz) due to their frans-dlaxial position, characteristic of the haemanthamine series. Two doublets for an AB system corresponding to the benzylic protons of position C-6. The pairs of alkaloids with a hydroxy substituent at C-6, like papyramlne/6epipapyramine (44/45), haemanthidine/6-epihaemanthldine (51/52) etc., appear as a mixture of epimers not separable even by HPLC. vii Also in relation with position C-6, It is interesting to note that ismine (68), a catabolic product from the haemanthamine series, shows a restricted rotation around the biarylic bond, which makes the methylenic protons at the benzylic position magnetically non-equivalent.

370 d.- Tazettine type Although tazettine (59) is one of the most widely distributed alkaloids in the Amaryllidaceae family, it was found to be an extraction artifact of pretazettine (61) (209). The presence of an A/-methyl group (2.4-2.5 ppm) in tazettine type alkaloids inmediately distinguishes them from the haemanthamine type, from which they proceed biosynthetically. Moreover the ^H NMR spectrum always shows the signal corresponding to the methylenedioxy group. We have also included the alkaloid obesine (63) in this group, although it exhibits some structural differences with the skeleton type. e.- Galanthamine type Among the Amaryllidaceae alkaloids, only the galanthamine type shows an orthocoupling constant between both aromatic protons of ring A. The general characteristics of their ^H NMR spectra are: i Two doublets for the two OAt/7o-oriented aromatic protons with a coupling constant of J^g-SHz. ii The assignment of the substituent stereochemistry at C-3 is made In relation with the coupling constants of the olefinic protons H-4 and H-4a. When coupling constant J^^ is about 5 Hz, the substituent is pseudoaxial while if It is ~0 Hz this indicates that the substituent at C-3 is pseudoequatorlal. ill Two doublets as an AB system corresponding to the benzylic protons of C-6. iv The existence of the furan ring results in a deshielding effect in H-1. V This type of alkaloids often show an A/-methyl group but occasionally A/-formyl or A/-acetyl derivatives have been reported.

TABLE 4a
'H NMR data of Lycorine type alkaloids.
Alkaloid
H-1 H-2a H-2P H-3 H-4a H-6a H-6P H-7 H-10 5.37 br s 2.60 d 3.32 d 4.02 d 6.68 s 6.81 s 2.50 m 2.44 m 2.19 ddd 3.19 dd 5.95 s 5.60 t 3.02 br d 3.68 br d 4.16 d 6.71 s 6.89 s 2.74 br d 2.6-2.7 m 2.6-2.7 m 3.37 dd 5.69 dd 2.90 br s 3.61 dd 4.17 d 6.70 s 6.74 s 2.90 br s 2.66 t 2.59 br t 3.33 m 3.84 s 5.45 t 2.85 d 3.54 d 4.14 d 6.61 s 6.83 s 2.69 d 2.63 rn 2.42 dt 3.35 dt 3.82 s

1
4.27 br s 3.97 br s

3 4.85 br s 4.50 t

4
5.58 m 4.15 dd

5 4.43 t 5.29 dd

6 4.53 dd 4.18 rn
I _

7
4.55 s 3.72 r n
I _

10
4.70 m 2.59 m 2.59 m 5.41 rn 2.78 dd 3.52 dd 4.13 d 6.58 s 6.82 s 2.41 ddd 2.59 rn 2.33 br q 3.32 ddd 5.91 (2d)

13 4.26 dd 2.3-2.6 m 2.3-2.4 m 5.54 br d 2.70 br d 3.31 d 3.93 d 6.59 s 6.82 s 2.98 dd 2.5-2.6 rn 2.3-2.4 rn 3.32 m 3.89 s

14
5.54 dd 2.3-2.5 m 2.3-2.5 m 5.39 br s 2.3-2.5 m 3.54 br d 3.59 br d 6.64 s 7.08 s 3.33 dd 2.3-2.5 m 2.79 rn 2.79 m
I -

15
5.51 rn 2.36 rn 2.36 rn 5.32 br t 2.2-2.3 m 3.5-3.6 br s 3.5-3.6 br s 6.71 s 7.14 br s 3.27 dd 2.2-2.4 rn 2.6-2.8 m 2.6-2.8 rn 3.74 s

16 4.66 rn 3.4-4.2 rn 4.66 m 3.4-4.2 rn 3.54 d 4.09 d 6.68 s 6.88 s 2.70 d 5.56 br s (1H) 3.4-4.2 m 3.4-4.2 m 3.86 s 3.82 s 3.44 s

5.55 rn
2.87 dd 3.55 dd 4.16 d 6.75 s 6.96 s 2.76 ddd 2.64 m 2.42 br q 3.35 ddd 3.85 s 3.80 s
I -

5.55 br s
2.65 s 3.40 br d 4.05 d 6.52 s 6.78 s 2.65 s 2.4-2.6 m 2.25 dd 3.25 ddd 3.78 s 3.74 s 3.40 s

H-lob
H-11 (2H) H-l2a H-12P

OCH,O

____

OMe OMe OMe

OAc OAc

3.84 s

3.86 s

____ ____ ---_

b
200

1.92 s

2.06 s

1.98 s d 200 d 270 d 400 d 400

2.23 s 1.92 s d 400 d 400

solvent
MHz

a 300

b
200

b
200

270

Ref.

371

Solvent a: DMSO-d,, b: CDCI,-CD,OD, c: CD,OD, d: CDCI,.

372 TABLE 4a (continued) ^H NMR data of Lycorine type alkaloids. Alkaloid H-1 H-2 H-3 H-4 H-6 H-7 H-10 H-11 (2H) H-12(2H) OMe OMe OMe solvent MHz Ref. d 200 (26) b 200 (26) b 500 (34) 4.09 s 6.64 s 7.17 s 3.00 br t 3.32 t 3.93 s 3.87 s 7.57 s 7.81 s 3.45 brt 4.45 br t 4.09 s 4.03 s 10.42 s 8.09 s 7.86 s 3.76 t 5.42 t 4.19 s 4.08 s 9.55 s 7.92 s 8.34 s 3.88 t 5.35 t 4.33 s 4.20 s 4.17 s c 500 (85) 2.05 ddd 2.70 dt 4.75-4.95 m 4.15 s 4.05 s 1 3.90 s 1 a P 18 7.31 dd 6.75 t 6.99 dt 19 7.85 br d 7.27 t 7.33 br d 20 8.32 d 7.84 t 7.70 d 7.59 brs 21 8.13 d I 22 2.85 ddd 3.13 dd 1.8-1.95 m 2.25-2.4 m 1.38 qd 2.25-2.4 m 3.4-3.5 m 9.50 s 6.95 s a a a p

1 ^

250 (96)

Solvent a: DMSO-c/e, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.

TABLE 4b

'H NMR data of Homolycorine type compounds: lactone alkaloids.

Alkaloid
H-1 H-2 (2H) H-3 H-4a H-7 H-10 H-lob H-11 (2H) H-12a H-12P OCH,O OMe OMe NMe OAc CHA CHB CHOH Me solvent MHz Ref. 3.96 s 3.95 s 2.00 s 2.00 s 2.16 s 2.00 s 2.01 s 2.06 s
I-__

23
4.81 ddd 2.49 rn 5.50 rn 2.72 dd 7.57 s 6.99 s 2.64 dd 2.6-2.7 rn 3.14 ddd 2.24 ddd

24
4.78 rn 2.59 rn 5.50 d 2.73 dd 7.60 s 6.98 s 2.63 dd 2.50 rn 3.14 ddd 2.25 dd 3.95 s

25
4.86 br d 2.5-2.7 rn 5.63 br d 2.96 br d 7.47 s 7.13 s 2.86 dd 2.5-2.7 rn 3.31 ddd 2.45 dd 3.97 s

26
4.80 ddd 2.51 rn 5.55 rn 2.71 br d 7.54 s 6.91 s 2.60 dd 2.5-2.6 rn 3.15 ddd 2.30 ddd 3.94 s

27
4.75 rn 2.60 rn 5.50 br d 2.74 rn 7.49 s 6.96 s 2.74 rn 2.50 rn 3.18 ddd 2.27 dd 6.07 (2d)

28
4.85 s 2.62 r n 5.64 rn 5.50 br d ? 7.52 s 7.11 s 2.66 d 2.52 rn 3.15 ddd 2.89 dd 6.05 d

29 4.59 br d 4.28 br t (HP) 5.68 br s 2.66 br d 7.47 s 6.95 s 2.83 dd 2.5-2.6 rn 3.17 ddd 2.31 dd 3.95 s 2.08 s

30
4.58 br s 4.38 br s (HP) 5.63 br s 2.62 d 7.45 s 6.92 s 2.85 dd 2.48 rn 3.13 ddd 2.23 ddd 6.04 (2d)

36
4.63 dd 5.46 dd (HP) 5.62 rn 2.74 br d 7.52 s 6.97 s 2.79 br d 2.5-2.7 rn 3.19 ddd 2.37 dd

37
4.83 rn 2.64 rn 5.76 br d 3.87 br d 7.44 s 7.24 s 3.50 dd 3.57 rn 2.88 rn 2.72 rn 3.96 s

--3.94 s

_--_
--__
2.94 s

_ I -

__-____
2.03 s

_______

2.06 s 2.00 s 2.53 dd 2.65 dd 5.24 rn

-___

_______

_ _ _ I _ _

_-_

I _ _

---d
200 (69)

1.29 d

____I_

d
400

b
250 (79)

b
200 (69)

d
400 (53)

d
400 (53)

b
200 (37)

d
500 (34)

b
400 (36)

b
200 (72)

(172)

373

Solvent a: DMSO-$, b: CDCI,-CD,OD

, c: CD,OD, d: CDCI,.

374 TABLE 4b (continued) ^H NMR data of Homolycorine type compounds: hemiacetal alkaloids. Alkaloid H-1a H-2a H-2p H-3 H-4a H-6p H-7 H-10 H-10b H-11 (2H) H-12a H-12|3 OCH2O OMe OMe OMe NMe solvent MHz Ref. 2.08 s c 250 (82) 3.88 s 3.87 s 3.89 s 3.88 s 3.55 s 2.10 s d 200 (70) 2.11 s d 400 (53) 2.05 s d 400 (53) 2.22 s d 500 (34) 31 4.35 br d 2.35 m 2.65 m 5.50 br s 2.78 br d 5.93 s 6.93 s 6.99 s 2.44 dd 2.4-2.6 m 3.15 ddd 2.27 dd 32 4.29 br d 2.35 m 2.65 m 5.50 br d 2.77 dd 5.54 s 6.80 s 6.93 s 2.44 dd 2.4-2.6 m 3.15 ddd 2.23 dd 33 4.35 d 2.31 dm 2.62 dm 5.46 br d 2.72 br d 5.99 s 6.85 s 6.90 s 2.4-2.5 m 2.4-2.5 m 3.14 ddd 2.25 dd 5.97 d 34 4.17 d 2.26 dd 2.53 dm 5.39 br s 2.69 br d 5.39 br s 6.67 s 6.77 s 2.35 dd 2.3-2.4 m 3.08 dd 2.17 dd 5.83 d 3.43 s 35 4.15 brs 4.21 brs 5.69 br s 2.87 d 5.43 s 6.73 s 6.94 s 2.85 d 2.54 m 3.33 m 2.38 dt 5.91 (2d) 3.51 s

Solvent a: DMSO-dg, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.

TABLE 4c 'H NMR data of Haemanthamine type alkaloids.

Alkaloid
H-1 H-2 H-3 H-4a H-4P H-4a H-6a H-6P H-7 H-10 H-11 endo H-11 exo H-12 endo H-12 exo OCH,O OMe OMe OMe
_ _ I _

39

41

42

43

44

45

49

50

51

52

53

54

6.44 d 6.06 dd 4.46 m 1.85 ddd 2.58 ddd 3.87 m 4.07 d 4.71 d 6.53 s 6.87 s 2.15 m 2.32 m 3.17 rn 3.87 m 5.95 s

6.65 d 5.99 dd 4.36 rn 1.75 ddd 2.03 ddd 3.37 rn 3.79 d 4.39 d 6.56 s 6.82 s 1.95 m 2.15 m 2.95 m 3.37 rn 3.89 s

6.58 d 5.91 ddd 4.31 td 1.73 td 3.43 dd 3.81 d 4.41 d 6.53 s 6.87 s 1.8-2.0 rn 2.19 ddd 2.91 ddd 3.31 ddd

6.49 d 6.08 dd 3.85 rn 1.73 ddd 3.90 dd 4.25 d 4.80 d 6.57 s 6.81 s 2.22 ddd 2.37 ddd 3.27 ddd 4.08 ddd 3.86 s 3.82 s 3.34 s d 200 (72)

6.65 d 6.00 dd 3.88 rn 1.77 ddd 2.21 br d 3.59 dd 5.86 s 7.03 s 6.80 s 2.00 rn 2.00 rn 3.02 ddd 3.73 ddd 3.88 s 3.88 s 3.37 s d 200 (61)

6.66 d 6.00 dd 3.85 m 1.60 ddd 2.09 m 3.90 m 5.16 s 6.89 s 6.83 s 2.00 rn 2.00 rn 2.84 ddd 3.39 rn 3.88 s 3.88 s 3.31 s d 200 (61)

6.36 d 6.25 dd 3.82 r n 2.11 ddd 1.96 ddd 3.25 dd 3.72 d 4.25 d 6.41 s 6.74 s 3.96 dd 3.30 dd 3.19 dd 5.81 (2d)

6.40 d 6.21 dd 3.91 rn 2.07 ddd 1.98 ddd 3.41 rn 3.77 d 4.40 d 6.52 s 6.95 s 5.05 dd 3.41 rn 3.41 m 5.95 s
I_---

6.33 d 6.27 dd 3.85 rn 2.36 ddd 2.12 ddd 3.56 dd 5.69 s 6.94 s 6.70 s 3.92 m 4.20 dd 2.96 dd 5.83 (2d)

6.33 d 6.27 dd 3.85 m 2.21 ddd 2.00 ddd 3.20 m 5.02 s 6.79 s 6.73 s 3.92 rn 3.30 m 3.20 rn 5.86 (2d)

6.22 brs 6.22 br s 3.98 rn 2.08 m 2.08 m 3.22 dd 3.66 d 4.28 d 6.47 s 6.79 s 3.92 m 3.40 rn 3.40 m 5.86 s

6.48 d 6.35 dd 3.86 rn 2.11 ddd 2.04 ddd 3.38 rn 3.70 d 4.31 d 6.53 s 6.78 s 3.99 ddd 3.39 m 3.26 dd 3.86 s

1.90 dddd 2.95 ddd

-_-3.36 s d 360 (164) 3.41 s 2.03 s d 500 (33)

---__-3.32 s d 360 (164) 3.28 s d 360 (164)

-___I

3.40 s d 300 (148)

3.35 s d 360 (55)

OAc
solvent d 360 d 360
(164)

d 200 (75)

MHZ

Ref.

(164)

375

Solvent a: DMSO-$, b: CDCI,-CD,OD

, c: CD,OD, d: CDCI,.

TABLE 4d

TABLE 4e

376

'H NMR data of Tazettine type alkaloids

Alkaloid
H-1 H-2 H-3 H-4a H-4P H-4a H-6 H-6' H-7 H-10 H-1O b H-I 1 H-12 H-12' OCH,O OMe NMe solvent 2.65 d 3.30 d 5.90 s 3.45 s 2.40 s d 90 2.83 d 3.30 d 5.92 s 3.45 s 2.38 s d 300 (152)
C:

'H NMR data of Narciclasine type alkaloids.

63
5.86 d 6.13 d 4.3-4.4 rn 2.39 br d 1.68 ddd
Alkaloid

59 5.60 ddd 6.15 ddd 4.13 rn 2.20 rn 1.60 rn 2.83 rn 4.65 d 4.95 dd 6.50 br s 6.85 s

60 5.78 d 6.20 dd 3.89 ddd 1.93 ddd 2.09 ddd 2.95 t 4.68 d 4.94 d 6.55 s 6.52 s

62
5.44 ddd 5.97 d 4.12 rn

64

66

67 8.73 dd 8.02 td 8.09 td 8.31 dd 10.42 s 7.97 s 8.16 s 6.41 s 4.73 s b 200 (29)

68
6.98 dd 6.81 ddd 7.28 ddd 6.73 dd 4.26 d 4.20 d 7.00 s 6.67 s 5.99 s 2.73 s d 200 (174)

H-1 H-2 H-3 H-4 H-4a H-6 H-6 H-7 H-10 OCH,O NMe solvent

I 6.17 ddd
4.23 ddd 3.92 ddd 3.90 dd 4.35 ddd

8.36 dddd 7.61 ddd 7.67 ddd 8.11 ddd 9.06 s 7.32 s 7.89 s 6.15 s d 200 (174)

3.10 rn

3.15 br s 4.02 d 4.38 d 6.66 s 6.70 s 2.81 br d 3.01 d 3.10 d 5.99 s

-_I--_-

--I---

7.52 s 6.73 s
__-_I__

6.75 s 6.01 (2d)

C

4.43 dd 2.76 dd 3.16 dd 6.01 s 3.40 s 2.50 s d 100

C

MHz Ref.

500

(88)

MHz
Ref.

250 (30)

(1981

f 175)
CD,OD, d: CDCIa

Solvent a: DMSO-de, b: CDCI&D,OD,

TABLE 4f 'H NMR data of Galanthamine type alkaloids.

Alkaloid
H-1 H-2a H-2P H-3 H-4 H-4a H-6 H-6 H-7 H-8 H-lla H-llP H-12a H-12P
70 71 72 73 74 75 77 78

80 4.37 t 1.88 m 2.50 ddd 4.09 m 1.5-1.7 rn (2H) 1.7-1.9 m (2H) 3.98 s 3.98 s 6.65 d 6.62 d 1.7-1.9 m 1.7-1.9 m 3.19 dt 3.43 m 3.85 s

4.73 rn 2.12 ddd 2.80 ddt 4.25 m 6.10 ddd 6.21 dd 3.79 dd 4.21 d 6.74 d 6.70 d 2.20 ddd 1.69 ddd 3.16 dt 3.39 ddd 3.95 s 2.52 s

4.58 m 1.69 ddd 2.77 dddd 4.61 dddd 6.05 dt 5.79 dt 3.61 d 4.06 d 6.55 d 6.61 d 2.16 dt 1.63 ddd 3.04 br d 3.25 dt 3.82 s 2.56 s

4.58 m 2.10 ddd 2.69 ddd 5.34 dd 5.92 d 6.28 d 3.77 d 4.22 d 6.61 d 6.68 d 2.18 dd 1.65 dd 3.14 br d 3.40 br t 3.85 s 2.45 s 2.04 s

4.67 m 2.24 ddd 2.60 m 4.28 m 6.06 ddd 6.23 dt 4.21 d 4.44 d 6.84 d 6.90 d 2.08 m 2.08 m 2.42 rn 3.57 rn 3.91 s

4.62 br s 2.04 ddd 2.68 dd 4.15 m 5.98 d 6.05 d 3.93 d 4.04 d 6.62 d 6.68 d 1.88 dt 1.80 td 3.22 m 3.38 dt 3.84 s

4.50 m 1.95 ddd 2.61 ddt 4.07 m 6.00 ddd 5.88 dd 3.94 dd 4.80dE15.10dZ 6.60 d 6.76 d 1.71 ddd 1.81 ddd 3.82 ddd E 13.15 ddd Z 3.61 ddd 3.84 s 0.02 s 18.07 s

4.72 rn 2.73 dd 3.14 m 6.02 d 6.92 d 3.76 d 4.12 d 6.64 d 6.68 d 2.26 dt 1.87 d 3.14 m 3.27 t 3.82 s 2.45 s

4.28 m 1.4-1.9 m 2.40 br d 3.98 m 1.4-1.9 m (2H) 1.4-1.9 m (2H) 3.54 d 3.92 d 6.51 d 6.57 d 1.4-1.9 rn 1.4-1.9 m 2.96 t 3.12 t 3.76 s 2.29 s

OMe
NMe NCHO

_-____-__

______-__ _______-_
d 400 d 400 d 200

OAc
solvent MHz Ref. d 200 d 400

d 400

d 200

d 200

200

377

Solvent a: DMSO-$, b: CDCI,-CD,OD,

c: CD,OD, d: CDCI,.

378

4.2 Carbon^^ Nuclear Magnetic Resonance ^^C NMR spectroscopy has been extensively used for determining the carbon framework of Amaryllidaceae alkaloids, and the major contributions are due to Grain et al (203), Zetta and Gatti (210), and Frahm et al. (143). The assignments are made on the basis of chemical shifts and multiplicities of the signals (by DEPT experiment). The use of 2D NMR tecniques such as HMQG and HMBC allow the assignments to be corroborated. Table 5 shows a compilation of the different ^^G NMR spectra classified according to the different types. The ^^G NMR spectra of Narcissus alkaloids can be divided in two regions. The low-field region (>90 ppm) contains signals of the carbonyl group, the olefinic and aromatic carbons as well as that of the methylenedioxy group. The other signals, corresponding to the saturated carbon resonances are found in the high-field region, the A/-methyl being the only characteristic group, easily recognizable by a quartet signal between 40-46 ppm. The effect of the substituent (OH, OMe, OAc) on the carbon resonances is of considerable importance in localizing the position of the functional groups. The analysis of the spectra allows conclusions to be drawn about the following aspects: - The number of methine olefinic carbons. - The presence and nature of the nitrogen substituent. - The existence of a lactonic carbonyl group. - The presence of a quaternary carbon signal assignable to G-lOb in the chemical shift range of 42-50 ppm.

Table 5a
NMR data of Lycorine type alkaloids.
Alkaloid c-1 c-2 c-3 c-4 C-4a C-6 C-6a c-7 C-8 c-9 c-10 C-lOa C-1Ob c-11 c-12 OCH,O OMe OMe OMe OEMe OOCk OEMe
1 70.2 71.7 118.5 141.7 60.8 56.7 129.7 107.0 145.2 145.6 105.1 129.6 40.2 28.1 53.3 100.6 3 70.7 71.8 118.6 141.7 61.4 56.4 127.3 110.5 146.2 145.1 111.3 126.5 39.4 28.3 53.9
56.1 5 68.5 73.9 114.0 144.6 60.9 56.7 127.9 110.4 146.0 146.0 111.3 127.2 41.1 28.8 53.9 56.0

7
~~

68.3 81 .o 115.1 143.9 60.9 56.6 129.3 110.8 147.8 147.6 108.0 126.6 41.5 28.5 53.8 57.3 56.0 55.9

13 69.8 33.5 116.2 139.6 59.5 55.3 126.0 112.4 146.0 144.4 110.2 128.8 41.6 27.3 52.1
55.9

14 70.3 28.8 115.0 139.2 60.4 51.9 125.0 113.4 145.4 144.0 110.2 129.2 38.0 28.4 52.4 56.0

15 69.9 28.8 114.6 139.4 60.2 51.8 129.2 111.5 149.4 137.5 121.2 132.5 38.2 28.6 52.3
55.9

19 119.4 123.9 123.9 124.3 131.3 157.5 129.0 108.6 149.8 153.3 103.3 120.3 117.0 27.5 46.8
56.3 56.2

20 120.0 131.2 125.6 123.2 136.0 144.7 121.3 110.5 151.7 157.9 102.4 130.6 136.0 27.4 55.4
56.7 56.4

21 102.2 164.5 118.0 139.7 133.0 142.6 122.9 111.0 153.1 159.1 104.6 131.4 126.1 27.8 57.0

22 31.7 21.8 23.0 40.0 162.4 138.5 119.3 96.8 150.5 146.8 142.0 127.1 135.5 26.8 57.4 62.5 62.4 56.8

I -

-57.8 57.4 57.0

---

_-170.6 21.4 170.6 20.6 169.2 21.3

170.9 21.3

-_-_ ____

oocm
solvent MHz a

__---

-----I -

--d

Ref.

379

Solvent a: DMSO-d,, b: CDCI,-CD,OD,

c: CD,OD, d: CDCI,

Table 5b
I3C N M R data of Homolycorine type alkaloids.
Alkaloid

380

23
77.7 31.3 115.2 140.9 66.6 165.9 116.9 111.9 148.9 153.1 110.8 137.8 43.8 28.1 56.6 56.4 56.2 44.2

24
79.2 32.1 117.1 141.3 68.0 167.9 117.9 116.9 147.9 153.8 112.3 137.6 43.7 28.6 57.3 56.7

25
77.5 30.9 116.5 138.7 66.8 166.3 116.5 115.9 146.3 152.2 110.9 135.7 42.2 27.4 56.0 56.0

26
77.9 31.3 116.1 140.0 66.9 167.0 115.6 112.7 148.1 152.0 115.0 138.0 43.0 27.9 56.5

27
77.3 31.1 115.6 140.2 66.8 165.4 118.5 109.7 151.8 147.8 108.6 139.7 43.8 27.9 56.3 102.0

28
75.6 31.2 115.1 139.4 59.1 165.1 118.0 109.9 152.2 147.8 107.4 138.7 43.0 29.6 44.1 102.0

29
82.5 66.2 118.5 143.3 66.4 165.7 118.5 112.0 147.6 151.8 114.7 137.2 38.2 27.0 55.8 55.2

30
82.2 66.2 119.4 142.4 67.1 165.0 118.0 109.8 148.0 151.9 108.5 138.8 38.4 27.3 55.9 102.1

31
67.6 32.6 117.2 140.8 68.5 92.3 131.3 111.9 149.6 149.6 114.0 128.6 44.7 28.7 57.6 56.5 56.5 44.3

32
66.6 31.3 115.7 140.7 67.3 98.2 130.5 109.7 148.3 148.3 112.4 125.6 44.0 27.8 56.6 55.8 55.5 55.1 43.8

33
66.7 31.7 115.7 140.6 67.5 91.8 132.0 107.4 147.0 147.0 109.8 128.2 44.2 28.1 56.7 101.0

34
66.4 31.3 115.6 140.3 67.5 98.2 131.8 107.3 146.8 146.7 109.5 126.9 43.9 27.9 56.5 100.8 55.2

35
72.8 68.3 119.4 144.0 68.3 98.5 126.9 107.6 147.1 147.1 109.8 131.2 39.2 27.7 56.3 101.1 55.5

36
79.7 69.2 115.1 147.4 67.5 165.4 115.4 115.0 148.2 152.0 112.7 136.7 39.9 28.0 56.3 56.2

37
78.8 31.4 121.0 135.6 79.3 167.1 117.6 117.1 147.9 153.4 I 12.6 134.9 37.4 26.2 70.7

c-I
c-2 c-3 c-4 C-4a C-6 C-6a c-7 C-8 c-9 c-10 C-lOa C-lob c-11 c-12 OCH,O OMe OMe OMe NMe OEMe OOCk OsCH,CHOHMe OOCaCHOHMe OOCCH,CHOHMe OOCCH,CHOHh solvent MHz
Ref

I_____

----___

56.2

_______

-______
43.3 43.5

_--____
------42.2

_______

---____

_______

_______
44.3

_______

-------____-43.8

44.1

------_

42.9 174.9 21 .o

42.9

I_____

-------------------------

-__-___

_______

_______

_______
d
63 (170)
C

_______
d
100 (53)

_______
d
100 (53)

------b

_______ __--___ _______ _______

b 50 (37)

_______ _______
d

44.0

_ _ _ I _ _

_______
_______

-------

____-__
. . . . . . .

_ I _ _ _ _

---

-------

-d
100 (53)

43.3 169.4 21 .I 170.8 40.8 66.7 19.9 ..

56.2

b
62 (79)

d
50 (34)

d
100 (53)

d
50 (34)

50 (172)

50 (69)

62 (82)

50 (70)

b 50
(36)

b 50 (72)

Solvent a: DMSO-$, b: CDCI,-CD,OD,

c: CD,OD, d: CDCI,

Table 5c

13C NMR data of Haemanthamine type alkaloids.

Alkaloid

c-1
c-2 c-3 c-4 C-4a C-6 C-6a c-7 C-8 c-9 c-10 C-lOa C-lob c-11 c-12 OCH,O OMe OMe OMe OMe OEMe OOCk solvent

39 132.1 127.4 64.0 32.7 62.3 62.8 126.3 106.9 145.6 146.0 102.7 138.3 44.2 44.2 53.5 100.6

41 130.3 127.6 63.3 31.6 62.8 60.9 121.1 109.8 144.8 146.0 109.2 136.5 44.0 42.8 52.8
55.8

43 128.2 127.3 70.7 25.6 64.8 57.1 116.5 110.0 148.9 149.0 106.2 138.0 44.9 40.6 52.3
56.1 56.1 56.1

44 132.4 125.6 72.4 28.7 62.2 87.0 127.4 111.0 147.8 148.5 105.4 136.4 44.7 42.3 42.0
56.6 56.6 56.1

45 132.0 125.9 72.4 28.1 56.3 88.9 126.5 112.5 147.8 148.7 105.4 137.4 44.1 40.9 47.9
56.6 56.6 56.0

46 132.4 125.2 72.4 28.5 57.1 96.4 125.5 112.4 147.3 148.2 105.0 138.1 43.7 41.1 48.4

_ _ I _

____

_______

_______
d 20 (143) b 50 (67)

56.8 56.0 55.8 55.7

49 128.0 127.2 73.0 29.5 62.7 63.3 126.9 106.9 146.5 147.0 103.3 135.0 50.0 80.0 61.5 101.0 56.0

50 127.5 129.5 72.4 28.2 62.8 61.0 126.2 106.6 146.5 146.5 103.4 134.2 49.2 80.2 60.4 100.8 56.5

51 127.7 130.4 72.7 27.5 62.2 85.8 127.5 108.4 146.8 148.0 103.1 135.2 50.1 78.9 51.4 101.4 56.9

52 127.8 130.5 73.1 27.5 56.5 88.3 127.3 109.6 146.6 148.1 103.1 136.6 50.0 78.2 58.3 101.4 56.8

53 123.6 136.0 76.0 30.1 66.1 63.4 126.5 106.9 146.2 146.5 103.2 135.3 50.3 80.0 61.2 100.9 55.8

55 25.4 26.4 69.9 30.3 66.0 59.1 118.4 109.0 146.3 145.4 109.6 137.1 42.4 35.5 50.8
55.8

---_

MHz

d 50 (72)

d 50
(61)

d
50 (61)

d 50 (72)

d 20 (143)

d 50 (33)

d 50 (65)

d 50
(65)

d 75 (148)

d 50 (31)

Ref.

381

Solvent a: DMSO-d, b: CDCI,-CD,OD,

c: CD,OD, d: CDCI,.

382

Table 5d ^^C NMR data of Tazettine type alkaloids.

Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-10a C-1 Ob C-11 C-12 OCH2O OMe NMe solvent MHz Ref. 59 130.5 128.4 72.4 26.6 69.9 65.0 127.8 103.7 146.3 146.3 109.1 125.4 50.1 101.7 61.7 100.6 55.6 41.9 d 16 (203) 60 130.1 128.9 72.1 25.4 68.2 62.6 126.2 108.5 146.6 146.2 104.2 130.9 50.0 102.6 64.5 100.9 56.7 40.6 d 75 (152) 62 131.3 126.0 72.7 29.8 63.3 168.5 118.6 103.8 147.1 152.3 111.0 142.2 46.2 80.1 53.5 102.1 56.2 42.8 d 50 (29) 63 132.4 136.5 63.6 34.4 68.5 62.2 131.0 107.3 148.4 147.3 111.0 125.0 50.3 82.7 55.7 101.9

c 62 (30)

Solvent a: DMSO-ofg, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.

Table 5e ^^C NMR data of Narciclasine type alkaloids.

Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-lOa C-1 Ob OCH2O NMe solvent MHz Ref. 64 124.7 69.1 72.3 68.8 52.8 172.1 129.2 168.9 152.3 144.8 95.7 132.1 133.3 102.0 a 68 (88) 66 122.0 126.7 128.1 129.9 143.8 151.8 123.1 105.5 148.1 148.2 99.9 130.3 124.3 101.9 d 50 (65) 67 120.2 125.9 131.0 133.0 136.5 152.8 126.6 108.3 159.2 152.0 102.2 122.0 135.3 105.7 45.9 c 50 (29) 68 129.9 118.0 129.1 110.7 146.7 63.5 134.0 109.7 147.5 147.4 110.2 131.2 127.2 101.3 30.8 d 50 (65)

383 Table 5f ^^C NMR data of Galanthamine type alkaloids. Alkaloid C-1 C-2 C-3 C-4 C-4a C-6 C-6a C-7 C-8 C-9 C-10 C-10a C-1 Ob C-11 C-12 OMe NMe NCHO OCMe OCMe solvent MHz Ref. 70 88.1 30.0 62.2 126.8 126.0 60.5 129.5 121.6 110.5 145.5 144.0 132.7 48.2 34.0 54.3 55.5 42.2 72 86.2 27.7 63.2 123.3 121.8 59.9 127.2 130.2 111.7 146.7 144.4 131.9 47.8 33.7 53.4 56.0 40.9 170.9 21.4 d 100 (58) 73 88.2 30.3 61.7 129.2 125.9 51.6 123.6 122.8 112.2 146.9 145.3 133.1 48.2 35.6 45.9 56.2 74 88.4 29.9 61.9 127.6 127.1 53.5 132.1 120.9 111.3 146.2 144.1 133.1 48.5 39.7 46.8 55.9 75 87.9/88.7 29.8 61.4 128.0/128.2 125.8/126.2 41.0/52.8 127.4 119.9/121.6 111.4 146.2/146.5 144.3/144.5 131.8/131.9 48.0/48.1 46.6/46.7 35.7/39.1 55.8 162.1/162.7 161.2 21.4 d 50 (56) 76 88.7 29.2 61.4 128.2 125.1 58.4 127.1 121.2 111.3 146.8 144.5 131.2 48.1 35.1 35.2 55.6 78 89.8 31.5 65.2 27.6 31.7 60.4 129.1 121.6 111.3 146.2 144.0 136.3 46.7 23.9 54.1 55.9 41.9 80 90.0 31.7 65.5 27.8 37.5 53.8 127.2 120.8 110.9 146.6 144.2 136.6 47.4 24.2 47.4 56.1

(154)

b 50 (47)

d 50 (60)

b 50 (38)

d 25 (159)

d 50 (60)

Solvent a: DMSO-ofe, b: CDCI3-CD3OD, c: CD3OD, d: CDCI3.

384

4.3 Mass Spectrometry Extensive studies on the mass spectrometry of Amaryllidaceae alkaloids by electron impact were reported in the sixties and seventies (92, 151, 178, 192, 211-218). The fragmentation patterns in the EIMS of various skeletal types are fairly well documented and have considerable diagnostic value. a.- Lycorine type The molecular ion appears as a quite intense peak, and generally suffers the loss of water, as well as C-1 and C-2 and their substituents by a retro Diels-Alder fragmentation (Fig. 13). The loss of water is not present in the spectra of acetyl derivatives. The ease of the loss of water from the molecular ion was found to be greatly dependent on the stereochemistry of the C-2 hydroxyl group. Thus, in the mass spectrum of lycorine (1) the relative intensity is low, while in 2-epilycorine it is the base peak (192). b.- Homolycorine type In this structure type the cleavage of the labile bonds in ring C by a retro Diels-Alder reaction is dominant, generating two fragments: one, the most characteristic, represents the pyrrolidine ring (plus substituents in position 2), and the other (a less abundant fragment) encompasses the aromatic lactone or hemilactone moiety (Fig. 14). A further general and noteworthy feature is the low abundance of the molecular ion in all compounds with a double bond A^'"* (211).

c- Crinine-Haemanthamine types Several general considerations should be taken into account for these types of alkaloids: The stability of the molecular ion, which is almost always the base peak. The important role played by the aromatic ring in the stabilization of the Ions, which is retained in all fragments of high mass while the nitrogen atom is often lost. The relatively large number of nitrogen-free ions. The fragmentation mechanisms are initiated by the rupture of a bond p to the nitrogen atom which implies the opening of the C-11/C-12 bridge (215, 216). c.1. Compounds with a saturated ring C and no bridge substituent. The configuration of the substituent on ring C plays a minor role in the fragmentation process.

385 C.2. Compounds with a double bond (A^'^) in ring C and no bridge substituent. The fragnnentation pattern involves ruptures of C-4a/C-10b and C-3/C-4 bonds. A characteristic feature is the loss of a nitrogen-containing nnoiety, C3H5N [M-55]. C.3. Compounds with a double bond (A^'^) in ring C and a hydroxyl substituent at C-11. The presence of a hydroxyl group on C-11 is responsible for dramatic changes in the fragmentation pattern (Fig. 15), and it is profoundly influenced by the stereochemistry. There are three fundamental patterns of fragmentation: Loss of CH3OH: it is more favorable when the two-carbon bridge and the substituent on C-3 are on the same side of the molecule. Loss of C2H6N: the relative significance of the loss of this neutral nitrogen moiety is governed by the ease with which the methanol is eliminated. Loss of CHO: A peak at m/z [M-29] due to the loss of an aldehyde radical is present In all compounds of this type. d.- Tazettine type Minor changes in stereochemistry are sufficient to cause appreciable differences in the stereoisomers in these kind of structures. Thus, in the MS of tazettine (59), with a p configuration of the methoxyl group at C-3, the dominant ion occurs at m/z [M-84], following a C-ring fragmentation by a retro Diels-Alder process. In contrast, the mass spectrum of criwelline (60), which differs only in the configuration of the mentioned methoxyl group, contains a peak of low abundance at A7yz[M-84] (Fig. 16). Ions occur in both steroisomers due to the successive loss of a methyl radical and water from the molecular ion (151). e.- Galanthamine type In this type of structures, the intense molecular ion as well as [M-1] peak, the breaking of ring C (losing a C4H6O fragment) and the elimination of elements of ring B (including the nitrogen atom) are characteristic (Fig. 17). This behavior is similar for the dihydro derivatives (213).

386

OH

OH

m/z 287
LYCORINE (1)

m/z 227

m/z 226

m/z 269

m/z 268
Fig. 13. Mass fragmentation pattern of lycorine (1).

n
Me0 M e O $

m/z 315
HOMOLYCORINE (23)

m/z 109

rn/z 108

+.

JJ - )O e M Me0

-cot

Meo
1 +-

Me0

m/z 206

m/z 178

Fig. 14. Mass fragmentation pattern of homolycorine (23).

387

388

d z 269

m/z 240

m/z211
OMe

m/z 181

m/z 257

OMe

m/z 225

m/z 30 1 HAEMANTHAMINE (49) m/z 258

OMe

m/z 227

'0-H
0

\
m/z 258 Fig. 15. Mass fragmentation pattern of haemanthamine (49).

OMe

m/z 331 TAZETTINE (59)

m/z 247

- CH,O
1 1 1

dZ331 CRIWELLINE (60)

m/z 30 1

m/z 247

Fig. 16. Mass fragmentation pattern of tazettine (59) and criwelline (60)
389

390

m/z 287
GALANTHAMINE (70)

m/z 2 17

-H'

m/z 1 74

m/z 21 6

Fig. 17.Mass fragmentation pattern of galanthamine (70).

391 5. BIOLOGICAL AND PHARMACOLOGICAL ACTIVITIES Plants of the genus Narcissus L. have been used throughout history to treat a variety of human medical problems (219). N. poeticus L., for example, was described in the Bible as a well-established treatment for symptomatologies now defined as cancer (220). In the fourth century BO, the Greek physician Hippocrates of Cos (the "Father of Medicine") recommended a pessary prepared from narcissus oil (probably N. poeticus L.) for the management of uterine tumours (221). In the first century AD, Pliny the Elder recorded the topical use of that extract and another derived from N. pseudonarcissus L. for this purpose (N. poeticus L. is now known to contain 0.12 g of the antineoplastic agent narciclasine (64) per kg of fresh bulb) (86). Arabian, North African, Central American and Chinese medical practitioners of the middle ages continued using Narcissus oil in cancer treatment (222). For example, bulbs of N. tazetta L. var. chiinensis Roem., cultivated in China as a decorative plant, were used for treatment of tumours in folk medicine. In this case, pretazettine (61) was proved to be one of the antltumour active compounds (57). It has been known for a long time that daffodil ingestions are very dangerous, resulting in toxic symptoms. After ingestion of N. tazetta L. (43) and N. jonquilla L. (223), the first visible symptoms are nausea, vomiting and diarrhea, followed by neurological (trembling, convulsions, etc.) and cardiac sequelae, and sometimes resulting in death if eaten in quantity. N. papyraceus Ker-Gawler is believed to be toxic for herbivorous mammalians; in this case, the toxicity might be related to the alkaloid content which is five times higher in the aerial part than in the bulbs (72). Moreover, N. pseudonarcissus L. showed irritant and allergenic properties on contact with animals and men (74, 224, 225). Apart from these harmful effects of daffodils, several Narcissus extracts have shown antiviral (226-231), antimicrobial (232, 233), cytotoxic (234), antitumour (228-230, 235) and allelopathic (236) activities. Table 6 shows the different pharmacological and/or biological properties exhibited by the alkaloids from the genus Narcissus L., but only some of the activities of a reduced number of Narcissus alkaloids are known. The most extensively studied effect is that of non-specific inhibition, e.g. antitumour, antimitotic, suppression of development of splenomegaly and increase in number of nucleated blood cells. The relationship of chemical structure and biological activity of these alkaloids is largely unknown (236), and further

392

studies of several alkaloids of this plant family for therapeutic purposes remain still to be done. TABLE 6 Biological and pharmacological activities of Narcissus alkaloids
Alkaloid 57 6a-hydroxybuphanisine 10 caranine Activity Moderate cytotoxic against human tumoral Molt 4 cells Weak analgesic Convulsant and hypotensive Acetylcholinesterase inhibitor Active against the murine P-388 lymphocytic leukaemia (as acetylcaranine) References (237) (89) (89) (89) (238) (89) (89) (148) (239) (148) (240) (240) (240) (240) (89,241,242) (243) (244) (245) (246, 247) (89, 248-254) (230,249,251) (255) (256) (255, 257) (244)

53 crinamine

Powerful transient hypotensive in dogs Respiratory depressant Moderate antimalarial Antimicrobial Strong cytotoxic Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines Weak cytotoxic against HepG2 hepatoma Cytotoxic against non-tumoral LMTK cells Moderately active against Molt 4 lymphoma Powerful analgesic Anticonvulsive Hypotensive Inductor ofhypothermia in rat Cholinesterase inhibitor with peripheral and central pharmacological effects Centrally-acting competitive acethylcholinesterase inhibitor under investigation as therapeutic agent in treating Alzheimer's disease Reverses cognitive deficits induced by nBM (nucleus basalts magnocellularis) lesions in mice Anticurare and antimorphine as well as memory-influencing Combines both physostigmine and neostigmine properties: * like physostigmine, reverses opioid-induced respiratory depression, but not the concomitant analgesia * like neostigmine, antagonises muscle paralysis induced by cZ-tubocurarine, also antagonises the ganglionic blockade and increases the contraction response As hydrobromide has several central and peripheral effects: * has central effects such as antagonism of the respiratory depressant effect of morphine-like compounds * is capable of penetrating the blood-brain barrier and it is used in the treatment of the central effects of scopolamine (hyoscine) intoxication. It has certain advantages over physotigmine for this purpose. * is able to reverse the central anticholinergic syndrome

36 dubiusine 70 galanthamine

(257- 259) (247, 260) 256, 257,

(256, 258)

393 TABLE 6 (continued) Alkaloid

70 galanthamine (cont.)

Activity
* is used for its anticholinesterase activity in the treatment of disturbances in the peripheral sympathetic synaptic transmission. * reverses the neuromuscular blocking effect of curare-type muscle relaxants and has been used safely in anaesthesia and in the treatment of various neurologic disorders (pareses, paralysis of different origins, myasthenia gravis, progressive muscular dystrophy, etc.). Energix, a preparation composed of galanthamine, increases endurance during exercise and delays the onset of fatigue Used in a pharmaceutical composition for treatment of alcoholism Cytotoxic against non-tumoral LMTK cells Produces poisoning of digestive, respiratory, neuromuscular and central nervous systems

References
(259) (242, 246, 250, 255-258,261-263)

71 epigalanthamine 73 norgalanthamine 75 7V-formylnorgalanthamine 7 galanthine 49 haemanthamine

(264-266) (267) (240) (43) (268) (268, 269) (240) (240) (240) (89) (240) (270) (271) (240) (240) (234) (272) (272, 273) (272) (167) (167) (274) (7) (167) (240) (240) (74) (240) (240) (240)

More hypotensive and less toxic than galanthamine Anticholinesterase activity lower than galanthamine Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines Moderate cytotoxic against Molt 4 lymphoma and HepG2 hepatoma Cytotoxic against non-tumoral LMTK cells Hypotensive Weak cytotoxic against Molt 4 lymphoid cells Hypertensive Cytotoxic against a variety of cultured cells (in vitro) Cytotoxic against fibroblastic LMTK cells Moderately active against Molt 4 lymphoid cells Moderately active against Rauscher leukaemia Inhibitor of HeLa cell growth Inhibitor of protein synthesis, blocking the peptide bond formation step on the peptidyl transferase centre of the 60S ribosomal subunit Slightly reduces DNA synthesis, whereas RNA synthesis is practically unaffected

51 haemanthidine 30 hippeastrine

Active against A-431, KB, Lul, Mel2 and ZR-75-1 cell lines Significantly active against LNCaP and HT cell lines Antiviral. Active against Herpes simplex type 1 (HS-1) Weak insect antifeedant Significantly active against the LNCaP and HT cell lines Cytotoxic against non-cancerous LMTK cells Weak cytotoxic against Molt 4 lymphoid cells

23 homolycorine 24 8-O-demethylhomolycorine

Inductor of delayed hypersensitivity in animals Cytotoxic against fibroblastic LMTK cells Cytotoxic against fibroblastic LMTK cells Weak cytotoxic against Molt 4 lymphoid cells

394 TABLE 6 (continued)

A kaloid 29 9-O-demethyl2a-hydroxyhomolycorine 68 ismine 78 lycoramine Activity Cytotoxic against fibroblastic LMTK cells Moderately active against Molt 4 lymphoid cells References (240) (240)

Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines Central anticholinesterase activity stronger than galanthamine Like neostigmine, antagonises muscle paralysis induced by dtubocurarine, also antagonises the ganglionic blockade, and increases the contraction response Produces acute poisoning of digestive, respiratory, cardiovascular. neuromuscular and central nervous systems Weak hypotensive Cytotoxic against murine LMTK and human HepG2 cell lines Cytotoxic against fibroblastic LMTK cells Weak cytotoxic against HepG2 hepatoma Respiratory stimulant Relaxant of isolated epinephrine-precontracted pulmonary artery Increases contractility and rate of isolated perfused heart. These effects are mediated by stimulation of p-adrenergic receptors Specific inhibitor of ascorbic acid (AA) biosynthesis. Seems to act as a non-competitive inhibitor on galactano-gamma-lactone oxidase Most of the effects of lycorine on physiological processes have been ascribed to its ability to inhibit ascorbic acid biosynthesis in The ability to inhibit the ascorbic acid biosynthesis has made this substance a valuable tool for studying the AA-dependent reactions Inhibitor of cyanide-resistant respiration. AA is needed for the in vivo synthesis of hydroxyproline-containing proteins, specifically utilised for the development of KCN-resistant respiration. Inhibitor of peroxidase enhancement, which seems related with the synthesis of hydroxyproline-containing proteins Inhibitor of cell division in rat fibroblasts. Ascorbic acid is required for cell division Inhibitor of protein blocking peptide bond formation Inhibitor of DNA synthesis. Moderate antitumoural Cytotoxic against a variety of cultured cell lines Inhibitor of HeLa cells growth Decreases the growth of several viruses through its inhibitory action on viral protein synthesis Active against several RNA and DNA viruses. Inhibits the growth of Herpes simplex type I, poliomyelitis, coxsackie, Semliki Forest and measles viruses Active against RNA-containing flaviviruses and bunyaviruses Does not inhibit the activity of reverse transcriptase Weak protozoicide Plant growth inhibitor by inhibition of protein synthesis Inhibitor of growth and cell division in plants, inhibiting the cell cycle during interphase. Ascorbic acid is required for cell division
VIVO.

(240) (244) (244) (43, 244) (270) (240) (240) (240) (89, 275) (275) (275) (275-279) (144) (279-282) (144, 281) 277, 279,

31 lycorenine 32 O-methyllycorenine 1 lycorine

(144,281) (240, 282) (272, 273, 283) (272, 283) (89, 274, 275) (148,271,240) (272) (284-287) (89, 274, 275, 286288) (289) (228) (89) (89) (144, 275, 277, 279, 282)

395 TABLE 6 (continued) Alkaloid

1 lycorine (cont.)

Activity
Inhibitor of germination of seeds and growth of roots. Lycorine-1O-P-D-glucose has the reverse effect, and may also produce mitogenic activity in animal cells Ungeremine, a natural metabolite of lycorine, is responsible, at least in part, for the growth-inhibitory and cytotoxic effects of lycorine Certain bacteries transform lycorine into pancrassidine, which is less cytotoxic than ungeremine. The changes observed in response to stress suggest its role in protective and repair mechanisms of producer plants Inhibits the feeding of the desert locust Schistocerca gregaria Weak cytotoxic against human Molt 4 and murine LMTK cell Imes Inductor of delayed hypersensitivity in animals Cytotoxic against Molt 4 lymphoid cells Weak cytotoxic agamst fibroblastic LMTK cells Antimitotic Strong tumour inhibitor. One of the most important antineoplastic components of Amaryllidaceae species Active against larynx and cervix carcinomas Inhibitor of HeLa cells growth Inhibitor of growth of Ehrlich tumour cells Inhibitor of protein synthesis in eukariotic ribosomes, blocking the peptide bond formation on the 60S ribosomal subunit. Resistance to narciclasine in a mutant strain of Saccharomyces cerevisiae is due to an alteration on the peptidyl transferase centre Reduces DNA synthesis, whereas RNA synthesis is practically unaffected Inhibitor of ascorbic acid biosynthesis in vivo Strong antibiotic. Active against Corynebacterium fascians Active against RNA-containingflavivirusesand bunyaviruses Inhibitor of cell division in tobacco tissue culture Inhibitor of Avena coleoptile sections and rice seedling test Inhibitor of seed germination and root growth at low concentrations. The O-glucoside of narciclasine has the reverse effect Narciclasine-4-O-P-D-glucopyranoside shows cytotoxic and antitumour activity very similar to narciclasine The peculiar activity of narciclasine seems to arise from the ftmctional groups and conformationalfreedomof its C-ring Increases the amplitude andfrequencyof respiratory movements Increases the amplitude and decreases the frequency of cardiac contractions Decreases the soporific effects of ethanol and barbiturics Increases the analgesic effect of morphine Protective against thiopental poisoning Enhances the effects of caffeine, corazole, arecoline, and nicotine Probably acts primarily on m-cholinoreactive structures of the brain

References
(283, 290) (291) (292) (293) (294) (240) (74) (240) (240) (88, 89, 295) (89, 222,296, 297) (298) (272) (221,299,300) (89, 273, 299-301) (299) (272) (88, 144) (88) (289) (297) (297) (302) (303) (88) (304) (304) (304) (304) (304) (90) (90)

62 3-epimacronine 27 masonine 82 mesembrenone 64 narciclasine

11 narwedine

44 papyramine 61 pretazettine

(240) Cytotoxic against fibroblastic LMTK cells Weak cytotoxic against human tumoral cell lines Molt 4 and HepG2 (240) Active against murine Rauscher viral leukaemia (89, 205, 230, 234, 288)

396 TABLE 6 (continued)

Alkaloid 61 pretazettine (cont.) j Activity Active against spontaneous AKR T cells in mice Active against intraperitoneally and subcutaneously implanted LLC (Lewis lung carcinomas) Effective against Ehrlich ascites tumour, a non viral transplantable tumour Cytotoxic against fibroblastic LMTK and Molt 4 lymphoid cell lines Inhibitor ofHeLa cell growth Inhibitor of protein synthesis in eukariotic ribosomes, blocking the peptide bond formation on the 60S ribosomal subunit. Slightly reduces DNA synthesis; has no effect on RNA synthesis Active against Herpes simplex type 1 (HS-1) Active against neurotropic RNA viruses Potent inhibitor of viral reverse transcriptase of RNA tumour viruses, binding to the polymerase enzyme Demonstrates synergistic effect in combination with standard cytotoxic drugs In combination with ryllistine inhibits nucleic acid synthesis Can be administrated over a long period of time without apparent toxicity Effective against murine Rauscher leukaemia in mice, suppressing the splenomegaly and the increase of nucleated blood cells, and decreasing the virus level in plasma without apparent toxicity Inhibitor of protein synthesis in tumour cells at the step of peptide bond formation. It has a different binding site than lycorine on the peptidyl transferase centre of the 60S ribosomal subunit Reduces DNA synthesis. RNA synthesis is practically unaffected Cytotoxic against human Molt 4 and murine LMTK cells Moderately active against HepG2 hepatoma Moderately active against Ehrlich ascites tumour cells Inhibitor ofHeLa cell growth Antiviral. Active against Herpes simplex type 1 (HS-1) Active against neurotropic RNA viruses Does not inhibit the activity of reverse transcriptase Cytotoxic against Molt 4 lymphoid and LMTK fibroblastic cell lines Weak cytotoxic against HepG2 hepatoma Weak hypotensive Active against the Co 12 cell line Weak cytotoxic against fibroblastic LMTK cell lines The stereochemical rearrangement from pretazettine to tazettine inactivates the biological activity of pretazettine References (199, 305-308) (307) (307-309) (240) (272) (205, 272, 307310) (272, 308) (274) (289,310) (167, 229, 230, 273, 288) (230, 307, 308) (311) (306) (230, 312) 235, 310,

3 pseudolycorine

(272,273,310) (272) (240) (240) (231) (272) (274) (289,310,312) (228, 230) (240) (240) (89, 270)) (167) (240) (205) (89) (89)

5 2-O-acetylpseudolycorine 59 tazettine

39 vittatine

Weak analgesic in mice Tachycardic in dogs

397

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

407

Total Synthesis of Naphthylisoquinoline Alkaloids

Mark A. Rizzacasa 1. INTRODUCTION The plant families Ancistrocladaceae and Dioncophyllaceae are the only identified sources of the unusual naphthylisoquinoline alkaloids (ref. 1). The family Ancistrocladaceae contains one genus, Ancistrocladus, which consists of approximately 20 species that are distributed in the Indian archipelago, tropical Asia and tropical West Africa. These isoquinoline alkaloids are structurally unique in that they appear to originate, biosynthetically, form the acetate-polymalonate pathway and not from amino acids (ref. 1). Another interesting structural feature of these compounds is that they exist as thermally stable atropisomers because of restricted rotation about the biaryl linkage.

OMeOMe

MeO" OMeMe R = H (-)-Ancistrocladine (1) R = Me (-)-O-Methylancistrocladine (2) OH OMe MeO' (+)-Ancistrocladisine (4)

OMeMe OH Me (-)-Ancistrocladidine (5)

MichellamineA(6)

MeO' {-)-Dioncophylline A (8)

408

Naphthyl-isoquinoline alkaloids can be grouped according to the location of the biaryl linkage with the largest group being 5-1' linked. Ancistrocladus alkaloids are exemplified by ancistrocladine (1) (ref. 2), the first of this family to be isolated, 0-methylancistrocladine (2) and ancistrocline (3) (ref. 3, 4), which possesses some tumour-inhibiting activity. Other examples include the 7-1' linked ancistrocladisine (4) (ref. 5, 6), ancistrocladidine (5) (ref. 7), which possesses an uncommon 7-2' linkage, and the recently isolated dimeric 5-8' linked alkaloid, michellamine A (6) (ref. 8, 9,10), which has been shown to inhibit the cytopathic effects of HIV-1 (AIDS virus) in vitro. Dioncophyllaceae naphthylisoquinoline alkaloids do not possess oxygenation at C-6 with some examples being dioncophylline A (7) (ref. 11) and dioncophylline C (8) (ref. 12), the only 5-1' Unked alkaloid isolated from this plant family thus far. 2. BIOMIMETIC SYNTHESIS As mentioned, naphthylisoquinoline alkaloids are structurally unusual on account of the methyl group at the 3-position and oxygenation at the 8- and/or 6-position of the isoquinoline ring which points to a polyketide origin. This postulate has been supported by extensive studies conducted by Bringmann on the in vitro biomimetic synthesis of the naphthalene and isoquinoline portions of these compounds (ref. 13, 14) and this work is worth briefly mentioning in a discussion on the total synthesis of these compounds.

OMe Me SCHEME 1: Proposed biosynthesis of naphthylisoquinoline alkaloids.

409

It was proposed that both the naphthalene and isoquinohne moieties of these compounds could arise from a common polyketide precursor 9 (Scheme I). Aldol condensation of 9 could provide diketone 10 or a reduction/aldol sequence could provide the C-6 deoxygenated analogue 11. Diketone 11 serves as a precursor to the naphthalene 12 or, by condensation with a biological ammonia equivalent (ie. pyridoxamine), isoquinoline 13 and various hydrogenated derivatives. Biaryl coupling between 13 and naphthalene 12 gives the C-6 deoxygenated alkaloids found in Dioncophyllaceae. Amination of diketone 10 then gives the 6,8-dioxygenated isoquinoline 14 and biaryl coupling with naphthalene 12 provides the alkaloids that occur in the Ancistrocladus genus.

2. NH4OH, MeOH

HO OMeMe 14

SCHEME 2 A source of the polyketide 9 was the protected equivalent 16 (ref. 13) which can be obtained by ozonolysis of the diene 15 (Scheme 2). Exposure of 16 to silica gel affords phenol 17 which serves as a precursor to a 6,8-dioxygenated isoquinoline. Methylation followed by condensation with ammonia gives isoquinoline 18 from which the isoquinoline 14 can be secured by selective cleavage of the hydroxyethyl group.

^^QQ-OMe
19

MeO,

SiOo

OMeOMe 1. KOH, MeOH

2. KOH, Me2S04

^-

21

1.KOH, MGOSO.

2. NH4OH, MeOH

SCHEME 3 Ozonolysis of diene 19 provides the reduced polyketide 20 which is cyclised to phenol 21 (ref. 13) (Scheme 3). Methylation and a further aldol condensation gives the naphthalene segment 12 while methylation followed by condensation with ammonia yields the C-6 deoxygenated

410 isoquinoline fragment 13. Not only did this short biomimetic route rapidly supply each of the segments from simple precursors it also served to demonstrate the possible biogenetic formation of an isoquinoline alkaloid from acetate units. For the biomimetic synthesis of 1,3-dimethyltetrahydroisoquinolines, Bringmann studied the condensation of diketones with pyridoxamine phosphate equivalents (ref. 15). It v^as found, however, that the desired reductive amination did not occur. Condensation of pyridoxamine 23 with dione 22 gave only the isoquinoline 24 which could be reduced by NaBH4 to the corresponding tetrahydroisoquinolines 25 (Scheme 4). Hydrogenolysis of the A^-benzyl group then gave the cw-isoquinoline 26 as well as the corresponding rran^-isomer 27. Since pyridoxamine did not display the biomimetic properties desired it could be replaced by the simpler benzylamine which gave analogous results.
MeOH NaBH4 88%

' . A ^ N CI
OMeMe

H3C

,Me NH OMeMe 27

SCHEME 4: Biomimetic synthesis of 1,3-dimethyltetrahydroisoquinolines 3. SYNTHETIC APPROACHES TO UNSYMMETMCAL CHIRAL BIARYLS Since the naphthylisoquinoline alkaloids occur as stable atropisomers, a key aspect of synthesis is the stereocontroUed construction of the biaryl linkage (ref. 16). A number of methods have been developed for the synthesis of unsymmetrical chiral biaryls and can be divided into inter- and /nframolecular approaches. Some intermolecular approaches are depicted in Figure 1 and majority utilise nucleophilic aromatic substitution on the aromatic ring (S^Ai reaction) activated by a functional groups such as oxazolines, esters, imines. Most of these approaches involve the use of a chiral auxiliary with the chiral oxazoline method developed by Meyers (ref. 17, 18, 19) finding a wide range of applications to date. The stereoselectivities observed in this coupling reaction can be explained considering both the steric and electronic effects of the ortho substituents on the Grignard reagent (ref. 20, 21). As depicted in Scheme 5, Grignard addition may lead to azaenolate 29a and 29b. The initial nucleophilic attack should occur mostly from the P-face (28P) as a-face (28a) attack is hindered by the substituent on the oxazoline moiety. The atropisomeric selectivity observed could be due to free rotation about the sigma bond

411 FIGURE 1: Intermolecular Approaches 1. Chiral 2-Oxazolines (Ref. 17)

^^^^ ....,J\^Ox Y-P 1 1 ^^ R = OMe or F

V
^^=^

OX=KT"
R ^ H; R' = A P r R = H;R' = f-Bu R = Ph; R' = CHaOMe

2. Chiral Ethers and Esters (Ref. 22,23)

-ROMgBr

l ^

X X )<

MgBr

" ^

_^Q^^^

R = H-Menthyl M = MgBrorLi 3. Chiral Sulfoxides (Ref. 24) -X

MgBr ^^^^

, , .. ^ ^ , R = (-)-Menthyl

\^,0

^X.CO,R

^CT
4. Planar Chiral Tricarbonyl(arene)chromium Complexes (ref. 25) B(OH),

pd(0)

*
MeO

[ ^

"

0^/^,

--

[I MeO.

MeO. X

^ R ^
Cr(C0)3

J>^m k>Cr(CO)3

412

of the complex 29 before magnesium methoxy bromide elimination occurs. When the chelating ability of the R substituent is poor, the preferred rotomer is 29b where the magnesium atom preferentially chelates to the methoxy substituent as shown. Rotomer 29b then collapses down to give the (P)-isomer 30 as the major product. Increasing the steric bulk of the R substituent increases the selectivity for atropisomer 30 but this effect is minor (ref. 20, 21).

V=C ^^N^'^ , -"^=^ S ^" ^^^C^n O MeO-Mg vjPr = ^ | V J,

MeO.

^ = : ^ Me^Mg Br 29a Br 29b J

-MeOMgBr

MeO , MeO. J ^ D

'Pr

R = CH3d.e. = 80% R = CH2OTBS, d.e. = 86%

SCHEME 5 An application of this methodology can be found in a total synthesis of the lignan (-)schizandrin in which a coupling between the oxazoline 31 and the Grignard reagent derived from bromide 32 gave the atropisomer 33 as the major product with good selectivity (ref. 26). Cram has also reported a biaryl coupling procedure which involves the use of an oxazoline in the presence of a chiral nucleofuge (ref. 22). OMe OMe OMe

MeO MeO^\^ OMe 31 OMe

(-)-Schizandrin

413 An alternative to the Meyers or Cram oxazoline methods is the use of 2-menthoxybenzoates for the synthesis of axially chiral biaryls. Treatment of the ester 34 with Grignard reagent 35 provides the (Af)-biphenyl 36 in 94% e.e (ref. 23). However, poor enantioselectivities were observed in cases where an ortho chelating substituent on the Grignard reagent was absent.
OMe OMe

RT, 24h

MeQ

36 34

The cross coupling reactions of aryl halides or aryl triflates with arylmetals catalysed by palladium(0) has found extensive use in the synthesis of unsymmetrical biaryls (ref. 27). A recent application of this coupling approach in the presence of chiral planar chromium complexes (ref. 25) has proved fruitful in the synthesis of chiral biaryls. Furthermore, Cr(CO)3-complexed biaryls can be isomerised under thermodynamic control, providing access to both atropisomers. Heating a solution of the complexed biaryl 37 in xylene under reflux resulted in a 1:99 ratio favouring the isomerised biaryl chromium complex 38 (ref. 28)

xylene
i

'\ OMe Cr(C0)3 37

reflux 2h 98% 38

Ph

MeO 40 OMe toluene, -45C then HgO"'

Ph

^-

OHO

90% ee

414

Recently, the use of a chiral catalysts in the asymmetric biaryl synthesis has received some attention. Unsymmetrical chiral binaphthyls can be obtained in high enantiomeric excess by SnAr reactions of naphthylimines such as 39 with lithium bromide free 1-naphthyllithium catalysed by a chiral ether Ugand 40 (ref. 29). Another example is the Ni(0) catalysed cross coupling of naphthyl Grignard reagents and naphthyl bromides in the presence of a chiral ferrocene ligand (ref. 30). FIGURE 2: Intramolecular Approaches 1. Oxidative Coupling (Ref. 31)

d-(OR)n
[O]

2. Palladium Catalysed Coupling (Ether bridge)

Pd(ll)

Reduction Internal v-^^ asymmetric '" induction' ll

3. Palladium Catalysed Coupling (Ester bridge)

Ring-opening with chiral or achiral nucleophiles Intemalor external asymmetric induction'

Pd(ll)

X Q

Axially Prostereogenic or Helical Lactones Often Stereochemically Unstable

R' = CH2OH or COXR X = O, 0, N or S

Intramolecular approaches involve utilising a bridge between the two aryl fragments which is either present or not present in the target molecule (Figure 2). Oxidative phenolic and phenolic ether coupling methods have been utilised for the synthesis of lignans and alkaloids where the bridge is part of the target molecule (ref. 31). A recent example of a reagent that can effect aryl dimerisation of electron rich compounds without free phenolic groups is iron(III) perchlorate in the

415 presence of trifluoroacetic acid. The intramolecular oxidative coupling of butyrolactone 41 using this Fe(ni) reagent system gave the biaryl 42 in excellent yield as one atropisomer (ref. 32).
OMe OMe Fe(CI04)36H20

MeO MeO

MeO, MeO

CF3CO2H-CH2CI2 O (1:10) RTIh

MeO

In another example reported by Evans and coworkers, a VOF3 mediated coupling of the linear tripeptide 43 provided the macrocycle 44 as one only atropisomer (ref. 33). Of note was the fact that substrates related to 43, where the 5-arylglycine ring contained a single para oxygen substituent, failed to undergo any intramolecular oxidative coupling under a variety of conditions.

^^.NCOCFg MeNH y ^'^^^^OMe

VOF3, BF3*OEt2

1 1
MeO' " " ^ OMe 43

^ODOB

0CthenZn
58%

TFA, TFAA, CH2CI2

"^^NH OMe 'OMe 44

MeO

For the stereoselective construction of the biaryl linkage of naphthylisoquinoline alkaloids via an intramolecular strategy, a temporary bridge must be installed and then removed after aryl coupling. Bringmann has studied this type of approach extensively and has applied it to the synthesis of naphthylisoquinoline alkaloids (ref. 16) detailed in Section 4 below. The types of bridge that have been utilised are ester and ether linkages with stereocontroUed formation of the biaryl linkage arising from internal or external asymmetric induction (Figure 2). Ether linkages cause the possible helical isomers to slowly interconvert at room temperature thus allowing for atropisomer separation (ref. 34) while, in some cases, ester linkages can allow for rapid helical interconversion and these compounds do not exist as stable atropisomers. Coined cucially prostereogenie (ref. 35), these lactones can be converted into stable atropisomers by ring opening with chiral H, O or N nucleophiles (external asymmetric induction) or, if the lactone possesses asymmetry elsewhere in the molecule, achiral nucleophiles (internal asymmetric induction).

416

The model benzonaphthopyranone system 46, obtained by Pd(II) catalysed intramolecular coupling of ester 45, has been utilised by Bringmann as a precursor for stereoselective biaryl synthesis by external asymmetric induction (ref. 36, 37). With bulky substituents (ie. R=isopropyl) the helical conformers of 46 are stable and exhibit chirality with the two methyl groups of the isopropyl residue ortho to the biaryl axis appearing as separate signals in the ^H NMR spectrum. The lactone bridge of compounds such as 46 can be opened atropisomerselectively with chiral Hnucleophiles to provide optically active diols (ref. 38, 39). Treatment of the lactone 47 with borane in the presence of the chiral oxazaborolidine 48 developed by Corey (ref. 40) gave an excellent atropisomeric ratio favouring the (M)-isomer 49 (ref. 38). The mechanistic course of this atropisomer selective reduction has been investigated by semiempirical AMI calculations and it was concluded that the stereochemically important step was the second hydride attack on the aldehyde intermediates generated by initial lactone reduction (ref. 41)

rf4
48

H Ph Ph Me OH

BH3*THF Me 49 M:Pratio = 98.5:1.5

Rapidly isomerising lactones can also be ring-opened to with chiral O- and A^-nucleophiles with high atropisomer-selectivity. Treatment of the axially prostereogenie lactone 50 with the potassium salt 51, derived from (+)-menthol, provided the (P)-biaryl 52 as the major atropisomer in a modest d.e. of 48% (ref. 42). Ring-opening of lactone 50 with the chiral potassium amide 53 provided the (Af)-biaryl 54 with greater selectivity (d.e. 86%). The use of the corresponding sodium or lithium salts of either 51 or 53 gave lower diastereoselectivities in both cases. Higher selectivities using chiral O- and A^-nucleophiles have been obtained for axially prostereogenic lactones that contain asymmetry elsewhere in the molecule (internal asymmetric induction) (ref. 43).

417
OMe

MeO" ^ f ^ ^C HO^ J N ^ Me

MeO--V-CO HO. Me 53

4. TOTAL SYNTHESIS OF NAPHTHYLISOQUINOLINE ALKALOffiS 4.1 Racemic Synthesis The first total synthesis of a naphthylisoquinoline alkaloid, the 7-1' linked Omethyltetradehydrotriphyophylline (55) isolated from the Dioncophyllaceae family (ref. 44), was reported in 1984 by Bringmann and coworkers (ref. 45). The requisite naphthalene 12 and isoquinoline 13 segments where available from biomimetic synthesis as previously detailed but attempted intermolecular coupling between the two moieties in their brominated forms under classical Ullmann type conditions (ref. 46) afforded only traces of the desired coupled product. Therefore, an intermolecular coupling approach utilising a temporary ether bridge was undertaken.
OMeOMe NBS, AIBN ,Me MeO MeO 58 OMe OMe

1. H2, Pt02 2. BnBr, K2CO3 3. 48% HBr reflux

PTC NaOH

hv 254 nm "^ MeO' NEt3 MeO 15%

1.Li,(C6H5)2

Me

()-59 SCHEME 6: Synthesis of 0-methyltetradehydrotriphyophylline (55)

Bn 2. 10% Pd-C 3. Me2S04, NaOH 46%

418

The synthesis of the bridged biaryl precursor 58 began with bromination of naphthalene 12 to provide dibromide 56 (Scheme 6). Selective hydrogenation of 13 followed by A^-benzylation and demethylation provide the tetrahydroisoquinoline 57 which was coupled with 56 under phase transfer conditions to give ether 58. Intramolecular aryl-aryl coupling was then achieved in low yield by photolysis of 58 to yield biaryl 59 along with starting material and a byproduct resulting from hydrodehalogenation. Completion of the synthesis of 55 involved reduction of the ether bridge with lithium biphenyl followed by simultaneous debenzylation/dehydrogenation and methylation. Based on the above approach, a racemic total synthesis of the ^r^zn^-configured alkaloid dioncophylline A (8) (or triphyophylline) was achieved by the same research group (ref. 47) (Scheme 7). On this occasion, a lactone bridge was utilised to construct the biaryl linkage intramolecularly. Oxidation of dibromide 56 followed by acid chloride formation provided the naphthalene segment 60 (ref. 48). The isoquinoline fragment 61 was readily available by benzylation and demethylation of the trans configured isoquinoline 27 obtained by biomimetic synthesis (see Section 2). Esterification of 61 with 60 gave the ester 62 which smoothly underwent palladium(II) catalysed intramolecular coupling to give the planarised lactone 63. Reduction then gave the alcohol 64 and its respective atropisomer which were separated by chromatography. Deoxygenation by hydroxy/halogen exchange followed by further reduction and subsequent debenzylation then provided racemic dioncophylline A (8) and its atropisomer 65.
1. DMSO, HaHCOg OMeOMe

56

100C
1^11-^

I
Br o \ D M A P

2. NaCI02 3. (C0CI)2, DMF,at 74% 1. BnBr, K2CO3 2. 48% HBr reflux

60
,.Me

>

72%

MeO MeO

2. LiAIH4 3. H2, Pd-C

()-8

MeO^>^

()-65

SCHEME 7: Racemic synthesis of dioncophylline A (8)

419
OMeOMe CuCN g|, DMF, reflux OMe 70 OMeOMe 78%

CN OMe

MeOH, H2O 84%

71
SCHEME 8 The first intermolecular synthetic approach to naphthylisoquinoline alkaloids was reported by Rizzacasa and Sargent and involved the use of a Meyers oxazoline coupling (Section 3) to introduce the biaryl linkage (ref. 49, 50). The target chosen to test this methodology was ()dehydroancistrocladine (66) (ref. 5, 6), a derivative of the 7-1' Unked alkaloid ancistrocladisine (4). The naphthyloxazoline 67 was synthesised from 1,5-diacetoxynaphthalene 68 as shown in Scheme 8. Oxidation of 68 with NBS in acetic acid/water affords the bromojuglone 69 in high yield (ref. 51). This interesting reaction proceeds through a number of discernible intermediates and provides the desired highly functionalised ring system in one step from a readily available starting material. Reduction and tandem hydrolysis/methylation under phase transfer catalytic conditions gives the naphthalene 70 in good yield (ref. 52, 53). Cyanide displacement then provides nitrile 71 which is converted into the oxazoline 67 under standard conditions (ref. 49).

Mg, THF MeO OMe then 67 reflux

1. Mel, MeNOg

^.

81%

MeO MeO MeO, MeOgC

2. NaOH 3. HgO"' 4. Mel, K2GO3 90% NO2

MeO, MeOgC

CHO

CH3CH2NO2 KOAc, AcOH

1.LiAiH4
^

2. AC2O, pyr. MeO MeO "^ 75 75%

MeO' MeO'

80%

SCHEME 9: Synthesis of dehydroancistrocladisine (66)

420

MeO, ROCH2

Me NHAc TMSCI, Nal then Zn, HOAc 97% MeCN, reflux 83%

MeO' MeO

naphthalene reflux 24% ()-4 + diastereoisomer

MeO' MeO

SCHEME 9 (cont): Synthesis of dehydroancistrocladisine (66) The completion of the synthesis of 66 is depicted in Scheme 9 and begins with the generation of the Grignard reagent from bromide 72. Addition of the oxazoline followed by heating provides the biaryl compound 73 in excellent yield which is then subjected to a series of deprotection steps involving quatemisation, base hydrolysis and acid hydrolysis of the acetal. Methylation then provides ester 74 and subsequent Henry reaction give the crystalline nitrostyrene 75. Reduction and acetylation yields the diacetate 76 which is O-deacetylated to give alcohol 77. A one pot hydroxy-iodine exchange/zinc reduction sequence gives acetamide 78 which smoothly undergoes Bischler-Napieralski cyclisation to provide racemic ancistrocladisine (4) and the corresponding diastereoisomer as an inseparable mixture. Dehydrogenation with Raney Ni then yields ()dehydroancistrocladisine (66). 4.2 Asymmetric Synthesis: 5,1' Linked Naphthylisoquinoline Alkaloids The efficient synthesis of racemic triphyophilline (60) paved the way for the first asymmetric total synthesis of the 5,1-linked napthylisoquinoline alkaloid (-)-ancistrocladine (1) (ref. 47). The approach once again relied on the successful intramolecular strategy used previously and required the development of asymmetric synthesis of the tetrahydroisoquinoline portion of 1. The route to isoquinoline segment 79 began with the synthesis of homochiral amphetamine derivative 83 via a reductive methylation protocol (Scheme 10) (ref. 54, 55) Thus, condensation of ketone 80 with (5)1-phenylethylamine gave imine 81 and stereoselective hydrogenation over Raney nickel (92% d.e.) provided enantiomerically pure salt 82 in 85% yield after one recrystallization. Hydrogenolysis then afforded amine hydrochloride 83 which was acetylated to give acetamide 84. Ring closure of 84 to 85 was then achieved under standard Bischler-Napieralski conditions. Stereoselective reduction of dihydroisoquinoline 85 using a protocol developed for the synthesis of 2,6-transdisubstituted piperidines (ref. 56) proved highly effective providing ^on^-tetrahydroisoquinoline 86 in 92% d.e. The final steps to 79 involved benzylation followed by selective demethylation of

421 the C-6 ether with hot aqueous HBr (ref. 57).
MeQ

M e
OMe 80

H Ph

X 5 Me

NH2 MeO, ^Me

1. Raney Ni 5 bar H2 2. HCIg 85%

toluene -H2O

K^
OMe 81

Me
Ph

MeO. H2N+ Me

10% Pd-C NH4HCO2 c MeOH, reflux

IIJ + N H 3
T OMe 83 PI-

AcCI, NEtg 96%

MeO.

Me NHAc OMe 84 95%

P_Oa^MeCN^

MeO>,

| T

..Me

J:Z^
LiAIH4

T T OMeMe 85 Me HO^ >r"'^V^^' NBn

-78-^0C 92%

MeO,

,Me NH OMeMe 86

1.BnCI,K2C03 2. 47% HBr 70G, 9h 65%

OMeMe 79 SCHEME 10

The stereoselectivity observed in the reduction of 85 to 86 is not easily explained in the dihydroisoquinoline case. In the case of tetrahydropyridines, hydride approach of the n bond occurs antiperiplanar to the to the axial vicinal ac-H bond as in C on stereoelectronic grounds to give cis configured products (Figure 3). In the presence of a Lewis acid such as AlMes the complexed iminium ion adopts another conformation due to A^^'^) strain between the R and the AlMes groups. Hydride attack antiperiplanar to the to the axial vicinal CQ-K bond again (ie. T) occurs to give the trans isomer. Since the carbon adjacent to the imine carbon in the dihydroisoquinoline 85 is no longer sp^ hybridised, such a high selectivity may not be expected.

Me^

N H

FIGURES

422 OMeOMe Pd(PPh3)2Cl2 Me

NaOAc MeaNCOCHa

^-

LiAIH4 separate 95%

OMeOMe 1. BrCHgCHaBr PhsP

OMeOMe

OMeMe 90 + OMeOMe

2. LiAIH4 3. H2, 10%Pd-C 91%

^.

OMeOMe 1. BrCHgCHgBr PhsP 2. LiAIH4 3. H2, 10%Pd-C

OMeMe OMeMe 91 92 SCHEME 11: Asymmetric synthesis of ancistrocladine (1) and hamatine (92) With the optically active tetrahydroisoquinoline 79 in hand the total synthesis of (-)ancistrocladine (1), and its naturally occurring atropisomer (+)-hamatine (92), was completed as shown in Scheme 11. Esterification of compound 79 with acid chloride 60 gave the ester 87 which smoothly underwent Pd(n) catalysed intramolecular coupling to yield the 5-1' coupled lactones 88 and 89 as a 3:1 mixture respectively. None of the possible 7-1' linked regioisomeric lactone was detected. These lactones are helicene-like atropisomers (not axially prostereogenic) but they

423

interconvert quite rapidly making separation at this stage difficult. Therefore, lactones 88 and 89 were subjected to hydride reduction to yield the configurationally stable alcohols 90 and 91 in the same ratio, which were easily separated by chromatography. Deoxygenation and debenzylation converts into 90 ancistrocladine (1) and 91 into hamatine (92). An interesting point to note is the ratio of atropisomers observed in the biaryl coupling is similar to the ratio of the two atropisomeric alkaloids that occur in the plants. The low atropisomerselectivity in the above synthesis of ancistrocladine (1) prompted a study into a more efficient process (ref. 58).The helical lactones 88 and 89 interconvert quickly (Ti/2 < 1 min) and represent thermodynamic ratio favouring atropisomer 88. This dictates the ratio of atropisomers obtained in the reduction step to stable isomers 90 and 91. Since this ratio cannot be improved upon to give either atropisomer selectively and unstable lactones 88 and 89 are difficult to separate, a less planar ether bridge was utilised in the hope that epimerisation would occur more slowly.
OMeOMe

OMeOMe 56 NaOH PTC 79 100%

Pd{PPh3)2Cl2 61% ratb 1.5:1 separate

SCHEME 12: Atropisomer selective synthesis of 1 and 92 by thermodynamic isomerisation. The biaryl precursor 92 was obtained by coupling naphthalene 56 and isoquinoline 79 under conditions used previously (Scheme 12). Palladium(II) catalysed coupling then afforded the helical isomers (P)-93 and (M)-94 regioselectively. These ethers now isomerise more slowly (T1/2 ~ lOh) than their lactone counterparts and can be separated to provide atropisomerically pure 93 and 94 in a ratio of 1:1.5 favouring the ancistrocladine (1) type (M)-helical isomer 94. Evidence for the assignment of the major isomer initially arose from iR NMR analysis (ref. 57). The chemical shifts of the protons at C-4 and the methyl at C-3 are greatly influenced by the anisotropic ring current of the naphthalene substituent. In 94 Ha and the C-3 methyl group protons are shielded by the

424

naphthaleneringabove the plane while the He proton is deshielded when compared to the shifts for the same protons in compound 92 (Figure 4). Conversely, Ha and the C-3 methyl group in isomer 93 are now deshielded while He is shielded.
3.12 1.78

M N,

Bn

H OO 1.89

^ 0.73

o QQ

'

Bn 93

1.11

1.29

94

FIGURE 4: iH NMR chemical shift differences in compounds 92, 93 and 94. Compound 93 can be converted into hamatine (92) by reductive cleavage of the ether bridge with dilithio biphenyl followed by catalytic hydrogenolysis on the A'^-benzyl group. Re-epimerisation of 93 in solution at room temperature then gives the same thermodynamic ratio from which 94 is separated and can converted into 1. Thus, a chirally economical synthesis of each atropisomer is achieved.
OMeOMe

93

Li/biphenyl

Hg/Pd-C 55% OMeMe OMe OMe

92 (+)-Hamatine

94

Li/biphenyl

Hp/Pd-C

(-)-Ancistrocladine (1)

OMeMe

Utilising a similar strategy, a total synthesis of the c/^-configured tetrahydroisoquinoline alkaloid (+)-ancistrocline (3) was then achieved by the same research group (ref. 59). The synthesis of the required isoquinoline 95 portion was first attempted from the known dihydroisoquinoline 85 (Scheme 13). C/^-selective reduction proceeded to give the tetrahydroisoquinoline 96 in high de (>95%) however attempted mono-demethylation gave a complex mixture due to the instability of the cis-configured tetrahydroisoquinoline 96 towards epimerisation at C-1 and oxidation (ref. 55). Therefore, a second route involving demethylation prior toring-closurewas utilised. Optically pure isoquinoline 84 was subjected to monoselective

425

ether cleavage to provide phenol 97. Bischler-Napieralski ring-closure gave dihydroisoquinolines 98 and 99 in a ratio of 33:67 respectively and stereoselective reduction (ref. 55) of isomer 99 followed by A^-methylation gives the required tetrahydroisoquinoline 95.
MeO, ,Me NaBH4 MeO.

OMeMe 85 MeO.Me NHAc OMe 84 MeO.Me HO

OH Me 98 OMeOMe Pd(ll)

NEta, DMAP OMeOMe

^-

COGI 60 Br

OMe Me 100 OMeOMe

OMeOMe 1. BrGH2CH2Br PhaP 2. LiAIH4

LiAIH4

CH2OH Me

>

,NMe OMeMe SCHEME 13: Synthesis of (+)-ancistrocline (3), The rest of the synthesis is described only briefly in the original communication (ref. 59) and no yields are quoted. Coupling of the isoquinoline with naphthoyl chloride 60 gives the ester 100 which undergoes intramolecular Pd(II) catalysed coupling to give the lactone 101. Reduction followed by deoxygenation and then provided (+)-ancistrocline (3).

426
OMeOMe

OM eOMe X^
^^, M e

1 MeO ^ J N ^ ^ ^ \

^^'^^<^Me

ffSl

1 ^ ^ v ^ Me

> ^

M eCX

UvsJi^^NH
OMeMe 2

rV

NHAc

OMe 102

OMeOMe

M e O y ^ ^ J ^ [f
OMeN OMe 104 OAc

MgBrO

OAc

105 SCHEME 14

I OMe

The first asymmetric intermolecular synthesis of 0-methylancistrocladine (2) involved the use of a Meyers biaryl coupling, successfully utilised in the earlier synthesis of dehydroancistrocladine (66), to construct the biaryl linkage atropisomer-selectively (ref. 60, 61). It was envisaged that 2 could arise from the acetamide 102 which in turn could be derived from biaryl 103 (Scheme 14). A coupling between the Grignard reagent 104 and chiral oxazoline 105 could then provide 103 stereospecifically. This approach required the synthesis of chiral oxazoline 105 which is outlined in Scheme 15 and begins with the nitrite 71 available in three steps from 1,5diacetoxynaphthalene (see Scheme 8).
OMeOMe f-BuOK CN OMe 71 reflux OH ^BuOH 100% CONH2 OMeOMe Et30BF4 CICH2GH2CI OEt OMe NH2BF4 OMeOMe

107 H2N\^p^
"OH 105 OMe

0
OH

109
81%

i-!!!El H 2 N v ^

Ph

^OMe 109

108

SCHEME 15 Partial hydrolysis of nitrite 71 gave the amide 106 which was treated with triethyloxonium tetrafluoroborate (Meerwein's reagent) to give the imino ether salt 107 (Scheme 15). This salt was

427

not isolated but simply allowed to react with the chiral amino alcohol 109 (ref. 62), derived from commercially available diol 108, in hot 1,2-dichloroethane to give the oxazoline 105. This one pot protocol was far superior to the acid chloride/ amide/ SOCI2 ring-closure route used previously. With the chiral oxazoline now in hand, the asymmetric biaryl coupUng reaction was investigated. Treatment of bromide 110 with 1,3-propanediol and acid gave the ketal 111 which was converted into the Grignard reagent 104 (Scheme 16). Addition of a solution of 105 in THF followed by heating provided the biaryls (AT)-103 and (P> 112 in a ratio of 45:20 respectively which were easily separated by chromatography. The debromo compound 113 and demethylated oxazoUne 114 were also isolated along with the desired biaryl products. It appears that magnesium bromide generated in the reaction facilitates demethylation of oxazoline 105 however the resultant naphthol 114 is easily recycled by remethylation. The stereochemistry of the major atropisomer 103 was later confirmed by its conversion 0-methylancistrocladine (2) (see below).
Br O - ^ M e o y ^ ^ j MgBrO^ UeO^J^J

MeO^^CHO

p,30^^

Mg, THF
trace I2, A

OMe 111 OMeOMe

105 THF
reflux

^
MeQ

X)ro^
OMe 103 M;P ratio 69:31 65% yield OMeOMe NaH,THF 105 100% 114 OMe 112

SCHEME 16 Acidic hydrolysis of the acetal group in 103 was attempted but this also lead to slow ringopening of the oxazoline. Quatemisation of the oxazoUne 103 with methyl iodide followed by base hydrolysis was also problematic, giving only the amide 115 which resisted further hydrolysis under these conditions due to the sterically hindered carbonyl group. However, treatment of the quatemized oxazoline or amide 115 with KOH in wet DMSO provided the desired acid which was

428

then converted into the methyl ester 116. Reduction of with lithium aluminium hydride then provided the alcohol 117.
OMeOMe Me 103 1. Mel, MeNOo 2. KOH. MeOH 99% MeO. OMe OH KOH, DMSO 2. Mel, K2CO3 MeO^ OMe OMe

115

LiAIH4

c:

116 R=C02Me 17 R = CH20H 92%

The corresponding hydrolysis of the iodide salt derived from biaryl 112 also gave the atropisomeric ester 118 which was reduced to alcohol 119. Although each of the alcohols were optically active, the high temperature required in the base hydrolysis step may have caused some rotation about the biaryl axis. For example, the biaryl acid 120 undergoes racemisation at 25C in chloroform with a half life of 220 min (ref. 63) while the binaphthyl 121 is thermally stable with no racemisation observed after 5 h heating at 140C in a sealed tube in sodium hydroxide solution (ref. 64). The rates of racemisation of biaryl acids in aqueous sodium hydroxide solution are known to be greater than those in an organic solvent (ref. 65). Therefore, it was deemed necessary at this stage to verify the optical purity of alcohols 117 and 119.
OMeOMe 1. Mel, MeN02 2. KOH, DMSO 3. Mel, K2CO3 96% OMeOMe

112

^-

HO2C

120

121

The method chosen was that of Johnson and coworkers (ref. 66) which involves the use of a chiral oxazaphospholidine-2-thione as a chiral derivatising agent for ^ip NMR analysis of

429 enantiomeric excess. The chloride 122, derived from thiophosphoryl chloride and (-)-ephedrine hydrochloride (ref. 67), possesses an asymmetric phosphorous atom and when allowed to react with alkoxides, displacement occurs at phosphorous with inversion of configuration. The resulting derivatives can then be examined by ^H and ^^P NMR spectroscopy to determine diastereoisomeric purity. Treatment of the sodium salt derived from biaryl alcohol 117 with the chloride 122 gave the oxazaphospholidine derivative 123. Similarly, the biaryl alcohol 119 was converted into the derivative 124. The racemic biaryl alcohol 125 was also synthesised and derivatised by a similar route starting with achiral oxazoline 67 (Scheme 17).
OMe OMe Q Me CI H2N-v^Ph HO-^Me (-)-Ephedrine OMeOMe NaH 119 122 MeO Me PSCI3 NEta ^ S, N-Y^^^ -^v J w CI b - ^ M e 122 NaH. 117 * MeO Me

0-a I

b-^Me

OMeOMe THF, reflux ^^. OMe N ^ 67 I OMe OMeOMe 104 87% MgBrO'^ ' ^ ^ ^ V ' ^ ^ 0 ^ . >< ' MeO, ^ ^ Y - V 0 : : \ ^ ^ OMe 126 OMeOMe 1. Mel, MeCN 2. KOH, 100X DMSO, HpO 3.Mel,K2C03 94%

NaH MeO, 122 MeO.

LiAIH4

'-^125R = GH20H 99%

SCHEME 17

430

Treatment of the oxazoline 67 with the Grignard reagent 104 gave the biaryl 126 in excellent yield (Scheme 17). Quaternisation followed by base hydrolysis in wet DMSO and subsequent methylation gave ester 127 which was reduced to the racemic biaryl alcohol 125. Treatment of 125 with sodium hydride followed by the chiral phosphorous reagent 122 then gave the derivative 128 as a mixture of diastereoisomers and the ^H and ^^P NMR spectra were then examined. The proton decoupled ^Ip NMR spectrum of 128 exhibited signals at 5 84.10 and 84.27 for the two diastereoisomers, whilst the 300 MHz iH NMR spectrum exhibited two doublets at 5 2.63 and 2.67 (7 = 12.4 Hz) assigned to the A^-methyl protons, and two singlets at 5 4.69 and 4.70, assigned to the acetal protons. The oxazaphospholidine-2-thione 123 derived from the alcohol 117 showed only the signals at 5 84.28 in the 3lp NMR spectrum and signals at 5 2.63 and 4.69 in the ^H NMR spectrum, while the derivative 124, which was obtained from the enantiomeric alcohol 119 showed only the other signals. This analysis firmly established the optical purity of the alcohols 117 and 119.
OMeOMe Ql_l MeO, ^ o2-\ LMsCI, pyr. 2. LiAIH4 3. H3O+ 95% MeQ OMeOMe

Me CHO

EtNO,

AcOH, NaOAc 81%

^-

OMeOMe LiAIH4 MeO, NO2 98%

OMeOMe

Me MeO, Me NHR OMe AC2O 132 R = H 133 R = Ac 88%

POCI3 MeCN, reflux

OMeOMe

OMeOMe

Me MeO Me

RaneyNi naphthalene reflux MeO

^,, 134

,,

27% from 133 OMeMe 129

OMeMe

SCHEME 17: Synthesis of (+)-0-methyldehydroancistrocladine.

431

To confirm the configuration about the biaryl linkage of the major atropisomer 103 obtained in the biaryl coupling, the derived alcohol 117 was first converted into (+)-0-methyldehydroancistrocladine (129), a degradation product of (-)-ancistrocladine (1) (ref. 2) (Scheme 17). Mesylation of 117 followed by hydride reduction and acid workup gave the aldehyde 130 which did not undergo any racemisation in boiling benzene for 5 h. Henry reaction yield the crystalline nitrostyrene 131 which was reduced to the amphetamine diastereoisomers 132 with lithium aluminium hydride in boiling THF. Acetylation then gave acetate 133 which smoothly underwent Bischler-Napieralski ring closure to the dihydroisoquinoline 134. Dehydrogenation finally furnished (+)-0-methyldehydroancistrocladine (129) which was identical in its properties, including sign and magnitude of optical rotation, with that obtained by degradation of (-)ancistrocladine (1). The amine mixture 132 was then converted into 0-methylancistrocline (2) as detailed in Scheme 18. Resolution of the diastereoisomeric mixture of amines was achieved using the 'directed resolution' method described by Helmchen and Nill (ref. 68). This involves initial conversion into (S, R) and (R, /?)-4-hydroxy-3-phenyl-A^-(l-phenylethyl)butanamides which can easily be separated by flash chromatography (ref. 69, 70). Amine 132 was allowed to react with (+)-(/?)-4,5-dihydro-4phenylfuran-2(3^-one 135 in refluxing toluene in the presence of 2-hydroxypyridine to give the butanamides 136 and 137 which were separated by chromatography. On the basis of the Helmchen analysis (ref. 67), the hydroxyamide 136 was expected to be eluted last and this proved to be the case since this diastereoisomer was converted into 2. Acid hydrolysis of 136 followed by acetylation provides amide 102. Ring-closure then gave dihydroisoquinoline 138 which was stereoselectively reduced to compound 2 under conditions described earlier.
OMeOMe O OMeOMe 1. IMH2SO4 MeO Toluene reflux separate OMeOMe POOL MeOMe MeO .Me OMeOMe

135 MeO.

OMe 136R = H;R' = Me28% 137R = Me;R' = H27% OMeOMe

AIMea LiAIH4 -78G MeO.

NHAc

^>K.^N OMe Me 138

SCHEME 18: Synthesis of (+)-0-methylancistrocladine (2)

432

OMeOMe

.Me S^NH OMeMe 139 OMeOMe

or

MeO,

RMe

OMeMe 140 OMeOMe

137

1M H2SO4 MeOMeO

The alcohol 119 derived from the minor product of the biaryl coupling was then converted into (+)-0-methylhamatine (92) (ref. 71) as well as the enantiomer 140 of 0-methylancistrocladine (2). Hydrolysis of the butanamide 137 gives the amine 141 which was converted into (-)-Omethylhamatine. This successful intermolecular approach was next applied in first total synthesis of the 5,r-linked (-)-ancistrocladinine (143) (ref. 21, 72). It was envisaged that deprotection and Bischler-Napieralski ring closure of the amide 144 would yield the dihydroisoquinoline 143, and the amide 144 was available from a coupling between the oxazoline 105 and the Grignard reagent 145 (Scheme 19).
OMeOMe OMeOMe OMeOMe -Ph OMeN.^ 105 ''''OMe + MgBr

BnO

^xo
OMe 145

SCHEME 19

433

CHO

LBnBr, K2CO3 2. propane-1,3-diol pTsOH 99%

BnO.

Mg, THF Then 105 reflux

OMe 146 OMeOMe

OMeOMe 1.Mel then KOH, DMSO

BnO.

BnQ P:M ratio 23:77 64% yield

Tir^'^
OMe 149 OMeOMe

2. Mel, K2CO3 3. LiAIH4 58%

^ ^

148 OMeOMe

1. ACgO, pyr. 7 steps 2. POCI3, 3. NaOH 71%

OMeOMe

OMeOMe

OMeOMe

SCHEME 20: Asymmetric synthesis of (-)-ancistrocladinine (143) The synthetic route began with the synthesis of the bromide 147 by benzylation and ketalisation of the known aldehyde 146 (Scheme 20). Generation of the Grignard reagent followed by addition of chiral oxazoline 105 afforded the biaryls 148 and 149 in 64% yield and a ratio of 77:23 respectively along with 22% of the demethylated oxazoline 114. Quaterisation, base hydrolysis and reduction then gave the alcohol 150 which was converted into the acetamide 144 by

434

an analogous sequence to that described in Schemes 17 and 18 above. Debenzylation provided phenol 151 which upon exposure to phosphorous oxychloride in acetonitrile gave only an intractable gum. However, acetylation followed by ring-closure smoothly gave a dihydroisoquinoline and treatment with base provided ancistrocladinine (143), which was further characterised by conversion to the known diacetate 152. Since ancistrocladinine (143) has been converted into ancistrocladine (1) by reduction, this also constituted a formal total synthesis of 1.
OMeOMe OMeOMe

''-OMe MgBr OMe

OMe OMe 153R^=Me R2= 154R^ = Me R2 |( J 156

OMe 157

158

159 161

155R^=OBn R^

160

TABLE 1
Products 156:157 103:112 158:159 149:148 160:161 Yield (%) Yield (%) Ratio M:P of 114 77 65 72 64 69 20 15 19 22 28 42:58 69:31 70:30 77:23 88:12 d.e. 16 38 40 54 76 Reaction Time 4 5 6 20 20

The factors that govern the stereoselectivity in this type of coupling reaction were next investigated using the chiral oxazoline 105 and variety of 2,6-disubstituted aryl Grignard reagents (ref. 21, 72). The bromides 153,154 and 155 were converted into their corresponding Grignard reagents and allowed to react with the oxazoline 105 and the results, along with earlier findings, are detailed in Table 1. The stereochemistry of the products followed from their conversion to known intermediates and the demethylated oxazoline 144 was isolated from all the reactions

435

conducted. For the six-membered acetals, it was the (M)-atropisomer that predominated and the diastereomeric excesses are higher for the bulky dimethyldioxanes than for the unsubstituted ones.

MeQ

O^p. ^Ph -MeOMgBr L^"-J

157

A*

Br

For the five-membered acetal, the (P)-atropisomer was the major product which indicated that the coupling is proceeding \ia transition state such as A* (ref. 20, 72) in which the fivemembered acetal competes more effectively with the methoxy group for chelation to magnesium atom. Meyers concurrently found that these reactions proceeded under chelation control (ref. 20, 26) and the selectivity of the couplings could be increased by changing one ortho substituent to a non-chelating group.
OMeOMe Br MeO^ A . ^CHpOTBS 2 ^ 1 DO
l^g

OMeOMe

BrCHgCHgBr OMe 163 OMeN^ 162 '"'APr OMeOMe MeO

N-^'""LPr N ^pr

CHgOTBS

MeO

OMe 154

yW.P ratio 92:8 76% yield

OMe

TBSOCH, MeO ~\ -MeOMgBr ^ 164

/ -

SCHEME 21

436

OMe OMe NHAc

^^Q

164

1.TFA, H2O/THF 2. Ac^O. pyr. 80%

aq. NaOH

THF 55C 98%

MeO,

CH2OTBS

OMe OMeOMe 1.TBSCI, NEt3 then DIBAL-H 2.MsCI.NEt3 MeO, 3. LiBEtgH 63% OMe 167 OMe 130 CH2OTBS 1.TBAF 2. Dess-Martin reagent 930/^ MeOOMeOMe 166

SCHEME 22: Stereoselective formal synthesis of 0-methylancistrocladine (2). The fact that the outcome in these coupling reactions is dependant on chelation control was further demonstrated in a recent formal synthesis of 0-methylancistrocladine (2) (ref. 73) (Scheme 21 and 22). A coupling between the simpler chiral oxazoline 162 obtained from the amide 106 and (5)-valinol and the Grignard reagent derived from the bromide 163 gave a much improved diastereoselectivity favouring the (M)-atropisomer 164. This selectivity can be explained by considering the transition state B* in which the magnesium atom is chelated to the methoxy group rather than the CH2OTBS substituent (ref. 20, 26, 73). Acid induced rearrangement of the major atropisomer 164 followed by acetylation gave the ester 165 and hydrolysis afforded acid 166 (Scheme 22). One pot silylation followed by reduction and deoxygenation then afforded ether 167. Deprotection and oxidation of 167 then yielded the 0-methylancistrocladine (2) intermediate 130 which was identical to the material prepared by the earlier route (ref. 61).
OBn OMe OBn OMe OBn OMe

Mg BrCHpGHpBr P:M ratio 91:9 70% yield

OBn

OBn

437

The stereocontrolled construction of the biaryl linkage required for the synthesis of dioncophylline C (7) was achieved by a coupling between the oxazoline 168 and the Grignard reagent derived from the bromide 169 (ref. 74). The desired (P)-atropisomer was obtained in high diastereoisomeric excess since there was only one substituent present on the aryl Grignard reagent available for chelation to magnesium. Proof of the stereochemical outcome of the coupling was obtained from a single crystal Xray structure obtained for the methiodide salt derived from the major isomer. The promising results obtained for the above couplings lead to the development of a more convergent intermolecular synthetic strategy to naphthylisoquinoline alkaloids. This proposal was successfully implemented in a total synthesis of O-methylancistrocline (170) (ref. 75) (Scheme 23). The key step involved an intermolecular coupling between the chiral oxazoline 162 and the Grignard reagent 171 derived from an optically pure tetrahydroisoquinoline. Under chelation control, this coupling should proceed through the intermediate C* to provide the desired atropisomer 172. The synthesis of the bromoisoquinoline 173 required was easily achieved as shown in Scheme 23 but there were initial problems in generating the Grignard reagent. These were overcome by the use of 1,2-dibromotetrafluoroethane as an entrainer and the coupling reaction proceeded smoothly to give the biaryls 172 and 174 in a 82:18 ratio as deduced by ^H NMR spectroscopy. The mixture of biaryls was then treated with trifluoroacetic acid and then acetylated to give the acetamides 175 and 176 which were separated by silica gel chromatography. Completion of the synthesis of 0-methylancistrocline (170) was achieved by LiAlH4 reduction of atropisomer 176 followed by deoxygenation via a halogen/oxygen exchange-Zn reduction protocol. The synthetic material was identical to a semi-synthetic sample prepared from the related alkaloid ancistrocladinine (143). Furthermore, the absolute configuration about the biaryl linkage was confirmed by comparison of the calculated and experimental CD spectra. The NMR spectrum obtained for 170 also compares well with that reported for the Ancistrocladus alkaloid ancistrocladonine (ref. 76), the stereochemistry of which has not be elucidated, however no extensive comparisons have been made as yet.
OMeOMe

OMe OMe

MeQ MeO.

438

MeO,

LCICOgMe NaHCOa 2. LiAIH4 3. Br2 55%

MeO,

Mg BrCF2CF2Br

'APr

1.TFA, H2O/THF MeO. MeO, 2. AC2O, pyr. OMeMe 172 OMe OMe

^.

OMeMe 174 OMeOMe

NHAc MeO, MeO,

NHAc

1.LiAIH4 2. MegSiCI/Nal then Zn/HOAc

P:M ratio 16:84 32% overall yield from 162

OMeMe ^ ^^ ^'^

50%

OMeOMe

OMeOMe

MeO,

OMeMe 170

OMeMe 143

SCHEME 23: Synthesis of (+)-0-methylancistrocline (170) 4.2 Asymmetric Synthesis: 7, 1' Linked Naphthylisoquinoline Alkaloids The first asymmetric synthesis of a 7,1' linked alkaloid was that of (-)-dioncophylline A (8) (triphyophylline) which resulted in the revision of the initially proposed stereostructure (ref. 77). The synthesis utilised the intramolecular approach that was successful for the synthesis of racemic 8 (see Scheme 7) and began with the production of optically pure tetrahydroisoquinoline 79

439
N-N CI HO,
PTC, NaOH ^sx

,Me NH OMeMe 177

BnCI /Pr2NEt y Y

,Me N.. Bn

HBr reflux

N.

Bn

2. H2, P d - C

OMeMe 79

89%

OMeMe

81%

..Me -N-Bn OH Me 178

60
DMAP NEt3 90% Bn Me

(Ph3P)2PdCl2

DMA, NaOAc 130C 75%

179 O

1 . C2Br2Cl4 PPh3 2 . LiAIH4

^-

3. H2, Pd-C 83%

1 . C2Br2Cl4 PPh3
*

2 . LiAIH4

3. H2, Pd-C 82%

v^NH XJ^ OH Me

(^

^.-^ .Me

Me

184

MeO MeO OH Me

OH

Me

183

SCHEME 24: Asymmetric synthesis of (-)-dioncophylline A (8) (Scheme 24). Reductive deoxygenation of the derived tetrazole provided 177 which was Nbenzylated and demethylated with hot aqueous HBr to give tetrahydroisoquinoline 178. Esterification with acid chloride 60 gave ester 179 which smoothly underwent intramolecular coupling under Pd(II) catalysis to give the axially prostereogenic lactone 180. Reduction of 180

440

gave the stable atropisomeric alcohols 181 and 182 which were easily separated by silica gel chromatography. The arrangement of the NH and OH groups in atropisomer 182 apparently lowers the polarity of this isomer relative to isomer 181, allowing for easy separation. Subsequent deoxygenation of atropisomer 182 followed by debenzylation gave compound 183 which was found to be significantly different to the natural product. Similar treatment of atropisomer 181 provided (+)-dioncophylline A (184) which was identical to the natural material except for sign of optical rotation. The total synthesis of natural (-)-dioncophylline A (8) was ultimately achieved by using the enantiomer of 178.

Red-AI -60to-40C

MeO'

AIMea, THF rt2min

185

then Red-AI -60to -40C 2 min, then 25C"

OH

Me 95% de

187

The low atropisomer selectivity obtained in the reduction of prostereogenic lactone 180 with LiAlH4 (59:41) prompted an investigation into atropdiastereoselective ring opening of the enantiomeric lactone 185 with achiral hydrogen nucleophiles (ref. 78) in the hope that internal asymmetric induction could provide higher selectivities. When lactone 185 was added to an excess of sodium bis(2-methoxyethoxy)aluminium hydride (Red-AI) alcohol 186 was obtained with an improved de of 87%. Conversely, reduction with the Lewis acidic reagent diisobutylaluminium hydride (DIBAL-H) gave the atropisomer 187, the precursor to (-)-dioncophylline A, in good de (71%) while pretreatment with trimethylaluminium followed by reduction with excess Red-AI gives atropisomer 187 in even higher de. The selectivity for the Lewis acidic hydrides can be explained by complexation of the aluminium reagent on the upper side of the lactone forcing attack of the hydride from the lower face as depicted in Figure 5. The intermediate lactolate then opens to an aldehyde that is rapidly reduced before the axial chirality is lost.
lAA/NA/WWN/V* <AA/VW/V\/WV AAAAA/NAA/W

441
MeO, Me Bn

CHoCHO APrOH/HaO pH 4 45%

MeQ

60 DMAP

(Ph3P)2PdCl2
j

DMA, NaOAc 130C 87% 1.NaOH 2. (COCI)2, NEt3 C02Me

MeOH 5mins 85%

OH Me COaMe

1.LiAIH4 2. Me2S04 MeO PTC/NaOH 3. C2Br2Cl4 MeO PPhg, LiAIH4 4. H2, Pd-C 68%

MeO

OMe Me

194

SCHEME 25: Synthesis of (+)-ancistrocladisine (4) The first total synthesis of the 7,1' linked (+)-ancistrocladisine (4) was also achieved using similar methodology to that described for dioncophylline A (ref. 35). To ensure that intramolecular coupling would occur regioselectively at the 7,1' position, the naphthalene moiety must be attached to the 8-oxygen position of the tetrahydroisoquinoline therefore compound 189 was required. The synthesis of this segment was accomplished by a regio- and stereoselective Pictet-Spengler condensation of the amphetamine 188 with acetaldehyde at pH 4 providing 189 as the major product (ref. 55). Esterification with naphthoyl chloride 60 then gave ester 190 which underwent intramolecular coupling to provide lactone 191 in high yield. Methanolysis of prostereogenic lactone 191 gave the stable atropisomers 192 and 193 in a 1:1 ratio. Atropisomer 193 was then subjected to reduction, deoxygenation and debenzylation to provide tetrahydroisoquinoline 194 which upon permanganate oxidation afforded (+)-ancistrocladisine (4) in low yield. Although the synthesis was not atropisomer selective at this stage, the undesired atropisomer 192 can be converted back to axially prostereogenic lactone 191 and ring opened again to provide the thermodynamically controlled mixture of isomers. A more efficient process was to simply expose isomer 192 to the NaOMe/MeOH conditions and this caused epimerisation to provide the

442

same equilibrium mixture. The selectivity of this ring-opening was finally greatly improved by kinetically controlled atropisomerselective ring-opening with various oxygen based nucleophiles (ref. 79). This study revealed that even small oxygen nucleophiles can open the lactone stereoselectively under kinetic control with /-propoxide being amongst the most selective (Table 2). Slightly higher selectivity was gained by using (+)-mentholate as the nucleophile however (-)mentholate gave only a modest reversal of atropisomerselectivity.

OH CO2R 196

Me

TABLE 2
RO-/ solvent NaOMe/MeOH NaOMe/MeOH NaHCOs/MeOH /-PrOK//-PrOH /-PrOK//-PrOH Li-(+)-mentholate/THF Li-(-)-mentholate/THF Reaction time 15 s 5min 60min 10 s 22 h lOmin lOmin Ratio 195:196 15.3:1 1.3:1 3.3:1 20.9:1 1.1:1 23.2:1 1:1.8

4.2 Asymmetric Synthesis: 5,8' LinkedNaphthylisoquinoline Alkaloids The dimeric naphthylisoquinoline alkaloids michellamines A (6) and B (197), isolated from the rare tropical liana Ancistrodadus korupensis (ref. 80, 81), have evoked great interest due to their cytopathic activity against human immunodeficiency viruses (HIV). These compounds are also interesting due to their high polarity, owing to the presence of 6 free phenolic groups and two secondary amino groups, and the rare 5,8' coupling between the naphthalene and isoquinoline rings. The corresponding monomers, the korupensamines A (198) and B (199), also isolated from Ancistrodadus korupensis (ref. 82), do not exhibit antiviral activity but do possess some antimalarial properties.

443
Me OH Me OH

OH OMe

OH OMe

HO,

HO,

The first total synthesis of michellamine A (6) was achieved by the biomimetic oxidative dimerization of a derivative of korupensamine A (198) (ref. 83) which itself was synthesised by an intermolecular strategy involving a Stille-type coupling (ref. 84, 85). The total synthesis of both 198 and atropisomer 199 began with production of tetrahydroisoquinoline 201 obtained from optically pure 200 (Scheme 26). Bromination then provided the required tetrahydroisoquinoline segment 202. The synthesis of the naphthalene segment was achieved by the application of a Wittig surrogate to the Stobbe approach (ref. 86, 87). Aldehyde 203 was converted into half ester 204 which underwent ring closure in boiling acetic anhydride. Hydrolysis followed by methylation and reduction gave the naphthalene 205 which was deoxygenated to provide bromide 206. Metalhalogen exchange followed stannylation of the aryl lithium gave stannane 207 which was coupled with the isoquinoline segment under Pd(II) catalysis to provide atropisomers 208 and 209 in low yield. These were not separated at this stage but simply deprotected with boron trichloride followed by hydrogenolysis to provide korupensamines A (198) and B (199) which were separated as previously described (ref. 82). The synthesis of michellamine A (6) from korupensamine A (198) commenced with the A^formylation of 198 with pivalic formic anhydride (Scheme 27). Subsequent treatment with acetyl chloride provided diacetate 210 where the chelated C-5' hydroxy group was not protected. Dimerization was then achieved under conditions described by Laatsch for simple naphthol dimerisation (ref. 88) which involved treatment of with Ag20 in chloroform in the presence of

444

NEt3. The resulting binaphylidendione 211 was then carefully reduced with sodium borohydride and deprotection was effected in a single step with methanolic HCl to provide michellamine A (6).

Me NBn OMeMe 200

I.BnBr, NaOH ^ 2. /-PrSNa, DMF 3. BnBr, NaOH 40% r ^COgf-Bu

BnO,

Me NBn OBn M e 201

Brp, DMF 94%

Bn

OBn M e 202

APrO

/-Pro CO2H rn Ft 1. AC2O reflux 2. NaOEt 4. LiAIH4

APrO

OMe

(EtO)2PO'''^C02Et CHO NaH then TFA 57%

APrO 1. Br2C2Cl2, PhgP 2. LiAIH4 86% 206 APrO OMe APrO OMe f-BuLi BUgSnCI 89%

OMe

202 PdCl2(PPh3)2

LiCI, CuBr DMF 135C,40h

^-

15%

1. BCIo BnO, Bna 2. H2 Pd-G 3. separation OBn M e 209 OH OMe

1.4:1
OBn M e 208 OH OMe

OH Me 199 SCHEME 26: Total synthesis of korupensamines A (198) and B (199).

445
OH OMe OH OMe

Ag20 2. AcCI, EtgN 90%

ACQ

NCHO OAc Me 210

0.2% EtaN 85%

Me OHCN

OAc

Me

OH

1. NaBH4

2. MeOH/HGI reflux 67% NCHO OAc Me 211

^ ^

SCHEME 27: Biomimetic synthesis of michellamine A (6) from korupensamine A (198). Closely following the biomimetic synthesis of michellamine A (6), a report appeared describing the convergent synthesis of michellamine A (6) (ref. 89) (Scheme 28). Due to its higher activity, the synthesis of michellamine B (197) was also undertaken. The approach involved the use of binaphthyl 212 and an intramolecular Suzuki-type coupling (ref. 90), again mediated by palladium. The synthesis of binaphthyl 212 began with the Diels-Alder reaction between the quinone 213 and diene 214 which gave the naphthoquinone 215 in good yield. Copper-bronze mediated dimerization of 215 followed by reductive acetylation provided binaphthyl 216 which was selectively deacetylated and converted to the desired triflate 212. The required tetrahydroisoquinoline 217 portion was prepared from bromide 202 by lithiation and treatment with B(0Me)3 followed by aqueous work-up. Coupling of 212 with 217 in the presence of palladium(O) gave the quateraryl 218 as a mixture of atropisomers. Removal of all the protecting groups gave michellamine A (6), B (197) as a mixture which was separated as reported previously (ref 80, 81). Although a mixture of michellamine A (6) and B (197) can be equilibrated to produce a mixture of 6,197 and the corresponding M/M atropisomer named michellamine C (219), none of this material was detected in the coupling reaction mixture. The question as to why 219 does not appear to co-occur naturally and was not detected synthetically is most intriguing and is yet to be answered.

446

OTMS

OMe

1. Cu(bronze) DMF, Pd(PPh3)4

O 213 OAc OAc OMe 214

68%

1. DBU Me CH2Cl2/MeOH 2. TfgO, GH2CI2 2,6-lutidine 79% Me OBn

^-

OMe OAc OTf 212

216

OAc

Pd(PPh3)4

\P/M'OAc OMe
I I II

1H2,Pd-C ^ 2.MeOH,HCI
o-'/o

6 ^ 197

OMe OAc OBn Me 217 74%

OBn Me 218

SCHEME 28: Convergent synthesis of michellamines A (6), B (197). Another synthesis of michellamines A (6) and B (197) as well as the unnatural michellamine C (229) was reported by Hoye and co-workers in 1994 (ref. 91). The approach also involved a Suzuki-type, intermolecular biaryl coupling followed by a biomimetic phenolic oxidative coupling effected by Ag20. The sequence commenced with the synthesis of the naphthalene portion 220 as shown in Scheme 29. Simultaneous generation of a benzyne and dienolate from dibromide 221 and amide 222 with lithium cyclohexylisopropylamide and subsequent cycloaddition provided the naphthalene 223. Although the yield was low, his annulation procedure compared well with longer alternative sequences. Methylation followed by halogen-lithium exchange and treatment with trimethylborate then gave boronic acid 220. The isoquinoline half 224 was synthesised from compound 201 by regiospecific iodination and this was coupled with naphthalene 220 to provide the atropisomers 225 and 226 after acid hydrolysis of the MOM ether. Silver induced dimerisation gave a mixture of the purple cross-ring quinones 227 which upon treatment with hydrogen over 10% Pd/C resulted in reduction of the quinones and simultaneous debenzylation to provide michellamines A (6), B (197) and C (219). HPLC separation of a portion of this mixture provided pure (6) as well as a 2:1 mixture of (197) and (219).

447

OMOM ,Br

OMOM

NEt2 LiO" ^Me 20%

MOMO

OH

'I

LICA (2.2 eq)

Me Me 222 MOMO 1. Me2S04 pMe BnO. Me I2, Ag2S04 NBn ^(0^)2 220 OH 1.220Pd(PPh3)4 2. HCIMeOH 53% -4:3 ratio g^Q 1^ BnO OMe OBn Me 201 OH OMe 66% ^ BnO

1.

223

2. n-BuLi 3. B(0Me)3 4. NH4GI, aq.HGI

^-

Ag20 CH2CI2 -100%

Me

OBn

Me

OH

OMe

Hp Pd-C Me -100%

(6) + (197) +

BnO^ A l

^ ^ ^ M e NBn

OBn Me 227

OH 219

Me

SCHEME 29: Total synthesis of michellamines A-C. Hoye and co-workers (ref. 92) later reported the total synthesis of ancistrobrevine B (228), isolated from Ancistrocladus abbreviatus (ref. 93) and korupensamine C (229), isolated from Ancistrocladus korupensis. The approach to these natural products also utilised a benzyne cycloaddition to construct the naphthalene moiety. Thus, treatment of the amide 222 and bromide 230 with lithium cyclohexylisopropylamide furnished naphthalene 231 in low yield (Scheme 30).

448

OMe LICA (2.2 eq) 222

OMe

NEt2

OMeOH

0' *"\e
Br OMe precipitate from GH2CI2 with hexane^ , Me

21-26%
231

MOMO 1. Me2S04

MOMO

OMe

^>
I B(0H)2 232

2. n-BuLi 3. B(0Me)3 4. NH4CI, aq.HCI 84%

Ar-^-O^^^r

MeO^

>Me i . H B r , A c O H NH OMeMe 86 2. BnBr K2CO3 3.12, Ag2S04 27% OMeOMe

^"^^

232 Pd(Ph3)4

*-

OMeMe 234

sat. NaHCOs PhOHs reflux

71%
OMeOMe

BnO,

Pd-C 100% OMeMe 235 HPLC separation

HO,

OMeMe 228 OMeOMe

OMeOMe

224 + 232

Pd(Ph3)4

^-

H2 BnO. Pd-C 100% HPLC separation

sat. NaHC03 PhCH3 reflux 76%

OBn Me 236

SCHEME 30: Total synthesis of ancistrobrevine B (228) and korupensamine C (229). Methylation and conversion to the boronic acid 232 followed by precipitation from dichloromethane with hexanes yielded the boronic anhydride 233. The isoquinoline portion 234 was synthesized from homochiral 86 by selective demethylation, benzylation and subsequent

449 iodination. Palladium mediated coupling of iodide 234 with either boronic acid 232 or anhydride 233 gave the biaryl 235 as a mixture of atropisomers. Deprotection and chromatographic separation provided ancistrobrevine B (228). Similarly, coupling of boronic acid 232 with iodide 224 gave biaryl 236 as an atropisomeric mixture and deprotection and separation furnished korupensamine C (229).
Mg, CuBr.DMS OMe 240 MeO fX^Me TsN 239 ^if ^ V ^ 7^ 1.Na/NH3 MeO^ Me

K^
OMe 241

NHTs

2.Ac.O,NEt3
78%

V
OMe 242

''''''"

100%
Me

POCI3 82%

>

1. H2, Pd-C 2. BBrg 92%

HO,

Me ;NH2Br OH Me 244

1.TESCI, NEtg 2. GIC02Et 3. TBAF 4. BnBr, KgCOg 63%

*-

BnO,

Me NOOsEt OBn Me 245

1.LiAIH4 2.l2.Ag2S04 75%

BnO^ T I OBn Me 238

Me NMe

232 Pd(Ph3)4

sat. NaHC03 PhCH3 reflux 73% OH

^-

OH OMe

OMe

1. HOI, MeOH 2. H2, Pd-C 92%

^-

HO

OBnMe 246

OH Me 247 SCHEME 31: Synthesis of m^korupensamine D (237).

OH Me 237

The total synthesis of enf-korupensamine D (237) followed a similar methodology and began with a new sequence for the preparation of optically pure tetrahydroisoquinoline (238) (ref. 94) (Scheme 31). Copper catalysed ring-opening of (/?)-aziridine 239 with the Grignard reagent derived from chloride 240 provided the amphetamine derivative 241. Reductive removal of the A^tosyl group and acetylation gave acetamide 242 which was cyclised to dihydroisoquinoline 243. Stereoselective hydrogenation followed by demethylation then gave the salt 244. A selective A'protection and benzylation sequence yielded carbamate 245 which was converted into the tetrahydroisoquinoline fragment 238 by reduction and regioselective iodination. Palladium catalysed coupling of 238 with the boronic acid 232 gave a mixture of atropisomers 246 which

450

upon acid hydrolysis, MPLC separation and hydrogenolysis furnished the enantiomer of korupensamine D (237) and the corresponding atropisomer (247).
MeOMeO OMe Me 1.LiAIH4 Me Me 12 steps MeO^Js^^cOgMe 2. PCC MeOMeO

OMeOMe 1. (EtO)2POCH2C02Et NaH, benzene 2. DIBAL-H 3. (+)-DIPT, Ti(0APr)4 f-BuOOH 53% from 249

OMeOMe

>. MeOOH OMe 251 ratio-1:1 + atropisomer

LMsCI, NEtg 2. LiAIH4 91%

^-

MeO

OMeOMe 1.(PhO)2PON3 PPha, DEAD 2. H2, Pd-G A2O, EtOAc 74%

OMeOMe

^-

1. POCI3

MeO, NHAc

OMeMe 248 SCHEME 32: Synthesis of 0,0,0-trimethylkorupensamine A (248).

2. AJMea LiAiH4, -78C 70%

^.

MeO.

The ether derivatives 0,0,0-trimethylkorupensamine A (248) and B have both been synthesised by a route which commenced with a lengthy sequence to the biaryl 249 from 3,5dimethylanisole (ref. 95) (Scheme 32). Reduction of 249 with LiAlH4 and oxidation gave aldehyde 250 which upon Wadsworth-Emmons-Horner extension, reduction and Sharpless asymmetric epoxidation provided epoxide 251 and the corresponding atropisomer in almost equal amounts which were separated by silica gel chromatography. The derived alcohol 252, obtained by mesylation of 251 and in situ reduction, was then converted into the acetamide 253 by displacement with azide under Mitsunobu conditions followed by reduction and acetylation. Ring closure followed by stereoselective reduction then yielded 0,0,0-trimethylkorupensamine A (248). The synthesis of 0,0,(9-trimethylkorupensamine B was accomplished in a similar manner using the atropisomer of 251 obtained in the epoxidation step.

451
OMe LPhNMegBrg Me 255 OH OMe OBn O M e

2. DBU, CH2CI2 3. Bu4NBr3 68%

^-

2. BuLi, B(0/-Pr)3 aq. NH4CI 256 62%

OBn O M e

OBn O M e

202 Pd(PPh3)4

Ba(0H)2. aq. DME 85C 37h 82%

^.
BnO. 3:2 OBn M e 258 BnO,

OgHgNHBrg

W 1 1 Sr^^Me
BnO^^

OBn OMe

OBn OMe BK

A^^^^vy^Me ^^^jA^^NBn
OBn Me

TiVS ULJLM nr ^^ Me
1^ M

1.Pd(PPh3)4 K3PO4, DMF 90C 16h

BnO^

^-

197

ksJi^^MBn
OBn Me 260 ^8%

26%

2. HCO2H MeOH, Pd-C then NH4OH 74%

n-BuLi 259 R = Br 2-MeTHF -95C B(0APr)3 '-*-261 R = B(OH)2 7 1 %

SCHEME 33: Stereospecific synthesis of michellamine B (197) A stereospecific synthesis of the highly active michellamine B (197) has also been achieved by a palladium catalysed cross coupling between derivatives of korupensamines A (198) and B (199) (ref. 96). The route is based an adaptation of previous syntheses and commences with a new sequence to provide the naphthalene fragment 254 (Scheme 33). Bromination of tetralone 255 and subsequent dehydrobromination and /7ara-bromination provided naphthol 256. Benzylation and lithiation followed by boronation gave the boronic acid 254 which was coupled with optically pure bromide 202 to give the atropisomers 257 and 258. To assign the stereochemistry about the biaryl axis, each of these compounds was converted into korupensamines A (198) and B (199). Bromination of the mixture of 257 and 258 provided the 6'-bromonaphthalenes 259 and 260 in low yield and compound 259 was converted into the boronic acid derivative 261 by a slight modification of the standard condition which involved lithium-halogen exchange at low temperature (-95C) followed by addition of B(0/-Pr)3 and aq. NH4CI. Palladium catalysed coupling of bromide 260 with boronic acid 261 under nonaqueous conditions and subsequent debenzylation gave michellamine B (197) in excellent yield.

452 5. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. G. Bringmann and F. Pokorny in The Alkaloids, G. Cordell, Ed.; Academic Press: New York, 1995, Vol. 46, pp 127-271. T. R. Govindachari and P. C. Parthasarathy, Tetrahedron, 27 (1971) 1013. Z. X. Chen, B. D.Wang, K. W. Quin, B. E. Zhang, Q. L. Su and Q. C. Lin, Yaoxue Xuebao, 16(1981)519. G. Bringmann and L. Kinzinger, Phytochemistry, 31 (1992) 3297. T. R. Govindachari, P. C. Parthasarathy and H. K. Desai, Indian J. Chem., 10 (1972) 1117. T. R. Govindachari, P. C. Parthasarathy, T. G. Rajagolpalan, H. K. Desai, K. S. Ramachandran and E. Lee, J. Chem. Soc, Perkin Trans. 7, (1975), 2134. T. R. Govindachari, P. C. Parthasarathy and H. K. Desai, Indian J. Chem., 11 (1973) 1190. K. P. Manfredi, J. W. Blunt, J. H. Cardellina H, J. B. McMahon, L. L. Pannel, G. M. Cragg and M. R. Boyd, / Med Chem., 34 (1991) 3402. G. Bringmann, R. Zagst, M. Schaffer, Y. F. Hallock, J. H. Cardellina II and M. R. Boyd, Angew. Chem. Int. Ed. Engl., 32 (1993) 1190. M. R. Boyd, Y. F. Hallock, J. H. CardeUina II, K. P. Manfredi, J. W. Blunt, J. B. McMahon, R. W. Buckheit, G. Bringmann, M. Schaffer, G. M.Cragg, D. W. Thomas and J. G. Jato, J. Med Chem., 37 (1994) 1140. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. J. Bruneton, A. Bouquet, A. Fomet and A. Cav6, Phytochemistry, 15 (1976) 817. G. Bringmann, M. Rtibenacker, R. Weirich and L. Ak6 Assi, Phytochemistry, 31, (1992) 4019. G. Bringmann, Angew. Chem. Int. Ed. Engl., 21 (1982) 200. G. Bringmann, Tetrahedron Lett., 23 (1982) 2009. G. Bringmann and J. R. Jansen, Heterocycles, 24 (1986) 2407. For a review on biaryl synthesis see G. Bringmann, R. Walter and R. Weirich, Angew. Chem., Int. Ed Engl, 29 (1990) 977. For a review on the chemistry of 2-oxazolines see A. I. Meyers and T. G. Gant, Tetrahedron, (1994) 2297. A. I. Meyers and K. A. Lutomski, /. Am. Chem. Soc., 104 (1982) 879. A. I. Meyers and R. J. Himmelsbach, J. Am. Chem. Soc., 107 (1985) 682. A. I. Meyers and H. Moorlag, Tetrahedron Lett., 34 (1993) 6989. M. A. Rizzacasa and M. V. Sargent, J. Chem. Soc, Perkin Trans. I, (1991) 2773. J. M. Wilson and D. J. Cram, /. Am. Chem. Soc., 104 (1982) 881. T. Hattori, N. Koike and S. Miyano, /. Chem. Soc, Perkin Trans. 1, (1994) 2273. R. W. Baker, G. R. Pocock, M. V. Sargent and E. Twiss, Tetrahedron Asymmetry, 4 (1993) 2423. M. Uemura, T. Watanbe and K. Kamikawa, J. Org. Chem., 61 (1996) 1375. A. I. Meyers and A. M. Warshawsky, J. Am. Chem. Soc, 111 (1990) 8090. D. W. Knight in Comprehensive Organic Synthesis: Selectivity, Strategy and Efficiency in

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

457

DNA - Damaging Natural Products with Potential Anticancer Activity

A.A. Leslie Gunatilaka and David G.I. Kingston
Contents 1. General Introduction 2. DNA-Damaging Agents and Cancer Chemotherapy 3. Detection of DNA-Damaging Agents 3.1. Introduction 3.2. Mechanism-based Yeast Bioassays 4. General Methodology 4.1 Introduction 4.2. Extraction 4.3. Bioassay 4.4. Bioactivity-guided Fractionation 5. Natural Products with DNA-Damaging Activity 5.1. Introduction 5.2. Sesquiterpenes of Bryophytes 5.2.1. Porella cordeana 5.2.2. Frullania nisquellensis 5.2.3. Chiloscyphus rivularis 5.3. Diterpenoids 5.3.2. Rosane Diterpenoids of Vellozia Candida 5.3.2. Diterpene Dibenzoates of Caesalpinia pulcherrima 5.4. Steroids 5.4.1. Steroids of Pseudobersama mossambicensis 5.4.2. Structure-Activity Relationship Studies of 7-Hydroxy Steroids 5.5. Alkaloids 5.5.1. Dioxoaporphines of Artabotrys zeylanicus 5.5.2. Oxoaporphines of Xylopia aethiopica and Miliusa banacea 5.5.3. Azafluorenone Alkaloid from Cyathocalyx zeylanica 5.5.4. Piperidine Alkaloids from Cassia leptoptiylla 5.5.5. Guanidine Alkaloids from Pterogyne nitons 5.5.6. Steroidal Alkaloids from Solanum unrtbellifemm 5.6. Marine Diterpenoids from Eunicea toumeforti 5.7. Limonoids from Tricliilia emetica 5.8. Bloactive O-Heterocyclic Compounds 5.8.1. Furanonaphthoquinones from Crescentia cujete 5.8.2. Pterocarpans from EryttJiina burana 5.8.3. Coumarins from Sri Lankan Rutaceae 6. Summary and Conclusions 7. Acknowledgements 8. References

458

1.

General Introduction Cancer is a dreadful disease which has no geographic, national, religious or

other boundaries. It accounts for a vast number of deaths and suffering. Each year 6.5 million people are diagnosed with cancer worldwide [1]. In the United States alone, more than ten million people are living with a history of cancer and in excess of one million new cancer cases develop annually [2], and the death rate due to cancer has slightly increased over the past three decades. This may be attributed to the increasing longevity of the American population and the relationship between cancer and environmental factors, in particular cigarette smoking and Increased exposure to carcinogens. As with any other disease, solutions to the cancer problem involve both prevention and treatment, and advances on these two fronts require the continued development of novel and improved chemopreventive and chemotherapeutic agents. Natural products and their semisynthetic analogs have provided some of the most effective and widely used of the established chemotherapeutic agents for cancer. This is exemplified by such compounds as Taxol (1), the vinca alkaloids vinblastine (2) and vincrinstine (3), the podophyllotoxin analogs etoposide (4) and teniposide (5), the camptothecin analogs topotecan (6) and CPT-11 (7) (Fig. 1), and the microbial products bleomycin (8), mitomycin C (9), and the anthracyclines adriamycin (10) and daunorubicin (11) (Fig. 2). It is noteworthy that these anticancer agents are all so complex that they would never have emerged from a synthetic program alone or from a combinatorial approach to drug discovery. Thus the natural products approach to discovery and development of new anticancer drugs is attractive in that it is complementary to synthetic and biosynthetic approaches. This review is concerned with our search for naturally occurring DNA damaging agents with potential anticancer activity as a part of a National Cooperative Drug Discovery Group funded by the U.S. National Cancer Institute and conducted in collaboration with the University of Virginia and SmithKline Beecham Pharmaceuticals. Many international collaborators from Brazil, Ethiopia, Guam, the Philippines, and Sri Lanka participated in this program directly or indirectly by providing extracts for bioassay and by working on the bioactive extracts. An essential step in an efficient natural product drug discovery program is the judicious selection of an initial screening strategy. The in vitro methods available for anticancer drug discovery can be grouped into two major categories. These are the

459
disease-oriented approach and the mechanism-based approach. The disease-

oriented approach involves cellular assays in which one looks for general cytotoxic agents or agents which inhibit growth of cancer cells. Tumor cell lines utilized by the U.S. National Cancer Institute belong to this category. Such bioassays are most

powerful when they are used, as in the N.C.I, program, to discover leads with unusual profiles of activity [3], but the implementation of a panel of multiple cell lines is laborintensive and thus costly. Compounds which show non-selective cytotoxicity do not turn out to have useful in vivo activity; thus recent compilations of "anticancer" natural products [4 - 6] contain many examples of compounds with no documented in vivo activity.

(1) Taxol (2) (3)

COzMe R = CHO (Vincristine) R = CH3 (Vinblastine)

\OH (4) R = Me (5) R = ^ ^ ^ - J (Etoposide) fTeniposide) (6) Ri = OH ; R2 = CH2N(CH3)2 1 ? (Topotecan) R3 = H (CPT-11) R2 = H ; R3 = CH3CH2 Fig. 1. Some clinically used natural product-based anticancer drugs of plant origin Thanks recombinant to recent developments in genetics, has molecular biology, and

DNA technology, the last decade

witnessed

the evolution of search for

anticancer natural product drug discovery research from an empirical

460

general cytotoxic agents to a more mechanism-based approach [7].

Unlike the

disease-oriented approaches involving mammalian cell-lines, the mechanism-based approaches utilize molecular assays involving DNA, oncogenic enzymes or their receptors [8,9].

0^55^NH2

(9) Mitomycin C o

(8) Bleomycin

NH2 (10) R = CH2OH Adriamycin (11) R = CH3 Daunorubicin

Fig. 2. Some clinically used natural product-based anticancer drugs of microbial origin 2. DNA-Damaging Agents and Cancer Chemotherapy One of the paradoxes of the cancer problem concerns the reciprocal behavior of the drugs used for its treatment; many of these drugs themselves are capable of producing cancer. Accumulated biochemical or pharmacological evidence suggests that DNA Is the principal cell target for many clinical antitumor agents. Those categories of antitumor agents which are known to interact with DNA include alkylating agents, antitumor antibiotics, some specific mitotic inhibitors, and miscellaneous drugs such as c/s-platinum complexes. Antimetabolites and steroidal hormones are two categories of antitumor drugs which exert their activity without Interacting directly with DNA. An ideal anticancer agent should exhibit high specificity and selectivity of action. There are various rational approaches to achieve these objectives of which the most promising has been the use of bifunctional or polyfunctional DNA-binding.

461 According to M. S. Waring "There are grounds for cautious optimism that future advances in our understanding of the molecular basis of drug-DNA interaction may lead to significant improvements in cancer treatment" [10]. However, until this promise is fulfilled there will still be a need for empirical approaches to drug discovery such as that described below.

3.

Detection of DNA-Damaging Agents 3.1. Introduction DNA, the biochemical repository of the genetic inheritance of all cells, is

subject to damage by a variety of chemicals and by radiation. Important DNA lesions include (a) alkylation of bases and/or phosphate residues, (b) inter- and intra-strand cross-linking, (c) single-strand breaks, (d) double-strand breaks, and (e) DNA-protein cross-links. lesion. Anticancer agents are known to produce more than one type of DNA The most popular genetically engineered Genetically engineered micro-organisms may be used as probes to detect

agents which interact with DNA.

microorganisms are yeasts and bacteria, and yeast is preferred in our work because of its closer genetic and biochemical resemblance to mammalian cells. What is the principle behind the use of genetically engineered yeasts to detect potential anticancer agents? An important and exploitable feature of many tumor cells is that they have defects in their ability to repair damage to DNA as compared with normal cells, suggesting that agents with selective toxicity towards DNA repair-deficient cells might be potential anticancer agents [11]. This rationale is strongly supported by the fact that DNA repair-deficient yeast mutants have been demonstrated to be hypersensitive to most known DNA-damaging agents [12], and yeast mutants can be developed that are hypersensitive to inhibitors of the enzyme topoisomerase I [11]. Presented in Fig. 3 are the principles underlying the use of DNA repair-deficient yeast mutants for the detection of DNA-damaging agents. 3.2 Mechanism-based Yeast Bioassays A recently developed mechanism-based approach for anticancer natural product drug discovery utilizes DNA repair- or recombination-deficient mutants of the

462 yeast Saccharomyces cerevisiae [12]. In our search for potential anticancer agents from natural sources we have employed this mechanism-based screen which depends on differential responses of DNA repair-deficient and repair-proficient yeast strains to the sample under investigation [13,14].

Normal Cells

DAMAGED DNA

Repair Y A Tumor Cells

^ ^

DNA

Agents with selective toxicity towards DNA repair-deficient cells

I
DEFECTIVE IN DNA REPAIR DETECTION OF DNA-DAMAGING AGENTS

I
Yeast Cells .

Hypersensitive to most DNAdamaging agents

Fig. 3. Principles underlying the use of DNA repair-deficient yeast mutants In the detection of DNA-damaging agents Three major DNA repair pathways have been defined in yeast and these are known as the rad3, rad6 and rad52 pathways [15]. The rad3 pathway is associated with excision repair, the rad6 pathway is the error-prone repair pathway and rad52 is recombinational pathway associated with repair of double-strand breaks and melotic recombination. The principles underlying the production of these yeast mutants are depicted in Fig. 4 and are briefly described here. The cell wall of yeast is impermeable to many drugs. Therefore, at first a mutation to make the cell wall of yeast more Starting with this "wild-type" RAD+ (or RS 188N) permeable to drugs is effected.

mutant, yeast mutants lacking all three known DNA repair pathways have been produced [12]. They are the rad3 mutant which lacks the excision repair pathway; the rad6 lacking the error-prone repair pathway and the rad52 lacking the DNA doublestrand break repair and meiotic recombination pathway. A fourth mutant is also known and it has been produced by the deletion of the topoisomerase I gene from the rad52 mutant and Is labeled rad52.top1. Hypersensitivity to topoisomerase II inhibitors likely occurs due to increase in topoisomerase II expression and/or activity to compensate for deletion of topoisomerase I. Thus, the differential sensitivity observed with rad52 and rad52.top1 can be used to detect the presence of both topoisomerase topoisomerase II Inhibitors. I and

463

Repair-deficient mutation UV Radiation Permeability mutation ^

Excision repairdeficient Rad3 mutant Error-prone repair-deficient \Rad6 mutant |

^
Rad+ mutant ("Wild-type" strain)

Yeast {Saccharomyces cerevisiae)

>H

Repair- and recombinationdeficient mutation

Double-strand break repair- and meiotic recombinationdeficient Rad52 mutant Deletion of topoisomerase I gene

Double-strand break repair- and meiotic recombinationand topoisomerase Ideficient Rad52.topl mutant

in
v

Fig. 4. A diagrammatic representation of the production of yeast mutants capable of detecting DNA-damaging agents and topoisomerase inhibitors

General Methodology 4.1 Introduction During the past decade scientific methodologies for the discovery and study of bioactive natural products have changed dramatically for several reasons. These reasons have been enumerated by Cordell in a recent review [16] and include technological advances, novel molecules of substantial interest, changing ethical principles for organism collection and heightened awareness of the chemical and biological potential of the tropical rain forests. According to Cordell the areas in which strategies for the conduct of natural product chemistry have changed include plant selection and collection, isolation techniques, structure elucidation, biological evaluation, semlsynthesis, dereplication, and biosynthesis. The methodologies involved in our search for DNA-damaging natural

products with potential anticancer activity include extraction, bioassay, bloactivity-guided fractionation, dereplication, structure elucidation and structure-activity relationship (SAR) studies. In this section the general methodologies used by us for extraction, yeast bioassay and bloactivity-guided fractionation will be mechanism-based

464 discussed. Important aspects of structure elucidation and SAR studies will be

presented under each compound or class of compounds. 4.2. Extraction Extraction of shade-dried plant material is carried out with inert solvents under mild conditions to avoid any chemical transformations and/or decompositions that may occur otherwise. Ideally 50-100 g of plant material is allowed to soak three times in methyl ethyl ketone (MEK), followed by methanol. Extracts obtained with each solvent are separately combined and evaporated yielding two extracts. These are dried, weighed and subjected to our mechanism-based yeast bioassays. 4.3. Bioassay We have found that the use of the three yeast strains RAD+, rad52, and rad52.top1 provides the most reliable measure of bioactivity for topoisomerase inhibitors and other DNA-damaging agents. Fig. 5 depicts a cartoon representation of the basis of our mechanism-based yeast bioassay. The assay is carried out by introducing the test sample (crude extract, fraction or pure compound) dissolved in a 1:1 v/v mixture of methanol-dimethyl sulfoxide to a 100 fxL well in agar plates, separately impregnated with normal "wild-type" RAD+ yeast cells and with mutant yeast cells (rad52 and rad52.top1) and incubating the plates for 48 hrs at 30C. If the test sample contains a DNA-damaging agent or a topisomerase inhibitor then it would inhibit the growth of one or more mutant strains producing a zone of inhibition i.e. a clear zone where growth of yeast cells had not occurred. The results are expressed as IC12 values which represent the concentration of the test sample in |ig/mL required to produce an inhibition zone of 12 mm diameter. An active lead should have an IC12 in the wild-type RAD+ strain equal to or greater than three times the IC12 in one of the mutant strains. For topoisomerase I inhibitors, the IC12 value in rad52.top1 should be at least threefold larger than that in rad52, while for topoisomerase II inhibitors the reverse should be true. For crude extracts doses ranging from 8000 ^ig/mL to 1000 M^g/mL are used whereas lower doses are required for fractions and for pure compounds, depending on the activity of the active compound and its concentration in the extract/fraction. Four or five different doses are used for each sample; knowing the dose and the zone of inhibition produced for each dose the IC12 values can be calculated by the application of regression analysis. The activity of yeast In each plate is tested by the use of a known

465 anticancer drug (positive control). For RAD+ and rad52 camptothecin (12) is used as the positive control and for rad6 streptonigrin (13) is recommended (Fig. 6). Table 1 shows the zones of inhibition and IC12 values for these standards in our commonly used yeast strains. Damaged DNA Damaged DNA

DNA

^
Repair pathways present I Normal yeast cells e.g. Rad+ Repair pathways absent
I

Mutant yeast cells e.g. Rad6, Rad52,\ RadSl.topl Inhibition of growth

Normal growth

Agar plate + yeast cells 48 h incubation

48h incubation

100 \k\ well containing DNA damaging agent Fig. 5. Basis of mechanism-based yeast bioassay for the detection of DNA-damaging agents

HsCOy^ ^

CxX9^
(12) Camptothecin

0
(13) Streptonigrin

Fig. 6. Positive controls used in yeast bioassay

466 TABLE 1. Response of yeast mutant strains to positive control drugs, camptothecin (12) and streptonigrin (13). Zone of inhibition RS167N RS321N RS322N RS322YK (rad6) (RS321) (rad52) (rad52Y) 213 213 163 110

Drug

Conc./ICi2 (uff/mL)

RS188N (RAD+)

Camptothecin (12) ICl2 Streptonigrin (13) ICi2

5.0 200.0 8.7 4.0 8.0 203 2.4 204

0.6

0.4

4.4. Bioactivity-guided Fractionation Isolation of potential anticancer compounds from bioactive extracts involves bioactivity-guided fractionation. The DNA-damaging natural products encountered in our studies were extracted by MEK and/or methanol, and the general methodology which we have employed in our bioassay-directed fractionation of these extracts is schematically presented in Fig. 7. These fractionations involved solvent-solvent partition, Sephadex LH-20 gel filtration, normal phase and reversed-phase (RP) column, preparative thin-layer and high pressure liquid chromatography (HPLC). Silica gel chromatography was employed only if bioactive compounds were found to be stable under these mildly acidic conditions. During the bioactivity-guided fractionation of an MEK extract, it was first partitioned between hexane and 80% aqueous methanol. Water was then added to the 80% aqueous methanol fraction to give 60% aqueous methanol and this was extracted thoroughly with chloroform. If the bioactive compounds were not extracted with chloroform the aqueous layer was subsesquently extracted with ethyl acetate. If a methanol extract was found to be active it was first subjected to an n-butanol/water partition. The n-butanol layer, which usually contained the active compound(s), was then evaporated and treated in a manner similar to that used for an MEK extract described above.

467

ME K Extract

MeOH Extract

_l_l

Butanol

1 1 1 Water

Hexane

80% ^ \queous Methanol Add water to make it into 60%Aqueous ]Vlethanol and Extract with Chloroform Chloroform Sephadex LH-20 Gel Permeation - Chromatography

Column Chromatography (RP) )|f Prep.TLC(RP) ^ ^ HPLC (RP)

60% Aqueous Methanol

Fig. 7. Fractionation scheme used for bioactive extracts

5.

Natural Products with DNA-Damaging Activity 5.1 introduction During our searcii for natural products with DNA-damaging activity utilizing

mechanism-based

yeast assays

we have investigated over 7,500 extracts of Those

bryophytes, higher plants and marine organisms collected mainly in Brazil, Ethiopia, Guam, Phillipines, Sri Lanka, mainland U.S.A. and the Virgin Islands. organisms which showed positive response to our DNA-damaging activity assays and from which we have isolated bioactive compound(s) are listed in Table 2 along with the families to which they belong and the class(es) of bioactive compounds encountered. Some important aspects of the structure elucidation of these bioactive compounds, along with their bioactivities and the structure-activity relationships (SAR) of some natural and synthetic analogs, will be discussed compound(s) encountered. below under each class of

468 TABLE 2.

Organisms exhibiting positive response to DNA-damaging yeast bioassay and the classes of compounds encountered in them. Family Bryophytes Porellaceae Jubulaceae Geocalycaceae Higher Plants Annonaceae

JEecies

name

Class of compound(s) Sesquiterpenes Sesquiterpenes Sesquiterpenes Dioxoaporphine alkaloids Oxoaporphine alkaloids Azafluorenone alkaloid Oxoaporphine alkaloids Oxoaporphine alkaloids Furano- and Furofuranonaphthoquinones Pterocarpans Diterpene dibenzoates Piperidine alkaloids Guanidine alkaloids Steroids Limonoids Coumarins Steroidal alkaloids Diterpenoids Diterpenoids

Porella cordeana Frullania nisquallensis Chiloscyphus rivularis Artahotrys zeylanicus Cyathocalyx zeylanica Miliusa banacea Xylopia aethiopica Crescentia cujete Erythrina burana Caesalpinia pulcherrima Cassia leptophylla Pterogyne nitens Pseudobersama mossambicensis Trichilia emetica Pleiospermium alatum Solatium umbelliferum Vellozia Candida Eunicea tourneforti

Bignoniaceae Fabaceae Leguminasae Meliaceae Rutaceae Solanaceae Velloziaceae Marine Organism Gorgonian

5.2 Sesquiterpenes of Bryophytes Bryophytes, although less evolved than the higher plants, constitute one of the largest groups of land plants, accounting for about 20,000 species. Musci (mosses, Taxonomically and bryophytes are placed between algae and pteridophytes and divided into 3 classes; 14,000 species), Hepaticae (liverworts, 6000 species), Anthocerotae (hornworts, 300 species). The class Hepaticae is characterized by the presence of oil bodies which are easily extracted with organic solvents. Although a number of bryophytes find applications In traditional medicines of China, Europe, and North America, very little chemistry of these is known due to the difficulty of collecting

469 sufficient quantities of uncontaminated plant material. Recent studies have provided evidence that bryophytes elaborate a variety of secondary metabolites, some which are of biological and chemotaxonomic importance [17-19]. The first report of/>? vivo antitumor activity of a bryophyte appeared in 1986 in a review of results of screening of bryophytes in the National Cancer Institute's antitumor screening program by Spjut, Suffness, Cragg and Norris [20]. Subsequent studies, however, led to the conclusion that this bryophyte species, a well known class of antitumor macrolides [21]. Since the inception of our program in 1990, we have screened several hundred extracts of bryophytes for potential anticancer activity in our mechanism-based yeast bioassay. Out of about 200 bryophytes screened a total of 27 samples had IC12 values in the range of 4000-8000 [ig/mL, 22 had IC12 values in the 1000-4000 |ig/mL range, and only 3 yielded extracts with IC12 values less than 1000 jig/mL. Regrettably, many of the species which showed bioactivity in the preliminary screening failed to reconfimn activity on recollection. Problems associated with recollecting bryophytes for bioassay have been reviewed by Spjut, Kingston and Cassady [22]. Out of several hundred species of bryophytes screened only three species gave consistent results in our bioassay and the extracts derived from these were fractionated in order to isolate constituent(s) be sesquiterpenes. 5.2.1. Porella cordeana Bioactivity-directed fractionations of the bioactive MEK extract of Porella cordeana (Hueb.) Moore (Porellaceae) collected in Oregon, USA, involving liquid-liquid partition, gel filtrations on Sephadex LH-20 and silica gel chromatography afforded five sesquiterpenoids, namely drimenin (14), 7-ketoisodrimenin (15), 7-ketoisodrimenin-5ene (16), aristolone (17) and norpinguisanolide (18). The structures of all four sesquiterpenoids were determined with the aid of spectroscopic data. This study also involved the complete assignment of ^^C-NMR spectra for drimenin (14) and aristolone (17) for the first time. Of these only drimenin (14) and aristolone (17) were found to be responsible for their bioactivity. Coincidentally the bioactive compounds encountered in all three species were found to Claopodium crispifolium, was contaminated with a microorganism which contained maytansinoids,

470 toxic towards DNA repair-deficient mutants of Saccharomyces cesevisiae, with IC12 values of 200 and 390 ^ig/mL for the racl52 (RS322YK) strain [23]. (RS188N) strains. Both sesquiterpenoids were shown to be inactive towards rad6 (RS167N) and RAD+ Drimenin (14) was also tested in P-388 murine leukemia and are Chinese Hamster Ovary cytotoxicity (CHOC) assays and were found to be inactive. Bioactivity data of P. cordeana extract and its constituent sesquiterpenoids presented in Table 3.

(15)

(16)

TABLE 3. Bioactivity data of Porella cordeana extract and sesquiterpenoids.

Extract/ Compound RS322YK (rad52Y) MEK Extract Drimerin (14) 7-Ketodrimenin (15) 7-Ketodrimenin-5-ene (16) Aristolone (17) Norpinguisanolide (18) 1641 200 >1000 >1000 390 >1000 Yeast Strain^ RS167N (rad6) 2438 >1000 >1000 >1000 >1000 >1000

RS188N (KAD+) 2475 >1000 >1000 >1000 >1000 >1000

^Results expressed as IC12 (^ig/mL)

471 5.2.2. Frullania nisquellensis The liverwort genus Frullania of the bryophyte family Jubulaceae has about 1000 described species [24] which have been subjected to extensive chemotaxonomic investigations [24-27] and are reported to be rich sources of sesquiterpene lactones some of which are known to cause allergic contact dermatitis [19]. An MEK extract of Frullania nisquallensis Sull. which showed activity in our yeast bioassay afforded the DNA-damaging sesquiterpene costunolide (19) on bioassay-guided fractionation. Costunolide showed moderate but selective activity with IC12 values of 50, 150, and 330 |ng/mL in the mutant yeast strains RS321N, RS322YK (rad52Y), and RS167N (rad6), respectively; it was inactive (IC12 > 1000 |ig/mL) in the "wild-type" strain RS188N (RAD+) [28]. Costunolide (19), when tested in a cytotoxicity assay employing the A-549 human lung carcinoma cell line, showed an IC50 of 12 ^xg/mL. It is noteworthy that the

costunolide derivative 8a-angeloyloxy-costunolide (20) has been reported to possess potent cytotoxic activity in a number of human cancer cell lines [29].

(19) R = H

( 2 0 )R = ^""yS

OMe MeO

(22) During the fractionation of the bioactive MEK extract of F. nisquallensis two inactive compounds, the sesquiterpene (-)-frullanolide (21) and the tridepside tenuiorin (22) were also encountered. (-)-Frullanolide has previously been isolated from the

472

same plant species as the major allergic compound causing contact dermatitis [30]. Although tenuiorin (22) has been isolated from a lichen [31], it has not been reported previously from a Frullania species. Structures of all compounds have been confirmed by means of ^H-, ^^C-NMR, DEPT, HETCOR and HMBC spectra. assignments of tenuiorin (22) have been made for the first time. The bioactivity of costunolide (19) in both the DNA-damaging yeast bioassay and the cytotoxicity assay has led to the suggestion that it acted by interaction with DNA in some manner. The lack of DNA-damaging activity of the structurally related ^^C-NMR spectral

(-)-frullanolide (21) has led to the conclusion that the focus of activity in 19 is not simply the a,p-unsaturated lactone moiety as suspected in many other cytotoxicity studies with a-methylene-y-lactones [32]. 5.2.3. Chiloscyphus rivularis

(23) R = OH (24) R = H
pH

(25) R = OH (26) R = H

(27)

(28) The MEK extract of Chiloscyphus rivularis of

(30) the bryophyte family

Geocalycaceae showed weak but reproducible activity in rad52 DNA repair-deficient yeast strain. Bioactivity-guided fractionation utilizing solvent-solvent partition resulted in concentration of bioactivity in the chloroform fraction. Further fractionation of this sesquiterpene, involving centrifugal partition chromatography (CPC), Silica gel column chromatography and preparative TLC afforded a moderately bioactive and new

473

12-hydroxychiloscyphone (23) [33]. Several new and inactive sesquiterpenes were also isolated and characterized as 12-hydroxychloscyph-2,7-dione (25), chiloscyph-2,7dione (26), chiloscyph-2,7,9-trione (27), and rivulalactone (28). The structure and stereochemistry of rivulalactone (28), with the novel trinorchiloscyphane carbon skeleton, was confirmed by spectroscopic methods as well as semi-synthesis starting from chiloscypone (24) (see Scheme 1) [34]. It is possible that the biosynthesis of rivulalactone follows a similar sequence of reactions. Three known sesquiterpenes were also encountered and were identified as chiloscyphone (24) and 4hydroxyoppositan-7-one (29), and isointermediol (30).

(a)

^-

(b)

(24)

(28)

Reagents: (a) Os04/A/-methylmorpholine-A/-oxlde/acetone:H20 (8:1)/-10to -20C/30 min; (b) m-CPBA/CH2Cl2/25oC/70 min.

Scheme 1. Semisynthesis of rivulalactone (28) from chiloscyphone (24). 12-Hydroxychiloscyphone (23) showed moderate but selective DNA-

damaging activity in the yeast-based assay with IC12 of 75 in 88 jug/mL in the rad52Y (RS 322YK) and rad52 (RS 321) assays and >1,000 jiig/mL in the RAD+ (RS 188N) assay. It also exhibited cytotoxicity to human lung carcinoma cell-line A-549 with an IC50 of 1.95 M-g/mL These bioactivity data are summarized in Table 4.

TABLE 4. Bioactivity data for 12-hydroxychiloscyphone (23) from Chiloscyphus

rivularis.

Yeast strain^ rad52 RS321 jRAD+

Cell line'^ A-549 1.95

88 75 >1,000 ^Results expressed as IC12 (M>g/mL) values ^Hiiman carcinoma ceU line; result expressed as IC50 (|Lig/mL) value

474

5.3. Diterpenoids 5.3.1. Rosane Diterpenoids of Vellozia Candida Plants belonging to the family Vellozlaceae occur predominantly in South America and Africa. They are interesting as they grow in rocky regions on dry soil, and in spite of their apparent fragility they show a surprising longevity. In our search for natural product-based DNA-damaging agents we have screened 20 extracts derived from 15 Brazilian species of this plant family. Eight of these extracts showed weak to moderate activity in our mechanism-based bioassay. Vellozia Candida Mikan which showed reproducible activity was selected for further study. Bioassay-guided fractionation of the bioactive alcoholic extracts of V. Candida involving solvent-solvent partition, Sephadex LH-20 gel filtration. Si gel column chromatography and reversed-phase HPLC as appropriate afforded a novel moderately bioactive 6,7-seco-rosane diterpenoid, candidalactone (31) [35]. The gross structure of candidalactone (31), Including relative stereochemistry, was determined by the application of ^H-,^^C-NMR, DEFT, COSY-45, HETCOR and NOESY spectroscopy. Another new but inactive diterpenoid, candidenoidiol, was also isolated and its structure was elucidated as 10S,11R-dihydroxy-5(6),15-rosanedien-7-one (32) with the help of ^H-,^^C-NMR, DEPT, COSY-45, HETCOR. HMBC and ORD spectroscopic techniques. HOaa.

(32) Candidalactone (31) exhibited moderate but selective activity in our

mechanism-based yeast bioassay for DNA-damaging agents with the following IC12 values: RS 322YK (racf52;, 87 |Lig/mL; RS 188N (RAD*) >200 ^ig/mL. Considering the moderate bioactivity shown by the crude extracts it has been concluded that candidalactone represented the major bioactive compound in the crude extracts of V. Candida [35].

475

5.3.2. Diterpene Dibenzoates of Caesalpinia pulchem'ma In their search for DNA-damaging natural products with potential anticancer activity, the SmithKline Beecham group has recently reported the isolation of four novel diterpene dibenzoates, pulcherrimins A - D (33 - 36) from Caesalpinia pulcherrima (L) Swartz. [36]. Roots of C. pulcherrima, a tropical tree of the Fabaceae family collected in Mexico were sequentially extracted with ethyl acetate and methanol. The latter extract, which demonstrated selective activity in a DNA repair-deficient yeast mutant, was fractionated by RP chromatography followed by preparative TLC and HPLC to afford pulcherrimins A - D (35 - 38) of which only pulcherrimins A - C were selectively active in racl52 and rad52.top1 yeast mutant strains. It was suggested that the pattern of bioactivity exhibited is similar to that seen with inhibitors of topoisomerase II such as amscarine, ellipticine or etoposide. Pulcherrimins A and C were tested for cytotoxicity in Vero cells in culture and were found to have weak activity. pulcherrimins A - D are given in Table 5. The bioactivity data for

[ OH
CO2H

""CH3

(33) R = OH (35) R = H (36) R = OAc

C02H

'CHs COC6H5 COCeHs

(34)

^OCOCeHs COCeHs

TABLE 5. Bioactivity data for pulcherrimins A - D (33 - 36). Compound radSl Pulcherrimin Pulcherrimin Pulcherrimin Pulcherrimin A B C D (33) (34) (35) (36) >100 66 >100 >100

Yeast strain^ rad52.topl 16 0.64 4.4 >100

RAD+ 88 >100 >100 >100

Cell lineb Vero cells 66 NTc 59 NTc

^Results expressed as IC12 (jig/mL) values Wero monkey cell line; results expressed as IC50 (|Lig/mL) values CNot tested

476

5.4. Steroids 5.4.1. Bioactive Steroids from Pseudobersama mossambicensis

Pseudobersama

mossambicensis

(Sim) Verde, a plant of the family

Meliaceae collected in Kenya, was subjected to our conventional extraction. The MEK extract was found to exhibit significant activity in the yeast-based bioassay employing the rad52 strain. Bioactivity-guided fractionation resulted in the isolation of three ergost5-ene-3p,7a-diol derivatives which were identified as ergost-5,24(28)-diene-3p,7a-diol (37), 24,28-epoxyergost-5-ene-3p,7a-diol (38), and ergost-5-ene-3p,7a,24,28-tetraol (39), with the aid of spectroscopic data [14]. Ergosta-5,24(28)-diene-3p,7a-diol (37) has been isolated simultaneously from another meliaceous plant [37] and comparison (TLC, RP-HPLC, ^H-NMR) of our sterol with an authentic sample confirmed its identity. The occurrence of ergost-5-ene-3p,7a,24,28-tetraol (39) as a diasteroisomeric mixture suggested that it may be an artefact arising from 24,8-epoxyergost-5-ene-3p,7a-diol (38) during the isolation process, most probably on silica gel chromatography.

(37) R =

(38)

..-r^
R ="-f^

(39)

The bioactivity data for Pseudobersama sterols are given in Table 6. All three sterols exhibited selective activity on the rad52 strain compared with the wild-type RAD+ strain. Ergost-5,24(28)-diene-3p,7a-diol (37) was also tested in P-388 murine

lymphocytic leukemia assay and was found to be moderately cytotoxic.

477

TABLE 6. Bioactivity data for Pseudobersama sterols 37 - 39. Compound rad52 (RS322YK) Ergost-5,24(28)-diene-3p,7a-diol(37) 24,28-Epoxyergost-5-ene-3P,7a-diol(38) Ergost-5-ene-3P,7oc,24,28-tetraol (39) Camptothecin (12) Streptonigrin (13) 8.0 0.4 1.0 0.6 0.4 Cell linet' RAD+ (RS188N) > 1,500 >50 P-388 4.3
NIC

Yeast strain^ radS (RS167N) 12.0 6.0 NTc 8.7 2.4

NTc

^Results expressed as IC12 (^ig/mL) values bWild-type P-388 murine leukemia cell line; result expressed as IC50 (M^M) value CNot tested 5.4.2. Stmcture-Activity Relationship (SAR) Studies of 7-Hydroxy Sterols The DNA-damaging activity of steroidal 5-ene-3p,7a-diol derivatives noted above, their limited supply and the report that cholest-5-ene-3p,7a-diol derivatives are inactive in some cytotoxicity assays whereas their 7p counterparts are active [38] prompted us to undertake SAR studies of some of their analogs. In addition to the

cytotoxic sterols, ergosta-5,24(28)-diene-3p,7a-diol (37) and 24,28-epoxyergost-5-ene3p,7a-diol (38) encountered in Pseudobersama mossambicensis, the following five 7hydroxy sterol analogs were synthesized starting from the readily available steroid stigmasterol (40); cholest-5-ene-24-one-3p,7a-diol (43), cholest-5-ene-24-one-3p,7pdiol (44), ergosta-5,24(28)-diene-3p,7p-diol (45), and 24,28-epoxyergost-5-ene-3p,7pdiol (46). In order to investigate the role played by the 7-hydroxy function,

ergosta-5,24(28)-diene-3p-ol (48) and 24(28)-epoxyergost-5-ene-3p-ol (49) were also synthesized and their bioactivity evaluated [39]. Our synthetic strategy Involved the conversion of stigmasterol (40) into the key Intermediate 42 through 41 with the correct side-chain structure and absolute stereochemistry by methodology developed by Djerassi etal. [40]. The key intermediate was then converted to the requisite sterols by employing reactions outlined in Scheme 2.

478

V^i^
Hd-^CU
(40)

(T

<if^d?^\
/ (41)
0

v^OL-

v-^A-^

xtV^ - r f ? P ^ . X ^
(47)

>r^

(42)

HO''^-^'^

*^'l

\(0,(9)

1 0

(43)

d6c
(44) 1

riC^
\

^^^^
\(e) (49)
(45)

r^x^

/ (^

\ \(^

^^iXXy
HO^ (46)

^^siXJO

(37)

(38)

Reagents: (a) See. ref. 40; (b) H2/Pd(C)/EtOAc/2h ; (c) Zn(OAc)2/ g. HOAc/120oC/2h; (d) CuBr/PhC020BuVH0Ac/Ar/120OC/0.5h; (e) Ph3P=CH2/DMSO/60C/1 h; (f) Me2S=CH2/DMSO/0 to 250C/1 h; (g) 5% methanolic KOH/25C/2h

Scheme 2. Synthetic routes to analogs of Pseudobersama sterols for SAR studies. All of the synthetic sterols were assayed in rad52 DNA-damaging and RAD* bioassays and some selected analogs have also been tested for cytotoxicity to Vero cells; the results are presented in Table 7. All synthetic 7a-hydroxy analogs showed activity in our DNA-damaging bioassay with 37 and 38 having activity comparable to natural sterols isolated from Pseudobersama mossambicensis. 7a-Hydroxy sterols were also active in Vero cell cytotoxicity assay. However, an inverse correlation between activity in the yeast assay and the cytotoxicity assay was noted. Thus, the 7a-hydroxy sterol which was the most active in the DNA-damaging assay was the epoxide 38, with

479 an IC12 value of 0.2 M,g/mL, but was inactive in the Vero cell assay, with an IC50 of >100 [AM. The second most active 7a-hydroxy sterol in the yeast assay was the olefin 37, which showed an IC12 of 7 p.g/mL and this was weakly active in the vero cell assay, with an ICsoOf 58 |iM. The 24-keto analog 44, the least active of the three 7a-hydroxy sterols in the DNA-damaging assay with an IC12 of 14 ^ig/mL, was the most active in the Vero cell culture with an IC50 of 9.9 inM. TABLE 7. Biological activity data for synthetic sterols 37, 38 and 4 3 - 4 9 .

Sterol

Yeast strain^ rad52

Cell line^ Vero cells

7.0 58.0 Ergost-5,24(28)-diene-3p,7a-diol(37) 0.2 >100 24,28-Epoxyergost-5-ene-3p,7cx-diol(38) 14.0 9.9 Cholest-5-ene-24-one-3p,7a-diol (43) >500 21.0 Cholest-5-ene-24-one-3p,7p-diol(44) > 8,000 31.0 Ergosta-5,24(28)-diene-3p,7Miol(45) > 8,000 16.0 24,28-Epoxyergost-5-ene-3P,7P-diol(46) > 8,000 NTc Cholest-5-en-24-one-3p-ol (47) > 8,000 NTc Ergost-5,24(28)-diene-3P-ol (48) > 8,000 NTc 24,28-Epoxyergost-5-ene-3p-ol (49) ^All sterols were inactive against "wild-type" strain KAD+; results expressed as IC12 (M,g/mL) values Wero monkey cell line; results expressed as IC50 (fiM) values CNot tested

In contrast to 7a-hydroxy sterols the 7p-hydroxy analogs 45 and 46 were completely inactive in the yeast assay, but showed moderate cytotoxicity in the Vero cell assay. These results suggested that the bioactivity of 7p-hydroxy sterols may involve a different mechanism of action than their a-counterparts. The sp-hydroxy sterols 47, 48 and 49 were found to be inactive in the yeast assay regardless of their side-chain functionalities and were not tested in the Vero cell assay. The results also indicated the requirement of a hydroxy function at C-7 of the sterol nucleus for biological activity in this class of compounds.

480

5.5. Alkaloids 5.5.1. Dioxoaporphines of Artabotrys zeylanicus As a part of our continuing efforts to discover molecules of biological interest from Sri Lankan flora, we initiated a program of screening Sri Lankan plants of the family Annonaceae for potential anticancer compounds employing the brine shrimp toxicity assay [41]. In our extension of this program carried out in collaboration with Dr. E. M. K. Wijeratne of the Medical Research Institute, Sri Lanka, we replaced this simple bench-top assay [42] with our mechanism-based yeast assay. One such plant which exhibited bioactivity in the latter assay was Artabotrys zeylanicus Hook. f. & Thoms., a plant endemic to Sri Lanka. Although there is no reported work on A. zeylanicus, previous investigations of Artabotrys species have resulted in the isolation of aporphine, noraporphine, oxoaporphine, protoberberine, and berberine alkaloids, as well as sesquiterpenes and steroids.
OMe

OMe

Chromatographic fractionation of the bioactive chloroform extract of the stem bark of A. zeylanicus guided by the yeast bioassay afforded two bioactive alkaloids [43]. One of these was identified as the oxoaporphine alkaloid, atherospermidine (50) The major bioactive alkaloid was found to be new and was named artabotrine; it was identified as the hitherto unprecedented A/-methoxylated alkaloid, A/-methoxynorcepharadione A (51). Structure elucidation of artabotrine involved the use of UV, ^HNMR, ^^C-NMR, HMBC and MS techniques. The ^H-NMR spectrum of artabotrine (51) in the aromatic region consisted of complex overlapping signals, coupling pattern and constants of which were determined by computer simulation experiments employing Varian VNMR software based on the FORTRAN program LAME (also known is LAOCOON) with magnetic equivalence added. presence of an unprecedented Although the spectroscopic data, established including HMBC NMR, supported the structure 51 proposed for artabotrine, the A/-methoxy function could not be

481 unequivocally. Single crystal x-ray analysis was thus undertaken and the three-

dimensional x-ray diffraction data collected at reduced temperature further supported the proposed structure. An ORTEP diagram of artabotrine (51) is shown in Fig. 8. The HREIMS of artabotrine showed significant peaks at miz 305 (C18H11NO4; loss of oxygen from the molecular ion) and at mIz 291 C17H9NO4; loss of formaldehyde from the molecular ion). Scheme 3 depicts the proposed fragmentation pathways to explain the occurrence of these fragment ions in the mass spectrum of artabotrine.

Fig. 8. X-ray structure of artabotrine (51).

M+-30;m/z291

Scheme 3. Proposed mass spectral fragmentation of artabotrine (51). The interesting biological activity exhibited by artabotrine (51) prompted us to acquire as many natural 4,5-dioxoaporphines as possible in order to submit them to our mechanism-based yeast bioassay. Those tested included norcepharadione A (52) [44], norcepharadione B (53) [45], cepharadione A (54) [46], cepharadione B (55) [46], ouregidione (56) [47], compounds 57 [46], 58 [47], and 59 [48]. The bioactivity profile for these natural 4,5-dioxoaporphines along with data for atherospermldine (50) and artabotrine (51) are given in Table 8.

482
R2 (52) (53) (54) (55) (56) (57) (58) (59) H H Me Me H Me H H H H H H OMe H H H R3 R4

0--CH2-0 OMe OMe O--CH2--O OMe OMe OMe OH OH OMe OMe H H OMe

TABLE 8. Bioactivity data for atherospermidine (50), and natural 4,5-dioxoaporphine alkaloids 51 - 59. Yeast strain^ RS322YK (radSlY) RS321N RS188N {RAD+) Cell lineb P-388 (wildtype) P-388 (camptotheci n -resistant)
NTC

Alkaloid

Atherospermidine (50) Artabotrine (51) Norcepharadione A (52) Norcepharadione B (53) Cepharadione A (54) Cepharadione B (55) Ouregidione (56) (57) (58) (59) Camptothecin (12)

1.6 2.16 1.50 >100 7.60 >100 >100 9.30 >100 >100 0.60

27 1.20 0.10 20 4.70 >100 >100 3.50 >100 >100 -

>50 >500 >250 >250 >250 NTc >250 >250

NIC

NTc 1.59 NTc

NIC

1.12
NTC NTC NTC NTC NTC NTC NTC NTC

NTc NTc
NTC NTC NTC NTC

NTc 100

0.012

>20

^Results expressed as IC12 (|Lig/mL) values t'Wild-type and camptothecin-resistant P-388 murine leukemia cell line; results expressed as IC50 (M^M) values CNot tested The above bioactivity data, although insufficient to make any firm conclusions, suggest some structural requirements of 4,5-dioxoaporphines for DNA-modifying activity. These are the presence of a methylenedioxy group at C-1 and C-2, and an unsubstituted ring C. Substitution on the amide N , whether it is H or Me, does not seem to have much effect on the bioactivity. It may be possible that the mechanism of action of these alkaloids involves intercalation into DNA.

483 5.5.2. Oxoaporphines of Xylopia aethiopica and Miliusa banacea Oxoaporphines represent another subclass of aporphine alkaloids peculiar to the Annonaceae and a few other alkaloid-bearing plant families. Oxoaporphines such as liriodenine (60) and oxoglaucine (64) have been reported to be cytotoxic [48,49]. Although no phytochemical investigations have been reported on Miliusa, a genus consisting of approximately 40 species indigenous to Australia and Indonesia [50], previous work on Xylopia aethiopica (Dunal) A Rich resulted in the isolation of kaurane and kaur-16-ene diterpenes from the fruits and kaur-16-ene, kolavane, and trachylobane-type diterpenes from the stem bark. Bioassay-guided fractionation involving liquid-liquid partition, Sephadex

LH-20 gel filtration chromatography, and Silica gel chromatography of the MEK and methanolic extracts of X. aethiopica led to the isolation of five previously known oxoaphorphine alkaloids. The structures of these oxoaporphinoids were elucidated with the aid of spectroscopic data (UV, ^H-NMR, MS). Three of the alkaloids showed selective activity against rad52 and radd mutant yeast strains [51]. Of these, oxophoebine (62) and liriodenine (60) showed significant activity whereas lysicamine (63) exhibited weak activity (Table 9). The remaining oxoaporphines, oxoglaucine (64) and 0-methylmoschatoline (65) were found to be inactive. In addition to its activity against rad52 and rad6 yeast mutants, oxophoebine (62) exhibited toxicity towards the yeast mutant lacking DNA topoisomerase I repair pathway, namely the. rad52.top.1 mutant.

Ri

(60) (61) (62) (63) (64) (65) (66)

H H H H

O-GH2--O O-CH2--O OMe OMe

OMe H H H H

OMe OMe

OMe O-CHg-O OMe H OMe OMe OMe

OMe OMe OMe H H 0~CH2--0 OH

484

TABLE 9. Bioactivities of Xylopia aethiopica and Miliusa Alkaloid Liriodenine (60) Lauterine (61) Oxophoebine (62) Lysicamine (63) Oxoglaucine (64) 0-Methylmoschatoline (65) lO-Hydroxyliriodenine (66) Camptothecin (12) Streptonigrin (13) rad52 16.7 214 6.4d 300 >500 >500 295 0.6 0.4

cf. hanacea alkaloids 6 0 - 6 6 .

Yeast strain^ radSl.topl radS NTb 113 2.6e 390 >500 >500 72 >20 <0.4 15.0at500c NTb 4.7 >500 >500 >500 NTb S.7 2.4

RAD+ 500 NTb >500 NTb >500 NTb NTb NTb NTb

^Results expressed as IC12 ([ig/mL) values and are the result of a single determination unless specified otherwise ^Not tested ^Zone of inhibition in mm at the given cone. (^ig/mL) ^Average of 3 determinations ^Average of 2 determinations

The bioactive MEK extract of Miliusa cf. banacea when subjected to bioassayguided fractionation as for X aethiopica above afforded 10-methoxyliriodenine The (lauterine) (61) and the novel oxoaporphinoid, 10-hydroxyliriodenine (66).

structures of 61 and 66 were determined by the usual spectroscopic data, and the structure of 66 was confirmed by conversion into 61 on treatment with diazomethane. Both alkaloids showed selective activity towards rad52 and rad52.top1 mutants. TABLE 10. Topoisomerase 11 unknotting activity of lauterine (61) and 10-hydroxyliriodenine (66).

Alkaloid

Topoisomerase II activity^

Lauterine (61) 25.0 10-Hydroxyliriodenine (66) 12.5 ^Inhibition of topoisomerase II unknotting activity in vitro; results expressed as IC50 (fig/mL)

485

cyathocaline (67) (see Scheme 4) as the only bioactive compound [52]. The structure of cyathocaline has been determined by the application of spectroscopic techniques for the parent alkaloid as well as its diacetyl derivative. A probable pathway for the biogenetic conversion of azaanthraquinones, which co-occur with azafluorenones in Annonaceous plants, into azafluorenones has also been proposed (Scheme 4).

Enz.

Azaanthraquinones

Azafluorenones (67) Ri = H ; R2 = OMe (Cyathocaline) Scheme 4. Proposed biogenetic origin of azafluorenones from azaanthraquinones. Cyathocaline exhibited moderate but selective activity in our yeast bioassay and also in a cytotoxicity assay against the A-549 human lung carcinoma cell line (Table 11). Three azafluorenone alkaloids have previously been tested for cytotoxic activity and were found to be inactive [53] but one has been reported to have anticandidal activity [54]. TABLE 11. Bioactivity of cyathocaline (67).

Yeast strain^ RS321N RS167N RS188N RS322YK (rad6) (RAD+) (rad52Y) Not active >400 87.0 90.0 ^Results expressed as IC12 (M^g/ii^L) values t'Human carcinoma cell line A-549; result expressed as IC50 (fiM) value

Cell lineb A-549 8.50.07

486 5.5.4. Piperidine Alkaloids from Cassia leptophylla In an effort to uncover anticancer active metabolites in Brazilian plants, in early 1993 we initiated active collaboration with several Brazilian natural products chemists. Out of the large number of extracts brought to our laboratory by Dr. Vanderlan da S. Bolzani and screened in our mechanism-based yeast bioassay, extracts derived from two leguminous plants were selected for further studies. Based on preliminary Cassia investigation the bioactive methanolic chloroform extract of the leaves of processed for alkaloids.

leptophylla which was shown to contain bioactive alkaloldal constituents was further The alkaloid fraction thus obtained was fractionated by column chromatography on alumina, followed by Silica gel preparative TLC and reversed-phase TLC to afford seven piperidine alkaloids [55]; (-)-spectaline (68), (-)-spectalinine (69), canavaline (70), leptophyllin A (71), 3-acetylleptophyllin A (72), iso6-canavallne (73), and leptophyllin B (74). Of these, (-)-spectaline (68), (-)-spectalinlne (69), and canavaline (70) showed significant bioactivity in our mechanism-based bioassay utilizing the yeast strains RS 322YK (rad 52) and RS 321N. Leptophyllin B (74) exhibited moderate activity in these two strains whereas iso-6-canavaline (73) showed a positive response only to the RS 188N (RAD*) strain, suggesting it to be an antifungal agent. Cytotoxic activities of (-)-spectaline (68) and (-)-spectalinine (69) were evaluated in Vero monkey and Chinese hamster ovary cell lines and (-)-spectalinine (69) was found to be moderately active In both cytotoxicity assays. The biological activity data for the bioactive Cassia leptophylla alkaloids are summarized in Table 12.

Xi^,
R. H (68) R = -(CH2)i2COCH3 (69) R = -(CH2)i2CH(OH)CH3 (70) R = -(CH2)ioCH(OH)CH3 (71) Ri = H; R2 = -(CH2)ioCH(OH)CH20H (72) R, = Ac; R2 = -(CH2)ioCH(OH)CH20H

HO.,,, H,C*

a,
H Yeast strain^ RS321N RS188N (RAD^) 17.5 27.0 26.0 >500 157 126 >50 >50 123 126 100 Cell lineb Vero CHO >20 9.9 NTc NTc
NTC

487

(73) R = -(CH2)ioCH(OH)CH3 (74) R = -(CH2)ioC02H

TABLE 12. Bioactivity data for piperidine alkaloids from Cassia leptophylla .

Alkaloid RS322YK (radSlY) (-)-Spectaline (68) (-)-Spectalinine (69) Canavaline (70) Iso-6-canavaline (73) Leptophyllin B (74) Camptothecin (12) 15.0 16.0 16.5 >500 >200 0.6

15.0 9.7
NTC NTC NTC

0.019

^Results expressed as IC12 (|Lig/mL) values Wero monkey and Chinese hamster ovary cell lines; results expressed as IC50 (M^M) values CNot tested The structures of the piperidine alkaloids 68 - 74 were elucidated by application of FABMS. ^H-NMR, ^^C-NMR, DEPT, DQCOSY. HETCOR and HMBC techniques. Out of the seven piperidine alkaloids encountered in C. leptophylla, (-)-spectaline (68), leptophyllin A (71), 3-acetylleptophyllin A (72) and leptophyllin B (74) were found to be new [55]. Although piperidine alkaloids are abundant in nature and many of them are known to exhibit some biological activity [56], C. leptophylla alkaloids were the first to be reported to have DNA-damaging activity.

488

5.5.5. Guanidine Alkaloids from Pterogyne nitens

(75) RT = R3 = H ; R 2 = R 4 = (76) Ri = R3 = H ; R2 = R4 = NR1R2 HN==<^ 'NR3R4 (77) R i = R 2 = H;R3 = R4 = (78) Ri = R3 = Me ; R2 = R4 = (79) R i = R 2 = H;R3 = R4=

^^^'^^

^ ^ ^ ^ ^

A methanolic chloroform extract of the leaves of the South American legume, Pterogyne nitens TuL, collected in Brazil exhibited a positive response to our yeast bioassay. Bioactivity-guided fractionation of this extract afforded the previously known pterogynidlne (75) and three new guanidine alkaloids named nitensldines A (76), B (77), and C (78) [57]. These alkaloids were tested in our yeast mutant strains RS 321, RS 167N (rad6), RS 322 YK (rad52) and RS 188N (RAD*) and were found to be active only in the strain RS 321, suggesting the potential of these alkaloids as DNA-modifying agents. The new alkaloids, nitensldines A-C (76 - 78) were also tested for cytotoxicity using the Chinese hamster ovary auxiliary B1 cell line, and all of them showed moderate cytotoxic activity. The bioassay data for these alkaloids are presented in Table 13. Although a number of unusual guanidine alkaloids displaying a broad spectrum of biological activities are known from marine organisms [58,59] and some plants of the families Euphorblaceae and Leguminosae [60-64], this constituted the first report of the DNA-modifying activity of guanidine alkaloids. TABLE 13. Bioactivity data for guanidine alkaloids 75 - 78.

Alkaloid RS321 Pterogynidlne (75) Nitensidine A (76) Nitensidine B (77) Nitensidine C (78) Camptothecin (12) Streptonigrin (13) 8,5 6.0 10.0 13.0 -

Yeast strain^ PIS167N RS322YK (rad6) (rad52Y) > 1000 > 1000 > 8000 > 1000 > 8000 > 500 > 8000 > 8000 8.7 0.6 2.4 0.4

RS188N (RADV >1000 >1000 >1000 >8000 -

Cell lineb CHOAux-Bl NTc 13.0 9.3 20.0 0.016 -

^Results expressed as IC12 (p-g/mL) values ^Chinese hamster ovary auxilliary Bl cell line; results expressed as IC50 (\ig/mL) values CNot tested

489 The structures of the guanidine alkaloids 75 - 78 encountered in this study were elucidated with the aid of spectroscopic data especially NMR techniques including DEPT, ''H-^^C H E T C O R and HMBC techniques. study. 5.5.6. Steroidal Alkaloids from Solanum umbelliferum In the course of our random screening of plants for potential anticancer activity using our yeast bioassay, a methanolic extract of Solanum umbelliferum Eschs. (family - Solanaceae) was found to exhibit promising activity. Bioactivity-guided fractionation afforded solasodine (80), 0-acetylsolasodine (81), and solasodine 3-0-pD-glucopyranoside (82) [65]. Of these, only solasodine (80) and 0-acetylsolasodine (81) were shown to have DNA-damagIng activity (Table 14). The inactivity of solasodine 3-0-p-D-glucopyranoside (82) may be attributed to its inability to permeate through the yeast cell wall. 92 Nv (80) Ri^ = R2 = H (81) Ri = Ac;: R2 = rOH1 (82) Ri < R2 == H Interestingly, pterogynine (79), which has previously been isolated from Pterogyne nitens [60], was not encountered in this

(83) Ri = H ; R2 = Ac = Ac (84) Ri = Ac ; R2 = TABLE 14. Bioactivity data of steroidal alkaloids 80 - 82 and their derivatives 83 and 84. Steroidal alkaloid RS322YK (rad52Y) Solasodine (80) 0-Acetylsolasodine (81) Solasodine 3-0-P-D-glucopyranoside (82) N-Acetylsolasodine (83) N,0-Diacetylsolasodine (84) Camptothecin (12) ^Results expressed as IC12 (M^g/mL) values 5.0 21.0 >8000 >8000 >8000 0.9

<m

Yeast strain^ RS321 RS167N (rad6) 1.9 3.0 > 8000 > 8000 > 8000 > 10.0 30.0 > 8000 > 8000 > 8000

RS188N (RAD+) 6.1 15.7 >8000 >8000 >8000 100

490

In an SAR study directed towards the determination of the functional moiety in solasodine (80) and its 3-0-acetate (81) responsible for their DNA-damaging activity, the two analogs, 83 and 84 were prepared and their bioactivity evaluated. On the basis of our previous studies on the biological activity of 3p-hydroxyergost-5-ene derivatives [14,39], it was hypothesized that the DNA-modifying activity of 80 and 81 may be due to the spiro-aminoacetal function present in the steroidal side chain of these compounds. This spiro-aminoacetal group may open up, producing an electrophilic iminium species capable of alkylating DNA (Scheme 5). To test this hypothesis, A/-acetylsolasodine (83) and A/,0-diacetylsolasodine (84) were prepared, since the lone pair of electrons on nitrogen is unavailable to form the putative bioactive iminium ion intermediate in these compounds. The derivatives 83 and 84 were synthesized starting from commercially availabale solasodine (80) by the sequence of reactions outlined in Scheme 6. When subjected to our DNA-damaging bioassay both derivatives (83 and 84) were found to be inactive (Table 14), supporting the possible participation of the spiro-aminoacetal function in DNA-damaging activity of these steroidal alkaloids.

\xr^ 1
^

B-(DNA)

Scheme 5. Proposed mechanism of DNA-damaging activity of steroidal alkaloids. It is noteworthy that preparations containing solasodine glycosides are currently being employed for the treatment of skin cancer [66]. The steroidal alkaloids verazine, veratroyi zygadenine, and germerin are reported to inhibit hepatoma and S 180 cells, probably by inhibiting DNA synthesis by affecting the DNA template [67]. Steroidal alkaloids and their glycosides occurring In numerous Solanum species are also known to possess a variety of other biological activities including antifungal, antiviral, molluscicidal, teratogenic and embryotoxic properties.

491

(a)

AcO'

(84)

(d)
Et3Si

Reagents: (a)Ac20/pyridine/25C/7h; (b)Et3SICI/DMF/imicla2ole/25C/3h; (c) AcCI/CHgCla/EtsN/DMAP/O^C/lh; (d) HF-pyridine/rHF/250C/2.5h.

Scheme 6. Preparation of A/-acetylsolasodine (83) and A/,0-diacetylsolasodine (84) from solasodine (80).

5.6. Marine Diterpenoids from Eunicea toumeforti The gorgonian Eunicea tourneforti, collected in the waters off the U.S. Virgin Islands, was one of the select group of marine organisms that showed activity In our assay. Bioactivity directed fractionation led to the Isolation of a number of new and known diterpenoids, although regrettably these proved to be only weakly active against the RS321 yeast strain [68]. Typical of the diterpenoids isolated was 16-acetoxy-7,8epoxy-3,12-dolabelladlen-13-one (85).

(85)

492 5.7. Limonoids from Trichilia emetica Out of a large number of extracts derived from Ethiopian plants screened in our collaborative effort with Dr. Ermias Dagne of the University of Addis Ababa, Ethiopia, an MEK extract of Trichilia emetica Vahl. (family - Meliaceae) was found to exhibit selective activity against the rad52 yeast strain RS 322YK compared with the wild-type RAD* (RS 188N) strain. The usual fractionation guided by bioassay involving solventsolvent partition, normal and reversed-phase column chromatography, reversed-phase preparative TLC and reversed-phase HPLC furnished the limonoids nymania 1 (86), drageana 4 (87), trichllin A (88), rohltuka 3 (89), Trichilia substance Tr-B (90), and a novel seco-A-protolimonold identified as methyl-1S,23R-diacetoxy-7R,24^,25-trihydroxy20S-21,24-epoxy-3,4-seco-apotirrucall-4(28),14(15)-diene-3-oate (91) [69]. Of these, only nymania 1 (86) and Tr-B (90) were found to be active in our mechanism-based yeast bioassay. Nymania 1 (86) was also tested in a Vero cell assay and was found to be moderately cytotoxic. summarized in Table 15. Bioactivity data for nymania 1 (86) and Tr-B (90) are

i V J / HO

OH O '

(87)

(88)

493 The structure of the novel seco-A-protolimonoid (91) was elucidated with the aid of HREIMS, ^H-NMR, ^^C-NMR. DEPT, DQCOSY, HMQC and HMBC spectra. In addition this study involved the assignment of ^^C-NMR spectral data of drageana 4 (87), rohituka 3 (89) and Tr-B (90) for the first time and revision of ^^C-NMR assignments for trichilin A (88). Previous work on T. emetica have led to the isolation of a number of limonoids, some of which have been shown to have a wide range of biological activities including antifungal, bacteriocidal and antiviral activities [70], and insect antifeedant and growth regulating properties [70,71].

pAc

(90)

TABLE 15. Bioactivity data for the limonoids nymania 1 (86) and Tr-B (90) from Trichilia emetica. Limonoid

Yeast strain^ RS322YK RS188N (rad52Y) (RAD+) 0.7 16.7 0.6 25.0 > 100 110

Cell lineb Vero CHOAux-Bl 12.0 >20 0.054

Nymania 1 (86) Tr-B (90) Camptothecin (12)

^Results expressed as IC12 (M^g/i^L) values Wero monkey and Chinese hamster ovary auxilliary Bl cell lines; results expressed as IC50 (^ig/mL) values

494 5.8 Bioactive 0-Heterocyclic Compounds 5.8.1 Furanonaphthoquinones from Crescentia cujete Defatted wood chips of Crescentia cujete, a plant of the family Bignoniaceae, when extracted with MEK afforded a bioactive extract. Fractionation of this extract guided by bioactlvity and involving solvent-solvent partitioning and flash chromatography afforded two furofuranonaphthoquinones with a novel fused ring system and seven furanonaphthoquinones. The two furofuranonaphthoquinones were identified as 3hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (92) and 9-hydroxy-3-hydroxymethylfuro[3,2-b]naphtho[2,3-d]furan-5,10-dione (93), both of which were demonstrated to be active In our mechanism-based bioassay [72].

(92) R = H (93) R = OH

(94) Ri = R2 = OMe; R3 = OH (95) Ri = R2: OMe; R3 = H (96) Ri = R3: H; R3 = OMe

(97) R = H (98) R = OH

(99) Ri = R2 = R3 = H ; undefined stereochemistry (100) Ri = R3 = H ; R2 = OH ; undefined stereochemistry

The structures of the seven naphthoquinones were identified as {2S, 3S)-3hydroxy-5,6-dimethoxydehydroiso-a-lapachone (94), (2R)-5,6-dimethoxydehydroiso-alapachone (95), (2R)-5-methoxydehydroiso-a-lapachone (97), (96), 2-(1 -hydroxyethyl)-

naphtho[2,3-b]furan-4.9-dione 4,9-dione (98),

5-hydroxy-2-(1-hydroxyethyl)naphtho{2,3-b}furan(99), and 5-hydroxy-

2-isopropenylnaphtho{2,3-b}furan-4,9-dione

dehydroiso-a-lapachone (100), all of which were found to be bioactive [73]. Both furofuranonaphthoquinones 92 and 93, and those furanoand the

naphthoquinones showing the requisite differential in bioactlvity towards rad52 these bioassays are summarized in Table 16. It is interesting that

RAD"" yeast strains were subjected to cytotoxicity assay with Vero cells. The results of furofuranonaphthoquinone 92 exhibited selective activity whereas 93 was almost as active in the wild-type strain RAD* as in the DNA repair-deficient strain rad 52. Thus, 93

495 is presumably an antifungal or a general cytotoxic agent. All furanonaphthoquinones 9 4 - 1 0 0 showed moderate but selective activity against the DNA repair-deficient rad 52 yeast strain, indicating that they act as DNA-damaging agents. The more active compounds, 94 - 98, were also subjected to cytotoxicity assay against Vero cells; the highest potencies were shown by furanonaphthoquinones 97 and 98, both of which have an OH group in their side chain. The activity of 97 against Vero cells is about an order of magnitude greater than its previously reported cytotoxicity to KB cells [74].

TABLE 16. Biological activity data for furofuranonaphthoquinones 92,93 and furanonaphthoquinones 94 -100 from Crescentia cujete.

Compound

Yeast strains RS322YK RS188N (rad52Y) (RAD+) 10.0 2.0 47.0 33.0 48.0 14.0 3.0 60.0 80.0 0.6 30.0 3.0 >1000 120.0 280.0 180.0 10.0 130.0 140.0 110

Cell line^ Vero

Furofuranonaphthoquinone (92) Furofuranonaphthoquinone (93) Isolapachone (94) Isolapachone (95) Isolapachone (96) Furanonaphthoquinone (97) Furanonaphthoquinone (98) Furanonaphthoquinone (99) Isolapachone (100) Camptothecin (12)

2.3 2.9 3.7 4.7 4.3 0.41 0.21 NTc NTc 0.019

^Results expressed as IC12 (Mg/niL) values Wero monkey cell line; results expressed as IC50 (M^g/mL) values CNot tested The structures of all new compounds were determined by application of MS, ^H-NMR. ^^C-NMR, DEPT. ^H-^^C HETCOR. HMQC and HMBC techniques. Structure elucidation and stereochemical assignments including absolute stereochemistry of the furanonaphthoquinone 96 involved the use of the selective INEPT (Insensitive Nuclei Enhanced by Polarization Transfer) NMR technique and comparison of the CD (Circular Dichroism) spectra with related compounds whose absolute stereochemistry has been determined by x-ray crystallography [75].

496 5.8.2. Pterocarpans from Erythrina burana Erythrina burana Chiov. (family - Fabaceae) is known to occur only in Ethiopia. The genus Erythrina is well known for elaborating alkaloids with cardiovascular effects. Recent studies on the neutral and phenolic compounds of this genus have revealed the occurrence of flavanones and isoflavanones and antimicrobial pterocarpans [76]. A chloroform extract of the bark of E burana showing selective activity against the DNA repair-deficient racl52 yeast mutant when fractionated by flash chromatography over Silica gel and Sephadex LH-20 gel permeation chromatography, followed by Silica gel preparative TLC afforded two bioactive pterocarpans identified as phaseollidin (101) and cristacarpin (102)[77].

(101) Ri = R2 = H (102) R i = O H ; R2 = Me

TABLE 17. Bioactivity data for phaseollidin (101) and cristacarpin (102) from Erythrina burana. Compound RS322YK (rad52) Phaseollidin (101) Cristacarpin (102) 500 80 Yeast strain^ RS167N RS321 (rad6) Cell lineb CHCX: CHOC -PGO

RS188N (RAD+)

P-388

> 1000 400 > 10.0 4.0 7.6 5500 > 10,0 > 20.0 4.0 330 540 108 ^Results expressed as IC12 (jig/mL) values bWild-type P-388 murine leukemia, Chinese hamster ovary and P-glycoprotein overproducing Chinese hamster ovary cell lines; results expressed as IC50 (fiM) values

497 The bioactivity data for phaseollidin (101) and cristacarpin (102) in our mechanism-based yeast bioassays are summarized in Table 17. Both pterocarpans showed selective activities in rad52 and RS 321 yeast assays compared with the wildtype RAD"" strain. Cytotoxic activities of phaseollidin (101) and cristacarpin (104) were determined in three cell lines, namely wild-type P-388 leukemia, wild-type Chinese hamster ovary (CHOC) and P-glycoprotein overproducing Chinese hamster ovary (CHOC-PGO) cells. Phaseollidin (101) was found to be moderately active in the wildtype CHOC cytotoxicity assay. Interestingly, cristacarpin (102) was inactive against wildtype CHOC but showed activity against a P-glycoprotein overproducing cell line; this reversal of activity is unusual. 5.8.3. Coumarins from Sri Lankan Rutaceae Our search for potential natural product-based anticancer agents employing a mechanism-based bioassay described in previous sections utilized the approach of random screening of extracts followed by bioassay-guided fractionation of those extracts exhibiting bioactivity. A second route to drug discovery is that of screening pure isolates obtained from other studies. This approach was tested previously with 4,5dioxoaporphines aquired from various sources (see Section 5.5.1). In an extension of this approach we have evaluated twelve coumarins in our mechanism-based bioassay employing DNA repair-deficient (rad6 and rad52Y) and repair-proficient {RAD*) yeast strains [78]. Coumarins constitute a major class of 0-heterocyclic natural products with widespread distribution and broad pharmacological profile, including anticancer activity [79]. Coumarins occur commonly in plants belonging to the families Rutaceae, During our studies on Sri Lankan Simaroubaceae, Meliaceae, and Burseraceae.

Rutaceae we have encountered coumarins belonging to three structural types, namely simple coumarins {umbelliferone (103), suberosin (104), suberenol (105), osthol (106), and aurapten (107)}, furanocoumarins {bergapten (108), xanthotoxin (109), isopimpinellin (110), and marmesin (112)}, and pyranocoumarins {seselin (113), xanthyletin (114), and xanthoxyletin (115)}. Umbelliferone (103), subserenol (105), marmesin (112), seselin (113), xanthyletin (114), and xanthoxyletin (115) were isolated from Pleiospermium alatum [80,81], suberosin (104) from Luvunga angustifolia [81], and osthol (106), aurapten (107), bergapten (108), xanthotoxin (109), and isopimpenellin (110) from Limonia acidissima [82].

498

R1 (103) H

R2

R3

H Me

H H

(108) (109) (110)

(111)

R^ =OMe R2 = H R2 = 0Me Ri = H R^ = R2 = 0Me

R1=R2 = H

(104) (105)
(106) 007)

^/V\

^/V^"
H H

M e
Me

H
S/V'\ H

HO

^/NA/^SA

>--coo,
(112) (114) R = H (115) R = OMe

(113)

Coumarins 103 -110 and 112 - 115 were tested in our mechanism-based yeast bioassay employing the rad52 strain at a dose of 500 |ig/mL, and only seselin (113) and xanthyletin (114) showed detectable activity. Thus, these two were tested with other yeast strains (rad52Y, radd, and RAD*). Seselin (113) exhibited selective activity against the rad52 yeast strain as compared with the wild-type RAD" strain, indicating that it acts as a DNA-damaging agent. Seselin was also weakly active in a mammalian cytotoxicity assay against Vero monkey cells, with an IC50 of 12 |Lig/mL. It is more potent than the related coumarin, xanthyletin (114), perhaps due to the ability of seselin (113) to produce DNA damage as suggested by its selective toxicity to the DNA repair-deficient yeast mutant. Xanthyletin showed somewhat higher activity in the wildtype RAD* cell line, suggesting that its cytotoxicity is due to some other mechanism than DNA damage. Table 18. The bloactivity data for these two coumarins are presented in

499 It is noteworthy that out of the three structural types of coumarins tested, only the pyranocumarins acted as moderate DNA-damaging agents, that the angular pyranocoumarin 113 was more active than its linear counterpart 114, and that the introduction of a methoxyl substituent at C-5 of the linear pyranocoumarin (e.g., 115) caused a total loss of its bioactivity. It is interesting that the linear furocoumarins included in this study {e.g., bergapten (108), xanthotoxin (109), and isopimplnellin (110)} were found to be inactive although the linear furocoumarin psoralen (111) is known to intercalate into DNA and to photobind with this macromolecule [83] yielding either monoadducts or interstrand cross-links [84] by one or two subsequent photocycloaddition reactions with the pyrimidine bases, particularly thymine [85]. TABLE 18. Bioactivity data for the coumarins, seselin (113) and xanthyletin (114).

Compound radSl Seselin (113) Xanthyletin (114) Camptothecin (12) 33 52 0.6

Yeast strain^ RS167N RS322YK (rad6) (ra^52y) 480 87 318 87 8.7

RS188N 220 21 110

Cell lineb Vero 12 >20 0.02

^Results expressed as IC12 (^ig/mL) values Wero monkey cell line; results expressed as IC50 (|ig/mL) values

6.

Summary and Conclusions The work described in the preceding pages has demonstrated the utility of

the yeast bioassay for the detection and isolation of DNA-damaging agents in plant and marine extracts. The assay has many advantages. Thus it is relatively easy to set up and maintain, and It Is economical to run since no expensive reagents or radioisotopes are required. It is also appropriately selective, with only approximately 1 % of extracts tested showing significant activity in the assay. Finally, since it is a mechanism-based assay, those compounds isolated through its use have a mechanism of action that is at least partially understood, and thus can proceed more rapidly to a decision point on possible development as anticancer agents. The compounds isolated have come from a variety of biological sources, and have yielded a correspondingly diverse group of bioactive natural products. Except in a

500

few cases discussed, there appears to be no obvious correlation between structure and bioactivity, but it is noteworthy that several of these compounds, such as the furanonaphthoquinones, the aporphine alkaloids, and the azafluorenone alkaloids, are planar aromatic compounds which would be expected to intercalate into DNA. As noted earlier, the bioassay is capable of detecting topoisomerase I inhibition activity as well as topoisomerase II inhibition activity. It is thus interesting that we found no extracts that showed the topoisomerase I pattern of activity, indicating the scarcity of natural products with this activity and enhancing the uniqueness new topoisomerase I inhibitor would be a noteworthy event. Finally, although none of the compounds described in this review are candidates for clinical development as anticancer drugs, some of them offer interesting target molecules for analog synthesis. We are thus investigating some of the compounds as pharmacophores for the development of improved analogs. of camptothecin (12) and its derivatives. Of course, by the same token, the discovery of a

7.

Acknowledgements

The work described in this review depended first of all on an effective collaboration as part of a National Cooperative Drug Discovery Group (NCDDG) grant (1 U01 CA 50771) awarded to the University of Virginia (Prof. S.M. Hecht, Principal Investigator), and we are particularly grateful to the National Cancer Institute for this financial support. We are also grateful to Prof. Hecht for his leadership, advice and encouragement and the provision of bioactive extracts, and to Dr. Randall K Johnson (SmithKline Beecham Pharmaceuticals) for the provision of active extracts and of the yeast strains described in this review. The work carried out at Virginia Polytechnic Institute and State University was made possible thanks to the skillful efforts of our following coworkers: Dr. A Ahmad, Ms. N. J. Baj, Profa. V. da S. Bolzani, Ms. Claudia Brochini, Dr. Q.-M. Che, Prof. E. Dagne, Mr. T. E. Glass, Prof. M. Govindan, Ms. G. Govidan, Dr. Habib-ur-Rahman, Mr. K. Harich, Dr. G. G. Harrigan, Dr. C. E. Heltzel, Dr. Y C. Kim, Mr. W. Lennox, Prof. J.-Y. Liang, Dr. W. R. Phillips, Dr. G. Samaranayake, Prof. E. Silveira, Profa. L. M. M. Valente, and Mr. C. WU. We gratefully acknowledge their valuable contribution to this program. We also gratefully acknowledge the collaboration of Dr. G.W Chan, Dr. D.S. Eggleston, Mr. L. Faucette, Dr. K Haltiwanger, and Mr. G.A Hofmann from SmithKline Beecham Pharmaceuticals, and Prof. L.M.V. Tillekeratne and Dr. E. M. K. Wijeratne from Sri Lanka. We are grateful to Profs. H. Achenbach (Germany), A Cave (France) and A Banerji (India) for samples of 4,5-dioxoaporphlnes for SAR studies.

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507

In Vitro Models of Human Disease States

John M. Pezzuto, Cindy K. Angerhofer and Haider Mehdi Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and Department of Surgical Oncology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612 1. SUMMARY The treatment of most systemic diseases involves administration of drugs, and it is apparent that drug-based therapeutic strategies will predominate into the 21st century. Unfortunately, efficacious agents are not available for the treatment of many conditions that debilitate humans. Examples are cancer, hepatitis and malaria. Drug discovery may be based on a variety of approaches, including random screening, combinatorial chemistry, "rational" design, or natural products, the latter of which comprises a main focus of our programs. In each case, a dominant feature of the programs deals with utilizing appropriate in vitro models of human disease states. The construct and design of these systems is of utmost importance for success. From the outset, it is typically appealing to consider the use of models employing laboratory animals. It can be demonstrated, however, that animal models are often precluded due to time, expense and ethical considerations. On the other hand, in vitro test systems are deficient in a number of respects, e.g., high rates of "false positives", little potential for metabolism, lack of ability to accurately reflect metabolic disposition, etc. Nonetheless, batteries or panels of test systems can be constructed to reflect selectivity or "in vitro therapeutic efficacy" by the generation of indices. We have illustrated these principals in the discovery of antimalarial, antihepatitis B, and cancer chemotherapeutic agents. In the area of cancer chemoprevention, the same notion of in vitro selectivity has been used, and active leads are then tested in a more physiologically-complicated mammary organ culture model. These approaches have been or can be applied to mimic other types of human disease states, e.g., AIDS. It is not a trivial matter to devise appropriate test panels, bearing in mind factors such as capacity, expense, safety and

*Some of the information described in this manuscript was presented at the American Association of Pharmaceutical Scientists Midwest Regional Meeting, Chicago, IL, May 20, 1996.

508

sensitivity, in addition to physiologic significance. However, if suitable models are not developed and employed, potentially useful drugs will be missed. 2. INTRODUCTION Terrestrial plants are a well-established source of drugs useful for the treatment of human ailments (1). Since conservative estimates suggest the existence of 250,000 species, various strategies have been devised for the selection of starting materials (2). Once starting materials are procured, however, it becomes of utmost importance to rapidly identify promising leads and to obtain the active chemical principles affiliated with these substances. The approach generally regarded as most practical for drug discovery is bioassay-directed fractionation. This entails evaluating plant extracts in a bioassay system, and those demonstrating a positive response are considered as active leads. After a number of active leads are identified, decisions are made to fractionate the most promising materials. Each fraction is monitored for potential to mediate a positive response in the bioassay test system, and this process continues until a pure active substance is obtained. The resulting substance is then subjected to procedures of structure elucidation. Once an active isolate is obtained, more thorough biological evaluation procedures are often performed and, based on the accumulated data, the material is considered as a candidate for more advanced testing and development. A question of paramount concern relates to the bioassay systems that are utilized for selection of active lead materials and for the activity-guided fractionation that leads to the procurement of active principles. We currently describe bioassay systems that are suitable for the discovery of antitumor, antimalarial and antihepatitis B agents, emphasizing aspects of selectivity that are designed to promote the discovery of agents capable of mediating physiological responses with therapeutic efficacy. 3. CELL-BASED MODELS FOR THE DISCOVERY OF CANCER

CHEMOTHERAPEUTIC AGENTS 3.1 The Cancer Problem As summarized by the American Cancer Society (3), it is estimated that approximately 1.4 million new cancer cases will be diagnosed this year in the United States, and approximately 550,000 individuals will die of cancer. A steady rise in cancer mortality rate over the past 50 years suggests a lifetime risk for the development of cancer ranging from 1 in 3 (for women) to 1 in 2 (for men). It is generally agreed that cancer will be the leading cause of death in the U.S. by the year 2000, and it currently is the leading disease-based cause of death on a global level. Survival rates vary on the basis of cancer type and stage at the time of diagnosis, but

509 malignant, metastatic disease is rarely associated with a favorable prognosis. Agents currently in use, many of which are natural products, may lead to prolongation of survival time, but untoward side-effects and morbidity are common. These statistics and unpleasant observations all lead to the same conclusion: there is an urgent need for the provision and development of new and effective cancer chemotherapeutic agents. Drug discovery programs must continue in an unabated manner so that eventual management of disseminated disease may be accomplished. Historical precedent suggests natural products can mediate antitumor activity, and organisms spread throughout the biosphere continue to represent viable sources of starting material. 3.2 Evaluation of Cytotoxic Activity Utilizing Cultured Human Cancer Cells A large number of in vitro test systems and the issues that need to be considered when attempting to interrelate in vitro test results with in vivo efficacy studies have been described (cf. 4). In general, recent advances in molecular biology have led to a greater understanding of the molecular basis of human disease states. As a correlate, in vitro systems that monitor a response that is either closely related to or identical with the molecular event yielding the disease condition can be devised. In contrast to well-defmed in vitro test procedures, assays dealing with cell cultures have one major advantage: all potential mechanisms concerning cellular proliferation are simultaneously monitored. Obviously, it is recognized that cytotoxicity is neither necessary nor sufficient for antitumor activity. Therefore, it should be of no surprise that isolates derived from cytotoxicitybased assay procedures are often toxic toward mammalian species and do not demonstrate therapeutic efficacy. However, cytotoxicity is an activity that is consistent with antitumor activity and virtually every known naturally-occurring antitumor agent demonstrates a positive response in a cell culture system. Agents such as taxol and camptothecin were discovered on the basis of cytotoxicity. Thus, it is likely that a previously uncharacterized plant extract that contains a novel antitumor agent would also demonstrate a positive response, and many research programs dealing with the isolation and identification of potential antitumor compounds from plants have relied on cytotoxicity for bioassay-directed fractionation. In the past, cultured P388 or KB cells have been employed routinely. Briefly, the procedure involves treating the cells with various concentrations of the test substance and assessing cell growth after 48 or 72 hr of incubation with P388 and KB cells, respectively. The results are expressed as ED50 values (concentration required to inhibit cell growth by 50%). As established by the National Cancer Institute, ED50 values of <20 jug/ml for extracts and < 4 ji^g/ml for pure compounds are considered active. Although these test procedures are proven to be effective for the isolation of cytotoxic compounds that may be of novel structure, it is often the case that compounds identified as active toward cultured P388 cells are not active with P388-infected mice, and compounds active

510

with KB cells are often not active with in vivo tumor models. In many instances, the isolates are simply toxic. In an effort to discover agents with selective antitumor activity, the National Cancer Institute initiated a program wherein the cytotoxic potential of compounds or extracts are evaluated with a battery of human cancer cell types in culture. The objective is to uncover agents that demonstrate selective cytotoxic activity with a cell line derived from a single type of primary human tumor (5,6). The use of a battery of human cell lines derived from a variety of human tumor types offers great theoretical and practical advantage. For example, the cells can be carried as solid tumors in athymic mice. Thus, more advanced testing of active principles is obviously facilitated. Also, it can be speculated that certain test materials could demonstrate celltype specificity, and this would lead to isolation and identification of selectively cytotoxic agents. Based on structure and activity, agents capable of mediating selective cytotoxicity would certainly be candidates for more advanced testing. It is possible that an agent capable of demonstrating cell-type selectivity (or a derivative thereof) could be useful in the treatment of the specific type of cancer modeled by the cultured cells. Irrespective of the clinical outcome, however, the concept of selective cytotoxicity implicitly suggests the presence of a cell-specific receptor that differentiates the proliferative capacity of one tumor-type (or cell-type) from another. Such a discovery would be of monumental importance in terms of developing tumor-specific therapeutic strategies, and a cytotoxic agent specific for one cell type would greatly aid in identifying the appropriate subcellular target. Thus, agents that demonstrate the desired selectivity are anticipated to serve as important tools for probing tumor-specific receptor sites, and this is an entirely rational approach toward defining tumor-specific targets for chemotherapeutic agents. Based on these considerations, there is substantial merit associated with an approach that relies on selective cytotoxicity. Paradoxically, however, all of the well-known natural product antitumor agents that are currently utilized in clinical settings do not demonstrate selective cytotoxicity (2). Rather, it is typical to observe a general cytotoxic response with absolutely no cell-type specificity. Since it is not practical to assign a high priority to a plant extract based solely on non-specific cytotoxic activity, it is necessary to devise a broader-based bioassaydirected drug discovery program. At the present time we are engaged in a National Collaborative Natural Product Drug Discovery Group (7) involving the partnership of Research Triangle Institute and Bristol-Myers Squibb [during the first five years of the program (1990-1995), the industrial partner was Glaxo Group Research]. As with all cooperative agreements of this type, the National Cancer Institute is also a member of the consortium. Also, at the University of Illinois, cytotoxicity assays are

511 conducted (8) similar to those performed at the National Cancer Institute, although on a greatly reduced scale. Additional assays are performed to evaluate antimitotic potential with cultured ASK cells (9) and to assess ability to reverse the multidrug-resistant phenotype with KB-VI cells (10). At the other research facilities involved in the consortium, extracts derived from the same plants are evaluated in mechanism-based assays. The accumulated data are then evaluated in order to decide which materials should be subjected to fractionation procedures. In an ideal case, a plant extract would demonstrate activity in a mechanism-based assay and a limited number of cell lines. This type of activity profile leads to a high priority for fractionation. Alternatively, either type of activity (only mechanism-based or limited cytotoxicity) yields a high priority rating. General cytotoxicity alerts us to the fact that active principles are present in the plant extract which may or may not be of interest. In general, such an extract would be placed on hold due to lack of correlative activity, but these may be re-evaluated as additional knowledge is accumulated and mechanism-based assays are modified. Thus, cytotoxicity-based assays are useful for grouping plant materials into two broad categories (active or inactive); at some point in time, additional information may be accumulated to re-activate such leads. This is considered a more judicious procedure than ranking potentially useful materials as "false negatives" which is an unavoidable consequence of utilizing a highly discriminatory screen. 3.3 Summary of Isolates Obtained from Terrestrial Plants Reviews have been published summarizing lists of cytotoxic compounds that have been isolated from terrestrial plants using cell culture for bioassay-directed fractionation (11-13). In nearly every case, no obvious or meaningful cell-type specificity could be achieved. One notable exception is betulinic acid, originally noted in an extract derived from Ziziphus mauritiana, but readily available from other sources such as the bark of white birch trees (14). This compound mediates semi-selective cytotoxic responses with cultured melanoma cells, and inhibits the growth of human melanomas carried in athymic mice. The mode of action appears to involve induction of apoptosis (14). This agent is currently undergoing preclinical development. It is being considered for use in both chemotherapeutic and preventative settings. 4. IN VITRO MODELS FOR THE DISCOVERY OF CANCER CHEMOPREVENTIVE AGENTS 4.1 Strategies of Cancer Prevention As described above, morbidity and mortality resulting from cancer is dismal, and it is imperative that the search for new chemotherapeutic agents continue at an incessant pace. At the same time, prevention strategies must be developed and implemented on a grand scale. Some examples of cancer prevention are obvious. For example, 800,000 cases of skin cancer

512 are expected to be diagnosed this year, 90% of which could be prevented by limiting exposure to the sun. Smoking of cigarettes, a highly addictive habit that can be terminated with due diligence, probably leads to over 170,000 deaths per year in the United States alone (3). Thus, primary prevention, in conjunction with early diagnosis, could lead to massive reductions in cancer cases. Irrespective of the success of such programs, the number of cancer cases will remain significant. For example, certain individuals may be at a high risk of developing specific types of cancer, and this risk may not be negated by changes in diet or other elements of lifestyle. In these cases in particular, the concept of cancer chemoprevention is applicable. Cancer chemoprevention, as a discipline of pharmaceutical-based therapy, remains in its infancy. A number of intervention trials are presently ongoing (15,16), but no chemopreventive formulation is currently available or consumed by the general population, other then fruits, vegetables, and agents such as aspirin. Our focus has been the discovery of natural product cancer chemopreventive agents utilizing bioassay-directed fractionation as the primary approach (17-19). In vitro test systems have been devised to monitor alteration of the initiation, promotion and progression stages of carcinogenesis. Once active leads are identified, they are evaluated for potential to inhibit 7,12dimethylbenz(a)anthracene (DMBA)-induced preneoplastic lesions with a mouse mammary gland organ culture model. This secondary discrimination is used to select extracts for fractionation, utilizing the in vitro test system in which activity was originally observed as a monitor. A brief description of this approach is given below. 4.2 Test Systems Indicative of Inhibiting the Initiation of Carcinogenesis Antimutagenicity. A large number of plant materials are known to mediate antimutagenic effects (20). Clearly, however, most compounds isolated solely on the basis of an antimutagenic response observed with an in vitro test system, could not demonstrate chemopreventive activity. Since the process of antimutagenicity is much less complex than cancer chemoprevention, the basis for this lack of correlation is quite obvious. However, with reasonable certainty, we have shown that inhibition of DMBA-induced mutagenicity with Salmonella typhimurium strain TM677 correlates with inhibition of DMBA-induced preneoplastic lesion formation in mammary organ culture (21,22). This does not imply that a majority of antimutagens will demonstrate such activity, but it is reasonable to suggest that many compounds capable of inhibiting lesion formation will also demonstrate antimutagenicity in this test system. Therefore, it is reasonable to conduct bioassay-directed fractionation using antimutagenicity as a monitor with plant extracts that have been shown to be active in the mammary organ culture test system. Induction ofquinone reductase with cultured Hepa lclc7 cells. A second assay we utilize

513 that yields results indicative of cancer chemoprevention at the stage of initiation is the induction of quinone reductase in cultured Hepa IclcV cells. This system has been used by Talalay and coworkers for the isolation of sulforaphane from broccoli (23), and it was established as a useful system for evaluation of extracts (24). Like other in vitro assay systems used in our laboratory, induction of quinone reductase in cell culture correlates with in vivo activity that is consistent with cancer chemoprevention. While it is not generally clear that induction of phase I enzymes would result in chemoprevention since carcinogen activation is also possible, induction of phase II enzymes is more logically associated with protection. As an initial attempt to establish selectivity for induction of phase II enzymes rather than dual induction of both phase I and II enzymes, BP'cl and TAOclBP'cl cells are used in our laboratory. BP'cl cells have normal TCDD receptor but appear to be unable to translocate the bound receptor complex to the nucleus. On the other hand, TAOclBP^cl cells contain TCDD receptor that is either of reduced or altered affinity, but translocation to the nucleus is possible (25,26). Therefore, induction of quinone reductase in the Hepa lclc7 cell line, but not in the BP'cl or TAOclBP'cl cell lines, implies a receptor-mediated mechanism associated with induction of phase I and II enzymes. Conversely, activity in all three cell lines implies selectivity, and this is the major objective in our drug discovery program. A second component of selectivity concerns toxicity. Most test materials capable of enzyme induction can also induce a cytotoxic response. This leads to the concept of a chemopreventive index (CI), in this case defined as the concentration of compound that reduced cell growth by 50% (IC50), divided by the concentration of compound required to increase enzyme activity by 2-fold (CD). In the case of sulforaphane, evaluation with cultured Hepa lclc7 cells leads to a CI of 9.9 ^M/0.23 juM = 42 (27). The greater the CI value, the stronger the indication of selectivity. 4.3 Test Systems Indicative of Inhibiting the Promotion of Carcinogenesis Ornithine decarboxylase. One well-established consequence of tumor promoter action is the induction of ornithine decarboxylase activity. Interestingly, known chemopreventive agents such as retinoids are established as inhibitors of tumor promoter-induced ornithine decarboxylase activity, and this may relate to mechanism of action. For monitoring this activity, we have routinely employed cultured mouse 308 cells. Cells are treated with 12-0-tetradecanoylphorbol13-acetate (TPA), which induces ornithine decarboxylase. This is assessed by monitoring the generation of ^'^C02 from radio-labeled substrate, and the potential of test substances to inhibit enzyme induction is monitored. Again, to assess specificity, a chemopreventive index (CI) can be determined. Deguelin, for example, yields a favorable CI value of 0.64 ^g/ml (IC5o)/0.0003 /xg/ml (EC50) = 2133 (28).

514 Arachidonic acid metabolism. A good deal of evidence suggests that certain oxidants can play a critical role in the promotion of carcinogenesis (29). Included in this category of tumor promoters are UV light and chemicals such as hydrogen peroxide, peroxyacetic acid, chlorobenzoic acid, benzoylperoxide, decanoylperoxide, cumene-hydroperoxide, /7-nitroperbenzoic acid, and lO*'. One effect of these tumor promoters is the activation of phospholipase A2 which catalyzes the production of arachidonic acid. In turn, arachidonic acid serves as a substrate for cyclooxygenase which catalyzes the production of prostaglandins, thromboxane and prostacyclin. The precise role of these substances in tumor promotion is not clear, but a correlation of elevated prostaglandins in carcinogenesis has been established (30) and certain nonsteroidal anti-inflammatory agents (e.g., indomethacin and piroxicam) demonstrate chemopreventive activity (31). An assay for inhibition of cyclooxygenase is also sensible from a mechanistic viewpoint since inhibition of TPA-induced ODC activity by indomethacin is overcome by concurrent application of PGE2 (32). Accordingly, we have evaluated plant extracts for potential to inhibit cyclooxygenase (33). One of the most promising agents we have identified as an inhibitor of cyclooxygenase is resveratrol (34). In addition to blocking the cyclooxygenase activity of the enzyme, the A related effect of hydroperoxidase activity is inhibited (34). The agent shows promising activities and is currently under investigation for development as a chemopreventive agent. contemporary interest is the inhibition of cyclooxygenase-2, a form of the enzyme that is induced during the process of tumor promotion. Accordingly, one can search for specific inhibitors of cyclooxygenase-2, versus cyclooxygenase-1, and a more favorable profile of activity would be anticipated. 4.4 Test Systems Indicative of Inhibiting the Progression of Carcinogenesis Differentiation of HL-60 cells. Terminal differentiation can be induced in HL-60 cells by treatment with a variety of clinically interesting agents such as lof,25-dihydroxyvitamin D3 [la,25-(OH)2D3] (or analogs thereof), DMSO, actinomycin D, retinoic acid, etc. (35). Treatment of HL-60 cells with such agents results in the induction of granulocytes, monocytes, eosinophils, or macrophage-like cells, and in certain cases, this induction process is mediated without toxicity. One obvious clinical implication of agents found to be active in this test system is the treatment of leukemia since terminal monocytic differentiation suggests a mechanism of controlling the proliferation of progenitor cells. However, as judged by 1QJ,25-(OH)2D3, one of the most potent compounds known to mediate HL-60 cell differentiation, agents found to be active in this test system should be of interest for the control of other cancer types, in particular, cancer of the breast (36-38). We have established this assay and routinely evaluate extracts and compounds for potential

515 to induce nonspecific esterase (indicative of monocytes and macrophage-like cells), esterase (monocytes and other cell-types), and ability to produce superoxide when challenged with phorbol ester as judged by nitroblue tetrazolium (NBT) reduction (indicative of monocytes and granulocytes) (39). The potential to inhibit thymidine incorporation is also monitored to assess specificity and antiproliferative activity. In addition, similar to other assays in our panel, a chemopreventive index can be generated to assess specificity. This value is obtained by dividing the IC50 (concentration to reduce viable cell number by 50%) by the ED50 (concentration required to induce terminal differentiation by 50%). Using la,25-(OH)2D3 as a positive control, a CI value of > 1000 is obtained. Assays designed for the discovery of antihormones. Although many aspects of this overall program are directed toward chemoprevention of breast cancer, no component thus far described takes into account a strategy to exploit the hormone-dependence of this disease or certain other human cancers (e.g., cervical, ovarian). Thus, we have added components to focus on this class of chemopreventive agents. The first assay we employed simply detects displacement of estrogen binding to the estrogen receptor. One shortcoming of this procedure, as with all receptor binding assay methods, is that compounds capable of displacing estrogen may demonstrate either antagonistic (antiestrogenic) or agonistic (estrogenic) activity. Thus, more recently, we have utilized cultured Ishikawa cells for accessing estrogenic and anti-estrogenic effects. Treatment of this cell line with estrogen or estrogenic compounds has been shown to result in significant elevation of alkaline phosphatase that can be monitored easily with a chromogenic substrate using a 96-well plate format (40-42). Further, the response induced by adding known estrogens is effectively blocked by the addition of antiestrogens to the medium. Thus, the assay is suitable for large-scale assessment of either agonistic or antagonistic activity. In a typical assay, tamoxifen is used as a positive control, and this yields an antiestrogenic response with an IC50 of about 0.324 jitg/ml (575nM). In addition, as with other cell lines, cytotoxicity can be assessed to establish specificity. In general, follow-up work is performed in which competitive binding is assessed with the anti-estrogen (tamoxifen) binding site (43). 4.5 Correlative Approach Utilizing Mouse Mammary Organ Culture The assays described above are listed due to their capacity to suggest specificity. material. The chemopreventive index (CI) provides a good indication of having identified a promising starting Some additional procedures are performed in our laboratory such as antioxidant assays, or assays to identify inhibitors of aromatase. In these types of assays, it is difficult to assess specificity at an early stage. In either case, however, once a promising lead is identified with an in vitro test system, it is then evaluated in the mouse mammary organ culture model. This system is not suitable for bioassay-directed fractionation due to time and expense (17), but

516 resulting data tend to show a good correlation with full-term chemopreventive studies designed to monitor inhibition of mammary tumorigenesis (44). With our in vitro tests, approximately 6700 evaluations have been performed with plant extracts, and about 230 have proven active (i.e., 3.5%). Of these 230, about 160 have been assessed in the mouse mammary organ culture system, and approximately 35 of these leads have proven active. Accordingly, these 35 extracts represent our most promising leads, and activity-guided fractionation is being performed utilizing the in vitro test system as a monitor of activity. 4.6 Summary of Assay Results Following this experimental design, approximately 700 plant materials have been evaluated and this has resulted in over 6,500 bioassay results. A number of active principles have been obtained that are active with the in vitro test systems, and several of the isolates have retained activity by preventing formation of preneoplastic lesions in mammary organ culture. Thus far, three lead compounds have been shown to mediate considerable cancer chemopreventive activity in full-term tumorigenesis models (28,34,45,46) and are being studied in more advanced test systems. We remain hopeful that one or more discoveries resulting from this project will be deemed worthy of human intervention trials. 5. MODEL SYSTEMS FOR THE DISCOVERY AND EVALUATION OF POTENTIAL ANTI-MALARIAL AGENTS 5.1 Overview of the Malaria Problem Malaria remains an enormous burden to global health. The 1995 World Health Report (47) indicates that the disease is endemic in more than 90 countries which comprise 40% of the world's population. The incidence of malaria has been steadily increasing to a current annual estimate of 300-500 million clinical cases; 1.5-2.7 million of these result in death with the vast majority of lethalities due to infection with Plasmodium falciparum. The reasons for resurgence of malaria are numerous and complex, but a primary factor is the spread of resistance to currently available antimalarial drugs. The discovery and development of selective new agents for therapy and propylaxis is, therefore, of paramount importance. Malaria is caused by protozoan parasites of the genus Plasmodium, four species of which infect humans. (P. falciparum, P. vivax, P. malariae, and P. ovale) (48,49). The disease is initiated when infective sporozoites are injected into the human host during feeding by an infected mosquito. The sporozoites enter parenchymal cells of the liver within minutes where they multiply asexually into merozoites. After development for 6-16 days, depending on the species, merozoites are released from the hepatic cells into the peripheral blood where they quickly bind to and invade erythrocytes. This initiates the cycle of erythrocytic schizogony in

517 which the merozoites proliferate asexually, and upon reaching maturity after 36-72 hours (again a species-dependent process), the host red cell bursts and the liberated merozoites invade other erythrocytes to continue the cycle. Some merozoites of the intraerythrocytic stage differentiate into gametocytes which may be reingested by a mosquito wherein sexual reproduction and sporogony occur. New infective sporozoites are produced thus completing the life cycle. The hepatic stage of the infection is not generally associated with clinical symptoms; thus, the disease is recognized during the erythrocytic phase when the synchronized rupture of infected red blood cells and release of merozoites produces the characteristic paroxysms of chills and fever. This self-perpetuating phase of malaria can continue for weeks to months if unchecked by appropriate drug therapy, with attendant anemia and splenomegaly. Renal involvement or nephrotic syndrome can be severe, especially in infections caused by P. malariae. The most grave consequence of the disease is hypoxia, caused by the propensity of P. falciparum parasites to adhere to the endothelial lining of blood vessels and capillaries, limiting blood flow to many tissues and organs, most noticeably to the brain. 5.2 Current Status of Treatment Many different drugs are presently used for the treatment and prophylaxis of malaria around the world, but none is truly satisfactory in terms of safety and efficacy. Furthermore, resistance of particular strains of P. falciparum has been noted for most of these drugs and is a significant impediment to the practical use of many. It would be remiss if not impossible to discuss the status of antimalarial drug therapy without referring to natural products. Since the disease we call malaria has been recognized for millennia, a great number of plant species have been identified by various cultures as having antimalarial properties. While it is surely not possible to substantiate all of these claims in terms of modem therapeutic efficacy, it is certain that current antimalarial therapy consists substantially of natural products and related derivatives. Quinoline compounds and the plants that contain them have historically anchored the antimalarial arsenal, and they remain principal drugs today. Quinine and its diastereomer, quinidine, are quinoline alkaloids which were isolated in 1820 from the bark of the Cinchona tree, by virtue of the traditional South American use of this bark to treat intermittent fevers. Quinine is an effective schizonticide (i.e., it kills the form of the parasite in peripheral blood), but because it also affects mammalian lysosomes, the drug has been associated with significant adverse toxicity (48,50). The development of synthetic derivatives of quinine has resulted in improvement in potency and selectivity over the parent compound. Chloroquine and mefloquine are more potent and less toxic than quinine (49,51), thus, chloroquine had largely replaced quinine in clinical use; however, resistance of P. falciparum to chloroquine has been reported

518 from nearly every region in which the species is endemic (the exception being Central America), so that it is no longer a first-line drug in many regions of the world. Mefloquine is a secondgeneration quinoline derivative that is effective against chloroquine-resistant parasites, although mefloquine-resistance is rapidly increasing in regions of Southeast Asia (52,54). Despite their extensive record of traditional and modem usage, the potential mechanisms of action of the quinoline compounds remain obscure. These drugs have been established to accumulate in acidic compartments of mammalian cells and malarial parasites by virtue of their weak base properties (55). Furthermore, the enhanced selectivity of chloroquine and mefloquine has been attributed to the observation that they are actively concentrated in parasitic vesicles to levels 100 times higher than in mammalian lysosomes (56). It has been suggested that the schizonticidal effects of these drugs derive from the resulting alkalinization of acidic organelles such as lysosomes and food vacuoles. The compartmental increase in pH could conceivably inhibit enzymes with low pKa values (57), and could disrupt receptor-mediated endocytosis or other targets critical for the survival of the plasmodial trophozoite. However, alkalinization alone does not explain the mechanism of action of quinoline antimalarials (58). Another potential mechanism of action of quinoline-containing antimalarials involves ferroprotoporphyrin IX or 'haem' which is a byproduct of hemoglobin digestion by the developing parasite. Free haem is toxic to malarial parasites, thus most of the haem in an infected erythrocyte is found as haemozoin, a polymer in which ferroprotoporphyrin IX monomers are cross-linked via ferric iron-carboxylate bonds (59). Several groups investigating haemozoin formation first reported the process to be actively catalyzed by a parasite-specific enzyme known as haem polymerase (60,61), and reported that chloroquine and to some extent, other antimalarial drugs, could specifically inhibit this enzyme. More recent evidence, however, appears to indicate that haemozoin can form spontaneously from haem, and that this is the most likely explanation for its occurrence in Plasmodium-infQctod red blood cells (62,63). Intensive work in this area has revealed that the role of haem as an agent of plasmodial toxicity is a good deal more complex than initially suspected, and that inhibition of haemozoin formation may not alone constitute a viable antimalarial mechanism. The current status of haemozoin as a potential target for antimalarial agents has recently been reviewed (63). Additional attempts to define the mechanism of chloroquine have focused on specific interactions of the drug with binding proteins and DNA (64,65). Artemisinin (qinghaosu) provides a more recent example of a plant-derived antimalarial agent. Based on the reputed antimalarial use of Artemisia annua in the Chinese system of traditional medicine, artemisinin was isolated from the plant as the active compound, developed as a drug, and released for clinical use as a blood schizonticide (66-68). Artemisinin is a

519 sesquiterpene lactone possessing an interesting 1,2,4-trioxane ring system. The mode of action of this compound is under active investigation, and it has been demonstrated that the endoperoxide moiety is essential for antimalarial activity and that damage to parasitic membranes is a hallmark of the drug's action (69,70). The dependence of activity upon the presence of the endoperoxide suggested that free-radical generation played a role in the antimalarial mechanism of action. That this is indeed the case has been confirmed by a number of independent research groups through experimental evidence such as antagonism of activity by free-radical scavenging antioxidants (71). What is more unique to its mode of action is that, instead of exerting a toxic effect by initiating the chain reaction of oxidative damage through superoxide and hydroxyl radicals as is usually associated with free-radical generators, artemisinin itself becomes a carboncentered free-radical in a haem iron-dependent reaction (72). So activated, the artemisinin molecule has been found to alkylate a specific group of plasmodial proteins which may account for its lethality to the parasite. While this compound is effective against chloroquine-resistant P. falciparum in man, poor solubility has precluded its routine use, thus efforts have been directed at semi-synthesis of derivatives with improved solubility in lipid (artemether, arteether) or in water (artesunate, artelinate). Notwithstanding, there are still considerable problems with the routine, practical use of presently available artemisinin drugs. The short half-life of the drugs has resulted in a high clinical rate of recrudescence (i.e., reestablishment of infection by residual viable parasites which have managed to evade treatment) so that they are increasingly recommended to be used in combination with other agents having slower, more sustained antimalarial effects. In addition, evidence of significant neurotoxicity has recently been reported in cultured neural cell lines as well as in beagles and rats given high doses of the artemisinin derivatives, artemether and arteether (73,74). The synthesis of a wide varitey of secondgeneration endoperoxides which retain the endoperoxide function within a six-membered ring has demonstrated that the remainder of the artemisinin molecule is not essential for antimalarial activity (75). It is, however, likely that the chemical structure surrounding the peroxide will affect interaction of the compound with the specific cellular site(s) of action; thus, it may be possible to synthesize drugs with designed alterations of potency and selectivity that retain antimalarial activity but have less potential for toxicity or associated recrudescence. Halofantrine, a synthetic phenanthrene-methanol, is a recently introduced antimalarial drug which is a blood schizonticide. The drug is effective against chloroquine-resistant P. falciparum but has been associated with cardiotoxicity, so it must be used with caution (76). Another class of drugs that has proven clinically valuable against malaria are the antifolates. Sulfonamides such as pyridoxine and sulfones like dapsone inhibit the plasmodial enzyme dihydropteroate synthetase on the pathway of folic acid biosynthesis (48). The 2,4-

520 diaminopyrimidine, pyrimethamine, and the biguanide compound, proguanil, are selective inhibitors of plasmodial dihydrofolate reductase, a subsequent enzyme on the folate pathway. All of these compounds hinder the parasite's ability to synthesize purines and pyrimidines, thus they are slow-acting but effective schizonticides against P. falciparum. Pyrimethamine, and to a greater extent, proguanil, also possess activity against primary hepatic forms of malaria. Antifolate combinations are often used in the treatment and prophylaxis of chloroquine-resistant malaria, but adverse reactions may contraindicate their use (77,78). Furthermore, resistance of Plasmodium to many sulfa drugs is widespread (79). Tetracycline antibiotics such as doxycycline are also slow-acting schizonticides which have proven to be useful in prophylaxis of malaria and in treatment as one component of combination chemotherapy (80). A better understanding of the mechanism(s) of drug action represents an important element of the rational development of new antimalarial agents. Moreover, if a specific antiplasmodial mechanism of action can be established, the potential toxicity to host cells may be more readily predicted. However, as can be appreciated from the foregoing discussion, progress in this area of research has been relatively slow and the precise mechanisms of most of the potent antimalarials remain to be characterized. Since, clinical experience has demonstrated that the currently available drugs outlined above can be effective under the proper circumstances in given geographical regions, potential antimalarial mechanisms such as weak base-mediated disruption of parasite metabolism, oxidative stress, inhibition of haemozoin formation, antifolate activity and inhibition of protein synthesis must all be considered viable. Certainly such a short list can't begin to exhaust the possibilities for selective antiplasmodial targets, and it is likely that a number of distinct mechanisms could contribute to the antimalarial efficacy of a single drug. For this reason, our strategy for new drug discovery from natural products is grounded on a relatively broad initial requirement that test substances simply inhibit overall proliferation of intracellular parasites, and the search is subsequently refined through an additional experimental component to establish selectivity. A variety of factors have contributed to the resurgence of malaria, and continue to foster the disease (47). These include socioeconomic and political problems, as well as inadequacies in public health care. Two principal causes of malarial resurgence were: (i) the emergence of insecticide-resistant strains of the anopheline mosquitos which are the vectors for transmission of the disease, and (ii) drug-resistant strains of the parasite responsible for the pathology of the most lethal form of the disease, Plasmodium falciparum. Due to the latter, P. falciparum strains which are resistant to the antimalarial effect of chloroquine are spread throughout most of the areas where the disease is endemic, and resistance to more recently introduced antimalarial

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agents is rapidly emerging. Since an effective human vaccine has been elusive despite intensive efforts in this area, new and more efficacious antimalarial agents are clearly needed as drug therapy will certainly remain a major component of comprehensive programs to limit the morbidity and mortality caused by malaria in all regions of the world. 5.3 Natural Products as a Resource for Antimalarial Agents A 1991 report of the Committee for the Study on Malaria Prevention and Control in the Institute of Medicine, National Academy of Sciences (81) recommended "increased emphasis on screening compounds to identify new classes of potential antimalarial drugs, identifying and characterizing vulnerable targets within the parasite, understanding the mechanisms of drug resistance, and identifying and developing agents that can restore the therapeutic efficacy of currently available drugs." Furthermore, the Committee endorsed "a systematic method for identifying plants of interest, screening them, and characterizing the structures or compounds responsible for their antimalarial activity" as a focus for botanical investigation in this field. Such strategies form the basis for our research program for the discovery of selective antiplasmodial agents from natural products. With over 250,000 species, the plant kingdom contains biodiversity which reflects known and novel compounds with potential therapeutic activity (2,82,83). Furthermore, the World Health Organization has estimated that 80% of people in developing countries are dependent upon plant-centered traditional medicines for their primary health care (84). The examples of quinine and artemisinin cited above illustrate the proven utility of compounds from plants in the treatment of malaria. Moreover, it is likely that additional plant-derived antimalarial drugs await discovery since the literature indicates that in vivo or in vitro antimalarial activities have been identified in a broad and varied spectrum of botanical families (85-92). Crude extracts of the root bark from Celastrus paniculatus Willd. (Celastraceae) demonstrated significant activity against cultured P. falciparum (93), and the active principle was shown to be pristimerin, a quinonoid triterpene. The family Simaroubaceae has also yielded a number of compounds with in vivo and in vitro antimalarial activity (94-96) including quassinoids. Bruceantin has been most extensively studied, but is very cytotoxic; however, other quassinoids are relatively less toxic to cultured KB cells while retaining potent antimalarial activity (88). Plants from the Meliaceae are commonly used as febrifuges in Africa, and several limonoids from this family, such as nimbolide and gedunin, have also been found to produce moderate inhibition of cultured P. falciparum (97,98). There are many additional examples of plant-derived antimalarial agents, most of which are alkaloids. Several acridine alkaloids obtained from members of the family Rutaceae exhibited strong activity against cultured P. yoelii (99), and protoberberine alkaloids (which are widely

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distributed across several plant families) have been shown to inhibit cultured P. falciparum (100). However, these compounds did not demonstrate in vivo activity against P. berghei. The quinazolone alkaloid, febrifugine, was found to be the antimalarial component of Dichroa febrijuga (Saxifragaceae), a plant used in traditional Chinese medicine (101), although its clinical use was precluded by hepatotoxicity. Recently, crude ethanol leaf extracts of Ficus pyrifolia (Moraceae) and of Rhus (= Baronia) taratana (Anacardiaceae), reputed antimalarial plants in Madagascar, have demonstrated substantial inhibition of cultured P. falciparum and of P. berghei in mice. Both extracts exhibited relatively low cytotoxicity towards cultured HeLa cells (89). In our laboratory, a number of potent and selective antimalarial bisbenzylisoquinolines have been isolated from many plants of the Menispermaceae and Berberidaceae, including Cyclea barbata (102), Stephania erecta and S. pierrei (103), Cyclea atjehensis and Hemandia peltata (104), and Nectandra salicifolia (105). Marine natural products are even more poorly characterized than terrestrial plants but are no less diverse. Chemical compounds with unique and significant biological activities are being discovered with increasing frequency as this immense resource is explored. Since many of these compounds are reported to possess antiprotozoal activities, (106-108) the marine environment may be reasonably expected to yield potential antimalarial agents. The range of taxonomic families which have demonstrated antimalarial effects in experimental systems suggests that many diverse natural products can inhibit the growth of the malarial parasite. The key to the discovery and development of clinically useful antimalarial drugs would appear to lie in our capacity to probe these resources and to identify the most potent and selective specimens. 5.4 Approaches to In Vitro Antimalarial Testing Faced with so much information concerning the potential occurrence of antimalarial principles in natural products, it is imperative that the drug discovery process accommodate high sample throughput while retaining the ability to distinguish the most promising active compounds. The test system must have the capacity to screen a diverse array of samples which act through any number of conceivable antimalarial mechanisms, and should then identify those which may exhibit specific inhibition of parasite growth without substantial toxicity toward host cells. This is achieved in practice by combining the use of a primary antimalarial assay with a secondary assay for general cytotoxicity (109). The primary assay is expected to expose any and all active test substances without regard to selectivity, so as to minimize the risk of omitting potentially effective agents. As a consequence, the *hits' in this assay will include false positives, i.e., substances which inhibit the growth of Plasmodium parasites and mammalian cells to the

523 same degree. In our experience, the major sources of false positives are general cytotoxins which inhibit the growth of many cell types non-selectively; these compounds are readily revealed as non-selective by the addition of an additional assay. This secondary assay should serve to detect additional bioactivities in those test substances which demonstrated antimalarial potential in the primary screen for the purpose of characterizing active compounds with respect to safety and antimalarial specificity. One strategy may be to test for a second activity that is thought to be necessary or complementary to that detected in the first assay, in which case samples are selected for further study only if they demonstrate activity in both assays. Conversely, the secondary activity may be an undesirable attribute of a putative antimalarial agent wherein a positive result would effectively exclude a test sample from further consideration. The antimalarial and cytotoxicity assays described below reflect the second strategy; however, either of these approaches could conceivably be applied to achieve the end result of enriching the test pool for the most promising samples. Primary assay. The primary assay is comprehensive with regard to its capacity to detect potential antimalarial activity, since there is no intent to exclude any antiplasmodial compounds at this stage, regardless of mechanism of action. This bioassay relies upon in vitro methodology for the culture of P. falciparum within human erythrocytes (110) and is widely used for investigation of potential antimalarial compounds. The method evaluates the ability of test substances to inhibit parasite proliferation by measuring the incorporation of a radiolabeled purine into plasmodial DNA (111). The protocol entails the addition of a cell suspension containing intraerythrocytic P. falciparum to a 96-well microtiter plate containing serial dilutions of the extract or compound(s) to be tested (103). The plates are then incubated at 37C under an atmosphere of 5% O2, 5% CO2, and 90% Njfor 24 hours. Following the addition of 25JLI1 (0.5 ^lCi) pH]hypoxanthine to each well, the plates are incubated for an additional 18 hour period during which time parasites that survived the initial treatment will incorporate the radioisotope into nucleic acids. The assay is terminated by aspirating the contents of each well onto glass fiber filters and washing thoroughly, whereupon the incorporated radioactivity is determined in a scintillation counter. Finally, IC50 values (the concentration of test substance which inhibits [^H]hypoxanthine incorporation by 50%) are determined for each test substance using non-linear regression analysis. Secondary assays. All test samples which demonstrate activity in the primary assay described above are submitted to a secondary cytotoxicity assay. A standard protocol for the quantitation of cellular toxicity measures the ability of cultured cells to proliferate in the

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presence of a test extract or pure compound (112). In this case, KB cells (human oral epidermoid carcinoma) are utilized and are added to wells of a microtiter plate (10^ cells/well) containing various concentrations of the test compound(s). After a three day incubation period, the percentage of cells surviving the treatment is determined by measuring total protein with sulforhodamine B dye (113). The rationale for employing the [^H]-hypoxanthine incorporation assay as a primary screen is based on several lines of reasoning. First, it is possible to envision a multitude of mechanisms by which plasmodial growth could be inhibited; it's equally apparent that any or all of these mechanisms might be found in nature. Accordingly, the detection of a highly relevant but not highly specific biological activity (i.e., general inhibition of growth) is an inclusive approach to the discovery of novel and effective agents. Second, the requirement for development and proliferation of Plasmodium within human red blood cells reflects the conditions of a clinical malarial infection; moreover, this stage of infection coincides with the major pathology of the disease, and is also the stage most amenable to therapeutic intervention. Third, in vitro bioassay enables the use of cloned, human isolates oi P. falciparum, the species which is without question the most important agent of human malarial disease. Routine in vivo antimalarial testing has customarily relied upon the P. berghei-infectod mouse model, because stringent species specificity implies that only humans and a few simian species are viable hosts for infection with P. falciparum or the other human malarial parasites. Thus, an in vitro assay system circumvents this species restriction and also obviates the practical and ethical issues associated with largescale animal testing. The assessment of general cytotoxicity as a secondary assay is intended to facilitate the discrimination between general toxins and those samples which may exert more selective inhibition of Plasmodium. Practically, this has been accomplished through the experimental generation of a "selectivity index". Designating the IC50 value for cytotoxicity toward KB cells as one parameter, this selectivity index has been defined (109) as: IC 50 (KB) = Selectivity Index (SI) IC 50 (P. falciparum) This number is an estimation of selective inhibition of P. falciparum by a test compound or extract. The SI value affords a qualitative measure of activity which may be compared empirically to those of known antimalarial drugs. The parameter is used to prioritize active test samples and to guide bioassay-directed fractionation with the aim of isolating the most promising antiplasmodial compounds. Selectivity indices have also been employed in the analysis of structure-activity relationships among a group of closely related compounds in an attempt to

525 determine those characteristics which confer specific activity (104). 5.5 Results of Screening for Antiplasmodial Agents The two bioassays described above have been used in tandem to screen extracts, impure fractions and pure compounds, natural and synthetic, for antiplasmodial potential. This system has directed the isolation of many new compounds with potent and selective antiplasmodial activity, and has also enabled the demonstration of such activity for the first time in many other compounds whose structures were previously known. Two divergent groups of natural compounds will serve to illustrate the practical application of this screening system. Plants which contain bisbenzylisoquinoline alkaloids have been used traditionally in many different cultures for a variety of illnesses, including malaria. After detecting antiplasmodial activity in this class of compounds to substantiate the ethnomedical evidence, we have pursued the isolation and biological testing of several dozen of these compounds, employing the screening system described above (102-105,109,114-116). Despite closely related structural skeleta, it is interesting to note that these compounds differ widely in their biological activities. Structureactivity relationships have been difficult to assign based on functional groups and on number and location of bridges which join the benzylisoquinoline monomers. Consequently, application of the selectivity index has proven to be a valuable means of differentiating the generally-toxic compounds in the series from those with more selective action. In this case, isolates which exhibit selectivity indices of 100 or greater are considered to be better lead compounds than those with relatively lower preference for inhibition of Plasmodium. Another chemical class which has been studied extensively in this screening system is that of isonitrile-containing marine compounds, the antimalarial potential of this group was first reported in 1992 (117) after several sesquiterpene isonitriles were isolated from the marine sponge, Acanthella klethra, guided by conjunction of the antiplasmodial and cytotoxicity bioassays. Subsequent investigations have focussed on the isolation and structure elucidation of additional members of this class, and biological testing has confirmed the presence of potent and selective antiplasmodial activity in a number of new and known isonitrile-containing compounds (118-119). After preliminary disclosure of promising antimalarial leads, there is an ongoing requirement for the evaluation of selectivity in more advanced phases of the development process. By monitoring the effects of natural and chemical derivatization of lead compounds upon potency and selectivity in an in vitro bioassay system such as that described here, the safest and most effective candidates can be promoted for further study in in vivo models. Drug combinations are another conceivable means of influencing the potency and selectivity of antimalarial activity (48,120). Combinations which synergistically inhibit the growth of P,

526 falciparum may exhibit proportionally greater toxicity toward mammalian cells as well with no net increase in SI; however, this is not inherently the case. A prominent example is the combination of pyrimethamine and sulfadoxine in the drug, Fansidar. While not without mammalian toxicity, in concert, this pair is much more selective against Plasmodium since the parasite possesses both of these enzymes in the pathway of folate biosynthesis, while humans have only one. Many such interactions would be amenable to testing with the in vitro model, and bioassays have been described which evaluate the qualitative and quantitative effects of combining antimalarial drugs (121,122). 5.6 Practical Utility and Limitations of Selectivity Indices Under conditions of in vitro testing, compounds which inhibit the growth and survival of a variety of cell types can legitimately be called "antiplasmodial"; however, the meaning of the term is obscured due to the promiscuous nature of the toxicity. The inclusion of a selectivity parameter along with "antimalarial" data reported in the literature, is suggested here to facilitate a more qualitative evaluation of compounds with genuine potential as antimalarial lead compounds. In the SI parameter, we have attempted to establish a working model system to estimate the potential of a test compound for killing an intraerythrocytic malaria parasite without host toxicity. It is imperative that we draw a clear distinction between the concepts of "selectivity index" and "therapeutic index". The therapeutic index (TI) of a drug is defined as the median toxic dose/ median effective dose (LD50/ED50) in mammals, whereas we have defined the in vitro selectivity index as ED50 (i^ KB ceiis)/ED5o (j^ p. falciparum) (109). Since intact animals/patients are used in its determination, the TI value encompasses a much broader spectrum of toxic effects than would be detectable in our selectivity index; therefore, it is inappropriate for us to draw conclusions about clinical significance of the basis of SI values. Nonetheless, the SI values for several of the known antimalarial drugs have been determined (109), and based on the knowledge that these agents are clinically-relevant, the indices constitute a significant guideline for the prioritization of potential antimalarial agents. Intuitively, even the poorest selectivities of these drugs (i.e., SI >_ 300) appears to be quite good; however, it is important to point out that the range of SI values spans two orders of magnitude, and none of the drugs is without undesirable side effects. We have defined the antiplasmodial selectivity index of a test substance in terms of mammalian KB cells. These cells were selected by precedent (123) and also because, in our experience, this line exhibits an intermediate sensitivity to a large number of cytotoxic agents when compared to cell lines derived from a variety of other human tumors. At the present time, we are not certain if the selectivity index can be properly defined by utilizing cultured KB cells

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alone. It is possible that a specific cell line could be chosen to yield a more useful index, or that it is actually necessary to use a battery of cell lines and then evaluate the profile of activity. Evaluation of the antimalarial drug, artemisinin, provides a pertinent illustration of this. In late phase toxicity testing of artemisinin and several of its synthetic derivatives, significant neurotoxicity was noted when the drugs were administered to beagles. Cytotoxicity had not been revealed in vitro in KB cells, nor in any of a number of other mammalian cell lines which derived from a range of other tissues, including rat glial cells (124). However, when the compounds were tested with cultured neuronal cell lines, substantial cytotoxicity was observed, and these lines were further utilized to define some of the structural characteristics of the drugs which were associated with the specific neuronal toxicity (73). This example substantiates the potential of such in vitro models to contribute to the development of safer, more efficacious drugs. The SI value that is used as a 'cut-off parameter for prioritizing those samples that possess the most potent and selective antimalarial activity is somewhat subjective due to the nature of the work involved. In the preliminary stages of the work, a cutoff is established such that the volume of samples that are subjected to bioassay-directed fractionation and further analysis is limited to a practical number. Ideally, the SI cut-off should be as high as possible and in our laboratory it is presently around 100; however, we are limited by the activities of the samples at hand. It is also meaningful to consider that if the cut-off is set too high, many potentially important lead compounds may be discarded for the sake of pursuing the ideal drug. In addition, we have not intended that the selectivity index be the only criterion applied in the decision to subject pure compounds with significant antimalarial activity to further study. The discovery of compounds of novel structure possessing potent antimalarial activity but with relatively low (i.e., < 100) SI values, such may represent lead compounds which could be synthetically modified to yield drugs with higher selectivity, and may also provide valuable insight into potential mechanisms of antimalarial action or structure-activity relationships, and thus, such compounds may also be included in mechanistic studies to a limited extent. 6. MODEL SYSTEMS FOR THE DISCOVERY AND EVALUATION OF POTENTIAL ANTI-HEPATITIS B AGENTS 6.0 The Hepatitis B Virus Problem Hepatitis B virus (HBV) (125) belongs to hepadnavirus family of DNA-containing viruses that also include woodchuck hepatitis virus (126), ground squirrel hepatitis virus (127), duck hepatitis B virus (128), and heron hepatitis B virus (129). These viruses replicate primarily in the liver cells, and establish chronic infection in their respective hosts. In humans, primary

528 HBV infection and development of acute infection with transient liver dysfunction is characterized by hepatocellular injury and inflammation. Basically, there are two phases of infection: replicative and non-replicative or integrated stages. During the replicative stage, the patient actively produces HBV and hepatitis B surface antigen (HBsAg), HBV-DNA and HBVDNA polymerase is observed in serum; HBV-DNA and hepatitis B e antigen (HBeAg) are detectable in liver tissues (130). Patients typically have active hepatitis with elevated serum aminotransferases during this phase. Subsequently, the viral replicative markers (HBsAg, HBeAg, HBV-DNA and HBV-DNA polymerase) are not detectable, and anti-HBe appears in the serum, which is identified as the non-replicative or integrated stage that is frequently preceded by an increase in aminotransferase levels. During this stage, there is no viral replication, part of the hepatitis genome has become integrated into human DNA, and the patient remains HBsAg positive (131-134). Occasionally, a patient with chronic hepatitis B antigenemia may suffer a clinical relapse associated with symptomatology of acute viral hepatitis, including jaundice, tender hepatomegaly and elevations in serum aminotransferases. These features along with appearance of HBV-DNA, HBV-DNA polymerase and HBeAg, mark patients experiencing reactivation of HBV infection. Approximately 0.8% of chronic HBsAg carriers will relapse due to reactivation of HBV each year (135). The cause of spontaneous reactivation during the course of chronic HBV is unclear, although this has been reported in male homosexuals (136) and during withdrawal of cancer chemotherapy and immunosuppressive therapy (137). Much of the pathology of HBV infection arises from loss of immune response to the core antigen of the virus (HBcAg), which is expressed in infected liver cells. About 5-10% of individuals who are not able to resolve primary infection develop a persistent, usually life- long, chronic infection, with long-term liver disease which is clearly a major health problem. About 300 million individuals (nearly 5% of the earth's population) are chronically-infected with HBV, of which between 0.1-0.5 % (0.3-1.5 million) reside in the USA. It has been estimated that 25 % of these carriers will die of complications related to this disease, representing the ninth leading cause of death (138-140). People chronically-infected with HBV have a greatly increased risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) (141-155). 6.1 HBV Infection and Liver Cancer Hepatocellular carcinoma (HCC) is one of the major malignant diseases in the world. There is, however, striking geographical variations in its incidence throughout the world; it occurs commonly in sub-Saharan Africa, Southeast Asia, Japan, Greece and Italy (153-157) while in most western countries it is rare but alarming (155). There is a striking correlation between the incidence of HCC and the prevalence of the chronic HBV. Globally, HBV is probably the

529 etiologic agent that is responsible for 75-90% of these primary liver cancers (HCC) (153-155) which is responsible for over a million deaths annually (158). It is now well-accepted that chronic-infection with hepatitis B, C, or D is oncogenic and leads to the development of HCC (142, 153, 159-162). Early evidence for this claim was derived from a multitude of case control retrospective studies dealing with patients with HCC, and from compelling statistics derived from prospective studies of chronic HBV carriers. That infection of animals with their species-specific hepatitis B-like viruses is hepatocarcinogenic also supports this suggestion (163-166). Nonetheless, in spite of the abundance of evidence in support of the relationship between the HBV genome and tumor cell DNA, no clear mechanisms of transformation are available to explain the high incidence of HCC in patients or animals with chronic HBV. However, persistent infection, rather than acute infection, is a major risk factor. Thus, it is reasonable to anticipate that development of liver cancer may be prevented by treatments that cure the chronic infection. As a result, many investigators have attempted to define how HBV replicates itself and establishes a state of persistent virus production in most infected hepatocytes. A number of molecular mechanisms have been proposed, including: an acutely transforming viral oncogene; chromosomal aberrations due to HBV integration (i.e., deletions, translocations, duplication); activation of cellular proto-oncogenes; inactivation of cellular anti-oncogenes; and transactivation of cellular genes by HBV gene products (153). HCC usually develops only after 20-30 years of persistent HBV infection accompanied by hepatocyte necrosis, inflammation and regenerative hyperplasia. Since HBV is not directly cytopathic, liver injury must be immune-mediated. Factors that predispose HBV-infected individuals to develop HCC are chronicity, an immune response and liver injury rather than a direct genetic event. Hepatic injury and continuous hepatocyte regeneration may allow an accumulation of multiple mutational events sufficient for the emergence of HCC (167-169). 6.2 Prevention of HBV Infection The spectrum of diseases associated with HBV, including acute hepatitis, chronic hepatitis, cirrhosis and HCC, is preventable. Both active and passive immunization can protect against HBV infection. The HBV vaccine offers active immunization and is the recommended method of pre-exposure prophylaxis. Currently, plasma-derived and two recombinant yeast vaccines are available, and approximately 90% of healthy adults will develop anti-HBs after the three-dose regimen (170). Even if universal vaccination against HBV could be achieved (which would be very costly for developing countries), implementation would require several decades, and a large worldwide population of chronically HBV-infected individuals still would require medical care including an effective anti-HBV agent, which remains to be developed.

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6.3 Current Treatment for HBV Infections Alpha-interferon has emerged as the most effective agent for the treatment of chronic hepatitis B, but a positive response is obtained with only 30-40% of infected patients. However, recently developed inhibitors of HBV DNA synthesis, such as nucleoside analogs (171-174), have clearly demonstrated antiviral effects, with selective inhibition of active HBV replication. Unfortunately, the effect of treatment is usually transient, and significant toxicity has been encountered in longer treatment regimens (140, 175-180). Thus, interferon (181), when used alone or in combination with other strategies (ara-A or corticosteroid withdrawal), offers much promise, but the moderate to high doses required are associated with significant toxicity, the underlying mechanisms of antiviral action are not well-defined, the effects are often transient, and predictive markers of a beneficial response have not been established. During the past decade, a variety of additional anti-hepatitis B virus treatment regimens have been described (Table 1) (182), but efficacious therapy is still lacking.

TABLE 1: Proposed ideal anti-hepatitis B virus treatment regimen Property Anti-viral activity Function Inhibition of viral genomic replication and all intermediates. Inhibition of viral supercoiled HBV DNA generation and processing. Envelope antigen binding Immunomanipulation Chelation and removal of excessive HBsAg load. Activation of cytotoxic T lymphocytes and NK cells (eradication of infected hepatocytes). Activation of B lymphocytes (prevention of horizontal transmission). Hepatoprotective function Free-radical scavenger. Inhibition of collagen deposition. Additionally, it is recognized that HBV is not directly cytopathic, and immune mechanisms are important in both the persistence of, and recovery from, infection. Infection with HBV becomes chronic when a patient fails to clear the viremia within the first six months and the infected hepatocytes are not eradicated by cytotoxic T cells (141). Therefore, early treatment of chronic hepatitis B has been attempted as follows: (a) modulation of immune response (by suppression or stimulation), (b) inhibition of viral replication, (c) liver transplant with or without

531 combination of (a) and/or (b), and (d) inhibition of HBsAg processing/secretion. 6.3.1 Modulation of Immune Response Corticosteroids. Corticosteroids are immunosuppressant drugs which have had beneficial effects in autoimmune chronic active hepatitis. They were investigated for the treatment of chronic active hepatitis B (183-185), resulting in increased HBV replication, membrane expression of viral antigen, and delayed HBeAg seroconversion (132, 186). Stopping steroid treatment usually leads to a rebound in hepatic disease activity but may be followed by termination of viral replication within a few months (187). Thus, despite the decrease in transaminase activity, corticosteroids have little role in the treatment of chronic hepatitis B. However, corticosteroids may be useful for pretreatment of certain patients prior to interferon therapy (188) or for enhancing the efficacy of interferon or adenine arabinoside (ARA-A) treatment by prior steroid withdrawal in patients with mild inflammatory activity (189). Reticulose. Reticulose is a peptide-nucleic acid solution in which ribonucleic acid is combined with short-chain peptides. Recently, reticulose has been described as an immune system modulator, and early clinical studies have shown that reticulose has an ability to rapidly inhibit the course of a variety of viral diseases, particularly in the acute stage. However, it has also been reported to be effective in sub-acute and chronic phases of certain infections and has exhibited no reported side effects in over 20 years of use. Reticulose appears to act by alteration of the host cell response to viral replication. It seems to stimulate the immune system via increases in endogenous interferon and increases in lymphocyte production. In clinical trials with patients infected with hepatitis A or B viruses, treatment with reticulose demonstrated positive results in that serum bilirubin levels reached normal levels and white blood cell count showed significant increases, indicating stimulation of the immune system (190). Cytokines, An improved understanding of the control of the immune response by humoral factors, and the synthesis of these compounds by recombinant gene technology, may allow a more targeted enhancement of the immune response with cytokines such as interleukin-2, tumor necrosis factor (TNF), interferon-jS, or interferon-7 (interferon-a will be discussed separately) in patients with chronic hepatitis B. Interleukin-2 causes cytotoxic T cells to mature and increase in number and may thereby enhance elimination of infected hepatocytes. Tumor necrosis factor is an immunoregulatory cytokine with antiviral properties. Its effect in chronic HBV infection is complex and cannot be explained by its antiviral properties. A clinical study has shown that HBV replication is inhibited by low doses of tumor necrosis factor but increased by higher doses (191). An open study in 11 patients suggested that it may be beneficial for the treatment of chronic hepatitis B (192), although these results need confirmation by randomized, controlled studies. Interferon-7, which has low antiviral activity, enhanced the effects of interferon-jS in

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chronic hepatitis, probably as a result of its immunomodulatory properties (193). Interferon-j8 has exhibited antiviral activity used as a single agent as well as in combination with ribavirin (194). However, the most promising results have been achieved with interferon-a. Intetferon-oL. Interferon was first used for chronic HBV in 1976 by Greenberg's group (195). Interferon has a direct antiviral effect by inhibiting viral protein synthesis. Class 1 major histocompatibility complex (MHC) antigen displayed on hepatocytes is enhanced, and it is thought to aid recognition of infected hepatocytes by the immune system. Other potentially beneficial effects include increased natural killer (NK) cell activity (196). Various regimens of interferon-a have been attempted (197) and it has been found that longterm ( > 1 month) low-dose therapy was more effective and better tolerated than short-term highdose therapy (195, 198). Similar results were obtained with recombinant and lymphoblastoid preparations (199-201). The success rate was 30-40%, as judged by decreases in serum viral DNA, and patients responding to therapy have shown losses of HBeAg as well as decreased serum aminotransferase levels. Follow-up liver biopsies demonstrate reduced inflammation (198). It is hoped that this reduces the risk of subsequent cirrhosis and carcinoma which is a timedependent process. Several studies have been performed to evaluate restoration of hepatic markers during and after interferon-a treatment, simply or in combination with other therapies to treat chronic hepatitis B (see section 6.3.5 below). Thymosins. Thymosins are hormone-like polypeptides produced by thymus epithelial cells. They regulate the maturation of T-cells; moreover, they modulate interferon production and stimulate the expression of interleukin-2 and its receptor. A trial of thymosin fraction-5 in four homosexual patients with chronic hepatitis B demonstrated no effect after six months of treatment (202), while treatment of WHV-infected woodchucks with thymosin alpha-1 resulted in clearance of circulating WHV-DNA and a 50-300-fold decline in the levels of replicative intermediates in liver tissue (203). Subsequently, thymosin alpha-1 and thymosin fraction-5 were used to treat chronic hepatitis B in a human pilot study (204). Results were encouraging, and this was followed by several randomized, controlled multicenter trials of thymosin alpha-1 in the U.S. The primary action of thymosin is unknown, but it is probably related to its immuneenhancing effects. 6.3.2 Inhibition of Viral Replication A variety of antiviral drugs inhibit in vitro HBV-DNA production. These substances include nucleoside and non-nucleoside analogs. Nucleoside Analogues, Nucleoside analogues have shown great promise in inhibiting the replication of several pathogenic viruses. Among the 13 antiviral drugs currently approved by the U.S. Food and Drug Administration, 10 are nucleoside analogues. These agents include

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acyclovir, gancyclovir, zidovudine, ribavirin, dideoxyinoside (ddl), dideoxycytosine (ddC), and vidabavirin, all of which have gained widespread use for the treatment of various viral diseases. These agents act by interfering with the replication of viral nucleic acid, either by inhibiting the relevant DNA or RNA polymerase or by affecting the function of other nucleic acid-modifying enzymes. Several nucleoside analogs have been examined for their ability to inhibit in vitro HBV replication (205-214). Although none has yet been shown to be clinically effective, several recent and ongoing studies suggest that these agents hold promise, either alone or in combination with other classes of antiviral agents such as the interferons (189, 215, 216), thymosins or other drugs with inhibitory activity on the expression/secretion of HBV/HBsAg particles. Treatment may be prior to or after liver transplantation, as discussed below. Non-nucleosides. Suramin has been reported as an inhibitor of duck hepatitis B virus DNA polymerase (DHBV DNAp) activity with an in vitro assay system (217). However, in vivo studies with three male patients with severe chronic active hepatitis showed no suppression of human hepatitis B virus DNA polymerase activity by suramin (218). This study also demonstrated that suramin treatment resulted in toxicity and side effects at the tested concentration. Therefore, higher concentrations were not tested, and the results suggest that suramin has no role in the treatment of chronic active hepatitis. 6.3.3 Liver Transplant Liver transplantation was considered as an ultimate choice for the patients with HCC, but this is problematic for patients with chronic viral hepatitis B, since the new liver is reinfected (selected reviews, 219-221). Therefore, liver transplantation should only be considered in a clinical setting wherein prevention of reinfection of the allograft is attempted (222). The use of hepatitis B immunoglobulin in high doses for prolonged periods delays rather than prevents recurrence (219). 6.3.4 Inhibition of HBsAg Processing/secretion Inhibition of a-glucosidase I. The imino sugar N-butyldeoxynojirimycin (NBDNJ), an inhibitor of the oligosaccharide-trimming enzyme a-glucosidase I, suppressed the secretion of HBV particles in HBV-producing HepG2.2.15 cells as well as HBV-infected HepG2 cells (223). This activity results because three hepatitis B surface antigens (HBs proteins) are singly or doubly N-glycosylated and are essential for the formation of infectious HBV particles. Currently, this substance is under investigation for in vivo studies. Other Inhibitors of HBsAg. Plant extracts have been used widely by traditional medical practitioners for the treatment of jaundice and liver diseases related to HBV (224); however, only a few systematic studies have been done to evaluate the anti-HBV activities of these plants under controlled in vitro or in vivo conditions. In these cases, lead plants as well as pure

534 compounds isolated from natural sources are reported to inhibit the secretion or processing of HBsAg (225-232). Further studies in this field might lead to the discovery of a clinically relevant anti-HBV drug. 6.3.5 Combination therapy Interferon-oL and steroids. As discussed above, the withdrawal of steroids from chronicallyinfected HBV patients has been associated with a surge of transaminase values and occasional clearance of virus, increased HBV DNA replication and membrane expression of viral antigen, while suppressing host cytotoxic T lymphocyte (CTL) activity (187, 233). Due to these effects, it was reasoned that withdrawal of steroids and consequent restoration of CTL activity might enhance the antiviral effect of interferon. The first large controlled trial to investigate combination therapy consisting of prednisone withdrawal and interferon administration was carried out by Perillo's group (189). This study confirmed the effectiveness of antiviral therapy, but it did not elucidate whether corticosteroids added to the benefit provided by interferon alone. Therefore, a subsequent study included comparison of interferon alone with the same regimen following prednisone withdrawal (200), and demonstrated that the prednisone withdrawal combination with interferon seemed no more successful than interferon alone. One patient with cirrhosis died of liver failure after prednisone and interferon therapy which emphasizes the potential risk of "immune lysis hepatitis" in such patients with severe liver disease. Therefore, interferon treatment is not recommended for patients with decompensated cirrhosis, in whom a high rate of adverse effects has been observed (234). Interferon also appears to be of no benefit for those patients with HBV who are East Asian, who have fulminant HBV, or who are chronically immunosuppressed (235, 236). At present, interferon remains the only accepted treatment for chronic hepatitis B with a success rate of approximately 30-40%, while the major problem with some other drugs include toxicity and lack of antiviral potency (138, 237, 238). Alpha-interferon represents a good compromise since it has both immunomodulatory and antiviral properties. Moreover, it is generally well-tolerated. Liver transplant in combination with other antiviral drugs. Nucleoside analogues. A clinical trial of famciclovir in combination with a short course of prostaglandin E in a patient with severe hepatitis B after liver transplantation has suggested complete recovery and normal functioning of the patient, who returned to work as a teacher (239). Immunomodulators. Since immunosuppression is associated with enhanced viral replication, Sheiner et ah, (240) have postulated that clinical recurrence of the disease may be associated with augmented immunosuppression consequent to anti-rejection therapy.

535 6.4 Need for Development of an Effective Treatment for HBV Infection As illustrated by the discussion above, it is important to develop an anti-HBV drug to control the disease. Systemic chemotherapy is the only practical approach. In searching for such agents, which may represent structurally complex or novel chemotypes, terrestrial plants comprise a viable starting point. The use of plants in traditional medicine has been recorded since 2100 BC. In some cultures in India and China, plant extracts have been used to treat jaundice associated with HBV infection (229, 230, 241, 242). Hudson (224) reports several genera of plants that have been evaluated for anti-HBV activity in humans or appropriate animal models, and at least one report exists which describes a plant extract that inhibits the HBV DNA polymerase (243). Thus, precedence exists among plants for anti-HBV activity. In this report we focus on a rapid, automated and selective evaluation of natural products and plant extracts for anti-HBV activity which could be utilized for the development of a drug. Such a drug could be used singly or in combination with other drugs (such as an inhibitor of HBV DNA and/or an inhibitor of HBsAg expression or secretion) to treat chronic HBV infection. 6.5 Development of an In Vitro Anti-HBV Assay System Most antiviral assays are performed utilizing classical virological methods involving the infection of host cells with virions at a certain multiplicity of infection, and subsequent viral quantification by procedures such as plaque formation and antigen expression. These protocols have the advantage of encompassing most, if not all, stages in the life-cycle of the virus. However, these protocols are often lengthy and their application as high-throughput assays is both tedious and cumbersome. Moreover, the analogous test system is not available for HBV. A major problem with test systems for evaluating potential anti-HBV compounds was that no suitable in vitro culture system was available that could accurately mimic acute HBV infection in humans. Prior to the development of a cell-based assay system, the effect of potential anti-HBV drugs was evaluated at the level of inhibiting the production of HBsAg by a HBV-carrying hepatocellular carcinoma cell line (PLC/PRF/5) (228, 244). This cell line was obtained from tumor tissue of a chronically-infected HBV patient (201, 245, 246). It contains multiple integrated copies of a partial HBV genome and produces HBsAg, but it does not produce extrachromosomal HBV DNA (247, 248). In addition, an in vivo woodchuck model was available to evaluate active "leads" obtained from in vitro studies. Woodchuck hepatitis virus (WHV) and duck hepatitis B virus (DHBV) are closely related to HBV. Therefore, these two in vivo models can be used to evaluate the active agents, but they are not very useful for the discovery process. These problems have been resolved by the development of HBV-producing cell lines which

536 have been developed by several investigators by stably transfecting hepatoblastoma cell lines, such as HepG2, with the molecularly-cloned HBV genome. These transfected cell lines produce replicative HBV DNA intermediates and release hepatitis B core (HBcAg, HBeAg) and surface (HBsAg) antigens, as well as mature infectious virions, into the culture medium (249-253). Due to these characteristics, HepG2.2.15 cells (stably transfected HepG2 cells) have been used as an in vitro model to screen for anti-HBV activity (205-213, 226, 254, 255). Recently, various methods have been reported for the screening of anti-HBV agents utilizing HepG2.2.15 cells. These procedures involve the analyses of intracellular extrachromosomal HBV DNA expression (205-207, 212, 226, 254, 255), extracellular HBV DNA secreted into the culture medium (207, 212, 254, 255), PCR amplification of extracellular HBV DNA captured on microtiter plates by an anti-HBsAg monoclonal antibody (209), or determination of HBsAg concentration in the culture medium (207, 226). We currently describe a procedure which was developed to evaluate a large number of plant extracts for anti-HBV activity, as well as cellular toxicity for hepatocyte-derived cells, using HepG2.2.15 cells (226). This assay is rapid, amenable to automation, and selective for the assessment of a large number of test materials for anti-HBV activity. Briefly, natural products and plant extracts are screened for anti-HBV activity, by assessing inhibition of expression/processing/secretion of HBsAg into the culture medium of HepG2.2.15 cells, as well as the inhibition of intracellular extrachromosomal HBV DNA. To eliminate variation, a single 96-well plate was used to evaluate both the cytotoxicity and HBsAg assessments, and a 24-well plate was used to assess intracellular extrachromosomal HBV DNA. 6.6 In Vitro Anti-HBV Assay System for Assessing Natural Products and Plant Extracts Cell Culture. The HBV-producing human blastoma cell line (HepG2.2.15) (253) was maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (PCS), 2 mM glutamine, 100 units/ml penicillin, 100 ^g/ml streptomycin and 350 jug/ml gentamicin sulfate (G418) at 37C under 5% CO2 in air. Similarly, HepG2 cells were maintained in RPMI 1640 medium supplemented with 10% PCS, 2 mM glutamine, 100 units/ml penicillin and 100 ^g/ml streptomycin. Anti-HBV Assay. To evaluate test materials for anti-HBV activity, HepG2.2.15 cells were seeded on 96-well microtiter plates at a density of 3-4x10* cells per well in 190 /xl of medium (5% PCS, no G418). The test materials were then added in 10 /xl of 10% (v/v) aqueous DMSO to a final concentration of 0.5% (v/v) along with DMSO at the same concentration (0.5% v/v) and ddC (200 /xM) which were included as negative and positive controls, respectively. The treated cells were incubated at 3TC under 5% CO2 in air. The medium was collected every two days for six days, and replaced with fresh medium containing plant extracts, DMSO or ddC, to

537 the respective wells. At the end of the sixth day, the medium was removed and each plate was tested for cell survival using a sulforhodamine B staining procedure (see below). Culture medium collected throughout the course of the experiment was stored at -TO^C for subsequent analysis of HBsAg levels. The effect of the withdrawal of the plant extracts after six days of treatment was also studied. At the conclusion of the treatment period, cells were washed three times with phosphate buffered saline (PBS) and fed with fresh medium lacking test materials, DMSO or ddC. The cultures were allowed to recover for six days with the medium changed every two days. Culture medium collected was stored at -70C and assayed for HBsAg levels as described below. At the end of 12th day, the plates were also examined for cell survival. A second set of experiments, representing a four-fold scale-up of the procedure described above, was carried out in 24-well plates, to determine the effect of test materials on the synthesis of intracellular extrachromosomal HBV DNA as outlined below. Assay for Hepatitis B Surface Antigen (HBsAg). The HBsAg released into the culture medium was assayed by using the Auzyme kit (Abbott Labs, Abbott Park, IL) which is based on capturing the HBsAg on monoclonal antibody-coated beads. Samples collected after six days of treatment of cultured HepG2.2.15 cells, were diluted 4-fold and assayed in triplicate wells. All samples from one experiment were analyzed using an antibody kit from the same lot in order to minimize variability among the experimental data points. The percent inhibition of HBsAg secretion after six days of treatment was calculated relative to the negative control (DMSO). Cytotoxicity Assay. Test materials were evaluated for cytotoxicity by measuring cell survival at the end of the each experiment using the sulforhodamine B staining method (8). DNA Extraction and Analysis. Intracellular extrachromosomal HBV DNA was extracted from cells by the method of Hirt (256) as adopted by Gripon et al. (257). Briefly, cells were lysed in buffer containing 0.5% (w/v) sodium dodecyl sulfate (SDS), 10 mM Tris-HCl (pH 8.0), 10 mM NaCl, 10 mM EDTA and 200 ixglml proteinase K, and incubated overnight at 3TC. NaCl was added to the lysate to a final concentration of 1 M, and the mixture was stored overnight at 4*'C to allow cellular DNA to precipitate. Chromosomal DNA was pelleted at 29,0(X) X g for 1 hr at 4C. The supernatant was extracted twice with an equal volume of phenol:chloroformlisoamyl alcohol (25:24:1, v/v/v) followed by two extractions with chloroform:isoamyl alcohol (24:1, v/v). Sodium acetate (pH 5.5) was added to the aqueous phase to a final concentration of 0.3 M, and nucleic acids were precipitated with 2 volumes of ethanol. Pellets recovered after centrifugation at 29,000 x g for 10 min were dissolved in 10 mM Tris-HCl (pH 7.4) containing 1 mM EDTA. DNA was analyzed by electrophoresis employing horizontal slab gels comprised of 0.8%

538

agarose, 40 mM Tris-acetate buffer (pH 7.4), and 1 mM EDTA. Gels were soaked in 0.25 N HCl for 15 min, and the DNA was denatured in 0.5 M NaOH containing 1.5 M NaCl for 1 hr at room temperature, followed by neutralization in 1 M Tris-HCl buffer (pH 8.0) containing 1.5 M NaCl for 15 min at room temperature and then transferred to Zeta Probe GT membranes (Bio Rad Laboratories, Hercules, CA) according to the manufacturer's recommended procedure based on that of Southern (258). After transfer, the membranes were rinsed twice with 2X SSC (IX SSC contains 150 mM NaCl and 15 mM sodium citrate, pH 7.0), air-dried and baked at 80C for 2 hr under vacuum. The membrane was then blocked with pre-hybridization solution containing 7% (w/v) SDS and 0.25 M Na2HP04 (pH 7.2) at 65C for 5 min, and hybridized at 53C for at least 16 hr with a p^P] HBV probe. The probe was derived from the 3.2 Kb HBV DNA insert released from pSM2-HBV (gift from Dr. H. Schaller, ZMBH, University of Heidelberg, Germany) by EcoRl digestion, resolved by electrophoresis on 0.8% agarose gel, and recovered by electroelution. This insert was labeled with p^P]dCTP (Amersham Corporation, Arlington Heights, IL) using the "Prime a Gene" labelling system (Promega Corporation, Madison, WI). After hybridization, the membrane was washed twice with a solution containing 20 mM Na2HP04 (pH 7.2) and 5% (w/v) SDS at room temperature. After a 15 min wash at 50''C with the same solution, membranes were air-dried and exposed to film (X-OMAT-AR, Kodak, Rochester, NY). As molecular weight markers: non-radioactive lambda DNA size markers (New England Biolabs, Inc., Beverly, MA), cloned-HBV DNA (3.2 Kb), and PCR-amplified HBV DNA (1.32 Kb) were used. Intracellular extrachromosomal DNA extracted from HepG2 cells, the untransfected cell line, was used as a negative control in Southern blots. 6.7 Data Resulting from Analyses Performed with HEP62.2.15 Cells A number of plant extracts and pure compounds isolated from natural products were tested for anti-HBV activity utilizing HepG2.2.15 cells. Two parameters indicative of viral proliferation were evaluated: the inhibition of secretion of HBV/HBsAg into the medium of the cultured cells and the reduction of intracellular extrachromosomal HBV DNA. Since ddC is known to inhibit HBV replication (209, 213, 254, 255), it was evaluated along with the test materials (0.5% v/v) as a positive control. The results obtained with 84 plant extracts and 57 pure compounds are summarized in Table 2.

539 TABLE. 2. Test Material* Plant Extracts and Pure Compounds Evaluated for Anti-HBV Activity Number Tested Number of "Active Leads" in Anti-HBV Assays HBsAg Secretion Intracellular Extrachromosomal (Inhibition) Plant Extracts Pure Compounds 84 57 2 1 HBV DNA (Reduction)

Inhibition of HBsAg Secretion, Cultured HepG2.2.15 cells were treated with two-fold dilutions of the test materials ranging from 160-1.25 ^g/ml. The treatment was for a total of six days, with the change of medium containing freshly dissolved test materials every two days. At the end of the sixth day, HBsAg levels were measured in the medium and cytotoxicity was assessed from the same 96-well plates. These data were then used for the estimation of CC50 (50% cell survival) and ED50 (50% inhibition of HBsAg secretion) values, which in turn could be used for the estimation of an "zn vitro therapeutic index" or TI (CC50/ED50). In general, it is expected that this value should be > 1 to provide an indication of potential efficacy. However, for practical purposes, we considered a plant extract to be an "active" lead if the TI value is more than L5, while for pure compounds, the TI value should be more than 3.0. As summarized in Table 3, two plant extracts (Clerodendron inerme and Clematis sinensis) and one pure compound (7-fagarine) fall into this category, and are considered as "active" leads worthy of further study.

540 TABLE 3. Test* Materials Clerodendron inerme (Aerial Part) Clematis sinensis (Aerial Part) 7-Fagarine 11 66 6.0 Examples of "active" leads capable of selectively inhibiting secretion of HBsAg with cultured HepG2.2.15 cells after six days of treatment. HBsAg Inhibition (ED50 fJLg/mlf 16 29 Cytotoxicity (CC50 fig/mlf 27 45 TT^CC^JED^'

1.69 1.55

Tlant extracts were dissolved in DMSO and evaluated for anti-HBV activity utilizing HepG2.2.15 cells. ''showed 50% inhibition of the secretion of HBsAg and 50% cell survival as the measure of cytotoxicity. T I is the in vitro therapeutic index. Results are expressed as the means of triplicate determinations relative to DMSO-treated controls. Reversibility of inhibition of HBsAg. Since HBV DNA is integrated into the genome of HepG2.2.15 cells, it was expected that when test materials are removed from the treatment wells after six days of incubation, the inhibitory effect on the secretion of HBV/HBsAg into the culture medium should be lost and the production/secretion of HBV/HBsAg should increase into the culture medium. To test this possibility, cultured HepG2.2.15 cells were treated with various concentrations of Clerodendron inerme, Clematis sinensis or 7-fagarine for six days and HBsAg levels were measured. The cells were then allowed to grow in fresh medium without test materials, for an additional six days, at which time HBsAg levels and cytotoxicity were assayed. During the entire course of the experiment, medium was replaced at two-day intervals, with or without plant extracts, as appropriate. The results are presented in Table 4. In this experiment, HBsAg was inhibited by 57 and 40%, respectively, as a result of treatment with 40 jLig/ml of Clerodendron inerme or Clematis sinensis extracts, for six days. Inhibition of HBsAg observed with 20 fjig/ml 7-fagarine was 82%. Six days after removal of the plant extracts from the medium, HBsAg secretion into the medium reached the level of the untreated control. As compared with the results observed in Table 3, a higher percentage of cell survival was observed in this experiment (Table 4), probably due to replacement of cells during this period. The inhibition of HBsAg at less cytotoxic concentrations suggests that the target for the inhibitory agent is a component or a process unique to the virus.

541 TABLE 4. Reversal of the inhibition of the secretion of HBsAg into the medium of cultured HepG2.2.15 cells. Concentration Tested (jug/ml) HBsAg (% Inhibition) Cytotoxicity
(% Survival after 12 days)

Materials Tested

After six days of treatment Clerodendron inerme (Aerial Part) Clematis sinensis (Aerial Part) 40 20 10 5 40 20 10 5 20 10 57 23 24 8 40 33 26 2 82 60

Six days after removal 7 0 0 0 0 0 0 0 6 0 54 98 96 100 81 100 89 94 86 100

7-Fagarine

Results are expressed relative to solvent-treated controls and represent the mean of triplet determination. The above results are in accordance with previous reports concerning nucleoside analogs in similar situations (212). Therefore, we considered this protocol to be appropriate for the purpose of screening large numbers of plant extracts and pure compounds isolated from the natural products for the anti-HBV activity. Reduction of Intracellular Extrachromosomal HBV DNA In addition to assessing HBsAg levels, a known inhibitor of HBV DNA (ddC) and test materials were evaluated for potential to alter the intracellular extrachromosomal HBV DNA levels expressed by cultured HepG2.2.15 cells. Extrachromosomal DNA was extracted by the modified procedure of Hirt (256) as described by Gripon et al. (257) and analyzed by Southern (258) blot analysis with a HBV specific probe. As presented in Figure 1, ddC strongly inhibited intracellular extrachromosomal HBV DNA production at a concentration as low as 25 pM (Figure lA, Lanes 11 and 12, arrows), while solvent, DMSO [0.5% (v/v)] (Figure lA, Lanes 9 and 10) had no effect. In addition, nine plant extracts (Table 5; Fig lA, B, C, D, and E) significantly inhibited the intracellular extrachromosomal HBV DNA production in HepG2.2.15 cells. DNA extracted from HepG2 cells (not expressing HBV DNA) was used as a control for Southern blotting and, as expected, no band corresponding to HBV DNA was observed (Figure lA, Lane 6).

542 TABLE 5.
Test Material Asparagus officinalis L. Bidens pilosa L. Caesalpinia bonducella (L.) Calotropis gigantea (L.) R,Br. Coleus X hybridus Hort. Gmelina arborea Roxb. Picea glauca (Moench) Voss Salix alba L. cv. tristis Tinospora cordifolia Miers

Plant Extracts Inhibiting the Intracellular Extrachromosomal HBV DNA Production in HepG2.2.15 Cells.
Family Part* Liliaceae Asteraceae Caesalpiniaceae Asclepiadaceae Lamiaceae Verbenaceae Pinaceae Salicaceae Menispermaceae Plant (Lanes) FU LS LF RT PL LP LS LS ST Figure 1 25-28 (Fig lA) 13-16 (Fig ID) 9, 10 (Fig IE) 33-36 (Fig ID) 37-40 (Fig ID) 25, 26 (Fig IC) 37-40 (Fig IC) 29-32 (Fig ID) 21-24 (Fig ID)

FIGURE 1. Southern blot analysis of intracellular HBV DNA following treatment with ddC or plant extracts for six days. For each lane, approximately 10 jug of intracellular DNA (also observed by ultraviolet-induced fluorescence emitted by intercalated ethidium bromide) was loaded. The experiment was performed in duplicate, and the intracellular DNA was analyzed on an 0.8% agarose gel along with lambda size and HBV-specific DNA markers. For all the Panels A, B, C, D, and E: Lane 1 contained non-radioactive lambda DNA size markers which are not visible in the Southern blot autoradiogram. Lane 3 (M) represents a mixture of electroeluted HBV DNA (3.2 Kb) from EcoRl-digested cloned HBV DNA sample and HBV DNA-specific PCR amplified product (1.32 Kb). Lane 6 represents intracellular DNA extracted from HepG2 cells which do not express HBV DNA, and was included as a negative control for Southern blot analysis. Lanes 2, 4, 5, 7, and 8 represent lanes without DNA which serve as an indication of background radioactivity. See Table 5 for additional designation of lanes. (Figure on following page)

543

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544

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FIGURE 2. Southern blot analysis of intracellular HBV DNA extracted from HepG2.2.15 cells following treatment with ddC, and after removal of ddC from the medium of the treated cells. Intracellular DNA ( - 1 0 fjLg) was loaded onto each lane. The experiment was performed in triplicate, and intracellular DNA was analyzed on a 0.8% agarose gel along with lambda size and HBV-specific DNA markers. Lane 1 represents lambda DNA size marker; Lane 3 represents cloned HBV DNA digested with EcoRl to release HBV cDNA (3.2 Kb) and plasmid DNA (3.6 Kb); Lane 5 represents a mixture of electroeluted HBV cDNA (3.2 Kb) from EcoRl digested cloned HBV DNA sample and HBV DNA-specific PCR-amplified product (1.32 Kb); Lane 8, which serves as a control for the probe specificity, contained intracellular DNA extracted from the parental cell HepG2 that lack the HBV DNA. Lanes 11-13 represent DNA extracted from HepG2.2.15 cells treated with DMSO; Lanes 14-22 represent DNA extracted from HepG2.2.15 cells treated with ddC at 100 juM (Lanes 14-16), 200 fxM (Lanes 17-19) and 300 [xM (Lanes 2022); Lanes 25-33 represent DNA extracted from HepG2.2.15 cells which were recovered for 6 days after a 6-day treatment with ddC at 100 fxM (Lanes 25-27), 200 (JLU (Lanes 28-30) and 300 fxM (Lanes 31-33). After removal of ddC from the medium, cells were cultured for six days post-treatment with changes of medium without ddC for every two days. Lanes 2,4,6,7,9,10,23 and 24 are lanes without DNA. The arrows indicate the HBV-specific DNA bands.

545

Reversibility of Reduction of Intracellular Extrachromosomal HBV DNA Additional experiments were then performed to assess the reversibility of ddC-inhibited expression of intracellular extrachromosomal HBV DNA. As shown by the Southern blot analyses presented in Figure 2, synthesis of intracellular extrachromosomal HBV DNA was completely inhibited after a six day treatment with ddC at all concentrations tested, including the lowest concentration, 100 /xM (Lanes 14-22). The expression of intracellular extrachromosomal HBV DNA, compared to DMSO-treated cells (Lanes 11-13, arrows), recovered after removal of ddC (Lanes 25-33, arrows). DNA obtained from HepG2 cells (Lane 8) presented no band corresponding to HBV DNA.

546 6.8 Summary of Anti-HBV Results and Procedures In summary, a simple cell culture assay system was developed for the evaluation of natural products for anti-HBV activity, the use of the stably-transfected HepG2.2.15 cell line not only simplifies the antiviral assay and makes it more amenable to automation, but also enables the evaluation of natural products as inhibitors of viral replication, expression, and maturation, in addition to the post-translational modification of viral protein(s), and virus release. Medicinal plants are used to treat viral jaundice in different parts of the world (227-231, 241), but few attempts have been made to confirm the anti-HBV activity of these plant extracts. These natural products remain a largely untapped source of anti-HBV compounds and we are focussing on the isolation of active components from medicinal plants with putative anti-HBV activity. Accordingly, the protocols described herein have been adopted for use with natural products, and they are suitable for bioassay-directed fractionation. Selectivity is an important criteria that was introduced at an early stage in the discovery process. All the test materials were evaluated for both cytotoxicity as well as anti-HBV activities, and a therapeutic index (TI) for the inhibition of secretion/processing of HBsAg was calculated. This value is useful for the selection of primary lead materials that can be subjected to more advanced testing.

7.

CONCLUDING REMARKS We currently describe drug discovery programs for three disease states that ostensibly have

little in common. In each case, however, it is clear that common strategies can be applied for the construct of biology-driven programs. The systems employed are obviously not designed for high-throughput or high-capacity screening; they are much too labor-intensive. Testing is limited to hundreds or perhaps thousands of starting materials on an annual basis, which leads to judicious decisions. Any available information, such as data from ethnomedical studies or scientific literature, is taken into account, and dereplication procedures are being used with increasing frequency. Moreover, the assay methods remain focussed on the identification of active leads with a relatively high probability of yielding therapeutically useful drugs. From a realistic viewpoint, the challenge of finding efficacious agents for the systemic treatment of life-threatening diseases such as cancer, AIDS, hepatitis, and malaria, is immense. The magnitude of past efforts that have led us to our current state of knowledge and technology is difficult to comprehend, in terms of human and economic resources and expenditures. This leads to the realization that a breakthrough discovery probably is not imminent, but the search must continue using the best tools and experimental designs that are currently available. The systems described herein, while labor-intensive and inappropriate for high-throughput programs, nonetheless yield leads in the range of 1-5%. This provides a reasonable workload for those

547

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

561

Hanspeter Pfander, Marc Lanz and Bruno Traber

1. INTRODUCTION The brightly coloured carotenoids have aroused the curiosity of scientists since the beginning of organic chemistry and the first publications to deal with the carotenoids date from the early part of the 19th century. They relate to well-known food materials and colours such as paprika, saffron, annatto, carrots and to autumn leaves. During the last century the emphasis was on isolation of the pigments and their characterization. The investigations during the first part of the 20th century were dominated by establishing structural formulae and developing synthetic methods. In 1930 Karrer established the correct constitution of lycopene (1) and p,p-carotene {= p-carotene, 2) (Figure 1) and in 1950 the total synthesis of p,p-carotene (2) was reported independently by Karrer,

Synthesis of Carotenoids

Inhoffen and Milas. This labile molecule with its long conjugated polyene chain presented difficult practical problems that had not been encountered with other groups of natural products and required the development of new strategies and methods, especially for the construction of the polyene chain and linking together different parts of the molecule. The second half of this century was characterized by a continuous development of carotenoid research and current research encompasses a wide variety of fields and interests besides organic chemistry, such as plant physiology, food science, environmental science, taxonomy, industrial chemical synthesis, biotechnology and especially medical research. The continuous development of carotenoid research is reflected in various monographs and reviews published over the years and three generations of books under the title 'Carotenoids' have been published by Birkhauser. The first one, by Karrer and Jucker, published in 1948 [1] and the second, edited by Isler and published in 1971 [2], became classics which are still widely used as valuable sources of information. The book by Isler contains a major chapter of 250 pages on total synthesis and this comprehensive and authoritative review describes systematically the construction of many synthons and

562 the synthesis of many natural and unnatural carotenoids and related compounds. The list of naturally occurring carotenoids that was included in the Isler book, later appeared in an expanded form as a 'Key to Carotenoids' [3]. The rate of discovery and characterization of new carotenoids since then has been rapid, and a second edition of 'Key to Carotenoids', listing 563 carotenoids, was published by Birkhauser in 1987 [4]. Recently a new book series 'Carotenoids', again published by Birkhauser, was started. The main objective of this new series is for the older generation of carotenoid workers to pass on experience and expertise in a way that will be of value not only to established carotenoid researchers, but especially to workers coming new to carotenoids. The books in the new series are intended to be workbooks and this is especially true of the coverage of general methods pf carotenoid isolation and analysis which forms the subject of the two parts of Volume 1 [5,6]. Volume 2 of the series is the first book to be published that is devoted entirely to the total synthesis of carotenoids [7]. The main text consists of four chapters each dealing with a major topic and divided into a number of parts. The essential foundation for work in the field is a thorough appreciation of the principles and strategies of carotenoid synthesis and this is provided in Chapter 1. A major task in carotenoid synthesis is the construction of the polyene chain. The coupling reactions commonly used for carbon-carbon double bond formation are dealt with In Chapter 2. The various parts of Chapter 3 describe the preparation of polyene synthons and the total synthesis of different groups of carotenoids. Technical synthesis and the synthesis of isotopically labelled carotenoids are also covered. Eight 'Worked Examples' which describe in detail experimental procedures for key reactions in carotenoid synthesis are presented in Chapter 4. Finally two appendices provide tables of useful synthons and a list of natural carotenoids that have been prepared by total synthesis. In addition the published proceedings of the International Symposia on Carotenoids, held at 3-yearly intervals under the sponsorship of the International Union of Pure and Applied Chemistry, provide further important information on the synthesis of carotenoids [8-32]. Most of the carotenoids have a trivial name which is often derived from its natural origin and which gives no information on the structure. Therefore a semi-systematic nomenclature has been developed, which has been approved by the International Union of Pure and Applied Chemistry and the International Union of Biochemistry [33] and which is accepted by Chemical Abstracts for official documentation. According to the lUPAC-lUB rules 'Carotenoids are a class of hydrocarbons (carotenes) and their oxygenated derivatives (xanthophylls) consisting of eight isoprenoid units joined in such a manner that the arrangement of isoprenoid units is reversed at the centre of the molecule so that the two central methyl groups are in a 1,6-positional relationship and the remaining non-terminal methyl groups are in a 1,5-positional relationship. All carotenoids may be derived formally from the acyclic C40H56 structure 1, having a long central chain of conjugated double bonds (Figure 2), by (i) hydrogenation,

563 (ii) dehydrogenation, (iii) cyclization, or (iv) oxidation, or any combination of these processes. This class also includes molecules which contain additional carbon atoms as

Figure 2

substituents to the normal C4o-skeleton and certain compounds that arise from rearrangements of the carbon skeleton 1, or by the (formal) removal of part(s) of this structure. All specific names are based on the stem name 'carotene', which corresponds to the structure and numbering shown in Figure 3. The broken lines at the two terminations represent two 'double-bond equivalents'.' As shown in Figure 3 Individual compounds may have acyclic or cyclic Cg-end groups.

9 10

11 12 14

Figure 3

564 The structure and nomenclature of the carotenoids according to the lUPAC-lUB rules were recently described with many examples by Weedon and Moss [34]. The main functional groups that occur in the xanthophylls, the oxygen-containing carotenoids, are the hydroxy, methoxy, carbonyl, carboxylic acid, ester and epoxy groups. Furthermore carotenoids with carbon-carbon triple bonds or an allenic groups are known. In addition carotenoids also occur as glycosides, glycosyl esters and carotenoproteins and a special case are the sulphates In which the hydroxy group of the carotenoid is esterified with sulphuric acid. The combination of the different end groups and functional groups leads to the great number of different structures of the carotenoids and up to date more than 600 carotenoids have been isolated from natural sources from which more than 400 bear one or more chiral centres [4,35]. Carotenoids are familiar to us through the orange-red colours of popular foods like oranges, tomatoes and carrots, and the yellow colours of many flowers. Carotenoids are essential to plants for photosynthesis, acting in light-harvesting and, especially, in protection against destructive photooxidation. Without carotenoids photosynthesis in an oxygenic atmosphere would be impossible. But carotenoids are not simply pigments of terrestrial plants. They also occur widely In archaea, bacteria, fungi and algae and the production of carotenoids in seaweed runs to hundreds of millions of tons per year. Some animals use carotenoids for coloration, especially birds e.g. flamingoes and canaries, and fish e.g. goldfish and salmon, and a wide variety of invertebrate animals, where complexation with protein may modify their colour to blue, green or purple. Above all carotenoids are important factors in human health. The essential role of p,p-carotene (2) and others as the main dietary source of vitamin A has been known for many years. More recently, protective effects of carotenoids against serious disorders such as cancer, heart disease and degenerative eye disease have been recognized, and have stimulated intensive research into the role of carotenoids as antioxidants and as regulators of the immune response system. Due to the ubiquitous occurrence and the various important biological functions of carotenoids, their synthesis is of high importance. On the other hand the great variety of structures and the relative instability of the carotenoids, i.e. their susceptibility to oxidation, addition of electrophiles including H"" and Lewis acids, and E/Z-isomerization caused by light, heat or chemicals make the synthesis demanding. In the following article the strategy and methodology for preparing carotenoids by total synthesis is discussed first; in the main part the syntheses of the most important carotenoids are outlined, followed by the discussion of the technical syntheses. Included is also an extended list of references which should allow the reader to obtain more and detailed information.

565 2. STRATEGY AND METHODOLOGY Strategy In principle an almost countless number of strategies can be developed for the preparation of a carotenoid, but in reality only a few strategies and methods have been worked out successfully and they have since been used repeatedly [36]. In the last step of the synthesis which leads to the entire carotenoid molecule, in principle either a carbon-carbon single bond or a carbon-carbon double bond has to be generated. Although the methodology for the formation of a carbon-carbon single bond between two double bonds is known, the alternative strategy, the formation of a carboncarbon double bond, is most often used in carotenoid synthesis. The planning of a synthesis for carotenoids consists mainly of two steps {Figure 4): I) formal dissection of the target carotenoid into a middle part and the end groups, ii) choice of the coupling reactions for the final step and definition of the appropriate functional groups (FG).
end group middle part

end group

middle part

end group

Figure 4

For the dissection one has to keep in mind that the molecule contains positions which permit a coupling in high yield [C(9)-C(10) and especially C(11)-C(12)] whereas others (especially C(7)-C(8) in cyclic carotenoids) give products only in low yields. Whereas the choice of the middle part, a conjugated polyene, and its synthesis have become a simple matter today, the design and the synthesis of the end groups is a challenging task. Experience has shown that the synthesis of end groups must be completed before they are attached to the middle part since chemical transformation of a complete carotenoid often results in a significant reduction of the overall yield. Most of the naturally occurring carotenoids are chiral and therefore targets for synthesis in enantiomerically pure form. This can sometimes be achieved by preparing the carotenoid in racemic form and then resolving the optical isomers via diastereoisomers or by chromatography on a chiral stationary phase. However, in most cases, the construction of the optically pure end group is the most efficient way and for

566 this task three different approaches have been applied. The first involves the preparation of a racemic intermediate from which the required enantiomer is resolved and used for the synthesis of the carotenoid in optically active form. In general this approach should only be selected if both optical isomers of the carotenoid are desired. More elegant are direct asymmetric syntheses, as e.g. the Katsuki-Sharpless epoxidation or dihydroxylation, or the synthesis ex chiral pool in which a chiral natural product, such as a carbohydrate, amino acid or terpene, is partially or as a whole built into the target molecule. Coupling Reactions The most important coupling reaction for the synthesis of carotenoids is the Wittig reaction' or 'Wittig-carbonyl olefination' or 'Wittig condensation' in which a phosphorus ylide 3 reacts with a carbonyl compound 4 to give an olefin 5 and triphenylphosphine oxide (6) (Scheme 1).
Ph
H H

Ph

0=^
Ph

PhjP=(
H

}={
H

+
Ph

Ph3P = 0 6

Scheme 1

The reaction, which was discovered in 1953 by Wittig and Geissler, has developed into one of the most important methods for the synthesis of olefins and it has become indispensable for the synthesis of sensitive carotenoids and for the preparation of carotenoids on an industrial scale. The application of the Wittig reaction to the synthesis of carotenoids has recently been reviewed [37]. In comparison to other carbonyl olefination reactions, the Wittig reaction has a number of advantages. First of all the formation of the new carbon-carbon double bond proceeds regiospecifically, i.e. at the position of the original carbonyl function. Furthermore the starting materials, namely carbonyl compounds and phosphonium salts generally are readily accessible and the phosphorus ylides do not need to be isolated. As the Wittig reaction is carried out generally under mild conditions, i.e. alkaline or virtually neutral medium, it is an excellent method for the synthesis of the sensitive carotenoids. Furthermore many functional groups, such as acetals, epoxides, esters etc. are stable when suitable reaction conditions are selected. The principle disadvantage of the Wittig reaction is its sensitivity to steric hindrance. The yields of trisubstituted olefins are frequently low and the method fails in the synthesis of tetrasubstituted olefins. Sometimes it is also difficult to separate the olefin from the triphenylphosphine oxide which Is formed as a joint product. In addition the (E/Z)-selectivity of the Wittig reaction is often difficult to predict. The disadvantages of the Wittig reaction led to the development of modified methods and the most important modification is the olefination by means of phosphonate carbanions, as developed by Horner and by Wadsworth and Emmons. In the Horner-

567 Wadsworth-Emmons olefination, or in brief, the Homer-Emmons reaction, a phosphonate carbanion 7, produced by deprotonating a phosphonate 8, reacts with a carbonyl compound 9 to give an olefin 10 and a dialkyi phosphate anion 11 {Scheme 2).

?\
I'

(RIO^PV^/R' -B^se^ H H 8

-5

base

?\
"

(R^0)2P....R' H ^ 7

> R^^""
9

R'
\

) = / R H 10

R'
+

ff
11

(RiO),P-oO

C^

Scheme 2

Phosphonate carbanions are suitable starting materials for the synthesis of trisubstituted and tetrasubstltuted olefins. In general, the olefins are formed with high (E)selectivity. Another important advantage of the reaction is the fact that the by-product is a water-soluble phosphate which can easily be separated from the olefin. Since carotenoid synthesis began, the enol ether condensation has frequently been used for the formation of carbon-carbon double bonds and this reaction was also applied for large-scale industrial production of carotenoids. The reaction is an addition of an enol ether 12 to an acetal 13, promoted by a Lewis acid, especially BF3-etherate or ZnCl2, and involves a chain lengthening of two or more carbon atoms to yield an intermediary 3-alkoxyacetal 14 which subsequently is converted into an unsaturated aldehyde 15 (Scheme 3).
2 2 ^^^ Lewis acid R \ PR

R^
OR 13

_ /
R^ 12

r=r:i

X14

A R Scheme 3

< \

2 OR^

R 15

The reaction mechanism and the application of the enol ether condensation in the synthesis of carotenoids have recently been reviewed [38]. The main advantage of the enol ether condensation, compared with the aldol condensation, is that the enol ether reacts exclusively as the nucleophilic reaction partner and the acetal exclusively as the electrophilic one and this leads unequivocally to the desired, uniform, reaction product. As the alkoxy group of the starting acetal takes part in the formation of the new acetal grouping that results from the enol ether moiety, it is preferable for all the alkoxy groups of both reactant to be identical. Most of the examples published have been carried out with vinyl methyl ether (16) and vinyl ethyl ether (17), used to extend the carbon skeleton by two carbon atoms, or propenyl ethyl ether (18) and 1-methoxy-1-methylethene (19) for the extension by three carbon atoms (Figure 5).

568

O
16 17

18

19

Figure 5

A modification of the enol ether condensation is based on the observation that trimethylsilyl enol ethers 20 react readily with acetals 21 at very low temperatures in the presence of Lewis acids to give alkoxyaldehydes 22 with much higher reaction rates compared to the alkyl enol ethers (Scheme 4).
OR 2
H
0R2

R^
\ ^

R 20

0 - Si(Me)3

^ ^

0R2 Ri 22

R3 CHO R^

21

Scheme 4

The finding that 1-trimethylsllyioxybuta-1,3-dienes such as 23 react with acetals such as 24 not only in the expected 1,4-addition manner but also to give 5-alkoxy-a,punsaturated aldehydes in high yield and free from side products, established the silyloxydienes as important building blocks for carotenoid synthesis as shown in Scheme 5 for the synthesis of 25.
OMe OMe

24

23

Scheme 5

The aldol condensation has been used in carotenoid synthesis In the formation of building blocks and in the construction of the entire carotenoid molecule. However the application of this reaction Is rather limited, especially because of side reactions which lead to low yields. The most important example for the application of the aldol condensation is the synthesis of carotenoids with K-end groups. The keto-end group 26 reacts with crocetindialdehyde (27) to give capsorubin (28) (Scheme 6).

27

OH

26

Scheme 6 (continued....,)

569

However, a major disadvantage of this synthesis is the fact that the keto building block, which is more difficult to synthesize, has to be used in a large excess. The most important organometallic reagents used for the carbon-carbon bond formation in carotenoid synthesis are the metal acetylides, metal alkenyls and the Grignard reagents. However the Refomnatsky reaction has also been applied and recently also transition metals such as Pd, Ni, Cu and especially low valent Ti have been used. The application of organometallic reactions for the synthesis of carotenoids and retinoids has recently been reviewed [39]. Because of their ready accessibility and their ease of reduction to give alkenes of predictable stereochemistry, metal acetylides have been widely applied for the synthesis of carotenoids. The reactions involve a nudeophilic addition of the metal acetylides RC^CM (M = Li, Na, K or MgHal) to aldehydes and ketones to give a-hydroxy alkynes. The metal acetylides are usually prepared by the deprotonation of terminal alkynes with strong bases, such as LiNHa, NaNH2, alkyllithium, potassium f-butoxide or with simple Grignard reagents. Examples of the application of these reactions for the synthesis of suitable building blocks and the construction of the carotenoid molecule are given in Scheme 22 and 23. A reaction with an acetylide was applied by Isler [40] for the first synthesis of vitamin A (29), which is still practised industrially. The C2o-skeleton is built up by addition of the Ci4-aldehyde 30 to an ethereal solution of the acetylide 31 to give the diol 32 which is afterwards transformed to vitamin A (29) (Scheme 7). Another prominent example is the synthesis of p,p-carotene (2), once practised on an industrial scale, by the reaction of the di-Grignard reagent of acetylene with a C19aldehyde according to the strategy C19 + C2 + C19 = C40 (see Scheme 13).

570

Scheme 7

Of utmost importance for the preparation of suitable building blocks in carotenoid synthesis is the preparation of vinyl alcohols by the reaction of aldehydes and ketones with vinyl magnesium halides, especially with the commercially available bromides. The most important application is the construction of a Ci5-building block by the reaction of a Ci3-synthon, most often a derivative of the ionones, with vinyl magnesium bromide or chloride (see Scheme 16). Alkenyl lithium reagents, which may be prepared by metal/halogen exchange, are much more reactive than the corresponding magnesium reagents and therefore mild reaction conditions can be applied. The reaction is exemplified by the synthesis of retinal (33) in which the alkenyllithium sllylenol ether 34 is condensed with p-cyclocitral (35) to give, after hydrolysis, the Ci5-aldehyde 25. A further condensation with 34 gives retinal (33) as a mixture of (E/Z)-isomers {Scheme 8).

34

34

OSiMe,

The sulphone coupling which was applied for the first time to the synthesis of vitamin A (29) by Julia [41] has frequently been used for the preparation of retinoids and carotenoids [42]. In this reaction a carbon-carbon double bond is produced by alkylation of the a-carbanion of a sulphone 36 by a halogen derivative 37 to give 38, followed by a base-promoted elimination to give the desired alkene 39 (Scheme 9).

571
SO,Ph SO^Ph
->
p^"

,Je . X r
36 37

38 Scheme 9

39

After the elimination, the water-soluble sulphinates can be readily recovered, in contrast to the Wittig reaction which suffers from the difficulty of recycling phosphine oxide. Modifications of the Julia olefination lead to more general routes to a variety of carotenoids. The success of this method is attributable to improvement of the reductive cleavage of the sulphonyl group by reduction with dithionites [29]. A prominent example of the application of the sulphone coupling is the synthesis of p,pcarotene (2) by the reaction of the Ci3-sulphone 40 with the dichloride 41 to give 15,15'didehydro-p,p-carotene, which was transformed to p,p-carotene (2) (Scheme 10).

Scheme 10

3.

SYNTHESIS OF POLYENE SYNTHONS

As outlined before, the construction principle that is most often used for the synthesis of carotenoids is to couple various end groups to central polyene synthons. As outlined in a recent review [43], most of the synthetic routes to C4o-carotenoids follow the strategy C15 + C10 + C15 = C40, confirming the importance of central Cio-compounds. A key intermediate for the synthesis of symmetrical central building blocks is the acetylenic did 42 which can easily be synthesized by a Grignard reaction of acetylene dimagnesium dibromide (43) with 2-methylprop-2-enal (44) (Scheme 11).
OH BrMg44 43 -MgBr 44

Scheme 11

From compound 42, the most often used Cio-dial 45, the dibromide 46 and the diphosphonium sait 47, as well as the corresponding 15,15'-didehydro derivatives 48 - 50 have been synthesized (Figure 6). In addition, the synthesis of unsymmetrically

572 functionalized central Cio-building blocks, such as the C-io-phosphonium acetal 51 has been reported.
O \ . - - ^ ^ ' ^ ^ .^'^^ / ^ Br. ^ ^ ^ ^-^^ ^.^-s. ^^^^ BrPh-P ^ / v > ^ / . c . ^ / v . \ / ^

46

47

BrPh^P, 48 MeO 49 50

Figure 6

Besides the Cio-dial 45, crocetindialdehyde (27), the central C2o-dialdehyde, is of utmost importance, especially for the synthesis of acyclic carotenoids. Partially protected dials, which are often necessary for the synthesis of unsymmetrical carotenoids, have also been prepared. The C2o-clial 27 is synthesized by the Wittig reaction of the Cio-dial 45 with the Cs-phosphonium salt 52 (Scheme 12).
OEt

4. 4.1.

SYNTHESIS OF THE END GROUPS AND THE CAROTENOIDS Carotenoids with the j^-end group P,p-Carotene p,p-Carotene (2) is the most common representative of the carotenoids and was

the first carotenoid to be synthesized. Three syntheses were reported nearly simultaneously by different authors [44-48] and, since then, many different approaches have been reported. p,p-Carotene (2) has been produced on a commercial basis since 1954 by F. Hoffmann-La Roche and since 1972 also by BASF, applying different processes. The synthesis of p,p-carotene (2) on a laboratory scale is described in

573

'Carotenoids' Volume 2 [49]. One of the most useful syntheses of p,p-carotene (2) starts from the Cig-unit 53 by application of the C19 + C2 + C19 = C40 strategy (Scheme 13) [46-48]. The C2-unit, acetylene dimagnesium dibromide (43), was condensed with the Cig-aldehyde 63, prepared from the Ci4-building block 30, to give the C4o-diol 54. Allylic rearrangement and simultaneous dehydration, partial hydrogenatlon over Lindlar catalyst and isomerization in high-boiling petroleum ether gave (all-E)-p,p-carotene (2).

Scheme 13 Zeaxanthin The 3-hydroxy-p end group is the most abundant chiral end group in carotenoids and is often called the zeaxanthin end group. Zeaxanthin (55) possesses two chiral centres at C(3) and C(3'), making possible three optical isomers, namely the (3R,3'R)isomer (most abundant in Nature) and the (3S,3'S)-isomer as well as the (3f?,3'S)-isomer which constitutes a meso-form. It is this optically inactive mixture of isomers which is usually obtained by synthesis of the so-called racemate [50]. The most important contributions to the synthesis of the optical isomers of zeaxanthin have been achieved by the research group of F. Hoffmann-La Roche. From 6oxoisophorone (56) as starting material, the chiral centre was introduced by an enantioselective fermentative reduction of the double bond with baker's yeast. Subsequent diastereoselective and regioselective reduction of the resulting diketone 57 gave a mixture of epimeric hydroxyketones, (3R)-58 and (3S)-58, which could readily be separated by Craig distribution (Scheme 14).

574

(3S)-58 Scheme 14

By reaction of the Cg-hydroxyketone (3R)-58 with isopropenyl methyl ether, the acetonide 59 was obtained. Subsequent reaction with but-3-yn-2-ol (60), acetylation and dehydration gave the diacetate 61 which was reduced with sodium bis-(2methoxyethoxy)aluminium hydride (SMEAH) to (3R)-3-hydroxy-p-ionol (62) {Scheme 15).

(3R)-58

OH 60 AcO

Scheme 15

For the synthesis of the C40 carbon skeleton the C13 + C14 +613 = 640 and the Ci5 + Cio + Ci5 = C4o strategies have been used, and the latter has been developed on a technical scale. The Ci5-phosphonium salt 63 was prepared by oxidation of 62 to (3R)-3hydroxy-p-ionone (64), followed by vinylation with 65 to the epimeric vinyl carbinols 66 and treatment with triphenylphosphine hydrochloride {Scheme 16).

Scheme 16

575

The reaction of 63 with the Cio-dialdehyde 45 gave, after isomerization, (allE,3R,3'R)-zeaxanthin (55) {Scheme 17).

Recently an efficient synthesis of the phosphonium salt 63, from the key building block (3R)-58 according to a Cg + C2 + C4 = C15 strategy, has been reported [51]. Violaxanthin The most abundant carotenoid with the 3-hydroxy-5,6-epoxy-5,6-dihydro-p end group is violaxanthin (67), which is formed in large quantities in higher plants. For the synthesis of this carotenoid in optically active form, the route Ci5 + Cio + Ci5 = C4o was used. As starting material for the synthesis of the Ci5-building block 68, the Cio-ester ketone 69 was selected, and this was protected, rean-anged and reduced to the allylic alcohol 70. Sharpless epoxidation of 70 gave, in high yield (93%) and high stereoselectivity (97% e.e.), the epoxide 71. The alcohol was oxidized by a Swern oxidation with oxalyl chloride and DMSO to the aldehyde 72. Chain elongation with the Cs-phosphonate 73 by a Horner-Emmons reaction resulted in the Ci5-ester 74 in an (E/Z)-r3i\o of 7:1. Deprotection of the ketal and simultaneous reduction of the ketone and ester groups resulted in a mixture of the diastereoisomeric diols (3/?)-75 and (3S)-75, from which the trans isomer (3S)-75 could be crystallized directly. A selective oxidation of (3S)-75 with I\/In02 gave the Ci5-aldehyde 68 which was reacted with the acetylenic C10diphosphonate 76. After hydrogenation and isomerization, (all-E)-violaxanthin (67) was obtained [52] {Scheme 18).
CO,Et OH

^
69
70

Scheme 18 {continued...,)

576

jTo

(EtO)2Pv.AxrC02Me 73
w O ^

CO,Me

Canthaxanthin Canthaxanthin (77), containing two 4-oxo-p end groups, is produced on an industrial scale by partial synthesis from p,p-carotene (2). Many different approaches for the total synthesis of canthaxanthin (77) have been investigated and recently the application of the sulphone method has proved successful. As starting material, racemic a-ionone (rac-78) was transformed, with peroxyacetic acid, to the 4,5-epoxide, which was opened to give the 4-hydroxy-p compound, that led upon oxidation to the ketone 79. Successive Grignard reaction with vinylmagnesium chloride (80), halogenation, and reaction with a sodium sulphinate gave the sulphone 81, which was transformed to the corresponding ketal 82. Reaction with the Cio-dialdehyde 45, reduction with sodium dithionite/NHa, deprotection, and isomerization gave (all-E)-canthaxanthin (77) [29,53] (Scheme 19). ^
MgCI 80

^^^
rac-78

Scheme 19 {continued...,)

577

. ^ ^ ^ CH2S02-PhCI

Scheme 19

Astaxanthin The most important carotenoid bearing 3-hydroxy-4-oxo-p-end groups is astaxanthin (83). All three stereoisomers, Le. the (3S,3'S)-83 and (3R,3'R)-83

enantiomers, and the (3/?,3'S)-meso-form [(3R,3'S)-83], have been isolated from natural sources; the (3S,3'S)-isomer [(3S,3'S)-83] occurs most abundantly. A mixture of the three stereoisomers is produced on an industrial scale and is used mainly as a feed additive in aquaculture. The first synthesis of (3S,3'S)-astaxanthin [(3S,3'S)-83] starting from the Cghydroxyketone (3f?)-58 was reported by F. Hoffmann-La Roche [56]. A technical procedure for the synthesis of (3S,3'S)-83 and (3/?,3'R)-83 starting from 6-oxoisophorone (56) has recently been developed. For the synthesis of the (3S,3'S)-isomer [(3S,3'S)-83], 6-oxoisophorone (56) was transformed to the (3R)hydroxyketone (3R)-58 which was reacted with sulphuryl chloride to produce the diastereoisomeric chloroketones (3S,5R)-84 and (3S,5S)-84. Subsequent dehydrochlorination with 5-ethyl-2-methylpyridine gave the chiral building block 85 in 92% yield referred to (3R)-58 [55,56] (Scheme 20).

CI (3S.5S)-84

Scheme 20

Different approaches have been investigated for the conversion of the building block 85 into the ketal 86, which constitutes a key intermediate in the synthesis of

578 (3S,3'S)-83. In the first approach, the functionalization was achieved by reaction of 85 with Br2 to give a mixture of the diastereoisomeric dibromoketones (4S)-87 and (4R)-87, from which, after repeated equilibration/crystallization, the desired c/s-compound (4R)-87 was isolated in 68% yield. Dehydrobromination of (4R)-87 in pyridine gave the monobromo compound 88 from which the dihydroxy compound 89 was obtained by mild hydrolysis with NaHCOa. By treatment of 89 with 2,2-dimethoxypropane, the desired synthon 86 was obtained in a yield of 4 1 % referred to 85 [Scheme 21).

Br {4S)-87

HO

/:,,

Br

Br

(4/^)-87

Br

88

OH 89

Scheme 21

According to previously described procedures [57], the chiral building block 86 was afterwards transformed to (3S,3'S)-astaxanthin [(3S,3'S)-83] in four steps in an overall yield of 48%. Alkylation of 86 with the Li derivative of the protected Ce-building block 90 gave the Ci5-dlhydroxyketone 91. Partial reduction of this with Zn/acetic acid followed by reaction with triphenylphosphine hydrobromide gave the phosphonium salt 92. According to the scheme Ci5 + Cio + Ci5 = C4o, the Wittig reaction of 92 with the dialdehyde 45, in the presence of NaOMe as base, gave (3S,3'S)-83 with an e.e. of 99.2% {Scheme 22).

Scheme 22 (continued...,)

579

(3S.3'S)-83 Scheme 22

Diatoxanthin Most of the natural acetylenic carotenoids have an acetylenic group in the 7and/or the 7'-position. An appropriate synthon to construct acetylenic carotenoids is (E)-3methylpent-2-en-4-yn-1-ol (93) which is a commercially available Ce-unit containing an acetylenic bond. Recently the synthesis of diatoxanthin (94) and its (9Z)-isomer have been reported [58,59]. A Grignard reaction of the acetylenic Ce-synthon 93 with EtMgBr and the protected 6-oxoisophorone 95 gave the Ci5-diol 96. Basic hydrolysis, recrystallization and subsequent peracetylation gave the diprotected triol 97 in optically pure form. Dehydration with POCI3 gave the diacetate 98. Deprotection and subsequent oxidation with Mn02 gave the desired end group 99 {Scheme 23).

580 For the synthesis of (aJl-E)-diatoxanthin [(all-E)-94] the strategy C15 + C10 + C15 = C40 was selected. The Cio-dial 45 was first converted into the monophosphonium salt 100 and then reacted with the acetylenic Ci5-end group 99 to give the acetylenic C25hydroxyaldehyde 101 which was reacted with the Ci5-hydroxyphosphonium salt 63 to (allE,3R,3'R)-diatoxanthin (94) {Scheme 24).

Mimulaxanthin A representative allenic carotenoid is mimulaxanthin (102), a symmetrical structure with allenic end groups. The allenic key building block 103 has been synthesized by several groups [60-66]. A rather short synthesis starts with the acetylenic Ci5-synthon 98, used for the synthesis of diatoxanthin (94). First, 98 was epoxidized with mchloroperbenzoic acid (m-CPBA) and, after separation of the diastereoisomeric (5R,6Sy 104 and (5S,6R)-104, the latter gave the allenic alcohol 105 in high yield upon reduction with DIBAH [23,67,68]. Mild oxidation to the aldehyde 103, followed by a Horner-Emmons reaction with the acetylenic Cio-bis-phosphonate 106, led to the 15,15'didehydromimulaxanthin (107). Optically active mimulaxanthin (102) was prepared by partial hydrogenation of 107 followed by a thermal (E/Z)-isomerization [69] (Scheme 25).

581

AcO

Peridinin A unique structural feature of butenolide carotenoids is a 4-alkylidenebutenolide system displaying extended conjugation at the C(9)-position. A representative butenolide carotenoid, peridinin (108), an auxiliary light-harvesting pigment for photosynthesis in some algae, is an unusual Csy-dicyclic nor-carotenoid containing an additional 4alkylidenebutenolide ring structure, and carrying an allene function in the main polyene chain. In order to accomplish the total synthesis of 108, a new synthetic methodology (the sulphone method) has been developed for the construction of the conjugated alkylidenebutenolides [27,70 - 72]. The vinyl triflate 109 is prepared in high yield by the reaction of the TBS ether 110 with A/-phenyltrifluoromethanesulphonimide (Tf2NPh) in the presence of LDA. A coupling reaction of the triflate 109 with methyl acrylate, in the presence of a palladium-(ll)-catalyst,

582

affords the diene ester 111 which, on LiAIH4 reduction followed by acetylation, is converted into the allylic acetate 112. The allylic sulphone 113 Is obtained by the reaction with sodium sulphinate, catalysed by Pd(PPh3)4. Introduction of methoxycarbonyl and allyl groups into 113 and subsequent deprotection provides the compound 114. After deprotection, regioselective oxidation of 114 at the terminal vinyl group, followed by elimination of the sulphone group, affords a mixture of the (9Z)-formyl ester (9Z)-115 and the (9E)-isomer (9E)-115. Iodine-catalysed isomerization of the latter gives a mixture (ca. 3:4) of (9Z)-115 and (9E)-115. Epoxidation of the separated (9Z)-115 with m-CPBA gives a mixture of the syn-(P)-epoxide (5S,6R)-116 and the a/?f/-(a)-epoxide (5R,6S)-116 (Scheme 26),

TBSO

TBSO

(5R.6S)-116

(5S,6R)-116 Scheme 26

The synthon (117) is derived from the optically active C22-allenic apocarotenal 118 which is prepared via a Wittig condensation of the (3S)-Ci5-allenic aldehyde 103 with the Cy-phosphonium chloride 119. Reduction of the aldehyde group in 118 (a mixture of 11Z and 11E) with NaBH4, followed by acetylation, yields the acetate 120, which is converted into the sulphone 117 by heating under reflux with sodium sulphinate in propan-2-ol and water. Condensation between the (all-E)-allenic sulphone 117 and the formyl ester (5R,6S)-116 under the conditions of the sulphone method furnishes a mixture (ca. 1:1) of the optically active peridinin (108) and its (11'E)-isomer and these are cleanly separated by preparative HPLC in the dark (Scheme 27) [70,72].

583

HO

118R' = H. R2 = CH0 120 Ri = Ac. R= = CHpAc 117 Ri=Ac. R2=CH,S0,Ph OAc

108 Scheme 27

Fucoxanthin The synthesis of fucoxanthin (121), reported by Ito is clearly a highlight in the field of carotenoid synthesis [32-74]. The carotenoid was synthesized according to the strategy Ci5 + Cio + Ci5 = C40 with the Cio-dialdehyde 45 as central unit. As the allenic precursor 103 for the Ci5-end group 122 had previously been prepared for the synthesis of peridinin (108) the emphasis was on the preparation of the 3-hydroxy-8-oxo-p end group 123,

AcO

Scheme 28 {continued...,)

584

OAc

121 Scheme 28

The key step of the synthesis is the rearrangement of the a-acetylenic alcohol 97 into the unsaturated carbonyl compound 124. This rearrangement was carried out with tris(triphenylsilyl)vanadate, triphenylsilanol and benzoic acid to give a mixture of the isomers 124 and 125. The latter was converted by iodine catalysis into the desired isomer 124. This key intermediate was afterwards transformed into the Ci5-phosphonium salt 123 by standard procedures. The Wittig olefination of the Cio-dial 45 first with the fucoxanthin end group 123 and then with the peridinin end group 122 gave, in five steps, the C4o-carotenoid 126. Finally the epoxidation of this compound resulted in optically active fucoxanthin (121) and its (5S,6R)-isomer (Scheme 28). 4.2. Carotenoids with the s end group a-Carotene In contrast to the unsubstituted p end group, the s end group possesses an asymmetric carbon atom at position 6 and therefore, in the synthesis of compounds with this end group, the stereochemistry has to be considered. The most prominent carotene with the s end group is p,E-carotene (a-carotene) (127) which possesses the (6'/?)configuration. By analogy with the synthesis of p,p-carotene (2), the strategy Ci6 + Cg + Ci6 = C40 was used for the first synthesis of a-carotene (127) [75-77]. By use of the enantiomeric (S)-(-)- and (f?)-(+)-a-ionones [(S)- and {R)-78], the naturally occurring (6'R)-p,8-carotene (127) and its enantiomer have been synthesized. This constituted the first synthesis of an optically active carotenoid [78]. The enantiomers of a-ionone (78) were obtained by resolution of the racemate via the menthylhydrazones [79]. Recently an improved route to the enantlomerically pure a-ionones [(S)- and (R)78] on a preparative scale has been developed [80]. For the synthesis of the naturally occurring (6'/^)-p,c-carotene (127), (Rj-a-ionone [(R)-78] was reacted with vinylmagnesium chloride (80) to give the Ci5-alcohol 128 which was converted into the phosphonium salt 129. The subsequent Wittig reaction with 12'apo-p-caroten-12'-al (130) and NaOMe as base gave 127 in 45% yield referred to (R)-78 (Scheme 29).

585

Lutein The most important carotenoid with the 3-hydroxy-8 end group is lutein (131), the major carotenoid found in the leaves of higher plants. For the synthesis of (3R,3'R,6'R)lutein (131), the C15 + C10 + C15 = C40 strategy was applied [81], as used previously for the synthesis of the mixture of stereoisomers [12]. Since the Ci5-phosphonium salt 63 containing the 3-hydroxy-p end group has been synthesized before, the Ci5-phosphonium salt 132, containing the 3-hydroxy-s end group, was the key building block in this synthesis. As starting material, the optically active hydroxyketone 85, which had already been used for the synthesis of optically active astaxanthin [(3S,3'S)-83], was applied. Compound 85 was first converted into the corresponding mesylate and, by reaction with tetrabutylammonium acetate, the corresponding acetate 133 with inverted stereochemistry at C(3) was obtained. After hydrolysis, the hydroxy group was protected as the isopropenyl methylether to give 134. The key step in the synthesis was the diastereoselective epoxidation of 134 with dimethylsulphonium methylide (135) to give the epoxide 136. The selectivity in this reaction can be explained by the fact that, in 134, the conformation with the protecting group in an equatorial position is highly favoured, so the attack of the ylide on the C=0 double bond takes place preferentially from one side to give an axial C-C bond. The stereoselective opening of the epoxide in 136 with a Grignard reagent gave the aldehyde 137. After chain elongation by means of a Horner-Emmons reaction with 138, the resulting nitrile was reacted with MeLi (139) and, after hydrolysis, (3R,6R)-3-hydroxy-a-ionone (140) was obtained. The reaction of 140 with vinyl magnesium chloride (80) gave the Ci5-compound 141 which was transformed into the desired phosphonium salt 132 in a yield of 30% referred to 140 {Scheme 30).

586

O AcO 133 O ^^^ IPMO 136 IPMO 137 140 (EtO)2P.^^CN 138 IPMO 134

CH^SMe, 136

PPhXI

141 Scheme 30

132

The Wittig reaction between 132 and (3/?)-3-hydroxy-12'-apo- -caroten-12'-al (142), with KOH as base, gave (all-E,3R,3'R,6'R)-lutein (131) in a yield of 25% referred to 142 (Scheme 31).
^,0H

. ^ > OH

Scheme 31

4.3.

Carotenoids with the K end group Capsorubin The 3-hydroxy-K end group is characteristic of capsorubin (28), and other

carotenoids isolated from paprika (Capsicum annuum). All syntheses are based on the 010 + 020 + 010 = 040 strategy, and use crocetindialdehyde (27) as central building block and the aldol condensation as the coupling reaction {Scheme 6). The synthesis of optically active capsorubin (28), reported in 1973, was the first synthesis of an enantiomerically pure xanthophyll [11]. For the optically active form of the key building block, the frans-Oio-hydroxyketone 26, two approaches have been reported. In the first reaction sequence, (+)-camphor (143) was converted into camphoric acid (144) by treatment with nitric acid. Camphoric acid (144) was then esterified with dimethyl sulphate

587 and the product selectively saponified with 1 equivalent of NaOH to give 145 which was decarboxylated to form the unsaturated ester 146. The crucial step in this synthesis was the regioselective and stereoselective introduction of the hydroxy group, whereby the second chirality centre was generated. The best results were obtained by hydroboration with (+)-diisopinocamphenylborane of the acetal 147, which was obtained from 146 by successive reduction, methylation and acetalization [11] (Scheme 32).

/I > ^fH 0
143 CGjMe
" /

T -r^

H02C '* \ y 144

CO2H

\
k

C02Me V "
w

\ /

"

HO2C

\ -V/ /
146

0
MeU 139

V^146

\ "/

)^ \

', : ->
" (

Scheme 32

OH 26

4.4.

Carotenoids with the y/end group Lycopene Some 50 carotenoids with an unsubstituted \\f end group have been found in

Nature, the most important one being lycopene (1). The first synthesis of lycopene (1) was reported by the school of Karrer [82] in 1950. By analogy with his pioneering synthesis of p,p-carotene (2) the Ci6 + C8 + Ci6 = C4o route was used. The first synthesis of lycopene (1) via the Wittig reaction used the strategy Cio + C2o + Cio = C4o [83]. Linalool (148) was converted, with phosphorus tribromide and triphenylphosphine, into the phosphonium salt 149, The Wittig reaction with crocetindialdehyde (27) and BuLi as base gave lycopene (1) in an overall yield of 36% referred to 148 (Scheme 33).
PPh^Br 148 149

Scheme 33

588 Phytoene (150), phytofluene (151), <;-carotene (152) and neurosporene (153), the biosynthetic precursors of lycopene (1), also contain the v|/-end group. They differ from lycopene (1) in the degree of saturation of the 7,8, 7',8', 11,12 and/or 11',12' double bond(s). Different building blocks as starting material have therefore been used for the synthesis of these compounds. (^-Carotene The synthesis of symmetrical (^-carotene (152), which has 7,8 and 7',8' single bonds, was carried out efficiently according to the C15 + Cio + C15 = C40 strategy by use of the Wittig reaction to couple the building blocks [84]. frans-Nerolidol (154) was converted, with phosphorus tribromide and triphenylphosphine, into the Ci5-phosphonium salt 155. The Wittig reaction with the Cio-dialdehyde 45 and BuLi gave ^-carotene (152) in an overall yield of 45% referred to 154 (Scheme 24).

Neurosporene The synthesis of carotenoids that are not symmetrical is more demanding and costly than that of symmetrical compounds, and different approaches have to be applied. This is illustrated by the two syntheses of neurosporene (153). By application of the C2o + C2o = C4o strategy the two different Independently and coupled In one step. In this synthesis farnesyl bromide (156) was converted, with 2-nitropropane and KOH, into farnesal (157). Horner-Emmons reaction with the Cs-phosphonate 73 and reduction with LiAIH4 gave the alcohol 158 (32% yield referred to 156) which was transformed, with phosphorus tribromide and triphenylphosphine, to the C2o-phosphonium salt 152 (Scheme 35). C2o-building blocks were synthesized

589

158

PPhaBr 159 Scheme 35

For the synthesis of the other C2o-building block, i.e. the lycopene half of the molecule, \|/-ionone (160) was used as starting material. The Grignard reaction of 160 with methoxyacetylene (161) and treatment with aqueous sulphuric acid gave the ester 162 which was reduced with LiAIH4 and reoxidlzed with Mn02 to the aldehyde 163. Subsequent condensation with the phosphonate 73, reduction and oxidation gave the C2o-aldehyde 164 in an overall yield of 12% referred to 160 (Scheme 36).
MeOZZ: H

163

164 Scheme 36

Wittig reaction of the C2o-phosphonium salt 159 with the aldehyde 164 and BuLi gave neurosporene (153) in a yield of 20% (Scheme 37).
BrPh,P V

590 Phytoene and phytofluene For the synthesis of phytoene (150) and phytofluene (151) the C20 + C20 = C40 strategy has been applied [85,86]. For the preparation of phytoene (150), transgeranyllinalool (165) was treated with phosphorus tribromide to give geranylgeranyl bromide (166) which was reacted with triphenylphosphine to give the Cao-phosphonium salt 167. The C2o-aldehyde 168 was prepared by treatment of 166 with KOH and 2nitropropane. The Wittig reaction of 167 and 168 with PrLi gave a mixture of (E/Z)isomers of phytoene (150) in an overall yield of 6% referred to 165 (Scheme 38).

Scheme 38

(all-E)-Phytofluene (151) was isolated from a mixture of (^E^j-isomers synthesized by the Wittig reaction of aldehyde 168 with the Cao-phosphonium salt 159 and BuLi (Scheme 39).
BrPh,P

168

169

Scheme 39

591 Spirilloxanthin Important carotenoids with the 1-methoxy-3,4-didehydro-1,2-dihydro-v|/ end group are spirilloxanthin (169), spheroidene and rhodovibrin. The starting material 6-methylhept-5-en-2-one (170) was converted, with methanol, into the methoxy compound 171 which was condensed with ethyl bromoacetate (172) in a Reformatsky reaction to give the ester 173. Reaction of 173 with NBS and then dehydrobromination led to the ester 174 which was reduced with LiAIH4 and transformed with triphenylphosphine hydrobromide to the Cio-phosphonium salt 175 and then coupled with crocetindialdehyde (27) in the presence of sodium methoxide as base in a Wittig reaction to give spirilloxanthin (169) in an overall yield of 2% referred to 170 [87] (Scheme 40).
MeO BrCKCOOEt 172 171 MeO

^
170 MeO

COOEt 173

COOEt 174 crocetindialdehyde 27

MeO OMe

Scheme 40

This synthesis has been improved by using the condensation of 171 with ethyl diethylphosphonoacetate (176) and sodium hydride to produce the ester 173 [88] (Scheme 41).
MeO 171 Scheme 41 (EtO)2P ^ COOEt 176 MeO

^^
173

COOEt

Rhodopin The 1-hydroxy-1,2-dihydro-v|/ end group is present in several carotenoids such as rhodopin (177). For the synthesis of the unsymmetrical carotenoid rhodopin (177) the (Cio + C2o) + Cio = C4o strategy was used and the Wittig and the Horner-Emmons reactions were applied in the key steps [89]. The Horner-Emmons reaction of 6-hydroxy-

592

6-methylhept3n-2-one (178) with methyl diethylphosphonoacetate (179) and sodium methoxide followed by reduction with LiAIH4 resulted in the alcohol 180. Treatment of 180 with phosphorus tribromide and triphenylphosphine gave the Cio-phosphonium salt 181. The Wittig reaction with apo-8'-lycopenal (182) and sodium methoxide gave rhodopin (177) in an overall yield of 20% referred to 178 (Scheme 42).
HO 178
II (Et0)2p ^

COOMe

179

180

apo-8'-lycopenal 182

Oscillol As starting material for the synthesis of oscillol (183) [90,91], the aglycone of oscillaxanthin containing two 1,2-dihydroxy-3,4-didehydro-1,2-dihydro-v|/-end groups, 3methylbut-2-en-1-ol (184) was chosen. Ester 185, obtained by the reaction of 184 with pnitrobenzoyl chloride (p-NBCI), was dihydroxylated in a Sharpless asymmetric dihydroxylatlon [92] to give the diol 186 in a yield of 59% and an e.e. of 91%. The two vicinal hydroxy groups were protected with 2,2-dimethoxypropane and the ester group was saponified to give the alcohol 187. Swern oxidation and Wittig reaction with phosphorane 188 gave the ketone 189. Grignard reaction with vinylmagnesium bromide (65), followed by treatment with phosphorus tribromide and triphenylphosphine, resulted in the Cio-phosphonium salt 190 which was deprotected with aqueous acetic acid to produce the phosphonium salt 191. The Wittig reaction of 191 with crocetindialdehyde (27) and NaOH gave (all-E,2R,2'R)-oscillol (183) in an overall yield of 3.7% referred to 184(Sc/7eme43).
HO "^^^^ 184
PhjP

'OH 185

OpNB OH 186

OpNB

OH 188 187

->

A"
\

O 1

<^

MgBr 65

189

Scheme 43 (continued....)

593

PPh^Br

pp

crocetindialdehyde 27

191 OH

183

Scheme 43

1,2-Epoxylycopene Although several acyclic epoxycarotenoids occur naturally, only two, namely 1,2epoxylycopene (192) and 1,2-epoxy-^-carotene have been synthesized. Optically active fSj-1,2-epoxylycopene (192) has been synthesized by application of the Cio + C2o + Cio = C4o strategy [22,93,94]. The chiral centre was introduced by a stereoselective fermentative reduction of a ketone with baker's yeast. Racemic geraniol epoxide (193), obtained by the reaction of geraniol with AH-CPBA, was acetylated with acetic anhydride and the epoxide opened with acid ion-exchanger Dowex 50W\o give the racemic diol 194 which was oxidized with bipyridinium chlorochromate (BPCC) to the ahydroxyketone 195. Fermentative reduction with baker's yeast gave the optically active diol 196. The epoxide 197 was obtained by treatment of 196 with mesylchloride and NaOH. Subsequent treatment with phosphorus tribromide and triphenylphosphine led to the Cio-phosphonium salt 198. The Wittig reaction with apo-8'-lycopenal (182) and sodium ethoxide led to (all-E,S)-1,2-epoxylycopene (192) in an overall yield of 1 % referred to 193 (Scheme 44).
HO OH 193 HO
^^^^^^ OAc OH 194

OAc HO
'^-^ OAc

195

OH

196
, ^ ^ ^ ^^^:>^ PPh-Br apo-8'-lycopenal 182

OAc 197

198

Scheme 44

594 2,2'-Diketospirilloxarithin The 1-methoxy-2-oxo-3,4-didehydro-1,2-dihydro-v|/ end group occurs in such carotenoids as spheroidenone and 2,2'-diketospirilloxanthin (199), which possesses a conjugated system of 15 double bonds. 2,2'-Diketospirilloxanthin (199) was synthesized via a C5 + (Cio + Cio + Cio) + C5 = C4o strategy [95]. The central Cso-building block 200 was obtained by a Wittig reaction between two moles of phosphonium salt 201 [96,97] ^and 15,15'-didehydro-12,12'-diapo-carotene-12,12'-dial (48). Aldol condensation of 200 with two moles of 3-methoxy-3-methylbutan-2-one (202) and NaOH, and then partial hydrogenation in the presence of Lindlar catalyst led to 2,2'-diketospirilloxanthin (199) in an overall yield of 38% referred to 202 (Scheme 45).

OMe Scheme 45

4.5.

Higher Carotenoids The acyclic and the cyclic C45- and Cso-carotenoids are substituted at the C(2)-

and C(2')-positions with an additional isoprenoid unit. C.p. 450 A representative of the Cso-carotenoids with a substituted [3 end group is C.p. 450 (203) which has been isolated from Corynebacterium poinsettiae. For the synthesis of that carotenoid in optically active form, the C2o + Cio + C2o = C5o strategy and the Wittig reaction were chosen [98]. For the synthesis of the chiral C2o-end group 204 {Scheme 48), (~)-a-pinene (205) was selected, and was transformed with Pb(0Ac)4 to the ester 206. Rearrangement to the (-)-frans-verbenyl ester 207 and subsequent reduction with LiAIH4 gave {-)-transverbenol (208) which was pyrolysed to give the aldehyde 209 with an e.e. of 92%. Reduction of the aldehyde to the alcohol, tosylation, reaction with sodium cyanide, and subsequent reaction of the nitrile with DIBAH, gave the corresponding Cn-aldehyde, which was reacted with ethylene glycol to give 210. This key building block was also used for the synthesis of Cso-carotenoids containing the substituted s end group. Reaction of 210 with borane-dimethyl sulphide and H2O2 gave the secondary alcohol 211 which was oxidized and deprotected to give the keto aldehyde 212 (Scheme 46).

595

209

210

211 Scheme 46

212

Compound 212 was reacted in a Horner-Emmons reaction with ethyl-2(diethoxyphosphonyl)propionate (213) to give 214. Protection of the keto group, reduction of the ester, deprotection of the keto group and protection of the hydroxy group as an acetal gave compound 215. For the chain elongation, 215 was reacted with the protected but-3-yn-3-ol (216) and the tertiary alcohol was transformed, with CICOOEt, to the carbonate 217, which was reacted with p-TsOH to give the Ci8-building block 218 (Scheme 47). o
(EtO)2P 213 COOEt EtOOC

212

1 1 JI
OH 217 Scheme 47 218

The desired building block 204 was obtained by partial reduction of the triple bond in 218, followed by successive protection of the primary alcohol, oxidation of the secondary hydroxy group to the ketone, deprotection of the alcohol, Grignard reaction with vinylmagnesium bromide (65) and acetylation. The C2o-building block 204 was converted, with triphenylphosphine hydrobromide, into the phosphonium salt 219, reaction of which with the Cio-dialdehyde 45 gave C.p. 450 (203) (Scheme 48).

596

Decaprenoxanthin For the synthesis of decaprenoxanthin (220), the best known Cso-carotenoid with substituted e end groups, the acetal 210 was epoxidized to 221. This was opened with filtrol and the resulting alcohol was oxidized to the corresponding ketone 222. For the introduction of the second chiral centre, the same approach as for the synthesis of lutein (131) was selected. Reaction of 222 with dimethylsulphonium methylide (135), followed by ring opening with a Grignard reagent, gave the aldehyde 223 with an e.e. of 87%. The Horner-Emmons reaction of 223 with 138 gave the nitrile 224 which was converted, with MeLi (139), into the a,p-unsaturated ketone 225. After deprotection of the aldehyde function, chain elongation at C(2) was achieved with another Horner-Emmons reaction with 213 to give 226 which was reacted with vinyl magnesium bromide (65) to give the protected C2o-building block 227 [99] (Scheme 49).

210

221

o II (EtO^P^CN " ^^ O 138

222

223 (EtO)2P ^COOEt I 213

224

225 Scheme 49 {continued...,)

597

EtOOC 226

MgBr 65

EtOOC 227

Scheme 4 9

The C2o-end group synthon 227 was afterwards transformed to the corresponding phosphonium salt 228 and the Wittig reaction with the Cio-dialdehyde 45 and epoxybutane as base gave the protected decaprenoxanthin 229, which was reduced to decaprenoxanthin (220) {Scheme 50).
PPh,Br

EtOX

EtOX

CO,Et

220 Scheme 50

Sarcinaxanthin Sarcinaxanthin (230), a Cso-carotenoid containing two cyclic y end groups with an additional Cs-unit was first prepared as a racemate [100]. For the synthesis of the optically active compound the C20 + C10 + C20 = C50 strategy was chosen. For the synthesis of the C2o-phosphonium salt 231, the key building block of the synthesis, camphoric acid (144) was selected as starting material [101] (Scheme 51).

Y^COOH
144

/f^COOH
Br Br, / = A 232

OTBDMS OH

pph^cH.,Br233 ^

OTBDMS J \ / < 234

^^^
235

s?<^'

Br

A,o^".
236

AcO"

S c h e m e 51

(continued...,)

598

AcO"

AcO"

PPh3 188

AcO"

238

240
(EtO),?. .COOEt I 2

247

231

Reduction of 144 with NaBH4 and BFs-etherate and the subsequent selective protection with f-butyldimethylsilyl chloride (TBSCI) gave 232. The Swern oxidation and a Wittig reaction with MePPhsBr 233 gave the protected alkene 234, which was deprotected with tetrabutyjammonium fluoride and acetylated to 235. In the key step the acetate 235 underwent a rearrangement with 2,4,4,6-tetrabromocyclohexa-2,5-dienone to give the cydohexane derivative 236 that was epoxidized with /77-CPBA to 237. Subsequent dehydrohalogenation with 1,8-diazabicyclo[5,4,0]undec-7-ene yielded 238 containing the desired exocyclic double bond. Opening of the epoxide 238 with a Grignard reagent gave the aldehyde 239 that was immediately reacted with the phosphorane 188 to give the a,p-

599 unsaturated ketone 240. Reaction with ethylene glycol, basic hydrolysis and tosylation with TsCI afforded 241, which was reacted with NaCN 242 to give the nitrile 243. The nitrile 243 was reduced with DIBAH, and Horner-Emmons reaction with the phosphonate 213 gave the a,p-unsaturated ester 244. AftenA/ards careful reduction with DIBAH gave the alcohol 245. The two diastereoisomers of 245 were separated by column chromatography to give (2R,6S)-245 and (2R,6/?)-245. The latter was deprotected to give the ketone 246. The Grignard reaction with vinylmagnesium bromide (65) and selective protection gave the end group 247. Reaction with triphenylphosphine hydrobromide led to the desired phosphonium salt 231, which was coupled with the Cio-dial 45 in a two phase reaction with 5% NaOH in water/CH2Cl2 to give directly the deprotected sarcinaxanthin (230) (Scheme 51). Bacterioruberin The synthesis of racemic bacterioruberin (248), reported in 1979, was the first synthesis of a Cso-carotenoid [102]. The optically active end groups of bacterioruberin (248), bisanhydrobacterioruberin (249) and tetrahydrobisanhydrobacterioruberin (250) have been synthesized from the common building block 251 [103,104]. The chiral starting material fRJ-3-hydroxybutyric acid (252) was esterified with ethanol to produce the p-hydroxyester 253, which was alkylated with dimethylallylbromide (254) in the presence of LDA to give the Cg-ester 255. The benzyl ester 256 was obtained by reduction of 255 with LiAIH4 and protection with benzoyl chloride. Oxidation with PCC on AI2O3 and protection of the keto group with glycol formed the acetal 257. Saponification of this with KOH followed by oxidation with chromic anhydride and pyridine gave aldehyde 258 which was elongated with acetylmethylene-triphenylphosphorane (188) in a Wittig reaction to give the Ci2-keto acetal 259. Reduction of 259 with NaBH4 and acid-catalysed hydrolysis of the acetal gave the hydroxyketone 260. The Grignard reaction with methylmagnesium bromide (261) and oxidation with chromic anhydride in pyridine led to the building block 251 in an overall yield of 13% referred to 252 (Scheme 52).
OH O

AJt.
252

OH

OH

A ^
253

-^'^-^Br

JL ^

254
>

--^^-'^^GEt Jl 255

Scheme 52 (continued...,)

600

PPh,

188

HO CHaMgBr 261

^^
251

Scheme 52

For the synthesis of the end group of (2S,2'S)-bacterioruberin (248) [25,105], the hydroxyketone 251 was epoxidized with /77-CPBA to the epoxide 262. Treatment with LiAIH4 provided simultaneous ring opening of the epoxide and reduction of the carbony! group to give the triol 263 which was oxidized with chromic anhydride in pyridine to the dihydroxyketone 264. Chain elongation with vinylmagneslum bromide (65) in a Grignard reaction and treatment with triphenylphosphine hydrobromide gave the Ci5-phosphonium salt 265. The Wittig reaction with crocetindialdehyde (27) and sodium methoxide gave (2S,2'S)-bacterioruberin (248) in an overall yield of 9% referred to 253 {Scheme 53).
HO HO HO OH

^^

^<:^262 OH 263

261

OH crocetindialdehyde 27

265 OH

Scheme 53

601

Bisanhydrobacterioruberin The end group of (2S,2'S)-bisanhydrobacterioruberin (249) [94,106] was obtained from 251 by treatment with vinylmagnesium bromide (65) followed by conversion into the phosphonium salt 266 with triphenylphosphine hydrobromide. Wittig reaction of 266 with crocetindialdehyde (27) and NaOH afforded (2S,2'S)-bisanhydrobacterioruberin (249) {Scheme 54). o
crocetindialdehyde 27

Tetrahydrobisanhydrobacterioruberin The (2R,2'R)-3,4,3',4'-tetrahydrobisanhydrobacterioruberin end group 267 has been obtained by regioselective reduction of the a.p-unsaturated ketone 259 with copper(l)-chloride, sodium f-butoxide, triphenylphosphine and hydrogen. The resulting ketone 268 was then elongated with vinylmagnesium bromide (65), and deprotected to give ketone 269 which was reacted with methylmagnesium bromide (261) and triphenylphosphine hydrobromide to give the phosphonium salt 267. A Wittig reaction with crocetindialdehyde (27) gave (2R,2'R)-3,4,3',4'-tetrahydrobisanhydrobacterioruberin (250) in 5% yield referred to 259 [105,107] {Scheme 55).

Scheme 55 (continued...,)

602

4.6.

Diapocarotenoids Methylbixin The most important acyclic apocarotenoids are the C2o-cliapocarotenoids

crocetindialdehyde (27), crocetin, and bixin, which contains 24 carbon atoms in the skeleton. The synthesis of the natural (9Z)-methylbixin (270) was accomplished by application of the Cy + Cio + 67 = C24 strategy [108,109]. Condensation of the lactone 271 with the phosphonate 272 led to the (E/Z) mono ester 273 which was converted, with thionyl chloride, into the acid chloride; subsequent reduction with lithium tributoxyaluminium hydride resulted in the Cy-aldehyde 274 in an overall yield of 22% referred to 271 {Scheme 56).
P0(0Et)2 \ 272

HO ^

o o
271 273

MeO,C GOGH 274

Scheme 56

The (a\\-E)'Cj building block 275 was synthesized from methyl 4-bromo-3methylcrotonate (276). The Krohncke reaction of 276 with p-nitrosodimethylaniline gave the aldehyde 277 which was reacted with ethyl orthoformate and reduced with LiAIH4 to give the alcohol 278. Treatment of 278 with acetic anhydride and tartaric acid resulted in the acetate 279 which was reacted with phosphorane 280 in a Wittig reaction to give the ester 281. The acetoxy group was converted into a phosphorane group by reaction with triphenylphosphine hydrobromide and NaOH. The Wittig reaction of the product 275 with the Cio-dialdehyde 45 and sodium methoxide gave the Ciy-aldehyde 282 which was reduced with NaBH4. The phosphorane 283 was then obtained by treatment with triphenylphosphine hydrobromide and sodium methoxide. The Wittig reaction of 283 with aldehyde 274 and sodium methoxide resulted in natural (9Z)-methylbixin (270) in an overall yield of 0.4% referred to 276 (Scheme 57).

603
OEt 1^16020-^"^ 276 AcO^ PhjP ^ Br _ 1^6020-^ ^ ^ ^ ^ O 277 COjMe 280 AQO

->

\ ^ ^ ^ ^ Y ^ OEt
278 CO,Me

->

- - T O 279
,C02Me

Cio-clialdehyde45

O^ 282 MeOX CO.Me 274 ^O

275

283

5.

TECHNICAL SYNTHESES Synthetic carotenoids have been produced on an industrial scale since 1954 by F.

Hoffmann-La Roche Ltd. and since 1960 by BASF and the field has recently been reviewed [30,110]. It was estimated that in 1995 the sales of synthetic nature-identical carotenoids approached in total US $ 500 million. Of the more than 600 naturally occurring carotenoids [4,35] only six are produced industrially. Figure 7 gives the formulae of these carotenoids and their main application.
p.p-Carotene (2) margarine, juice, health food (antioxidant) fertility (cattle)

Canthaxanthin (77)

poultry (egg yolk and broiler skin pigmentation)

604

Astaxanthin (83)

aquaculture (salmonoidae, crustaceae)

Ethyl 8'-apo-p-caroten-8'-oate (286)

poultry (egg yolk and broiler skin pigmentation)

v:^.^ N>s^ v ^ ^ > ; s ^ s > ^ ^ s ^ ^ ^ ^ O

8'-Apo-p-caroten-8'-al (287)

cheese, dressings

^^/^^vv/^:^/<N.x-<>/^^/^^^ <^^ < ^o

Cltranaxanthin (292)

poultry (egg yolk pigmentation)

Figure 7

5.1

Synthesis

offi^Carotene

The first industrial synthesis of p,p-carotene (2) followed the C19 + C2 + Cig = C40 strategy with a Grignard reaction for the coupling of the building blocks (see Scheme 13). Other processes have been developed, following the strategy C15 + C10 + C15 = C40 and C20 + C20 = C40 applying the Wittig reaction for the construction of the carbon skeleton [111-114] (Scheme 58).

Scheme 58 {continued...,)

605

XPh,P

285

Scheme 58

The Ci5-phosphonium salt 284, a key intermediate also in the industrial synthesis of vitamin A (29), is reacted in a double Wittig olefination with the Cio-dial (45) to give p,pcarotene (2) in an overall yield of ca. 80% [111,112]. Alternatively also the Wittig reaction of retinal (33) with retinyltriphenylphosphonium salt (285) gives 2 in yields up to 85% [113,114]. 5.2. Synthesis of apo-j3-carotenoids The commercial apo-p-carotenoids ethyl 8'-apo-p-caroten-8'-oate (286) and 8'-apop-caroten-8'-al (287) may be prepared from the Cig-aldehyde 53, used in the synthesis of p,p-carotene (2). By reaction of 53 with the Ce-acetal 288 the C25-aldehyde 15,15'didehydro-12'-apo-p-caroten-12'-al (289) is obtained [115]. This compound can be transformed into the Cso-aldehyde 287 by consecutive enol ether condensations first with vinyl ethyl ether (17), to give the C27-aldehyde 290, and then with prop-1-enyl ether (18), followed by partial hydrogenation and isomerization [116] (Scheme 59
OEt ,0

606

Ethyl 8'-apo-p-caroten-8'-oate (286) can be synthesized by Wittig olefination of 15,15'-didehydro-C27-aldehyde 290 with 291 [117] {Scheme 60 o
PhgP 291

In another approach to the technical synthesis of the apocarotenoids 286, 287 and 292 [118] the C25-aldehyde 12'-apo-p-caroten-12'-al (293) is the key intermediate. Several ways to synthesize this compound have been developed, applying the Wittig reaction to couple the building blocks. By the reaction of the C25-aldehyde 293 with the protected Cs-phosphonium salt 294 the Cao-aldehyde is obtained [119,120], and this can be transformed by a base-catalysed aldol condensation with acetone (295) to give the C33-ketone citranaxanthin (292) [121]. Alternatively the Cas-aldehyde 293 can be reacted in a Horner-Emmons reaction with the Cs-phosphonate 296 to give 292 [122] {Scheme 61).

286

Scheme 61 (continued...,)

607

5.3.

C4(rXanthophylls Although total syntheses of canthaxanthin (77) have been developed, no industrial

implementation of these methods has followed and currently 77 is produced by oxidation of p,p-carotene (2). For this transformation several procedures have been elaborated, such as reaction of 2 with NBS [123], followed by hydrolysis of the resulting intermediate or oxidation with oxyhalo acids [124,125] (Scheme 62).

NBS CHCI3/HOR

NBS. CHCI3/HOAC

RO

CJC^
OR
hydrolysis

(DAc

i ^
f >60% hydrolysis dehydrogenation

j NaCIOJNal] CH^CIj/HjG > 65 %

1r

0 II

Scheme 62

In the 1970s, F. Hoffmann-La Roche developed a new strategy for the synthesis of a great number of xanthophylls, starting from the readily available 6-oxoisophorone (56) [16]. Since 1984 the synthesis of astaxanthin (83), as a mixture of the three stereoisomers, has been carried out industrially. First, the starting material 6oxoisophorone (56) was transformed to the ketal rac-86 and the subsequent reaction with the acetylide 297 gave the Ci5-building block rac-91 which was aftenA^ards transformed to the phosphonium salt rac-92. The Wittig olefination with the Cio-dial 45, followed by thermal isomerization, gave astaxanthin (83) [26,126] {Scheme 63).

608

Acknowledgements: We are grateful to F. Hoffmann-La Roche Ltd., Basel and the Swiss National Foundation for the support of our research in carotenoid synthesis. The authors thank Dr. G. Britton, University of Liverpool for linguistic help and BIrkhauser Verlag, Basel for the copyright of parts of the manuscript. References [1] P. Karrerand E, Jucker, Carotinoide, Birkhauser, Basel 1948; English Translation, (Carotenoids, translation E. A. Braude), Elsevier, Amsterdam, 1950. [2] Carotenoids, ed. O. Isler, Birkhauser, Basel, 1971. [3] Key to Carotenoids, ed. O. Straub, Birkhauser, Basel, 1976. [4] Key to Carotenoids, 2nd Edition, ed. H. Pfander, Birkhauser, Basel, 1987. [5] Carotenoids Vol. 1A, Isolation and Analysis, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1995. [6] Carotenoids Vol. IB, Spectroscopy, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1995. [7] Carotenoids Vol 2, Synthesis, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel. 1996. [8] O. Isler, R. Ruegg and U. Schwieter, Pure Appl. Chem., 14 (1967) 245. [9] B. C. L Weedon, Pure Appl. Chem., 14 (1967) 265. [10] B. C. L. Weedon, Pure Appl. Chem., 20 (1969) 531. [11] B. C. L Weedon, Pure Appl. Chem., 35 (1973) 113. [12] B. C. L Weedon, Pure Appl. Chem., 47 (1976) 161. [13] S. M. Makin, Pure Appl. Chem., 47 (1976) 173. [14] F. Kienzle, Pure Appl. Chem., 47 (1976) 183. [15] H. J. Bestmann, Pure Appl. Chem., 51 (1979) 515. [16] H. Mayer. Pure Appl. Chem., 51 (1979) 535. [17] H. Pfander, Pure Appl. Chem., 51 (1979) 565. [18] R. K. Mulier, K. Bernhard and M. Vecchi, in Carotenoid Chemistry and

609 Biochemistry, ed. G. Britton and A. T. W. Goodwin, lUPAC-Pergamon, Oxford, 1982, p. 27. H. Mayer, in Carotenoid Chemistry and Biochemistry, ed. G. Britton and A. T. W. Goodwin, lUPAC-Pergamon, Oxford, 1982, p. 55. A. Ruttimann, in Carotenoid Chemistry and Biochemistry, ed. G. Britton and A. T. W. Goodwin, lUPAC.Pergamon, Oxford, 1982, p. 71. G. Pattenden, in Carotenoid Chemistry and Biochemistry, ed. G Britton and A. T. W. Goodwin, lUPAC-Pergamon, Oxford, 1982, p. 87. H. Pfander, Pure Appl. Chem., 57 (1985) 735. E. Widmer, Pure Appl. Chem., 57 (1985) 741. M. Julia, Pure Appl. Chem.. 57 (1985) 763. H. Pfander, in Carotenoids: Chemistry and Biology, ed. N. I. Krinsky, M. M. Mathews-Roth and R. F. Taylor, Plenum Press, New York, 1990, p. 125. K. Bernhard, in Carotenoids: Chemistry and Biochemistry, ed. N. I. Krinsky, M. M. Mathews-Roth and R. F. Taylor, Plenum Press, New York, 1990, p. 337. M. Ito, Pure Appl. Chem., 63 (1991) 13. H. Pfander, Pure Appl. Chem., 63 (1991) 23. K. Bernhard and H. Mayer, Pure Appl. Chem., 63 (1991) 35. J. Paust, Pure Appl. Chem., 63 (1991) 45. H. Mayer, Pure Appl. Chem., 66 (1994) 931. M. Ito, Y. Yamano, S. Sumiya and A. Wada, Pure Appl. Chem., 66 (1994) 939. lUPAC Commission on the Nomenclature of Organic Chemistry and lUPAC-lUB Commission on Biochemical Nomenclature, Pure Appl. Chem., 41 (1975) 407. B. C. L. Weedon and G. P.Moss, in Carotenoids Vol 1 A, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, BIrkhauser, Basel, 1995, p. 27. D. Kull and H. Pfander, in Carotenoids Vol. 1A, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1995, p. 295. M. Soukup, P. Spurr and E. Widmer, in Carotenoids Vol. 2, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1996, p. 7. H. Ernst, in Carotenoids Vol. 2, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1996, p. 79. L. Labler, A. Ruttimann and A. Giger, in Carotenoids Vol. 2, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1996, p. 27. P. S. Manchand, in Carotenoids Vol. 2, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel. 1996, p. 55. O. Isler, W. Huber, A. Ronco and M. Kofler, Helv. Chim. Acta, 30 (1947) 1911. M. Julia and D. Arnould, Bull. Soc. Chim. Fr., 33 (1977) 2799. J. Otera, in Carotenoids Vol. 2, ed. G. Britton, S. Liaaen-Jensen and H.Pfander, Birkhauser, Basel, 1996, p. 103. R. K. MuHer, in Carotenoids Vol. 2, ed. G. Britton, S. Liaaen-Jensen and H. Pfander, Birkhauser, Basel, 1996, p. 115. P. Karrer and C. H. Eugster, Helv. Chim. Acta, 33 (1950) 1172. N. A. Milas, P. Davis, I. BeliD and D. Fie, J. Am. Chem. Soc, 72 (1950) 4844. H. H. Inhoffen, H. Pommer and F. Bohlmann, Liebigs Ann. Chem., 569 (1950) 237. H. H. Inhoffen, F. Bohlmann, K. Bartram, G. Rummert and H. Pommer, Liebigs Ann. Chem., 570 (1950) 54. H. H. Inhoffen, H. Pommer and F. Westphal, Liebigs Ann. Chem., 570 (1950) 69. J. Paust and P. S. Manchand, Carotenoids Vol. 2, ed. G. Britton, S. LiaaenJensen and H. Pfander, Birkhauser, Basel, 1996, p. 327. 0. Isler, H. Lindlar, M. Montavon, R. Ruegg, G. Saucy and P. Zeller, Helv. Chim. Acta, 39(1956)2041. M. Soukup. E. Widmer and T. LukaD, Helv. Chim. Acta, 59 (1976) 1832.

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611 R. Gebhard, K. van der Hoef, A. W. M. Lefeber, C. Erkelens and J. Lugtenburg, Red. Trav. Chim. Pays-Bas, 109 (1990) 378. [89] R. Bonnett, A. A. Spark and B. C. L. Weedon, Acta Chem. Scand., 18 (1964) 1739. [90] M. Pfister, Ph.D. thesis, University of Berne 1991. [91] B. Traber and H. Pfander, Helv. Chim. Acta, 79 (1996) 499. [92] K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J. Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu and X.-L. Zhang, J. Org. Chem., 57 (1992) 2768. [93] M. Kamber, H. Pfander and K. Noack, Helv. Chim. Acta, 67 (1984) 968. [94] H. Pfander, M. Kamber and Y. Battegay-Nussbaumer, Helv. Chim. Acta, 63 (1980)1367. [95] U. Schwieter, R. Ruegg and O. Isler, Helv. Chim. Acta, 49 (1966) 992. [96] P. S. Manchand. R. Ruegg, U. Schwieter, P. T. Siddons and B. C. L Weedon, J. Chem. Soc, (1965) 2019. [97] U. Schwieter, H. Gutmann, H. Lindlar, R. Marbet, N. Rigassi, R. Ruegg, S. F. Schaeren and O. Isler, Helv. Chim. Acta, 49 (1966) 369. [98] H. Wolleb and H. Pfander, Helv. Chim. Acta, 69 (1986) 646. [99] M. Gerspacher and H. Pfander, Helv. Chim. Acta, 72 (1989) 151. [100] J. P. Ferezou and M. Julia, Tetrahedron, 46 (1990) 475. [101] M. Lanz and H. Pfander, Abstr. 11th Int. Carotenoids Symp., P57, Leiden,1996,. [102] J. E. Johansen and S. Liaaen-Jensen, Tetrahedron Lett., 12 (1976) 955. [103] A. Kramer and H. Pfander, Helv. Chim. Acta. 65 (1982) 293. [104] A. Kramer and H. Pfander. Helv. Chim. Acta, 67 (1984) 21. [105] I. Lakomy, D. Sarbach, B. Traber, C. Arm, D. Zuber, H. Pfander and K. Noack, Helv. Chim. Acta, submitted. [106] R. Muggli, R. Balmer and H. Pfander, Abstr. 10th. Int. Symp. Carotenoids, P2-3, Trondheim 1993. [107] D. Sarbach, Diploma work. University of Berne 1994. [108] B. C. L. Weedon, Chem. Brit, 3 (1967) 424. [109] G. Pattenden, J. E. Way and B. C. L.Weedon, J. Chem. Soc. C (1970) 235. [110] J. Paust, in Carotenoids Vol. 2, ed. G. Britten, S. Llaaen-Jensen and H. Pfander, Birkhauser, Basel, 1996, p.259. [ I l l ] H. Pommer and W. Sarnecki to BASF AG, Ger. Pat. 1068 710 (1959). [112] H. Pommer and W. Sarnecki to BASF AG, Ger. Pat. 1068 702 (1958). [113] H. Pommer and W. Sarnecki to BASF AG, Ger. Pat. 1068 709 (1958). [114] W. Sarnecki, A. Nurrenbach and W. Reif to BASF AG, Ger. Pat. 1155 126 (1962), 1158 505(1962). [115] R. Ruegg, H. Lindlar, M. Montavon, G. Saucy, S. F. Schaeren, U. Schwieter and O. Isler, Helv. Chim. Acta, 42 (1959) 847. [116] R. Ruegg, M. Montavon, G. Ryser, G. Saucy, U. Schwieter and O. Isler, Helv. Chim. Acta, 42(1959)854. [117] O. Isler, W. Guex, R. Ruegg, G. Ryser, G. Saucy. U. Schwieter, M. Walter and A. Winterstein, Helv. Chim. Acta, 42 (1959) 862. [118] J. Paust, Chimia 48 (1994) 494. [119] S. M. Makin, Zh. Obshch. Khim., 32 (1962) 3159. [120] H. Freyschlag, W. Reif, A. Nurrenbach and H. Pommer to BASF AG, Ger. Pat. 1211 616(1963). [121] H. Yokoyama and M. J. White, J. Org. Chem., 30 (1965) 2481. [122] W. Stilz and H. Pommer to BASF AG, Ger. Pat. 1109 671 (1958). [123] F. J. Petracek and L. Zechmeister, J. Am. Chem. Soc, 78 (1955) 1427. [124] J. Morel to Rhone-Poulenc S. A., US Pat. 3646 149 (1972), 3790 635 (1972). [88]

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

613

Structure Elucidation of Phenylpropanoid Wood Extractives

Shuji Ozawa, Takashi Sasaya and Sansei Nishibe
1. INTRODUCTION Woody plants are capable of synthesizing a wide range of phenylpropane derivatives including lignans, neolignans, coumarins and flavonoids. Among them, lignans can be generally characterized as stereospecifically structures and show can bridged varied oxidative be coupling products as 1). of two phenylpropane units, linking them by lignan dibenzylbutyrolactones, naphthalenes neolignans bonds, and are known 8, 8' bonds. The principal dibenzylbutanes, tetrahydroand 8-0-4' Alternatively, furofurans, 3.3', 8.3' as

recongnized (ref. such

tetrahydrofurans, biphenyls structures as being linked via

dihydrobenzofurans,

biphenyls, and phenylalkylethers. Although a number of reviews of lignan and neolignan structures are available (refs. 1,2,3,4,5) the recent book edited by Ayres and Loike gives a comprehensive description of the chemistry of lignan and neolignan (ref. 6 ) . In many woody plants, gymnosperms, and angiosperms, lignans and neolignans structural are important of constituents (refs. 7-10) exhibiting lignans, sachallnensis, various biological activities (ref. 11). This review deals with the elucidation phenylpropanoid derivatives, neolignans and sesquilignans from woody plants, Abies

Salix

sachalinensis,

Chosenia

arbutlfolia

and Eucommia

ulmoides,

which has been carried out by our laboratory.

2. Studies on Lignans, Neolignans and Sesquilignans from

Abies

sachalinensis
Abies

Masters
(Japanease name: todomatsu) has long been a

sachalinensis

major forest species and widely planted in Hokkaido. The timber is largely used for pulp and in housebuilding. In previous studies on extractives of Larix leptolepis (Japanease name: karamatsu) (refs. 12-16), various lignans, neolignans, and higher oligomeric forms of phenylpropanes were isolated. They were in good agreement with the hydrolysis products of lignins. In connection with our interest in

614
the relationship between lignans and lignin, we recently focused our attention on the chemical studies of lignans and neolignans from A. sachalinensls. Thus^ fourteen lignans, three neolignans and two sesquilignans were isolated from the ethanol extract of the wood of

A.

sachalinensls.
The wood of A. sachalinensls was extracted with 95 % EtOH. of the diethyl ether

2.1 Lignans (refs. 17,18,19-22) Repeated silica-gel column chromatographies

solubles of the EtOH extract resulted in the isolation of fourteen lignans(1-14). Among them, four compounds (1-4) were represented in the examples of naturally occurring lignan lactols and acetals, and were characteristic lignans of A. sachalinensls. Compound 1, todolactol B, was obtained as colorless crystals, mp 181-182*'Cf [a]j5 +38.8'' (c=0.33, acetone). The molecular formula, ^20^22^6("^/z 358.1449), was based on the result of high-resolution mass spectrometry (HR-MS). The ^H- and ^-^C-NMR analyses of 1 and its triacetate la epimers spectrum proton compound having of in a 1, indicated that compound a 1 existed as a mixture of structure. and The ^H-NMR were that hydroxytetrahydrofuranyl doublets at 6 5.34 and

spectral data of 1 and la are summarized in Table 2.1. In the ^H-NMR broad 5.04, which suggested integrated in a total of one proton, were assigned to a hydroxy hydroxyfuranyl structure, this

1 existed as a mixture of epimers. This observation was

further supported by the appearance of broad double doublets at 6 5.20 and 5.41 due to a hemiacetal proton (H-9). The interpretation of the proton spin-spin coupling pattern of la was made with ^ H ^ H COSY (ref. 18). Thus, the correlation between H-9 (6 6.09 and 6.39) and and H-8 (6 2.10-2.36) was observed, and also H-7 (6 2.86-3.24) was correlated with only H-8. H-8' (6 2.46) was correlated with H-8, H-7', and H-9'. The ^^C-NMR spectral data of 1 are listed in Table 2.3. The confound carbons 1 gave rise partly as a mixture to a set of of signals The because absolute existed epimers.

configuration of 1 was determined by CD spectrum. Compound 1 had a negative Cotton effect at 292 nm, suggesting the S-configuration at the 7'-position (ref. 23). Also, CD curve of 1 exibited positive

615

MeO

OMe 0R1 1 :R=H la: R=Ac 2 : Ri=H, R2=Me 2a: Ri=Ac, R2=Me 3 : Ri=H, R2=Et 3a: Ri=Ac, R2=Et 4 :R=H 4a: R=Ac

OMe

H O f ^ O H .^N.^^^^OMe HI.-)("H HlH.)

(H.IH

MeO HO

HO OMe

OMe

R0H2Cv_^^^^v,^,^^v:. OMe HO OMe 8 :R=H 9 : R=p-coumaroyl 10: R=feruloyl

HOH2C

OMe 11

OMe 12

616
Cotton effects it at with 275 and 238 CD nm. curve This of confirms the that the

stereochemistry at 8- and 8' -positions was in an R configuration by comparing the corresponding tetrahydronaphtalene-type lignan (ref. 24). From the above results. Compound 1 was identified with structure 1, and named todolactol B (refs. 17,18). In the investigation of the extractives of the same souce, an optically active lignan, todolactol B lignin (ref. 25). Compound 2, todolactol C, was isolated as colorless crystals, mp 195-196*'C, [a]j5 +49.0 (c=0.51, MeOH), and its molecular formula, ^21^24^6 ( " ^ / 2 372.1555), was based on the result of HR-MS. The EI-MS (1) was obtained from the hydrolysis products of the solvent-soluble polymer, Brauns

of 2 exhibted a M " * " at m/z 372 and a base ion peak at m/z 340 attributable to [M^ - MeOH]. The ^H- and ^^C-NMR analyses of 2 and its acetate 2a indicated that compound 2 was a lignan having a

methoxytetrahydrofuranyl structure. In the ^H-NMR of 2 (Table 2.2),

Table 2.1

^H-NMR data for compounds 1 and la 1^) la^ 2.86-3.24 m 2.10-2.36 m 6.09 d(5.9) and 6.39 d(4.4) (IH) ^) 2.46 m 4.03 pt(8.1), 3.66 dd(8.1, 9.9) 6.50 s(lH), 6.62-6.78 m(3H) 3.74 s and 3.76 s(3H), 3.81 s and 3.82 s(3H)

7 8 9 7' 8' 9' arom. OMe OH

alc-OAc ph-OAc

2.74-3.08 m 2.00 m and 2.29 m(lH) 5.20 br dd(6.0, 6.0) and 5.41 br dd(4.4, 4,4)(1H) 3.56-3.84 m 2.55 m 3.48 dd(8.0, 10.0), 3.56-3.84 m 6.23 s(lH), 6.60-6.82 m(4H) 3.78 s and 3.79 s(3H), 3.81 s(3H) 5.04 br d(4.8) and 5.34 br d(6.0)(lH), 7.21 br s and 7.25 br s(lH), 7.44 br s(lH) b ) : In CDCI3.

2.09 s and 2.12 s(3H) 2.23 s(3H), 2.31 s(3H)

(270 MHz) a ) : In acetone-dg.

c ) : Overlapped with OMe signals.

617 Table 2.2 H 7a 7b 8 9 7' 8' 9'a 9'b arom. ^H-NMR data for compounds 2, 2a and 3a 2a) 2.91 m 2.91 m 2.03 m 4.94 d(4.4) 3.65 d(11.4) 2.76 m 3.55 dd (9.9, 7.9) ca 3.76) 6.22 S(1H), 6.73 m(4H) 3.31 s, 3.78 3.80 s 7.23 s, 7.45 Sr

2a^) 2.93 dd (16.1, 5.1) 3.10 dd (16.1, 12.5) 2.12 m 5.00 d(4.8) ca 3.77> 2.49 m 3.60 dd (9.9, 7.9) 3.90 pt(7.9) 6.47 S(1H), 6.70 m(3H) 6.96 d(8.1)(lH) 3.38 s, 3.74 s, 3.81 s 2.23 s, 2.31 s -

3ai^)
2.92 dd

OMe OH OAC CH2 in Et Me in Et

(16.1, 5.1) 3.13 dd (16.1, 12.5) 2.10 m 5.11 d(4.8) 3.77 m 2.49 m 3.58 dd (9.9, 8.1) 3.90 pt(8.1) 6.48 S(1H) 6.71 m(3H) 6.96 d(8.1)(lH) 3.75 s, 3.81 s 2.23 s, 2.31 s 3.46 m, 3.77 m 1.19 t(7.0)

(270 MHz) a ) : In acetone-dg. b ) : In CDCI3.

c ) : Overlapped with OMe signals.

a singlet at 6 3.31 was due to an acetal methoxyl group. The signal for an acetal methine was observed at 6 4.94 as a doublet (J'=4.4 Hz) which must exist in the axial orientation because the chemical shift of C-9 (6 105.71) in the ^^C-NMR spectrum (Table 2.3) suggested that the acetal methoxyl group was attached to the 9-position in the eguatrial orientation (ref. 17). Furthermore, the NOESY experiments were performed to show the spatial relationships of protons. orientation of the axial a trans configuration The existence of a weak NOE effect between H-9 and H-8' requires the H-9 consistence with the above assingnment. for them. The absolute configuration of Moreover, there was no NOE effect between H-8 and H-8* which implies Compound 2 was determined on the chiroptical properties which agreed with those of todolactol B (1). Thus, compound 2, named todolactol

618
Table 2.3 I^C-NMR spectral data for compounds 1, 2 and 3 la) 128.59 128.17 112.55 148.50 146.20 146.23 116.43 116.53 137.53 137.00 c) 32.15 47.28 50.39 99.02 104.35 133.67 113.10 113.06 146.88 146.91 145.38 145.58 115.70 122.01 51.36 50.15 46.51 72.32 71.20 56.31 56.23 2^) 128.39 112.51 148.52 146.23 116.43 137.38
c)

c
1 2 3 4 5 6 7 8 9 1' 2' 3' 4' 5' 6' 7' 8' 9' arom.-OMe 9-OMe Me in Et CH2 in Et

3b) 129.03 112.50 149.04 146.79 117.26 137.77 30.63 47.78^) 105.11 134.63 113.48 147.41 145.94 116.51 123.11 52.30 47.73d) 73.29 56.85 56. .82 16.34 63.84

47.08^) 105.71 133.65 113.06 146.89 145.44 115.76 122.01 51.43 46.95^) 72.58 56.31 56.23 54.70 -

(270 MHz) a) In acetone-dg.

b) In dioxane-dg. d) Signals may be reversed.

c) Hidden under solvent signal,

C, was concluded to be structure 2 (ref. 18). Compound 3, todolactol D, [a]jj +56.1 (c=0.46, acetone), was

isolated as yellowish amorphous. The molecular formula was found to be C22H260g (m/z 386.1726) from the HR-MS. The EI-MS had a M " ^ peak at m/z 386 and a base ion peak at m/z 340. The latter was caused by the elimination of a mole of water from the M " * " . Interpretation of the ^HNMR and ^^C-NMR indicated that compound 3 had an acetal structure. Acetylation of 3 yielded diacetate 3a. In the ^H-NMR of 3a (Table

2.2), the triplet at 6 1.19 originated from the methyl protons in the ethoxy group. This signal was coupled with two multiplets (6 3.46 and 3.77) which can be assigned to the non-equivalent methylene protons in the ethoxy1 group. The other peaks were very similar to

619 those of 2a. Comparison of the ^^C-NMR spectra of 3 with that of 2 showed their close structural resemblance (Table 2.3). Moreover, the chiroptical features of 3 were compatible with those of todolactol B (1) and C (2). Consequently, compound 3 was to be the structure 3, and named todolactol D (ref. 18). The possibility exists that the ethoxy acetal 3 may be artifacts since ethanol was used as the as a true extraction solvent. Thus, the status of this compound natural product is uncertain. Compound 4, todolactol A, [a]^ -80.6** (c=1.02, dioxane) was

isolated as colorless crystals, and its molecular formula, C20H24O7 (m/z 376.1555), was determined by HR-MS. The ^H-NMR spectrum of 4 suggested the presence of six aromatic protons groups. Also the structure of 4 was and two methoxyl to be a suggested

dibenzylbutyrolactol derivative by the '^H-NMR spectrum of 4 and its acetate 4a. The wood of A. sachallnensis such as todolactol B contains some cyclolignans (4), and it (1) together with todolactol A

seems that the former arises from todolactol A by dehydration in the wood. Thus, to investigate the conversion of 4 into todolactol B (1), Compound 4 was treated with trifluoroacetic acid in dioxane at room temperature. The resulting product yielded only todolactol B (1). It seems that acid-catalyzed cyclization of 4 presumably takes place through an electrophilic reaction of the resultant carbocation onto the aromatic ring and results in the exclusive formation of the more stable 4S configuration with a quasi-equatrial rather than a 4i? configuration with a quasi-axial todolactol A (ref. 19). Todolactol A, B, C and D have not been reported as naturally occurring lignans, but similar types of lignans have been isolated aryl substituent aryl substituent.

Cosequently, compound 4 was concluded to be structure 4, and named

from Carissa
and A. koreana sachalinensis

edulls

(ref. 26), Piper

clusli

(ref. 27), P. cubeba mariesii (ref. 30)

(ref. 28), Dacrydlum intermedium

were characterized

(ref. 29), Abies

by

(ref. 31). It seemed that lignans from the wood of A. a preferential occurrence of

lactol and acetal types of lignans. Several other types of lignans have been isolated from the wood of A. sachalinensis. These were (+)-pinoresinol (5), (+)-

620 epipinoresinol (6), (-)-a-conidendrin (7), (+)-lariciresinol (8), (+)-lariciresinol p-coumarate ( 9 ), (+)-lariciresinol ferulate (10), ( + )-tetrahydro-a^, 2-bis-(4-hydroxy-3-methoxyphenyl)-3,4furandimethanol (11), (-)-tetrahydro-2-(4-hydroxy-3-methoxyphenyl)4-(4-hydroxy-3-methoxybenzoyl)-3-furanmethanol resinol (13), and (+)-secoisolariciresinol (refs. 19-22). 2.2 Neolignans (refs. 20,21) Three neolignans (15, 16 and 17) were isolated from the wood of A. sachallnensis, and their structure was elucidated by spectroscopic analyses, they were identified with 2,3-dihydro-2-(4hydroxy-3-methoxyphenyl)-3-hydroxymethyl-5-(2-formylvinyl)-7hydroxybenzofuran (15), 2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-3(p-coumaroyloxymethyl) -5-w-hydroxypropyl-7-hydroxybenzof uran and (16) 1-(4-hydroxy-3-methoxyphenyl)-2-[4-(2-formylvinyl)-2-methoxy(12 ), ( + )-isolarici(14) di-p-coumarate

phenoxy]-propane-l,3-diol (17). The absolute configurations of the former two neolignans (15) and (16) have been demonstrated, using CD data and ^H-NMR shifts (ref. 20).

CHO
HO//

\^

COH2C //,,

II

;ax^'
16

^x^^^^:^.^-^''"'^^^^^ CH2OH

OMe

CHO

Q ^ O H HO
OMe

17

621 2.3 Sesquilignans (ref. 32) Repeated silica-gel column and prep.TLC of the diethyl ether insoluble fraction of the EtOH extract from the wood of Abies sachallnensis have resulted in the isolation of two new sesquilignans, abiesol A (18) and B (19). The findings from the spectral analysis indicated that abiesol A had dihydrobenzofuran and tetrahydrofuran structures, and abiesol B was shown to have dihydrobenzofuran and butyrolactol structures which are considered to exist as an equilibrium mixture of the tautomeric forms.

ROHgCv^s' R0^v^2" OMe

1>v^8' 8 ^ CH2OR

18 :R=H

18a: R=Ac

9"

ROH2C

R0^^v^2" OMe

ff

\ 8"

^^-^p^^^ySUAQ' OMe [9 RO

?^

ji r ^ 2

W^OMe OR
19c, 19e: R=Ac 22*: R=H

19b, 19d: R=Ac 20*: R=H

*: Compound 19, abiesol B, existed as a mixture of tautomeric four isomers which were comprised of the two diastereomers of structures 20 and 22.

Compound 18, abiesol A, [o.]^ +15.0"* (c=1.04, MeOH) was isolated as being amorphous. The molecular formula, ^2o^24p9' ^^^ based on the result of HR-MS. In the ^H-NMR spectrum of tetraacetate 18a (Table

2.4), the two multiplets at 6 2.56 and at 6 2.70, and one doubledoublet, at 6 2.85 were confirmed to be two protons of a

tetrahydrofuran ring and two protons at the 7' position, which was further confirmed by the signals at 6 49.05, 42.49 and 33.40 in the

622
Table 2.4 H 7 8 9 7' 8' 9'a 9'b 7" 8" 9" arom. OMe alc-OAc ph-OAc ^H-NMR data for compound 18a 18a 4.86 2.56 4.21 4.37 2.56 2.85 2.70 3.78 4.09 5.52 3.78 4.37 6.63 3.82 2.04 2.31 d(5.5) m d d ( 7 . 7 , 11.4) m m d d ( 4 . 9 , 13.0) m m d d ( 6 . 4 , 8.6) d(6.6) m m s ( 2 H ) , 6 . 9 5 m(6H) s , 3.84 s , 3.90 s s(6H) s(6H)

(In CDCI3, 270 MHz)

OMe
18b (m/z315) 18 (m/z538) H2O

H2C<^

fV T
K^ OMe
Fig. 2.1.

^0-"^

a
OMe

'CH2

18c (m/z297)

Important ion peaks in the MS spectra of abiesol A (18)

623 ^^C-NMR Of 18a with a part (Table 2.6). A doublet at 6 4.86 was found to couple of the signal at ring. 6 2.56 The by a double further These ring decoupling showed a

experiment, and which was assigned to a methine proton at an arylsubstituted tetrahydrofuran spectrum structure. doublet at 6 5.52 which was due to a methine proton (H-7") at an aryl-substituted suggested the dihydrobenzofuran presence of a results and a aryldihydrobenzofuran

tetrahydrofuran structure in compound 18. The mass spectrum of 18 exhibited an important fragment at m/z 315 (18b) due to the cleavage between C-7' and C-8' and a base ion peak at m/z 297 can be assigned to cation 18c formed by the elimination of a mole of H2O from cation 18b 18a (Fig. 2.1). The ^^C-NMR spectral data of 18 and its tetraacetate are listed in Table 2.6. Signals due to an aryl-substituted moiety and a tetrahydrofuran structure were

dihydrobenzofuran

observed. Thus, compound 18, named abiesol A, was concluded to be structure 18. Biogenetically, abiesol A would be derived from the oxidative coupling of lariciresinol and coniferyl alcohol. Compound 19, abiesol B, [a]^ -2.4** (c=1.66, MeOH) was isolated as being predicting amorphous. The HR-EI-MS yielded a molecular formula, C3QH340^Q. a M " ^ at m/z 554.2112, The EI-MS spectrum of

confound 19 showed a prominent ion peak at m/e 297 attributable to cation 18c which was shown by the fragmentation of abiesol A (18). In the ^H-NMR spectrum of acetate 19 a, resolved singlets were observed at 6 6.14, 6.12, 6.09, and 6.06 and integrated in the total of one proton. These singlets were assigned to an acetal proton (H9'). Moreover, resolved doublets at 6 5.81, 5.74, 4.97 which were integrated in the total of one proton. suggested that compound 19 methods, we were unable and 4.90 data These

existed as a mixture of four isomers. chromatographic condition which to identify the HPLC

Although we attempted to separate each isomer by

permitted the separation of all four isomers. This difficulty was overcome by coverting the 19 into their corresponding acetates 19a, and separating the acetates by chiral column (Daicel Chiralcel OD) chromatography. The isolated isomers, 19b, 19c, 19d and 19e, were analysed by means of ^H- and ^^C-NMR spectroscopies and their

624 Table 2.5 H 7 8 9a 9b 7'a 7'b 8' 9' 7" 8" 9"a 9"b arom. iH-NMR d a t a f o r compounds 19b, 1 9 c , 19d and 19e 19b 5.81 d (9.9) 2.68 m 3.80 m 3.80 m 2.68 m 19c 4.97 d (9.5) 2.84 m 4.22 dd (6.6, 10.1) 4.35 m 2.58 dd (10.3, 13.2) 2.84 m 2.84 m 6.12 s 5.54 d (7.0) 3.84 m 4.35 m 19d 5.74 d (10.3) 2.71 m 3.79 m 3.79 m 2.71 m 19e 4.90 d (9.5) 2.85 m 4.19 dd (5.9, 11.4) 4.31 m 2.63 dd (10.3, 13.2) 2.85 m 2.85 m 6.14 s 5.56 d (7.0) 3.84 m 4.31 m

2.68 m 2.68 m 6.06 s 5.54 d (7.0) 3.80 m 4.32 dd (8.1, 11.0) 4.45 dd 4.45 dd (5.1, 11.0) (5.1, 11.0) 6.66 s(2H) 6.69 s(2H) 6.96 m(6H) 6.94 m(6H)

OMe alc-OAc

ph-OAc

3.82 3.83 3.91 1.99 2.04 2.05 2.30

s s s s(3H) s(3H) s(3H) s(6H)

3.82 3.84 3.92 1.94 2.04

s s s s(3H) s(6H)

2.31 s(6H)

2.71 m 2.71 m 6.09 s 5.55 d (7.0) 3.79 m 4.33 dd (7.7, 11.2) 4.43 dd 4.44 dd (5.1, 11.0) (5.0, 11.2) 6.80 s(lH) 6.88 m(8H) 6.83 S(1H) 6.88 S(1H) 6.98 m(5H) 3.83 s 3.81 s 3.85 s 3.84 s 3.91 s 3.91 s 1.93 s(3H) 1.99 s(3H) 2.05 s(3H) 2.04 s(3H) 2.07 s(3H) 2.05 S(3H) 2.31 s(6H) 2.31 s(6H)

(In CDCI3, 270 MHz)

assignments are summarized in Tables 2.5 and 2.6, respectively. The first, isomer 19b, had [a]^ -13.1 (c=0.35, CHCI3). The ^HNMR spectrum of 19b (Table 2.5) confirmed the presence of three

alcoholic acetoxyl groups, two phenolic acetoxyl groups and three methoxyl groups. A singlet at 6 6.06 was assigned to an hemiacetalic proton (H-9'). A doublet at 6 5.81 was attributed to a benzylic methine proton at the C-7 position, indicating the presence of a secondary benzylic alcohol structure in 19b. A doublet at 6 5.54 was assigned to H-7" on the dihydrobenzofuran ring. The ^^C-NMR spectrum

625
Table 2.6 I^C-NMR spectral data for compounds 18, 18a, 19b, 19c, 19d and 19e 18*) 135-03 110.72 148.63 147.70 115.84 119.74 83.75 54.43 60.91 130.70 118.35 137.09 146.96 145.44 114.56 34.23 44.05 73.64 135.54 110.96 148.83 148.01 116.11 120.07 88.73 55.45 65.19 56.92 56.75 56.71 18ab) 139.68=) 109.80 151.14 139.04 122.66 117.84 82.92 49.05 62.72 127.30 116.47 133.77 146.53 144.33 113.03 33.40 42.49 72.85 141.58 110.12 151.30 139.65) 122.90 118.24 87.79 50.75 65.44 56.21 55.92 170.92 170.75 169.09 168.96 20.89 20.81 20.68 19bb) 139.59) 111.50 151.27 137.62) 123.11 119.33 19cb) 19db) 138.52) 112.05 151.17 137.86) 122.95 121.05 19eb)

c
1 2 3 4 5 6 7 8 9 1' 23' 4' 5' 6' 7' 8' 9' 1" 2" 3" 4" 5" 6" 7" 8" 9" arom.-OMe

CO in Ac

Me in Ac

139.68) 110.57 151.21 139.55) 122.89 118.69 84.20 d) 48.23 47.17 69.95 61.28 127.31 127.43 117.02 116.76 132.68 132.16 146.75 146.76 144.36 144.39 113.40 113.20 38.60 31.58 50.03 48.39 102.76 101.19 139.94) 139.68) 110.08 110.13 151.33 151.31 139.71) 139.55) 122.92 122.73 118.20 118.35 87.80 87.90 50.73 50.71 65.43 65.33 56.25 56.23 55.98 56.02 55.97 55.79 170.82 170.75 170.69 170.19 169.64 169.73 168.99 168.95 168.81 168.95 21.30 21.35 20.81 21.11 20.78 20.68 20.66

138.40) 111.30 151.18 137.58) 122.99 120.87 84.47 d) 47.28 48.42 61.19 70.03 127.18 127.35 115.09 115.43 134.32 132.88 148.04 148.20 144.46 144.32 113.07 113.19 31.69 38.67 48.22 50.09 101.21 102.80 139.78) 139.76) 110.12 110.05 151.34 151.33 139.32) 139.42) 122.95 122.88 118.31 118.21 88.10 88.13 50.72 50.65 65.11 65.24 56.07 56.30 56.01 55.98 170.67 170.23 169.64 169.04 168.96 21.30 21.18 20.75 20.66 170.76 170.66 169.70 169.09 168.95 21.37 20.82 20.68 20.65

(270 MHz) a) In acetone-dg.

b) In CDCI3.

c) Signals may be reversed.

d) Hidden under solvent signal.

626
(Table 2.6) showed signals at 6 87.80, 50.73 and 65.43 which were attributed to C-1", 8" and 9", respectively, in an aryl-substituted dihydrobenzofuran structure. On the basis of these findings, isomer 19b was concluded to be structure 19b. The second, isomer 19c, had [a]^ +14.5 (c=0.40, CHCI3). In the ^H-NMR spectrum of 19c (Table

2.5), no signal was observed at about 6 5.8, indicating the absence of a secondary acetate group in the benzyl position. However, 19c showed an additional benzylic methine (6 4.97, d, ^=9.5 Hz) substituted by oxygen. This interpretation indicated the presence of an aryl-substituted tetrahydrofuran methine in 19c. Also, a double doublet at 6 4.22 for two protons, a multiplet at 6 4.35 for one proton, and a double doublet at 6 4.45 for one proton was assigned to two -CH2OAC groups. This was further confirmed by the appearance of signals at 6 65.33 and 61.28 in the ^^C-NMR spectrum (Table 2.6). Isomer 19c therefore was presumed to have structure 19c. The third, isomer 19d, had [a]^ -16.3 (c=0.43, CHCI3). The close similarity of the ^H-NMR and ^^C-NMR spectral data between 19b 2.5 and 2.6, respectively). However, and 19d suggested differences

that they had a diastereomeric relationship with each other (Tables stereochemical between 19b and 19d could not be determined. The forth, isomer 19e, had [a]j5 +9.5 (c=0.40, CHCI3). Comparison of its NMR spectral data with that of 19c deduced. On the basis of these spectral examinations of acetylated isomers, 19b, and 22, 19c, 19d and 19e, the mixture of four isomers in Furthermore, indicated open-chain the above 21 evidence could (Fig. and be 2.2). suggested that they were a diastereomer for each

other (Tables 2.5 and 2.6). The stereochemistry of 19e could not be

compound 19 is comprised of the two diastereomers of structures 20 respectively. behavior via the chromatographic interconvertible that these isomers

aldehyde

Consequently, compound 19, named abiesol B, existed as a mixture of the tautomeric four isomers, comprised of the two diastereomers of structures 20 oxidative and 22. Considering the likely course of the formation of abiesol B (19) natural may be couplings,

attributed to the couplings of todolactol A (4) and coniferyl

627

HOH2C

OMe
Fig. alcohol. 3. Studies on Lignans, Neolignans and Sesquilignans from Salix in the 2.2. Tautomerism of Abiesol B (19)

sachallnensls
The temperate family and

Fr.Sch.
salicaceae subarctic the family is is zones very of widely the divided distributed northern into four hemisphere. genera,

Taxonomically,

usually

Populus,
The

Salix,

Tolsusu
have

and Chosenla.
the

A number of studies on the

structure, distribution, (ref. on and 33). the

extractives of members of Salicaceae have been published to date. studies discussed of the of the biological Especially, salicin to activity much chemical constituents

phytochemical

investigation

Salicaceae has been concerned with the phenolic glycosides such as (ref. 34). Recently, intense interest has focused on some biomass resources. Among them, Salix sachalinensis species in the Salicaceae as rapidly growing hardwoods with regard forest

Fr.Schm., Salix

pet-susu

Kimura and Populus

maximowiczii

Henry have

been studied for their production in Hokkaido (ref. 35). To obtain basic information on their chemical features, alcohol extractives

628
from the leaves, (ref. twigs and wood many of these species have been as S.

investigated

36). Thus,

phenolic

compounds

such

flavonoids, lignans and phenolic glycosides were isolated. It is worthy to note that the extractives of the leaves and twigs of sacallnensis ampeloptin was estimated to be about 2.5 % of dry matter (ref. 36). This section deals with the structural elucidation of lignans, neolignans sachallnensis The silica-gel and sesquilignans obtained from the wood of S. (refs. 37,38,39). EtOH extracts diethyl and of the wood and of the S. sachallnensis subjected chromatographies was to to were comprised mainly of flavonoids and the content of

3.1 Lignans (refs. 37,39) fractionated with ether solubles

column

preparative

thin-layer

give (+)-syringaresinol and two lignan esters 23 and 24.

23 '. R-|=R2=H 23a: Ri=R2=Ac 24 : Ri=H, R2=Et 24a: Ri=Ac, R2=Et Compound 2 3 , [a]^ +3.52 (c=0.30, MeOH), was isolated as a

colorless powder. The FD-MS spectrum showed a [M"*"] at m/z 556. Also, the EI-MS of compound 23 showed prominent peaks at m/z 121 and 138 implying its p-hydroxybenzoyl 23a and p-hydroxybenzoic acid moieties, of a p respectively. Table 3.1 presents the ^H-NMR data for compound 23 and acetate and their assignments. The presence hydroxybenzoic acid moiety was further confirmed by two doublets of A2B2 patterns at 6 7.22 (2H, J=8.6 Hz) and 6.73 (2H, J=8.6 Hz) in the ^H-NMR spectrum of 2 3 . Also, the ^H-NMR spectrum of 23a confirmed the presence of one alcoholic acetoxyl group, two phenolic acetoxyl

629
Table 3.1 ^H-NMR data of compounds 23^ 23a and 24a H 2 and 6 7 8 9 23a) 6.49 s 4.90 d (3.4) 2.62 m 4.46 m 4.77 dd (3.9, 10.8) 6.60 s 4.46 m 2.69 m ca3.72^) ca3.58^) 2" and 6" 3" and 5" OMe OAc CH2 in Et Me in Et 7.22 d (8.6) 6.73 d (8.6) 3.65 s(6H) 3.72 S(6H) ~ 23a 6.51 s 5.17 d (3.0) 2.84 m 4.41 dd (8.8, 11.0) 4.73 dd (4.7, 11.0) 6.57 s 5.70 d (11.0) 3.00 m ca3.72^) ca3.82^) 8.07 d (8.6) 7.19 d (8.6) 3.72 S(6H) 3.82 s(6H) 2.05 S(3H) 2.33 s(9H) ~ 24a 6.55 s 5.02 d (4.8) 2.78 m 4.50 pt (10.5) 4.74 dd (5.4, 10.5) 6.52 s 4.45 d (5.0) 2.60 m 4.20 d (8.4) 4.20 d (8.4) 8.00 d (8.5) 7.17 d (8.5) 3.73 S(6H) 3.80 S(6H) 2.32 s(6H) 2.33 s(3H) 3.35 m(lH) 3.43 m(lH) 1.22 t(6.9)

2' and 6* 7' 8' 9'

(In CDCI3 , 500 MHz) pt: pseudotriplet. a ) : In DMSO-d^ + D2O. b ) : Overlapped with OMe signals. groups and four methoxyl groups. The ^-^C-NMR spectrum of 23a is

summarized in Table 3.2. The ^^C-NMR spectrum of 23a, which was coupled with a DEPT experiiaent, also showed the existence of a phydroxybenzoyl moiety and a tetrahydrofuran structure in compound 23. The binding position on the tetrahydrofuran lignan structure of a p-hydroxybenzoic acid moiety was established by a comparison of ^H-NMR spectra between 23 and 23a. Methylene protons (H-9) were

630
Table 3.2 ^^C-NMR spectral data for compounds 23a and 24a 23a 127. .61^) 101, .54 .71 151. 137. .62 .41 152. .54 101. .68 83. .34 48. .34 63. .73^) 128, .99 102. .17 152. .19 141. .17 152, .99 102. .75 73. .64 45. 70. .05 127. .31^) .19 131, .90 121, .63 154, .90 121. .19 131, 165, .49 56. .10, 56. .26 20. .49, 20. .51 21, .14, 21 .16 168. .62, 168. ,76 .93, 169, 168. .85 24a 127 .68^) 102. .03 152. .07 .08 141. .07 152, .03 102, 84, .22 47, .14 64, .06 127. .39^) 102, .83 .34 152, .44 139, .34 152, .83 102. 79, .84 48..60 .18 69. 127. .99^) .08 131. .83 121, .51 154. 121. .83 .08 131. 165. .64 15. .40 64. .43 56 .06, 20 .43, 56.18 21.14

c
1 2 3 4 5 6 7 8 9 1' 2' 3' 4' 5' 6' 7' 8' 9' 1" 2" 3" 4" 5" 6" 7" Me in Et CH2 in Et OMe Me in Ac CO in Ac

168 .74, 168.76

(In CDCI3, 500 MHz) a ) : Signals may be revearsed. observed at 6 4.46 and 4.77 for 23 and at 6 4.41 and 4.73 for 23a. Thus, the absence of a significant downfield shift after acetylation for H-9 indicated that the p-hydroxybenzoic acid moiety was attached to the methylene carbon at the 9-position as an ester. Furthermore, the relative configuration of 23 was seen the by basis NOE of differential the above spectral measurements (ref. 37). On

631
spectroscopic studies, compound 2 3 was deduced to have structure 2 3. Compound spectrum of 24 24 was obtained revealed as colorless crystals. The FD-MS 584 corresponding to the ^^C-NMR spectra for acetyl an M " ^ at m/z

molecular formula C3^H3gO^^. The ^H-and derivative 24a

are summarized in Tables 3.1 and 3.2, respectively.

The NMR spectral data for 24a were very similar to those of compound 23a. The main differences observed were readily explained on the basis of the existence of an ethoxyl group in 2 4 instead of an alcoholic hydroxy group in 23. Furthermore, the ethoxyl group must be at the 7'-position because the HMBC spectrum of 24a ethoxyl group and the benzyl methine proton showed a long-range correlation between the methylene carbon (6 64.43) of the (6 4.45) at the 7'position. On the basis of these results, compound 2 4 was concluded to be Structure 24, which corresponded to an ethyl ester of compound 23. Compounds 23 and 24 have not been reported to date. However, may be an artifact since ethanol was used the possibility exists that the benzyl ethoxyl compound 24 from the wood of S. sachallnensis as the extraction solvent. 3.2 Neolignans (ref. 38) Repeated silica-gel column and preparative thin-layer chromatographies of the EtOAc soluble fractions of the EtOH extracts from the wood of S. sachallnensis two neolignan esters 25 and 26. Compound 25 was isolated as amorphous, m.p. 87-89C, [al^ -14.4 (c=0.50, MeOH). The FD-MS spectrum showed a M+ at m/z 728. The EI-MS showed prominent ions at m/z 194, 179, 150(base ion) and 135. An ion peak at m/z 194 corresponded to ferulic acid. The ^H- and ^^C-NMR spectra of 25a are summarized in Tables 3.3 and 3.5, respectively. Compound 25 was a mixture consisting of the erythro and threo isomers. The ratio was found to be about 2.1 : 1.0 by the ^H-NMR (d, J=5.4 Hz, have resulted in the isolation of

spectrum of the acetate 25a, which clearly showed distinguishable peaks of the benzyl methine proton {H-7') at 6 6.12 erythro) and 6.17 (d, J=6.4 Hz, threo). In the dowen field, four

doublets at 6 7.68 (IH, J=15.9 Hz), 7.53 (IH, J=15.9 Hz), 6.42 (IH, J=15.9 Hz) and 6.35 (IH, J=15.9 Hz) were due to olefin protons of

632

9 II . 8 . CHgOC-ziA
^

Q'" O

\\

OMe 25 : R=H 25a: R=Ac

OMe 26 : R=H 26a: R=Ac

two feruloyl groups. A doublet at 6 6.62 double doublet at 6 6.20 25a were substantiated structure carbons of

(IH, J=15.8 Hz) and a

(IH, J"=6.3, 15.8 Hz) were derived from by ^H-^H was from the COSY experiments. through A the and detailed ^^C NMR for the

olefin protons of the coniferyl ether moiety. These assingments for chemical bearing 25 established the HMQC

measurement of 25a. The resonances were assigned to the protondirectly using spectrum, quaternary between the carbons HMBC spectrum. ether The skelton long-range and two

connectivities observed in the HMBC spectrum enabled the connection guaiacylglycerol-p-coniferyl feruloyl groups. Methylene protons at 6 4.21, 4.43, and 4.53 (H-9') were correlated with a carbonyl carbon at 6 166.42 (9"-C=0) which showed a connection with the olefin proton at 6 6.35 to the methylene protons at 6 4.85 proton at 6 6.42 (H-8''') (H-8") (Fig. 3.1). Another carbonyl carbon at 6 166.56 (9'''-C=0) was correlated (H-9) and also to the olefin Thus, the HMBC experiment (Fig. 3.1)

permits the complete assignment of two feruloyl groups in structure

633 Table 3 . 3 H 7 8 9 7' 8' 9' 7" 8" 7"' 8'" arom. OMe alc-OAc ph-OAc ^H-NMR data of compound 25a 25a 6.62 d(15.8) 6.20 dd(6.3, 15.8) 4.85 d(6.3) 6.12 d(5.4, e ) , 6.17 d(6.4, th) 4.70 m(th), 4.74 m(e) 4.21 dd(5.6, 11.9, th), 4.43 m(th, e ) , 4.53 dd(5.7, 12.0, e) 7.53 d(15.9) 6.35 d(15.9) 7.68 d(15.9) 6.42 d(15.9) 6.81-7.13 m 3.79 s, 3.82 s, 3.85 s, 3.86 s 2.08 s(th), 2.10 s(e) 2.29 s, 2.31 s, 2.32 s

(In CDCI3, 500 MHz)

e: erytro.

th:

threo.

O 110
2'" OMe

OMe

25a

Fig. 3.1. Important ^H--^^C long-range correlations observed for 25a and 26a

634 Table 3.4 H 2 and 6 7 8 9 2' and 6' 7' 8' 9' 2" and 6" 3" and 5" 2 ' ' and 6 " ' 3 " and 5' " OMe alc-OAc ph-OAc 6.56 6.62 6.29 4.97 6.69 6.18 4.69 4.26 4.64 7.88 7.11 8.12 7.18 3.67 2.04 2.29 ^H-NMR data of compound 26a 26a s d(15.8) dd(6.0, 15.8) d(6.0) s d(4.8, e ) , 6.21 d(6.2, th) m(th), 4.77 m(e) dd(5.2, 12.0, th), 4.53 m(th, e ) , dd(6.1, 11.9, e) d(8.5) d(8.5) d(8.5) d(8.5) s, 3.71 s, 3.74 s, 3.79 s s(th), 2.16 s(e) s, 2.32 s

(In CDCI3, 500 MHz)

e: erythro,

th:

threo.

25.

In

conclusion,

the

structure

of

compound

25

was

guaiacylglycerol-p-coniferyl alcohol ether diferulate. Compound 26 was isolated as a pale yellowish powder, m.p. 14014rC, ^H-and [a]j5+2.9 (c=0.50, MeOH). The FD-MS showed M^ at m/z 676. The ^^C-NMR spectral data for the acetylated compound 26a are

summarized in Tables 3.4 and 3.5, respectively. The ^H and ^^C NMR spectra of 26a suggested the existence of a syringylglycerol-pgroups, and also and

sinapyl alcohol moiety and two p-hydroxybenzoyl erythro isomers. The ratio of threo and erythro

indicated that compound 26a was thought to be a mixture of threo

isomers was found to

be 1.0 : 2.8 by the relative intensities of signals for H-7' in the arylglycerol benzoyl structure. Complete NMR was established COSY by assignment of two p-hydroxy ^H-^H of COSY, HMQC and HMBC showed

groups The

experiments.

^H-^H

spectrum

compound

26a

significant correlations between the aromatic protons at 6 8.12 (H2 ' and 6' ' ') and 7.18 (H-3' ' ' and 5' ' ' ) , and between the aromatic protons at 6 7.88 (H-2" and 6") and 7.11 (H-3" and H-5"). The long-

635
Table 3.5 ^^C-NMR spectral data for compounds 25a and 26a 25a 131.91 110.24 151.00) 147.10(e), 147.30(th) 122.65^) 119.84 133.95 122.29 65.21 135.38(th), 135.20(e) 111.96 151.10) 139.78 122.92^) 119.33 73.83(e), 74.53(th) 80.45(th, e) 62.83(e), 63.34(th) 133.15 111.13 151.40) 141.49^) 123.25^) 121.58 144.73 117.56 166.42 133.31 111.24 151.40) 141.57^) 123.28^) 121.26 144.40 118.09 166.56 55.82, 55.90, 55.93 20.64, 20.65, 20.68 21.07(th), 21.11(e) 168.77, 168.82 169.53 26a 132.27 103.57 153.16 135.46 153.16 103.57 134.11 122.83 65.45 128.63 103.87 151.96 135.57 151.96 103.87 74.70(e), 75.80(th) 81.01(th), 81.11(e) 63.62(e), 64.62(th) 127.36 131.23 121.59 154.36 121.59 131.23 165.46 127.68 131.21 121.50 154.29 121.50 131.21 165.55 55.87, 55.92, 56.14 20.45 21.11(th), 21.12(e) 168.58, 168.76, 168.83 169.52

c
1 2 3 4 5 6 7 8 9 1' 2' 3' 4' 5' 6' 7' 8' 9' 1" 2" 3" 4" 5" 6" 7" 8" 9" 1" 2" 3" 4" 5" 6" 7" 8" 9" OMe Me in Me in CO in CO in

ph-OAC alc -OAC ph-OAC alc -OAc

(In CDCI3, 500 MHz)

e: erytro.

th: threo.

a ) , b ) , c ) : Signals may be reversed.

636
range connectivities between the carbonyl carbon at 6 165.46 (7"CH2COCO) and the protons at 6 7.88 (H-2" and 6"), 4.26, 4.53 and 4.64 (H-9'), and between the carbonyl carbon at 6 165.55 (7' ' '-CH2COCO) and the protons at 6 4.97 (H-9) and 8.12 (H-2''' and H-6' ' ' ), were established by the HMBC experiments (Fig. 3.1). Thus, these results allowed us to complete and verify the assignments of the two phydroxybenzoyl moieties. Consequently, alcohol Compound 26 was to be syringylglycerol-p-sinapyl ether di-p-hydroxybenzoate.

Syringylglycerol-p-sinapyl alcohol ether and its acylated derivative 26 have not been previously reported. Although extensive studies on cinnamic acid derivatives in woody plants have been previously reported (refs. 8,9,11) and that benzoylated Salicaceae compounds occur characteristically and 26 in the family (ref. 9 ) , Compounds 25 are only known at this

time as neolignan esters from Salicaceae. 3.3 Sesquilignans (refs. 38,39) Chromatographic separation of the EtOAc soluble part of the EtOH extracts from the wood of S. sachalinensis compounds 27, 28 and 2 9. These three were afforded three new comprised of three

phenylpropane units acylated with p-hydroxybenzoic acid. Compound 27 was isolated as a colorless powder, m.p. 108-110 * * C f [a]j3 -1.06(c=0.50, MeOH). The FD-MS of compound 27 showed an M^

at m/z 702. Also, the EI-MS of compound 27 showed a base ion at m/z 121 implying a p-hydroxybenzoyl moiety, which was further confirmed by two doublets of A2B2 patterns at 6 7.98 (2H, J=8.6 Hz) and 7.17 (2H, J"=8.6 Hz) in the ^H-NMR spectrum of acetate 27a (Table 3.6).

Also, the spectrum showed two doublets at 6 9.66 (IH, J=7.7 Hz) and 7.41 (IH, J=15.8 Hz) and a double-doublet at 6 6.60 (IH, J=7.7, 15.8 Hz), suggesting the existence of a formylvinyl group as the partial structure. A doublet at 6 5.63 was assigned to a methine proton (H7) at an aryl-substituted dihydrobenzofuran ring. The doublet at 6 6.14 was assigned to a methine proton at an arylglycerol structure as a threo isomer, and another one(d, J"=5.4 Hz) at 6 6.10 which isomer (ref. 43). These results and erythro corresponded to that of an erythro

suggested that compound 27 existed as a mixture of threo

637

RiO

OMe

27: Ri=H, R2=CH0 27a: Ri=Ac, R2=CH0 28 : Ri=H, R2=CH20H 28a: Ri=Ac, R2=CH20Ac

;^0R OMe

OMe

29 : R=H 29a: R=Ac

isomers. The ^^C-NMR spectrum of 27a

was assigned with the aid of

DEPT and HMQC spectra (Table 3.7). Also, the connecting position of p-hydroxybenzoic acid moiety was determined by the HMBC spectrum. Thus, the methylene acid protons moiety at 6 4.60 was and 4.72 to (each C-7 m, in H-9) the correlated with carbonyl carbon at 6 165.38, indicating that the phydroxybenzoic attached dihydrobenzofuran ring. These results supported that compound 27 was to be structure 27 . Compound 28 was isolated as colorless crystals. The spectral data of compound 28 closely resembled those of compound 27. The FDMS of compound 28 showed an M^ at m/z 704 and the EI-MS spectrum furnished a significant ion at m/z 370. These ion peak were 2 amu more than the corresponding peaks in the mass spectrum of compound 27. ^H-NMR spectral details for the acetylated compound 28a are given in Table 3.6. The general appearance of the ^H-NMR spectrum of

638
Table 3.6 H 2 and 6 7 8 9 2' 5' 6' 7' 8' 9' 2",5"and 6" 7" 8" 9" ^H-NMR data of compounds 27a, 28a and 29a 27a 6.54 s 6.55 s 5.63 d(7.0) ca3.9^^ 4.60 m 4.72 m 6.90-7.13 m 6.90-7.13 m 7.41 d(15.8) 6.60 dd (7.7, 15.8) 9.66 d(7.7) 6.90-7.13 m 6.10 d(5.4, e) 6.14 d(6.3, th) 4.50 m(th) 4.60 m(e) ca3.9^)(th) 28a 6.55 s 5.57 d(7.0) ca3.9^> 4.50 m ca4.7^) 6.88-7.13 m 6.88-7.13 m 6.60 d(16.4) 6.16 dd (6.6, 16.4) 4.71 d(6.6) 6.88-7.13 m 6.07 d(5.0, e ) . 6.13 d(6.3, th) 4.50 m(th) 4.58 m(e) 4.25 m(e) 4.33 dd (4.7, 11.6, th) 4.50 m(e, th) 29a 6.49 s 4.93 d(4.8) 2.54 m 4.45 m 4.69 m 6.84-7.02 m 6.84-7.02 m 6.84-7.02 m 4.48 d(5.0) 2.80 m 4.20 m 6.84-7.02 m 6.08 d(4.9, e) 6.14 d(6.3,th) 4.45 m(th) 4.57 m(e) 3.91 dd (4.4, 11.8, th) 4.20 m(e) 4.33 dd (4.6, 11.8, th) 4.45 m(e) 7.99 d(8.6) 7.17 d(8.6) 3.23 s 3.67 s, 3.68 s. 3.80 s, 3.81 s (12H) 1.96 s, 1.98 s. 2.04 s, 2.13 s (6H) 2.29 s, 2.31 s 2.33 s(9H)

4.23 m(e) 4.34 m(th) 4.48 m(e) 2"* and 6'" 7.98 d(8.6) 3 " ' and 5 " ' 7.17 d(8.6) 7'-OMe arom.-OMe 3.65 s, 3.66 3.67 s, 3.81 3.96 s (12H) alc-OAc 1.97 s, 1.99 2.00 s, 2.04 (6H) ph-OAc 2.29 s, 2.30 2.33 s(6H)

s. s. s. s s

8.00 7.16 3.64 3.66 3.81 1.96 2.00 2.13 2.29 (6H)

d(8.6) d(8.6) s, 3.65 s, 3.81 s (12H) s, 1.98 s, 2.10 s (9H) s, 2.33 s. s. s. s. s

(In CDCI3, 500MHz) e: erythro. th: threo. a ) : Overlapped with OMe signals. b ) : Overlapped with H-9' signal.

639
Table 3.7 27a 89.23 50.32 65.73 152.54 126.78 193.39 75.17(th) .73 .90(e) 80.83(th,e) 62.53(e), 63. 34(th) 165.38 ^^C-NMR spectral data for compounds 27a, 28a and 29a 28a 89.01 50.69 66.16 134.18 121.41 65.16 75.13(th) ,73.93(e) 80.79(e), 80. .90(th) 62.58(e), 63, .42(th) 165.43 29a 84.14 48.44 63.71 81.34 47.22 69.22 75.30(th),73.99(e) 80.64(e),80.82(th) 62.57(e),62.61(th) 165.55

c
7 8 9 7' 8' 9' 7" 8" 9"
7111

(In CDCI3, 500 MHz)

e: erythro.
28a was

th: threo.
similar to those of compound 27 a. A conspicuos

very

difference was the presence of signals for a propenol moiety instead of a propenal moiety. Also, the presence of a propenol structure in the compound 28 was further supported by signals at 6 134.18, 121.41 and 65.16 in the ^^C NMR specrum of compound 28a (Table 3.7). On the basis of these results, and in conjunction with two dimensional NMR experiments, the stucture of compound 28 was ascertained. Compound 29 was isolated as yellowish crystals, mp 156 **C. The FD-MS spectrum of compound 29 exhibited an M"^ at m/z 736. Analysis of the ^H-NMR spectrum of 2 9 and its acetate 29a structure and a p-hydroxybenzoyl group. ^H- and established the ^^C-NMR spectral presence of a substituted tetrahydrofuran moiety, an arylglycerol details for 29a HMBC are summarized in Tables 3.6 and 3.7, respectively. long-range connectivities (7*"'-CO) and between the methylene

The binding site of p-hydroxybenzoyl group was clearly determined by spectrum of 29a. The carbonyl carbon benzyl at 6 165.55 the

protons at 6 4.45 and 4.69 (H-9), and also olefin protons at 6 7.99 (H-2''' and 6''') were observed. Thus, a p-hydroxybenzoyl group was linked to the 9-position. Consequently, the structure of compound 2 9 was identified. Three sesquilignans 27, 28 and 29 are the first confounds to be reported from Salicaceae. The occurrence of these sesquilignans

640
suggest the existence of a higher polymer of phenylpropane units, which related with soluble polymers such as Brauns lignin (refs. 25,44). 4. Studies on Neolignans and Sesquilignans from Chosenla A.Skvortz. Taxonomically, the family Salicaceae is usually divided into arbutifolla

four genera, Populus,

500 species. Chosenla

Salix,

Toisusu,

and Chosenia.
A. Skvortz on

Populus contains
(Japanease name: of

about 35-45 species, and Salix

including Tolsusu

contains about 300is mainly found extractives is known

arbutifolla number of

Keshoyanagi), the only plant in the genus Chosenla, in Hokkaido, Japan. A Salicaceae studies the

have been reported to date. However, little

about the extractives of C. arbutifolla.

We have now investigated and isolated four five novel compounds arbutifolla

the constituents of the wood of C. arbutifolla neolignans and three sesquilignans including

(refs. 45,46). This section reviews the structural elucidation of neolignans and sesquilignans from the wood of C. 4.1 Neolignans(ref. 46) The wood of Chosenla the extract was arbutifolla by was extracted with EtOH, and LPE, Et20 and EtOAc. Repeated fractionated

silica-gel column and prep.TLC of the Et20 solubles resulted in the isolation of four neolignans 30, 31, 32 and 33. The EI-MS spectrum of 30 showed an M* at m/z 386 and a base ion at m/z 368 caused by the loss of H2O from M"^. In the ^H-NMR of 3 0 (Table 4.1), two doublets at 6 9.58 (J=7.8 Hz) and 6 7.61 (J=15.8 Hz) and a a double-doublet at 6 6.68 (J=7.8, 15.8 Hz) suggested the presence of a formylvinyl group. A doublet at 6 5.61 was assigned to benzyl methine proton at an aryl-substituted Also, signals for one alcoholic dihydrobenzofuran one phenolic (2H) ring. acetoxyl,

acetoxyl and three methoxyl groups were discernible in the ^H-NMR of diacetate 30a singlets for (Table 4.1). In addition, a singlet at 6 6.63 aromatic protons in the derived from aromatic protons in a syringyl ring as well as two 1,3,4,5-tetrasubstituted benzene structure were observed. From the spectral data described above, compound 30 was deduced to have structure 30. Although this

641 9 8>CH0 r-x ?\ Ro<Q>^CpH2C

OMe
30 : R=H 30a: R=Ac

OMe

31 :R=H

31a: R=Ac

CHO

RO

CHO

OMe
32 : R=H 32a: R=Ac

OMe

33 : R=H 33a: R=Ac

compound has been obtained from the hydrolysis products of hardwood lignin (ref. 47), the isolation as a naturally occurring neolignan has not been reported. The FD-MS of Compound 31 exhibited a prominent ion showed an M^ at m/z 506. The EI-MS at m/z 138 implying the pand its peak

hydroxybenzoic acid moiety. The ^H-NMR data of compound 2

acetate 31a are summarized in Table 4.1. The NMR spectral data for compound 31 were very similar to those of compound 3 0 except for signals derived from a p-hydroxybenzoyl moiety. Also, the ^H-NMR spectrum of diacetate 31a showed the presence of the two phenolic

acetoxyl groups. No signal was observed for the alcoholic acetoxyl group. Moreover, the absence of a significant downfield shift after acetylation for the methylene protons attached to the 7-position, indicated that the p-hydroxybenzoxyl group was attached to the was methylene carbon at the 7-position. Cosequently, compound 31 naturally occurring neolignan has not been previously reported. Compound 32 showed very similar spectral characteristics to compound 30. The EI-MS of compound 32 exhibited an M " ^ at m/z 338 and a base ion peak at m/z 338, both of which were 30 amu less than the corresponding ions in compoud 30. This could be due to the lack of a methoxyl group in the molecule. The 'H-NMR spectrum of the

concluded to be structure 31. The isolation of this compound as a

642
Table 4.1 H 2 and 6 7 8 9 ^H-NMR spectral data for compounds 30, 30a, 31 and 31a 30^) 6.67 s 5.61 d (6.5) ca 3.95^) 3.57 m ca 3.85^) 30a^) 6.63 s 5.56 d (7.1) ca 3.95^) 4.38 dd (11.3, 7.1) 4.46 dd (11.3, 5.7) 7.07 s 7.10 s 7.42 d (15.8) 6.60 dd (15.8, 7.7) 9.67 d (7.7) 3.81 3.95 2.07 2.33 s(6H) s(3H) s s 31) 6.80 s 5.74 d (7.3) ca3.95^) 4.57 dd (11.1, 7.6) 4.73 dd (11.1, 5.0) 7.35 s 7.36 s 7.63 d (15.8) 6.70 dd (15.8, 7.7) 9.64 d (7.7) 7.80 d (8.8) 6.88 d (8.8) 3.76 S(6H) 3.95 s(3H) 31a^) 6.61 s 5.68 d (6.8) ca3.95^) 4.59 dd (11.3, 7.6) 4.73 dd (11.3, 5.1) 7.09 s 7.12 s 7.40 d (15.8) 6.60 dd (15.8, 7.7) 9.66 d (7.7) 7.98 d (8.7) 7.17 d (8.7) 3.72 s(6H) 3.96 S(3H) 2.33 s(6H)

7.23 s 7.28 s V 7.61 d (15.8) 8' 6.68 dd (15.8, 7.8) 9' 9.58 d (7.8) 2" and 6" ~ 3" and 5" OMe OAc
"

2'and 6'

3.81 S(6H) 3.95 s(3H)

(500 MHz) a ) : In MeOH-dg.

b ) : In CDCI3.

c ) : In acetone-dg.

d ) : Overlapped with OMe signals. acetylated five derivative protons 32a showed the presence of an data alcoholic closely

acetoxyl group, a phenolic acetoxyl group, two methoxyl groups and aromatic (Table 4.2). The spectral resembled those reported for Balanophonin Balanophora japonica (ref. 48) isolated from

Makino. Cosequently, compound 32 was identified

as the known compound, Balanophonin. The syntheses of this compound and the analogous derivatives previously have been reported (ref. 49). Compound 33 showed spectral characteristics very similar to compound 31 and so they have the same basic type of structure. The FD-MS of compound 33 exhibited an M " ^ at m/z 476. The EI-MS showed a

643 Table 4.2 H

2, 5 and 6

^H-NMR spectral data for compounds 32a and 33a 32a

6.81-7.09 m 5.61 d (6.7) ca3.95^)1 4.35 dd .0) (11.5, 7, 4.45 dd .6) (11.5, 5. 6.81-7.(39 m 7.41 d (15.8) 6.61 dd (15.8, 7. .7) 9.66 d (7.7)

33a
6.97-7.32 5.71 d (7.7) m

7 8 9

2'and 6'

7' 8' 9'

2" and 6" 3" and 5" OMe OAc

3.82 3.95 2.07 2.31

s s s s

ca3.96^) 4.58 dd (11.3, 7.5) 4.71 dd (11.3, 5.2) 6.97-7.32 m 7.41 d (15.8) 6.60 dd (15.8, 7.7) 9.66 d (7.7) 7.98 d (8.7) 7.17 d (8.7) 3.73 s 3.96 s 2.30 s 2.33 s

(In CDCI3, 500 MHz) a ) : Overlapped with OMe signals* large those peak at m/z 338 suggesting ^H-NMR of the elimination 33a of a pthe

hydroxybenzoic acid moiety from M"^. These ions are 30 amu less than for compound 31. The diacetate showed presence of two phenolic acetoxyl groups, two methoxy groups and nine aromatic protons including four protons on the p-substituted aromatic ring (Table 4.2). The other ^H-NMR signals were comparable with those of 31a. Thus, compound 33 was concluded to be structure 33. The isolation of this compound 33 has not been previously reported. Compounds 30-33 belong to a dihydrobenzofuran type of neolignan. These compounds have been obtained for the first time in the family Salicaceae, in spite of (refs. 2,50). the widespread occurrence of neolignans

644
4.1 Sesquilignans (ref. 45) Repeated silica-gel column and prep^TLC of the 'E>t,^0 solubles of the EtOH extracts from the wood of Chosenia arbuti folia have

resulted in the isolation of three sesquilignans 34, 35 and 36. Two of them are p-hydroxybenzoates (35 and 36) and the remaining one is a known compound, buddlenol A (34).

OMe

34 : R=H 34a: R=Ac

j>CHO

OMe

35 : R=H(f/7reo) 35a: R=Ac(threo) 36 : R=H{erythro) 36a: R=Ac(erythro)

Compound 34 was isolated as being yellowish amorphous. The FDMS spectrum of 34 exhibited an M " ^ at m/z 582. In the EI-MS spectrum of 34, peaks at m/z 386, 180, 151 and 137 were observed as principal ions. A prominent peak at m/z 386 could be assigned to neolignan structure 30. A large peak at m/z 180 could be due to a coniferyl alcohol ion derived from an arylglycerol moiety in structure 34. The "^H-NMR spectrum of the acetate 34a mixture of threo and erythro and threo (Table 4.3) showed it to be a isomers. Two doublets at 6 6.08 (J=5.5 isomers, respectively. The relative

Hz) and 6.15 (J=6.1 Hz) were attributed to H-7" in an arylglycerol structure for erythro

645 Table 4.3 H

7 8 9 7' 8' 9' 7"

^H-NMR spectral data for compound 34a 34a

5.51 d (7.1) 3.90^) 4.26-4.52 m 7.42 d (15.8) 6.61 dd (15.8, 7.6) 9.66 d (7.6) 6.08 d (5.5, e) 6.15 d (6.1, th) 4.26-4.52 m(e, th) 4.26-4.52 m(e, th) 6.56 s(2H) 6.91-7.10 m(5H) 3.70-3.95 s(12H) 1.98-2.07(9H) 2.30 s(3H)

8" 9" arom. OMe alc-OAc ph-OAc

(In CDCI3, 500 MHz) e: erythro. th: threo. a): Overlapped with OMe signals. intensities of these signals indicated that the ratio of the and erythro stems threo

isomers was 2 : 1 . All of the other spectral data agreed davldli (ref. 51) . Consequently, compound 34 was

with those of the known compound, buddlenol A isolated from the of buddleja identified as buddlenol A. Compound 35 was isolated as amorphous. The ^H-NMR data for 3 5 and its acetate 35a are summarized in Table 4.4. Compound 3 5 showed spectral characteristics very similar to compound 27 isolated from Salix sachalinensis. In the 27 chemical obtained investigation as a of S. of sachalinensls, compound was mixture

diastereoisomers. On the other hand, comparison of the values of the chemical shift and the coupling constant of H-7" and H-8" with values for acetylated compounds 27a and 35a indicated that compound 35 belongs to the threo series (Table 4.4) (refs. 52,53).

646
Table 4.4 H 2 and 6 7 8 9 ^H-NMR spectral data for compounds 35, 35a, 36 and 36a 35^) 6.65 s 5.62 d (8.0) 3.98 m 4.54 dd (8.8, 11, .2) 4.77 dd (5.4, 11. 2) 7.08 s 7.14 s 7.42 d (15.8) 6.61 dd (7.8, 15. 8) 9.65 d (7.8) 6.94 m 6.87 d (8.1) 6.94 m 5.02 d (8.6) 3.98 m 3.33 d (12.7) 3.54 dd (2.8, : L2. 7) 6.82 d (8.6) 6.84 d (8.6) 7.76 d (8.6) 7.79 d (8.6) 3.77 S(6H) 3.86 S(3H) 3.96 S(3H) 35a 6.55 s 5.63 d (7.1) ca3.95^) 4.60 dd (11.2, 7.6) 4.71 dd (5.4, 11.2) 7.08 s 7.13 s 7.42 d (15.8) 6.60 dd (7.6, 15. 8) 9.67 d (7.6) 7.02 m 7.02 m 36^) 6.65 s 5.66 d (7.0) 4.05 m 4.54 dd (8.6, 11 .1) 4.77 dd (5.1, 11, .1) 7.09 s 7.16 s 7.43 d (15.8) 6.61 dd (7.8, 15 .8) 9.65 d (7.8) 6.83 m 6.83 m 36a 6.54 s 5.64 d (6.8) ca3.96^) 4.59 m 4.71 dd (5.4, 11 .2) 7.09 s 7.14 s 7.42 d (16.1) 6.60 dd (7.8, 16 .1) 9.66 d (7.8) 6.94 m 6.94 m

2'and 6' V 8' 9' 2" 5" 6" 7" 8" 9"

3'"and 5' "

6.94 m 7.02 m 6.83 m 6.08 d 6.14 d 4.96 d (4.4) (6.4) (3.5) 4.59 m 4.50 m 4.10 m 4.24 dd ca3.95^) 3.52 dd (7.8, 11. 4.35 dd (2.5, 12. 1) .7) 4.47 dd (7.0, 11.; 9) ca3.92^) (4.2, 11. .7) 7.17 d 7.17 d 6.83 m (8.3) (8.7) 7.99 d (8.7) 8.00 d (8.7) 3.67 s(6H) 3.81 s(3H) 3.96 s(3H) 1.97 2.01 2.30 2.33 s s s s 7.79 d (7.2) 7.81 d (7.2) 3.74 s 3.75 s 3.86 s 3.96 s 7.99 d (8.3)

2'"and 6' "

OMe

OAc

3.65 3.70 3.80 3.96 1.97 2.14 2.29 2.33

s s s s s s s s

(In CDCI3, 500 MHz) a ) : CDCI3 + D2O. b ) : Overlapped with OMe signals.

647
Consequently, compound 35 structure 3 5. Confound 36 was isolated as amorphous. The spectral data of compound 36 and its acetate 36a suggested that the structure of 36 was close to those of conpound 35. Remarkable differences were seen in the ^H-NMR spectrum where the coupling constant between H-7" and H-8" was smaller (J=3.5 Hz) and the chemical shift of H-7" was in a higher field respectively) (6 4.96) than in compound 35 (Table 4.4). Thus, compound (J"=8.6 Hz and 6 5.02, 36 was the erythrowas concluded to be the threo isomer of

diastereomer of compound 35. Three sesquilignans 34, 35 and 36 are the first compounds to be reported from Salicaceae. Also, the occurrence of these compounds 34, 3 5 and 36, along with neolignans 3 0 and 31, lends support to the biosynthetic hypothesis of their formation by the sequiential coupling of individual phenylpropane units. 5. Studies on Neolignans and Sesquilignans from Eucommia 01 iv. The bark of Eucommia ulmoides has been used as a tonic and antihypertensive medicine in Japan and China, which is available on the market as the Chinese Crude Drug "Cortex Eucommia". The bark contains many lignans and their glucosides, which consist of derivatives of pinoresinol, medioresinol, syringaresinol and olivil (ref. 54). In these lignans, ( + )-pinoresinol-di-0-p-D-glucoside syringaresinol-di-0-p-D-glucoside are reported to be active principles of the bark of Eucommia ( + )-Syringaresinol-di-0-p-D-glucoside swimming exercise in rats and the endorphin content in plasma. This section reviews the structural elucidation of neolignans and sesquilignans from the bark of Eucommia 5.1 Neolignans (ref. 57) The air-dried bark of Eucommia ulmoldes was extracted with 50% methanol in water. After extracting the extract solution with ethyl acetate and then 1-butanol, the butanol extract was subjected to ulmoldes. ulmoldes to and ( + )biologically ulmoldes

(refs. 55,56). increase the p-

showed anti-stress activity on tendency

648

37 ! Ri=R2=H 37a: Ri=Ac, R2=H 38 : Ri=H, R2=0H (erythro) 38a: Ri=Ac, R2=0Ac 39 : Ri=H, R2=0H (threo) 39a: Ri=Ac, R2=0Ac silica gel chromatography with chloroform-methanol-water (100:10:1, 80:20:3) to give three neolignans, 37, 38 and 3 9. Compound 37 was isolated as a colorless syrup, [a]j^ +5.5

(MeOH). Acetylation of 37 gave a triacetate (37a), which gave peaks at m/z 486 (M+), 426 (M'^-CH3C00H) and 348 in MS spectrum. Compounds 37 and 37a were identified as dihydrodehydrodiconiferyl alcohol and its triacetate, respectively. Compound 3 8 was obtained as a colorless syrup, [a]jj 0 (water). The IR spectrum showed the presence of hydroxyl groups and aromatic rings. The UV spectrum of 3 8 showed an absorption maxima at 228, 283 and 288 nm. The bathochromic shift of the absorption maxima in the presence of the base was very similar to that of 37. Compound 3 9 was obtained as a colorless syrup, [ajjj 0 (water). The IR and UV spectra of 39 were very similar to those of 38. Acetylation of 3 8 and 3 9 gave pentaacetates, 3 8a and 3 9a, respectively. The MS of 38a and 39a were almost identical with each other, showing peaks at m/z 602 ( M " * " ) and 542 (M^-CH3C00H). The ^H-NMR spectrum of 38a showed signals due to four alcoholic acetyl groups (6 2.00, 2.05 and 2.13), a

phenolic acetyl group (6 2.30), two aromatic methoxyl groups (6 3.82 and 3.91), and five aromatic protons (6 6.83 and 6.99). That of 39a showed similar signals. tetraacetate It and was its reported threo that isomer erythrocould be guaiacylglycerol

distinguished on the basis of the chemical shifts and the coupling constants of the benzylic protons (refs. 58,59). The benzylic proton

649
signals of 38a and 39a appeared at 6 5.93 (d, J=5.72 Hz) and 6 5.89 (d, J=7.48 H z ) , which showed threo were established to be 38a and 3 9a to be the erythro and alcohol isomers, respectively. From these results, compounds 38 and 39 erytiiro-dihydroxydehydrodiconiferyl

and its threo isomer, respectively. 5.2 Neolignan and Sesquilignan Glucosides (refs. 60,61). The air-dried bark of Eucommia and then solvent 1-butanol, on system This with was the aqueous Daiaion the HP-20, ulmoides was extracted with hot subjected a to column being gel water. After shaking the aqueous extract solution with ethyl acetate solution was eluting of chromatography increased. with water-methanol gradually by silica

proportions with

methanol

followed

purification

chromatography, to give two neolignan glucosides, 40 and 41 and two sesquilignan glucosides, 42 and 4 3 .

CH2OR1
9 '

MeO R20H2Cv..^8;0

RiO
40 : Ri=glc, R2=H 40a: Ri=glc(Ac)4, R2=Ac 40b:Ri=R2=H 40c: Ri=R2=Ac

41 : R^=gic, R2=H 41a: Ri=glc(Ac)4, R2=Ac 41b:Ri=R2=H

Compound 40 was isolated as a white powder, mp 134.7**C, [o.]^ -62.3 (MeOH), whose FD-MS gave peaks at m/z 683 (M"^ + 1 ) , 521 {it -

CgH^QOj + 1) and 359 (M+ - 2 x CgH^QOg - 1 ) . The IR spectrum showed the presence of hydroxyl groups and aromatic rings. The ^H-NMR spectrum showed 6.19 two signals at 6 3.74 and 3.80 due to two aromatic methoxyl groups, at 6 5.52 (IH, d, J=6.15 Hz) due to a benzylic proton, at 6 (IH, dt, J=15.83, 6.59 Hz) and 6.59 (IH, d, J=15.83 Hz) due to olefinic protons, of and 40 at 6 6.80-7.20 due to five aromatic ^H-NMR gave a nonaacetate of 40 (40a). with The

protons. Acetylation acetyl groups. The

spectrum showed signals at 6 1.96 and 1.98, due to nine alcoholic enzymatic hydrolysis p-glucosidase afforded a gave an aglycone (40b) and glucose. Acetylation of 40b

650
triacetate (40c), whose MS gave peaks at m/z 484 (M"*"), 424 ( M " ^ -

CH3COOH) and 382. The ^H-NMR spectrum showed signals at 6 2.05 and 2.10 due to two alcoholic acetyl groups, and at 6 2.30 due to a phenolic acetyl group. Compounds dehydrodiconiferyl 40b and 40c were identified as alcohol and its triacetate, respectively. From

these results, compound 40 was determined to be dehydrodiconiferyl alcohol diglucoside in which one glucose moiety is attached to the phenolic group. This conclusion was supported by the ^^C-NMR glucosylation shifts of C-1 (+3.0) and C-3 (+1.6 ppm), in going to 40 from 40b; they are identical with the 4-0-p-D-glucopyranosylation shifts of the guaiacyl group (ref. 62). The position of the other glucose linkage was determined from the ^-^C-NMR glucosylation shifts of the C-8' and C-9' atoms. As shown in Table 5.1, the signals of 40 at 6 123.6 and 68.7 were assigned to C-8' and C-9', respectively. The shifts of the corresponding carbons in going to 40 from 40b were was -4.3 and +7.2 ppm, as respectively, which indicated that one glucosyl group in 40 was linked to the C-9' atom. Thus, compound 40 established dehydrodiconiferyl alcohol 4,9'-di-O-p-Dglucopyranoside. Compound 41 was isolated as an amorphous powder, [a]jj -16.3 (MeOH). The UV and IR spectra suggested the lignan structure.

Acetylation of 41 gave a heptaacetate (41a), whose ^H-NMR spectra showed the presence of seven alcoholic acetyl groups (6 1.97, 2.03, 2.10 and 2.13). The enzymatic hydrolysis of 41 with p-glucosidase afforded an aglycone (41b) and glucose. The MS of 41b gave peaks at m/z 406 (M"^), 358 (M+ - CH2OH - OH) and 210. The ^H-NMR spectrum

showed signals at 6 3.74 and 3.77 due to three aromatic methoxyl groups, at 6 6.15 (dt, J=15.83, 5.71 Hz) and 6 6.58 (d, J=15.83 Hz) due to two trans olefinic protons, and at 6 6.57 and 6.75-7.20 due to five aromatic protons. The ^^C-NMR signals of 41 and 41b were assigned as shown in Table 5.1. From these results, compound 41b was determined to be guaiacylglycerol-p-O-4-synapyl ether. The ^^C-NMR chemical shift differences of the corresponding carbons in going to 41 from 41b were +3.1 (C-1') and +1.6 ppm (C-3'), respectively,

which indicated that a glucose moiety in 41 was attached to the

651 Table 5.1

I^C-NMR

and 41b

spectral data for compounds 38, 39, 40, 40b, 41

40 40b 41 41b

c
1 2 3 4 5 6 7 8 9 1' 2' 3' 4' 5' 6* 7' 8' 9' OMe

38 and 39 ^) 134.7 110.7 148.9 147.6 116.1 119.7 89.1 55.2 64.8 136.8 112.9 145.2 149.1 129.8 116.6 77.4 7 5 . 5 , 76.1 6 4 . 3 , 64.6 56.4 56.8

135.3 110.6 149.1 146.3 115.6 118.1 86.9 53.1 63.0 130.3 110.6 143.7 147.4 131.8 115.2 129.3 123.6 68.7 55.8 100.2 101.9 73.5 76.8 69.7 70.2 76.8 60.8 61.1

132.3 110.5 147.5 146.3 115.3 118.4 87.1 52.9 62.9 129.5 110.5 143.6 147.1 130.5 114.9 128.9 127.9 61.5 55.6

132.3 103.7 152.7 134.9 152.7 103.7 130.0 128.4 61.3 136.2 111.6 148.4 145.4 115.0 119.1 71.9 85.9 59.6 55.7 55.9 100.3 73.2 76.7 69.7 76.7 60.6

glc- 1 glc- -2 glc- -3 glc- -4 glc- -5 glc- -6

(In DMSO-dg, 60 MHz) a): In MeOH-d4.

132.2 103.8 152.6 134.9 152.6 103.8 129.9 128.4 61.1 133.1 111.2 146.8 145.2 114.5 119.2 72.0 85.9 59.6 55.5 55.8 56.0

phenolic

group. The

^H- and

^^C-NMR

chemical

shifts

of

41

were

identical with those of citrusin B. Thus, compound 41 was identified as citrusin B. Compound 42 was obtained as an amorphous powder, [a]^ -11.5 (MeOH), which gave peaks at m/z 908 (M+), 746 (M+ - C^E^^O^), 584 (M^ - 2 X CgH^QOg) and 388 in the FD-MS spectrum. The IR spectrum of 42 showed the presence of hydroxyl groups and aromatic rings. The

652
^H-NMR spectrum of 42 showed signals at 6 3.76 (s) due to four

aromatic methoxyl groups^ and 6 6.64

(s) and 6.70-7.16 (m) due to with acetic anhydride-

eight aromatic protons. Acetylation of 42

pyridine gave a decaacetate (42a), which gave signals at 6 1.86 (s), 2.00 (s) and 2.11 (s) due to ten alcoholic acetyl groups, 6 3.75 (s) due to four aromatic methoxyl groups, and 6 6.63 of 42 with p-glucosidase of 42b with gave an aglycone (s) and 6.70-7.16 and glucose. gave a (s) and (s) and 42 c 42 was was (m) due to eight aromatic protons in the ^H-NMR spectrum. Hydrolysis (42b) Acetylation 2.15 2.31 acetic anhydride-pyridine signals at 6 1.99 groups. these Compound results,

tetraacetate (42c), whose (s) due as to ether two

^H-NMR showed acetyl

(s) due to two alcoholic acetyl groups, and at 6 2.29 phenolic C hedyotol tetraacetate From

identified medioresinol

(guaiacylglycerol-p-

tetraacetate).

considered to be hedyotol C diglucoside in which the two glucosyl groups are attached to two phenolic groups. The ^^C-NMR data of 42 and were 42 b +3.0 supported (C-l* this conclusion. As and +1.5 shown in Table 5.2, the chemical shifts of corresponding carbons in going to 42 and C-1") ppm (C-3' and indicated that the two glucosyl groups in from 42b which

C-3"),

42 were linked to two

guaiacyl rings at the C-4' and C-4" positions. Furthermore, the ^-^C-

MeO
9 "

R40H2C\8"0

OMe

OR4

42 : R-|=R2=R4=H, R3=glc 42a: Ri=R2=H, R3=glc(Ac)4, R4=Ac 42b: Ri=R2=R3=R4=H 42c: Ri=R2=H, R3=R4=Ac 43 : Ri=R2=0Me, R3=glc, R4=H 43a: Ri=R2=0Me, R3=glc(Ac)4, R4=Ac

653 Table 5.2 I^C-NMR s p e c t r a l d a t a f o r compounds 4 2 , 4 2 a , 4 2 b , 43 and 43a

42

c
1 2 3 4 5 6 7 8 9 1' 2' 3* 4' 5' 6' 7' 8' 9' 1" 2" 3" 4" 5" 6" 7" 8" 9" OMe

42a

42b

43

43a

g l c --1 g l c - -2 g l c - -3 g l c - -4 g l c - -5 g l c - -6 Me i n Ac CO i n Ac

134.8 103.5 152.6 136.9 152.6 103.5 84.8 53.7 71.2 135.3 110.9 149.0 145.9 115.6 118.1 85.1 53.7 71.2 136.2 111.6 148.5 145.5 115.0 119.3 72.0 85.9 59.8 55.9 56.0 100.4 101.9 73.3 73.5 76.8 69.8 76.8 60.7 61.1

132.6 103.0 152.6 137.6 152.6 103.0 84.7 53.7 71.2 137.6 111.1 149.9 145.2 118.1 118.3 85.1 53.7 71.2 133.9 111.8 149.5 145.5 118.1 119.3 73.3 79.8 62.3 55.9 56.1 98.8 99.1 70.9 72.0 68.3 71.2 61.7 20.3 20.6 168.8 169.1 169.4 169.8

135.0 103.5 152.7 137.0 152.7 103.5 85.2 53.5 71.2 132.3 110.6 147.5 146.0 115.2 118.7 85.2 53.8 71.0 133.2 111.2 147.0 145.4 114.7 119.4 72.2 86.1 59.9 55.6 56.0

134.8 103.4 152.5 137.0 152.5 103.4 84.9 53.5 71.1 133.6 104.3 152.5 137.0 152.5 104.3 84.9 53.5 71.1 133.8 105.3 151.9 138.1 151.9 105.3 72.1 85.7 59.7 55.9 56.3 102.7 102.9 74.0 76.4 69.8 76.9 60.9

34.1 103.4 153.1 137.5 153.1 103.4 86.0 54.6 72.4 134.1 103.8 153.1 137.5 153.1 103.8 86.0 54.6 72.4 134.4 105.5 153.6 138.2 153.6 105.5 72.2 80.8 62.6 56.3 56.7 101.2 69.9 72.2 72.2 73.4 62.6 20.7 169.3 169.5 169.6 170. 170, 170,

( I n DMSO-dg, 60 MHz) a ) : I n MeOH-d4

654
NMR signals of the glucose moieties were consistent with the pglucopyranosyl form. Thus, compound 42 was concluded to be hedyotol C 4' ,4"-di-0-p-D-glucopyranoside (guaiacylglycerol-p-medioresinol ether 4 ', 4 "-di-0-p-D-glucopyranosi-de). Compound 43 was obtained as an amorphous powder, [a]^ -11.1 (MeOH), which gave a spot a little higher than that of 42 on TLC with chloroform-methand-water (70:30:5) as a developing solvent. The IR spectrum of 43 showed the presence of hydroxyl groups and aromatic rings. The ^H-NMR spectrum showed signals at 6 3.74 due to six aromatic methoxyl groups, and at 6 6.64 due to six aromatic protons on three syringyl rings. The FD-MS spectrum gave peaks at m/z 1007 (M+ + K ) , 991 (M+ + Na), 829 (M+ - CgH^oGs + Na), 667 (M+ - 2 X CgH^QOg + Na) and 418. These peaks are 60 mass units larger than the corresponding peaks of 42. These findings suggest that compound 43 is syringylglycerol-p-syringaresinol ether glycoside. Acetylation of 43 with acetic anhydride-pyridine gave a decaacetate(43a), whose ^H-NMR showed signals at 6 1.99, 2.03, 2.15 and 2.18 due to ten alcoholic acetyl groups, at 6 3.76, 3.80 and 3.83 due to six aromatic methoxyl groups, at 6 5.04 (2H, d, J=6.0 Hz) due to two

anomeric protons of glucose, and at 6 6.53, 6.56 and 6.60 due to six aromatic protons in three syringyl rings. Except for the glucose moieties, the ^H-NMR spectrum of 43 a was similar to that of syringylglycerol-p-syringaresinol ether tetraacetate. Furthermore, [( + )-

the ^"^C-NMR signals of 43 and 43a were assigned as shown in Table 5.2, in comparison with those of 42, 42a and liriodendrin syringaresinol-di-0-p-D-glucoside]. From these results, compound 43 was determined to be syringaresinol-p-syringaresinol ether 4',4"-di0-p-D-glucopyranoside.

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46 47 48 49 50 Y. Hashimoto, S. Ozawa and T. Sasaya, Mokuzai Gakkaishi, 40 (1994), 549-553. M. Aoyama and A. Sakakibara, Mokuzai Gakkaishi, 22 (1976) 591592. M. Haruna, T. Koube, K. Ito and H. Murata, Chem. pharm. Bull., 30 (1982) 1525-1527. F. Nakatsubo and T. Higuchi, Mokuzai Gakkaishi, 25 (1979) 735742. O.R. Gottlieb and M. Yoshida, in: J.W. Rowe(Ed.), Natural Products of Woody Plants, Vol.1, Springer-Verlag, (1989) 399511. 51 52 53 54 P.J. Houghton, Phytochemistry, 24 (1985), 819-826. A.C. Baraga, S. Zacchino, H. Badano, M.G. Sierra and E. Ruveda, Phytochemistry, 23 (1984) 2025-2028. K.V. Sarkanen and A.F.A. Wallis, J. Chem. Soc. Perkin Trans.I, (1973) 1869-1878. S. Nishibe, in: Atta-ur-Rahman (Ed.), Studies in Natural Products Chemistry, Vol. 5, Structural Elucidation (Part B ) , Elsevier, Amsterdam, (1989) 505-548. 55 T. Deyama, S. Nishibe, S. Kitagawa, Y, Ogihara, T. Takeda, T. Ohmoto, T. Nikaido and U. Sankawa, Chem. Pharm. Bull., 36 (1988) 435-439. 56 57 58 59 60 61 62 S. Nishibe, in: A. Scalbert (Ed.), INRA Editions, Paris, (1993) 247-255. T. Deyama, T. Ikawa, S. Kitagawa and S. Nishibe, Chem. Pharm. Bull., 35 (1987) 1785-1789. T. Deyama, T. Ikawa, S. Kitagawa and S. Nishibe, Chem. Pharm. Bull., 34 (1987) 523-527. Y. Sano and A. Sakakibara, Mokuzai Gakkaishi, 16 (1970) 81-86. T. Deyama, T. Ikawa, S. Kitagawa and S. Nishibe, Chem. Pharm. Bull., 34 (1986) 4933-4938. T. Deyama, T. Ikawa, S. Kitagawa and S. Nishibe, Chem. Pharm. Bull., 35 (1987) 1803-1807. a) S. Nishibe, H. Tsukamoto and S. Hisada, Chem. Pharm. Bull., 32 (1984) 4653-4657. b) T. Deyama, T. Ikawa and S. Nishibe, ibid., 33 (1985) 3651-3657.

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

659

Chemical and Biological Investigations of Salvia Species Growing in Turkey

Ayhan Ulubelen and Giilacti Topcu
*Faculty of Pharmacy, University of Istanbul, 34452 Istanbul, Turkey; **Tubitak, Marmara Reseach Center, Department of Chemistry, P.O. Box 21,41470, Gebze- Kocaeli, Turkey

1. INTRODUCTION The name Salvia is derived from the latin word salvare (healer). Salvia species have been used as folk medicine since ancient times in order to cure tuberculosis^ cancer^, diabetes^, coronary heart diseases, angina pectoris, myocardial infarction'^'^ skin diseases such as psoriasis and eczama^ and have oestrogenic activity^. Salvia (Lamiaceae) species are 30-100 cm tall, herbaceous, suflfruticose, perennial, rarely biennial or annual plants, growing in calcareous sunny lands in southern Europe and other parts of the world. There are about 500 Salvia species grown naturally in the world, Turkey has 90 species, 44 of them being endemic. In this review article we have dealt with the chemistry and biology of 16 Salvia species which were studied since 1992. In the previous review articles^'^ , the data of about 20 other Turkish Salvia species were given. 2. CHEMICAL STUDIES Until now, we have isolated over 50 triterpenoids, about 100 diterpenoids, more than half being new compounds, a total of 15 sesquiterpenoides and sesterterpenoides, 40 flavanoides and several aromatic compounds. Recently we have studied quite a number of Salvia species and isolated various group of compounds. The structures of the new compounds are discussed below.

660 2.1. SESQUTTERPENOIDS Although sesquiterpenoids are rather rare in Salvia species, three sesquiterpene lactones, an eremophilanolide and two eudesmanolides as well as caryophyllene oxide and (-)-glechomafiiran were isolated from S. palaefolia^^'^^. Recently, we have obtained several sesquiterpene lactones from S. yosgadensis^^, Istanbulin D, lp-acetoxy-8p-hydroxyeudesm-4(15),7-dien-8,12-olide (isolated previously from S. potentillifolia^^) and 13-acetoxyeudesm-4(15),7-dien-8,12-olide as well as sesquiterpene spathulenol. We have also isolated the sesquiterpenes caryophyllene oxide and spathulenol from S. sclarea^^. From S. divaricata^^, a new linear sesquiterpene was isolated and named salvinine (1). The EIHR mass spectum of 1 indicated the molecular formula C15H26O3 Qn/z 254.1888, calc. 254.1877). The ^H NMR spectrum showed the structure clearly. A terminal ethylene group was present at 5 5.85 (lH,dd, J=10 and 17 Hz), 5.17 (IH, dd, J=1.5 and 17 Hz) and 4.99 (IH, dd, J=1.5 and 10 Hz), the signals at 5 6.40 (IH, d, J=16 Hz, H-9) and 6.90 (IH, d, J==16 Hz, H-10) showed a ^awis-ethylenic group. Methyl signals were at 5 1.37 (6H, 2xMe at C-11), 1.28 (3H, s, Me at C-3) 1,17 (3H, d, J=7 Hz, Me at C-7), hydrogen geminal to the latter methyl group was at 5 4.10 (IH, m, H-7), three adjacent methylene groups at 5 3.03 (2H, t, J=7Hz, H2-4), 1.60 (4H, m, H2-5 and H2-6). Mass degradation of 1 fully supported the assigned structure. The base peak at m/z 71.0779 (a) (C4H7O) showed the ethylenic group attached to carbon atom carrying a methyl and a hydroxyl groups, while the fragments at m/z 85.064 (b) (C5H9O), m/z 113.0063 (c) (C6H9O2), m/z 141,009 (d) (CgHisOz) were consistent with the tail part of the new sesquiterpene, salvinine (1).

HO 10

OH

2.2. DITERPENOIDS 2.2.1 Abietane Diterpenoids Turkish Salvia species contain mainly abietane type diterpenoids^^ while the majority of Salvia from the American continent have clerodane type diterpenoids^^. From Salvia candidissima Vahl subsp. occidentalis^^ Hedge, six abietane diterpenoids were isolated, five of which were known compounds ferruginol, horminone, 7-acetylhorminone, cryptanol.

661 montbretyl-12-methyl ether and one was a new compound 11-hydroxy-12-methylabieta-8,l 1,13-triene (2). Compound 2 has the molecular formula C2iH3202( w/z 316.2494, calc. 316.2514) as decided from its HR mass spectrum. The UV max at 276 nm indicated an aromatic ring system. The IR spectrum showed a hydroxyl at 3510 cm'^ and aromatic absorbances at 3080, 3050, 1605, 1520 cm"\ The structure was deducedfrom^H and ^ ^ C NMR spectral data. The signals at 5 0.82 (3H, s), 0.85 (3H, s) (Me-18 and Me-19), 1.20 (3H, s, H-20), 1.22 (3H, d, J= 6.8 Hz) and 1.24 (3H, d, J=6.8 Hz) (Me-16 OMe HO^ . ^ ^ ^.^ 0^

HOOC 3 R=R'=H, R^=0 4 R=Me, R'=H, R^O

5 R=R2=H, R * = 0 H

and Me-17), together with the methine proton at 5 3.16 (IH, septet, J=6,9 Hz, H-15) indicated an abietane skeleton. Other signals were observed at 5 3.75 (3H, s, OMe), 6.46 (IH, s, H-14), 6.00 (IH, s, OH) (D2O exchangeable). The H-lp proton at 5 3.20 (IH, ddd, J=3.5, 5, 13 Hz) indicated a hydroxyl ^ C NMR (APT) spectrum showed six methyl, five methylene, group at C-11 rather than at C-14. The ^ three methine and seven quaternary carbon signals (Table 1). Three new abietane diterpenoids were isolatedfromS. divaricata^^, which were 6-oxoroyleanone 18-oic acid (3), 6-0x0-12-methyh-oyleanone-18-oic acid (4) and horminone-18-oic acid (5). Compound 3 indicated the molecular formula C20H24O6 (m/z 360.1566, calc. 360.1572). The UV spectrum having maxima at 405 and 343 nm indicated a quinoid type structure rather than an aromatic abietane diterpene. The IR spectrum at 1680 and 1660 cm"* revealed the p-quinoid structure, while the carboxyl group and the carbonyl signals were observed at 1700 and 1720 cm'\ respectively. The *H NMR spectrum of 3 showed a resonance at 5 12.88 (IH, br s) (acid proton), while the isopropyl group was evident with the signals at 5 1.32 (6H, d, J=7 Hz, Me-16 and Me-17) and 3.54 (IH, septet, J=Hz, H15). Other signals were at 6 1.27 (3H, s, H-19), 1.37 (3H, s, H-20). The sequence of Ci- C3 was

662
decided from spin decoupling experiments with the signals at 5 2.35 (IH, ddd, J=15, 5 and 1 Hz, HIp), 1.60 (IH, ddd, J=15,13 and 5 Hz, H-la), 2.12 (IH, m, H-2p), 1.72 (IH, dddd, J=13,12, 7.5 and TABLE 1. ^ ^ C NMR Data of Compounds 2,3, 4 and 5

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OMe

2 41.6t 19.21 39.41 34.4 s 52.91 19.41 36.51 133.5 s 137.7 s 32.0 s 142.4 s 147.0 s 133.0 s 117.5 d 26.4 d 19.9 q 22.7 q 33.4 q 22.1 q 26.0 q 62.8 q

3 35.401 19.851 41.851 36.77 s 47.94 d 200.90 s 29.60 d 142.80 s 148.40 s 38.66 s 182.30 s 150.20 s 124.20 s 186.70 s 28.85 d 21.50 q 21.50 q 177.90 s 16.28 q 23.18 q -

4 35.791 20.011 40.911 36.80 s 48.25 d 201.70 s 29.60 d 142.75 s 149.10 s 39.01 s 183.60 s 150.80 s 123.90 s 187.00 s 29.02 d 21.45 q 21.55 q 178.20 s 15.30 q 23.00 q 57.73 q

5 35.901 20.401 39.721 36.70 s 45.62 d 41.20 t 65.40 d 143.40 s 148.00 s 39.80 s 184.20 s 151.40 s 124.40 s 184.50 s 27.75 d 21.80 q 21.80 q 181.70 s 16.10 q 26.20 q -

4.2, H-2a), 1.56 (IH ddd, J=14, 12.7 and 3.9 Hz, H-3P) and 1.22 (IH, m, H-3a). The ^ ^ C NMR spectrum (Table 1) was in agreement with the given structure.

663 The *H NMR spectrum of compound 4 was quite similar to that of 3 with the exception of a methyl group at C-12. Although the stmcture of compound 5 was quite similar to those of 3 and 4, the 6-0X0 group was missing and there was a hydroxyl group at C-12. The spectral data resembled that of horminone, except for the additional acid group at C-4 instead of Me-18. From the aerial parts of Salvia pomifera^^ in addition to two known diterpenes ferruginyl 12methyl ethef^ and 18-hydroxyabieta-8,11,13-triene-7-one(6)^^ five new abietane diterpenes were isolated, pomiferin A-E (7-11). The ^H NMR spectrum of the new compounds clearly indicated their structures which are given in Table 2. Spin decoupling experiments were run to show the ^H-*H ^ C NMR spectra correlated with the given structures (Table 3). relations. The ^

Rl
6 H 7 H 10 OH

^ CH2OH 0
CH2OH

R'

Rl
8 H 9 Me

R' H OH

Ri
CH2OAC COOH

Rl
11 OH 12 OH 13 H

Bl Me Me

R3 H 0

H H

Me

CH2OAC H

Another study^ with the same plant has yielded two more of the same group of compounds pomiferin F and G (12, 13). The ^H NMR spectrum of pomiferin E (12) exhibited an additional hydroxyl group at C-15, as decidedfi'omthe lack of H-15, and the presence of Me-16 and Me-17 as singlets at 5 1.29 (3H), and 1.33 (3H) instead of doublets. A signal at 5 4.16 (IH, dddd, J=4, 4, 11.5, 11.5 Hz, H-2P) indicated the presence of a secondary hydroxyl group at C-2 which was also observed in compounds 10 and 11. The C ring protons were at 5 7.38 (IH, d, J=8 Hz, H-11), 7.75 (IH, dd, J=2 and 8 Hz, H-12), 8.08 (IH, d, J=2 Hz, H-14), the latter signal being indicative of an 0x0 group at C-7. Pomiferine G (13) showed the methyl signals at 5 1.26 (6H, d, J=7 Hz, Me-16 and Me17), 1.02 and 1.26 (3H, each) (Me-19, Me-20) and isopropyl methine signal was at 5 2.94 (IH, septet, J=7 Hz, H-15). A methylene pair appeared at 6 3.78 and 3.86 (each IH, J=12 Hz,

664

TABLE 2. ^H NMR Data of Compounds 7-11 H 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 18' 19 20 C=0 CH3 OMe 6.80 d 2.88 sept 1.22 d 1.22 d 3.22 d 3.47 d 1.23 s 0.85 s 2.02 s 3.72 s 6.65 s 3.12 sept 1.23 d 1.23 d 3.63 d 3.95 d 1.22 s 0.90 s 6.51s 3.16 sept 1.18d 1.21 d 0.96 s 0.86 s 6.90 br s 2.83 sept 1.22 d 1.22 d 0.97 s 0.99 s 1.20 s 7.89 d 2.94 sept 1.16d 1.16d 1.01s -1.06 s 1.20 s 7.17 d 6.90 dd 6.85 s -~ 7.15 d 6.98 dd 7.30 d 7.42 d 7 2.28 ddd 8 2.19 ddd 9 3.54 3.54 ddd ddd 1.33 ddd 1.33 ddd - 4.05 4.05ddd ddd 1.85 m 1.28 ddd 4.05 10 2.62 ddd 2.62 ddd 11 2.68 ddd

665
H2-18) while the aromatic protons were at 5 7.31 (IH, d, J=8 Hz, H-11), 7.42 (IH, dd, J=2 and 8 Hz, ^ C NMR data of 13 are given in Table 3. H-12) and 7.89 (IH, d, J=2 Hz, H-14). The ^ TABLE 3 ^ ^ C NMR Data of compounds 6 - 10,13

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 C=0 CHs OMe

6 38.51 18.71 35.lt 37.4 s 43.9 d 19.01 29.41 127.0 s 148.3 s 37.9 s lll.Od 150.8 d 131.6s 126.6 d 26.8 d 22.6 q 22.7 q 72.2 t 17.4 q 25.2 q

7 38.21 18.61 35.lt 30.5 s 43.9 d 18.lt 30.01 135.6 s 147.9 s 38.0 s 123.9 d 123.7 d 145.9 s 126.7 d 33.5 d 24.1 q 24.1 q 72.2 t 17.3 q 25.9 q

8 38.31 18.51 35.51 36.7 s 44.0 d 18.91 30.21 127.2 s 148.6 s 37.4 s lll.Od 150.6 s 131.4s 126.7 d 26.3 d 23.8 q 23.8 q 72.3. t 17.4 q 25.3 q 170.8 s 21.6 q

9 41.51 20.01 38.81 41.6 s 47.6 d 20.01 31.9t 125.4 s 129.5 s 34.1s 118.1s 147.8 s 134.6 s 142.4 d 32.7 d 23.1 q 23.5 q 180.9 s 18.4 q 26.5 q

10 51.4t 65.8 d 47.91 36.1s 50.3 d 19.21 20.01 134.7 s 147.1s 39.1s 127.2 d 124.0 d 145.8 s 124.0 d 33.7 d 33.7 q 23.8 q 33.6 q 22.1 q 24.5 q

13 37.41 18.lt 36.01 31.5s 43.9 d 19.61 192.6 s 132.6 s 138.5 s 38.3 s 123.6 d 124.9 d 152.0 s 134.5 d 33.6 d 23.8 q 24.0 q 71.6t 18.1 q 24.3 q 171.8 s 20.6 q

~ -

--54.8 q

---

666 Salvia monthretii?^'^^ yielded two new compounds, one of which is a derivative of salvinolone (14). The compounds isolated were salvinolonyl 12-methyl ether (15) and 14-hydroxyferruginol (16) in addition to the known compounds ferruginol, ferruginyl 12-methyl ether, taxodione, hypargenin F and demethylcryptojaponol. The *H NMR spectrum of the new compounds showed typical signals

OMe

15

16

for an abietane-type structure. H-ip in 15 was observed at 6 3.27 as a double triplet (J=3 and 13 Hz), indicating the presence of a hydroxyl group at C-11, while the signal at 7.72 (IH, s, H-14) showed the presence of an oxo group at C-7. The rest of the ^ H NMR signals were typical for the abietane structure. The ^ ^ C NMR spectra of both compounds are given in Table 4.

17

18

In a recent study with a fresh collection of the same plant^, we have isolated 6-hydroxysalvinolone (17) and 7-hydroxytaxodione (18). The structures were determined by ID and 2D NMR techniques. The HRCI mass spectrum of 17 indicated the molecular formula C20H26O4 {m/z 331.1906, M+1). The chemical shift of the C-4 methyl groups at 5 1.42 and 1.43 (3H each, s) indicated a double bond at C-5 and a hydroxyl group at C-6. The signal at 6 7.71 (IH, s, H-14) revealed the presence of a carbonyl group at C-7. The C-11 hydroxyl group was deducedfromthe chemical shift of H-lp at 5 3.05 (IH, septet, J=7 Hz). The ^ ^ C NMR and HETCOR experiments

667
TABLE 4 ^ ^ C NMR Data of Compounds 15,16 and 19

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OMe

15 40.51 18.71 34.21 38.2 s 175.4 s 123.5 d 185.4 s 124.4 s 136.7 s 42.2 s 145.8 s 148.2 s 139.7 s 115.8d 26.8 d 23.6 q 23.6 q 24.8 q 29.3 q 33.2 q 61.9q

16 37.81 17.lt 38.81 31.2s 51.4d 17.81 30.41 114.4 s 133.5 s 38.8 s 109.2 d 141.8 s 121.5 s 143.2 d 66.5 s 22.2 q 22.2 q 31.3 q 21.8 q 23.8 q

19 214.6 s 42.81 33.91 47.4 s 44.9 d 20.91 30.71 134.5 s 146.9 s 50.2 s 122.6 d 124.6 d 145.5 s 126.8 d 29.6 d 24.1 q 24.1 q 182.5 s 16.2 q 26.1 q

gave the correlations between the carbons and protons (Table 5). A new abietane diterpene l-oxo-abieta-8,1 l,13-triene-18-oic acid (19) and the known compounds horminone and ferruginol were isolated from the roots of S. tomentosc^. The molecular formula of 19 C20H26O3 was derivedfromits HRMS (m/z 314.1887). The ^H NMR spectrum of 19

668 TABLE 5 *H and ^ ^ C NMR Data of Compounds 17 and 18 17 18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

3.0 ddd, 1.50 m 1.90 ddd, 1.68 m 2.0 m, 1.30 m

36.61 17.91 30.41 37.6 s 170.8 s 141.0 s 180.0 s 123.2 s 132.9 s 38.3 s 143.4 s 145.6 s 138.3 s 116.6d 27.4 d 22.4 q 22.4 q 22.7 q 28.0 q 27.9 q

* * * 2.90 s

42.3 18.71 32.91 32.9 s 62.2 d 182.0 s 142.3 s 126.5 s 141.9 s 41.8 s 145.4 s 183.4 s 138.4 s 133.1 d 26.9 d 21.4 q 21.4 q 32.5 q 21.8 q 21.9 q

7.72 s 3.04 sept 1.28 d 1.32 d 1.42 s 1.43 s 1.67 s

6.45 s 2.92 sept 0.95 d 0.85 d 1.32 s 1.28 s 1.10s

Overlapped signals indicated the aromatic signals at 5 7.17 (IH, d, J=8.5 Hz, H-11), 7.02 (IH, dd, J=2 and 8.5 Hz, H-12), 6.9 (IH, d, J=2 Hz, H-14) and the other signals were at 5 2.86 (IH, sept J=7 Hz, H-15), 1.24 (6H,d, J=7Hz, H-16andH-17), 1.23 (3H,s,H-19), 1.28 (3H, s, H-20). The location of

669
an 0X0 group was deduced at C-1 due to the chemical shift of H-11 as well as the chemical shifts of A ring protons. The *^C NMR spectrum of 19 showed the C-1 carbonyl at 5 214.6, the carboxyl group was at 6 182.5 (C-18) and the rest of the signals were in agreement with the suggested structure (Table 4). The structure of nemorosine (20) was established as 2a,14-dihydroxydehydroabietic acid which was isolated fi*om S. nemoroscF. Its structure was deduced fi-om the ^H NMR spectrum, spin decoupling experiments and by comparison with structurally resembling compounds. The C-ring signals were observed at 5 7.12 (IH, d, J=8.5 Hz, H-11), 6.8 (IH, d, J=8.5, H-12), and 5.82 (IH, br s, C-14 OH) (D2O exchangeable). The signal at 5 4.10 (IH, dddd, J=4,4, 9.5,10 Hz, H-SP) indicated an a-OH group at C-2 . The methyl signals were at 6 1.04 (3H, s), 1.09 (3H, s) (Me-18 and Me-20), 1.22 (6H, d, J=7 Hz, Me-16 and Me-17) together with an isopropyl methine signal at 5 3.80 (IH, sept. J=7 Hz, H-15). The plant material also yielded the known diterpenoids pachystazone, horminone and acetylhorminone.

Another new abietane diterpenoid was isolatedfi-omS. sclared^. Its structure was established as 7-oxoferruginol-18-al (21) on the basis of ^H NMR spectral data. The signal at 5 7.84 (IH, s, H-14) indicated the presence of an 0x0 group at C-7, while another signal at 5 9.78 verified the presence of an aldehyde group in the molecule. The aldehyde group could be placed either at C-4 or C-10. When the aldehyde group is placed at C-10 the two methyl signals at C-4 (Me-18 and Me-19) would be close together in their ^H NMR spectrum^' ^ while in the present case, the methyl groups were at 5 1.02 and 1.20 (each 3H, s) (Me-19, Me-20) showing the placement of the aldehyde group at C-18. Other signals were at 5 1.28 (6H, d, J=6.8 Hz, Me-16 and Me-17), 6.90 (IH, s, H-11) and 3.16 (IH, sept. J=6. 8 Hz, H-15). Two known compounds ferruginol and 7-oxoroyleanone were also isolated.

670
A new abietane diterpene heldrichinic acid (22) was isolated from .SI heldreichiana Boiss.^^. The molecular formula of 22 was calculated from its HREI mass spectrum {m/z 332.1980). The ^^C NMR spectmm of 22 indicated the presence of three methyl quartets, seven methylene triplets, three methine doublets and seven quaternary carbon singlets for 20 carbon atoms. The signals of the carbonyl group was at 5 214.2 while that of the carboxyl group was at 5182.3. Two downfield signals at 5 148.7 s and 110.3 t indicated the presence of an exo methylene group. The double bond was verified from the signals at 5 111.2 s and 110.5 d, whereas a tertiary hydroxyl was indicated by the signal at 5 76.5 s. The ^H NMR spectrum together with mass degradation signals indicated the structure of 22 clearly. The ^H NMR spectrum showed signals at [5 4.81 (2H, br s, C-16 exo-CH2), 1.72 (3H, s, Me-17), and 5.12 (IH, dd, J=4 and 7 Hz, H-11) (the vinylic proton)]. Two other methyl signals were at 6 1.27 (Me-19) and 0.94 (3H, s, Me-20). The mass fragmentation indicated that the double bond should be at ring C and since no conjugation was observed in the UV spectrum (207 nm), it should be situated between C9 and C-11. Spin decoupling experiments established the vicinal relations between the olefinic H-11 and H2-I2. The location of the hydroxyl group at C-8 was similar to that of compactone^V The ^^C NMR

COOH 22
data of 22 are given in Table 6. S. nc^ifolict^ yielded five new abietane diterpenoids, 6,12,14-trihydroxyabieta-6,8,ll,13(26), 11,12acetyl-

23

24

tetraene (23), 7,20-epoxyroyleanone (24), 1-oxoferruginol (25), 6-oxoferruginol

dioxoabieta-8,13-diene (27) together with seven known abietane diterpenes horminone,

horminone, ferruginol, pachystazone, cryptanol, cryptojaponol and sugiol. The molecular formula of 23 was C20H28O3 as indicated by its HREI mass spectrum {jn/z 316.2311). The UV spectrum showed a maximum at 332 nm indicating a conjugated aromatic system as observed in cryptanol^^. The ^H NMR

671 spectrum showed signals at 5 6.87 (IH, s, H-7), 6.20 (IH, s, H-11) and 5.28 (IH, br s, OH) (disappeared with D2O), while the protons for the isopropyl group of the abietane skeleton were observed at 6 1.14 (3H, d, J=7 Hz), 1.16 (3H, d, J=7 Hz) (Me-16 and Me-17), and at 5 3.07 (IH, sept, J=7 Hz, H-15). Other methyl signals were at 5 1.09 (3H, s, Me-20) and 1.24 (6H, s, Me-18 and Me19). The observation of H-ip at 6 2.92 (IH, dt, J=1.5 and 10 Hz) indicated the lack of a hydroxyl group at C-11. In the latter case H-ip shifts to ca 3.1-3.8 ppm^'*'^^ The lack of a proton doublet in the lowerfieldindicated that the third hydroxyl group should be at C-6. Compound 24 had the molecular formula C20H26O4 {m/z 330.1818) as evidentfi'omits HRMS. Its ^H and *^C NMR showed its structure clearly. The other ^H NMR signals were shown at 5 4.41 (IH, dd, J=1.5 and 4.0 Hz, H-7a), 3.73 (IH, d, J=7 Hz), 3.65 (IH, d, J=7 Hz) (oxymethylene protons), 3.16 (IH, sept, J=7 Hz, H-15), 2.68 (IH, dt, J=3, 4 and 12 Hz, H-lp), 1.18 and 1.22 (each 3H, d, J=7 Hz) (Me-16 and Me-17), 0.92 and 0.88 (each 3H, s) (Me-18 and Me-19). The ^ ^ C NMR spectrum (Table 6) is in agreement with the given stnicture. The HREI mass spectrum of compound 25 indicated the molecular formula C20H28O2 {m/z 300.2104). The ^H NMR spectrum showed two proton singlets in the downfield area at 5 7.40 (H-11) and 7.18 (H-14), the methyl protons were at 5 1.28 (3H, s, Me-20), 1.17 and 0.87 (each 3H, s) (Me-18 and Me-19), and the isopropyl group was at 1.24 (6H, d, J=7 Hz, Me-16 and Me-17), 3.28 (IH, sept, J=7 Hz; H-15). The lack of H-lp signal and the downfield appearence of H-11 indicated the 1oxoferruginol structure for compound 25. Another similar compound (26) with the molecular formula C^nOiQn/z 300.2110) was also isolatedfi-omthe same extract. Its ^H NMR signals were quite similar to those of ferruginol, resonating at 5 6.92 (IH, s, H-11), 6.71 (IH, s, H-14), 3.17 (IH, sept, J=7 Hz, H-15), 1.18 and 1.22 (each 3H, d, J=7 Hz) (Me-16 and Me-17), 0.88, 0.91 and 1.27 (each 3H) (Me18, Me-19 and Me-20). The isolated doublet signals at 6 3.02 and 2.57 (each IH, J=14 Hz, H2-7) and the singlet signal at 5 2.61 (IH, H-5) as weU as the slightly downfield shift of Me-20 (5 1.27) indicated that the 0x0 group should be at C-6. The ^ ^ C NMR spectrum of 26 was in accordance with the suggested structure (Table 6). The last new compound 27 obtainedfi'omthis plant had the molecular formula C20H28O2 {ni/z 300.2070). Its UV spectrum with a maximum at 395 nm indicated a quinonoide structure rather than aromaticity in the C ring. The IR spectrum was consistent with an orthoquinonoide structure with the signals at 1685 and 1645 cm"\ The *H NMR spectrum showed the signals at 5 6.31 (IH, d, J=1.5 Hz, H-14), 2.98 (IH, sept, J=7 Hz, H-15), 2.70 (IH, dt,Hz, H-lp), 1.28 (3H, s, Me-20),

672 1.10, 1.01 (each 3H, d, J=7 Hz) (Me-16 and Me-17), 0.91 and 0.89 (each 3H, s) (Me-18 and Me-19). The *^C NMR spectrum verified the quinone structure with the signal at 182.0 ppm for two carbonyl groups (Table 6).

25 R=0, R1=H 26 R=H. R1=0

27

A new abietane diterpenoid was isolated fi-om Salvia forskahlei L. syn. S. hierosolymitana Boiss. var. pontica Freyn and Bomm^^. The new compound forskalinone (28) had the molecular formula C21H28O6 as establishedfi-omits HREI mass spectrum {m/z 376.1880). The UV [ 369, 400 (sh) ] and the IR (1680,1650,1622 cm'^) spectra indicated a quinonoid structure for 28. The ^H NMR spectrum of forskalinone (28) was consistent with the given structure. A sharp singlet at 5 13.40 indicated a hydrogen bond between the hydroxyl at C-14 and the carbonyl at C-7^^"^^. Another signal at 5 5.67 also showed a hydrogen bond between a hydroxyl at C-11 and a methoxyl at C-12. The presence of the hydroxyl group at C-11 was correlated with the signal at 5 3.24 (IH, br d, J=12 Hz) for H-ip'^^'^^V Two singlets at 5 3.64 and 3.60 (each IH) indicated the presence of a hydroxymethylene group which could be placed either at C-4 or at C-10. When it is at C-4, the methyl group at C-10 is shifted upfield to 6 0.80-0.85, while at C-10, the two methyl groups would have a chemical shift difference of 0.1-0.2 p p m " " ^ as observed in compound 28. Other signals were at 5 3.78 (3H, s, OMe), 3.30 (IH, sept, J=7 Hz, H-5) 1.38 (3H, d, J=7 Hz) and 1.36 (3H, d, J=7 Hz) (Me-16 and Me-17), 1.34 (6H, s, Me-18 and Me-19). The singlet at 5 2.61 (H-5) indicated the presence of an 0x0 group at C-6, thus supporting the ring B is an a-diketone. The ^ ^ C NMR spectrum was in agreement with the given structure (Table 6). The ^H-^H COSY experiment confirmed the connectivity between C-1, C-2, C-3.

673
TABLE 6 *^C NMR Data of Compounds of 22, 24,26, 27 and 28

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OMe

22 43.1 19.6 41.2 35.4 58.0 46.1 214.2 76.5 111.2 39.8 110.5 30.0 40.0 43.1 148.7 18.3 110.3 182.3 29.7 15.6

24 35.6 18.5 40.9 32.9 45.4 22.9 69.2 134.2 147.8 39.1 184.2 150.6 124.6 182.4 24.2 19.6 19.8 33.1 22.9 65.4

26 35.4 18.7 41.9 32.2 58.0 207.2 42.5 135.8 149.3 41.4 118.9 151.2 132.8 126.5 26.7 21.6 21.1 32.3 22.8 22.5

27 37.0 18.2 40.8 33.4 46.4 23.7 33.4 148.3 154.0 39.3 182.0 182.0 136.0 118.3 25.0 20.4 20.6 33.1 22.0 20.1

28 41.1 19.0 35.8 35.8 49.6 186.0 184.2 138.0 152.1 41.1 161.0 152.1 134.1 153.2 26.0 20.3 20.3 32.8 21.5 70.5 62.0

Salvia limbatct^ yielded two known abietane diterpenoids ferruginol and abieta-8,11,13-triene. Salvia multicaulis Vahl"*^ syn. S. acetohulosa has yielded six new abietane and norabietane diterpenoids in addition to 1-oxoferruginol, 3-oxo-ferruginol, horminone, pisiferal, 18-oxoferruginol and sempervirol.

674

HQ HOH2C

28 Thefirstnorditerpenoid compound multicaulin (29) gave the molecular formula C20H22O (/w/z 279.1678, M+1) as observedfi-omits HRCI mass spectrum. The ^H NMR spectrum of 31 indicated a fiilly aromatized structure giving the signals at 6 8.39 (IH, d, J=9 Hz, H-1), 7.95 (IH, s, H-11), 7.88 (IH, d, J=8.7 Hz, H-6), 7.70 (IH, d, J=9 Hz, H-2), 7.67 (IH, s, H-14), 7.41 (IH, d, J=8.7, H-7). The ^ ^ C NMR (APT) spectrum verified the aromatic structure of compound 29. The carbons and protons were correlatedfi'omthe HETCOR experiment (Table 7). Compound 30 was found to be the demethyl derivative of 29, its ^H and ^ ^ C >MR spectra being quite similar to those of 29 with the exception of a methoxyl group. The HETCOR data of 30 are given in Table 7. Compounds 31 and 32 possess an orthoquinonoid ring C with aromatic A and B rings. Compound 31 afforded the molecular formula C20H20O3 (m/z 308.1422) as calculatedfi"omits HREI mass spectrum. The ^H NMR spectrum showed the aromatic protons at 5 7.50 (IH, d, J=9 Hz,H-6), 7.17 (IH, s, H-2), 7.10 (IH, d, J=9 Hz, H-7), and 7.05 (IH, s, H-14). The chemical shifts of H-6 and H-7 were characteristic for the orthoquinonoid system in ring C as observed in saprorthoquinone'*^. The HETCOR experiment (Table 8) showed the correlation between carbons and protons.

29 R=Me 30 R=H

31 R=Me 32 R=H

TABLE 7
'H and 13CNMR data of compounds 29, 3 0 , 31 and 32
29 30 31 32

'H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 8.39 7.70

I3c
120.9 d 128.0 d 140.0 s 135.6 s 122.7 s 125.5 d 127.9 d 126.1 s 147.8 s 133.4 s 110.6 d 151.4 s 130.3 s 125.5 d 25.5 d 22.7 q 22.7 q 20.9 q 18.3 q 55.4 q

'H
8.30 7.60

"c
121.0 d 128.2 d 140.0 s 135.5 s 123.0 s 125.6 d 127.9 d 126.3 s 147.8 s 133.4 s 109.9 d 148.9 s 130.0 s 124.9 d 26.0 d 22.8 q 22.8 q 21.0 q 18.4 q

'H

l3c
133.9 s 152.8 d 140.6 s 133.4 s 127.6 s 125.5 d 132.4 d 128.5 s 126.0 s 152.4 s 183.3 s 181.4 s 135.3 s 126.6 d 26.3 d 23.0 q 23.2 q 20.8 q 17.9 q 56.0 q

'H

l3c
133.2 s 153.0 d 141.0 s 133.5 s 127.0 s 122.6 d 133.0 d 128.9 s 127.0 s 150.1 s 183.2 s 183.0 s 134.9 s 126.5 d 25.8 d 22.9 q 23.0 q 21.0 q 17.6 q

7.17

7.12

7.88 7.41

7.85 7.40

7.50 7.10

7.42 7.10

7.95

7.91 7.57 3.39 1.38 1.38 2.64 2.52

OMe

7.67 3.46 1.32 1.32 2.65 2.52 4.06

7.05 3.30 1.22 1.22 2.33 2.25 3.88

7.03 3.21 1.27 1.26 2.32 2.25

675

676 Compound 34 was the demethyl derivative of 33. Both compounds have spectral similarities with the lack of a methoxyl group in compound 34. The molecular formula of 32 was found to be C19H18O (m/z 294.1260)fromthe HREI mass spectrum. Table 7 shows the ^ H and ^ ^ C NMR data of 32. Other new abietane diterpenoids obtained from S. multicaulis^^ were 12-methyl-5-dehydrohorminone (33), 12-methyl-5-dehydroacetylhomiinone (34). The HREI mass spectrum of 33 indicated the molecular formula C21H28O4 {m/z 344.1992). The ^H and *^C NMR spectra of 33 clearly showed its structure giving the characteristic H-7 signal for horminone at 5 4.70 as a broad singlet together with other similar signals at 5 3.30 (IH, septet, J=7 Hz, H-15), 1.21 and 1.18 (each 3H, d, J=7 Hz) (Me-16 and Me-17), 1.09 (3H, s, Me-20) and 1.05 (6H, s, Me-18 and Me-19). Additional signals were at 5 6.91 (IH, br s, H-6) and at 5 3.82 (3H, s). The latter (OMe) could only be placed at C-12. Compound 34 was found to be the 7-acetyl derivative of 33. Its HRMS gave the molecular formula C23H35O5 {m/z 386.2122). The signal for H-7 was shifted to 5 5.35

OMe

33 34

R=H R=Ac

(IH, br s) thus indicating the placement of the acetyl group. Other signals were similar to those of compound 33 appearing at 5 6.91 (IH, br s, H-6), 3.83 (3H, s, OMe), 3.30 (IH, septet, J=7 Hz, H-15), 1.19 and 1.21 (each 3H, d, J=7 Hz, Me-16 and Me-17), 1.08 (3H, s, Me-20), 1.05 (6H, s, Me-18 and Me-19), 2.03 (3H, s,OAc). The *^C NMR data of both compounds are given in Table 8. S.tchihatchefftf^ yielded two new abietane diterpenoids tchitatine (35) and salvitchitatine (36). The molecular ion peak at m/z 284.2147 of 35 indicated the molecular formula C20H28O. The ^H NMR spectrum indicated two downfield signals as narrow doublets at 5 7.20 (IH, d, J=1.5 Hz, H-12), 6.20 (IH, d, J=1.5 Hz, H-14), two broad singlets at 5 4.78 and 4.72 (each IH, CHr 16), at 5 1.85 (3H, s,

677
TABLE 8 ^ ^ C NMR data of 33,34 and 38

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 OMe CO Me

33 37.41 18.21 40.81 33.4 s 127.7 s 106.7 d 77.8 d 124.7 s 142.6 s 41.2 s 183.2 s 154.5 s 129.4 s 181.4 s 26.4 d 21.4 q 21.6 q 21.6 q 33.4 q 20.1 q 56.4 q

34 37.51 18.21 40.71 33.4 s 127.6 s 108.0 d 76.9 d 124.8 s 142.6 s 41.2 s 183.2 s 154.4 s 129.5 s 182.0 s 25.9 d 21.5 q 21.5 q 22.0 q 33.0 q 20.2 q 55.9 q 172.6 s 22.3 q

38* 42.31 18.61 36.7 s 33.5 s 62.1 d 181.1s 141.0 s 126.7 s 145.5 ss 41.7 s 136.8 s 200.4 s 144.8 s 133.1 d 27.0 d 21.4 q 21.2 q 32.8 q 21.5 q 21.0 q

*A11 assignments correspond to C and C\ Me-17) and three other methyl singlets at 5 0.96, 0.72 and 0.70 (Me-18, Me-19, M&-20). Spin

678 decoupling experiments showed the relation between the C-1 - C-3 and C-6 - C-7 protons and between the H-12 and H-14. The ^ ^ C NMR displayed 20 C atoms consisting of four methyl quartets, six methylene triplets, three methine doublets and seven quaternary carbons. The assignment of carbons

35

36

and protons were made by the observation of their direct correlations in the HETCOR experiments (Table 9). The hydroxyl group should be at C-11 due to following reasons; the J values of the two aromatic protons showed their meta positions. There is no hydrogen geminal to the hydroxyl group and the observation of H-ip at 5 3.16 (IH, br d, J=12 Hz) established the presence of a C-11 hydroxyl group. The structure of tchitatine was concluded to be as 1 l-hydroxyabieta-8,ll,13,15-tetraene. Salvitchitatine (36) had the molecular formula C20H28O {m/z 284.2148). The *H NMR spectrum showed the presence of aromatic signals similar to those of 35, at 5 7.20 (IH, d, J=1.5 Hz, H-11), 6.21 (IH, d, J=1.5 Hz, H-14) and an olefinic proton signal at 6 6.59 (IH, t, J=4 Hz, H-6). An isopropyl side chain was observed at 5 2.88 (IH, sept. J=7 Hz, H-15) and 1.14 (6H, d, J=7 Hz, Me-16 and Me-17). Other methyl signals were at 5 1.10, 1.18, 1.27 (each 3H, s) (Me-18, Me-19, Me-20). Spin decoupling ^ C NMR (APT) experiments showed the relations between the C-1 - C-3, and C-6 - C-7 protons. The ^ and HETCOR experiments made possible the assignment of the protons and carbons (Table 9). The structure of salvitchitatine (36) was deduced as 1 l-hydroxyabieta-5,8,11,13-tetraene. From a Turkish Salvia species S. montbretii^, two abietane type dimeric diterpenoids were isolated for thefirsttime. One of them, 7,7-bistaxodione (37) had the molecular formula C40H50O6 (m/z 626.3730). The *H NMR spectrum of 37 resembled to those of taxodione and 7-hydroxytaxodione (18), with the methyl signals resonating at 5 1.41, 1.24 and 1.05 corresponding to Me-18, Me-19 and Me-20; two methyl doublets resonated at 5 1.08 and 1.10 (each 3H, J=7 Hz, Me-16, Me-17),

679
TABLE 9 *H and ^ ^ C NMR data of Compounds 35 and 36

c
'H 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1.85 s 0.72 s 0.70 s 0.96 s 6.20 d 7.20 d 2.601

35 ^ ^ C 38.71 18.61 41.2t 31.6s 46.2 d 20.21 31.8t 126.1s 147.0 s 38.8 s 151.2 s 140.9 d 131.4 s 106.1 d 144.2 s 110.31 16.1 q 33.4 q 23.5 q 24.5 q 6.21 d 2.80 sept 1.14d 1.14d 1.10s 1.18s 1.27 s 7.20 d 6.591 2.25 m 1.58 m, 1.28 m 3.60 m, 2.25 m ^H

36 ^'C 40.3 t 20.21 40.81 33.0 s 147.1 s 135.2 d 34.61 126.5 s 146.5 s 36.4 s 150.9 s 140.9 d 130.8 s 106.3 d 28.6 d 23.6 q 23.6 q 32.1 q 24.0 q 24.6 q -

3.16 brd, 1.60 m 2.55 m 2.25 m, 1.60 m

3.10 brd, 1.80 m 2.50 m 2.30 m, 1.80 m

4.72 brd, 4.78 brd

methine proton appeared at 5 2.98 (IH, d septet, J=1.2 and 7 Hz, H-15), while H-5 occured at 6 as a sharp singlet at 5 2.71. Two downfield signals were at 5 6.60 (IH, d, J=1.2 Hz, H-14) and 7.63 (IH, s, C-11 OH, D2O exchangeable). The presence of afragmentpeak at m/z 313 in its mass spectrum assignable to half of the structure indicated that the compound could be a dimeric taxodione. In the case of a symmetrical dimer the linkages of the two taxodione molecules could be either at C-14, C-11, C-7

680 or if the compound is asymmetric the linkage could be between C-7 - C-14, C-11 - C-7 or C-11 - C-14. The signals of the *H NMR spectrum indicated that the substance was a symmetrical dimer otherwise more signals should have been observed for the olefinic protons. In the *H NMR spectrum H-11 and H14 signals were clearly seen as in taxodione, so the only plausible way of joining the two units together wasC-7-C-r.

The second dimeric compound, 11,1 r-didehydroxy-7,7-dihydroxytaxodione (38), had the molecular formula C40H50O6 (m/z 626.3722). The *H NMR spectrum showed methyl signals at 6 1.02, 1.20, and 1.26 (each 3H, s) for Me-18, Me-19, Me-20, respectively. Two other methyl signals were at 5 0.78 and 0.88 (each 3H, d, J=7 Hz, Me-16 and Me-17), a methine signal appeared at 5 2.96 (IH, d septet, J=1.2 and 7 Hz, H-15) and a singlet resonated at 6 2.92 (IH, s, H-5). Downfield signals were observed at 5 6.37 (IH, d, J=1.2 Hz, H-14) and at 6 7.18 (IH, s, D2O exchangeable, C-7 OH). The spectral data including ^ ^ C NMR (Table 8) indicated a symmetrical dimeric compound with the presence of a C-7 hydroxyl group (5H 7.18; 5 C 141.0 ) as well as a H-14 signal (6H 6.37 ; 5C 133.1). The two parts of the molecule were therefore joined together at C-11 - C-IT to form ll,ir-didehydroxy-7,7'dihydroxytaxodione (38).

2.2.2. Rearranged Abietane Diterpenes Salvia candidissima Vahl. subsp. occidentalis^^'^'^^ yielded six rearranged abietane diterpenes, three of them being new. The known compounds were 1-oxoaethiopinone, salvipisone, microstegiol and the new compounds, 1-oxosalvipisone (39), 3-oxosalvipisone (40) and candidissiol (41). The structures of

681 three new compounds were established by spectral data including the HETCOR, HMQC and HMBC correlations. The HREI mass spectrum of compound 39 indicated the molecular formula C2oH2204( m/z 326.1532 ). The UV maximum at 432 and 355 nm showed extended conjugation in the molecule. Some of the *H NMR signals were identical to those of salvipisone at 5 7.98 (IH, d, J=8 Hz, H-7), 7.58 (IH, d, J=8 Hz, H-6), 2.43 (3H, s, Me-20), 1.29 (6H, d, J=7 Hz, Me-16 and Me-17), 3.38 (IH, septet, J=7 Hz, H-15), 1.77 (3H, br s, Me-19). The signals which showed differencesfromthose of salvipisone were at 5 7.30 (IH, br s, C-12 OH) (D2O exchangeable) and 4.82 (2H, s, H-18 and H-18'). The signals for the side chain were observed at 5 2.75 (2H, dd, J=6 and 7 Hz) and 1.60 (2H, m) (C-2 and C-3 protons). The lack of the benzylic protons at 5 3.13, the presence of an 0x0 group at 1705 cm"^ in its IR spectrum ^ C NMR spectrum indicated the structure 39 (1-oxosalvipisone). The and the signal at 5 195.5 in the ^ ^ ^ C NMR data of 39 are given in Table 10. Compound 40 was found to have the same molecular formula as 39, C20H22O4 (/w/z 326.1522) as evident from its HREI mass spectrum. The ^H NMR spectrum had many similarities in both compounds, but also exhibited some chemical shift differences. However, TLC comparison showed that the two compounds were different. The signals at 6 8.06 (IH, d, J=8 Hz, H-7), 7.59 (IH, d, J=8 Hz, H-6), 4.77 and 4.22 (each IH, br s, H-18 and H-18'), 1.79 (3H, s, Me-19), 2.33 (3H, s, Me-20) showed the main differences between the compounds 39 and 40. The 0x0 group should therefore be either placed at C-2 or at C-3. Because of the lack of the isolated methylene signals for the C-1 and C-3 protons it cannot be placed at C-2 and it should therefore be at C-3. The HMBC experiment verified this conclusion (Table 10).

39

40

43

The third new compound candidissiol (41) may arised by the possible rearrangement of aethiopinone (42) as shown in Scheme 1. The structure of 41 was determined from ID and 2D NMR techniques including *H-^H and ^H-^^C COSY as well as NOE and spin decoupling experiments. The ^H NMR

682
spectrum of 41 indicated aromatic signals 5 7.12 (IH, d, J=7.8 Hz, H-6), 7.02 (IH, d, J=7.8 Hz, H-7) and 7.09 (IH, d, J=l Hz, H-14) and exomethylene signals at 5 4.92 and 4.97 (each IH, br s). Table 10 presents the ^H, ^ ^ C and HETCOR NMR data. The HREI mass spectrum of 41 indicated the molecular formula to be C20H24O2 (/w/r 296.1437). TABLE 10 ^ ^ C NMR Data of 39, ^H and ^ ^ C NMR Data of 41

39 ^ ^ C ^H 2.77,4.08 1.68, 1.82 1.33,2.24 7.12 7.02 7.09 3.00 1.21 1.13 2.48,2.25 4.92,4.97 2.30

41 ^ ^ C 25.81 30.01 32.41 152.3 s 137.9 s 130.2 d 127.9 d 125.8 s 139.1s 144.1s 80.1s 209.2 s 142.4 s 140.7 d 26.8 d 21.7 q 20.2 q 54.31 117.7t 20.0 q

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

195.5 s 36.51 36.51 145.6 s 135.4 s 131.0d 128.3 d 133.4 s 130.7 s 153.5 s 183.6 s 156.8 s 130.3 s 184.3 s 25.3 sept 19.7 q 20.3 q 110.2t 22.4 q 26.2 q

683

42 Scheme 1

41

A new compound 43 similar to that of salvipisone was also isolatedfromS. sclarea^^ together with microstegiol and candidissiol. The molecular formula of 43 was found to be C20H22O3 (jn/z 310.1560). From the ^H NMR and spin decoupling experiments its structure was determined as 2,3dehydrosalvipisone. The ^ H NMR spectrum exhibited resonances at 5 7.97 (IH, d, J=10 Hz, H-7), 7.58 (IH, d, J=10 Hz, H-6), 7.64 (IH, s, C-12 OH) (D2O exchangeable), 2.42 (3H, s, Me-20), 1.84 (3H, s, Me-19), 4.81 (2H, br s, CH2-I8). The isopropyl protons resonated at 5 1.28 (6H, d, J=7 Hz, Me-16 and Me-17) and 3.37 (IH, septet, J=7 Hz, H-15). The signals for the side chain (C-1 - C-3 ) protons were quite different than those of salvipisone, resonating at 5 6.82 (IH, d, J=16 Hz, H-3), 5.10 (IH, dt, 7, 7, 16 Hz, H-2) and 3.02 (2H, br d, J=7 Hz, CH2-I) and indicating the presence of a double bond at A''^ or A^. The UV spectrum as well as tlie presence of the benzylic CHrl group and spin decoupling experiments proved that the double bond was located between C-2 and C-3. Salvipisone was also found in S. nemoroscP. Six new rearranged abietane diterpenes were isolated from S. limbata C.A. Meyer'*^. These compounds werel2-hydroxysapriparaquinone (44), 3,12-hydroxysapriparaquinone (45), 2-hydroxysaprorthoquinone (46), limbinol (47), salvilimbinol (48) and dehydrosalvilimbinol (49). The structures of

44 R=H 45 R=OH

46

TABLE 11
'H and 13CNMR Data of Compounds 44,45,46 and 47
44 45
l3C

684

46

47
l3C

'H
1 2 3 4
5

'H
8.37 d 7.57 d

I3c
129.6 d 128.8 d 150.0 s 126.5 s 142.2 s 127.9 d 118.3 d 134.0 s 132.7 s 143.7 s 184.8 s 153.1 s 132.7 s 184.0 s 24.1 d 20.9 q 20.9 q 29.7 q 29.7 q 18.4 q

'H
1.18,3.08 4.88 d 5.50 d 7.07 d 7.50 d

'H
32.3 t 73.0 d 124.4 d 136.2 s 137.8s 124.4 d 124.1 d 120.1 s 129.0s 137.8s 183.0 s 184.3 s 136.2 s 115.7 d 26.9 d 25.6 q 25.6 q 27.7 q 18.3 q 22.5 q

l3C

3.19 2.18 5.29 brt -

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

7.50d 7.96 d -

3.38sept 1.29d 1.29d 1.72s 1.60s 2.44s

30.2 t 27.8 t 123.7 d 126.3 s 144.4 s 136.2 d 126.4 d 136.3 s 132.5 s 143.2 s 184.6 s 153.2 s 132.5 s 183.3 s 24.4 d 19.8 q 19.8 q 26.9 q 17.6 q 20.3 q

5.35 d 5.40 d 7.00 d 7.12 d

7.45 d 8.15 d

7.10 d 6.95 d 2.97 sept 1.15 d 1.13 d 1.74 s 1.76 s 2.22 s

3.45 sept 1.34 d 1.34 d 1.79 s 1.79 s 2.81 s

7.20 d 2.97 sept 1.32 d 1.36 d 1.82 s 1.77 s 2.35 s

195.5s 65.6 d 124.9 d 136.5s 136.0 s 126.5 d 130.5 d 127.7 s 133.7 s 139.6s 136.0d 139.6 s 133.7s 136.5 d 26.9 d 21.4 q 21.5 q 25.8 q 18.1 q 18.8 q

685 all six compounds were decided from the ID and 2D spectral data. The chemical shift of the protons at C-6 and C-7 indicated a paraquinonoid structure at ring C for compounds 44 and 45 while in 46 the signals for H-6 and H-7 were relatively upfield, thus indicating its orthoquinonoid structure at ring C. Diterpenes limbinol (47), salvilimbinol (48) and dehydrosalvilimbinol (49) do not have quinonoid C rings ^ C NMR spectral data showed the quinonoid as seenfromtheir NMR data (Table 11). The UV, IR and ^ (44-46) and aromatic (47) characters. The COSY and HETCOR as well as spin decoupling experiments supported their structures (Tables 11 and 12). Compounds 48 and 49 showed differences from the other four compounds, especially from the signals for the C-1, C-2 and C-10 protons at 6 1.86 (IH, m, H-lb), 1.94 (IH, dd, J=5 and 11 Hz, H-la)

47

48

49

2.57 (IH, ddd, J=5.5, 10, 10 Hz; H-2b), 2.89 (IH, ddd, J=2, 5.5, 11 Hz, H-2a), 2.42 (IH, dd, J=5, 10 Hz, H-10) for compound 48 and the signals at 5 1.80 (IH, m, H-la), 2.30 (IH, ddd, J=3, 11 and 12 Hz, H-lb), 2.67 (IH, dd, J=9, 16 Hz, H-2a), 2.90 (IH, m, H-2b) and 2.44 (IH, dd, J=4 and 12 Hz, H-10) for compound 49, indicating saturated C-9 - C-10 positions. The structures of these two compounds were established by the COSY, HETCOR and COLOC experiments (Table 12). OH OHO

CCr
50

AcO.

51

TABLE 12

686

'H, I3CNMR and COLOC Correlations of 48 and 49

48 49

'H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1.86, 1.94 2.57,2.89

l3c
23.5 t 25.3 t 210.7 s 74.2 s 138.7 s 126.6d 130.0d 135.5s 76.2 s 45.4 d 136.3 s 141.0 s 128.1 s 134.9 d 27.4 d 20.7 q 21.6 q 26.5 q 32.6 q 19.8 q

COLOC c-3, c-5, c-9 c-3, c-4, c-10

'H
1.80, 2.30 2.67, 2.90

I 3 c

COLOC c-3, c-9 c-1, c-4, c-10

6.92 7.05 2.42

c-8, c-9, c-10, c-20 c-5, c-9 c-2, c-3, c-9, c-1 1

6.98 7.10 2.44

6.78 2.90 1.12 1.17 1.37 1.42 2.24

c-7, c-9, (2-12 C-13, C-14 C-12, C-13, C-14 C-13, C-14 c-2, (2-3, c-4 c-2, c-3 C-6, C-7, C- 10

6.89 2.98 1.11 1.11 4.90,4.91 2.01 2.25

24.4 t 25.1 t 201.7 s 149.1 s 137.3 s 126.5 d 130.1 d 135.6 s 74.5 s 45.8 d 137.3 s 141.9 s 126.6 s 135.5 d 26.6 d 21.4 q 21.4 q 111.7t 24.4 q 19.8 q

C-8, C-10, C-14, C-20 C-5, C-14 c-2, c-5, c-11

c-7, c-8, c-12 C-14 C-13, C-15 C-13, C-15 C-3, C-4, C-19 c-3, c-18 c-6, c-7

687
TABLE 13 ^H and *^C NMR of 50 and 51 501 ^H ^'C 'H 51 ^'C

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

2.95 m 2.30 dd 5.45 brd

30.21 27.81 123.7 d 126.3 s 144.4 s 136.2 d 126.4 d 136.3 s 132.5 s 143.2 s 184.2 s 153.2 s 132.5 s 183.8 s 24.4 d 201.9 d 19.8 q 26.9 q 17.6 q 20.3 q

5.38 d 5.50 dt

196.0 s 65.3 d 125.2 d 126.3 s 144.6 s 135.6 d 130.8 d 135.6 s 130.8 s 125.2 s 127.1 d 136.3 s 136.3 s 126.3 d 27.2 d 19.8 q 20.1 q 26.8 q 17.6 q 20.3 q

7.52 d 7.82 d

6.96 d 7.12 d

2.90 m 10.69 brs 1.32 d 1.78 s 1.83 s 2.40 s

7.10 d

6.90 d 2.95 sept 1.15d 1.15d 1.77 s 1.80 s 2.20 s

protons and carbons (Table 14). Extensive selective INEPT experiment allowed the unambiguous assignment of the groups. Irradiation of H-15 (5 3.35) enhanced C-12, C-14, C-16, while irradiation of Me-18 (5 1.15) enhanced C-4 and C-19, and irradiation of Me-19 (5 1.62) enhanced C-4 and C-18. All the rest of the carbons which were irradiated indicated the structure clearly.

688

Hydration of olefin

w
52 R=H 53 R=0

Reduction of double bond

Scheme 2 1-Oxosalvipisone (53) had the molecular formula C20H24O3 (m/z 312.1744). The ^ ^ C NMR spectrum showed the presence of two carbonyl groups at 5 210.8 and 202.3. The lack of a typical signal for H-1 at 5 3.85 as ddd indicated that the second 0x0 group should be at C-1 which was verified by the SINEPT experiment. All other signals are in agreement to those of 52. 2.2,3 Pimarane Type Diterpenoids Salvia wiedemannif^'^^ yielded pimarane type diterpenoids together with abietanes. 14-Oxoisopimaric acid (54) was found to be a new compound. It was obtained along with two known compounds, isopimaric acid^^ and 7P-hydroxysandracopimaric acid^^. Compound 54 had the molecular formula C20H30O3 {rn/z 318.3201) deducedfi'omits HREI mass spectrum. The IR spectrum indicated the presence of an acid group (a large shoulder between 2500 and 2800 cm'* and carboxyl group at 1700 cm'*), and a carbonyl signal at 1725 cm'*. The *H NMR spectrum clearly indicated the presence of an ethylene side chain in the isopimarane skeleton at 6 5.88 (IH, dd, J=l 1 and 17 Hz, H-16), 5.14 (IH, dd, J=1.5 and 17 Hz, H-17), 4.92 (IH, dd, J=1.5 and 11 Hz, H-IT) in addition to three methyl signals at 5 1.28 (3H, s, Me-15), 1.22 (3H, s, Me-18), 0.87 (3H, s, Me-20). The latter signal indicates the presence of the acid group at C-4 rather than at CA(f^. The position of the carbonyl group at C-14 was

689 concluded from the downfield shift of the signals of the ethylene protons as well as from the mass degradation pattern of 54 (Scheme 3). The diagnostic massfragmentsat m/z 182 (a), 138 (b) as well as 137 (c) indicated the presence of the C-14 carbonyl group. The same compound was also isolated from S. candidissimd*^. TABLE 14 ^H and ^^C NMR of 52 and 53 52 53

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

3.83 ddd, 3.02 ddd 2.20 ddd. 1.72 m 1.60 ddd, 1.20 m

26.51 23.01 33.31 85.0 s 132.7 s 126.7 d 125.8 d 134.1s 129.7 s 147.3 s 41.6 s 202.9 s 134.9 s 120.7 d 27.6 d 22.3 q 22.4 q 26.3 q 27.4 q 19.1 q

2.19 ddd, 1.65 dt 3.04 ddd, 2.67 dt

210.8 s 35.lt 41.21 84.3 s 132.2 s 126.3 d 128.1 d 126.8 s 130.4 s 147.4 s 41.2 s 202.3 s 136.6 s 121.1 d 27.8 d 22.3 q 22.3 q 25.9 q 26.2 q 18.7 q

7.08 d 7.48 d

7.11 d 7.62 d

7.33 s 3.35 sept 1.31 d 1.35 d 1.15s 1.62 s 2.42 s

7.41s 3.35 sept 1.28 d 1.33 d 1.22 s 1.67 s 2.32 s

690
Another new pimarane diterpenoid salvipimarone (7P-hydroxy-3,ll-dioxo-pimara-8(14),15dien) (55) was isolated from S. multicaulis Vahl."*^. The structure of salvipimarone was deduced from ID and 2D NMR spectra. The compound was found to have the molecular formula C20H28O4 {m/z 332.1991). The ^H NMR spectrum indicated its ethylenic side chain by signals at 5 5.79 (IH, dd, J=l 1

HOOC

CO2
HOOC

Scheme 3 and 16.5 Hz), 4.96 (IH, dd, J=2 and 16.5 Hz), and 4.92 (IH, dd, J=2 and 11 Hz). The broad singlet at 5 5.50 assigned to an olefinic proton (H-14) while a narrow triplet at 6 4.20 (IH, t, J=1.5 Hz, H-7a) was indicative of the presence of a P-hydroxyl group at C-7. Similar compounds with C-7p hydroxyl group and a double bond between C-8 - C-14 have been isolatedfromArelia cordatc^'^^ with similar chemical shifts. The IR spectrum of 55 showed the carbonyl signals at 1737 and 1720 cm"^ which were detected in the *^C NMR (DEPT) spectrum by the resonances rat 6 214.0 and 210.1. The two 0x0 groups were assigned to C-3 and C-11 on the basis of HMBC experiment (Table 15). S.heldrichiancf^ yielded three known pimarane diterpenoids, isopimaric acid, 7P-hydroxy sandracopimaric acid and 7-oxo-13-e/?/-pimara-8,15-dien-18-oic acid.

N ^ ^ ' ' ^

55

691
2.2.4. Labdane Type Diterpenoids Labdane and pimarane type diterpenoids are rather rare in Turkish Salvia species, and only a few of these compounds have been obtained. Sclareol and manool were isolated from S. sclared^. Manool was also obtainedfromS.limbatcf', while manoyl oxide was reportedfromS. candidissima^'^^ together with 1 ip-hydroxymanoyl oxide^^ and 8,13-di-^/?/-manoyl oxide^^. Although these two compounds were TABLE 15 ^ ^ C NMR and HMBC Data of 55

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

13(.

Irradiated H H-7 H-15 H-16 H-17 H-18 H-19 H-20

Correlated C C-5, C-6, C-9, C-14 C-11,C-12 C-13 C-11,C-13,C-14,C-15,C-16 C-2, C-3, C-5, C-6 C-3, C-5, C-6 C-1, C-2, C-9

39.lt 34.3 t 214.0 s 42.1s 46.2 d 29.3 t 73.4 d 144.1s 78.0 s 39.1s 210.1s 42.lt 37.3 s 134.0 d 148.3 d 110.6t 25.6 q 33.4 q 21.9 q 14.2 q

692

56 already known the spectral data given in the literature was not sufficient. We have recorded the HMQC (inverse phase HETCOR) and HMBC (inverse phase COLOC) spectra of 56 (Table 16). Norlabdane diterpenoids were isolated from S. yosgadensi^^. These included two known

compounds, ambrenolide and norambrenolide and three new compounds 6a-hydroxyambrenolide (57), 6a-hydroxynorambrenolide (58) and 6a-hydroxy-8a-acetoxy-13,14,15,16-tetranorlabdane-12-oic acid (59). 0 ^0

57

58

59

The ^^C NMR (APT and DEPT) spectra of 6a-hydroxyambreinolide (57) displayed four methyl, six methylene, three methine and four quaternary carbons (Table 17). The HREI mass spectrum showed the molecular ion peak at m/z 280.2031 analyzing for the molecular formula C17H28O3 which was consistent with a hydroxyl derivative of ambrenolide. The IR spectrum indicated the presence of a six membered lactone at 1716 cm"^ and a hydroxyl at 3454 cm'\ The ^H NMR spectrum of 57 exhibited a methine proton at 5 3.90 (J=4, 11 and 12 Hz). The multiplicity and the J values indicated the presemce of a secondary hydroxyl group located between the methine and a methylene groups possibly either at C-6 or C-11 positions of ambrenolide. The location of the hydroxyl group at C-6 was decided from the chemical shift of C-7 at 5 51.87 with a downfield shift ca \1 ppm relative to ambrenolide, and the chemical shift of C-5 which was shifted to 5 61.14, also indicative the presence of the hydroxyl group at C-6. Spin decoupling and phase sensitive COSY experiments confirmed the relationship between H-6 (5 3.90) and H-7a (6 1.78), H-7p (5 2.33) as weU as between H-5 (6 1.10) and H-6.

693

TABLE 16 HMQC and HMBC Data of 56

c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

^ ^ C

Direct correlated protons H.la,H-lp H-2a,H-2p H-3a, H-3P H-5a H-6a, H-6p H-7a, H-7p H-9a H-lla H-12a, H-12P H-14 H-15a,H-15b H-16 H-17 H-18 H-19 H-20

Long range correlated protons H-20 H-la H-la,H-18 H-2a,H-2p,H-19 H-la, H-18, H-19, H-20 H-5, H-7a, H-7p H-9, H-17 H-9, H-17 H-la, H-7a, H-12a, H-12P, H-17,H-20 H-9, H-20 H-12a, H-12P H-15b,H-16 H-12a, H-12P, H-14, H-15a, H-15b H-12a,H-12p,H-15a,H-16 H-12a,H-12p H-7, H-9 H-3a H-3a, H-5, H-18 H-la, H-5, H,9

39.22 18.42 41.92 33.19 57.03 20.14 44.56 74.80 56.45 37.76 65.24 44.20 72.38 147.77 110.47 29.73 27.44 33.50 21.38 17.12

The stereochemistry of the hydroxy! group at C-6 was decided as a on the basis of the coupling constants and NOESY results (Fig 1). All carbons were assigned by HMQC (Table 17) and HMBC (Table 18) experiments.

694 TABLE 17 *H and ^ ^ C NMR Data of Compounds 57, 58 and 59 57 ^H 1 2 3 4 5 6 7 8 9 10 11 12 13 17 18 19 20 CHs C=0 1.59,0.98 1.61, 1.48 1.22, 1.39 ^ ^ C 39.28 18.18 43.42 33.67 61.14 68.45 51.87 82.53 53.09 37.71 15.93 28.71 171.40 24.01 36.47 21.96 16.22 ^H 1.42, 1.09 1.68, 1.47 1.32, 1.43 58 ^ ^ C 39.46 17.89 43.65 33.82 62.10 69.82 49.90 84.25 58.81 35.51 28.80 176.39 2.26 1.17 3.80 2.93, 1.94 ^H 1.5,1.10 1.62,1.45 1.22,1.32 59 ^'C 40.44 19.15 44.81 34.66 61.38 69.53 50.40 86.65 55.82 39.76 31.55 171.94

1.10 3.90 2.33, 1.78

1.24 3.99 2.42, 1.82

1.53

2.02

2.34, 2.42

1.76, 1.67 2.68, 2.54

2.25, 2.44

1.37 1.18 1.02 0.95

1.56 1.19 0.99 0.88 1.92 -

1.45 1.19 1.02 0.89

22.90 36.20 21.54 16.39

21.80 37.00 22.40 17.30 22.60 170.00

The HR mass spectrum of 6-hydroxynorambrenolide (58) exhibited the molecular ion peak at m/z 266.1869 indicating the molecular formula C16H26O3 consistent with a hydroxyl derivative of norambrenolide. The ^H NMR spectrum displayed a signal at 6 3.99 (IH, ddd, J=4, 11, 12 Hz) showing a secondary hydroxyl group between a methine and a methylene groups. After acetylation

695

Figure 1 TABLE 18 HMBC Data of Compounds 57, 58 and 59 Irradiated H 57 1 2 3 5 7 9 11 17 18 19 20 C-6, C-8, C-17 C-8,C-10,C-ll,C-17,C-20 C-8, C-9, C-12 C-7, C-8, C-9 C-3, C-4, C-5, C-19 C-3, C-4, C-5, C-18 C-1, C-5, C-9, C-10 C-19 C-5, C-6, C-8, C-17 C-8, C-10, C-11, C-17, C-20 C-8, C-9, C-12 C-7, C-8, C-9 C-3, C-4, C-5, C-19 C-3, C-4, C-5, C-18 C-1, C-5, C-9, C-10 C-8, C-9, C-10 C-7, C-8, C-9 C-3,C-4, C-5,C-19 C-3,C-4, C-5, C-18 C-5, C-9, C-10 Long Range Correlated Carbons 58 C-20 C-1, C-10 C-19 59

this peak was shifted to 5 5.19. The *H and ^ ^ C NMR spectra are given in Table 17. The spectra of compounds 57 and 58 were quite alike. However in compound 58, the lactone carbonyl appeared at 1785 cm'^ indicating afivemembered lactone ring. Unambiguous assignment of ^H and *^C NMR data was made possible by a combination of HMQC (Table 17) and HMBC (Table 18). The structure of 58

696 was established as a tetranorlabdane, 6a-hydroxynorambrenolide. Compound 59 had the molecular ion peak at m/z 326.2088 (HREI mass spectrum) analyzing for the molecular formula CigHsoOs. The IR spectrum showed a large hydroxyl band at 3240-3400 cm'^ and two carbonyl absorptions at 1685 cm'^ (carboxylic acid) and at 1725 cm'^ (acetyl). These carbonyl groups were substantiated by two signals present at 6 171.9 and 170.0 in its ^^C NMR spectrum. A methine proton at 5 3.80 (IH, ddd, J=4,l 1,12) was consistent with H-6, as in compounds 57 and 58. Connectivity of H-9 and H-11 as well as H-5, H-6 and H-7 was confirmed by COSY experiment, and the location of the 6a-hydroxyl group was deduced fi-om the NOESY results (Figure 1). The HMQC and HMBC experiments allowed the assignments to all the carbons and protons. The structure of 59 was deduced as 6a-hydroxy-8a-acetoxy-13,14,15,16tetranorlabdane-12-oic acid.

2.3. SESTERTERPENOroS Sesterterpenes and norsesterterpenes are not common in Salvia species. Rustaiyan et af^'^ isolated some sesterterpenes fi-om Iranian Salvia species. This is the first isolation of two norsesterterpenes^^ and two sesterterpenes^^ fi-om S.yosgadensis. Two new 19,20-dinorsesterterpenes, yosgadensonol (60) and 13-ep/yosgadensonol (61), were isolated together with compounds 57-59. The HREI mass spectrum of yosgadensonol (60) gave the molecular ion peak at m/z 362.2895 corresponding to the molecular formula C23H38O3. Its ^^C NMR spectrum indicated the presence of six methyl, seven methylene, five methine, and five quaternary carbons. The presence of a secondary hydroxyl group was shown by a methine signal at 5 3.87 (IH, ddd, J=4, 11,12 Hz). The location of the hydroxyl group at C-6 and the relation between H-5, H-6 and H-7 were deduced fi-om the COSY spectrum. Acetylation yielded a mono acetate 60a in which H-6 was shifted downfield to 5 5.12. The presence of an ether ring in 60 was suggested by two quaternary carbon signals at 5 73.03 and 74.75. When the *^C NMR spectrum of 60 was compared with those of manoyloxide and its derivatives, it was deduced that compound 60 possesses the same A, B and C rings. The rest of the molecule carries a side chain containing five carbons, the presence of a conjugated ketone system could be assignedfi-omthe IR band at 1625 cm'^ (C=C) and trans coupled two vinylic protons at 5 6.25 and 6.77 (J=16 Hz) indicating the presence of a CH=CH group. This was confirmed by two olefinic carbons at 6 125.31 and 154.17. The downfield shift of one of the olefinic carbons fiirther suggested a conjugated system v^th a ketone carbonyl group (5C 195.31; IR max 1695 cm"^). The HMQC (Table 19) and HMBC (Table 20) experiments allowed the assignment of all protons and carbons in compound 60. The HMBC technique was particularly usefiil in determining the partial structure of the side chain. Thus H-14 showed long

697 range couplings with the C-16 carbonyl and C-21 methyl carbons. Compound 60 was therefore deduced as 19,20-dinorsesterterpene containing the partial structure of manoyl oxide, and it was named yosgadensenol. Compound 61 exhibited spectral data similar to those of 60. The *H and *^C NMR spectra of both compounds (Table 19 and 20) resembled each other closely. In the ID NOE difference spectrum obtained by irradiation of H-6P, the signals for H-22, H-24 and H-25 and H-7 eq. were clearly enhanced, suggesting a P-orientation for these groups in both compounds. However a difference was detected by NOE irradiation of H-22 which is the most downfield signal in both compounds, which led to enhancements on H-21 and H-25 in compound 60 indicating a P-orientation of these groups. However, when H-22 of compound 61 was irradiated, only H-25 was enhanced. The lack of NOE between H-22 and H-21 suggested the a-dispositions of H-21 at C-13. The results of ID NOE experiments of both compounds indicated a stereochemical difference at C-13. Compound 61 is therefore 13-epimer of 60 and it was named 13-e/?/-yosgadensonol.

"23 OH

60 13P-Me, 61 13 a-Me The sesterterpenes obtainedfromthe same plant material^^ were 6a,14-dihydroxymanoyl oxide15,17-dien-16,19-olide and 6a,16-dihydroxymanoyl oxide-14,17-dien-16,19-olide were named as yosgandensolide A (62) and yosgandensolide B (63). Compound 62 afforded the molecular formula C25H38O5 (m/z 418.2700). Its ^ ^ C NMR spectrum consisted of 25 carbon atoms as given in Table 21. The IR spectrum showed a five member lactone ring by a band at 1780 cm'^ and unsaturation by the absorption at 1615 cm'^. The UV spectrum exhibited a maximum at 274 nm consistent with an a,Punsaturated five member lactone ring. The IH NMR spectrum showed five methyl singlets at 5 0.81, 1.00, 1.18, 1.24, 1.38 and a vinylic methyl doublet at 5 2.16 (J=1.5 Hz). A carbinol methine was at 5 3.88 (IH, ddd, J=3.8, 11.2, 12 Hz) indicating a secondary hydroxyl group situated between a methine

698 TABLE 19 ^H and ^^C NMR Data of 60, 60a and 61 60 ^H 1 2 3 4 5 6 7 8 9 10 1.19 1.00 3.87 2.20, 1.58 1.60, 1.34 1.52 1.42, 1.27 ^'C 39.91 18.20 43.54 33.70 61.69 69.15 54.29 74.75 54.86 37.70 15.39 34.86 73.03 154.17 125.31 195.31 33.96 8.11 28.81 26.87 36.44 21.86 16.58 ^H 1.58, 1.28 1.40 1.38, 1.21 1.12 5.12 2.12, 1.60 1.14 1.62, 1.34 2.02, 1.58 6.97 6.22 2.58 1.08 1.29 1.40 1.00 0.84 0.86 2.04 60a ^'C 38.80 18.11 43.30 33.28 58.85 70.72 49.69 74.47 54.88 37.80 15.38 34.85 73.07 154.17 125.38 201.68 33.90 8.20 28.78 26.68 36.00 21.98 16.50 21.89 170.13 ^H 1.60, 0.91 1.47 1.39, 1.16 1.02 3.84 2.13,1.48 1.25 1.60, 1.38 2.20, 1.57 6.98 5.99 2.61 1.11 1.22 1.18 1.15 0.97 0.74 61 ^^C 39.23 18.33 43.60 31.68 61.69 69.13 53.97 75.64 57.65 32.92 16.05 36.44 72.84 154.62 125.18 201.51 35.13 8.08 25.26 33.78 37.55 21.80 17.23 -

11 1.62, 1.36 12 2.08, 1.56 13 14 6.77 15 6.25 16 17 2.58 18 1.10 21 1.29 22 1.25 23 1.16 24 0.99 25 0.80 CHs -

c=o .

699 TABLE 20 HMBC Data of Compounds 60 and 61 Irradiated H 60 5 6 7 14 15 17 18 21 22 23 24 25 C-4, C-7 C-5, C-6, C-8, C-9, C-22 C-16, C-21 C-13,C-17 C-18 C-16, C-17 C-12, C-13 C-7, C-8, C-9 C-3, C-4, C-5, C-24 C-3, C-4, C-5, C-23 C-1, C-9, C-10 Long Range Correlated Carbons 61 C-5 C-6, C-8 C-16, C-21 C-16, C-17 C-16, C-18 C-7, C-8 C-24 C-6, C-23 C-1, C-5, C-10

^ C NMR spectrum helped to and a methylene groups which could be either at C-6 or at C-11. The ^ differentiate between these two locations. In the case of a C-11 hydroxyl group, C-12 should be shifted to 40-45 ppm while the hydroxyl at C-6 induces a chemical shift at C-7 of more than 50 ppm. In the present case C-7 was observed at 5 54.1. No other methylene carbon which could be shifted to around 50 ppm was present in the molecule. The second carbinol methine proton was at 5 4.45 (IH, d, J=9.5 Hz, H-14) which was coupled with a vinylic proton at 6 5.20 (IH, d, J=9.5 Hz, H-15). Another vinylic proton was observed at 5 5.96 as a narrow doublet (IH, d, J=1.5 Hz, H-18). Spin decoupling experiments showed the relations between H-6 and H-5, H-6 and H2-7, as well as H-14 and H-15. The HETCOR and HMBC experiments allowed the unambiguous assignment of protons and carbons. Long range correlations were observed between H-14 and C-15, C-16 as well as between H15 and C-16, C-17, between Me-20 and C-16, C-17, C-18 and between Me-21 and C-15. Acetylation

700

62

63

of 62 yielded two derivatives which were separated by preparative TLC, indicating that compound 62 was a mixture of two isomers. The spectral data of both isomers 62aAc and 62bAc (Table 22) were quite similar, only the protons and carbons for C-14, C-15, C-18 and C-20 showing differences, indicated a possible epimerization at C-15 to form the E and Z isomers. Based on the spectral data the structures of 62a and 62b were established as 6a,14-dihydroxymanoyl oxide-15,22-dien-15(Z),19-olide and 6a,14-dihydroxy-15,22-dien-15(E),19-olide. Another epimer of this group was isolated separately (62c). Its ^H NMR spectrum was found to be quite similar to that of 62 (Table 22), the main differences observed being at H-14 and H-15 as well as in some methyl group (Me-21 and Me-22), indicating a possible epimerization at C-13. However, the small quantity of 62c did not allow further investigation of its stereochemistry. Yosgadensolide B (63) had the molecular formula C25H38O5 (m/z 418.2705). The IR spectrum showed afive-memberedlactone ring at 1780 cm'* and its UV spectrum exhibited a shoulder at 274 nm. The *H NMR spectrum (Table 23) showed a carbinol methine at 5 3.85 (IH, ddd, J=3.8, 11.2, 12 Hz) which was assigned to H-6P, as also found in (62a-62c). There were three olefinic protons, one being at 5 5.79 (IH, d, J=1.5 Hz, H-18) similar to that of compound 62, and the other two protons appearing were at 6 6.15 and 5.72, indicating a trans double bond with a J value of 16 Hz. These were placed on the side chain. The placement was deduced to be between C-14 and C-15. The *^C NMR spectrum (Table 21) indicated a sesterterpene structure derivedfrommanoyl oxide like yosgadensolide A (62), but its side chain differedfromthat of 62. Compound 64 which is an epimer of compound 63 was isolated separately. The UV, IR, and MS spectra of the new compound 64 were exactly similar to those of 63, while the *H and *^C NMR data showed chemical shift differences particularly for H-14 (5 6.35), H-15 (5 5.52) and for some methyl groups. The two methyl groups next to the oxygenated carbons were observed at 5 1.22 (Me-21) and

701 TABLE 21 ^^C NMR Data of Compounds 62,62aAc and 63 62 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 C=0 CHs C=0 CHs 39.0 18.3 43.5 30.7 61.6 69.0 54.1 73.2 58.0 33.8 14.9 37.6 75.3 72.9 109.3 151.0 154.7 117.3 176.7 11.7 25.9 24.6 36.4 21.8 17.2 62aAc 38.8 18.2 43.3 33.3 61.7 70.7 49.4 74.1 58.8 33.3 14.8 36.0 75.0 75.4 106.6 152.2 154.7 117.7 172.2 11.9 25.9 23.9 36.0 21.1 16.8 170.1 21.8 169.8 21.9 63 39.4 18.7 43.3 33.2 59.6 70.6 53.3 73.6 60.4 34.0 14.2 37.6 75.2 147.2 119.7 107.0 164.0 118.2 171.3 12.8 30.9 24.0 35.9 21.6 14.9

702

TABLE 22 *H NMR Data of Compounds 62, 62a Ac, 62b Ac and 62c H 6 14 15 18 20 21 22 23 24 25 OAc OAc 62(62a+62b) 3.88 ddd 4.45 d 5.20 d 5.96 d 2.16d 1.38 s 1.24 s 1.18s 1.00 s 0.81s 62a Ac 5.08 ddd 5.57 d 5.32 d 5.97 d 2.18 brs 1.37 s 1.28 s 1.00 s 0.85 s 0.85 s 2.10s 2.02 s 62b Ac 5.08 ddd 5.68 d 5.51 d 6.04 br s 2.08 d 1.38 s 1.28 s 1.01s 0.84 s 0.84 s 2.08 s 2.05 s 62c 3.88 ddd 4.31 d 5.30 d 5.96 d 2.17d 1.36 s 1.17s 1.17s 1.01s 0.82 s -

1.15 (Me-22) in compound 64, while in compound 63, they were observed at 6 1.36 and 1.28 indicating a possible epimerization at C-13. The NOE experiment verified the epimerization at C-13 (Table 23). Based on spectral data, compound 63 was established as 6a,16-dihydroxymanoyl oxide-HjHdien- 16,19-olide and 64 as 6a, 16-dihydroxy-13-epi-manoy\ oxide-14,17-dien-16,19-olide. 2.4. TRTTERPENOroS Triterpenoidal compounds are common in Salvia species. The recently isolated triterpenes fi'om Turkish Salvia species have mainly the oleane, ursane and lupane-type skeletons and some steroids which are abundant compounds. These include oleanolic acid its methyl ester, a-amyrin, lupeol, taraxasterol and p-sitosterol fi^om S. pomifera^^, ursolic, oleanolic acids and P-sitosterol fi'om S. divaricata^^, vergatic acid, a-amyrin, stigmasterol fi'om S. limhata^^^ . S. nemoroscP yielded a new triterpene salvinemorol (65) in addition to a-amyrin, ursolic and oleanolic acids and steroidal compounds stigmast-7-en-3-one, 24-methylenecycloartenol, stigmast-4-en-3-one and stigmast-7en-3-ol and P-sitosterol..

703

TABLE 23 ^H NMR Assignments of Compounds 63, 64, 63 Ac, 64 Ac H 6 11 14 15 18 20 21 22 23 24 25 OAc 63 3.85 ddd 2.18 dd 6.15 d 5.72 d 5.79 qd 2.04 d 1.36 s 1.28 s 1.17s 1.00 s 0.82 s 64 3.85 ddd 2.11 dd 6.35 d 5.52 d 5.82 brs 2.01 brs 1.22 s 1.15s 1.15s 0.98 s 0.74 s 63 Ac 5.08 ddd 2.12 dd 6.19 d 5.49 d 5.90 d 1.99 s 1.19s 1.32 s 1.26 s 1.22 s 0.74 s 2.10 s 64 Ac 5.08 ddd 2.12 dd 6.17 d 5.40 d 5.90 s 1.97 s 1.17s 1.24 s 1.14s 1.00 s 0.85 s 2.03 s

The HREI mass spectrum of the new compound (65) indicated the molecular formula C30H50O3 {m/z 458.3753). The ^ ^ C NMR (APT) spectrum substantiated the presence of 30 C atoms corresponding to eight methyl quartets, eight methylene triplets, seven methine doublets and seven carbon singlets. The HETCOR experiment showed the relation between the carbons and protons. In the ^H NMR spectrum of salvinemorol (65) eight methyl signal were observed at 6 0.78, 0.82, 1.05, 1.20 (each 3H, s) and 0.88, 0.98 (each 6H, s). The three hydroxyl groups present in the molecule were decided to be at C-3, C-11 and C-21. The relations between the signals at 6 5.28 (IH, d, J=4 Hz, H-12) and 5 4.31 (IH, dd, J=4 and 8.5 Hz, H-1 ip) were shown by spin decoupling experiments, as well as between H-11 and H-9 (5 1.70, IH, d, J=8 Hz, H-9). Other significant signals were at 5 3.17 (IH, dd, J=5 and 12 Hz, H-3a) and 3.41 (IH, dd, J=5 and 11 Hz, H-2ip). Spin decoupling experiments showed the relations between H-3a and H-2p (6 1.97, IH, dd, J=5 and 10 Hz). The stereochemistry of the hydroxyls at C-3 and C-11 were decided by measuring the J values and studying a Dreiding model. The C-21 position of the third hydroxyl group was decided by comparing its ^ ^ C NMR values to those reported in the literature^^^^.

704

65
When there is a-hydroxyl group at C-21 it appear ca 74.3-74.5 ppm, C-20 resonates around 34-36 ppm and C-22 resonates at 46.6 ppm. In compound 65 these signals were observed in similar frequencies at 5 32.2, 76.0 and 46.5 respectively. The relation between H-21p and H-22a (5 1.82, IH, dd, J=5 and 11 Hz) was shown by spin decoupling experiments. Its stereochemistry was deduced based ^ C NMR values of 65 were given in Table 24. on J values and studying of a Dreiding model. The ^

66 R=H 67 R=//-aw5-coumaryl 68 R=cw-coumaryl

S. montbretii^ also yielded ursolic and oleanolic acids, a-amyrin, lupeol and P-sitosterol as well as another known triterpene monogynol A (66) together with its two new esters SP-O-trans-pcoumroylmonogynol A (67) and 3P-0-c/5-coumaroylmonogynol A (68). Although monogynol A was ^ C NMR data were not reported in the literature, therefore its spectral first isolated in 1959, its ^H and ^ data were recorded and its X-ray single crystal analysis was performed . The ^H NMR spectrum of 66

705 consists of eight methyl singlets at 6 0.75, 0.80, 0.82, 0.94, 0.96, 1.05, 1.10 and 1.22. The signal at 5 3.20 (IH, dd, J=5 and 11 Hz) indicated the axial hydrogen at C-3. No vinylic signal was present. The ^ ^ C NMR (APT) spectrum (Table 24) showed two signals at 5 78.9 (d) and 73.2 (s) indicating the hydroxyl group-carrying carbon atoms at C-3 and C-20. The structure of 66 was established as 3P,20lupandiol. Compound 67 aflforded additional signals in its *H NMR spectrum, at 5 7.60 (IH, d, J=16 Hz, H-3'), 6.27 (IH, d, J=16 Hz, H-2'), 7.42 (2H, d, J=8.5 Hz, H-3" and H-5"), 6.82 (2H, d, J=8.5 Hz, H-2" and H-6") indicating a //-oAw-p-coumaroyl moiety. H-3 was shifted to 5 4.60 (IH, t, J=8 Hz) indicating the ester formation at C-3. The rest of the signals were similar to those of 66. Compound 68 showed a d5-p-coumaroyl moiety with the signals at 5 6.80 (IH, d, J=12.5 Hz, H-3'), 5.82 (IH, d, J=12.5 Hz, H2'), 7.64 (2H, d, J=8.5 Hz, H-3" and H-5"), 6.78 (2H, d, J=8.5 Hz, H-2" and H-6").

CH2OH 69 SalviapomifercP yielded a new and three not so common triterpenes, 23-hydroxygermanicone (69), erithrodiol, moradiol and moronic acid, respectively. The HR mass spectrum of 69 gave the molecular ion peak at m/z 440.3671 corresponding to C30H48O2. The IR spectrum showed hydroxyl (3450 cm'*), carbonyl (1710 cm"*) and unsaturation (1640 cm'*) absorbances. The *H NMR spectrum showed seven methyl signals at 6 0.77, 0.93, 0.94, 1.04, 1.07, 1.10 and 1.11 (each 3H, s). The lack of a C-3 hydrogen geminal to a hydroxyl group indicated the presence of a possible 0x0 group at C-3. A proton signal was observed at 5 4.87 as a broad singlet, its chemical shift being typical for olean-18-en without an acid group at C-17. In case of the presence of the substituent other than a methyl group at that position, the H-19 shifts to ca 5.15-5.20 as observed in case of moronic acid^^ Other *H NMR signals were at 5 3.61 (IH, d, J=l 1 Hz, H-23) and 4.17 (IH, d, J=ll Hz, H-23') indicating the presence of a hydroxymethylene group at C-23. The chemical shift of these two groups showed showed that they were deshielded by the 0x0 group at C-3. The *^C NMR

706 Spectrum of 69 is given in Table 24. The signal at 6 76.2 in its *^C NMR spectrum confirmed the presence of the hydroxymethylene group, which wasfiirthersupported by the downfield shift of the MeTABLE24 ^ ^ C NMR Data of Compounds 65, 66, 67 and 69 C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 C-2' C-3' C-l" C-2",C-6" C-3",C-5" 65 36.71 26.61 76.9 d 38.9 s 56.7 d 17.71 34.61 43.8 s 52.3 d 36.8 s 66.9 d 123.8 d 150.3 s 44.1s 32.81 26.41 31.1s 46.3 d 35.81 32.2 s 76.0 d 46.51 28.5 q 13.0 q 18.0 q 15.1 q 26.2 q 28.0 q 33.2 q 23.6 q 66 38.71 27.51 78.9 d 38.7 s 55.2 d 18.3 t 34.51 41.3 s 50.2 d 37.0 s 21.41 27.41 37.4 d 44.6 s 27.71 35.51 43.4 s 48.3 d 49.9 d 73.1s 29.01 40.21 28.0 q 15.4 q 16.1 q 16.1 q 14.8 q 19.2 q 24.7 q 31.5q 67 38.3 t 23.61 80.71 38.0 s 55.2 d 18.21 34.41 41.3 s 50.1 d 37.3 s 21.3 t 27.51 36.9 d 44.6 s 28.81 35.51 43.4 s 48.3 d 49.9 d 74.0 s 29.lt 40.lt 28.0 q 16.2 q 16.7 q 16.2 q 14.8 q 19.2 q 24.5 q 31.5 q 167.2 s 116.1 d 144.0 d 127.2 s 115.9d 129.8 d 69 37.81 36.61 208.1s 50.6 s 53.2 d 18.21 34.61 42.3 s 52.1 d 37.3 s 22.lt 27.lt 37.4 d 28.6 s 28.41 35.51 34.2 s 142.0 s 134.1 d 32.2 s 28.41 40.lt 76.21 15.4 q 16.1 q 17.2 q 14.3 q 24.7 q 31.5 q 28.4 q

c-r

707

24 signal to 5 15.4. Due to the a-eflfect of the oxo group and the p-eflfect of the hydroxyl group, the C-4 signal was observed at 5 50.6, the same carbon appears at 5 47.2 in germanicone. The spectral data indicated that compound 69 was 3-oxo-23-hydroxymethylene-olean-18-ene.

70 S. glutinosa^ yielded eleven known triterpenoids and three steroidal compounds a-amyrin, aamyrin acetate, 11-oxo-a-amyrin (3p-hydroxy-ll-oxo-ursa-12-ene), 11-oxo-P-amyrin (SP-hydroxy-lloxo-oleana-12-ene), 3-acetoxy-olean-9,ll-diene, ursolic acid, oleanolic acid, ursolic and oleanolic acid methyl esters, lupeol, erithrodiol 28-acetate, stigmasterol, sitosterol, 7a-hydroxysitosterol along with a new compound l-oxo-7a-hydroxysitosterol (cholest-5-ene-3p,7a-diol-l-one) (70). The HREI mass spectrum of 70 suggested the molecular formula C29H48O3 (rn/z 444.3562). The IR spectrum showed ^ C NMR signals for a hydroxyl (3450 cm"^) and a six-membered ring carbonyl (1712 cm"^). The *H and ^ spectra indicated the structure clearly. The signals at 5 5.55 (IH, br s, H-6), 4.33 (IH, br s, H-7) were typical for A^-7a-0H groups. The relation between H-6 and H-7 were shown by spin decoupling experiments. A p-OH group was evident with the signal at 5 4.19 (IH, m, H-3a). The signals for H-3 and H-7 were somewhat further downfield than expected and when compared to 7a-hydroxysitosterol (5 3.85 for H-7 and 3.66 for H-3). The presence of an 0x0 group at C-1 is the only explanation for these chemical shifts. Other ^H NMR signals were at 5 0.67 (3H, s, Me-18), 0.99 (3H, s, Me-19), 0.82 (3H, d, J=6.5 Hz, Me-27), 0.85 (6H, d, J=6.5 Hz, Me-26 and Me-29), 0.91 (3H, d, J=7 Hz, Me-21). "C NMR (APT) showed a six-membered ring carbonyl signal at 6 208.4 (s). The unsaturated carbon atoms were at 5 142.4 (s) (C-5) and 132.6 (d) (C-6) while the carbon atoms carrying the secondary hydroxyl groups were observed at 5 67.9 (d) (C-7) and 87.0 (d) (C-3) (Table 25). S. tchihatcheffif^ yielded four triterpenoids one of them being a new compound. The known compounds were identified as 3-acelylerythrodiol, 28-acetylerythrodiol and 3-acetyloleanolicaldehyde (3P-acetylolean-12-en-28-al). The new triterpene (71) had the molecular formula C34H54O4 {m/z

708

526.4034). The IR spectrum exhibited acetyl absorbances for the acetyl group(s) at 1737 and 1242 cm'\ The ^H NMR spectrum displayed a signal at 6 2.07 corresponding to the two acetyl methyl protons, and an olefinic proton at 5 5.19 (IH, t, J=3 Hz, H-12) and a methylene pair of protons at 5 3.7 (IH, d, J=l 1 Hz) and 4.03 (IH, d, J=l 1 Hz) indicating the presence of one of the acetyl groups at C-28. The

CH2OAC

AcO'

71
TABLE 25 ^ ^ C NMR Data of Compound 70

1 2 3 4 5 6 7 8 9 10

208.4 s 39.61 87.0 d 42.41 142.5 s 132.5 d 67.9 d 36.1 d 45.8 d 37.0 s

11 12 13 14 15 16 17 18 19 20

23.01 39.61 42.4 s 50.8 d 24.lt 28.21 55.lt 11.9q 18.6 q 36.1 d

21 22 23 24 25 26 27 28 29

18.7 q 33.91 26.01 45.7 d 29.0 d 19.5 q 20.2 q 20.71 11.9q

0.95, 1.16 Oand 1.17 as singlets. Acetylation of erythrodiol yielded 71 as evident from its spectral ( and TLC comparison which established that the new compound (71) was 3.28-diacetylerythrodiol.

709
2.5. AROMATIC COMPOUNDS AND FLAVONOroS Aromatic compounds are not common in Salvia species while flavonoids are abundantly present, especially in the aerial parts and the most abundant flavone is salvigenine in Turkish Salvia species. 2.5.1 Aromatic Compounds From the aerial parts ofS. divaricata^^, the known aromatic compounds 3-methoxysalicylic acid, p-hydroxybenzoic acid, cis- and //"owis-p-coumaric acids and from S, candidissima*^, o,pdimethoxybenzoic acid were isolated. A new aromatic compound di(4,4'hexyloxy- carbonylphenyl) ether (72) was obtained from S. heldrichianc^^. The HREI mass spectrum of 72 indicated the molecular formula C26H34O5 (m/z 426.2411). The UV maximum showed a substituted aromatic system (278 nm). The signals of the IR spectrum at 1730 cm"^ (carbonyl), 3050, 1616, 1558, 1520 cm"^ (aromatic) were consistent with the aromatic structure. The ^H NMR spectrum of 72 clearly indicated the structure by the signals at 5 7.07 (4H, d, J=8 Hz, H-3, H-5, H-3', H-5'), 6.76 (4H, d, J=8 Hz, H-2, H-6, H-2', H-6'), 4.23 (4H, t, J=7 Hz, CH2-8 and CH2-8'), 2.85 (4H, t, J=7 Hz, CHr9 and CH2-9'), 2.28 (4H, br t, J=7 Hz, CHrlO and CH210'), 1.58 (4H, br t, J=7 Hz, CH2-II and CHrll'), 1.15 (4H, br t, J=7 Hz, CH2-I2 and CH2-I2'), 0.9 (6H, t, J=7 Hz, Me-13 and Me-13').

3 2 13 8-12

2' 3'

, 8'-12'

13'

CH3(CH2)^5 6

0-HCH2)5CH3

_ai

72

The ^^C NMR (Table 26) spectrum is in agreement with the given formula. The mass spectrum showed important ions at m/z 340 [M-C6Hi3-H]+ (a), 323 [M-C6H13O-2HI+ (b), 221 [M-Ci3Hi702]+ (c) which corraborated with the given formula.

710 S. forskahlef^ yielded two other dimeric aromatic compounds, which were octanol esters of cis- and /ira^w-cinnamic acids. They were separated by preparative TLC plates. The cis isomer 73, had the molecular formula C36H50O7 (m/z 594.3550). The UV spectrum showed a conjugated aromatic

MeO

H=CH-(CH2)7-CH
7 8 (1-7)"

MeO

H=CH-(CH2)7-CH3
7 8(1-7)"

73 7,8,7,8' cis 74 7,^,7,S'trans system giving the maximum at 5 325 nm. The IR spectrum indicated the aromatic character by the signals at 1605, 1585, 1520 cm"\ and the presence of an ester was indicated by the signals at 1705 and 1275 cm"\ The ^H NMR spectrum displayed signals at 5 6.78 (2H, d, J=12 Hz, H-8 and H-8'), 5.82 (2H, d, J=12 Hz, H-7 and H-7), 7.77 (2H, d, J=2 Hz, H-3 and H-3'), 7.10 (2H, dd, J=2 and 8 Hz, H-5 and H-5'), 6.87 (2H, d, J=8 Hz, H-6 and H-6'), 4.10 (4H, t, J=7 Hz, CH2-l"and CHz-l'"), 3.92 (6H, s, C-1 OMe and C-l'-OMe), 1.68 (4H, m, 2XCH2), 1.35 (4H, m, 2xCH2),1.28 (12H, m, 6XCH2), 1.15 (4H, m, 2XCH2), 0.87 (6H, t, J=7 Hz, Me-8" and Me-8'"). The ^ ^ C NMR spectrum also supported the structure (Table 26). The trans isomer 74, showed ^H NMR spectral differences only in cinnamic acid part, particularly for the protons of C-7,8 and C-7',8'. These signals were displayed at 5 7.61 (2H, d, J=16 Hz, H-8 and H-8'), 6.29 (2H, d, H-7 and H-7), 6.92 (2H, d, J=8 Hz, H-6 and H-6'), 6.88 (2H, dd, J=2.5 and 8 Hz, H-5 and H-5'), 4.18 (4H, t, J=7 Hz, H-1" and H-1'"), which was consistent with the presence of the />*am'-cinnamic acid. Other NMR signals and mass degradation were similar in both isomers. From S. yosgaciensis^\ two aromatic compounds p-hydroxyquinone and p-acetylphenol were isolated.

711 2.5.2. Flavonoids Almost all Salvia species naturally grown in Turkey contain salvigenin as a marker flavonoid which was first isolatedfi"omS. triloba^^ by our group. S. heldrichianc?^, S.wiedemannii^'^^ yielded only salvigenin while other Salvia species yielded additional flavonoids, these were 6-hydroxyluteolin6,7,3',4'-tetramethyl ether, 6-hydroxyapigenin-7,4'-dimethyl ether, 4'-methylapigenin, apigenin and TABLE 26 *^C NMR Data of Compounds 72 and 73 C 72 154.2 s 130.0 d 115.3 d 142.2 s 115.3 d 130.0 d 174.0 s 64.91 34.3 t 31.0t 24.91 22.61 14.0 q 147.5 s 152.3 s 115.7d 129.5 s 114.7d 109.3 d 144.8 d 123.2 d 168.4 s 73

1, r
2, 2' 3, 3' 4, 4' 5, 5' 6, 6' 7, T 8, 8' 9, 9' 10, 10' 11,11' 12, 12' 13, 13' 1",1"' 2", 2'"
OH

64.61 31.9t 29.51 29.51 28.71 25.91 22.71 14.1 q 55.9 q

OHI

4" ,4'" 5" ,5'" 6" ,6"' 7" ,7'" 8" ,8'" 2xOMe

712 luteolin from S. sclarea^^, crysoeriol and diosmetin from S. candidissima^^, luteolin, eupatilin, pectolinarigenin and quercetin-3-methyl ether from S.limbata*^^, eupatilin, apigenin and luteolin from S. nemoroscF', luteolin, apigenin, apigenin-7-methyl ether, apigenin-4'-methyl ether, apigenin-7,4'dimethyl ether, apigenin-6,4'-dimethyl ether and kaempferol 3-methyl ether from S. yosgadensi^^. S. montbretif^ did not yield salvigenin, however, apigenin, luteolin and drsiliol were isolated. So far, in the investigated Turkish Salvia species, mainly apigenin and luteolin-type flavones were found while flavonol derivatives were rather rare. 3. BIOLOGICAL A C n v m E S Turkish Salvia species have been used as folk medicine for their antiseptic, antibacterial, diuretic, hemostatic, spasmolitic, carminative and wound healing properties'^. Due to these folklorixc uses a number of diterpenoids were tested against standard Gram-negative and Gram-positive bacteria, such as Bacillus subtilis ATCC 6633, Stcq?hylococcus aureus ATCC 6538P, Staphylococcus epidermidis ATCCC 12228, Proteus mirabilis ATCC 14153, Escherichia coli ATCC 8739, Klebsiella pneumonia ATCC 4352, Pseudomonas aureginosa ATCC 9027, Enterococcus faecalis ATCC 29212, Candida albicans ATCC 10231 using Disc-diflRision method'^'^^. When the inhibition zones are greater than 7 mm, the tube dilution tests^^ were performed to determine the antibacterial activity quantitatively for inhibition concentrations (MIC). Table 27 shows the results of 14 diterpenoids. Among them, salvipisone was found to be highly active against B. subtilis, S. aureus and S. epidermidis, pisiferic acid 12-methyl ether was active against 5. subtilis while 2,3-dehydrosalvipisone and 7-oxoroyleanone were most active against the yeast, Candida albicans. The latter two abietane diterpenes were isolated from S. sclarea and in the same study, labdane diterpenes sclareol and manool as well as sesquiterpenes spathulenol and caryophyUene oxide were also isolated and tested for their activity and found to be active against S. aureus with the MIC values of 48.25, 13.75, 13.75 and 136.00 ng/ml, respectively. In fact, sclareol is an important bioactive diterpene having different pharmacological and microbiological effects. Ferruginol, taxodione, horminone and their derivatives were very common diterpenes of Salvia species which were also isolated from numerous Turkish Salvia species possessing antimicrobial^"*'^^^ and antitumour activities^'*'^^ In a recent study, with S. multicaulis, four of the new compounds (29-32) showed structural resemblence to tanshinone-type compounds. Therefore, they and the other new compounds (33-34 ) isolated from the same plant, were tested against bacterial strains (Table 28). All the compounds from this plant were also tested in the Mycobacterium tuberculosis H37Rv test system. Their antituberculous activity was established according to broth microdilution method^^'^. When the MIC results were

TABLE 27.

MIC vaIues of the Diterpenoids against Standard Bacterial Strains ( p g h l )

7-Oxoroyleanone

54.00

713

NT

6.75

714

compared to known tuberculostatic agents^* such as streptomycine (2-10 |ig/ml), kanamycine (5-10 ^g/ml), rifampicine (0.5 |ig/ml), PAS (p-amino saliyclic acid) (5-10 ^g/ml), INH (isonicotinic acid hidrazide) (0.2-5 ^g/ml), ETA (ethionamide) (5-10 ^ig/ml) and ethambutal (5-10 ^ig/ml), almost all the tested compounds given in Table 29 were found to be more active. The least active compound was salvipimarone (55) which is a pimarane diterpene. TABLE 28 Antibacterial Activity of the Diterpenes from Salvia multicaulis (ng/ml) Compound S. E. P. Kl ia 29 30 31 32 33 34 0.17 NA 0.7 NA 1.4 NA NA NA NA 3.6 NA 15.6 NA NA 7.15 NA 0.17 1.95 0.125 NA NA NA NA NA 2.03 NA NA 3.6 NA 15.6 0.5 NA NA NA p-hem. Enl. Ps.

aureus coli mirabilis.pneumon Streptococcusfaecalis aeruginosa

0.123 NA NA NA NA 4.6 NA NA

NA=not active We have isolated two 3,7-dihydroxysteroidal compounds from S. glutinosa^ , one known 7-ahydroxysitosterol and one new l-oxo-7a-hydroxysitosterol (70) . According to the literature^'^^ , cholest-5-ene-3P,7p-diol derivatives showed activity in the P-388 murine lymphocytic leukemia test TABLE 29 Antituberculous Activity of Compounds 29-34 and 55 Compound M C (|ng/ml) 29 5.60 30 0.49 31 2.03 32 1.17 33 6.15 34 0.89 55 73.00

system while 3P,7a-dihydroxy derivatives has little activity. Therefore, both compounds obtained from S. glutinosa were tested in P-388 and KB system and showed marginal activity, verifying the literatuire findings. However, one of our testedrearranged diterpenes, microstegiol from S, microstegia^^ was

715 found to be active in P-388 with ED50 value of 3.0 ng/ml. Also, a number of diterpenoids, isolated during these studies are being investigated for their cytotoxic and antiviral activities.

REFERENCES 1. V. N. Dobrynin, M. N. Kolosov, B. K. Chernov and N. A. Derbentsava, N.A., Khim. Prir. Soedin, 5 (1976), 686-687. 2. M. K. Chien, P. C Yang, K. C. Chin and C. H. Chen, Yao Hsueh Tung Pao, 15 (1980)1; CA. 94 (1981) 145225 c. 3. J. Jimenez, S. Risco, T. Ruiz, and T. Zarzuelo, PlantaMedica, 52 (1986) 260-262. 4. W. Z. Chen, ActaPharm. Sinica, 19 (1981) 876. 5. H. M. Chang and P. P. But, "Pharmacology and Applications of Chinese Materia Medica" World Sci. Pub. Co. Singapore Vol. 1, (1986) p. 773; C A. 106 (1987) 27798 k. 6. J. Janosik, CiheckPat. (1980) 185-262; C A. 95,68027. 7. W. I. Hanson and G.M. Hocking, Economy Botany, 11 (1957)648. 8. A. Ulubelen and G. Top^u, "Frontiers in Natural Products Chemistry" Ed. Atta-ur-Rahman,b Elsevier Science Publishers, Amsterdam pp. (199 ) 714-722. 9. A. Ulubelen and G. Topgu, "Essays on Science " Ed. Hakim Muhammed Said, Hamdard Foundation, Pakistan (1992) pp. 236-257. 10. A. G. Gonzales, T. A. Grillo, A. G Ravelo, J. G Luis, M. L. Rodriguez,, J. Calle, and A. Rivera, J. Nat. Prod., 52 (1989) 1307-1310. 11. A. G Gonzales, T. A. Grillo, J. G. Luis, J. T. Vazques, M. L. Rodriguez, J. L. Ravelo, J. Calle and A. Rivera, Phytochemistry, 29 (1989) 3581-3585. 12. G Topcu, A. Ulubelen, T.C-M Tam and C T.-Che, Phytochemistry, 42 (1996) 1089-1092. 13. A. Ulubelen and E. Tuzlaci, Planta medica, 53 (1987) 578. 14. A. Ulubelen, G. Topcu, C Eris, U. Sonmez, M. Kartal, S. Kurucu, and C. Bozok-Johansson, Phytochemistry, 36 (1994) 971-973. 15. A. Ulubelen, G Top9u, and E.Tuzlaci, J. Nat. Prod., 55 (1992) 1518-1521. 16. A. Ulubelen and G Topgu, J. Fac. Pharmacy (Istanbul) 26-28 (1992) 59-79. 17. B. Esquivel, J. Cardenas, T. P. Ramamoorthy, and L Rodriguez-Hahn, Pytochemistry, 25 (1986) 2381-2384. 18. A. Ulubelen, G Topgu andN. Tan, Phytochemistry, 31 (1992) 3637-3638.

716 19. A. Ulubelen and G. Top9u, Phytochemistiy, 31 (1992)3949-3951. 20. A.UlubelenandE.Tuzlaci, J. Nat. Prod., 53 (1990) 1597-1599. 21. J. W. Rowe and B. A. Nagasampagi, Phytochemistry, 10 (1971) 1647-1651. 22. G. Top9u, A. Ulubelen, and C. Eris, Phytochemistry, 36 (1994) 743-745. 23. A Ulubelen and G Topgu, J. Nat. Prod., 55 (1992) 441-444. 24. R.R. Gill, G A Cordell, G Topcu and A Ulubelen, J. Nat .Prod., 57 (1994), 181-185. 25. G.Top9u and A. Ulubelen, J. Nat. Prod., 59(1996) 113-116. 26. A Ulubelen and G Topcu, Natural Product Letters, 1 (1992), 141-147. 27. A. Ulubelen, G. Topgu, U. Sonmez and C.Eri, Phytochemistry, 35 (1994), 1065-1067. 28. M. Bruno, G Savona, F..Piozzi, M.C. de la Torre, B. Rodriguez and M. Marlier, Phytochemistry, 30 (1991), 2339-2343. 29. Ulubelen, A, Topcu, G, Chen, S., Cai, P. and Snyder, J.K., J. Org. Chem., 56 (1991), 73547356. 30. A. Ulubelen, G. Top^u and N. Tan, Phytochemistry, 40 (1995), 1473-1475. 31. A. Pinto, A. J. R Silva, L: M. U. Meyer and R. Braz-Filho, Phytochemistiy, 18 (1979) 2036-2037. 32. A. Ulubelen, G. Topcu, U. Sonmez, M. I. Choudhaiy and Atta-ur Rahman, Phytochemistry, 40 (1995) 861-864. 33. A. Ulubelen, G Top9u and B. Terem, Phytochemistry, 26 (1987) 1534-1535. 34. V. Stevens and G S. Bisacchi, J.Org.Chem., 47 (1982) 2396-2399. 35. J. A. Hueso-Rodriguez, M. L. Jimeno, B. Rodriguez, G. Savona and M. Bruno, Phytochemistry, 22 (1983) 2005-2009. 36. A. Ulubelen, U. Sonmez, G Topcu and C. Bozok-Johansson, Phytochemistry, 42 (1996) 145147. 37. T. Myase, P. Ruedi and C. H. Eugster, Helv.Chim.Acta 62, (1977) 2770-2779. 38. S. Canigueral, J. Iglesias, F. Sanchez-Ferrando and A. Virgili, Phytochemistry, 27 (1988) 221-224. 39. E. Mendes, J. L. Marco, B. Rodriguez, M. L. Jimeno, A. M. Lobo and S. Prabhakar Phytochemistry, 28 (1989) 1685-1690. 40. F. Gao, M. Leidig and T. J. Mabiy, Phytochemistry, 25 (1986) 1371-1376. 41. A Ulubelen and G Top^u, Phytochemistry, 30 (1991) 2085-2086. 42. A. Ulubelen, G Top9u, U. Sonmez, C. Eris, andU. Ozgen, Phytochemistry, 43 (1996) 431-434. 43. A. Ulubelen, G Topcu and C. Bozok-Johansson, Tetrahedron (in press). 44. L.-Z. Lin, G Blasko and G A. CordeU, Phytochemistry, 28 (1989) 177-181.

717

45. G. Topcu, M. Kartal and A.Ulubelen, Phytochemistry (in press). 46. A. Ulubelen, G. Top9u andN. Tan, Tetrahedron Letters, 33 (1992) 7241-7244. 47. G Top9u, N. Tan, A. Ulubelen, D. Sun, D. and W. H. Watson, Phytochemistry, 40 (1995) 501-5 504. 48. G Top9u, C, Eris and A. Ulubelen, Phytochemistry, 41 (1996) 1143- 1147. 49. A. Ulubelen, G Top9u, N. Tan, L.-J. Lin and G A Cordell, Phytochemistry, 31 (1992) 24192421. 50. G Top9u and A. Ulubelen, Phytochemistiy, 29 (1990) 2346-2348. 51. G Topgu and A. Ulubelen, Phytochemistiy, 30 (1991) 2412-2413. 52. F. Bohlmann, W. Kramp, J. Jakupovic, H. Robinson and R. M. King, Phytochemistry, 21 (1982) 399-403. 53. B. Rodriguez, A. Alemany and M. Pinar, Teti-ahedron Letters (1978) 3069-3072. 54. S. Shibata, S. Mihashi and O. Tanaka, Teti-ahedron Letters (1967) 5241-5243. 55. S. Mihashi, Teti-ahedron Letters (1969) 1683-1686. 56. J. De Pascual Teresa, A. San Feliciano and Y. M. Miguel del Corral, Farm. Nueva, 41 (1976) 343344; Chem. Abst. 86 (1977) 29949 c. 57.Y. S. Cheng, Y.S. E. von Rudloflf, Tettahedron Letters, 14(1970) 1131-1132. 58. G Top9u, A. Ulubelen, T.C.-M. Tam and C. -T. Che, J. Nat. Prod., 59 (1996) 113-116. 59. A. Rustaiyan, A. Niknezad, L. Nazariands, J. Jakupovic and F. Bohlmann, Phytochemistry, 21 (182)1812-1813. 60. A. Rustaiyan and A Sadjadi, Phytochemistiy, 26 (1987) 3078-3079. 61. G Top9u, A. Ulubelen, T.C. -M. Tam and C. -T. Che, Phytochemistiy, 42 (1996) 1089-1092. 62. V. Kumar, M.I. M. Wazeer and D. B. T. Wijeratiie, Phytochemistiy, 24 (1985) 2067-2069. 63. K.Ohtani, K. Ogawa, R. Kassi, L. -R. Yang, K. Yamasaki, J. Zhou and O. Tanaka, Phytochemistry, 31(1992)1747-1752. 64. A. Ulubelen, G Topgu, H. Lotter, H. Wagner and C. Eri, Phytochemistiy, 36 (1994 413-415. 65. S. K. Chatteijee, N. Anand and M. L. Dhar, J. Sci. Ind. Res. (India), 18 B (1959) 262-263; Chem. Abst., 54 (1960 )15432 h. 66. G. Top9u, N. Tan, G. Kokdil and A. Ulubelen, Phytochemistry (in press). 67. A. Ulubelen, S. Ozturk and S. Iildatici, J. Pharm. Sci., 57 (1968 1037-1038). 68. T. Baytop," Therapy with Medicinal Plants in Turkey" (1st. Univ. Pub. No. 3255, Istanbul, 1984), pp. 156-158.

718 69. J. G. Colee, "Applied Medical Microbiology" Science Pub. London (1976) pp. 3-97. 70. J. D. Sleigh, M. C. Timburg," Notes on Medicinal Bacteriology" Chuchill Livingston, London (1981) pp. 43-48. 71. F. Kavanagagh, "Analytical Microbiology" Acadamic Press, New York (1963) p. 125. 72. M. Mski, A. Ulubelen, C. Bozok-Johansson and T. J. Mabiy, J. Nat. Prod., 46 (1983) 874-877. 73. A. G. Gonzales, T. Abad, I. A. Jimenez, AG. Ravelo, J. G Luis, Z. Aguiar, L. S. Andres, M. Plasencia, J. R. Herrare and L. Moujir, Biochemical Systematics and Ecology 17 (1989) 293-302. i 74. S. M. Kupchan, A. Karim and C. Marcks, J. Am. Chem. Soc, 91 (1968) 5923-5924. 75. L. T. Jonathan, C. T. Che, J. M. Pezzuto, H. H. S. Fong and N. R. Famsworth, J. Nat. Prod. 52 (1989) 571-576. 76. C. R. Cooksey, T. J. Crawford, R.W. Jacops and M.T. Shinnick, Antimicrob. Agents Chemother., 37 (1993) 976. 77. J. R. Wallace, R. D. Nash, C. L. Steele, J. Clin. Microbiol, 24 (1986) 976. 78. V. Lorian "Antibiotics in Laboratory Medicine" Ed. Williams and Wilkins, Baltimore, London (1986). 79. G. Schoroeder, M. Rohmer, J. P. Beck and R Anton, Phytochemistry, 19 (180) 2213-2215. 80. A. A L. Gunatilaka, G Samaranayake, D. G I. Kingston, H. Gleen and R K. Johnsson, J. Nat. Prod., 55 (1992) 1648-1654.

Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

719

The Chemistry of Some Natural Colourants

J.H.P. Tyman
1. INTRODUCTION This account is concerned with colourants and pigments mostly with those having E numbers in the European permitted range which are associated with manufactured edible products. The natural diet of human beings may contain a great variety of colourant substances although in manufactured products the range is considerably restricted. Until 1973 a wide spectrum of synthetic dyestuffs was allowed in foods so that for example in the mid fifties (1957) 32 synthetic dyes were permissible whereas by 1973, 19 of these had been removed and in that year the Colouring Matters in Food Regulations were introduced restricting the number to 14 with the provisional addition of 4 others which are under closer examination (ref.1). Many amendments have been made since that time and for instance by 1979 the list of synthetic dyes had been reduced to eleven (ref s .2, 3) . The position on natural colourants has remained more open although also as with synthetic dyes specified in 1973, the number of compounds or natural mixtures has diminished over the intervening years. Natural botanic families contain a vast number of organic chemical structures so that in gastronomy and in diet many of these are encountered gratuitously and assimilated. Their occurred by a process of experience, legend and entry or non-entry prohibition. From into the human food chain with different peoples of the world has the time when food processing and preservation moved largely from the home to the manufacturer there has always been an aim to maintain the colour of the original raw material. In manufactured foods the extent of usage of natural products is smaller than with synthetic products. Remarkably, some of the present colourants are obtained by extractive preparation while others are of synthetic origin and have come to be termed nature-identical. The usage of substances sometimes arose from emergency certain coloured in which situations

legislation was involved. Thus in the case of the plant pigments, the

720
carotenoids for example came into more extended usage through the vitaminisation of margarine with p-carotene because of its usefulness as a source of vitamin A. Apart from the derivatives of p-carotene, other pigments are the anthocyanins, the chlorophylls, cochineal, the betalaines, turmeric, caramel and riboflavin. In this account the historical background in brief, the chemistry of these pigments, their extraction ^permitted' natural substances and nature-identical from natural sources and their synthesis will be discussed. The present synthetic materials (also described by the Food and Drugs Administration, the FDA, as colorants ^exempt from certification') is quite small in number. Reference is also made to colourants no longer listed but which have an historical organic chemical significance such as for example brazilin and its relative haematoxylin. 2 THE PERMITTED NATURAL COLOURANTS Table 1 shows alphabetically the name, botanical origin (or occurrence) the production method and the E number of some of the principal permitted natural colourants. TABLE 1 Some Permitted Colourants of Natural (N) and /or Synthetic(S)Origin Compound(s) Anthocyanins (Malvin) Biological origin Production Official 'E' Number E 163 E 162 S,N N S S E 160(a) E 160(b) E 160(e) E 161(g) Widespread pigments

Vltls

vinlfera)

Beta Betanine (Beetroot red)

p-Carotene

vulgaris

Bixin(Annatto) Bixa orellana 'Apocarotenal' p-Carotene Canthaxanthin Mushroom source Capsanthin

Widespread in plants, insects

Capsicum annum

N
N Semi-S N Semi-S N S

E 160(c)
E 140 E 141

Chlorophyll All plants Chlorophyllin (copper complex) Carminic acid (Cochineal) Curcumin (Turmeric) Riboflavin

Dactylopius coccus Costa Curcuma longa

Widespread vitamin

E 120
E 100 E 101

721 With reference to the materials in Table 1, the structures of which are shown in the following section, the anthocyanins are a large family of glucosides whose members constitute the pink, red, mauve violet and blue colouring matter of flowers, fruit and vegetables. Perhaps for economic considerations those from the red grape skin of the common species, Vitis' vinifera^ comprising delphinin, cyanin, malvin, pelargonin and peonin have become the compounds of commercial interest as food colourants. The blackberry (Rubus fructicosus), the blackcurrant (Rihes nigrum), the raspberry {Rubus ideaus), the cherry (Prunus cerasus) and strawberry (Fragaria genus of the Roseacae)also each contain more resticted numbers of anthocyanins. The red-purple pigment of beetroot {Beta vulgaris) comprises the betalaines the principal member of which is betanine, together with a very small amount of isobetanine and the vulgaxanthines. The carotenoids are a very large family consisting of C 4 0 hydrocarbons, typified by a,Pand ycarotene (most commonly in the carrot, Daudas carota, Apiaceae), and the oxygen-containing xanthophylls. These are generally a lesser occurring group, with * permitted' members such as canthaxanthin (in the mushroom, Cantharellus clnnabarlnus) [E161(g)], capsanthin and capsorubin (Paprika oleoresin) [E160(c)], cis-bixin, a major component of the colourant annatto, a resinous material which coats the seeds of Blxa orellanar and norbixin, its corresponding dicarboxylic acid. The apocarotenoids are also in this category, for example, 'apocarotenal', (p-apo-8'-carotenal) [E160(e)], and ethyl p-apo-8'carotenate [E160(f)] Chlorophyll (E140) itself which exists as the compounds a and b (where the 3-methyl group in a has been replaced by a formyl substituent) is a less satisfactory colourant for commodity purposes than one of its derivatives lacking the phytyl group prepared by coppering), namely copper semi-synthesis (hydrolysis and chlorophyllin. Carminic acid, the active colourant principle of cochineal, is employed in the form of its derivatives, notably, the aluminium chelate which is obtained by semi-synthesis. Curcumin is the yellow pigment of the root of the tumeric plant, a spice material of legendary importance. Riboflavin (lactoflavin) enjoys a place as a vitamin rather than as a somewhat little used colourant. The carotenoids in Table 1, p-carotene, 'apocarotenal and

722
canthaxanthin have also achieved chemical significance through their commercial production by total synthesis, while the inorganic derivatives of carminic acid and the transformation of chlorophyll to sodium copper chlorophyllin are obtained by straightforward onestep semi-syntheses. Numerous xanthophylls, although not commercially prominent, in the listed 'permitted' range are lycopene [E160(d)](tomato), flavoxanthin [E161(a)], lutein [E161(b)](egg yolk, orange), and cryptoxanthin the natural [E161(c)] (the mango, orange), rubixanthin, [El61(d)], violaxanthin [E160 (e)], (the materials It should orange), rhodoxanthin [E161(f)] effect having be a secondary colouring many such as paprika, for example,

turmeric, saffron and sandalwood which are also included in the list. emphasised that xanthophylls zeaxanthin (egg yolk, mango), antheraxanthin (orange), neoxanthin and astaxanthin (lobster) are encountered in the diet or gastronomy and are not in the listed permitted colourant matters or commercially extracted for food colourant purposes. The occurrence of some of these xanthophylls is shown in Table 2 Table 2 The Occurrence of Some Xanthophylls permitted as Food Colourants (1973 amended regulations) Compound Lycopene Flavoxanthin Lutein Botanical Origin Structure 'Openchain p-carotene' 5,8-Epoxy-3,3'-dihydroxya-carotene 3,3'-Dihydroxy-a-carotene 3'-Hydroxy-a-carotene 3-a-Hydroxy-Y-carotene 3,3'-diketoretrodehydrop-carotene 5,6,5',6'-diepoxy-pcarotene-3,3'-diol

Lycoperslcon Taraxacum
(dandelion)

escalentum officinale

many plants,egg yolks maize

(tagetes) a-Cryptoxanthin Capsicum annum^ (red pepper) Rubixanthin Rhodoxanthin Violaxanthin

Rosa Taxus Viola

ruhinosar baccata trichloris,

ripe fruit (yew, red fruit) green leaves

It should be emphasised that carotenoids and xanthophylls are a vast family of materials and three of the most naturally abundant are fucoxanthin, violaxanthin and neoxanthin (ref. 4) although they are not

723 in evidence as food colourants. Lutein, the fourth is permitted and is commercially available by extraction. The chemistry and biochemistry of the whole group have been described in great detail (refs.5,6,7). 3 THE STRUCTURES OF THE MAJOR FOOD COLOURANTS The structures of the substances of interest in the permitted range together with some associated structures are shown in the following sections 3.1 The Anthocyanidins and Anthocyanins Anthocyanidins (aglycones), flavyliun salts (chlorides), are shown generally by (1), the anthocyanins (3-monoglucosides) by (2), and 3, 5-diglucosides by (3) . The major anthocyanidins are cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin and the substituents in their structures are shown below for the formula (1) . Table 3 The Structures of some anthocyanidins Anthocyanidin Cyanidin Delphinidin Malvidin Pelargonidin Peonidin Petunidin

-w OH
OH OMe H OMe OMe

R^
H OH OMe H H OH

Malvin , a major component of the grape skin (Vitis vinifera) depicted by (4) as a 3,5-diglucoside structure which has been
Rl Cl~

is

HO^

iT 1 II 1^
OH (2) Cl"

1T
Rl

i^j^^OH

NJCgHiiOg

J s ^ OH

s:?^^
Malvin (4) (CgHiiOs)

-6H1105
(3)

724
synthesised (ref.8)and compared with a sample of natural origin from Primula vinifera, viscosa (ref. 9) . The structural type malvidin in all present as 3-glucosides the components (of the Vitls referred to earlier, is listed (ref.10) as accompanied by although 3-

all but pelargonidin, with peonidin and petunidin as

another source (ref. 11) mentions the 3-glucosides of only malvidin, fruit). Diglycosidyl to acidic (rutinosides, sophorosides and sambusiosides) and 3present. The instability of the glucosides may account for reported compositional (4) (ref. 8) to a conditions

triglycosides are also differences.

Thus in their synthetic work on malvin 3,5-diglucoside the authors reported its hydrolysis and not in acidic monoglucoside which chloride from its properties

solution

'was certainly malvenin 'oenin chloride' (3-p-

(5-glucoside)

glucosidylmalvidin chloride) which was synthesised (ref .12) . The name oenin chloride was used for this anthocyanin and oenidin for the anthocyanidin in an early historical summary by a pioneer in the chemical investigation of flower pigments (ref. 13). 3.2 The Betalaines The betalaines comprise two groups, the betacyanines (the major colourant constituents of beetroot) and the lesser group, the betaxanthines. The former constitute the majority of the compounds in beetroot and only much smaller proportions of isobetalaines , (5%) and vulgaxanthines are present. The betanidines are the aglycones and the betanines contain alcohol a 5-0-glucosidic group, in which the primary is present to a small extent as a sulphate. The structures

of betanidine (5) and its corresponding glycoside betanine (6), the stereoisomeric aglycone at C^s , isobetanidine (7), and its glycoside (8) are depicted.

ac; s-."o^"

725
The minor compounds shown are the amide, vulgaxanthine I (9; R = NH2) and the aldehyde, vulgaxanthine II (9; R = H ) . The compound (10), indicaxanthin, although not present in the betalaines, is structurally related and occurs in other colouring matters.

H ^ : : ^ ; ^ : ^ " ,

H''

N-^ ^COoH

C02H (10)

HOoC' ^ N ' ' ' ^ C 0 2 H H

RO2C'

^N^ H

CO2R

3 . 3 The Carotenoids The formulae of the carotenoids, from which the yellow, orange and red colours of vegetable and fruit derive, comprise hydrocarbon types and the oxygen-containing xanthophylls. They are depicted namely, for the hydrocarbons, p-carotene (11), a-carotene (12),

(12) y-carotene (13), lycopene (14); for the xanthophylls, canthaxanthin

726
(15), capsanthin (16) and capsorubin (16a), and for the

apocarotenoids

(P-apo-8'-carotenal), (17; X = H) , ethyl p-apo-8'-

carotenate (17; X = OEt).

The structures are shown of cis-bixin (18; R = Me), norbixin (18; R = H) and crocetin (19), the parent acid of the colourant principle of saffron, sometimes described as a natural substance having a secondary colouring effect, which exists as the bis-gentibiose ester, crocin, although crocetin and crocin do not have E numbers and are

727

not permitted colourants.

HO2C

;02R .CO2H (19)

HO2C

The formulae of some less well-known xanthophylls, flavoxanthin (20), [E161 (a)], lutein (21), [E161 (b)], a-cryptoxanthin (22), [E161(c)], rubixanthin (23), [E161(d)], violaxanthin (24), [E161(e)]

(24)

728
and rhodoxanthin (25), [E161(f)] are also represented.

3.4 The Chlorophylls Chlorophyll (E 140) exists as chlorophyll a (26) and chlorophyll j b (27) and although it is not widely used as a commercial a derivative, copper chlorophyllin (29) is employed. colourant,

<26)Chlorophyll

COgBfe

H MG

Me

In this the magnesium is replaced by a copper atom and the phytyl chain has been removed. Chlorophyll c (28) is of marine origin.

729

NaOsC
(28)ChlorqphYll c C2 , R = CH=CH2 Ci , R = Et

CX)Me ^

(29)Sodium salt of copper chlorophyllin

3.5 Cochineal The colourant p r i n c i p l e o f cochineal w h i c h is used as carmine metallic chelates (calcium-aluminium) is carminic acid (30) t h e same w a y that in the form of its aluminium and other in m u c h

alizarin w a s formerly employed as a m o r d a n t d y e b y chelation of the 1,2-dihydroxy system.

HO2C.

Me

OH

(30)

3.6 Curcumin Curcumin (31, t h e active p r i n c i p l e in turmeric, is used b o t h for its colour and flavour. It exists as an intramolecular keto-enol chelate containing a six-membered ring.

MeO
(31)

Me

730
3.7 Riboflavin Riboflavin (32) (R = H) or lactoflavin [and its 1 phosphate (33)] is more familiar as vitamin B2 than as a food colourant.

^N"^ ^^5!;^ ^Me CH2[CH(0H) IgCHgOR

[32, R = H ; 33, R = P(0)(OH)2]

3.8 Sandalwood The red colourant component of sandalwood (in the 'insoluble^ red woods group) has attracted interest for its colourant potential although this application does not appear to be active. Polyphenols (ref.l4) together with less complex compounds are present such as pterostilbene, (34), (4'-hydroxy-3,5-dimethoxystilbene), pterocarpin (35) and homopterocarpin (36),the formulae of which are shown. The nature of the colourant structure does not seem to have been established.

MeO

MeO

(36)

The natural materials referred to have E numbers which relate to European (EEC) practice. They also have universal CI (Colour Index) numbers and in the USA, numbers Practice (ref. 15). listed in the Code of Federal

731 4 THE EXTRACTION of NATURAL FOOD COLOURANTS As with many natural products for pharmaceutical or medicinal use, extraction of ^permitted* natural food colourants takes priority over synthesis except in the instance of the carotenoids. In this class a remarkable available. 4.1 Anthocyanins In general, anthocyanins can be obtained from natural sources by aqueous acidic or alcoholoc extraction. Specifically, grape colour extract (El63)is a dehydrated water-soluble powder (obtained by spray drying) or the itself can be aqueous solution from which it is prepared. This obtained by extraction of the pigments in the synthetic activity makes the three important compounds p-carotene, 'apocarotenal', and canthaxanthin commercially

precipitate resulting from the storage of, for example. Concord grape juice. Alternatively in the case of grape skin extract the purple skins of Vitis vinifera consisting of the deseeded residues from pressing the grapes to obtain wine or grape juice, are steeped, during which some fermentation also occurs with formation of ethanol. An extract is produced termed, containing inorganic evaporation anthocyanins, salts. Sulphur in vacuo enocianina, a purplish red liquid acid, is tannins, in the sugars, process ca. and and added tartaric dioxide

gives

a concentrate

containing

1% of

colourant material. Analysis by the uv absorption of citrate buffered solutions enables the % anthocyanin to be determined distribution of component from the maximum at 520nm. The can be found by TLC on anthocyanins

cellulose with various strongly acidic solvents (eg. cone HCl, formic acid, water, 19:19.5:61.5) of extracts of plant material obtained with 1% hydrochloric acid in methanol. The Rf values found for 3monoglucosides of the anthocyaninidins of Vitis the petunidin compound 4.2 Betalaines The red betacyanines, the major components and the minor yellow betaxanthine pigments of the red table beet. Beta vulgaris, present to 0.12% in the natural product, are obtained from aqueous extraction at mild temperatures, as a concentrate by evaporation of the solution in vacuo, or as a powder by spray drying of the concentrate. The product is stable to heat below 50C at pH 4-7 and if not exposed to light. peonidin (0.25) (ref. 11). vinifera were, for (0.22) and of (0.13), for that of malvidin

732
Betanine can be analysed from its uv absorption maximum at 535nm (at pH 3) while betaxanthine absorbs at 480nm. Preparation for chromatographic examination (ref. 11) by TLC on cellulose is effected by firstly homogenisation of the beetroot sample (50g) with aqueous methanol (1:1), filtration and concentration at less than 40C. The residual solution is applied to the plate as a streak and doubly developed with isopropanol-ethanol-water-acetic acid (30:35:30:5). After drying of the plate under nitrogen, betanine appeared as a violet zone at RpO.27 with four other bands present. 4.3 Carotenoids Carotene was first extracted from the carrot by Wackenroder in 1831 and later from green leaves, although the identical nature of the material from the two sources was not established until 1907 by Willstatter. The former source comprises in fact a mixture of a- and p-carotenes which was later separated by Kuhn in the early thirties by the then new technique of column chromatography although this procedure was first described in 1906 by Tswett for the separation of carotene and chlorophyll. For the recovery of p-carotene, vegetable sources are largely used. The material is macerated in a blender with methanol-acetone (2:1), filtered and reextracted until a colourless filtrate results. The combined filtrates are evaporated at less than 40C in residue isolated nitrogen. For the isolation of carotenoids from animal sources, the tissue is extracted with propanone and a similar work-up procedure adopted as for plant carotenoids. Xanthophylls often occur as lipidic materials esterified with fatty acids and a hydrolysis step of the isolated extract, (obtained by ethereal extraction) is required. Treatment with methanolic sodium hydroxide pigment and at ambient is temperature by are during 6 hours liberates washing of the to the which recovered material ethereal removed extraction, by is dissolved plant in diethyl are ether, washed with at low vacuo^ the The 10% sodium under

hydroxide solution and then with water, dried and concentrated. materials stored temperature

neutrality, drying and concentration under reduced pressure. Sterols proteinaceous filtration concentrate dissolved in propanone and kept at low temperature. Several different solvent systems have been described for TLC of carotenoid hydrocarbons Kieselguhr G (refs. 16,17). Thus on magnesium oxide(1:1) layers with light petroleum(40-60C)-propanone

733 (85:15), the Rf values found for the carotenes were a- (0.86), p(0.82), Y- (0.33), 6- (0.65)and for lycopene (0.04). Reversed-phase systems have found use with hydrocarbon/xanthophyll mixtures. For example on RP-18 silica gel F254 layers with light petroleum(40-60C)acetonitrile-methanol (20:40:40) as developing solvent the Rf values shown (ref.ll) were (0.51), (0.68). for p-carotene (0.55), (0.13), lycopene (0.23), and canthaxanthin violaxanthin lutein capsanthin (0.64)

Prior to the synthesis of p-carotene, early

recoveries were examined of carotenoid-rich fractions from palm oil species (ref. 18) with a view to potential large-scale chromatography of the unsaponifiable material recoverable after alkaline hydrolysis of the oil. For the commercial preparation of Annatto (E160b) , the fruit from the tree Bixa orellandr a fast-growing tropical shrub indigenous to with a coloured resinous layer or marc which materials such as edible vegetable India, East Africa and the Caribbean is used. The fruit contains seeds which are coated is extracted with various

triacylglycerols or with aqueous alkaline solvents. In the latter case acidification affords the annatto pigments (ref.20) comprising predominantly, water-soluble norbixin and oil-soluble bixin. Annatto extract is one of the oldest known pigments used for food , textiles and cosmetics. Saffron, from the dried stigma of Crocus for yet example. North Africa, quite stable material sativa^ the colourant It is an principle of which is crocetin is produced in several sub-tropical countries, expensive Spain, although France. not a permitted

colourant with an E number. Paprika and its oleoresin in the red and yellow varieties owe their colour to carotenoids such as capsanthin and capsorubin. They are obtained from the sweet red pepper by solvent extraction which affords an oleoresin containing mainly the two carotenoids. They are more important as flavour materials greater interest than colour alone. 4.4 Chlorophyll and derivatives A simple laboratory recovery of chlorophyll can be achieved by the maceration of the green plant source with twice its weight of propanone at ambient temperature, a process which is repeated until the filtrate from the operation is colourless. One convenient green source is dried alfalfa, more popularly known as the perennial and illustrate, as do turmeric and its oleoresin, the feature that flavour is often the property of

734
lucerne, Medicago sativa, although nettles and grass are also

employed. The combined filtrates from the extraction are evaporated under reduced pressure at less than 40C. The residue is treated with 10% sodium chloride solution, extracted with diethyl ether, the solution dried and concentrated and the residue stored under a' nitrogen. Chlorophyl a and b [and their transformation products

and jb' respectively (stereoisomers at CIO) which result from heating pyridine solutions at 60C for 1 hour in sealed tubes] have been separated (ref. 11, 19) on sucrose layers (for example, icing sugar) with light petroleum (40-60C)-isopropanol (99:1) . The various chlorophyll (chl) members have the Rf values, chl a (0.56), chl a' (0.72), chl j b (0.30) and chl jb' (0.44) while the pheophytins (lacking an Mg atom) a and j b respectively have values 0.84 and 0.72. Pheophorbides (the free acids without the phytyl group and Mg atom)

a and b possess considerable polarity with R^ values 0.05 and 0.02 respectively. Cellulose can be used with the solvent light petroleumpropanone-isopropanol(90:10:0.45) on an analytical and a preparative basis. For deriving copper chlorophyllin (E141), chlorophyll is hydrolysed under mild alkaline conditions and the product ^copperised* to obtain the coordinated copper derivative. 4.5 Cochineal Cochineal extract (Colour Index 75470, E 120)is the final coccus Costa a alcohol-free material obtained after aqueous ethanolic extraction of the dried bodies of the female scale insect Dactylopius which lives on cacti such as Opuntia or Nopalea coccinelllfera

species indigenous to Peru and Mexico, although also found in the Canary Islands. In practice a simpler procedure consists of aqueous alkaline extraction. The colourant principle is carminic acid which is more well-known in the form of carmine, an aluminium side. A uv spectrophotometric study has been made chelate of carminic acid, a material insoluble in water and stable on the acidic (ref .21) . Thin layer chromatography of cochineal has been examined on acetylated cellulose with the solvent system, ethyl acetate-tetrahydrofuranwater (6:35:47) 4.6 Curcumin Curcumin is the colourant principle of turmeric (Colour Index 75300, E 100) and tumeric oleoresin. The dried and ground powder from the rhizome or root of Curcuma longa of the Zingiberaceae family in which the Rf was 0.94 (refs.22,23). The history of the chemistry of cochineal has been discussed (ref.24).

735 constitutes extracting purification turmeric the powder while with turmeric various oleoresin organic is obtained by

solvents.

Further

is adopted to obtain curcumin. Turmeric powder can

contain as much as 90-95% curcumin. 4.7 Miscellaneous materials Caramel (Colour Index natural brown, 10,E 150) , the dark brown colour additive resulting from the controlled heat treatment of various carbohydrate sources is in effect a complex semi-synthetic mixture rather than an extract. As indicated earlier many colourants are encountered gratuitously in domestic practice as for example in the surface darkening observed in cut fruit or vegetables due to the oxidative action of the enzyme phenolase upon polyphenolic compounds. Reactions involve o-quinone formation, and polymerisation of the substrates chlorogenic acid (a structural relative of caffeic acid), and 3,4-dihydroxybenzoic acid. Participation of tyrosine residues in enzyme proteins results in melanin formation. Enzymic oxidation of polyphenolic compounds in tea. Camellia sinensiSf gives a range of coloured products, the theaflavins and the thearubigins all of which are desired in the process of tea-making. The extraction processes described in the first part of this section are based upon very traditional methods. However in recent years a number of new approaches have been developed in which the properties of the natural ingredients are more faithfully preserved. Thus supercritical fluid extraction has become adopted in the flavour and perfumery industries (ref.25) 5 THE SYNTHESIS OF THE NATURAL PERMITTED COLOURANTS Although only three carotenoids are commercially synthsised for use as permitted food colourants, namely p-carotene, 'apocarotenal* and canthaxanthin, the availability of nature-identical counterparts of the natural products has always attracted interest. For the study of biological properties and for chromatographic studies access to versions is highly desirable. In the course of the synthetic

isolation of the natural product its total synthesis finally always remained historically as a target. Such chemical work had been carried out well before the introduction of the 5.1 Anthocyanins The naturally-occurring anthocyanins are complex mixtures and classical synthesis was aimed at the construction of the 3-glucosides invariably 'permitted'

range concept focussed attention on certain natural products

736
and the 3, 5-diglucosides. The first approach to the formation of the parent aglycone, the anthocyanidin pyrylium salt was made by the reaction of resorcinol with benzoylacetaldehyde in the presence of hydrogen chloride (ref.26), a process that was improved upon (ref.27) by employing 2,4-dihydroxybenzaldehyde and acetophenone in glacial acetic acid, ethyl acetate or dioxan containing hydrogen chloride at 0C. An alternative earlier approach to pyrylium salts had involved the reaction of 5,7-dihydroxy-3-methoxycoumarin with Grignard reagents followed by dehydration of the resultant chromenol by the action of hydrogen chloride (ref.28) . Much of the first investigative work has been summarised (ref.29). The development of methods for anthocyanidins, by the preferred use of aromatic aldehydes and co-hydroxyacetophenones led by way of their 0-(D)-glucopyranosyl analogues to the synthesis of the anthocyanins themselves. Although pelargonin chloride is an anthocyanin which does not occur in the natural prepared sources sources used (eg grape for the extraction of skins), it represents commercially the simplest

structural member and the methodology for its synthesis (ref.30) was intrinsic to the preparation of its five analogues. The route is shown in Scheme 1. Scheme 1

OMe

/ ^ OH
CI AcO'

^ v^ " ^ "
OAc

Pelargonln-S-glucoside H Glucose (G) 2 3 OH'I ^ OH H G(Ac)4 _ * - AcO OAc OAc

R e a g e n t s : ( i ) CICH2COCI, AICI3, (ii)KOAc, AcOH, ( i i i ) d i l . N a O H , (iv)Ac20, NaOAc, (v)Ag2C03 , a - B r , 2 , 3 , 4, G-CgH-^O (OAc) 4, ( v i ) 2-BzO-4, 6-(OH) 2C6H2CHO, HCl, ( v i i ) d i l . NaOH; H C l ; p u r i f n . t h r o u g h p i c r a t e .

737 Anisole was converted to 4-(S)-chloracetyl) phenol Hydrolysis with and thence in

glacial acetic acid containing potassium acetate and some ethanol to 4-(co-acetoxyacetyl) phenol. of which 10% sodium hydroxide afforded the monosodium salt of o, 4-dihydroxyacetophenone acetylation (a method under aqueous alkaline conditions termed the acetate. Reaction of Chattaway method) gave 4-hydroxyacetylphenyl

this with 2,3,4,6-tetra-O-acetyl-a-(D)-glucosyl bromide in benzene containing silver carbonate afforded the p-glucoside. With the 2-0benzoyl derivative of phlorglucinaldehyde in ether and chloroform containing hydrogen chloride this p-glucoside gave the pyrylium salt shown. Hydrolysis with aqueous sodium hydroxide, acidification and exhaustive purification afforded 3-p-(D)-glucosidylpelargonidin chinensis the (ref.31). of chloride which proved to be identical with callistephin chloride isolated from the purple-red aster Callistephus Reference has been made to oenin chloride, malvidin, which was synthesised phloroglucinaldehyde hydrogen chloride. and and 3-glucoside

(ref.l2) by an analogous type of

route to that shown in Scheme 1, from the 2-benzoyl derivative of co-tetra-O-acetyl-p-(D)-glucosyloxy-4in with ethyl dilute acetate sodium containing hydroxide, 3-pacetoxy-3,5-dimethoxyacetophenone Hydrolysis extensive acidification

purification

afforded

glucosidylmalvidin (oenin chloride). For the synthesis of malvin (4), the 3, 5-diglucoside of malvidin, the same p-(D)-glucosidyloxyacetophenone was required and in addition a 2-p-(D)-glucoside of phloroglucinaldehyde. This was obtained in low yield from phloroglucinaldehyde and 2,3,4,6-tetra-O-acetyl-a-(D)glucosyl bromide. The synthesis {ref.8)is depicted in Scheme 2. Scheme 2 (G = Glucose; GAC4 = Glucosetetraacetate as Scheme 1)

OH

OH

738 Reagents: (i) a-Br-2,3,4,6-(OAc) 4C6H,0, MeCN, aq.KOH, (ii)4-OAC-3,5(OMe)2C6H2COCH20G(OAc)4, EtOAc, HCl, (iii) 10%NaOH; HCl. Malvin chloride has been described as forming dark reddish-brown needles having a grenish lustre. The colour in solution is dependent upon the pH. Cyanin chloride (ref. 32) (3, R^ = OH^R^ = H) , its methyl ether, peonin chloride (ref.32) (3, R^ = OMe, R^ = H), petunin chloride (3, R^ = OMe, R2 = OH) and delphinin chloride (3, R^ = R^ = OH), were synthesised similarly. OMe HO
O^^ Petunin (chloride)

Cyeuiin (chloride)

OMe OH

O"
O^

Delphinin (chloride)

Peonin (chloride)

The a c e t y l a t e d glucosyloxyacetophenones shown were used in a s i m i l a r methodology, t o g e t h e r with in a l l c a s e s , the 2 - p - g l u c o s d i d e of phloroglucinaldehyde.

OAc
T -

OMe y.-w

OAc Y^*-

OMe urae

OAc OAc

^Y^^OAc
O"

GAc.
(For cyanin chloride)

O
GAC4

o I

GAC4

GAc,
(For petunin chloride)

(For peonin chloride)

(For delphinin chloride)

The generation of the required (o-hydroxyacetophenone for the preparation of the respective tetraacetylglucosyl derivative was

739
found to need a modified procedure involving the use of the

corresponding (o-diazoketone, prepared from the acid chloride (ref .33) , and thence the formyloxy compound which was selectively hydroxy intermediate for glucosylation. Although the formation of the acetylated pyrylium salts in the acidic condensation of 2-glucosyloxyphloroglucinaldehyde and the acetylated glucosyloxyacetophenone generally proceeded in good yield, for example malvin 65%, and for pelargonin-3-glucoside of the same order, the initial yield of the glucosylphloroglucinolaldehyde component was low. It seems likely that the liberation of two molar proportions of water in the acidic reaction could have resulted in partial hydrolysis. This might now be groups leading to more soluble avoidable by products and the inclusion of a the possible molecular sieve in the reaction medium. Removal of the protective also hydrolysis of sugar groups under the final acidic conditions were some of the difficulties encountered. Chromatographic monitoring of a typical reaction mixture during all the stages would be of interest to establish the total pathway. Both anthocyanidins and anthocyanins undergo structural and thus colour changes with alteration of pH. At very low values the pyrylium salt exists while at high values the oxyanion of a quinonoid form is present leading finally to a ring-opened structure. Scheme 3 and more easily hydrolysed than the corresponding acetate to the necessary (o-

740
These transformations, typically given by cyanine chloride, are reversed upon lowering the pH as shown in varying proportions. 5.2 Betalaines It was thought originally that the pigments of beetroot vulgaris were related to the anthocyanins, and were Beta indeed Scheme 3. At any given pH it appears that three or four structural entities may be present in

nitrogenous members of that series. However many studies showed their complete structural dissimilarity with that group and although their colour is similar it is constant over a wide pH range unlike the wide variability found with anthocyanins. They have been classed as alkaloids and reviewed (refs. 34,35). The betacyanines, comprise the indoles, betanine (6) the major red pigment component and its stereoisomer at C^s, isobetanine (8), a minor material. Both possess mono-p-(D)-glucopyranosyl groups at C5. The corresponding aglycones are betanidine (5) and its stereoisomer at Ci5, isobetanidine (7) . The betaxanthines are pyrrole-based, unlike the indole-based betacyanines, and are minor yellow pigments

of Beta

vulgaris.
(ref. 36) the former was synthesised the methyl ester of (ref.37). The 5,6(ref. 38) and

After studies of the structure and stereochemistry of betanidine and isobetanidine indole component, L-cyclodopa,

dihydroxyindoline-2-carboxylic acid, has been prepared by another distinct route. The reactions used

the piperidine moiety, betalamic acid (ref.39) has been synthesised for the synthesis of betanidine (5) (ref. 37) are

depicted in Scheme 4. Chelidamic acid (obtained from chelidonic acid available from propanone and diethyl oxalate by Claisen condensation and then amination) , was reduced in 42% yield to the and the derived dimethyl ester oxidised in meso compound acid the to cis,cis-4-hydroxy-1,2,3,4-tetrahydropiperidine-2,6-dicarboxylic 90% yield

corresponding piperidone. The semicarbazone of 2, 3-dihydrobetalamic acid was obtained (44%) through the use of a Horner-Wittig reagent and thence the semicarbazone of dimethyl betalamate itself in 41% yield through oxidation with dimethyl sulphoxide in trifluoroacetic in methanolic hydrogen chloride afforded a Hydrolysis with warm concentrated acid containing dicyclohexylcarbodiimide. Reaction with the methyl ester of L-cyclodopa iso compound) diastereoisomeric mixture, (the trimethyl ester of betanidine and the in 87% yield. hydrochloric acid gave betanidine (5) and some of the iso compound

741 (7) which were characterised chromatographically and spectroscopically. Betanidine is partly isomerised to the iso compound under alkaline and acidic conditions (ref.36). The reaction of L-cyclodopa appeared to proceed unambiguously, that is with the double bond in the piperidine ring at the 2,3-position. The final conversion to the glucoside betanine(6) was not described and does not appear to have been yet achieved. Scheme 4

OH -^ HOsC^N-^COgH NNHCONH2

MeOgC"

C. ^
N'^ '"COgMe NNHCONH2

OH

MeOgC"

'COgMe

MeOgC'"" N H

'COsMe

MeOgC'"' ^N^'^COgMe H

MeOsC"

COgMe

CO2H (5)[+ some (7)]

CO2H

Reagents: (i) 5%Rh/Al203, H2O, E^,A atm., 75C; MeOH,/HCl, (ii)C6HiiN=C=NC6Hii on polymer, DMSO, CgHgN^CFsCOs", (iii) (EtO)2P(0)CH2CH=NNHCONH2, NaH, (MeOCH2)2, (iv) C6HiiN=C=NC6Hii, DMSO, CF3CO2H, PhH, (v) L-cyclodopa Me ester, MeOH/HCl, (vi)Conc. HCl,(vii)not effected. By reaction of the dehydropiperidine compound with L-proline in

propanone/methanol containing hydrogen chloride the betaxanthine (10/ R = Me) resulted, together with its diastereoisomer, in low yield. L-Cyclodopa methyl ester hydrochloride was prepared (ref.38) from LP-(3,4-dihydroxyphenyl)alanine methyl ester by the route shown in

742 Scheme 5a. L-p-(3, 4-Dihydroxyphenyl)alanine itself was derived from L-tyrosine either Scheme 5a by the action of tyrosinase (ref.39)or by means of silver oxide oxidation.

,cn:;^ Zyyr:
HO-^ - ^ (C)

"XXir - -IX):^^ CI

T\4.y-C02Me

Reagents: (i) Tyrosinase, or Ag20 (ii) SOCI2/ MeOH, (iii) K^FeCNg^pHS, (iv)pH8,Na2S204; HsO". A different approach to cyclodopa (alkyl 5,6-dihydroxy-2,3(ref. 40) since the

dihydroindole-2-carboxylates has been devised described process

(ref.38) only results in acceptable yields when

operated in very dilute solution. In the modified method, Scheme 5b, racemic 3,4-dihydroxyphenylalanine (dopa) methyl ester hydrochloride (C) was iodinated with potassium iodate in a two phase system, then treated with sodium dithionite and acetylated to afford methyl 5,6diacetoxy-7-iodo-2, 3-dihydroindole-2-carboxylate. Reductive treatment of this with Pd-C, and hydrogen in ethanolic solution containing triethylamine and conversion to the hydrochloride (methyl Scheme 5b gave the product ester diacetate hydrochloride)in 40% overall yield.

= ' * nW-^^ "" IID>"="

R e a g e n t s : ( i ) K I 0 3 , C H C l 3 , H2O; Na2S204; ACjO, EtOH; H C l ( g ) , E t 2 0 . Py., (ii) Pd-C,H2, NEts,

743 Another approach to the synthesis of betalamic acid was effected

from N-benzylnorteloidinone (ref. 41) a structure prepared earlier as the N-Me analogue (ref.42). 2,5-Dimethoxy-2,5-dihydrofuran, obtained from furan by bromination in methanol containing potassium carbonate, was converted in ethanolic solution at -5C with aqueous potassium permanganate containing magnesium sulphate heptahydrate to cis-3,4dihydroxy-2, 5-dimethoxytetahydrofuran. This was hydrolysed with warm M hydrochloric acid to afford meso-tartaraldehyde which in buffered solution at pH 5 was reacted with acetone dicarboxylic acid in a Robinson-Schopf type synthesis and then with aqueous benzylamine hydrochloride to give With of with carbon dioxide evolution, this diol Nin in benzylnorteloidinone. 10:1 epimeric mixture methyl the orthoformate esters.

refluxing dichloromethane containing trifluoroacetic acid yielded a ortho Hydrogenolysis methanol-trifluoroacetic acid in the presence of palladium-carbon gave the secondary amine which was reacted at 0C in diethyl ethertetrahydrofuran with allylmagnesium bromide to produce the carbinol. The N-benzoyl derivative of this compound was obtained by condensation with dibenzoyl peroxide in dimethylformamide containing potassium carbonate. After prolonged acetylation in refluxing diethyl ether with acetic anhydride containing 4-dimethylaminopyridine this 0-benzoylhydroxylamine with aqueous oxalic acid gave the monoformate which was hydrolysed to the diol by treatment with aqueous sodium bicarbonate. The a-diketone was then derived by oxidation of the diol in toluene solution at -30C with N-chlorosuccinimide-dimethyl at -78C and reduction with sulphide followed by treatment with triethylamine. Ozonolysis of the diketone in ethyl acetate-methanol dimethyl sulphide resulted in the aldehyde from which with lead tetraacetate in benzene-methanol at 0C racemic dimethyl betalamate was obtained. The final product in the characterised form of its dimethyl ester semicarbazone was condensed under aqueous with racemic 0,0-diacetylcyclodopa methyl acidic ester conditions 6. Scheme6

hydrochloride to give betanidine.

The route is depicted in Scheme

no I o y MeO-L o V-OMe

OH

MeO-L VoMe"^ ^o

744

NOCOPh Meo-

ix

^^^^^^

1 ) _ > ' \ ^ \ ^ OHCOOH NOCOPh X HO. ^v^Av^^ HO NH MeOsC MeOgC MeOgC"" ^ N ^ "COgMe xiii MeOgC" I OAc OAc NOCOPh

41

O^^/k.
"^ OAc

xii O^
OAc NNHCONHo xiv

N-'^^COaMe H

AcO.,^x%,^^

HO.

AcO

MeOgC"

C02Me

HOoC

^COoH

Reagents: (i) Br2-MeOH, Na2C03, (ii) KMn04, (iii) H30% {iv)pH5, CO(CH2C02H)2; aq. BnNH3^Cl, (v) HC (OMe) 3, CH2CI2-CF3CO2H, A , (vi) Pd-C,H2, MeOH/CF3C02H, (vii) CH2=CHCH2MgBr, Et20-THF, (viii) (BzO)2/DMF, K2CO3, (ix)Ac20, Py., 4-DMAP; aq.(C02H)2, (x)aq. NaHCOj, (xi) NCS-Me2S, PhMe,30C; NEt3 , (xii)03 , EtOAc-MeOH, -78C, (xiii) Pb (OAc) 4 PhH-MeOH, 0C/ NH2NHCONH2HCI, NaOAc , (xiv), (xv) as in Scheme 4. The total synthesis of betanine does not yet seem to have been

achieved and a sequence whereby this might be effected is shown in Scheme 7. 0-Benzoylvanillin would be asymmetricaly converted to L-p(4-0-benzoyl-3-methoxyphenyl)alanine methyl ester and thence to the 4-O-benzoyl-3-0-methyl derivative of L-cyclodopa methyl ester. (perhaps Reaction with the semicarbazone of betalamic acid diester

745 also N-protected) would afford the 5-0-benzoyl,6-inethyl ether of betanidine/isobetanidine dimethyl esters. Selective demethylation with aluminium triiodide and reaction with 2,3,4,6-tetra-O-acetyl-a(D) -glucosylbromide (BrAc4G) followed by mild hydrolysis/deprotection might be expected to lead to betanine/isobetanine. Scheme 7

- rxn:'^- ixx)-MeO,^^^*,,,^ HO,

I >C02Me

5.3 Carotenoids The commercial development of synthetic routes to carotenoids of interest as food colourants must be renowned as one area where synthetic organic chemical methodology has proved of outstanding manufacturing perfumery significance. An integrated approach certain based of on acetylenic chemistry embraced the syntheses of vitamin A, the Cio alcohols, linalol, geraniol/nerol, the C15 members for example, nerolidol as well as that of the permitted colourants p-carotene, canthaxanthin, p-8'-apocarotenal, and ethyl p-apo-8'-carotenate. These four colourants could be obtained in a (nature-identical) pure state unlike the mixtures normally encountered with natural carotenoids and enabled the colour range from yellow to orange and red to be met (ref.43) . The first synthesis

746 of p-carotene methodology (ref. 44) was also based on p-ionone and acetylenic but was not developed industrially. Numerous

intermediates are involved in the synthetic array of the diversified acetylenic methodology. p-Ionone was a key intermediate in several diferent approaches. 5.3.1 p-Carotene The route from propanone to p-ionone is shown in Scheme 8, which depicts at the end, the classical route to pseudoionone citral (C) (P) from which was originally produced from lemon grass oil but

is now also derived from p-pinene by way of myrcene. In one of several ways to p-ionone, propanone affords by nucleophilic addition of the acetylide ion the acetylenic alcohol which can be selectively hydrogenated in the presence of Lindlar catalyst (Pd-BaS04, controlled by lead acetate) to the vinylic alcohol. Alternatively this compound is accessible by direct reaction of propanone with vinylmagnesium bromide in tetrahydrofuran. The acetoacetyl derivative results from reaction with diketene and rearrangement of the resultant 'allylacetoacetate* with loss of carbon dioxide gives the Cg compound *methylheptenone' (a natural component of of oil of rue) . A repitition of acetylide addition, and of acetoacetylation followed by thermal rearrangement affords pseudoionone (?) by way of an allenic intermediate. Cyclisation under selective conditions gives mainly p-ionone with some of the a-isomer. Scheme 8

i^ \y^

Ji

l/'^'iii {(""="

X- % ^

- v ^ -^ojj

^o
Reagents: (i)CsC', solvent,KOH, {CH2CO) 2/solvent, (iv) A,

(c>
(ii) Pd-BaS04, Pb(0Ac)2, H2, (iii)

747
BFg Et20, solvent. For the technical synthesis of p-carotene (11), p-ionone is converted to a Ci4 aldehyde by the Darzens reaction, thence first to a Cig and finally a C19 aldehyde two moles of which with a C2 reactant affords the required C40 structure. p-Ionone undergoes the Darzens reaction with ethyl chloracetate in the presence of sodium ethoxide to afford the p-hydroxy-a-chloroester and thence an a,p-epoxyester hydrolysis of which followed by acidification and decarboxylation gives a C14 a,p-unsaturated aldehyde. Conversion to the diethyl acetal by the with ethyl vinyl action of ethyl orthoformate and reaction of this

ether in the presence of boron trifluoride-zinc chloride followed by hydrolysis and deethanolation gives a C^g a, P unsaturated aldehyde. Submission of the diethyl acetal of this aldehyde to chain extension with ethyl prop-l-enyl ether by a similar procedure as for the C14 compound results in a conjugated C^g aldehyde. Two moles of this react with acetylene dimagnesium bromide to give a C40 diol, (11). It dehydration of which followed by Lindlar hydrogenation and final thermal isomeristion of the cis-product yields p-carotene 416 and 485nm. Scheme 9 The route is depicted in Scheme 9 . is a red-brown crystalline air-sensitive material, m . p . 181C, X^^^

rU.
[ 1 1 OEt

>OHJv^^^2Et

*'-

^o

OEt
IV

r T

OEt OEt
OEt

748

iW -i^
(ii) HO"; H3O"; (i) ClCH2C02Et, NaOEt, NH, BF3,ZnCl2, (v) CO2, {iii)HC(OEt) 4-TSA, (iv)CH2=CH0Et, HCl, (vi)HC(OEt)3,4-TSA/ MeCH=CHOEt, BF3, ZnCl2, (vii)HCl, (viii) C19 aldehyde, BrMgC=CMgBr, (ix) HCl, {x)H2 , Lindlar, (xi)A, (80^C) light petroleum.

Reagents:

Acetylenic routes do not represent the only approach to a p-carotene synthesis. Thus the Wittig reaction with the employment of phosphonium salts has been technically exploited by BASF (ref. 45). Vitamin A acetate can be used for this purpose synthesised from a Grignard reaction of p-ionone with vinylmagnesium bromide, isomerisation and formation of a C15 phosphonium salt. Reaction of the intermediate phosphoran with the C5 a,p-unsaturated aldehyde, 3formylcrotyl acetate, then gave vitamin A acetate as shown in Scheme 10a. From this by hydrolysis, vitamin A is obtained which was then used to obtain the phosphonium hydrogen peroxide in aqueous salt. This salt solution on the (A) can undergo phosphonium salt autoxidation to yield p-carotene (ref. 46), but the specific use of containing a base affords a higher yield (ref. 47) of p-carotene

through oxidative coupling of the phosphoran as depicted in Scheme 10b. The customary Wittig reaction involving the use of the isolated aldehyde is thereby avoided. Procedures have been developed for converting triphenylphosphine oxide to triphenylphosphine for reuse (ref. 45). The two stages are depicted in Schemes 10 (a and b ) . Scheme10 (a)

5^ 5rH 5r^::
OAc

P(Ph)3

P"^^^

749 (b)

Reagents: (a) (i) CH2=CHMgBr, THF(ii) PPh3.HCl,EtOH,RT, (iii) OHCC (Me) =CHO Ac, NaOMe, MeOPH, -15C. (b) (i) H2O2, HO". There are of course many other approaches to the p-carotene structure (ref.48) such as one based on the combination of 2Ci6 and a Cg intermediate, another on the combination of 20^4 with a C12 component and also by the use of 20^^ reactants with a C^o dialdehyde. However these routes have not apparently been given in Scheme 9. 5.3.2 Canthaxanthin Canthaxanthin (15) which forms purple crystals, m.p. 218C, X^^^AlOnm, was the last of the carotenoids to be brought to technical production. A simple commercial approach to this compound has been based on the bromination of p-carotene with N-bromosuccinimide in acetic acid solution containing chloroform (ref. 49) to give isozeaxanthin diacetate. This was hydrolysed to the the diol which submitted to the Oppenauer oxidation afforded canthaxanthin in good yield as depicted in Scheme 11. developed technically as that

OAc

750
Reagents: (i) BrNiCOCHjls, AcOH, CHCI3, (ii) HO"; Al (OBu^ 3, Me2C0. A route to canthaxanthin using Wittig reaction methodology has been described oxidised (ref. 50) . In this in dichloromethane approach retinol (vitamin A) to was by with manganese dioxide retinal

(vitamin A aldehyde) which was converted to 4-acetoxyretinal acetic acid. By reaction with

bromination with N-bromosuccinimide in dichloromethane containing retinyltriphenylphosphonium triphenylphosphine acid with acetate was obtained. formed in hydrogensulphate Treatment of derived by this with which reaction of 68% with

retinol hydrogensulphate, dehydroretrocarotene

isocryptoxanthin

hydrobromic

N-bromosuccinimide

chloroform/acetic acid afforded isozeaxanthin diacetate. Alkaline hydrolysis and Oppenauer oxidation with aluminium isopropoxide in propanone then gave canthaxanthin (15). Scheme 12 depicts the sequence. The Wittig reaction with the acetoxy derivative of the phosphonium salt could give isozeaxanthin diacetate directly. Schemee 12

OH

j.^^^^Y'^^'***''^^^

C2O

>0>x^V'''vxk^, P

(Pha)

-^

VI

Vll

751 Reagents: (i) Mn02, CH2CI2, (ii) NBS, CHCI3/ACOH, (iii) L, NaOMe, PhH, (iv)CH2Cl2, HBr, -45C; Na2C03/A , (v) NBS, CHCI3/ACOH; PhNEt2 / (vi)KOH, (vii)Al(0Pr^)3, Me2C0. Although invariably routes to carotenoids have been based on the use of p-ionone, in one early synthesis of canthaxanthin the cyclohexenyl ring was formed from an acyclic component obtained from isobutyraldehyde (ref. 51) which provided a C4 chain and thence the Cg component necessary for the ring was derived in the following way. Acrylonitrile and isobutyraldehyde underwent Michael addition in the presence of the basic resin Amberlite IRA-400 (OH) and the product 4-cyano-2,2-dimethylbutanal nitric/sulphuric acids to was both hydrolysed and oxidised with afford 2,2-dimethylglutaric acid. containing sulphuric acid gave the

Esterification with methanol

dimethyl ester which was then selectively semi-hydrolysed at the less sterically hindered ester group with methanolic potassium hydroxide to give the half ester. The acid chloride produced under mild conditions with thionyl chloride was then reacted in benzene with diethylcadmium to produce methyl 2^ 2~dimethyl-5-oxoheptanoate. After protection of the keto group by ketalisation with ethane-1,2-diol, the ester was hydrolysed to give 5~ethylenedioxy-2,2(K) . These stages dimethylheptanoic acid which was converted with ethereal methyl

lithium to 6-ethylenedioxy-3,3-dimethyloctan-2-one are shown in Scheme 13a Scheme 13a

ii

iii

iv

COCl

^^

^V"*^^ O

^^^ ^ ^ ' ' ^ ' ' ^ ^ 0 0

viii

Two moles of this ketone (K) were then condensed by Claisen reaction in 5% ethanolic potassium hydroxide with crocetindial with acetone containing 4-toluenesulphonic acid. (ref.52) and resultant the terminal ketal groups in the product then removed by refluxing The

752
tetraketone was transformed into canthaxanthin (15) by refluxing in methanolic potassium hydroxide containing benzene. These steps are illustrated in Scheme 13b. Scheme 13b

(Vo.

(0

Reagents: (i)Amberlite IRA-400, OH, 50-55^C, ( i i ) 65%HN03, H2SO4,60C, (111) MeOH, H2S04,A (iv)MeOH,KOH,20C; Yi-^O^ (v)S0Cl2, 20C, (vi)

PhH, Et2Cd, H3O" , (vii) MeCH2C (OCH2CH20)Me, 4-TSA,A (viii)5MNaOH,MeOH,A; ^^0^ , (ix)MeLi,Et2) , (x) Crocetindial, 5%KOH,EtOH, 20C, (xi)4-TSA, MesCO, (xii) 10%KOH,MeOH,A. 5.3.3 p-Apo-8'-carotenal (p-Cgo-apocarotenal)

Many

routes

to

this

C30 colourant,

which

is and

violet-coloured have been

crystalline

substance, m.p.l39C,

X^^y. 462

488nm,

described. A technical pathway to P~apo-8'-carotenal (17/ X = H)(ref. 53) involves the use of the same C19 aldehyde as for the technical synthesis of p-carotene (Scheme 9 ) . Thus reaction of this compound with a Cg acetylenic acetal led to a C25 intermediate which was then submitted to firstly a C2 and then a C3 chain extension to give the dehydro C30 structure. The required Cg acetal was prepared from the monodiethylacetal of malonaldehyde which was first converted by deethanolation to the conjugated enol ether. This was reacted with acetylide ion in anhydrous ammonia, followed by mild acidic dehydration and then diethylacetal Scheme 14a. formation with ethyl orthoformate, as depicted in

753
OH
OEt OEt OEt OEt C6 The Ci9 conjugated aldehyde component was reacted with the lithium derivative of this Cg acetal in ammonia to afford an hydroxy compound which was dehydrated under mild acidic conditions to the fully conjugated C25 substance. Chain extension with ethyl vinyl ether in the presence of boron trifluoride-zinc chloride and mild acidic deethanolation gave the C27 acetal which was then converted with prop1-enyl ethyl ether under the same conditions to the required C30 structure of dehydro-p-apocarotenal. Lindlar partial reduction followed by isomerisation afforded the final product. The route is shown in Scheme 14b Scheme 14b

OEt

OEt

(17,X = H)

754
Reagents: (a) (i)NaC=CH, NH3 , (ii) HC(0Et)3, H3P04,4-TSA. (ii) 4-TSA, (iii)CH2=CH0Et, BF3,ZnCl2; HCl; (b) (i)Li, NH3 HC(OEt)3,4-TSA, {iv)MeC=CHOEt, BFs^ZnClz/HCl, (v) Lindlar, H2;A. Apart from the technical route described available acetal vitamin of a A alcohol to p-apo-8'-carotenal, has served as an

readily

(C20)

intermediate in the form of the phosphonium salt by reaction with the monodiethyl mono trans Cio dial (ref. 54) . The the enol required Cio ether of monodiethylacetal was obtained aldehyde-protected (ref.5, p409) by the reaction of the

derivative,

methylmalonaldehyde, (C4) with the acetylenic Grignard reagent from 3-methyl-2-penten-4-yn-l-ol (Cg) followed by acidic dehydration catalyst to give firstly 8acetyl (Cio). Protection of the solution with and partial reduction with Lindlar hydroxyl chloride group by acetylation

hydroxy-2,6-dimethylocta-2,4,6-triene-l-al

in pyridine

and formation of the diethyl acetal with ethyl orthoformate

followed by hydrolysis of the acetyl group and oxidation afforded the final CIO aldehyde component (D)shown in Scheme 15a. The reverse approach, illustrated in Scheme 15b was also used (ref. 54, ref.247, p446) by employing vitamin A aldehyde to the allylic hydroxy monodiethylacetal. Scheme 15 Cl + o. P (Pha) (D) Cio OEt OEt (A) and the phosphonium salt formed from the Cio component (D) after its reduction

x^K,^.-'^^

C30

t
^ v / \ (Vitamin A aldehyde)

(Ph) 3P >

Et OEt ClO

Br

Clearly a great number of combinations are possible, the viability of which is dependent on the ready availability of intermediates. Thus for example the use of vitamin A aldehyde by reaction with a C5 phosphonium component (ref. 5, p400) to afford a C25 compound and

755 then repetition of the process to give p-apo-8'-carotenal, has been described as depicted in Scheme 15c. Scheme 15c ci
(Ph) 3P

^^--^

(A)

C20

(Ph)3P,

p-Cyclocitral, obtained in one procedure together with the a-isomer by the cyclisation in sulphuric acid of the Schiff's base of citral with aniline, by reduction with aluminium isopropoxide afforded pcyclogeraniol which was then converted to the triphenylphosphonium bromide with triphenylphosphine in dimethylformamide containing hydrogen chloride. Wittig reaction with the C20 comoponent, crocetin dial afforded another approach to p-apo-6'-carotenal, as depicted in Scheme 15d ci-

Although not used as a commercial colourant, crocetindial is important as an intermediate for several carotenoid syntheses and for obtaining bixin compounds. It was originally derived from 2,7dimethylsuberate ( C g dimethyl ester) by a lengthy process involving formation of 2,7-dimethylocta~2,4,6-triene-l, 8-dial and its reaction with two moles of a C5 phosphonium salt (ref. 55) . It can be obtained (ref.56) more easily from the Wittig reaction of the two

756
related Cio components as depicted in Scheme 16a. Both these C^o reactants were used for the synthesis of p-apo-S'-carotenal (Scheme 15a,b). Alternatively reaction of the bis diethyl acetal of the C^o dial can be used (Scheme 16b), firstly with vinyl ethyl ether (C2) to produce a C14 intermediate and secondly with prop-1-enyl ethyl ether (C3), (as in the methodology for the synthesis of p-carotene) (Scheme 9) followed by hydrolysis of the bis-acetal. Several other routes to the important C^Q dial and its bis diethylacetal have been listed (ref. 5, pp.431,433). Schemes 16a,b

(EtO)2CH

CH(0Et)2

OEt

CIO

5.3.4 Ethyl p-apo-8'-carotenate The ester, ethyl p-apo-8^-carotenate (17; X = OEt) corresponding to p-apo-8*-carotenal is an important colourant which has been referred to earlier. Technically it has been derived from the C27 compound, dehydro-p-C27-carotenal, an intermediate in the synthesis of p-apo8'-carotenal (Scheme 14b) by Wittig reaction with the phosphoran formed from the triphenylphosphonium salt of ethyl a-bromopropionate with sodium ethoxide (ref. 5,p459). The resultant dehydro compound was partially reduced with Lindlar catalyst and the product then themally isomerised to ethyl p-apo-8'-carotenate as shown in Scheme 17.

C27

757
rPh3Ps^C02Etj

COgEt

COgEt (17, X = OEt) Reagents: (i) HCl, (ii)NaOEt, (iii) Pd-BaS04, H2,Pb(OAc)2/A. 5.3.5 Citranaxathin In addition to p-carotene, canthaxanthin, p-apo-8'-carotenal ethyl p-apo-8'-carotenate, the ketone citranaxanthin occurs in certain citrus species, condensation of C30, has been cited with and (C33), which

(ref. 57) as a in the

compound produced on a manufacturing scale. It is obtained by the p-apo-8'-carotenal propanone presence of aqueous potassium hydroxide (Scheme 18) . Its use does not appear to be applicable to the UK. Scheme 18

5.3.6 Capsanthin and Capsorubin Capsanthin (16) and capsorubin {16a), the colourants in paprika oleoresin, although not produced by commercial synthesis have been prepared in the course of carotenoid studies (ref. 58). Capsanthin has been synthesised from p-citraurin ('3-hydroxy-p-apo-8'carotenal') which is available from zeaxanthin (3R,3RM"P-carotene3,3'-diol), by oxidation with potassium permanganate (ref. 59). The required cyclopentane component was derived (ref. 60) by the sequence of reactions depicted in Scheme 19. The diketo ester shown is available from the cyclisation with sodium ethoxide of the Michael adduct of diethylmethylmalonate with mesityl oxide. The less hindered

758
keto group was first ketalised and the remaining keto group and the ethoxycarbonyl group then reduced with lihiuiti aluminium hydride. The product was bond dehydrated and deketalised under acidic conditions to the unsaturated keto alcohol. Catalytic reduction of the ring double and oxidation of the methylol group afforded the keto acid, ring of contraction phosphoric the by alkaline treatment, bismuthite, acid.Sodium (X) and trans followed to by autoxidation of which gave the diosphenol (1,2-diketo structure) .This underwent addition acid/sodium els 3,3,4-

trimethylcyclopentanone-4-carboxylic reduction produced racemic trans alcohols. The racemic compound

borohydride (Y) epimeric

(Y) was then converted by

methyllithium to the hydroxy ketone. From Claisen condensation of two moles of the hydroxy ketone with crocetindial, racemic capsorubin was obtained which was chromatographically (TLC) similar to the natural product (Scheme 19a). The cis-alcohol afforded a racemic epimer Scheme 19a

CO2H

Reagents:

(i) EtOH, 4-TSA;LiAlH4; HsO",

(ii) Pd-C,H2;Cr03 , (iii)02.

759
KOBu% ( i v ) 5 % KOH; c r o c e t i n d i a l , 5%K0H, H3PO4, EtOH NaBi02,

(v)NaBH4

(vi) MeLi,

(vii)

With p-citraurin from natural sources or obtainable semisyntheticallly by the oxidation of zeaxanthin with permanganate, the same racemic hydroxy ketone derived from (Y) afforded by Claisen condensation, capsanthin as a mixture of diastereoisomers (ref. 61). The process is shown in Scheme 19b. Both capsanthin and capsorubin have yet to be synthesised in optically active form. Scheme 19b

Capsamthin 16

5.3.7 Norbixin derivatives Bixin, present in Annatto, is an important natural colourant which is obtained commercially from Bixa orellana. It is unusual in not having a typical isoprenoid structure composed of multiples of the fundamental C5 unit. All trans diethyl norbixin has been synthesised readily from crocetindial (ref.55,p221) by the Wittig reaction with two moles of the phosphoran from the triphenylphosphonium salt of ethyl chloracetate as shown in Scheme 20. The natural product is the form in which the colourant is used. Scheme 20
Et02C'''''*^Cl i ^ EtOoC'"^^ P'^PhoCl" EtOoC PPh,

C20

EtOgC
C24

COgEt

760
Reagents: (i) PPhj , (ii) NaOEt, (iii) condn. The technical syntheses described for p-carotene, canthaxanthin, papo-8'-carotenal and the corresponding ethyl ester, represent only a small part of the synthetic work carried out (ref. 5) by the Swiss group and others. Some of the many methodologies for the construction of carotenoids have been discussed deep bluish red. Typically (ref. 57). The range of colour of aqueous suspensions/solutions varies from a greenish yellow to a p-carotene gives a yellow, p-apo-8*carotenal an orange and canthaxanthin a tomato-red colour. Conformational studies by a number of techniques have established (ref.62)that the ring double bond in carotenoids is clsoid respect to the exterior linear unsaturated chain 5.4 Chlorophylls Chlorophylls {E140) have been described as dark green greasy (lipidic) powders and are only used to a minor extent. They have been largely replaced by copper chlorophyllin which is obtained by semisynthesis. biochemical The colour in chemistry of the and phthalocyanines in vitamin B12 and had interest haemoglobin, and not with transold,

concentrated attention on the remarkable properties exhibited by five-membered and related heterocyclic structures having centrally a metal in chelation. on However the structural following elucidation early work and by synthetic 63) studies chlorophyll,

Willstatter, occupied Fischer and coworkers for three decades (ref. culminating in the synthesis of inactive chlorphyll a (ref. 64) work of which had been dependent d^ preparation phaeporphyrin (ref.65). by his on the This successors accomplished

achievement was overshadowed

by the simultaneous publication of the

total synthesis of the optically active form of chlorophyll a (ref. 66) . Full experimental details of this landmark in synthesis were not published until 1990 (ref.. 66) more than ten years after the death of the originator. The absolute configuration of chlorophyll a was established (ref. 67) as 7S,8S,lOR,7R,ll'R through a correlation of a The degradation product of from the ring C of a phaephorbide molecule a with a transformation product of the terpenoid lactone (-)-a-santonin construction chlorophyll required the availability of four different pyrroles. A, B, C, and D, all of

which were obtained from 2,4-di(ethoxycarbonyl)-3,5-dimethylpyrrole synthesised originally by Knorr (ref. 68) . This had been prepared historically from ethyl acetoacetate by conversion to the nitroso

761 derivative, the reduction of this to the corresponding amino derivative and its condensation with ethyl acetoacetate. The formulae of these four pyrroles are depicted and the route to the fundamental intermediate, 'Knorr's pyrrole*.

NC

<K
CN,

NH

>i^" ^.
NH (B)

CHO

H02C-(^/-C02H (D) COgEt EtOgCNH 'Knorr's pyrrole'

EtOsC

>
NH

(A)

(C)
COjBt co, 2 NHo o^_^ AcOH,NaOAc

--^ EtOgC( (i)HN02,(ii)Zn

The synthetic pathways leading to these four structural building molecules A, B, C, and D are depicted in Scheme 21. Scheme 21
.COgEt CO2H ^ NH (J) EtOgC-

Et02c4 V ^

"2304 Et02c4 V

jR

AcCl ^1^13 EtOsC v^rn.rJ

COMe V N2H4

Et r \ Ni

Vilsmeier

\ Et \ v ' CH2(CN)2

^COgEt EtOpC

y_
^NH

Br2_^2Cl2

K
NH HO2C

'^OgEt CO2H

C02Et EtOgC-^^^

J-y

Aq_^tOH,
K5k

II \
NE

(B)

762

Scheme 21{contd.)
CHO (J) ^ Et02C-< > Vilsmeier EtOgC(I) CH2(CN)2 NH

i.

EtOgC

Ah
V-<
y NH ^

CH=C(CN)2

^ Br^eOH

EtOjC-C, >-C02Me ^ NH

4>c

CH-C (CN) g HQ-

rH-r/rM\

(D)

CH2(C02H)2 \

CO2H H2^i \ _ / ^

CO2H SO2CI2

CO2H \ y - ^

(I)

EtO,C-4 >

COgMe
NaOH^heat ;CH2N2 vilsmeier

^COaMe

COgMe

NH

("VcHO
NH

OHC-<>
NH

(C)

The strategy of the approach to the synthesis of chlorophyll a was to react A and B to form one dipyrrylmethane {A-CH2-B) and C with D to form another {C-CH2-D) . The A-CH2-B component was then reacted with the C-CH2-D molecule through formation of a flexible methylenic link to a Schiff^s base group enabling neighbouring groups to react. The * square* structure of a hydroporphyrin was thus derived from the electrophilic reaction of a protonated carbonyl group at the aposition of the 'B pyrrole' with the a-position of the 'pyrrole C and of the protonated Schiff's base at the a-position of 'pyrrole A' with the a-position of 'pyrole D'. The sequences leading to A-CH2-B and to C-CH2-D are depicted in the Schemes 22a and 22b. (ref. Formation of Component A-CHg-B (X) : Pyrrole A, 2-(p,p-dicyanovinyl)-3,5-dimethyl-4-ethylpyrrole, 69) , was converted with sulphuryl chloride to the with pyrrole B (3-ethoxycarbonyl-4-methylpyrrole), 5-chloromethyl (ref.70), to

derivative and then reacted in aqueous ethanolic hydrochloric acid afford 3',4-dimethyl-3-ethyl-4'-ethoxycarbonyl-5-(P,p-dicyanovinyl)-

dipyrrylmethane which with 3-methoxycarbonylpropionyl chloride gave 3', 4-dimethyl-3-ethyl-4 ' -ethoxycarbonyl-5- (P, p-dicyanovinyl) -5' - {3-

763
methoxycarbonylpropionyl)-dipyrrylmethane. This was hydrolysed with concentrated diazomethane condensation aqueous to with yield alkali, and the acid methylated with By was 3 \ 4--dimethyl-3-ethyl-4'-methoxycarbonyl-5 derivative

formyl-5'-(3-methoxycarbonylpropionyl)-dipyrrylmethane. ethylamine, the ethylformimino

obtained, the hydrobromide of which with hydrogen sulphide in the presence of sodium methoxide gave the thioaldehyde (A-CHj-B) (X) . Scheme 22a

(X)
COgMe COgMe lOgMe ^OgMe :02Me A-CH2-B

Reagents: (i) S02Cl2,AcOH, 550C;B, Aq.HCl, EtOH, (ii)Me02C {CH2) 2COCI, ZnCl2 CH2CI2, (iii) Aq.NaOH;CH2N2, (iv) EtNH2, AcOH; HBr;H2S, PhH^MeOH^MeO". Formation of Component C-CH2-D: Pyrrole D, 2,5-Dicarboxy-3-methyl-4-formylpyrrole (ref. 71) was reacted with nitromethane in the presence of diethylamine to give 2,5-Dicarboxy-3-methyl-4-{2-nitrovinyl)pyrrole, the corresponding 2-nitroethyl derivative. reduction of the and external double bond of which with aqueous sodium borohydride gave Decarboxylation hydrogenation of the nitro compound in methanol in the presence of Adams* catalyst afforded 3-methyl-4- (2-aminoethyl) -pyrrole which with pyrrole C (2-formyl-3-methyl-4-(2-methoxycarbonylethyl)-pyrrole (ref 72) in methanolic hydrogen bromide resulted in 3,3'-dimethyl-4-(2aminoethyl-4'- (2-methoxycarbonylethyl) -dipyrromethene dihydrobromide. Reduction of the methene with aqueous sodium borohydride gave the corresponding highly sensitive dipyrrylmethane forthwith reacted with the thioformyl compound (C-CH2-D)which was (X) to give the

764 Schiffs base (H) (shown in Scheme 23) Scheme 22b ^N02 ^V^COsH vi X^NHg

CHO . A . CO2H _v H02C

OHC

(H) MeOsC

Reagents: (v)MeN02,EtOH,Et2NH, A; NaBH4,aq, NaHCOs, (vi)NaOAc,KOAc, 120C; PtO2,H2, MeOH,(vii)D, MeOH,HBr, (viii)Aq.NaBH4, (ix)X,CH2Cl2, Reaction of A-CHg-B with C-CHg-D The key step of double ring closure by treatment of the readily formed Schiffs base compound (H) with 12M methanolic hydrogen chloride gave the hydroporphyrin salt (I) oxidation of which with iodine followed by acetylation with acetic anhydride/pyridine gave the porphyrin (J)in 50% overall yield from (X). Aereal oxidation in acetic acid afforded (K) which upon equilibration in the same solvent led to the purpurin of the (L) having a semi-saturated with M pyrrole ring. led to Hydrolysis acetyl compound methanolic hydrogen

chloride, exhaustive methylation

and Hofmann elimination

formation of the vinyl compound (M). By oxidation with air in the presence of light, cleavage occurred of the bond indicated resulting in the purpurin aldehyde (N) which underwent with dilute methanolic potassium hydroxide reverse condensation leading to loss of the oxalyl ester group and cyclisation of the formyl and the 6methoxycarbonyl groups to give (racemic) isopurpurin 5 methyl ester (0) which was spectrally identical with a sample from a natural source (ref.73). Hydrolysis with very dilute sodium hydroxide afforded chlorin 5 (P) which was resolved with quinine to give the

765

(+) salt from which (+)-chlorin 5 was obtained. Scheme 23

MeOgC

COgMe (K) \ Me02C COsMe ( Porphyrin') (L) \ COgMe Me02C ( Purpurin')

COgMe (M) \ COsMe (N) MeOgC

:H0C02Me CO ) COoMe Me02C

(P) HO2C Reaction of (P) with diazomethane then produced active purpurin 5

766
dimethyl ester, (Q) brief reaction of which with hydrogen cyanide in dichloromethane containing triethylamine resulted in the cyanolactone (R) . This was was treated under with zinc and acetic with acid followed by diazomethane to produce chlorin eg dimethyl ester nitrile (S) which hydrolysed mild conditions methanolic hydrogen chloride to give chlorin eg trimethyl ester natural sample. Scheme 23(contd.) (T)identical with a

xviii

ff

HO2C

^yj

QT^O^

(2 6)Chlorophvll a

The conversion

to phaeophorbide a (U) and thence by esterification

with phytol to afford first phaeophytin, lacking the magnesium atom, then to chlorophyll a (26) had been described (ref 74).

767
Reagents: (x) 12MHCl,MeOH, (xi) I2; ACjO/py., (xii) 02,AcOH, warm, (xiii) 02,hi), AcOH,N2,110C, (xiv)MHCl,MeOH,hot;Me2S04,MeOH,NaOH, (xv) (xvi)ciil.MeOH,KOH, (xvii) M/25 NaOH,H20. dioxan; quinine, (xviii) { + )salt,H30% CH2N2, (xix)HCN, CH2Cl2,Et3N, (xx) Zn, AcOH; CH2CI2 ,(xxi)MeOH,HCl,ambient,(xxii)Dieckmann,(xxiii)phytol; Mg^\ Optically active phytol has been synthesised methodology then is depicted in Scheme 24. In (ref. 75) and the route hydrogen (R)-(+)3(R) acid.

this

citronellol was converted to 4(R),8-dimethylnonanoic acid which was anodically to cross-coupled give with methyl methylglutarate 3(R),7(R),11-trimethyldodecanoic

Similar cross-coupling with levulinic acid afforded 6(R),10(R),14trimethylpentadecan-2-one and reaction with methoxyacetylene followed by acidic treatment gave a mixture of cis and trans methyl phytenoates which were separated. Reduction of the trans natural product. Scheme 24 ester with

lithium aluminium hydride resulted in phytol identical with the

CO2H

COgMe HO2C

VA
COgMe

Reagents: (i) Pd-C,H2;PBr3;CN";H30% (ii) 'O2CCH2CH (Me) CH2C02Me,-e, (iii) -02CCH2CH2COMe, -e, (iv)MeOC2C-/H30% (v)LiAlH4. The phytyl ester at C7 in chlorophyll can be removed enzymically by chlorophyllase to afford phaeophytin, or chemically, without affecting the methoxycarbonyl group at CIO under mild acidic or alkaline conditions in an inert atmosphere. In acidic treatment removal of the magnesium atom occurs, thus the semi-synthesis of

768
sodium copper chlorophyllin (29) requires, in the final step, the

insertion of the copper(II) atom and neutralisation. Chlorophyll b does not appear to have been synthesised. 5.5 Cochineal The colourant principle of cochineal is carminic acid (30) and although carminic acid was first obtained as a red crystalline substance in 1858 (ref.76) having been in use as a dye for several centuries, its structure was not fully elucidated for many years until the side-chain at C7 was found to be linked as a C-glucoside (ref. 77) and the carboxyl group was relocated from the 4- to the 2position (ref.78). The p-configuration of the glucoside was established later as the final refinement (ref.79). Carminic acid, (30) (7p-D-glucopyranosyl-l-methyl-3,5,6,8-tetrahydroxy-9,10-anthraquinone-2-carboxylic acid) has been synthesised (ref. 80)although it is unlikely that the route will challenge the traditional extraction process which has been operated for very many years. The cochineal carmine of commerce is a hydrated calcium complex of carminic acid useful for its high colour yield, pigmentation properties and photostability. The aglycone of carminic acid is kermesic acid itself an ancient dyestuff, obtained from a European source, Kermes from Central and South America. by two routes illiciSf which was gradually displaced historically by carminic acid imported Kermesic acid has been synthesised acid) (ref. 81, 82) and together with isokermesic acid

(3,5,7,8-tetrahydroxy-l-methyl-9,lO-anthraquinone-2-carboxylic recently been reexamined (ref.84). Me O OH

(Kermesic acid)

by a non-regiospecific method (ref .83) . This procedure and others has

Due

to

the of

spiraling carminic

price acid

of

cochineal to be

in

the mid

eighties, commercial

synthesis

appeared

a viable

proposition. This seemed at first to be readily soluble simply by the glucosylation of kermesic acid, a process conceived to be the probable biosynthetic pathway. However, numerous studies of this potential route had no useful outcome (ref. 85) . Nevertheless in view of the failure of several routes from different retrosynthetic

769 schemes it appeared probable from theoretical considerations that a related structure, 6-deoxykermesic acid, could be selectively glycosylated at the 7-position to provide a route to 6-deoxycarminic acid whence carminic acid itself had been derived earlier (ref. 86). This total pathway proved to be feasible and 6-deoxykermesic acid was synthesised by the Diels-Alder addition reaction of 2chloronaphthazarin (E) with E/Z-3-alkoxycarbonyl-2,4bis(trimethylsilyl)-penta-1,3-dienes (D). Alkyl acetoacetates (R^ = Me,Et,Bn) were acetylated to produce the alkyl dialkyl acetoacetates(ref. 87) which were converted to bis(trimethylsilyl) derivatives (D) as depicted in Scheme 25a. 2-Chloronaphthazarin (E, X = CI) was prepared from 1,5-dinitronaphthalene by treatment in fuming sulphuric acid with sulphuric acid resulting first in the formation of naphthazarin (ref. 88) which was then dichlorinated and the product dehydrochlorinated (ref. 89) (Scheme 25b). An alternative route was from the acylation of 2-chlorohydroquinone with maleic anhydride in a sodium/aluminium chloride melt (ref.90)(Scheme 25c). 2-Bromonaphthazarin (E, X = Br) was obtained from the acylation of hydroquinone with 2-bromomaleic anhydride under similar conditions. 2-Halogenonaphthazarins can be equally represented 2-halogeno-l,4dihydroxynaphth-5,8-quinones or 2-halogeno-5,8-dihydroxynaphth-l,4quinones. Scheme 25a,b,c

(a)

X.CO.R. v "^Y^ ii
o O H

'"'';xf''o, TMSO

" ^ f 1 ^ CO O OH
3.3.3.

::w
O OH
OH

on

O
<C)

OH

OH

(E)

<i

770
Reagents: (a)(i)Mg,AcCOCl, PhH.A; NaHCO, , (ii) Method 1, N,0-bisMe3SiMeCONH2, Et20;Method 2,Et3N, TMSCl.PhH. {b){i)H2S04, SO3,S,60C, {ii)Cl2,AcOH, (iii) EtOH, A, (iv) AlCls^NaCl, 180C. By (E) the Diels-Alder reaction of 3-alkoxycarbonyl-2,4-

bis(trimethylsilyl) -1, 4-pentadienes (D) with 2-halogenonaphthazarins in hot toluene followed by desilylation, the methyl,ethyl and benzyl esters (F) respectively were formed in high yield by addition at the chlorine-containing ring. Methylation with dimethyl sulphate afforded the trimethyl ethers (G) reductive methylation of which (by sodium dithionite pentamethyl followed by methylation) (H) (ref. 91) . gave the 3,5,8,9,10occurred ethers Glucosylation

regiospecifically at the 7-position with 2,3,4,6-tetra-O-benzyl-a-ltrifluoroacetyl-D-glucopyranose in dichloromethane containing boron trifluoride etherate to afford, for example with the benzyl ester of (H) , the p-glycoside (I, R^ = Bn) . Oxidation of this with pyridinium chlorochromate then restored the 9,10-anthraquinone structure selectively to give acid (K) which by (J, R^ = Bn) . Hydrogenolysis with palladiumacetylation with acetic anhydride/pyridine (L) .

carbon in THF containing hydrochloric acid gave the parent glycosidic containing 4-dimetylaminopyridine afforded the tetraacetate

Demethylation of the trimethyl ether with boron tribromide gave the trihydroxy compound (M), and acetylation produced the heptaacetate (N) which was identical with natural 6-deoxycarminic acid heptaacetate prepared from carminic acid. Hydrolysis resulted in 6deoxycarminic acid (0), acetylation of which under relatively mild conditions tetraacetate with natural to preserve in the the 5,8-dihydroxy (P) . sensitive system gave with the lead 3 , 2 \ 3',4',6*-pentaacetoxy resulted carminic compound Oxidation

bis-quinone

(Q) , which . Acidic

underwent Thiele acetoxylation to give the octaacetate (R) identical acid octaacetate,m.p.189-90C hydrolysis with ethanolic hydrochloric acid then produced carminic acid (30). The route is depicted in Scheme 26. Scheme 26

'-* xJk VA 0
(E) 0 OH

OH

R^OoC^ ' - H O ^

000
Me
r ^

OH

/ ^

R^OgC

(F)

II

OH

MeO-^

-^V-NA^

COV
(G) 0

Me

OMe

OMe

771

Scheme 26

(contd.

Me iii

OMe OMe iv OMe OMe

Me R^O

OMe OMe

jOBn ,OBn OBn

MeO'"^-s^'''^N|^^^ C^eOMe

(H) RiOgC Me o = o OMe owe pBn .OBn O (J) HOgC Me ra o O OMe UMe OMe

HOgC

Me Me

o o

OH

PAc .OAc

(L) HOgC Me e o O OAc OAc ^

(M)

Me o Me o
^ T nr
O

OH

Y"
T \ , A

.OAc

I f

^--^\

/xi PAc ,OAc

OH O

Me

9^

Me

AcO'X.AyA^^
* (P) Me HOgC AcO o OAc OH

^OAc _^
^ i

AcO'\^!*^^\jX'^^ (Q) Me o O OH Ott

OAc xiii ^ .OH -OH

OH

bAc

."'HO'''^^^^**^^!^''^^

Carminic acid (30)

R e a g e n t s : ( i ) P h M e . IIO^'C; aq.THF, (ii)Me2S04, Me2CO,K2C03, ( i i i ) Bu4N^Br, Na2S204,HO"; Me2S04, ( i v ) s t e p l , (CF3CO) 2O, 2 , 3 , 4, 6 - t e t r a - O - B n (D) g l u c o s e ; s t e p 2 , H , CH2Cl2/BF3.Et20,reagent from s t e p l , (v) PCC,CH2Cl2/ ( v i ) P d - C , H 2 , THE, HCl, (vii)AC20, p y . , DMAP, ( v i i i ) B B r 3 , CH2CI2, ( i x ) AC2O, H2SO4 ( c a t . ) , (x)MeOH, HCl, A, (xi)Ac20, lOO^'C, ( x i i ) AC2O, Pb(0Ac)4, ( x i i i ) H2SO4, ( x i v ) EtOH, HCl.

772 5.6 Curcumin The turmeric root is the underground stem or rhizome of Curcuma longdr the active colourant principle of which is curcumin (31), an orange crystalline compound, m.p. 183C . The compound was obtained crystalline and the structure was elucidated by a number of separate studies (refs. 92,93,94,95). An early history of its chemistry has been described synthesise the (ref.96). A number of investigators attempted to parent compound, dicinnamoylmethane. Thus the

reaction of ethyl cinnamate with cinnamoylacetone was unsuccessful although this ester reacts readily with acetone (ref. 97) to give the latter. However, the parent compound was eventually prepared by the alkylation of sodio cinnamoylacetone, obtained from ethyl cinnamoylacetoacetate (ref. 98), with cinnamoyl chloride (ref. 99). By the use of appropriately substituted reactants and the employment of the methoxycarbonyl group for phenolic group protection, this methodology was then applied to the synthesis of curcumin itself successfully (ref.100) from vanillin by firstly its conversion to 4hydroxy-3-methoxycinnamic of the product then acid. The 4-hydroxy obtained. chloride The group in this was 3-methoxy-4the sodio protected by reaction with ethyl chloroformate and the acid chloride resultant methoxycarbonyloxycinnamoyl ethoxide,to afford ethyl (P) reacted with

derivative of ethylacetoacetate prepared in diethyl ether from sodium 3-methoxy-4-methoxycarbonyloxycinnamoylwhich by reaction in with 3-methoxy-43,3'-dimethoxyacetoacetate. Mild 'ketonic' hydrolysis with decarboxylation gave 3methoxy-4-methoxycarbonyloxycinnamoylacetone anisole containing sodium chloride sand methoxycarbonyloxycinnamoyl

(P) produced

4, 4 '-di (methoxycarbonyloxy) cinnamoylmethane. Mild hydrolysis with dilute potassium hydroxide followed by precipitation with carbon dioxide Scheme 27 gave 3-methoxy-4-hydroxycinnamoylmethane, which exists predomonantly in the H-bonded form (31) as shown in Scheme 27.

MeCCoV OMe

M e O , C o V '"' oMe

MeO.CoV OMe

773 0
. ^ s w
Ill

0
i-V f^ Y^ ^"^

O
^'^

O
^"^ H I

.x^ J L

J^ .^^f^''^.^'^'*''^:^^^^^^^^^.^^

^^^^^''^^X^^N.X^ ^ ^

MeOgCO

OMe O Q

L._

AM^ OMe

OMe

OCOgMe

OMe

OMe

(31) OMe OMe

R e a g e n t s : ( i ) S 0 C l 2 , ( i i ) AcCH2C02Et, NaOEt, Et20 , ( i i i ) d i . NaOH, -CO2 , (iv)PhOMe, Na s a n d , 3-MeO-4-MeOC02C6H3CH=CHCOCl ; H,0% (v) 2M KOH, 50C; CO2.

5.7 Riboflavin Riboflavin or vitamin B2 is obtained entirely by synthesis and its usage and role is predominantly as a vitamin rather than as a permitted colourant. The synthesis by Karrer was later improved by Tischler and proceeds from 3,4~xylidine (available through the nitration of o-xylene and reduction of the product), the Schiff^s base of which with D-ribose is catalytically reduced. Benzenediazonium chloride is coupled with the hydrogenation product and the resultant azo compound is then condensed with barbituric acid in acetic acid (with loss of aniline) to give the final product. The process is illustrated in Scheme 28. Scheme 28

CH2 [CH (OH) ] 3CH2OH

CH2 [CH (OH) ] 3CH2OH

(I

Riboflavin (32, R H)

O^^^^^N-^V-^e
CH2CCH(OH)]3CH20H

774
5.8 Sandalwood Red sandalwood Pterocarpus santalinus has attracted interest as a colourant and contains the colourless components, pterostilbene (34), pterocarpin (35) and homopterocarpin (36) the occurrence of which (ref. 101) and the chemistry (ref. 102) have been reviewed. The nature of the possible involvement of these compounds in the development of colour in sandalwood is not known although quinone and quinone dimer structures seem highly probable. Pterostilbene is the dimethyl ether of resveratrole, a natural widely-occurring The anticancer properties (ref. 103) and beneficial phenolic effect on component of many plants including grapes, mulberries and peanuts. coronary heart disease of this have been intensively studied recently (ref 104). The structures of pterocarpin and of homopterocarpin were elucidated (ref.105) and the synthesis described of pterostilbene (ref.106) by the reaction of 3,5-dimethoxybenzaldehyde with 4-hydroxyphenylacetic acid in hot acetic anhydride, followed by hydrolysis of the acetyl derivative formed and decarboxylation in quinoline containing copper as depicted in Scheme 29. Scheme 29 MeO MeO HO2C A\

MeO

MeO

(Pterostilbene)

MeO
Reagents: (i) AC2O, A, ;H0' , (ii) Cu, quinoline, A . Racemic chalcone an homopterocarpin has been obtained with two by the synthesised condensation (III) nitrate (ref. 107) of was from a

2-hydroxy-4followed by

methoxyacetophenone with 2, 4-dibenzyloxybenzaldehyde. Conversion to isoflavone with thallium hydrogenation to generate the racemic furanochroman (C)in low yield together other products (A) and (B). Chromatographic separation of (C) and methylation afforded the final product as shown in Scheme 30.

775

Scheme 30

MeO.

x^
MeO.

Bn0^^x%^^OBn

txpo
MeO, MeO. HO^Xx-^OH

OBn

MeO.

MeO.

(Homopterocaurpin)

OMe

R e a g e n t s : ( i ) EtOH, HO" s e p n . , ( i v ) M e l , K2CO3.

(ii) T1(N03)3, MeOH, (iii) Pd-C, H2; SiO,.

Racemic pterocarpin was synthesised (ref. 108) and later by other improved methods (ref. 109, 110). In the first of these latter methods (ref. 109) 2-benzyloxy-4,5-methylenedioxyphenylacetaldehyde was converted with pyrrolidine to an enamine which underwent reaction with 2-acetoxy-4-methoxybenzoyl chloride. Cyclisation led to an isoflavone acidic treatment of which followed by borohydride reduction and ring closure effected formation of the required pterocarpin as depicted in Scheme 31. Scheme 31

<xi::.r <::^^
^-...^x'^^OBn

'

"

OMe

776

Reagents: (i) HN{CH2)4, A, (ii) (iii) 2-OAc-4-MeOC6H3COCl,A, (ivHCl, NaBH4 , AcOH A remarkably simple approach to racemic pterocarpin is indicated by a two-step synthesis by (ref.llO) was in which of the in the 7-methoxy-2H-chromen, product of of 7presence lithium and readily formed dehydration reduction

methoxychroman-4-one, reactant was itself

reacted from

chloropalladite with 2-chloromercuri-4,5-methylenedioxyphenol. This obtained 3,4-methylenedioxyphenol mercuric acetate followed by treatment with sodium chloride. The process is illustrated in Scheme 32. Scheme 32

"-"X^O ^ZO:} ^
Reagents: (i) Li2PdCl4 , MeCN; SiOs sepn. 5. 9 Miscellaneous conqpounds Like sandalwood, brazilwood Caesalpinia logwood {haematoxylon of colourants colourant haematoxylin. principle Both campechianum), of brazilwood structures are braziliensis has had a long history of use for dyeing purposes and although as with it is not in the permitted range is brazilin closely and of to logwood, those of it has an association with food colourants. The related

pterocarpin and homopterocarpin and in the fundamental structural unit a -CH2_ simply replaces the - 0 - of the furan ring and a thydroxyl group is present at the cis bridgehead at the 3-position of the chroman ring. The structure of these two compounds has been discussed at length (ref.29,96) and although the mode of synthesis

777 of brazilin was apparent from early work (ref. Ill, 112), the

completion of this was achieved much later (ref. 113).

.OH

^
HO Brazilin OH HO OH

Haematoxylin

In

the

total

synthetic

route

(ref. from

113)

to

(+)-brazilin, of acetic

7-

methoxychromanone, was condensed with

obtained

the

cyclisation in

3-(3acid

methoxyphenoxy)propionic acid with 80% sulphuric acid in 60% yield, 3,4-dihydroxybenzaldehyde containing hydrogen chloride to give the 3,5-dihydroxybenzylidene

compound(J). 3-(3, 4-Dihydroxybenzyl)-7-methoxychromanone was obtained from this by catalytic hydrogenation in ethanol with palladium. Methylation in potassium hydroxide solution with dimethyl sulphate followed by cyclisation of the trimethyl ether through of deoxytrimethylbrazilone solution (B) a known dehydration product in hot benzene containing phosphorus pentoxide afforded a low yield transformation obtainable from natural brazilin. Catalytic hydrogenation of (B) in acetone containing Pd-SrCOj gave trimethylbrazilane, demethylation of which in acetic acid with boiling hydrobromic acid followed by acetylation of the product gave 0-triacetylbrazilane. Upon oxidation in aqueous acetic acid with chromium trioxide at 50C, the diketone, 0-triacetylbrazilone resulted which was reduced to the pinacol with zinc dust in ethanol solution containing acetic acid. This compound was hydrolysed in aqueous ethanolic potassium hydroxide and upon acidification with acetic acid was converted by dehydration to brazilein which in warm methanol by addition of potassium borohydride was transformed to brazilin separated (-)-diastereoisomer (R) . This was resolved by with aqueous ethanolic

acylation in pyridine solution with 1-menthoxyacetyl chloride and the hydrolysed potasium hydroxide to give (+)-brazilin identical with the natural product. The synthesis is depicted in Scheme 33.

778 Scheme 33

MeO.

"CO2H

rxX) ^
MeO,

MeO.

MeO.

(B)
OMe OMe
AcO^
vii

MeO

OMe

MeO

OMe

-0^
^

V^
^
HO

1' ^ 1
AcO

OH

OAc

AcO

OAc

AcO.

Reagents: (i) 80%H2SO4 , (ii) 3,4-diOHC6H3CHO, AcOH, HCl, (iii) Pd,H2, EtOH; Me2S04, KOH, (iv) PhH, P2O5, (v) Pd-SrCOj, Me2C0, (vi)HBr, AcOH, (viiJACjO, NaoAc , (viii) CrOj, aq.AcOH, (ix)Zn, aq EtOH, (x)KOH, EtOH;aq.AcOH , (xi) KBH4, MeOH; 1-menthoxyacetyl chloride,py.; diastereoisomer sepn.; KOH,EtOH. A difficulty with this synthesis is the low yield in the cyclisation leading to (B). With the objective of finding another route to this ring, the Pechmann condensation of resorcinol with 5, 6-dimethoxy-2itiethoxycarbonylindan-1-one was examined (ref.114). The latter was

779
prepared by the cyclisation of 3-(3,4-dimethoxyphenyl)propionic acid and methoxycarbonylation of the resultant 5,6-dimethoxyindan-l-one with dimethyl carbonate or by reaction with dimethyl oxalate, followed in this latter case by decarbonylation. Lithium hydride reduction of the coumarin carbonyl group afforded (B) as shown in Scheme 34.

MeO, MeO' P

CO2H
i

MeO.

CO2H
ii

MeO.

MeO
HO, COgMe ^

MeO O^^O MeO.

MeO. MeO

MeO

OMe

Reagents: (i) Na/Hg, NaOH, (ii) PhH, P2O5 , (iii)method 1, NaOEt, C0(0Et)2 , method 2, NaOMe, {ZQ^^t) 2 / Glass, A , 180^C, (iv)l,3diOHC6H4, HCl, EtOH, (v) Me2S04, K2CO3, Me2C0, (vi) LiAlH4, THE; Yi^O'Haematoxylin was also synthesised form. However the required (from (ref. 113) in optically active key the intermediate, methylation of deoxy-00natural ( + )-

tetramethylhaematoxylone was obtained from the oxidation of tetramethylhaematoxylin

haematoxylin) rather than by synthesis from 7,8-dimethoxychromanone as for the brazilin synthesis from the 7-methoxy Haematoxylin was obtained with 1-menthoxyacetyl compound. chloride, as for

racemic brazilin. The route is shown below in Scheme 35.

OAc
MeO.

HO

OH

780
Reagents: (i) Pd-SrCOs, H2, (ii)HBr, AcOH, (iii) Ac20,NaOAc, (iv),Cr03, aq.AcOH, (v) Zn, EtOH, (vi KOH, aq.EtOH, (vii) KBH4 , MeOH; resolution; hydrolysis. Prior to this publication the syntheses of racemic brazilin (ref. 115) and of racemic haematoxylin alternative methodology. In (ref. 116) were described by an approach to brazilin the the

dihydroxybenzylidene derivative (J, Scheme 32) was methylated to form the trimethyl ether (1; R = Me) and the analogous tribenzyl ether (1; R = Bn) was synthesised from appropriate starting materials. (I; R = Me was then epoxidised by treatment with hydrogen peroxide in alkaline solution. From treatment with sodium catalyst a mixture of dihydroxy products borohydride and then resulted. By mild catalytic hydrogenation in acetic acid in the presence of Adams' cyclisation with perchloric acid, racemic brazilin trimethyl ether (T , R = Me) was derived. From the tribenzyl ether (I; R = Bn) by a similar series of reactions, racemic brazilin tribenzyl ether (T; R = Bn) was obtained and from hydrogenolysis, racemic brazilin was derived. The process is depicted in Scheme 36. Scheme 36

^0^:^

Reagents: (i) H2O2, NaOH, {ii)NaBH4, iPrOH ; PtOj, H2, (iii) AcOH, HCIO4, (iv) (for,H), Pd(OH)2-BaS04, H2, AcOH. By related reactions racemic haematoxylin was synthesised (ref. 116) by first formation of 7,8-dihydroxychromanone from reaction of 3chloropropionic acid with pyrogallol in the presence of hydrofluoric acid. Claisen condensation with 3, 4-dihydroxybenzaldehyde in ethanol

781 containing hydrogen chloride and perbenzylation of the product resulted in 1, 8-dibenzyloxy-3-(3,4-dibenzyloxybenzylidene)-chroman-4one. Epoxidation of a propanone solution with hydrogen peroxide in methanolic sodium hydroxide gave the 3a-epoxide and reduction of the chromanone with sodium borohydride in isopropanol afforded a mixture of the cis and trans compounds, 4-hydroxy-7, 8-dibenzyloxy-3a-epoxy-3(3,4-dibenzyloxybenzyl)-chroman. Reductive cleavage of the epoxide with lithium aluminium hydride in tetrahydrofuran gave the cis and trans 3,4~dihydroxy compounds (two possible racemates) which by treatment in acetic acid with perchloric acid produced haematoxylin tetrabenzyl ether. Hydrogenolysis with palladium-carbon and hydrogen in ethyl acetate containing methanol at ambient temperature and pressure afforded racemic haematoxylin. The reactions are shown in Scheme 37. Scheme 37

U
OBn BnO, OBn OBn OBn BnO. BnO. OBn

OH

- "txxa:;
OH OBn

iBn

HO

OH

Haematoxylin

Reagents: (i) CICH2CH2CO2H, HF, (ii)EtOH, HCl, ( i i i ) BnBr, K2CO3, Me2C0, (iv)H202, NaOH, (v) NaBH4,iPrOH; LiAlH4, THF, (vi) HCIO4, AcOH, (vii)Pd-C, H2, EtOAc. The chromane and indane r i n g s i n both s y n t h e t i c b r a z i l i n and haematoxylin a r e c o n s i d e r e d t o be cis fused ( r e f . 1 1 5 , 1 1 7 ) . However

782
it would appear that the absolute configuration of both (+)-brazilin and (+)-haematoxtlin has not been established although it seems to be suggested (ref. 115) that in (+)-brazilin the t-OH group has the a-configuration and at the ring junction the designations would be (R) for the C-OH group and (S) for the C-H. The majority of the permitted colourants discussed in this account are natural products copper chlorophyllin with and the exception of the in four synthetic natural carotenoids. The only semi-synthetic materials used appear to be caramel. Although all the materials discussed in this whole account mixtures are undoubtedly

present, the composition of caramel (E150, CI natural brown 10) must be even more complex, probably justifying the expression describing it as 'a composition of matter'. It is made desired by heating sugar to around 115C with incorporation of to the flavour or other requirement. Hardly other materials and reactants such as milk , fats or starches as according surprisingly, the nature of both the composition and the origin of the resultant colour are largely unknown (ref. 118). Several colourant materials for example those in fruit, tea and in wine which have been used historically world-wide and bear no E numbers have more recently been judged to have useful health properties probably through their role as antioxidants (ref. 119). Thus in this class can be instanced the flavonol, epicatechin, the flavanoid quercitin, the stilbene referred to earlier, resveratrol. and theaflavin, the colourant of black tea (ref. 120), (the absolute configuration of this is not known).
OH

OH
Epicatechin

OH

HO
Resveratxole

783 The present colour range of the permitted natural colours (Appendix 1) enables by the use of either single materials or mixtures the whole visible spectral region to be matched and much is now known about their other properties. By contrast there is a vast range of natural colourants which may be encountered gratuitously in the diet or in gastronomy about which comparatively little is known. Conclusions The synthetic chemistry of some of the E number permitted food colourants has been described with respect to members of the anthocyanins, the betalaines, the carotenoids, to chlorophyll a, cochineal, curcumin and to sandalwood components. Although it is only with the four commercial carotenoids that synthesis has been adopted and for the rest the extraction of the natural product remains the source for use, the potential availability by synthesis of very pure nature-identical materials is important. The products of nature are complex and it seems probable that analytical techniques are only now revealing their nature and complete structure. Nevertheless although it appears unlikely that synthetic versions, other than carotenoids, would ever be employed it is important that their structural basis should be understood. and simultaneously Moreover structure/property studies require the availability of pure standards. Synthesis has provided this basis evolved a vast methodology for application in other fields of organic chemical endeavour. It is perhaps significant that during the last hundred years concerned with the elucidation of the structure and the synthesis of the natural colourants discussed in this account the work partially led to the awards of Nobel laureates to R. Willstater (1915), H. Fisher(1930), P. Karrer, joint with W. Haworth, (1931), R. Kuhn (1938,but declined), R. Robinson (1947), and R.B. Woodward (1965). Involved also indirectly through theory and experimentation is the work of many others similarly honoured as for example that of G. Wittig (1979). References 1 The Colouring Matters in Food Regulations 1973,S.I. 1973,1340. Food Additives and Contaminants Committee, Interim Report on the Review of the Colouring Matter in Food Regulations 197(FAC/REP/29,HMSO 1979). J.N. Counsell, (Ed.), Natural Colours for Food and other Uses, Applied Science Publishers Ltd., London, 1981 G.A.F. Hendry and J.D. Houghton, (Eds.), Natural Food Colourants, Blackie, Glasgow, 1992.

2 3

784 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 B.C.L. Weedon, in Carotenoids, (Ed. 0. Isler)^Birkhauser, 29-59,1971. 0. Isler, in Carotenoids, (Ed. 0. Isler), 11-29, Birkhauser, 1971. N.I. Krinsky, M.M. Micheline-Roth and R.F. Taylor, (Eds.),Carotenoids, Chemistry and Biology, Plenum Press, New York,1989. T.W. Goodwin, (Ed.), Chemistry and Biochemistry of PLant Pigments, Vols.,1 and 2, Academic Press, London, 1976. R. Robinson and A.R. Todd, J. Chem. Soc, 1932, 2299-2305. P. Karrer and A. Widmer, Helv. Chim. Acta, (10),1927, 32. T.P. Coultate, in Food, The chemistry of its components. The Royal Society of Chemistry, Cambridge, 2nd. Edn., 1996,pl50. O.M. Andersen and G.F. Francis, in The Natural Pigments, in Handbook of Thin Layer Chromatography, Eds. J. Sherma and B.J. Fried, M. Dekker, New York, 2nd. Edn., 1996, p724. L.F. Levy, T. Posternak and R. Robinson, J. Chem. Soc, 1931, 2701. R. Willstatter and H. Zollinger, Annalen, (408),1915,83-109; (412), 1916, 195-216. T.R. Seshadri, Phytochemistry, (11), 1975, 881-98. D. Marmion, in 'Colorants for Foods, Drugs and Cosmetics*, in Kirk-Othmer Encyclopedia of Chemical Technology,4th Edn. Vol.6, p925. F.H. Foppen, in Chromatographic Reviews, (14), (Ed. M. Lederer) , Elsevier, Amsterdam, 1971, pl33. R.F. Taylor, in Advances in Chromatography, (22), (Eds. J.C. Giddings, E. Grushka, J. Cazes and P.H. Brown), M. Dekker, New York, 1983, pl57. R.F. Hunter, A.D. Scott and N.E. Williams, Biochem. J., (38),1944, 209-11. A.H. Jackson, in Chemistry and Biocheistry of Plant Pigments, (Ed, T.W. Goodwin),2nd. Edn., Academic Press, London, 1976, Vol, 1, p6. D.A.V. Dendy, East Afr.Agric. Forest J., (32), 1966, 126-132. M.J. Schwing-Weill, Analusis, (14), 1986, 290-95. L. Massehelein-KLeiner, Mikrochim Acta, 1967, 1080-85. P. Wollenweber, J. Chromatogr.,(7), 1962, 557-560; see also K. Jentzsch, P. Spiegel and R. Kamitz, Sci. Pharm., (36), 1968, 251-6. F.L.C. Baranyovits, Endeavour, (2), 1978, 85-9. D.A. Moyler, Chem. and Ind., (London), 1991, 11-14. C. Bulow and W. von Sicherer, Ber., (34), 1901,3889-3897. W.H. Perkin and R. Robinson, Proc. Chem. Soc, (23),149, 1907. R. Willstatter and L. Zechmeister, Sitz.-Ber. Preuss. Akad. Wiss. Physik-Math. Kl., (34), 1914, 886-893. K.W. Bentley, (Ed. K.W. Bentley),The Natural Pigments,in Pyran Pigments II,Interscience, New York, 1960, 24-51. A. Robertson and R. Robinson, J. Chem. Soc, 1928, 1460-72. R. Willstatter and Ch. L. Burdick, Annalen.,(412), 1916, 149164. R. Robinson and A.R. Todd, J. Chem. Soc, 1932, 2488-2496. W. Bradley, R. Robinson and G. Schwarzenbach, J. Chem. Soc, 1930, 793-817. T.J. Mabry, in Chemistry of the Alkaloids, Ed.S.W. Pelletier, Van Nostrand Reinhold, New York, 1970, Chap. 13; M. Piatelli, in Chemistry and Biochemistry of Plant Pigments, Ed. T.W. Goodwin, Academic Press, London, 1976, 2nd edn., vol.1, chap. 11.

785 36 M.E. Wilcox, H. Wyler and A.S. Dreiding, Helv. Chim. Acta, (48), 1965, 1134-1147. 37 K. Hermann and A.S. Dreiding, Helv. Chim. Acta, (58), 1975, 1805-1808; (60), 1977, 1805. 38 H. Wyler and J. Chiovini, Helv. Chim. Acta, (51), 1968, 14761488. 39 H.S. Raper, Biochem. J., (20), 1926, 735-42. 40 G. Biichi and T. Kamikawa, J.Org. Chem., (42), 1977, 4153-4. 41 G. Biichi, H. Fliri and R. Shapiro, J. Org. Chem., (42), 1977, 2192-4. 42 J.C. Sheehan and B.M. Bloom, J. Am. Chem. Soc, (74), 1952, 3825-28. 43 0. Isler, R. Ruegg and U. Schwieter, Pure Appl. Chem.,(14), 1967, 245-264. 44 P. Karrer and C.H. Eugster, Compt. rend., (230), 1950, 19201. 45 H. Pommer, Angew.Chem. Int. Ed. Engl., (16), 1977, 423-492. 46 H.J. Bestmann, 0. Kratzer, Chem. Ber., (96), 1963, 1899-1908; H.J. Bestmann, L. Kiesiowski and W. Distler, Angew. Chem. Int. Ed. Engl., (15), 1976, 298-9. 47 B. Schulz, J. Paust and J. Schneider, DOS, 2505869, (1976). 48 Ref.29, 257-271. 49 0. Isler and P. Schudel,in Advances in Organic Chemistry, Methods and Results, Eds. R.A. Raphael, E.C. Taylor and H. Wynberg, Interscience, New York, 1963, vol. IV, pll5. 50 J.D. Surmatis, A. Walser, J. Gibas, U. Schwieter and R. Thommen, Helv. Chim. Acta, (53), 1970, 974-990. 51 C.K. Warren and B.C.L. Weedon, J. Chem. Soc, 1958, 39863993. 52 0. Isler, H. Gutmann, H. Lindlar, M. Montavon, R. Rtiegg, G. Ryser and P. Zeller, Helv. Chim. Acta, (39), 1956, 463-473. 53 R. Ruegg, M. Montavon, G, Ryser, G. Saucy, U. Schwieter and 0. Isler, Helv. Chim. Acta, (42), 1959, 854-64. 54 U. Schwieter, H. Gutmann, H. Lindlar, R. Marbet, N. Rigassi, R. Riiegg, S.F. Schaeren and 0. Isler, Helv. Chim. Acta, (49), 1966, 369-89. 55 L.F. Fieser and M. Fieser, in Topics in Organic chemistry, Reinhold, New York, 1963, p221. 56 0.Isler, H. Gutmann, M. Montavon, R. Ruegg, G. Ryser and P. Zeller, Helv. Chim. Acta, (40) , 1957, 1242-1249. 57 F. Kienzle, Pure and Appl. Chem., (47), 1976, 183-190; see also H.Pfander, Advances in the Synthesis of opticaly Active carotenoids, in Carotenoids, Chemistry and Biology, (Eds. N.I. Krinsky, M.M. Matthews-Roth and R,F, Taylor,Plenum Press, New York, 1989, pl25. 58 B.C.L. Wedon, Pure and Appl. Chem., (14), 1967, 265-78. 59 P. Karrer, A. Ruegger and U. Solmssen, Helv. Chim. Acta,(21), 1938, 448-51. 60 R.D.G. Cooper, L.M. Jackman and B.C.L. Weedon, Proc. Chem. Soc, 1962, 215. 61 R.D.G. Cooper and B.C.L. Weedon, (unpublished work). 62 C. Sterling, Acta Crystallogr., (17), 1964, 1224-1228. 63 H. Fischer, Naturewissenschaften, (26), 1940, 401-3. 64 M. Strell, A. Kalonjanoff and H. Roller, Angew. Chem., (72) 1960, 169-70. 65 H. Fischer, E. Stier and W. Kanngiesser, Annalen, (543), 1940, 258-70. 66 R.B. Woodward, W.A. Ayer, J.M. Beaton, F. Bickelhaupt,R. Bonnett, P. Buchscacher, G.L. Closs, H. Dutler, J. Hannah, S. Ito, A. Langemann, E. Le Goff, W. Leimgruber, L. Lwowski, J.

786 Sauer, Z. Valenta and H. Volz, J. Am. Chem. Soc, (82), 1960, 3800-2; Tetrahedron, (46), 1990, 7599-7659. I. Fleming, J. Chem. Soc, 1968, C 2765-2770. L. Knorr, Annalen, (236), 1886, 318; see also A.H. Jackson, The total Synthesis of Pyrrole Pigments, in The Total Synthesis of Natural,Products, (ed. J. ApSimon) ,Voll,1973, pl49,J. Wiley, H. Fischer and M. Neber, Annalen, (496),1932,1-26. A. Treibs, R. Schmidt and R. Zinsmeier, Chem. Ber., (90), 1957, 79-84. H. Fischer and K. Zeile, Annalen, (483), 1930, 251-71. H. Fischer and Z. Csukas, Annalen, 508, 1934, 167-84. H. Fischer and M. Strell, Annalen, (540), 1939, 232-49. R. Willstatter and A. Stoll, Annalen, (380), 1911, 148-154; H. Fischer and A. Stern, Annalen, (519), 1935, 244-253; H. Fischer and S. Goebel, Annalen, (524), 1936, 269-284; A. Stoll and E. Wiedemann, Fortschr. Chem. Forsch., (2),1952, 538. J.W.K. Burrell, L.M. Jackman and B.C.L. Weedon, Proc. Chem. Soc, 1959, 263-4. P. Schutzenberger, Ann. Chim. Phys., (54), 1858, 52. M. Ali and L.J. Haynes, J. Chem. Soc, 1959, 1033-35. J.C. Overeem and G.J.M. Van der Kerk, Rec Trav. Chim., (83), 1964, 995-1004; A.R. Mehendale, A.V. Rama Rao, I.N. Shaik and K. Venkataraman, Tetrahedron Lett., (18), 1968, 2231-2234. A. Fiecchi, M. Anastasia, G. Galli and P. Gariboldi, J. Org. Chem., (46), 1981, 1511. P. Allevi, M. Anastasia, P. Ciuffreda, A. Fiecchi, A. Scala, S.J. Bingham, M.Muir and J.H.P. Tyman, J. Chem. Soc. Chem. Commun., 1991, 1319-20; J.H.P. Tyman and A, Fiecchi, EP 0 602027/91, USP 5 424 421/92; S.J. Bingham, Ph.D. thesis, Brunei Univ. 1992;J.H.P. Tyman, Synthetic and Natural Phenols, Elsevier Science, Amsterdam, 1996, p624. P.Allevi, M. Anastasia, P. Ciuffreda, A. Fiecchi, A. Scala, S.J. Bingham, M.Muir and J.H.P. Tyman, J. Chem. Soc. Perkin Trans I (submitted for publication). G. Roberge and P. Brassard, J. Chem. Soc, Perkin Trans I, 1978, 1041-46. D.W. Cameron, D.J. Deutscher, G.I. Feutril and P.G. Griffiths, Aust. J. Chem., (34), 1981, 2401-21. A.V. Rama Rao and K. Venkataraman, in Recent Progress in Natural Product Chemistry, Prentice Hall of India, 1972, p341; D.D. Gadgil, Ph.D. thesis, Univ. Poona. J.H.P. Tymam and S.J. Bingham, (unpublished work). A. Fiecchi (unpublished work). 0. Dimroth and H. Kammerer, Chem. Ber., (53), 1920, 471-80. M. Viscontini and N. Merckling, Helv. Chim. Acta, (3) 1952, 2280-82. R. Roussin, C.R. Seances Acad. Sci., (52), 1861, 1033. D.B. Bruce and R.H. Thomson, J. Chem. Soc, 1955, 1089-1096. K. Zahn and P. Ochwat, Annalen, (461), 1928, 72-97. G.A. Kraus and T.O. Man, Synth. Commun., (16), 1986, 1037-42. G. Ciamician and P. Silber, Chem Ber., (30), 1897, 192-195, C.J. Jackson and A.E. Menke, Amer. Chem. Amer. Chem. J., (6),1884,78-88. W.H. Perkin, Chem. Soc. Trans., (85), 1905, 63. J. Milobedzska, S. von Kostanecki and V. Lampe, Chem. Ber., (43), 1910, 2163-2170. A.G. Perkin and A.G. Everest, The Natural Colouring Matters, Longmans Green, New York, 650pp., 1918; see also, P.J.

67 68

69 70 71 72 73 74

75 76 77 78 79 80

81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

787 Roughly and D.A. Whiting, J. Chem. Soc.,Perkin I Trans., 1973, 2379-88. H. Ryan and J.M. Dunlea, Proc. Roy. Irish Acad., (32), 1913, 9. E. Fischer, Chem. Ber., (16),1883, 166. V. Lampe and J. Milobedzka, Chem. Ber., (46), 1913, 2233. V. Lampe, Chem. Ber., (51), 1918, 1347-55; see also C. Kashima, N. Mukai, Y. Yamamoto, Y. tsuda and Y. Omote, Heterocycles, (7), 241-246, 1977. F.E, King, Chem. and Ind.(London), 1953, 1325-28. F.M. Dean, The Synthesis of Oxygen Ring Compounds, in The Total Synthesis of Natural Products, ed. J. ApSimon, Vol.1, 1973, p513, J. Wiley. M. Jang, L. Cai, G.O. Udeauni, K.V. Slowing,C.F. Thomas, C.W.W. Beecher, H.H.SD. Fong, N.R. Farnsworth, A.D. Kinghorn, R.G. Mehta, R.C. Moon and J. Pezzuto, Science, (275), 1997, 218-20. E.H. Siemann L.L. Creasy, J. Enol. Vitic, (43), 1992, 49; A.L. Waterhouse, Chem. and Ind.,(London), 1995, 338. A. McGookin, A. Robertson and W.B. Whalley, J. Chem. Soc, 1940, 787-95. E. Spath and K. Kromp, Chem. Ber., (74), 1941,189-196. A.V. Prasad and R.S. Capil, J. Chem. Soc, Perkin Trans I, 1986, 1561-63. K. Fukui and M. Nakayama, Bull. Chim. Soc. Japan, (42). 1969, 1408-1411. M. Uchiyama and M. Matsui, Agric. Biol, Chem., (31), 1967, 1490-1498. H. Horino and N. Inoue, J. Chem. Soc. Chem. Commun., 1976, 500-501 W.H. Perkin Jnr. and R. Robinson, Proc. Chem. Soc, (28), 1912, 7. R. Robinson and F. Morsingh,(unpublished work, referred to in ref.29, p90). F.Morsingh and R. Robinson, Tetrahedron, (26), 1970, 281-289. J.H.P. Tyman and M. Patel, (unpublished work); Abstract E15, lUPAC Symp.Chem.Nat.Products, Dunedin, N. Zealand 1976. 0. Dann and H. Hofmann, Annalen, (667), 1963, 116-25. 0. Dann and H. Hofmann, Chem. Ber., (98), 1965, 1498-1504. J.C. Craig, A.R. Naik, R. Pratt and E. Johnson, J. Org. Chem., (30), 1965, 1573. W.R. Eichenberger, in. Caramel Colours: Manufacture, Properties and Composition, Amer. Chem. SocMeeting, Aug.29th.,1972. A.L. Waterhouse, Chem. and Ind. (London), 1995, 338-341. D.D. Collier, T. Bryce, R. Mallows, P.E. Thomas, D.J. Frost, 0. Koever and C.K. Wilkins, Tetrahedron, (29), 1971, 125-142.

97 98 99 100 101 102 103

104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120

Appendix 1 The report referred to (ref.l) contains an Appendix V which lists the whole range of 'Colouring Matter permitted in food by the colouring matter in food regulations 1973' (as amended). The natural materials given in that appendix are as follows. Curcumin (ElOO), riboflavin or lactoflavin (ElOl), riboflavin-5'phosphate [ElOl(a)], cochineal or carminic acid (E120),

788
chlorophyll (E140), copper complexes of chlorophyll and chlorophyllin (E141), caramel (E150), alpha-, beta- , gammacarotene, [El60{a)], annatto, bixin, norbixin, [E160(b)],capsanthin or capsorubin (Paprika oleoresin), [E160(c)], lycopene,[E 160(d)], beta-apo-8'-carotenal, [E160 (e)], ethyl [E161(b)], cryptoxanthin, [El61(c)], rubixanthin, [E161(d)], violaxanthin, [E161(e)], rhodoxanthin, [E161(f)], canthaxanthin, [E161{g)], and beetroot red or betanin, (E162). Natural substances listed having a secondary colouring effect are (a) paprika, (b) turmeric, (c)saffron and (d) sandalwood. betaapo-8'-carotenate, [E160(f)], flavoxanthin, [E 161(a)], lutein

Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

789

Bioactive Natural and Synthetic Acronycine Derivatives Modified at the Pyran Ring
Sylvie Michel and Francois Tillequin 1. INTRODUCTION

Acronycine (1.) is a natural alkaloid which was first isolated in 1948 from the bark of a small Australian Rutaceous tree, Acronychia baueri Schott (1). Since that time, the status of this plant within the Rutaceae family has been revised several times, in the course of successive taxonomic studies (25). It is now widely accepted that the plant belongs to the genus Sarcomelicope and should be named Sarcomelicope simplicifolia (Endl.) Hartley ssp. simplicifolia (4).

The presence of an acridone basic skeleton and of a dimethylpyran ring in the acronycine structure was demonstrated fairly early (6-9). Tremendous effort was then necessary to determine whether the pyran ring was fused linearly or angularly on the acridone skeleton. In 1966, the regioselective synthesis of l,3-dimethoxy-2-methoxycarbonyl-10-methyl-9(10//)-acridinone (2j permitted Macdonald and Robertson (10) to assign unambiguously the angular structure 3,12-dihydro-6-methoxy-3,3,12-trimethyl-7//-pyrano[2,3c]acridine-7-one to acronycine. This structure was confirmed later on, both by nmr study of various acronycine derivatives (11) and by X-ray crystallographic analysis of 5-bromo-l,2-dihydroacronycine (33 (12).

790

COOCH3

OCH.

Acronycine was first synthesized in 1967-68 by Beck et al. who published simultaneously three interrelated syntheses of that alkaloid (13, 14). Around ten other total syntheses have been reported up till now (1526). Most of the synthetic strategies developped are sufficiently versatile to permit access to acronycine structural analogues as far as substitution on the A ring is concerned. Syntheses of analogues modified at B, C and D rings have been comparatively less explored. Most of them rely on chemical modifications performed on a preformed pyranoacridone skeleton, at the latest steps of the synthesis. The biological interest of acronycine was revealed in 1966 by Svoboda at the Eli-Lilly Laboratories (27, 28). Acronycine was found to be active against a broad spectrum of solid tumors including sarcoma, myeloma, carcinoma and melanoma. In contrast, it only exhibited poor activity against leukemias. The activity against X-5563 myeloma was of particular interest, since this plasma cell tumor has several properties that relate to those of multiple myeloma in human patients. This is the reason why Scarffe in 1983 (29) performed phase I-II clinical evaluation of acronycine in patients with refractory multiple myeloma. Oral acronycine capsules produced one clear response in sixteen patients. The remission was maintained 72 weeks, using daily dose of 300 mg/m^. The limited success of that trial is probably related to the moderate potency of acronycine and to its very low water-solubility {ca. 2-3 mg per liter of water) which do not permit an efficient parenteral formulation of the drug. Despite the broad antitumor activity of acronycine, the mechanism of its action at both cellular and molecular levels has not yet been clearly established. First observations suggested that the drug did not interact with DNA but acted primarly by alteration of subcellular organelle membranes and that its delayed effects were due to interference with the structure, function, and turnover of cell-surface components (30-33). More recently Dorr and Liddil reinvestigated the DNA-binding property of acronycine.

791

using solutions obtained with a solvent which did not contain dimethylsulfoxide (34). Under such conditions, acronycine was shown to display classic non-covalent binding patterns on DNA thermal degradation. Those experiments strongly suggest that acronycine should interact with DNA either by intercalation or by some other non-covalent process in order to stabilize the double helix against thermal denaturation. This hypothesis seems in good agreement with the approximately flat structure of 5-bromo1,2-dihydroacronycine previously established by X-ray diffraction (12). It is also consistent with recent experiments which gave evidence for the DNA binding activity of acronycine azine (4), a dimeric analogue of acronycine which exhibits increased cytotoxic activity (35).

2.

STRUCTURE ACTIVITY RELATIONSHIPS IN THE ACRONYCINE SERIES

Since the discovery of the broad experimental antitumor spectrum of acronycine in 1966, more than one hundred compounds derived from the 3,12-dihydro-7//-pyrano[2,3c]acridin-7-one basic skeleton have been synthesized or isolated from natural sources. Unfortunately, many of these compounds have not been studied from a biological point of view. Only a few have been tested in vitro for cytotoxic activity. Even fewer have been studied in vivo for antitumor properties. In addition, the experimental conditions and the cell lines used for the tests greatly vary from one compound to another. It nevertheless seems possible to draw some limited

792

conclusions in the field of structure-activity relationships in the acronycine series. 2.1 Modification at the A-ring Some acronycine derivatives substituted at 9, 10 or 11-position have been tested for cytotoxic and/or antitumor activity. 9-Hydroxyacronycine (5_) prepared by addition of acronycine to a metabolizing culture of Aspergillus alleaceus (36) or Cunninghamella echinulata (37) was devoid of antitumor activity when tested in mice implanted with X-5563 plasma cell myeloma or C-1498 myelogenous leukemia (36). In a similar way, 9-chloroacronycine (6.) synthesized by Fryer et al. (38) exhibited no significant antitumor activity when tested in mice bearing the solid form of sarcoma 180 or injected with Ehrlich ascites.

11-Methoxyacronycine (7J was first obtained by total synthesis (39) and was later isolated from various Citrus species (40, 41). It was tested for human promyelocytic leukemic cell line HL-60 growth inhibition. Under such conditions, it was shown to be significantly active (IC50 = 17.2 p-M), as was 10,11-dimethoxyacronycine (8.) (IC50 = 15.5 |iM), when compared with acronycine (IC50 = 26.2 |iM) (42, 43). In contrast, it should be noted here that 11-azaacronycine ( = 6-methoxy-3,3,12-trimethyl-3,12-dihydrochromeno[5,6b][l,8]naphtyridin-7-one) () synthesized by Reisch et al (44, 45) was found inactive when tested against P388 leukemia transplanted in mice.

793

OCH.

R=H R = OCH3

2.2 Modifications at the B-ring Informations available on the role of the substituent on the nitrogen atom at 12-position are very limited. In fact, A^-desmethylacronycine (10) was the only compound modified at that position to be studied from a biological point of view. The inhibitory effect of 1 ^ against HL-60 cell growth in vitro (IC50 = 17.6 |i.M) (42, 43) was of the same order of magnitude as that reported for acronycine itself.

M
2.3 Modifications at the C-ring The substituent at C-6 on the C-ring has a dramatic influence on the antitumor activity in the 3,12-dihydro-7//-pyrano[2,3c]acridin-7-one series. Noracronycine (11). bearing a phenolic OH group instead of a methoxy group at C-6, was shown not to possess any antitumor activity (27, 28). It is also devoid of significant activity against HL-60 cell growth in vitro (42, 43). A series of 6-alkoxy analogues of acronycine 12-16. was obtained by Fryer et al. (38) upon treatment of noracronycine (11) with an appropriate alkyl sulfate or alkyl halide under basic conditions. Among the derivatives 1 2 - 1 6 . only 15_ exhibited significant antitumor activity causing a 52% reduction in tumor size in mice bearing the solid form of sarcoma 180 and a 60% prolongation of the lives of mice injected with Ehrlich ascites (38).

794 11 R = H 12 R = C2H5 1 2 R = CH2-CH=CH2 1 4 R = CH2-0-CH3 1 5 R = CH2-CH2-N(CH3)2 16 R = CH2-COOC2H5 Both active compounds l_ and H bear an alkoxy substituent at C-6, whereas inactive noracronycine (11) bears a free OH group at that position. The lack of antitumor activity of noracronycine should be therefore related either with the reduction of the steric hindrance at C-6, or with the dramatic change in the electronic density within the aromatic structure, due to chelation of OH-6 by the neighbouring carbonyl group. In order to determine which of those two parameters was the most important in terms of structure activity relationships, we considered the synthesis and biological evaluation of 6-demethoxyacronycine (17) as highly desirable. Coppola previously prepared that compound in 1984 (46) through reaction of iV-methylisatoic anhydride with the enolate derived from 2,6,7,8tetrahydro-2,2-dimethyl-5//-l-benzopyran-5-one, but no biological data was published at that time. Our synthetic approach (Scheme 1) (47) was completely different and potentially more versatile. Alkylation of 3-nitrophenol (18) with 3-chloro-3-methylbut-l-yne (19) gave the propargylic ether 20.. The nitro group of 20. was selectively reduced by iron powder to yield 3-(3-aminophenoxy)-3-methyl-but-l-yne (21). Claisen rearrangement of 2 1 was highly regioselective and provieded the required 5-amino-2,2-dimethylchromene (22) in 60% yield. Ullmann condensation of 22. with 2-bromobenzoic acid (23) gave the carboxylic diphenylamine 24. in 75% yield. The last steps of the synthesis were essentially similar to those described by Loughhead for the synthesis of acronycine itself (18). Cyclization of 24 using trifluoroacetic anhydride gave rise to 6-demethoxy-12-demethylacronycine (25) in 85% yield. Finally methylation of 2J_ with methyl iodide under phase-transfer catalyzed conditions afforded H in 83% yield.

795

r^^=^

r ^ ^ ^

12

H,N

.COOH

The cytotoxic activity of 6-demethoxyacronycine (17) was determined in vitro in comparison with acronycine, against wild type (DC-3F) and actinomycine D-resistant (DC-3F/ADX) Chinese hamster fibroblastic lung cell lines and against murine L1210 leukemia cells (47, 48). 6-Demethoxy acronycine (12.) was found to have a potency within the same order of magnitude as acronycine itself against the different cell lines (Table 1). Table 1
Cell lines DC-3F DC-3F/ADX L1210 Acronycine 1 IC50= 11-25 |iM IC50 = 3.5^M IC50 = 27^M 6-Demethoxyacronycine 17 IC50 = 8.75 ^iM IC50 = 2.75 ^iM IC50 = 29.9 ^M

796 In contrast with noracronycine, some of its derivatives substituted on the A ring by hydroxy or methoxy groups at 10 and/or 11-position, such as compounds 26-28. have been claimed to exhibit cytotoxicity against HL-60 cells in vitro (42, 43). O OH

26 Ri=R3 = H 2 7 Ri=H

R2 = 0H R3 = CH3

R2 = 0H

2 8 Ri = OH R2 = OCH3 R3 = CH3 9-Nitronoracronycine ( 2 9 ) . 10-nitronoracronycine (30) and 11nitronoracronycine (31) were synthesized by Reisch et al. (49, 50) and tested by the N.C.I, against P388 leukemia transplanted in mice. At lower doses, no significant antitumor activity could be detected whereas higher doses proved to be toxic.

1 9 Ri = N02 ^ R2 = N02 3 1 R3 = N02

R2 = R3 = H Ri=R3=H Ri=R2 = H

2.4 Modifications at the D-ring The two geminal methyl groups at C-3 appear as an important structural requirement for antitumor activity in the series. Indeed, 3hydroxymethylacronycine (32.), obtained by addition of acronycine to a metabolizing culture of Streptomyces spectabilicus, was devoid of antitumor activity when tested in mice implanted with X-5563 plasma cell myeloma or C-1498 myelogenous leukemia (36). More recently, Reisch et al. prepared

797

acronycine analogs 33-35 by total synthesis (51). Compounds 33-35 were tested in vitro on sixty human tumor cell lines of various types of cancer by the N.C.I. (52). Except 3 3 , all substances were determined inactive. Compound 3_3. was also inactive against most of the sixty cell lines, but showed weak cytostatic activity against the renal cancer UO-31 cell line (51).

OCH.

Only little chemical and biological investigations have been conducted on acronycine derivatives modified at the 1 and/or 2 positions on the pyran ring. From a chemical point of view, previously described compounds modified at those positions only include bromo (7), nitro (8, 27), dihydro (36) (7, 27), and dihydronitro (8, 27) derivatives. The 1,2-double bond has been so far generally considered as an essential structural requirement to observe antitumor activity, since 1,2dihydroacronycine (36) and dihydronitroacronycine were determined inactive in the course of early in vivo experiments performed at the Eli-Lilly Laboratories (27). Effect of substitution on the 1,2-double bond remains unclear. Nitration of acronycine using nitric acid leads to a mononitroacronycine, whose structure was reported as 1-nitroacronycine by Drummond and Lahey (8) and as 2-nitroacronycine by Svoboda (27). This compound was described as biologically inactive by Svoboda (27). It has been more recently evaluated by Cordell et al. (35) who found that nitroacronycine demonstrated a greater

798

activity than acronycine itself against a battery of cultured mammalian tumor cells and selected it as a promising agent in that series (35). In summary, only a few compounds modified at positions 1 and 2 have been prepared and studied from a biological point of view. This is the reason why we have been interested in the preparation of such compounds, in order to determine unambiguous structure activity relationships and to be able to prepare novel active acronycine derivatives. OCHa

3. NATURAL AND SYNTHETIC ACRONYCINE DERIVATIVES MODIFIED AT THE PYRAN RING 3.1 Nitro. amino and amido derivatives The nitro and dihydronitro derivatives of acronycine appeared to us of particular interest, since water soluble amino and amido compounds should be easily obtainable from them. Treatment of acronycine (1) with fuming nitric acid in acetic acid at 0C gave mononitroacronycine in 90 % yield, as previously described (8, 27). Observation of a strong cross-peak between the singlet of the pyran proton and the signal of the N-CH3 group at the 12-position in the 2D NOESY iH NMR spectrum permitted us to unambiguously establish the structure of this compound as 2-nitroacronycine ( 3 7 ) . Similarly, nitration of 6demethoxyacronycine (17) afforded 2-nitro-6-demethoxyacronycine (38) in 50 % yield (53).

799

NOo 1 12 R = OCH3 R=H 2 7 R = OCH3 2S R = H

Reduction of 37. using sodium borohydride afforded the known 2-nitro1,2-dihydroacronycine (39). which could be reduced into 2-amino-l,2dihydroacronycine ( 4 0 ) by hydrogenation using Pd/C as a catalyst. Alternatively, 40L was obtained more easily from 3JL by direct reduction using sodium borohydride in the presence of cupric acetate. This latter reaction also afforded small amounts of 2-oxo-l,2-dihydroacronycine oxime (41) which was more conveniently prepared in high yield by reduction of 2nitro acronycine (37.) with tin and hydrochloric acid in methanol (53). OCH

H2/Pd-C/MeOH

800

2-Amino-l,2-dihydroacronycine (40) could be easily converted into variously substituted amines and amides. Treatment of 4 0 with formaldehyde and sodium borohydride afforded 2-dimethylamino-l,2dihydroacronycine (42.). Both aliphatic and aromatic amides were obtained from 40_ upon treatment with acid anhydrides in pyridine. This latter reaction is exemplified by the preparation of 2-acetylamino-l,2dihydroacronycine (43) and 2-benzoylamino-l,2-dihydroacronycine (44) using acetic anhydride and benzoic anhydride, respectively (53). OCHa

4 2 R = N(CH3)2 4 3 R = NHC0CH3 4 4 R = NHCOC6H5 Compounds 3 7 - 4 4 were tested for inhibition of L-1210 cell proliferation in vitro, in comparison with acronycine (1_) and 6demethoxyacronycine ( 1 7 ) . The results are summarized in Table 2. Considering the structure-activity relationships, it appears that only compounds bearing both a methoxy substituent at the 6-position and a 1,2double bond, such as 3 7 and 4 1 (as its tautomeric 2hydroxylaminoacronycine form) (54) exhibit a significantly more potent activity than acronycine itself.

Table 2 - Inhibition of L-1210 cell proliferation by compounds 37-44 in comparison with acronycine (1) and 6-demethoxyacronycine (17)
Compound M IC50 M

1
27

11
29.9

12
0.09

il
13.7

1^
32.7

4J1 11
12.5 2.8

41 11
>50 >50

A
47.9

The very high cytotoxicity of 2-nitroacronycine (37) in vitro and the discrepancies in the litterature data as to its biological activity (27, 35)

801

prompted us to re-evaluate this compound in in vivo experimental tumor models, in comparison with acronycine (JJ. As shown on Table 3, 2nitroacronycine (37) was devoid of antitumor activity against P 388 leukemia and C 38 colon adenocarcinoma in mice, unlike acronycine (IJ which is moderately active against P 388 leukemia, but markedly active against C 38 colon cells (53). Table 3 - Antitumor activities of 2-nitroacronycine (37) in comparison with acronycine (1) against P 388 leukemia and C 38 colon carcinoma in mice.

1
P388 T/C % C38 T/C % 125 (200mg/kg) 4 (200mg/kg)

17
113 (50mg/kg) 137 (25mg/kg)

3.2. Hydroxydihydro derivatives and glycosides The alcohols resulting from the addition of water to the double bond of the pyran ring of acronycine, 1-hydroxy-1,2-dihydroacronycine (45) and 2hydroxy-l,2-dihydroacronycine (46J were prepared in our laboratory (55). Our final aim was to combine those alcohols with various sugar units, since numerous anticancer agents possess a 0-glycosidic moiety which strongly influence both their bioavailability and their selective toxicity towards tumor cells.

4 5 Ri = OH R2 = H 46 R i = H R2 = 0H

The benzylic alcohol 45. was prepared in two steps, using acronycine (JD as starting material. Treatment with N-bromosuccinimide in aqueous

802

tetrahydrofuran led to racemic r r f l n 5 - 2 - b r o m o - 1 - h y d r o x y - 1 , 2 - d i h y d r o acronycine (47). In a second step, the bromohydrin 47_ was smoothly debrominated to 45_ using tributyltin hydride (55). OCH. O PCH3

4 7 (relative configuration) OCH^ Bu^SnH/AIBN Toluene/Rx

45
Unfortunately, 1-hydroxy-1,2-dihydroacronycine (45.) proved rapidly to be very unstable in organic solutions, and all our attemps towards its glycosidation have remained unsuccessful (56). A good precursor of 2-hydroxy-1,2-dihydroacronycine (46) was cis1,2-dihydroxy-1,2-dihydroacronycine (48), which was first prepared as a racemate by osmium tetroxide oxidation of acronycine (57). This reaction was difficult to apply for a large scale preparation of 48., due to the cost and toxicity of osmium tetroxide and to the difficulties encountered during the work-up under such conditions. Catalytic osmium tetroxide oxidation of 1, using iV-methylmorpholine-N-oxide to regenerate the oxidizing agent proved recently more convenient for the preparation of 48. (58). A first reaction sequence involving sulfuric acid dehydration of the diol 8_ to the homobenzylic ketone 49., followed by borohydride reduction of 49^ to 46. was successfully accomplished but the overall yield remained very low (55). From a quantitative point of view, better results were obtained when converting 48. into the corresponding cyclic thiocarbonate 50. by use of N,N'-

803

thiocarbonyldiimidazole. Benzylic reduction of 5j0 with tributyltin hydride smoothly afforded 46. in a second step (55). O OCH. OsO. O OCH.

(relative configuration) H2SO4/H2O

OH

N^'-thiocarbonyl diimidazole JButanone O OCH3

OCH.

(relative configuration) O Bu3SnH/AIBNCH3^ Toluene/20C>

ill

MeOH

OH In contrast with 45., the homobenzylic alcohol 46. was stable enough to give satisfactory glycosidation reactions (56). Condensation of 46. with 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide under Konigs-Knorr conditions only led to the diasteroisomeric

804

orthoesters 51a. 51b which could not be separated. In contrast, the use of 3,4-di-O -acetyl-2,6-dideoxy-a-L-araZ7/no-hexopyranosyl bromide as glycosylating reagent under the same conditions afforded the expected a-Lglycosides 52a. 5 2 b . together with trace amounts of the corresponding p anomers (56).

AcO 51a 2R 51b 2S When 46. was treated with l,3,4-tri-0-acetyl-2,6-dideoxy-a-L-araZ7/n^hexopyranose in the presence of tin tetrachloride in acetonitrile, the reaction was stereoselective, and only the a-L-glycosides 52a. 52b. were obtained (56). In a similar way, bromoglycosides 53a. 53b (59), chloroglycosides 54a. 5 4 b (59), and azidoglycosides 5 5a. 5 5 b (56) and 56a. 5 6 b (56) were prepared using 1,4-di-O-acetyl-3-bromo-2,3,6-trideoxy-L-araZ7/6>-hexopyranose, l,4-di-0-acetyl-3-chloro-2,3,6-trideoxy-L-ar<3Z7/6>-hexopyranose, l,4-di-0-acetyl-3-azido-2,3,6-trideoxy-L-araZ7/n6>-hexopyranose, and 1,4-diO -acetyl-3-azido-2,3,6-trideoxy-L-/>'X6>-hexopyranose, respectively, as glycosylating reagents. Catalytic hydrogenation of the azidoglycosides 56a. 56b afforded the corresponding aminoglycosides 57a. 57b. whereas catalytic hydrogenation of 55a. 5 5 b followed by deacetylation gave the fully deprotected aminoglycosides 58a. 58b. The diastereoisomeric glycosides (2R and 25) could be separated by column chromatography in the cases of 52a. 52b. 53a. 53b. 54a. 54b and 58a. 58b (56, 59). The absolute configuration at C-2 on the aglycone part of each individual glycoside was deduced from ^H and l ^ c NMR data, compared with those of related angular hydroxydihydropyranocoumarin glycosides of known configuration (60).

805

Finally, reaction of 46. with di-0-acetyl-L-rhamnal in the presence of A^iodosuccinimide, furnished the two diastereoisomeric iodoglycosides 59a. 59b which were easily separated by column chromatography and whose configurations were determined as previously (56). OCH.

AcO ^

52a IR 51b 25
AcO ]

l a 2/?
^

b 2S

AcO

AcO

51a IR

O^ , S l a 27^ AcO I NHo

R=

K"

5 i b 25

Sib 25

Br AcO R= Q S l a IR S i b 25

-p
HO

^ Q

i8.a 2R SS.b 25

NHo ^ IR 2.b 25

AcO

_Q ^

^a

AcO IR

5.b 25

2-Hydroxy-l,2-dihydroacronycine glycosides were tested for inhibition of L-1210 cell proliferation in vitro in comparison with acronycine (1_). The results are summarized in Table 4. Compounds 53a. 53b. 54a.b and 59a.b including a halogenated sugar moiety displayed cytotoxic activities of the same order of magnitude as acronycine itself. Azidoglycosides 55a.b and 56a.b were significantly more

806

potent than acronycine in inhibiting cell proliferation. More hydrophilic aminoglycosides 57a.b and 58a.b only exhibited marginal activity. The cytotoxic activity of 2-hydroxy-l,2-dihydroacronycine glycosides therefore appears to be related with the lipophilicity of the sugar unit (56). Table 4 - Inhibition of L 1210 cell proliferation by 2-hydroxy-l,2dihydroacronycine glycosides in comparison with acronycine (56). IC50 ^M 24.1 20.8 82.5 11.3 19.8 13.4 3.0 2.8 77.2 40.7 5.6

Sia i2.b ila ii.b

4.a,b 55a.b 56a.b

il.a,b
58a.b

a,b

3.3. Dihydroxydihydro derivatives and esters In the course of a systematic study of the alkaloid contents of Rutaceae species belonging to the genus Sarcomelicope (57, 61-71), we isolated several new acronycine derivatives modified at the pyran ring. Indeed, cisl,2-dihydroxy-l,2-dihydroacronycine (48) and r r a n ^ - l , 2 - d i h y d r o x y - l , 2 dihydroacronycine (60) were obtained as optically active compounds from the bark of Sarcomelicope glauca Hartley (57) and Sarcomelicope dogniensis Hartley (69).

OH

807

Acronycine epoxide 6X was isolated in minute amounts from Sarcomelicope agyrophylla Guill. and from Sarcomelicope simplicifolia (Endl.) Hartley ssp. neo-scotica (P.S. Green) Hartley (68). This compound should be considered as a biogenetic intermediate between acronycine itself and the cis and fran^'-dihydrodiols 48. and 60. in Sarcomelicope species. It is a highly unstable compound whose reactivity most probably explains the difficulties encountered by us (72) and by others (73, 74) in attempts towards its synthesis. Reisch et al. finally succeeded in synthesizing 6JL in 14 % yield by treatment of acronycine with dimethyldioxirane in the presence of potassium carbonate (75).

The high reactivity of acronycine epoxide (61) led us to speculate that this compound should be the active metabolite of acronycine in vivo and that it should be responsible for the alkylation of nucleophilic targets within the tumor cell (68). This hypothesis was in good agreement with the mode of action previously established (76) for the insecticidal chromenes precocenes I (62.) and II (63), whose structures share a dimethylbenzopyran unit in common with acronycine (1).

R=H R = OCH3

The pyran double bond plays a crucial role in the insecticidal activity of precocenes, since the corresponding epoxides, formed in situ through cytochrome P 450 mediated oxidation, are the active metabolites of these compounds (76-78). These extremely reactive epoxides are responsible for the alkylation of nucleophiles present in biological matrices and ultimately

808 for irreversible damage and cell death (76, 79). From a chemical point of view, the alkylating p r o p e r t i e s of e p o x y p r e c o c e n e II ( 6 4 ) towards nucleophilic agents were unambiguously demonstrated by reaction with various thiols, leading to adducts with the sulfur atom linked to the benzylic position of the benzopyranyl skeleton (80). OCH H3CO H3CO

OH

M
The great chemical instability of acronycine epoxide, for instance its fast reaction with water to yield the corresponding diols (72), exclude its possible use as an anticancer agent. This is the reason why we synthesized a series of c i \ y - l , 2 - d i h y d r o x y - l , 2 - d i h y d r o a c r o n y c i n e l,2-dihydro-6-demethoxyacronycine esters, in and order c/\y-l,2-dihydroxyto obtain new

anticancer candidates with better stability than acronycine epoxide, but with similar reactivity towards nucleophilic agents (58). 4S 65 66 67 ^ 69 70 Ri = OCH3 Ri = H Ri = OCH3 Ri = H Ri = OCH3 Ri = OCH3 Ri = 0CH3 R2 = R3 = OH R2 = R3 = OH R2 = R3 = OCOCH3 R2 = R3 = OCOCH3 R2 =0H R3 = OCOCH3 R2 =0H R3 = OCOC6H5 R2= OCOCH3 R3= OCOC6H5

Racemic

cf5"-diols 48. and 65. were prepared as previously described by (17). one 2afforded

catalytic osmic oxidation of acronycine (V) and 6-demethoxyacronycine respectively. Treatment of those diols with excess acetic anhydride the corresponding of diesters was 6_6_ and 6 7 . used, respectively. at the When less equivalent anhydride monoesters only

hindered

position, such as acetate 68. and benzoate 6 ^ were obtained. Treatment of the monobenzoate 69. with excess acetic anhydride furnished the mixed ester 70..

809

Finally, reaction of the c/\s'-diols 48. and 65. with A^,A^'-carbonyldiimidazole 2-butanone led to the cyclic carbonates XL and 22. (58).

in

21 72

R = 0CH3 R=H

In order to ensure that the reactivity of c z \ s - l , 2 - d i h y d r o x y - l , 2 dihydroacronycine diesters towards nucleophilic agents was similar to that of acronycine and precocene epoxides, the diester 6 ^ was reacted with benzylmercaptan (73) in acidic medium. The cis and trans adducts 74 and 7.5 with the sulfur atom linked to the benzylic position of the pyranyl ring were obtained in almost quantitative yield under these conditions (58).
OCHcr

H3COCO OCOCH3

OCOCH3

810

Compounds 4 8 . 6 5 - 7 2 were tested for inhibition of L-1210 cell proliferation in vitro, in comparison with acronycine (V), dihydroacronycine (36) and 6-demethoxyacronycine (17). The results are summarized in Table 5. Table 5 - Inhibition of LI210 cell proliferation dihydroacronycine derivatives (58). by l,2-dihydroxy-l,2-

1
IC50 M ^ M 24.1

lA
34.4

LI
29.7

4^
80.6

6^
>50

M
5.8

6-2 6S. 6_9 2-fi 1 1 2-2

>50 8.9 7.1 5.0 0.32 >50

Compounds 66. 68 and 70. were slightly more potent (3-5 fold) than acronycine, while the most cytotoxic derivative, cyclic carbonate 7X, was 75 fold more potent than acronycine in inhibiting L 1210 cell proliferation. All these active compounds bear a methoxy group at position 6 and at least one ester group at C-2. The presence of the methoxy group markedly increased the cytotoxicity, as shown by 7 1 . which is one hundred fold more potent than 22. These preliminary results prompted us to test some 1,2-dihydroxy1,2-dihydroacronycine derivatives for antitumor activity in vivo. We used two standard experimental models, the i.p. P 388 leukemia and the s.c. colon 38 adeno-carcinoma. The results are summarized on Table 6, in terms of percent T/C (survival or tumor volume) obtained at the optimal dosage, i.e. the dose giving the best therapeutic effect without toxicity. Against P 388 leukemia, acronycine was moderately active while compounds 66., 69L, 70. and 7_L were markedly active, at doses 4 to 16 fold lower. Against the colon 38 adenocarcinoma, compounds 66., 6 and 70. were highly efficient. C/\s-l,2-diacetoxy-l,2-dihydroacronycine (66) was the most active, all treated mice being tumor-free on day 23. As previously reported (81), acronycine was also markedly active on this model, but less than 66., and at a 16 fold higher dose.

811

Table 6 - Antitumor activity of l,2-dihydroxy-l,2-dihydroacronycine derivatives in comparision with acronycine (58). P 388 leukemia Compound dose T/C % survival 200mg/kg ip 125 25mg/kg ip 289 25mg/kg iv 220 12.5mg/kg ip 258 50mg/kg ip 201 12.5mg/kg ip 202 Colon 38 adenocarcinoma dose T/C tumor volume

1 L6.

200mg/kg ip
4 12.5mg/kg 0 ip

LI lA II

6.25mg/kg ip 18 12.5mg/kg ip 13 6.25mg/kg ip

68

4.

CONCLUSION

Only little was known about the structure activity relationships in the acronycine series, as far as modifications at positions 1 and 2 were concerned. A rational study based on naturally occurring models has led for the first time in that series, to the synthesis of compounds more active in vivo than acronycine itself as antitumor drugs. Indeed, l,2-dihydroxy-l,2dihydroacronycine esters exhibit promising antitumor properties with a broadened spectrum of activity and an increased potency when compared with acronycine, on several tumor strains in vivo. C / 5 ' - l , 2 - d i a c e t o x y - l , 2 dihydroacronycine appears of particular interest in this respect, due to its high activity against P 388 leukemia and against the highly resistant solid tumor colon 38 adenocarcinoma.

ACKNOWLEDGEMENTS The authors wish to thank the many colleagues and students who have stimulated their interest in the acronycine series for the past few years, and

812

more particularly Pr. M. Koch and Drs G. Baudouin, M. Brum-Bousquet and A. Elomri (Universite Paris V, France), Prs. A.-L. Skaltsounis, S. Mitaku and E. Mikros (University of Athens, Greece), Drs J. Pusset and T. Sevenet (Mission CNRS in New-Caledonia), and Pr Gh. Atassi and Dr A. Pierre (Institut de Recherches Servier, Issy-les-Moulineaux, France).

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813

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

43 44 45 46

J.H. Adams, P.M. Brown, P. Gupta, M.S. Khan, and J.R. Lewis, Tetrahedron, 37 (1981) 209-217. J. Adams, P. Gupta and J.R. Lewis, Chem. Ind. (London), (1976) 109110. R.C. Anand and A.K. Sinha, Heterocycles, 31 (1990) 1733-1735. R.C. Anand and A.K. Sinha, J. Chem. Soc. Perkin Trans I, (1991) 23392342. S. Blechert, K.-E. Fichter, and E. Winterfeldt, Chem. Ber., H I (1978) 439-450. G.H. Svoboda, Lloydia, 29 (1966) 206-224. G.H. Svoboda, G.A. Poore, P.J. Simpson, and G.B. Boder, J. Pharm. Sci., 55 (1966) 758-768. J.H. Scarffe, A.R. Beaumont, and D. Crowther, Cancer Treat. Rep., 67 (1983) 93-94. P. Tan and N. Auersperg, Cancer Res., 33 (1973) 2320-2329. D. Kessel, Biochem. Pharmacol., 26 (1977) 1077-1081. B. Kennedy, Biochem. Soc. Trans., 7 (1979) 1002-1003. R.S. Low and N. Auersperg, Exp. Cell Res., 131 (1981) 15-24. R.T. Dorr and J.D. Liddil, J. Drug Dev., 1 (1988) 31-39. H.-L. Shieh, J.M. Pezzuto, and G.A. Cordell, Chem.-Biol. Interactions, 81 (1992) 35-55. D.R. Brannon, D.R. Horton, and G.H. Svoboda, J. Med. Chem., 17 (1974) 653-654. R.E. Betts, D.E. Walters, and J.P. Rosazza, J. Med. Chem., 17 (1974) 599602. J. Schneider, E.L. Evans, E. Grunberg, and R.I. Fryer, J. Med. Chem., 15 (1972) 266-270. J.H. Adams, P.J. Bruce, and J.R. Lewis, Lloydia, 39 (1976) 399-404. M. Ju-ichi, M. Inoue, K. Aoki, and H. Furukawa, Heterocycles, 24 (1986) 1595-1597. T.-S. Wu, Phytochemistry, 26 (1987) 871-872. T.-L. Su and K.A. Watanabe, in : Studies in Atta-ur-Rahman and F.Z. Basha (Eds), Studies in Natural Products Chemistry, Vol. 13, Elsevier, Amsterdam, 1993, pp. 347-382. T.-C. Chou, C.-C. Tzeng, T.-S. Wu, K.A. Watanabe, and T.-L. Su, Phytother. Res., 3 (1989) 237-242. J. Reisch, I. Mester, and S.M. El-Moghazy Aly, J. Chem. Soc. Perkin Trans I, (1983) 219-223. J. Reisch and S.M. El-Moghazy Aly, Arch. Pharm. (Weinheim), 319 (1986) 25-28. G.M. Coppola, J. Heterocyclic Chem., 21 (1984) 913-914.

814

47 48 49 50 51 52

53 54 55 56 57 58

59 60 61 62 63 64 65 66 67 68 69

A. Elomri, S. Michel, F. Tillequin, and M. Koch, Heterocycles, 34 (1992) 799-806. F. Tillequin, Actual. Chim. Ther., 23 (1996), in press. J. Reisch and W. Probst, Arch. Pharm. (Weinheim), 322 (1989) 31-34. J. Reisch and P. Dziemba, Arch. Pharm. (Weinheim), 324 (1991) 67-71. J. Reisch and A.A.W. Voerste, Sci. Pharm., 62 (1994) 255-260. A. Monks, D. Scudeiero, P. Skehan, R. Shoemaker, K. Paull, D. Vistica, C. Hose, J. Langley, P. Cronise, A. Vaigro-Wolff, M. Gray-Goodrich, H. Campbell, J. Mayo, and M. Boyd, J. Natl. Cancer Inst., 83 (1991) 757. A. Elomri, A.-L. Skaltsounis, S. Michel, F. Tillequin, M. Koch, Y. Rolland, A. Pierre, and Gh. Atassi, Chem. Pharm. Bull., 44 (1996) in press. H. Erlenmeyer and H. M. Weber, Helv. Chim. Acta, 21 (1938) 614-615. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, and M. Koch, Planta Med., 54 (1988) 24-27. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, M. Koch, Y. Rolland, A. Pierre, and Gh. Atassi, Pharm. Res., 13 (1996) 939-943. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, M. Koch, J. Pusset, and G. Chauviere, J. Nat. Prod., 49 (1986) 1091-1095. A. Elomri, S. Mitaku, S. Michel, A.-L. Skaltsounis, F. Tillequin, M. Koch, A. Pierre, N. Guilbaud, S. Leonce, L. Kraus-Berthier, Y. Rolland, and Gh. Atassi, J. Med. Chem., 39 (1996) in press. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, and M. Koch, Synthesis, (1992) 1068-1070. A.-L. Skaltsounis, S. Mitaku, G. Gaudel, F. Tillequin, and M. Koch, Heterocycles, 34 (1992) 121-128. M. Bert, M. Koch, and M. Plat, Phytochemistry, 13 (1974) 301-302. F. Tillequin, G. Baudouin, M. Koch, and T. Sevenet, J. Nat. Prod., 43 (1980) 498-502. B. Couge, F. Tillequin, M. Koch, and T. Sevenet, PI. Med. Phytother. 14 (1980) 208-212. G. Baudouin, F. Tillequin, M. Koch, M.E. Tran Huu Dau, J. Guilhem, J. Pusset, and G. Chauviere, J. Nat. Prod. 48 (1985) 260-265. M. Brum-Bousquet, F. Tillequin, M. Koch, and T. Sevenet, Planta Med., 51 (1985) 536-537. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, M. Koch, J. Pusset, and G. Chauviere, Heterocycles, 26 (1987) 2057-2063. S. Mitaku and J. Pusset, PI. Med. Phytother., 22 (1988) 83-87. M. Brum-Bousquet, S. Mitaku, A.-L. Skaltsounis, F. Tillequin, and M. Koch, Planta Med., 54 (1988) 470-471. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, M. Koch, and J. Pusset, Ann. Pharm. Fr. 47 (1989) 149-156.

815

70 71 72 73 74 75 76 77 78 79 80 81

A.-L. Skaltsounis, L. Sedrati, F. Tillequin, M. Koch, J. Pusset, and T. Sevenet, Nat. Prod. Lett., 5 (1995) 281-287. S. Mitaku, A.-L. Skaltsounis, F. Tillequin, M. Koch, J. Pusset, and T. Sevenet, Nat. Prod. Lett. 7 (1995) 219-225. M. Brum-Bousquet, S. Mitaku, A.-L. Skaltsounis, F. Tillequin, and M. Koch, unpublished results. J. Reisch and A. Wickramasinghe, Monatsh. Chem., 121 (1990) 709-712. J. Reisch and M. Top, Pharmazie, 46 (1991) 745. J. Reisch and K. Schiwek, Liebigs Ann. Chem., (1994) 317-318. W.S. Bowers, Amer. ZooL, 21 (1981) 737-742. G.E. Pratt, R.C. Jennings, A.F. Hamnet, and G.T. Brooks, Nature, 284 (1980) 320-323. D.M. Soderlund, A. Messeguer, and W.S. Bowers, J. Agric. Food Chem. 28 (1980) 724-731. W.S. Bowers, P.H. Evans, P.A. Marsella, D.M. Soderlund, and F. Bettarini, Science, 217 (1982) 647-648. A. Conchillo, F. Camps, and A. Messeguer, J. Org. Chem. 55 (1990) 17281735. R.T. Dorr, J.D. Liddil, D.D. Von Hoff, M. Soble, and C.K. Osborne, Cancer Res. 49 (1989) 340-344.

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

817

Chiral Synthons by Selective Redox Reactions Catalysed by Hitherto Unknown Enzymes Present in Resting Microbial Cells
Helmut Simon and Helmut Gunther Institut fur Organische Chemie iind Biochemie, Technische Universitat Miinchen D 85747 Garching, Germany Abstract: Resting cells of various strict anaerobic or anaerobically grown facultative microorganisms are useful biocatalysts for redox reactions in a preparative scale. This will be shown for Clostridia and Proteus species. Electron donors may be hydrogen gas, the cathode of an electrochemical cell, often formate, but in some cases also carbon monoxide. In addition to well-known reactions catalysed by yeasts, hitherto unknown reactions are also catalysed very effectively. These reactions are performed with substrate concentrations between 0.1-0.6 M. The productivity numbers are usually 10-500 times higher than with yeasts. For maximum productivity and long stability of up to 600 h under operational conditions, artificial electron mediators such as viologens or quinones and others in 1 mM concentration are essential. The stereo- and regioselectivity is excellent. In a few cases special conditions have to be observed which can be understood biochemically. The enzymes catalysing the reductions of many different 2-enoates, 2-enals, the oxo group of 2-oxo carboxylates, carboxylates without activation to aldehydes have been isolated and partially characterized. The enzymes are reversible and are not dependent on pyridine nucleotides. They are able to transfer single electrons. For dehydrogenations very different electron mediators can be used. For example anthraquinone-2,6-disulphonate is very effective. But useful NAD(P)H dependent enzymes are also present in Clostridia. Some of them contain high enzyme activities by which NAD^ or NADP^ can be reduced with the above mentioned electron donors and mediators to NAD(P)H. Because these enzymes are reversible, selective NAD(P)^ dependent dehydrogenations are also possible. By reduction many carboxylates carrying a chiral carbon atom in a-and/or in B-position, (R)hydroxy carboxylates especially those with additional functional groups and chiral alcohols have been prepared. 2-Oxo aldonates and aldarates and other 2-oxo carboxylates have been obtained by dehydrogenation. Preparative redox reactions under pyridine nucleotide regenerating conditions will be demonstrated with different substrates. Since all reaction sequences contain single electron transferring steps they can be carried out in electrochemical cells. Their over-all reaction rate can be continuously monitored by measuring the electrical current. The systems are very useful for the preparation of stereospecifically deuterated products.The optimal growth conditions of the commercially available microbial cells are indicated. 1. INTRODUCTION

Many stereo- and regioselective redox reactions have been carried out on a preparative scale by the catalysis of enzymes or microorganisms. The majority of these reactions involves the reduction of keto groups to chiral secondary alcohols or derivatives thereof Not only the reductions of CX-double bonds, but also selective dehydrogenations are of interest. A well-known example of a regioselective biocatalytic dehydrogenation is the formation of L-sorbose from D-sorbitol which is actually the key step in the synthesis of vitamin C. In the last two decades many new redox enzymes have been isolated, characterized and also applied for preparative work (1-4). The use of isolated enzymes for redox reactions requires the regeneration of reduced or oxidized coenzymes, e. g. the pyridine nucleotides NADH, NADPH, NAD^ or NADP^. This has been studied intensively

818

(Section 5-5.2). In most cases an additional enzyme has to be applied for this regeneration. If microbial cells are used for redox reactions instead of isolated enzymes, one can differentiate between growing or resting cells and crude cell extracts. In the latter case cells are broken for instance by freezing and thawing or by another procedure. For microbial transformations it may be an advantage to work with resting or broken cells instead of growing cells. Actually the cells do not have to be alive. The general aspects for using cells and the advantages or disadvantages of applying growing or resting cells are discussed in the literature (1,4-6). Applying microbial cells instead of isolated enzymes may have advantages (Section 1.1). The number of organisms available from the various collections of microorganisms exceeds the number of commercially available enzymes by far. For a preparative organic chemist it may be relatively easy to grow a suitable microorganism. In contrast, the isolation of an enzyme can be more troublesome especially if an isolation procedure for the necessary enzyme has not been published. Using whole cells often, but not always, solves the problem of coenzyme regeneration. A microbial transformation is different from a fermentation. For a more detailed discussion see references (1,3,4,6). 1.1 Some differences of the here described systems to those usually applied The microbial redox reactions described in this article are mostly conducted with strict or facultative anaerobic, prokaryotic cells. They have been grown in volumes of up to 300 litres and stored in the form of wet packed cells under an atmosphere of nitrogen in gas tight containers at about -15 C for weeks or even years. After thawing of the frozen cells a suitable part can be applied for redox reactions and the residual material can be frozen again. That means that resting cells or actually mostly crude cell extracts are used because the applied organisms break rather easily by freezing and thawing. Freeze dried cells can be stored for a long time at room temperature. All operations are conducted under an atmosphere of nitrogen. In special cases enzymes, coenzymes and/or the crude extract of another cell type can be added to these broken cells. By such measures the efficiency of the systems can be increased by 1-2 orders of magnitude. For examples see Section 5.2. The reactions described here show typical differences from the well-known reductions carried out by yeasts especially Baker's yeast. The efficiency of the conversion of substrates (educts) using microorganisms can be characterized by a productivity number PN (7,8): PN = amount of product (mmol) dry weight of catalyst [kg] x time [h]

Bioconversions with a high productivity number compared to a low one mean that less biocatalyst is necessary and/or a better volume-time yield can be reached. If, for example, 50 mmol of a product is to be synthesized in 24 h, approximately 100 g of catalyst is required, if its productivity number is 20 which may be the case if yeasts are

819 applied in a classical way. Only 2 g biocatalyst are needed if the productivity number of the applied microorganism is 1000. Moreover, it is much simpler to separate for instance 10 g of a product from 2 g of a microorganism than from 100 g. With high productivity numbers the reaction volume can also be often drastically reduced. In the presence of catalytic concentrations of artificial electron mediators (Section 1.2) the majority of the preparations described here show productivity numbers from 500 to 20 000 or more. Yeast (9) usually only shows productivity numbers in the range from 0.5-50. The main reason for the low productivity numbers of yeast can be seen from Scheme 1. In reductions catalysed by yeasts carbohydrates are normally used as reducing agents (source for electrons). NADH is formed as a catabolic intermediate. The reaction is accompanied with the formation of acetaldehyde most of which is reduced with NADH to ethanol. This unwanted reaction may consume as much as 95-99 % of the NADH, and the intended reduction of a CX-double bond takes place only to an extent of < 1-5 %. XH

carbohydrate

CH3CHO CU.CU.OU

SCHEME 1: Flow of reducing equivalents in Baker's yeast from carbohydrates to NAD^ forming NADH which is consumed in a competitive way. Often 100-1000 molecules of ethanol are formed for each molecule ofRR 'CHXH According to Reactions [l]-[3] we showed the possibility of stereospecific reduction with various yeasts which were supplied with electrons from continuously electrochemically reduced methylviologen (MV^*) instead of carbohydrates (10). The following reactions take place if a ketone such as hydroxyacetone is reduced. 2 MV^^ + 2e 2MV^* + H^ + NAD^ H"^ + NADH + CH3COCH2OH Sum: CH3COCH2OH + 2H* + 2e
cathode yeast

yeast ^

NADH + 2MV"" + CH3CHOHCH2OH CH3CHOHCH2OH

[1] [2] [3] [4]

As will be shown in Sections 5 and 6 methylviologen can be reduced at the cathode of an electrochemical cell to the mono cation radical MV^* which transfers electrons by the action of an enzyme type which we call AMAPOR for artificial mediator accepting pyridine nucleotide oxidoreductase. Finally the NADH is used for reducing the substrate by the catalytic action of an NADH dependent reductase. By this procedure (10) the productivity number of a yeast was about 60 times higher than by the classical procedure involving the application of a carbohydrate as an electron donor (11).

820

Yeasts, especially Baker's yeast can be bought at many places but it may cause a series of problems: Cells bought at different times or from different places may vary in their activity for various reductions. A well-known example is the reduction of ethyl 3oxobutyrate or other 3-oxo esters. It is often described in the literature together with very empirical measures to improve the enantiomeric excess of ethyl (5)-3-hydroxybutyrate (7). Baker's yeast may contain altogether 4 reductases which reduce 3-oxo esters. Two of them form the R- and two the iS-enantiomer (12). The enantiomeric excess of the product depends on the activity of the various enzymes under the reaction conditions, such as substrate concentration, pH value, temperature, storage conditions of the yeast before its application, etc. Since two of the enzymes are NADH and the other two are NADPH dependent (12) the ratio of the products also depends on the relative concentrations of both reduced pyridine nucleotides. The concentrations of NADH and NADPH again depend generally on the metabolic state of the yeast and on the enzyme activities forming them. In addition resting cells strongly differ in their capability to degrade pyridine nucleotides (13). According to our experiences the concentration of pyridine nucleotides is often too low especially if a reaction runs over 1-2 hours. See for example Table 29. These simple facts clearly show that it is a disadvantage if cells contain various enzymes catalysing the same reaction with different stereochemistry of the products. If the yeast strain, the growth and reaction conditions are not strictly defined, the results often cannot be reproduced. Therefore the procedures have to be described exactly. In this respect the existing literature is sloppy in many cases. In the following reductions are described with cells which do not show the briefly mentioned problems of yeasts applied in the classical way. All the strictly anaerobically grown cells of anaerobic or facultative organisms are able to accept hydrogen gas, many accept formate and some carbon monoxide as electron donors and contain redox enzymes in often high activities which take up the electrons and deliver them to viologens and other artificial mediators which transfer them further (Section 1.2). The standard redox potential E' of the electron delivering reactions H2 HCOO" CO + 2H^ ^ H^ 2H^ + + + 2e CO2 CO2 + + 2e 2e [5] [6] [7]

H2O

are -420, -420 and -560 mV, respectively. Therefore the equilibrium constants for the reduction of CO- or CC-double bonds are very favourable and there is no by-product formed which consumes electrons. The enzymes hydrogenase, the non-pyridine nucleotide dependent formate dehydrogenase and carbon monoxide dehydrogenase transfer electrons produced by Reactions [5]-[7] to viologens or other mediators (Reactions [5a]-[7a] and Scheme 2a). H2 + 2V^^ HCOO" + 2V^^ CO + H2O + 2V^^ 2H' + H^ + ^ 2H^ + 2V CO2 CO2 + + 2V^* 2V^* [5a] [6a] [7a]

821

The application of enzymes detected by us in recent years together with the above indicated electron donors in the presence of catalytic concentrations of artificial electron mediators will be described. Clostridium tyrobutyricum, C. kluyveri, C. formicoaceticum or C. thermoaceticum are strict anaerobes. Proteus species are facultative microorganisms since they are able to grow in the complete absence of oxygen as well as in its presence. The expression of some redox enzymes in facultative anaerobes is quite different depending on aerobic or anaerobic growth conditions of the cells. As an example the application of two anaerobically grown Proteus species will be given. The mentioned electron donors have the following advantages: (i) The equilibrium of the reductions of CC- or CO-double bonds with hydrogen gas, formate or carbon monoxide is far on the product side, (ii) In resting cells the electron donor can be used solely for the desired reaction since there is no other competing, unsaturated compound present. Side reactions, which can occur, for example with acetaldehyde (Scheme 1) or other products that are formed from carbohydrates, do not take place, (iii) The consumption of hydrogen gas can be monitored manometrically. Also the progress of a reduction with formate can roughly be estimated by the carbon dioxide formed. The reaction can also be carried out in electrochemical cells (Section 6). The microorganisms applied by our group are well defined and available from internationally known collections of microorganisms. All of them transfer electrons from hydrogen gas to the unsaturated substrates. Under anaerobic conditions in the presence of an antibiotic the reductions can be performed for periods of up to several hundred hours. However, most reactions can be carried out within 5-24 h. More than 99 % of the protons which are fixed to the substrate together with two electrons are derived from the water. Therefore the here described methods are effectively suitable for preparing compounds stereoselectively labelled with deuterium if ^H20 is used instead of ordinary water during a reaction. The applied microorganisms are freeze dried before suspending them in ^H20 (14,15). This will be shown in Section 2.5.3. Finally the redox enzymes in anaerobes seem to be less regulated, show less substrate or product inhibition than enzymes from yeasts, and often the enzymes possess a broad substrate specificity. Nevertheless the regio- and stereoselectivity is usually very strict. 1.2. Artificial electron mediators According to our experience the productivity numbers obtained with the aforementioned microorganisms can be enhanced by the use of catalytic concentrations (0.5-2 mM) of artificial electron mediators. Their properties and aspects of their use have been described in a review article (6). Table 1 lists some mediators with their redox potentials. The cells or crude cell extracts which will be described proceed by ways revealed by Schemes 2a and 2b, respectively. Electrons supplied by hydrogen gas, formate, carbon monoxide or the cathode of an electrochemical cell are channelled via an artificial electron mediator such as a reduced viologen (V^*) or others to the enzymes reducing

822 TABLE 1 Structure and standard potentials of some artificial mediators Structure Abbreviation Standard potential EO'^CmV) CH3N( ))(C )NCH, MV ^ v .Al-XLlll -443/-772 )

C''^J^

HN m i NH

Co-sep

a)

-440 -302

b) c)

-377/-686 ^) b) H2N(CH2)3-NQ)(0^(CH2)3-NH2 DAPV -331 c)

^'-^'Q)-Q^<^^
H2NOC-CH2-N( ) ) ( C )N-CH2-CONH2 O

^^
CAV

"

" )

-3027-632^

o
DCPIP CI a) b) c) d) e) Cobalt-sepulchrate Phosphate buffer, 0.1 M, pH 7.0 Tris/HCl buffer, 0.1 M, pH 7.0 Average of different values in the literature Standard potential of a second electron transfer +217

823

med^ electron donor or 2e

*ox

NAD(P)H^

^ ^

:x

E2
NAD(P) ^red med,red

XH

SCHEME 2a: Regeneration of reduced artificial mediators for reductions with nonpyridine nucleotide dependent or pyridine nucleotide dependent reductases. IfES is a pyridine nucleotide independent reductase accepting electrons from artificial mediators, only this enzyme is necessary, if the mediators are reduced electrochemically. If they are reduced enzymicly El has to be included. Reduced pyridine nucleotides are formed by E2. These artificial mediator accepting pyridine nucleotide oxidoreductases (AMAPOR) catalyse Reaction [8] and [8a] forming NAD(P)H. Further examples are given in the text. Artificial mediators are indicated by med". Y are natural mediators except pyridine nucleotides. They may assist the electron transfer, but they are not necessary.

Anode electron acceptor

SCHEME 2b: Regeneration of oxidized mediators for dehydrogenations with nonpyridine nucleotide dependent or pyridine nucleotide dependent dehydrogenases. If EI is a pyridine nucleotide independent dehydrogenase reducing medox to medred it can be reoxidized by an anode of an electrochemical cell or by an enzyme E3, which delivers the electrons to an acceptor such as dimethyl-sulphoxide or others. Pyridine nucleotide dependent enzymes El produce NADH or NADPH by the dehydrogenation of their substrates. The reduced pyridine nucleotides are reoxidized by the AMAPOR E2, which in turn reduces an artificial mediator medox to medred- Medred delivers electrons to E3 or an anode. For the reoxidation ofE3 see text.

824

CX-double bonds. If the reductase is pyridine nucleotide dependent, the electrons are used to regenerate NADH or NADPH by rather ubiquitous AMAPORs according to Reactions [8] and [8a]. NAD"" NADP^ medred + + r H^
4

NADH

medox medox

[8] [8a]

medred

NADPH +

2. REDUCTION OF THE CC-DOUBLE BOND OF a,B-UNSATURATED CARBOXYLATES, ALDEHYDES OR a,B-UNSATURATED METHYL KETONES. Cells of Clostridium tyrobutyricum (DSM 1460) from Deutsche Sammlung ffir Mikroorganismen (16) grown on (')-2-butenoate contain enoate reductase (EC 1.3.1.31). We detected this enzyme some time ago and characterized it partially in respect to its kinetics and reaction mechanism (17,18). Structurally it is a dodecamer of 73 kDa subunits containing an Fe/S cluster together with FAD and FMN (19-21). It reduces 2enoates, 2-enals and 3-enones according to Reactions [9] to [10] (Table 2). Reactions [9] and [9a] show that the enzyme accepts electrons from NADH or from reduced methylviologen (8,17,20). Whereas the reduction of enoates is not reversible, saturated aldehydes can be dehydrogenated by enoate reductase as shown by Reaction [12] (18). Additional reactions catalysed by this enzyme are also shown in Table 2. In earlier papers we termed this microorganism in which we found enoate reductase as Clostridium La 1. For details and for differences between this organism and C. kluyveri see (22,23). 2.1 Reduction of 2-enoates Table 2 reveals the multitude of catalysed reactions and Table 3 shows the surprising broad substrate specificity of enoate reductase from Clostridium tyrobutyricum DSM 1460. For a series of substrates Table 3 shows kinetic data (6,8,18,20,24). Only a few of these substrates can not be prepared in a sterical pure form with whole cells or crude extract from C. tyrobutyricum without additional measures. There are two aspects which have to be emphasized: Whole cells contain a 2-enoyl-CoA reductase (EC 1.3.1.8) besides enoate reductase (EC 1.3.1.31) (Scheme 3). After offering (')-2-butenoate, ()2-pentenoate or (')-2-methyl-2-butenoate to the cells a part of these enoates is converted to the CoA-esters which are reduced to the saturated acids. As shown by Scheme 3 the trans-diMiiion of the hydrogen occurs by this 2-enoyl-CoA reductase in the opposite way as that catalysed by enoate reductase. But there are only a few enoates which are activated by C. tyrobutyricum to the CoA-esters and then reduced. As the above mentioned cases show, they have to be rather similar to (')-2-butenoate. If C. tyrobutyricum is grown on glucose instead of crotonate it forms no enoate reductase but only 2-enoyl-CoA reductase. With cells of C. tyrobutyricum grown on crotonate the above mentioned substrates can be reduced in a stereochemically defined way when

825 TABLE 2 Reactions catalysed by enoate reductase. The stereochemical course of reactions [9a]-[10b] is the same as that indicated for reaction [9].
COO COO

+ NADH +

+ NAD^

[9]

'R^RC = C'RCOO"

^RCX = CHCOO^R^RC = C^RCHO ^R^RC = C^RCHO fs[AD^

+ 2MV'* + 2 ^ 4- NADH + H^

^R^RCH - CH^RCOO' + 2MV"" ^RCH = CHCOO" + NAD^ + HX + + + + + NAD^ 2Y' 2V^^ DCPIPred
H2O

[9a] [9b] [10a] [10b] [11] [12a] [12b]

+ NADH + H" 4=^ 'R'RCH - CH'RCHO + 2V^* + 2H^ ^=^ ^R^RCH - CH^RCHO + 2V^* + H^ ; NADH ^R^RC = C^RCHO 'R'RC = C'RCHO CHO

^R^RCH-CH^RCHO + DCPIPox ^R^RCH-CH^RCHO -f O2 CHO

[13]

the formation of the enoyl-CoA is inhibited. This can be achieved by the presence of arsenate and only low concentrations of phosphate. Section 2.5.3 gives an example of the preparation of sterical pure (2iS',3iS)[2,3-^H]-pentanoate. According to Scheme 3 it is possible to prepare sterical pure (iS)-2-methylbutyrate or (/^)-2-methylbutyrate from (E)-!methyl-2-butenoate, or the pure enantiomers of (2,3)-[2-^H]-butyrate or valerate. O 1 1 C-X O II C-X I

H-C^R H-C^R

X=0 ,H enoate reductase 2

CX

X=SCoA enoyl-CoA reductase

'R-C-H ^R-C-H

SCHEME 3: A few l-enoates (see text) are reduced by enoate reductase or after activation to a 2'enoyl-CoA-ester also by enoyl-CoA reductase. The stereochemical course of both reactions is different (25). In resting cells ofC. tyrobutyricum the reaction ofenoylCoA reductase can be blocked (Section 2,5,3).

826

TABLES Substrates of enoate reductase that are reduced according to the reactions shown in Table 2. All CC-double bonds in addition to the a,P position are E configured. The relative rate 100 % corresponds to 22 U*mg'^ of purified enoate reductase at pH 6.0 and 0.25 mM NADH. The K^ value for NADH is 0.012 mM and for reduced methylviologen 0.4 mM (8). With reduced methylviologen the F^ax values are about 2 times higher than with NADH. In two cases (No. 39 and 49) X is CHO instead of COO". The substrates 45 and 46 are a-enones. Other enoates which have been reduced by cells only but not by isolated enzyme are given in Table 4. Residues R correspond to those in Table 2.
No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
R'

R^ CH3 CH3 C2H5 CH3 (CH3)2CH CH3CH=CH COOCH3 COOCOOCH3 COOCH3 CeHs CeHs CftHs CeHs p-ClCeHt P-O2NC6H4 ;7-CH30C6H4 /7-(CH3)2NC6H4 o-HOCfiHi 0,W-(CH30)2C6H3 CfiHs CH3 H CH3 H CgHs CfiHf P-CIC6H4 H HOCH2CH2 HOCH2CH2 CH3 CH3 (CH3)2C=CHCH=CHCH2

R^ H H CH3 C2H5 H H H H H CH3 H H CH3 CH3 H H H H H H H H CH3 H CH3 H H H /j-ClCsHt H CH3 HOCH2CH2 CH3OCH2CH2 H

V ' max

Km

CH3 H H H H H H CH3 CH3 H H CH3 H CH3 H H H H H H NHCHO F CI Br I F Br CI CI CH3 H H H H

100 1.5 280 0.8 11 11 130 3 1 ' 0.15 9 26''-'^55 250 1.7 190 16 125 0.2 167 0.03 9 0.04 8 0.08 88 30 44 29 35 8 21 150 6.2"^ 180 5.2 150'' 28 180 21 30 0.10 76 0.50 20 0.10 0.03 120 10 10 9 15 5 14 T

827 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 H H H H H H (CH3)2C=CHCH=CH(CH2)3 CH3 (CH3)2C=CH(CH2)2(CH3)C=CH C6H5(CH2)9 (CH3)2C=CH(CH2)3 CH3(CH2)2C=CC6H5CH= CH3 (H3)2C=CH(CH2)3 19a 0.01

(CH2)I4 CH3 H C3H7-S-(CH2)5 CH3 CH3(CH2)6

H H H H H H H H

0.19 16'^'' 3.3 97 0.01 60^^ 0.06 163'-'' 1.4 17.5 0.26 20' 115 0.03 140 0.05
ga,hI
a.h

i.r

Cyclohex-2 enone 2-CH3-cyclohex-2-enone H CH3 H CH3 CH3 H H H H H H H H H CH3 Br CaHs (CH3)2C= CH3 5' '-CH3(CH2)6-2 '-C6H4N2-4-C6H4' HOC2H4 HOC2H4 C2H5 H p-nOCeYU CaHsCH^C C6ri5CH2CH=C (CH3)2C=CH CH3(HOCH2)C=CH C2H5CH=CH

H H H
CH3

83"f 0.04 1.1" 58f 0.09

'JQb.g

0.13

110 15
i

H H H H H H H H
CH3 (CH3)2C=CH(CH2)2

a a a a a

H
CeHs (CH3)2C=CH(CH2)2 CH3

63 H 64 H

0.5 0.014 0.1

Only the a,P-double bond is reduced. Reaction could not be performed under saturating conditions. ^ 90 % (E)' and 10 % (Z)-isomer. Marked substrate inhibition above 40 mM. ^ Marked substrate inhibition above 10 mM. X = CHO. ^ For increased substrate solubility the reaction solutions contained 7 % ethanol (v/v) for No. 8 and 10 % methanol (v/v) for No. 50. The complete substrates are shown. ^ Reduced in the presence of arsenate. ^ ()-2-methyl-3-[4-(5heptylpyrimidine-2-yl)-phenyl]-propenoate. Table 3 (No. 16) shows that (jE')-p-mtro-cimiamate or derivatives can be reduced by enoate reductase, too. However, this reaction can be performed only with isolated enoate reductase using NADH as electron donor. Reduced methylviologen spontaneously reacts with nitro groups. Aliphatic as well as aromatic nitro compounds are also reduced by ferredoxins present in Clostridia (26). We prepared many different saturated acids carrying a chiral centre at carbon atom 2 and/or 3 from 2-enoates. Many of these acids have been carefiiUy checked for their opti-

828

TABLE 4 Stereospecific hydrogenation of 2-enoates with whole cells of Clostridium tyrobutyricum on a preparative scale. Productivity numbers (PN) are given for 1 atm of hydrogen gas and 1 mM methylviologen. Cobalt sepulchrate (2mM) instead of methylviologen shows 85 % of these rates. Residues R correspond to those in Table 2. Productivity numbers may be higher for cells grown under optimised conditions (Section 2.4). No. R' 1 2 3 4 5 6 7 8 9 H H H H H H H H H R^ H H CH3 H CH3
C2H5 C3H7

K'
H CH3 H
p-CfiHiBr

PN
6100 3200 3100

10 H 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 H H H H H H CHj CH3 CH3 CH3 CH3 CH3 CH3

OCH3 OCH3

9^ or
H H CH3 CH3

^0 CH2

CH3 H H H H H H H H H CH3 H CH3 H CH3 H H H H

OC2H5

210 380
1900 1700 1900 2470 1900

380 1630 1000 3800

CeHs (C2H5)CftHs ;p-C6H40H p-CfiRiBr p-C6H2-(3,5-Br)-NH2

730
5700

570
2800

CeHs 5' '-(CH3(CH2)6)-2 '-C6H4N2-4-C6H4'' C2H5CH= ;?-ClC6H4 p-C6H4Br

400 560
180

1700 1400

CN Br Br
C2H5 C2H5 C2H5

H
CeHs

380
1700

Br
CeHj CH3CH= C6H5CH = CeHs (C2H5)=

Br

450 1500

^ Reduction equivalents were supplied by formate in the presence of Proteus vulgaris cells (Section 2.5.2). (^-2-methyl-3-[4-(5-heptylpyrimidine-2-yl)-phenyl]-propenoic acid.

829

cal purity. Such analyses have also been carried out in other laboratories which used the products. In all cases only one enantiomer could be detected (27-30). Regarding the enoates which can be readily reduced by cells of C tyrobutyricum or by the isolated enzyme the following rules have been observed: Residue ^R (Table 2) should not be too large; enoates in which ^R is a phenyl ring, NHCOCH3 or an OC2H5 residue are not accepted in place of NHCHO and OCH3, respectively. The halogens F, CI, Br and I are tolerated in the a-position, but are reductively eliminated in the 6-position. In this case the following reaction takes place: RCX=CHCOO+ 4[H] RCH2-CH2COO+ HX [14]

For a discussion of this mechanism see (20,24). The choice of ^R (Table 2) is subject to the least number of restrictions. It can be extremely large, i. e. enoate No. 22 in Table 4 . From this substrate almost 100 g have been reduced in a strictly enantiomeric fashion. If ^R and ^R are interchanged (i. e. if the {)and (Z)-isomers of substrates of the type ^R^R=CXCOOH are used) different enantiomers or diastereomers are produced. Therefore, ElZ mixtures of substrates in which the 6-carbon becomes chiral by reduction cannot be employed if enantiomerically pure products are expected. As can be seen by comparison of substrates 12 and 13 or 30 and 32 in Table 3, branching in the 6-position diminishes the rates without much influence on the A ^ m value. In the case of mono-methyl esters of 2- or 3-methylfumarate, substrate 9 and 10, the Fmax is diminished, too, if the methyl group stands in the 6- instead of the aposition. In this case the ^m value for the 6-branched substrate increases about tenfold. A negative charge in y-position increases the K^a and decreases Fmax drastically as can be seen by the comparison of substrates 8 and 9 (Table 3). If a long chain in a 2-enoate is m a x decreases. rigid due to additional double bonds, the K^^ value increases and that of K This can be seen by comparing substrates 37 and 38. Double and triple bonds in conjugation to the double bond in 2-position do not render an enoate a non-substrate (substrates 37 and 40.) The double bond can also be part of a ring as is shown by the fact that cyclohexene-1-carboxylate 41 is a suitable substrate. From a practical point of view very selective reactions are possible. As aheady mentioned the CC-double bond of/>-nitro-cinnaniic acid can be reduced with enoate reductase and NADH without attacking the nitro group. The following formally a,P-unsaturated acids are not substrates of enoate reductase: benzoic, orotic, nicotinic, and shikimic acid. Aliphatic acylates show no measurable inhibition, if they are present at concentrations of 100-fold the K^ values of the corresponding enoates. Measurable inhibitions can be observed with phenyl group-containing acylates. 3-Phenylpropionate in concentrations of 38 mM shows about 86 % inhibition. Fumarate, which is only a poor substrate, inhibits the reduction of enoates by NADH as well as by reduced methylviologen (Reactions [9] and [9a]). However, the reduction of NAD^ by reduced methylviologen (Reaction [11]) is not inhibited by fumarate. Interestingly, inhibitors such as morin or dicoumarol, which probably bind to the flavin domain of enoate reductase, do not impair the reduction of enoates by reduced methylviologen, but all reductions with NADH are inhibited.

830

Reaction [9] is inhibited by 0.4 mM morin or dicoumarol to 80 and 60%, respectively. The same concentration of dicoumarol inhibits Reaction [9a] by less than 5 % (17). These facts and other results (20) are indicative of three binding domains of enoate reductase: one for NADH which can be blocked by dicoumarol or morin, another for enoates which can be occupied by fumarate, and a third one for reduced methylviologen. For studies on the iron/sulphur centres see (21). Enoate reductase exclusively splits off the (4iS)-hydrogen atom from NADH. There is no direct hydrogen transfer from NADH to the products. If (45)-[^H]-labelled NADH with a total tritium activity of 4.67*10^ decays per minute was dehydrogenated with an excess of enoate, the isolated product showed a tritium content of less than 0.005 % of that of the NADH. Almost all the tritium was in the water. In the absence of an enoate as acceptor, the tritium exchange from (45)-[4-^H]-NADH catalysed by enoate reductase is very slow. Depending on the substrate concentration, the isotope effect of the reduction of (')-2-methyl-2-butenoate with (45)-[4-^H]-NADH varies from 6.8 to 1.3. The presence of NAD^ decreases the isotope effect (17). From a mechanistic point of view, the behaviour of the P-halogenated enoates is of interest (24). (Z)-3-Chloro-cinnamate and (Z)-3-chloro-butenoate as well as (Z)-3-bromocinnamate consume in the presence of enoate reductase 2 mol NADH per mol instead of 1 mol as other enoates do. The products are the saturated halogen-free carboxylates (Reaction [14]). Most of the substrates shown in Table 3 have also been hydrogenated with resting cells of C. tyrobutyricum. Further examples are shown in Table 4 with productivity numbers between 180 to 6100. Two consecutive reactions are taking place. The first is the reduction of MV^^ by hydrogen gas or an other electron donor (Scheme 2a) and the second is Reaction [9a]. By observing the colour of the suspension at the beginning of the hydrogenation one can judge which reaction is rate limiting. If the suspension is not or hardly coloured Reaction [9a] is faster than the reduction of MV^^ by hydrogen gas catalysed by hydrogenase (Reaction [5a], Scheme 2a). When the reaction comes to its end the suspension shows the blue to violet colour of MV^*. The reason is the decrease of the substrate concentration leading to a decrease of the rate of Reaction [9a]. If the suspension is blue right from the beginning of the hydrogenation Reaction [9a] is slower than the reduction of the viologen. If neither hydrogen consumption takes places nor a blue colour appears the system was more or less inactivated by oxygen or due to another reason. The influence of H2-pressure is shown in Table 8. Table 5 reveals the products of substrates which have been deuterated in ^YiiO. In other cases deuterated enoates were reduced in H2O. The reductions in ^H20 lead to acylates with two chiral carbon atoms due to stereospecific deuteration of methylene groups. Most of these have been used in studies of biosynthetic pathways of natural products. For examples see (29,30). Reactions in ^H20 proceed usually slower than in H2O. The differences may be less than a factor 2 if optimal pH and p^H values are determined and applied. The p^H and pH value for optimal reaction rates are not the same (31).

831

2.2.1 Reduction of fumarates and derivatives with Clostridium formicoaceticum (32) (5)-2-Methyl-, (iS)-2-ethyl- and (iS)-2-chlorosuccmate were prepared in concentrations of 1 M or higher with Clostridium formicoaceticum grown on fiiictose and fiimarate (Section 5.3). The enantiomeric excess of the products was higher than for most of the homogeneous chemical catalyses (33,34). Some time ago we observed with Proteus vulgaris a higher productivity number for the reduction of 2-methylfumarate (1500 instead of 1080), but we tested no additional substrates (35). The stereoselective dideuteration of the substrates is possible by using freeze-dried C. formicoaceticum cells, which show for reductions nearly the same rate in ^H20 and H2O. Fructose and fructose/fumarate grown C formicoaceticum cells contain a dimethyl maleate and a dimethyl fumarate reductase. To our knowledge both enzymes have not been described in the literature so far. Besides the artificial mediators mentioned so far safi'anine T in 0.75 mM concentration shows about 80 % of the activity observed with 1 mM methylviologen or 1 mM anthraquinone-2,6-disulphonate for the reduction of 2-methylfumarate. The absence of a mediator decreases the reduction rate to 3-4 %. C formicoaceticum is also usefiil for stereoselective hydrations of fumarate and maleate derivatives (36). 2.2 Reduction of 2-enals and allyl alcohols As shown in Table 6 enoate reductase or Clostridia containing this enzyme (C tyrobutyricum or C kluyveri) catalyse the reduction of a,P-imsaturated aldehydes (enals) (Table 2 Reactions [10a] and [10b]). In contrast to saturated carboxylates, saturated aldehydes can be dehydrogenated to a,P-unsaturated aldehydes (enals) by enoate reductase in the presence of electron acceptors such as oxygen or dichlorophenol-indophenol, (Table 7, and Table 2 Reactions [12a] and [12b]), (18). In low concentrations the reduction of 2-enals proceeds with similar rates as those of 2enoates. At concentrations above 1-5 mM the rate decreases to about 30-50 %. There are other marked differences in the reactions with carboxylates and aldehydes, respectively. All enoates tested so far have been reduced with enantiomeric excess >96 %. No racemization could be observed with saturated carboxylates, even by very sensitive methods using tritium-labelled compounds. The difference between aldehydes and carboxylates can be understood, if one takes into account that the acidity of the a-protons of aldehydes is orders of magnitude higher than that of carboxylates. On the basis of the aforementioned halogen elimination from 3- halogeno-2-enoates by enoate reductase, we suggested an 1.4-addition mechanism for enoates, in which during the reduction the Pcarbon atom picks up a hydride ion followed by the stereospecific fixation of a proton in a-position (20, 24). If this is the case, one can assume that for the dehydrogenation or racemization of a saturated carboxylate or aldehyde, an a-proton has to be split off in the

832

TABLE 5 Various stereoselectively a-, a,P- or P-deuterated carboxylates prepared form deuterated substrates in H2O or by reduction of nonlabelled substrates in ^H20 buffer and freeze dried microorganisms. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Product (25',3i^)[2,3-^H,^H]- Propanoic acid (i^)[2,3-^H]-2-Methylpropanoic acid (2S,3^)[2,3-^H]- 3-Phenylpropanoic acid (2i?,3/?)[2,3-^H]- 2-Methyl-3-phenylpropanoic acid (25,3i?)[2,3-^H]-3-(3-Hydroxyphenyl)-propanoic acid (2S,3/?)[2,3-^H]-3-(4-Hydroxyphenyl)-propanoic acid (2R,3S)[2,3-^n]-2' Methyl butanoic acid (2S)[2,3-^H]-4-Phenylbut-3-enoic acid (2S,35)[2,3-^H]-Pentanoic acid (2i?)[2-^H, l-^^C]-4-Phenyl-(Z)-pent-3-enoicacid (25,3i^)[2,3-^H]-5-Methylhex-4-enoic acid (2/?,3S)[2,3-^H]-5-Methylhex-4-enoic acid (2S,3/^)[2,3-^H]-6 Hydroxy-5-methylhex-4-enoic acid (2S,3i^)[2,3-^H]-hept-4-enoic acid (25,35)[2-^H]-Oct-4-inoic acid (3^[3-^H]-Oct-4-inoic acid (27^)[2-^H]-Oct-4-inoic acid (2S,3i^)[2,3-^H]-Oct-4-inoic acid (35)[2-^H]-5,9-Dimethyldec-4,8-enoic acid (25',3i^)[2,3-^H]-5,9-Dimethyldec-4,8-enoic acid (2i^)[2-^H]-12-Phenyldodecanoic acid (2S,35)[2,3-^H]-12-Phenyldodecanoic acid (27?,3i^)[2,3-^H]-12-Phenyldodecanoic acid (3/^)[3-^H]-9-Thiadodecanoic acid (25',3S)[2,3-^H]-9-Thiadodecanoic acid (IS) [2-^H] -Succinic acid monomethyl ester {2S,3S)[2-^UM', 3-^H]-Succinic acid monomethyl ester (2/?,35)[2,3-^H]-2-Succinic acid" (25,3S)[2,3-^H]-2-Methylsuccinic acid" (25,3S)[2,3-^H]-2-Ethylsuccinic acid" (25,35)[2,3-^H]-2-Methylsuccinic acid dimethyl ester" Amount (mMol) 1 7 45 8.3 7.4 18 4.6 1 50 1.7 8.6 17 2 32 30 2 11.6 25 0.35 3.5 2.5 1.6 1.9 1.3 2.6 2.4 2.4 2.4 2.4

^ The compounds were reduced with C formicoaceticum.

833 first step. This is no problem with an aldehyde, but obviously it cannot be achieved with a carboxylate. Not as easily understood is the racemization of saturated aldehydes and the fact that both a-protons of 3-phenylpropanal are exchanged by enoate reductase. The reason may be an unspecific Schiffs base mechanism (18). Nevertheless enoate reductase can be used to prepare chiral alcohols from a,B-unsaturated aldehydes or alcohols (allyl alcohols) (37,38). TABLE 6 Reductions of unsaturated aldehydes and unsaturated alcohols with enoate reductase. All of the here mentioned products possess (i^)-configuration (18). No. Substrate 1 Ph 2^ Ph CHzCH C. kluyveri Ph 4' ^CHO ,,^=\ Ph ^CHO P h ^ 6' CHjCM Enoate reductase ^/=< andHLADff Ph ^ CHjOi Enoate reductase /*^\^ from C. kluyveri, Ph andHLADff NADH'^ Ethanol Ph NADH^ Ethanol Ph CH2OH 95 Enoate reductase andHLADH' Enoate reductase NADH Ethanol Ph MV^'/hexane H2 Ph NADH^ Ethanol Ph CH2OH 53 CHO Enoate reductase MV"^ ^CHO Biocatalyst C. kluyveri Other additives Electron donor H2 or Ethanol Cathode Product ^CHO \ ^CHO Ph"\ CH2OH 74 ee% 10-33" 21

p/

5"'^

^ More than 10 experiments. Values of enantiomeric excess depend on temperature, reaction time etc.. The ee values decrease with increase of temperature and reaction time. A total volume of 50 ml contained: 50 mM substrate, 1 mg (~ 12 U) enoate reductase. After 17 h at 18 C > 95 % product. ^ A total volume of 4 ml contained: 70 |Limol ethanol, 1.4 fimol NADH, 100 mg C. kluyveri or 1 U enoate reductase. After 22 h at 25 C > 95 % product. ^ The NADH contained about 5 % NAD, which is necessary for the dehydrogenation of the substrate to 2-methyl-3-phenyl-enal which is then reduced to the (i?)-2-methyl-3-phenyl-propanol. ^ Horse liver alcohol dehydrogenase, 2.5 U. After 22 h at 25 C > 95 % product.

834

Clostridium tyrobutyricum or C. kluyveri cells are able to reduce allyl alcohols according to Reaction [15]: RCH=CHCH20H + NAD(P)H RCH2-CH2CH2OH + NAD(P)H [15]

The following sequence of reactions was observed (38): RCH=CHCH20H -* RCH=CHCHO -RCH2CH2CHO -* RCH2CH2CH2OH [16]

The first step is catalysed by the pyridine nucleotide dependent alcohol dehydrogenase (NAD^-dependent in C kluyveri and NADP^-dependent in C. tyrobutyricum) leading to the 2-enal which in turn is reduced by enoate reductase to the saturated aldehyde (Reactions [10a] and [10b]). The saturated aldehyde is fiirther reduced to the alcohol. The rate of the reduction depends not only on the activity of the involved enzymes but also on the concentration and on the ratio of NAD(P)^/NAD(P)H. In the presence of MV^* which is formed by the reduction of MV^^ by the system H2/hydrogenase (Reaction [5a]), the ratio NAD(P)^/NAD(P)H is too small for the fast and complete dehydrogenation of an allyl alcohol since the first step of the reaction sequence [16], which needs NAD(P)^, is too slow. It turned out that ethanol is a better electron donor than hydrogen gas in this case. For the reduction of 50-70 mM (')-2-methyl-2-butenol to {R) -2-methyl1-butanol by C kluyveri the optimum concentration of ethanol was 1-2 M and the pH was kept at about 8. For C. tyrobutyricum the optimal conditions have not been determined yet. They should not be too different. 2.3 Dehydrogenation of aldehydes The rate of the dehydrogenation of saturated aldehydes (Table 7) depends to a great extent on the pH. It rises fi-om pH 6 to pH 9 and probably has not reached its maximum. However, at pH 10, enoate reductase is inactivated within a few minutes. The K^a values of saturated aliphatic aldehydes are rather high, i. e., about 66 mM for {R,S) 2-methylbutanal. That of aromatic aldehydes such as 3-phenylpropanal is 1.4 mM, which is about 15 times higher than that observed for the corresponding unsaturated aldehyde. It has not been determined yet, whether the step reducing enoate reductase by the saturated aldehyde or its reoxidation is rate limiting. Rather surprising is the relatively high stability of enoate reductase in the presence of oxygen for the dehydrogenation of aldehydes (1. exp. Table 7). In the presence of NADH, enoate reductase can be inactivated by oxygen within a minute. Even after 30 min, the dehydrogenation of 2-methyl-3-phenylpropanal with oxygen continues, and about 50 % of the activity for the reduction of an enoate is left, if oxygen is carefiiUy eliminatedfi*omthe system before the test (18). Reaction [13] in Table 2 is actually a consequence of the ability of enoate reductase to dehydrogenate saturated aldehydes with NAD^. Kinetic and analytical studies showed that the apparent isomerisation is actually a redox reaction needing traces of NADH besides enoate reductase. The 2-methenyl-aldehyde is reduced by NADH and the NAD^

835

formed dehydrogenates the intermediate saturated aldehyde to the a,P-unsatiirated 2methylaldehyde, which is probably thermodynamically more stable. TABLE? Dehydrogenations, racemizations, exchange of a-protons and rearrangements of aldehydes catalysed by enoate reductase. Depending on the rate of reaction different amounts of enzyme have been used. The racemizations have been studied at pH 7.0, the H/^H-exchange and the dehydrogenations at pH 8.0 (18). Substrate CHO Electron acceptor ^ m (mM) (mM) Relative rate (%)" Product CHO Ph ^ CHO Ph CHO (^ CHO (R) / < Ph ^ DCPIP * " (0.05) none ^

(R,s) ,<r
Ph Ph

Air
DCPIP * " (0.05)

3.6 1.4
66

1.5
12 9

^ CHO

(R.S) /

CHO
CHO (R,S) , ^ Ph ^ CHO ^ ^ H Ph ^H

3.6
-

2-3 3-4

CHO
Ph
CHO

none'

NADH (0.5)

0.4

CHO

^ Compared to reductions. T)ichlorophenol-indophenol. Reaction studied in ^H20 at p'^H 7.0.

2.4 Growth and harvest of Clostridium tyrobutyricum up to 300 litres In C tyrobutyricum (DSM 1460) the specific activities of hydrogenase and enoate reductase depend on the growth phase and the composition of the medium. During growth in batch cultures on 70 mM crotonate the specific activity of hydrogenase increased, and then dropped to about 10 % of its maximum value, whereas the activity of enoate reductase reached its maximum in cells of the stationary phase. Under certain conditions during growth the activity ratio hydrogenase/enoate reductase changed fi'om 120 to 1 (23). Depending on the growth conditions of the cells the rate limiting enzyme for the hydrogenation can be either the hydrogenase or the enoate reductase. The specific activities of ferredoxin-NAD oxidoreductase and butyryl-CoA dehydrogenase (enoyl-CoA reductase. Scheme 3) increased 3-4 fold during growth on crotonate

836

instead of glucose. Glucose as carbon source led to high hydrogenase and negligible enoate reductase activities. The latter could be induced by changing the carbon source of the medium from glucose to crotonate. A series of other carbon sources was tested. They can be divided into ones which result in high hydrogenase and rather low enoate reductase activities, and others which cause the reverse effect (23). When the Fe^^ concentration in crotonate medium was growth limiting, cells with relatively high hydrogenase activity, and very low enoate reductase activity were obtained in the stationary phase. At Fe^^ concentrations above 3*10"^ M enoate reductase increased, and hydrogenase activity reached its minimum. The ratio of activities changes by a factor of about 200. In a similar way the dependence of enzyme activities on the concentration of sulphate was studied (23). Growth of Clostridium tyrobutyricum DSM1460 on crotonate The following procedure is a reasonable compromise of enzyme activity and simplicity of growth: One litre of medium contains 70 mM sodium crotonate, 150 mg (NH4)2HP04, 100 mg K2HPO4, 33 mg MgCl2*6H20, 0.6 mg MgS04*7H20, 40 mg CaCl2*2H20, 0.4 mg MnS04*2H20, 0.4 mg FeS04*7H20, 50 mg NH4CI, 10 mg (NH4)6Mo7024*H20, 0.04 mg biotin, 0.8 mg p-aminobenzoic acid, 1 mg resazurin, and 8 ml of a 50 % K2CO3 solution. The resazurin is an indicator for oxygen. As long as the solution is not pink its oxygen content is rather low. Starting from 100 ml volumes, 2, 20 and up to 300 litres of C. tyrobutyricum cultures have been grown. The growth time is usually 15-20 h. The culture should stay for 4-5 h in the stationary phase. 2.5 Practical aspects and examples of enoate reductase application Wet packed cells of C. tyrobutyricum grown as described in Section 2.4 are used. They were grown in 200-300 1 and after centrifiigation stored in gas tight containers under an atmosphere of nitrogen at -15 C. If not mentioned otherwise the indicated weights are given for wet packed cells. The dry weight is about 20 % and the protein content of the wet packed cells is about 10 %. The sensitivity of the enzymes in the cells against oxygen can be diminished by adding to the cell suspension about 10 ^M hexacyanoferrate III which oxidizes enoate reductase and probably some other enzymes. This treatment is especially recommended if the cells are lyophilised for deuterations. The cells can be lyophilised without loss of hydrogenase and enoate reductase activity. Without this treatment usually 60-80 % of the enzyme activity can get lost during freeze drying, even if contact with oxygen is tried to omit. Freeze dried cells are used for reductions in ^H20. Cells of C tyrobutyricum can be immobilised and stored. In operation at 35 C the enzymes have a half-live of about 10 days. The catalyst can be reisolated and used again. The presence of an organic solvent such as decalin does not diminish the enzyme stability (39).

837

As shown in Table 8 the addition of 1 mM methylviologen and the increase of the pressure of hydrogen gas enhances the rate of the reduction of (')-2-methyl-2-butenoate. One mM methylviologen under 1 atmosphere of hydrogen gas causes an increase of the productivity number of about 110 %. Increasing the concentration of the dissolved hydrogen by increasing the pressure of hydrogen gas leads to a further enhancement of the enoate reduction rate by about 4.5. Often the hydrogenase reaction is limiting. As explained in Section 2.1 the reductions in
+

progress will be coloured by the violet MV only faintly or not at all. That means Reaction [5a] is rate limiting. Since the A ' m value for dissolved H2 of hydrogenase from C. tyrobutyricum is even higher than the solubility of hydrogen gas under atmospheric pressure in water the rates of hydrogenations can be increased by using higher hydrogen pressure. The regeneration of MV^* can also proceed in an electrochemical cell by Reaction [1]. For practical aspects see Section 6. If larger amounts of enoates are reduced the regeneration of MV^' can also be carried out by Reaction [6a]. However, this reaction is not catalysed by C tyrobutyricum. Therefore cells oi Proteus vulgaris, P. mirabilis or C thermoaceticum have to be added. As an example the reduction of 286 mmol (')-2methyl-3-[4-(5-heptylpyrimidine-2-yl)-phenyl]-propenoate will be described (Table 3 No. 50 and Table 4 No. 22). Depending on the substrate the productivity number for the reduction of many enoates with cells of C. tyrobutyricum is in the range of 400-1500. The optimal temperature is 35-37 C, the optimal pH is 6.0-6.2. Purified enoate reductase shows a pH maximum at 5.2 for reductions with methylviologen. At pH 4.5 and 6.2 the rate is two thirds of that at pH 5.2. However, at pH values of 5.0 or lower enoate reductase is labile. When resting cells are used together with hydrogen gas the pH optimum for two consecutive reactions has to be considered, i. e. Reaction [5a] followed by the reactions as indicated by Table 2. Stereospecific deuterations of 2-enoates (14,15,29,30,40) have to be carried out in ^H20 buffer with freeze dried cells (Table 5). Freeze drying under exclusion of oxygen leads to cells without loss of enzyme activity if again under anaerobic conditions 1 g wet packed cells is slowly stirred or shaken with 0.5 ml of a 10 JLIM solution of potassium hexacyanoferrate-III for 20 minutes at 35 C. Under these conditions enoate reductase and probably also hydrogenase are transferred into the oxidized state. It is also possible to reduce enoates which are only sparingly soluble in water. This was shown by reducing 286 mmol of ()-2-methyl-3-[4-(5-heptylpyrimidine-2-yl)-phenyl]propenoate in about 3 litre buffer. The A T m value estimated by extrapolation is about 130 ^M but its solubility only about 30 |iM. Since it is difficult to shake or stir a volume of 3 litres effectively in order to saturate it with hydrogen gas, Proteus vulgaris cells were used as a second microorganism possessing a viologen dependent formate dehydrogenase. This enzyme catalyses Reaction [6a]. Another possibility would have been to conduct the reaction in a stirred autoclave with increased pressure of hydrogen gas (Table 8).

838

Reductions of enoates with enoate reductase or with resting cells in an electrochemical cell allows to study the influence of various parameters from one single experiment (Section 6). TABLE 8 Dependence of the productivity number on the pressure of hydrogen gas for the reduction of (')-2-methyl-2-butenoate by Clostridium tyrobutyricum with and without methylviologen. Pressure (atm) normal 80 normal 20 40 80 Methylviologen _ + + + + Productivity number (mmoUkg'^h'^) 730 1250 1540 4300 6630 7080

The stirred mixture contained in 30 ml 0.1 Mpotassium phosphate buffer, pH 7,0, 0.2 g wet packed cells of C. tyrobutyricum, 0.5 M (E)-2-methyl-2-butenoate and, if indicated above, 1 mM methylviologen. At pH 6.0 the productivity numbers should generally be higher. 2.5.1 Hydrogenations in a scale from 0.1 to about 20 mmol For planning a hydrogenation experiment in a larger scale it is useful to know roughly the productivity number which can be expected. To get an idea for a hitherto not applied substrate one can do an experiment in a scale of 50-100 jxmol. Warburg vessels combined with mercury filled manometers which can be shaken in a thermostated water bath are very useftil for such a hydrogenation. The volume for the hydrogen gas should be about 4-6 times that of the volume of hydrogen gas which will be consumed by a quantitative reduction. The amount of wet packed cells applied for a hydrogenation depends on the time in which the reduction shall proceed. It is no problem to run an experiment for 50-100 h. All experiments lasting longer than 8 hours should be carried out in the presence of an antibiotic, which does not contain reducible functional groups. Tetracycline in a concentration of 30-40 ^M can be recommended. Standard experiment for determining the hydrogenation conditions of a 2-enoate A two-necked flask of 20-50 ml connected to a mercury filled manometer is flushed with nitrogen or argon and filled with a suspension of 0.4 g wet packed cells of C. tyrobutyricum in 3 ml 100 mM potassium phosphate buffer, pH 6, containing 1 mM methylviologen and 50-300 ^mol of an enoate. If it is expected that the experiment runs longer

839

than 6-8 h about 0.4 mg tetracycline per 10 ml suspension should be added. The protective gas is substituted by hydrogen gas, the system closed and the flask immersed in a thermostated bath of 35 "C. After thermal equilibration a slight over-pressure of about 20-25 mm mercury is applied. The system can be shaken or stirred. If the volume of the system is known the rate of dihydrogen uptake can be followed by the attached manometer. If the hydrogenation proceeds slowly and for a longer time changes of the atmospheric pressure should be included calculating the dihydrogen consumed. If the second neck of the hydrogenation flask is closed with a suitable air tight septum a small sample of the solution can be withdrawn with a syringe and analysed. Another possibility is to open the flask under a stream of hydrogen gas and withdraw a small sample which can be analysed by GLC or HPLC. The results of such an experiment provide information for experiments on a larger scale. 2.5.2 Reduction of 0.286 mol of sparingly heptylpyrimidine-2-yl)'phenyl]-propenoate soluble (E)-2-methyl'3'f4'(5'

A saturated solution of the sodium salt of the substrate forms a concentration of 30 |LiM in a 0.05 M potassium phosphate buffer, pH 6.5, at 35 C. The substrate was reduced as a suspension. Less than 1 % of the material was in solution. In 3 litres 0.05 M potassium phosphate buffer 286 mmol substrate was suspended together with 270 g wet packed cells of C. tyrobutyricum and 33 g oi Proteus vulgaris. The reduction was carried out with 0.5 M sodium formate in the presence of 1 mM methylviologen under slight stirring. After 74 h 95 % of the substrate was reduced. The ee value of the product was >98 %. 2.5.3 Stereospecific deuteration of two enoates (i) 5,9-Dimethyl-deca-2,4,8-trienoate in ^HjO to (25',3i?)-[2,3-^H]-5,9-dimethyl-deca4,8-dienoate. Twenty five mmol (4.88 g) of the trienoate were dissolved in 250 ml potassium phosphate buffer, p^H 7.0, together with 1 mM methylviologen, 25 mg tetracycline*HCl and 27.7 g of freeze dried cells of C. tyrobutyricum. The system was hydrogenated under H2 (not ^Yii)- After finishing the reduction the suspension was acidified to pH 1.5 and extracted with ether. After purification by chromatography on a silica gel column with hexane/diethyl ether 3:2 (v/v) the yield was 87 %. (ii) Deuteration of ()-2-pentenoate to (2iS',3iS)-[2,3-^H]-pentanoate. Under exclusion of oxygen 10 g freeze dried cells of C. tyrobutyricum were suspended for 30 min in 300 ml 50 mM arsenate in ^H20 at 35 C. Afterwards to this solution 50 mmol (6.1 g) sodium E-pentenoate and 1 mM methylviologen were added. The shaking flask was connected with a volume of 4 litres H2 and a manometer. After the disappearance of the substrate (18 h) the suspension was acidified, centrifiiged and the aqueous layer extracted with ether. To the washed ether extract some water was added and the pentanoic acid titrated. After the evaporation of the ether the yield was 81 %.

840

3. REDUCTION OF 2-OXO CARBOXYLATES TO (jR)-2-HYDROXY CARBOXYLATES AND DEHYDROGENATION OF (^)-2-HYDROXY CARBOXYLATES TO 2-OXO CARBOXYLATES
Chiral 2-hydroxycarboxylic acids are valuable synthons (41,42). This is especially true if they contain additional functional groups which by chiral induction can be converted to further chiral centres in diastereoselective chemical reactions. From this point of view chiral 2-hydroxy-3-en carboxylates or 2-hydroxy-4-oxo carboxylates are of interest. With anaerobically grown cells oi Proteus mirabilis or P. vulgaris we prepared according to Reaction [17] many (i^)-2-hydroxy carboxylates including those mentioned before.
Proteus spec.

RCOCOO"

2YC +

2e

(i?)-RCHOHCOO-

[17]

Also very different (/?)-2-hydroxy carboxylates could be dehydrogenated on a preparative scale. Scheme 4 summarises the unusually broad range of applications. With {K)-2hydroxy-3-enoiccarboxylates (43) we performed a series of reactions which led to highly functionalised acids with 3 chiral centres (44,45) (Table 13). The product of 22 (Table 10) was used to prepare various 5-methoxy-pentano-l,4-lactones (45). Tables 10, 11, 15 and 16 give an impression and suggestions for applications oi Proteus species with other substrates. For preparative work the so far applied 2-hydroxy carboxylate oxidoreductases are pyridine nucleotide dependent (l,2a,3). The substrate specificity of the individual representatives of the various oxidoreductases is rather narrow. For thermodynamical reasons the quantitative dehydrogenation of 2-hydroxy carboxylates by pyridine nucleotide dependent redox enzymes is not so easy. But such a reaction is interesting, too. For details see Section 3.2. It was of interest to purify and characterize the (7?)-2-hydroxy carboxylate oxidoreductase fi-om Proteus vulgaris since it turned out that it does not react with NAD(H) or NADP(H) (46). Enzymes catalysing reversible reductions of carbonyl groups have been characterizedfi^omarchaea, eubacteria and eukaryotes. The enzymes fi-om eubacterial or eukaryotic sources depend on pyridine nucleotides; the enzymes from archaea also use pyridine nucleotides or deazaflavin F420. This coenzyme has a structure related to that of NAD(P)^. Since viologens are suitable artificial electron mediators for this previously unknown enzyme we named it (/^)-2-hydroxy carboxylate viologen oxidoreductase (HVOR). In the purified form the membrane bound enzyme shows a specific activity of 1800 U*mg"^ protein for the reduction of phenylpyruvate (46). (One U (unit) reduces 1 fimol 2-OXO carboxylate per minute).

841

DMSO

HO R

w COO-

CO.

DMS + H,0

H2 and/or HCOO" or electrochemical cell a) Many different mediators are possible with redox potentials E' between -440 and +217 mV Examples R =fromCH3 to at least C6H13 R = (CH3)3C; fR,5>C2H5CHCH3, C6H5 R = (7?,5>C3H7CHOH; various aldonic acids can be dehydrogenated R = R' ( / V / ) ^^j ^^ 2^ith alipathic or aromatic R\ also R"0CH2O

Other electron acceptors may be amine N-oxides Types of residues R (i) imbranched and branched alkyl, aryl

(ii) OH groups in 3 and other positions (iii) One or two conjugated CC-double bonds

(iv) Additional CO group (v) -00C(CH2)n

R = C6H5COCH2. n = 1 to 3 at least

and others

So far no satisfactory reactions with R = R'CHX-(X = CI or Br) Scheme 4: Reductions of2-oxo carboxylates to (R)-2-hydroxy carboxylates and dehydrogenations of (R)-2'hydroxy carboxylates to 2-oxo carboxylates. Properly grown Proteus cells contain hydrogenase and formate dehydrogenase which can be used to deliver electrons carried by viologens or anthraquinone-2,6-disulphonate to HVOR. The latter carrier also transfers electrons from HVOR to DMSO reductase during dehydrogenations of (R)-2'hydroxy carboxylates.

TABLE 9
Kinetic parameters determined for reactions catalysed by hydroxy carboxylate viologen oxidoreductase and dimethyl-sulphoxide reductase in Proteus vulgaris. Substrate Methylviologen,d Methylviologen,d Methylviologend Benzylviologen,d b Benzylviologen,d b Benzylviologen,d b Carbamoylmethyl viologend Anthraquinone-2,6-disulphonated Pyruvate Pyruvate Pyruvate Pyruvate Phenylpyruvate Phenylpyruvate Phenylpyruvate 4-Methyl-2-oxopentanoate 4-Methyl-2-oxopentanoate 4-Methyl-2-oxopentanoate 3-Methyl-2-oxobutanoate 3-Methyl-2-oxobutanoate 2-Oxobutanoate 2-Oxobutanoate 2-0~0-3,3-dimethylbutanoate 2-Oxoglutarate

842

K, (mM)
0.0 16 0.033 0.2 0.06 0.0 12 0.0 1 <0.07 1.8 c,e 0.6 0.44 0.72 22.0 0.14 0.13 0.04 0.68 0.25 0.20 0.74 4.0 0.70 1.82 7.5 2.5

V,,

mM"

2"d Substrate Phenylpyruvate 4-Methyl-2-oxopentanoate 3' , 4 '-Dihydroxyphenyl-2-oxo-propanoate 4-Methyl-2-oxopentanoate 3-Methyl-2-oxobutanoate Phenylpyruvate Phenylpyruvate Pyruvate Methylviologen,d Carbamoylmethylviologen,d Benzylviologen,d Anthraquinone-2,6-disulphonate,d Methylviologen,d Carbamoylmethylviologen,d Benzylviologen,d Methylviologen,d Benzylviologen,d b Carbamoylmethylviologen,d Methylviologen,d Benzylviologen,d Benzylviologen,d b Methylviologend

2.0 1.o 5.0 2.5 50.0 4.0 10.0 0.72 0.4 0.8 10.0 0.35 0.08 0.34 0.05 0.08 0.36 0.35 0.08 0.08 0.35

0.04 4.6

3.6

Phenyl-CH=CH2-Fql-CH=CHPhenyl-CH=CH-CH=CH-

(cyclohexan-2-one-yl)-CH=CHFCH2HOCH1(CH3)2CH-

0.8 0.4 0.5 0.7 0.7 0.7 2.3 0.76 2.2 390 ' 0.42 0.65 0.4 0.58 0.9 0.05 0.02 6.6 0.02 0.03

2.9 2.3 2.1 3.6 0.7 1.5 2.6 2.48 1.4

1.o 1.o 1.o 1.o 1.o 1.o 1.o

1.o 10.0 10.0 10.0 2.0 10.0
1.o

Benzylviologen,d b Benzylviologen,d b Benzylviologen,d b Benzylviologen,d b Benzylviologen,d b Benzylviologen,& Benzylviologenr&

Carbamoylmethylviologerb, Anthraquinone-2,6-disulphonateox Anthraquinone-2,6-disulphonate, Carbamoylmethylviologeq,, Cyanomethylviologeh, Anthraquinone-2,6-disulphonate, Carbamoylmethylviologerb,

(R)-Lactate (R)-Lactate @)-Lactate (R)-Phenyllactate (R)-Phenyllactate (R)-Phenyllactate (R)-2-Hydroxy-4-methylpentanoate Anthraquinone-2,6-disu1phonate0, Carbamoylmethylviologerb, Methylene blue Methylviologe%, Thionine Toluidine blue

2.3 1.6 1.3 8.8 0.85 1.00

50.0 15.0 15.0 15.0 15.0 15.0

@)-Lactate (R)-Lactate (R)-Lactate (R)-Lactate (R)-Lactate (R)-Lactate

Dimethyl-sulphoxide 1.4 c,d Anthraquinone-2,6-disulphonate~ 0.14 c,d

a

saturating Anthraquinone-2,6-disulphonatered saturating Dimethyl-sulphoxide

Concentrations of the second substrate. Benzylviologen was reduced to an extend of = 2/3. The apparent K,,, values for the substrates of the enzymes were determined with crude extracts at pH 8.5. Values for dimethyl-sulphoxide reductase. T h i s K,,, value of (@lactate was determined in the presence of 500 mM pyruvate (pyruvate inhibition).
843

844

The oxidoreductase contains 1 molybdenum cofactor and 4 iron and 4 sulphur ions per subunit of 80 kDa (46). The natural electron mediator is not known yet. The enzyme reacts not only with viologens, but also with many other artificial mediators. Their redox potentials are in the range from -440 to +220 mV (Section 3.2, Table 14). Depending on the redox potential of the mediator in use the equilibrium constants of Reaction [17] varies by more than 20 orders of magnitude. That means reductions as well as dehydrogenations are possible very effectively. The yields of product are greater than 98 % in almost all cases studied so far. The ee values are also >0.98. As a matter of fact the (S)-enantiomer could never be observed in products. The (iS)-enantiomers become available by the dehydrogenation of racemic 2-hydroxy carboxylates with P. vulgaris (7a). By using special growth conditions extraordinary high enzyme activities in Proteus mirabilis or P. vulgaris can be achieved (Table 18) (47). Rather different examples of substrates and reaction products are shown in Scheme 4 and Tables 10 and 11. The residue R of 2-oxo carboxylates can be aliphatic unbranched or branched. No size limitation has been observed yet. Also aromatic residues are accepted. Phenylglyoxylate as well as phenylpyruvate and homologues can be reduced. The presence of various functional groups as part of R are tolerated. As already mentioned these may be additional carbonyl groups or CC-double bonds. They are not reduced by Proteus mirabilis or P, vulgaris cells. That means the HVOR is extremely regio- and stereospecific. Other enzymes which form the opposite enantiomers or by-products are not present in these cells. Unsaturated hydroxy carboxylates of the type (/^)-R-CH=CH-CHOH-COO" which were prepared from the corresponding 2-oxo carboxylates could be converted to various products with additional chiral centres with reasonable or excellent diastereoselectivity (Table 13) (44,45). A series of kinetic data for reductions and dehydrogenations are shown in Table 9. The mechanism of HVOR is not known yet. It seems not to be a ping pong mechanism since the K^ values of 2-oxo carboxylates depend on the applied mediator. The temperature dependence of HVOR with reduced methylviologen and 3phenylpyruvate shows an increase from 24-39 C of about 2 fold per 10 "^C (48). In the a-position deuterated (7^)-2-hydroxy carboxylates have been prepared in ^H20. Examples are (/?)(2-^H)-3-dimethyl-2-hydroxypropanoic acid, (i^)(2-^H)-(2)-hydroxybutanoic acid, (/^)(2-^H)-3-phenyl-2-hydroxypropanoic acid. 3.1 Preparation of (J?)-2-hydroxy carboxylates In the presence of a catalytic concentration (0.5-2.0 mM) of an artificial mediator resting cells of both Proteus mirabilis or P. vulgaris reduce 2-oxo carboxylates to sterically pure (/^)-2-hydroxy carboxylates at the expense of formate and/or hydrogen gas. The reductions can also be carried out in an electrochemical cell where the regeneration of the reduced mediator proceeds at the cathode (Section 6, Fig. 6). Under these condi-

845

tions the productivity numbers can be extremely high. For the reduction of 2-oxo-4methyl-pentanoate we observed a productivity number of about 120 000 (unpublished) with cells grown as described in Section 3.3. The reductions shown in Table 10 would show about 2-3 times higher productivity numbers if cells grown according to this procedure would have been used. Before conducting dehydrogenations we grew cells on glucose instead of lactate. The cells used for the reductions described in Tables 10 and 11 have lower HVOR activities. Details for the reduction of various 2-oxo carboxylates have been published (7,7a,43,45,49). The 2-0X0 carboxylates which were not commercially available were prepared by several routes according to Reactions [18]-[21]. ^RCHO + ^RCHsCOCOOH ' ' ^RCH=C^RCOCOOH ^RCH=C^RCOCOOEt ^RCOCH^RCOCOOEt RCHOHCOCOOR + [18] [19] [20] CI"" [21]

^RCH=C^R-MgBr + EtOOCCOOEt ^RC0CH2^R + EtOOCCOOEt + OH "-

RCHCl-COCOOR

2-0x0 acids (12-17, 19, 21) (Table 10) were obtained in analogy to (50-52), by condensing aromatic aldehydes or derivatives such as cinnamic aldehyde with pyruvate or 2oxobutyrate (Reaction [18]). A rather general method seems to be the condensation of the Grignard products of 1-bromo-l-alkenes with diethyl oxalate (Reaction [19]) (53). The 2,4-dioxo carboxylates were prepared from suitable ketones and diethyl oxalate (Reaction [20]) (54) and the 2-oxo-3-hydroxy acids such as 10 by hydrolysing the corresponding ethyl 3-chloro-2-oxo carboxylates (Reaction [21]) which in turn were prepared from epoxides formed by condensing aldehydes with ethyl dichloroacetates (55,56). Esters of 2-oxo acids are not converted by the HVOR. If esters were the products of the 2-0X0 acid synthesis the hydrolysis was carried out as a separate step by alkaline hydrolysis or by Lipozyme at neutral pH. Especially unstable carboxylates such as the 2,4dioxo carboxylates 18 and 20 (Table 10) were formed enzjnnically by Lipozyme from the esters during the bioreduction. If ethyl 2,4-dioxo carboxylates are used for bioreductions the ratio of Lipozyme activity and amount of P. vulgaris cells has to be optimised. If too little lipase is present, the reaction proceeds slowly. If too much lipase is used, labile carboxylate accumulates, and side reactions may occur. The racemic mixtures of the 2-hydroxy-3-enoic acids used for analytical studies were prepared by reduction of the oxo acids with sodium borohydride in the presence of equimolar concentrations of eerie trichloride in analogy to (57). Ce-III inhibits the reduction of the CC-double bond adjacent to the carbonyl group. This method did not work for the regioselective reduction of 2,4-dioxo carboxylates or esters. The bioreductions were performed on scales from 0.3 up to 120 mmol in the presence of 1 mM benzylviologen. Usually 0.1 g wet packed cells, corresponding to -20 mg dry weight, were used for the reduction of 0.3 mmol 2-oxo carboxylate in 3 ml buffer at the

846 expense of hydrogen gas in order to compare various substrates or to study parameters such as pH dependence etc.. The substrate concentrations was mostly 0.1 M. TABLE 10 Reductions in a preparative scale of various 2-oxo-carboxylates (RCOCOO) by Proteus vulgaris (43,45). No. R 1 2 3 4 5 6 7 8 9 10 11 12 12 12 13 14 15 16 17 18 19 20 21 21 22 23 CH3C2H5CH3-CH=CH(CH3)2CH(CH3)3C(7?,5)-C2H5-CHCH3CH3(CH2)5HOCH2FCH2(/?,5)-n-C3H7-CHOH-' C6H5-CH2 CgHs-CH^CHC6H5-CH=CHC6H5-CH=CHC6H5-CH=C(CH3)p-Cl-C6H5-CH=CHp-Br-C6H5-CH=CHC6H5-CH=CH-CH=CHC6H5-CH=CH-CH=C(CH3)C6H5-CO-CH22-Furyl-CH=CH(Cyclohexaii-2-one-yl)2-Thienyl-CH=CH2-Thienyl-CH=CHCH30CH2-CH=CHHOCH2C(CH3)2Scale (mmol) 0.3 10-120 0.3 0.3 0.3 10-45 0.3 0.3 10 up to 16 100 0.3 0.3 10-100 10 10 10 10 10-45 10 10 10 10 19 f 3 Electrondonor H2orHCOOH2 H2 H2 H2 H2 HCOOH2 H2 H2 H2 or HCOO HCOOH2 H2 + HCOO' HCOO" H2 H2 H2 H2 HCOOH2 HCOOH2 HCOOHCOOHCOO" Yield ^ (%) 19 000 10 500 70-90 11500 10 000 2 400 8 450 90 26-35 000 8 550 7 000 6 250 20 000 * >90 17 800 >90 9 800 >90 68 600 >90 11 700 87 9 200 96 7 600 90 8 300 98 4 000 95 _d 87 78 13 800 _d 74' 90 11000 31000 90 63 98 740 >90 PNso'

Isolated products; bioconversion >97 %. Sometimes the reduction of the last 20 % occurred over night without observing the rate. Therefore the productivity number after 80 % product formation is given. "" Synthesized according to RCHCl-COCOOR -^ RCHOHCOCOOR. ^ Ethyl ester combined with an esterase. The carboxylates were formed by hydrolysis from the ethyl esters by Lipozyme.The hydrolysis rate was limiting. PNs of 1 000 - 3 000 were usually observed. ^ Yield determined by weight of the residue of the ether extract. ^ The total amount of 19 mmol in 10 ml was added in 4 portions to a starting volume of 30 ml with 1 g wet packed cells (see for comparison Fig. 1). Optimising the system in an electrochemical cell PNs of >150 000 have been reached (see also Section 6). ^ Ketopantoate (49).

847

TABLE 11 Relative initial rates of reductions of 2-oxo carboxylates to (i^)-2-hydroxy carboxylates with partially purified 2-hydroxy carboxylate viologen oxidoreductase (HVOR) fi-om Proteus vulgaris and P. mirabilis (58,59, unpublished). No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Substrate Phenylpyruvate Pyruvate 2-Oxobutyrate 2-Oxo-4-(methylthio)-butyrate Indolylpyruvate 5-Benzyloxyindolylpyruvate 3-Fluoropyruvate 2-Oxo-4-methylpentanoate (i^)-2-Oxo-3-methylpentanoate (/^,iS)-2-Oxo-3-methylpentanoate 2-Oxo-2,3-dimethyl-4-hydroxybutanoate Phenylglyoxalate 2-Oxononanoate Oxalacetate 2-Oxoglutarate 2-Oxoadipate 2-Oxo-(4-hydroxy-methyl-phosphinyl)-butanoate 3-Oxoglutarate Hydroxyacetone Not measured. Relative activity (%)' P. mirabilis P. vulgaris 100 92
_ b _ b

35 30 22 81 28
_ b

100 85 65 85 67
_ b

20
_ b

7 16 _ b 83 73 50 78 62 _ b 70 _ b 24 not aI substrate not a substrate

25 46 4 5

^ In the presence of MV^*orBV^*.

In order to obtain higher product concentrations on a preparative scale the substrate can be added repeatedly after most of the original 0.1 M substrate is reduced (43,45). An example is shown by Fig. 1. The bioreductions in a preparative scale were conducted by various protocols: (i) With hydrogen gas at atmospheric pressure, (ii) with sodium formate (Table 12) under an atmosphere of nitrogen and (iii) by the combination of hydrogen gas and sodium formate. In order to judge the dependence of reduction rates on various factors one has to be aware of the fact, that the reduction of a 2-oxo acid according to Scheme 2a consists of a series of consecutive reactions. First the oxidized viologen is reduced by hydrogenase or formate dehydrogenase at the expense of hydrogen gas or formate. In the second reaction the reduced viologen transfers electrons to the HVOR which in turn reduces the 2-oxo acid. Usually the first reaction is rate limiting.

848

Fig. 1. Time course of the reduction of altogether 0.1 mol 12 (Table 10) in a final volume of 450 ml 0.2 M phosphate buffer, pH 7.0 by 9.2 g wet packed cells of P. vulgaris, 1 mM BV at the expense of formate. Start: 0.033 mol 12 and 0.025 mol formate after about 1.5 and 3 h additional 0.033 mol 12 were added. The pH was kept at 7.0 by adding formic acid.
T ^=^-~r 5 10 15 Time Ch]

Fig. 2. pH dependence of the reduction of 12 by P. vulgaris in the presence of hydrogen gas. For pH 6.0 8.0 potassium phosphate buffer and for 8.0-8.5 Tris buffer was applied.

Fig. 3. Reaction progress for the reduction of 12 with P. vulgaris at the expense of 1 atm of hydrogen gas m-^ formate o-o, and the combination of hydrogen gas and formate 4-^.

0.5

Time Ch]

1.0

1.5

2.0

849

Generally the commercially available benzylviologen can be used for such reductions. If 1 mM benzylviologen or another viologen is used as a mediator the reaction mixture is usually not or only faintly blue until the reaction is almost completed. Then it turns to an intensive blue colour, indicating that the reduction of the viologen by the hydrogenase or formate dehydrogenase at the expense of hydrogen gas or formate is faster than the consumption of the reduced viologen by the HVOR catalysed reaction. In a few cases methylviologen can lead to spontaneous reactions (see later and (48)). TABLE 12 Productivity numbers (PN) observed for the reduction of 2-oxo-4-phenyl-(3)butenoate in a concentration of 0.1 and 0.2 M using hydrogen gas, formate or their combination. Electron donor 0.1 M H2 HCOOH H2 + HCOOH 10 000 30 000 91000 PN after product formation of 50% 80% 0.2 M 0.1 M 6 400 3 000 10 000 9 800 25 900 68 600 100% 0.1 M 8 600 20 000 30 000

The use of hydrogen gas for the reduction has several advantages. The progress of the reaction can be followed by the manometrically measured hydrogen consumption. The pH value of the reaction solution does not change during the reduction. However, hydrogen gas under normal pressure is less effective than formate and the larger the volume of the liquid phase the more difficult it is to saturate it with hydrogen gas, if no increased pressure is applied. The use of formate also has several advantages. A homogeneous system can easily be enlarged. The reaction rate does not depend on the shaking frequency or stirring rate as it is the case for larger volumes with hydrogen gas as electron donor. Gentle stirring is sufficient. It is more convenient to handle sodium formate than hydrogen gas. Disadvantages of the use of formate are that the progress of the reaction cannot be observed directly, and that for the reduction of a 2-oxo carboxylate with formate, an additional proton is necessary leading to an increase of the pH value during the reaction. The use of high buffer concentrations increases costs and means less elegant product isolation. Therefore, an automatic pH control system was applied which added formic acid during the reaction. Under these optimised conditions phosphate buffer concentrations of 20 mM and 0.1 g wet packed cells of P. vulgaris for the reduction of 1 mmol substrate in 0.1 M concentration were used. Conditions for conversions in a preparative scale (see above) were optimised with 2oxo-4-phenyl-3-butenoate. Reaction rates depended on pH and reached their maximum at pH 7 (Fig. 2). Table 12 shows the productivity numbers for the reduction of 0.1 and 0.2 M 2-oxo-4-phenyl-3-butenoate with hydrogen gas, formate or a combination of both

850

TABLE 13
Products w i t h 3 c h a l carbon atoms synthesized fiom various (R)-2-hydroxy-(3E)-en-carboxylates (R)-RCH=CR-CHOHCOOH (44).See notes a-c on the next page.

No. Substrates

Products
R

Yield a
(%)

de

R
Bromolactonization

1 2 3 4

H H p-c1c6& 2-thienyl H CH3 C 6 H S H 5 C~HSCH=CH

~~~

C 6 H S

(2S,3R,4S)-2-Hydroxy-3-bromo-4-phenyl-y-butyrolactone (2S,3R,4S)-2-Hydroxy-3-bromo-4-(p-chlorophenyl)-y-butyrolactone (2S,3R,4s)-2-Hydroxy-3-bromo-4-(2-thienyl)-y-butyrolactone (2S,3R,4S)-2-Hydroxy-3-bromo 3-methyl-4-phenyl-y-butyrolactone (2S,3R,4s)-2-Hydroxy-3-bromo-4-(2-E-phenylethenyl)-y-butyrolactone

~ ~~~~~~

55 60 83 7 1 85

80 88 90 90 80

Br2addition
6 C 6 H 5
7

C6HsC 8 C6Hsd 9 CH3

Iodolactonization
10 C 6 H s 11 p c l c 6 & 12 CH3 13 CH3

H H H H H H H H

(2S,3R,4S)-2-Hydroxy-3,4-dibromo-4-phenyl-y-butanoic acid Methyl (2S,3R,4s)-2-hydroxy-3,4-dibromo-4-phenyl-y-but~oate (2S)-5-( 1 ,2-dibromo-2-phenylethenyl)-l,3dioxolanone-4 Methyl (2s)-2-hydroxy-3,4-dibromo-pentanoate

45 98 82 87

>96 90 60 50

(2S,3R,4S)-2-Hydroxy-3-iodo-4-phenyl-y-butyrolactone (2S,3R,4S)-2-Hydroxy-3-iodo-4-(p-chlorophenyl)-y-butyrolactone (2S,3R,4~-2-Hydroxy-3-iodo-4-(2-thienyl)-y-butyrolactone (2S,3R,4S)-2-Hydroxyy-3-iodo-4-methyl-y-butyrolactone

71 58 64 53

>96 >96 >96 >96

851

reducing agents. Formate causes a 2.5-3 times faster reduction than hydrogen gas. This could be different if a higher hydrogen pressure was used. We did not check this problem. The formate dehydrogenase activity can be rather high in Proteus species (Table 18). Up to a substrate conversion of 80% the reduction rates achieved with a combination of hydrogen gas and formate exceeded those calculated from the sum of the rates observed with hydrogen gas or formate, respectively (Table 12). The reduction of the last 20 % of the substrate also proceeds relatively fast. This can be explained as a consequence of low K^ values (Table 9) and low enzyme inhibition by the product. On the other hand the reduction shows a rather pronounced substrate (educt) inhibition by 2oxo-4-phenyl-3-butenoate in the region from 0.1 to 0.2 M (Table 12). In the presence of hydrogen gas and a 0.2 M solution of the substrate the rate is reduced resulting in a productivity number only 64 % of that for a 0.1 M solution. When formate is applied as reducing agent the productivity number for a 0.2 M solution of the substrate is only 10 % of that of a 0.1 M solution. This indicates that the formate dehydrogenase is more inhibited by increased 2-oxo acid concentrations than the hydrogenase. Fig. 1 shows the time course of the reduction of the substrate, if it is added in portions to a proceeding reaction and gives a protocol if high productivity numbers, high product and low buffer concentrations are aimed at. As can be seen from Table 10 most of the different 2-oxo acids can be reduced with productivity numbers in the region from 2 400 to more than 30 000. The conditions were not optimised in all cases. Cells grown as described in Section 3.3 show probably 3-5 times higher productivity numbers. The indicated yields correspond to the isolated material if more than 0.3 mmol substrate was converted. The product isolation is rather simple since relatively low amounts of biocatalyst are necessary. The conversion of substrate is complete, and no side products could be detected. In general there is no drastic effect of the residue adjacent to the 2-oxo group on the rate of reduction. The rates are almost all in the range of one order of magnitude. One or two CC-double bonds conjugated to the 2-oxo group are tolerated (Table 10, substrates 3, 12-17, 19, 21). An additional oxo group in 4-position is not reduced (products 18,20). Carbon atom 3 may be secondary, tertiary or quartemary. In the latter case (5) (Table 10) the reduction rate is relatively low. Also fluorine or hydroxy groups at carbon atom 3 (8, 9) are accepted. However, as observed with 3-bromopyruvate and 2-oxo-3-halo-4methylpentanoate chlorine as well as bromine in 3-position lead to an inhibition of the HVOR and products cannot be detected. On the basis of the broad substrate specificity of HVOR it is not surprising that the two enantiomers of 2-oxo carboxylates with a chiral centre at carbon atom 3 are reduced with similar rates Table 10 (10). The time course of the reduction of 10 mmol of (i?,5)-3hydroxy-2-oxohexanoate with hydrogen gas was studied. Taking small aliquots and anaNotes for Table 13 ^ Yields are those of the recrystallised products. The de values were obtained by HPLCanalyses of the reaction solution after disappearance of the starting material. ^ The substrate was used as methyl ester. The l,3-dioxolanone-4 derivative was used.

852

lysing them, reverse phase HPLC shows a de-value of 69 % after 19 % conversion. At the end of the reaction both diastereomers were present in equal amounts. The course of reduction of (i^,iS)-2-oxo-3-methylpentanoate was similar to that of the 3-hydroxy-2oxohexanoate (43). Almost all of the 2-hydroxy carboxylates prepared were analysed on a Chiral-1/HPLC column by ligand exchange chromatography using a dilute copper sulphate solution as eluent. As already shown a-values for both enantiomers of aromatic as well as for aliphatic 2-hydroxy acids are in the range of 1.3-1.8 with higher retention times for the (Ryi-hydroxy acids (60). For details see (43). Spontaneous reaction between 2-oxo acids and reduced viologens Concentrations of 5 mM phenylglyoxylate or 2 mM 2-oxo-4-phenyl-3-butenoate show in the presence of 0.5 mM reduced benzylviologen and in the absence of the biocatalyst in oxygen fi-ee cuvettes a slow spontaneous reaction by which reduced benzylviologen seems to disappear irreversibly. 2-Hydroxy acids as products could not be observed. Such a reaction does not seem to play an essential role in the here described biological reductions. During microbial reductions the total concentration of benzylviologen was always 1 mM but the solutions were hardly coloured. That means, the steady state concentration of reduced benzylviologen was rather low. At the end of a preparative reaction there was always a strong colour from the reduced benzylviologen indicating the presence of much of the original 1 mM benzylviologen. No spontaneous reaction was observable with the above mentioned 2-oxo carboxylates and reduced carbamoylmethylviologen which has an E of -302 mV, about 40 mV less negative than benzylviologen. For more details regarding various viologens see (6). General procedure for reductions Oxygen was excluded from the Proteus cells. Before use, buffers were boiled and cooled under an atmosphere of nitrogen. Bulbs and other containers were flushed with nitrogen. In order to judge a new substrate and to compare its reaction rate with that of the reduction of another 2-oxo carboxylate the following standard procedure was applied: A total volume of 3.0 ml containing 0.1 M substrate, 1 mM oxidized benzylviologen, 0.1 M potassium phosphate buffer, pH 7.0, and 0.1 g wet packed cells (-20 % dry weight) of was shaken in a water bath at 35 C in little bulbs connected to mercury filled Warburg manometers under an atmosphere of hydrogen gas. The rate of dihydrogen consumption indicating the rate of product formation was registered by reading the dihydrogen pressure in suitable time intervals. If necessary besides measuring the dihydrogen consumption the concentrations of substrates and products were analysed by taking small aliquots via suitable syringes from the reaction mixture, heating the samples in closed Eppendorf caps for protein precipitation and injecting 5 or 10 fxl on a HPLC-column. Reductions up to 10 mmol of substrate at the expense of hydrogen gas were usually carried out by shaking the reaction mixtures in suitable vessels to which a manometer and a storage vessel for hydrogen gas was connected. As long as less than 1-2 mmol sub-

853

strate were applied reductions with formate as electron donor or with hydrogen gas and formate in combination were conducted in the same manner. Substrate amounts up to 0.12 Mol were reduced with formate by stirring the reaction mixture in 3-necked flasks containing a pH electrode connected with the formic acid reservoir of an automatic pH control system. Examples for preparative reductions with formate (45) Variation A without using a pH-control system. Under an atmosphere of nitrogen in a two-necked round bottom flask closed with rubber septums 1.5 equivalents of sodium formate and 1 equivalent of 2-oxo carboxylate as sodium or potassium salt, making the final concentration 100 mM, were dissolved in 80 % of the total amount of 0.1 M potassium phosphate buffer, pH 7.0. Wet packed cells of P. vulgaris were suspended in the residual oxygen fi*ee buffer and injected into the flask through the septum. After warming to 35 C a solution of benzylviologen was injected to reach a 1 mM concentration. The suspension was stirred under a slow stream of nitrogen, passing a water trap in order to moisten the nitrogen, through an inlet and outlet syringe needle. For 10 mmol substrate 2.0-2.6 g wet packed cells of P. vulgaris were applied. The reaction rate slows down due to a pH increase. Variation B. Instead of 0.1 M phosphate buffer a 20 mM concentration is sufficient. Into the reaction mixture a pH electrode was immersed and by an automatic pH control system set to pH 7.0, 1 M formic acid was automatically added. Variation C. The set up was as described for variation B. But after the conversion of the substrate present at the beginning at 0.1 M a second and a third or even fourth portion was added in form of a concentrated solution (Fig. 1). By this procedure in 8.5 h, 0.12 mol of 2-oxo-4-phenyl-3-butenoate was converted by 9.2 g wet packed cells. Reduction of2y4-dioxo acids under in situ hydrolysis of the ethyl esters Variation A was applied. The cell suspension which was added to the reaction mixture contained per mmol of substrate 1 ml of Lypozyme. Per mmol substrate 2 g wet packed cells of/*, vulgaris were used. 3.2 Dehydrogenation of (J?)-2-hydroxy carboxylates to 2-oxo carboxylates Also dehydrogenations of 2-hydroxy carboxylates can be rather usefiil. Nevertheless much fewer biocatalytic dehydrogenations than reductions are described. As already mentioned, HVOR in Proteus mirabilis or P. vulgaris reacts with many different artificial electron carriers (mediators) as artificial cosubstrates, varying in their redox potential by more than 600 mV (Table 14) (47,61). Therefore, depending on the redox potential of the artificial mediator the equilibrium constants {K) of the reactions shown by Scheme 4 can be changed by more than 20 orders of magnitude. Taking the relation

for the mediators methylviologen (E"" = -440 mV) and dichlorophenol-indophenol (E'' '= +217 mV) the equilibrium constants K of Reaction [17] are 7.5*10^^ and 4.6*10"^ respectively, calculated for n = 2 at pH 7 and 298 K. If the mediators are not protonated

854

in the reduced and oxidized form as it is the case with viologens, also the pH value under which the reaction is conducted has a very pronounced influence on the actual equilibrium constant K'= ^/[H^]^. The situation becomes more complicated, if the reduced form of the mediator is dissociated partially into an anionic form and protons. Reactions up to 0.6 M substrate concentrations can be carried out (Table 15) and (62). TABLE 14 Relative initial rates of the dehydrogenation of (i^)-lactate with various mediators determined with crude extracts of Proteus vulgaris (6,62). For preparative purposes the redox potential of the applied mediator should be not more negative than -200 mV. E' Mediator (mV) Methylviologen Benzylviologen NAD(P)^ Carbamoylmethylviologen Safranine T Phenosafranine Anthraquinone-2-sulphonate Anthraquinone-2,6 -disulphonate Cresyl violet Meldola blue Methylene blue Toluidine blue Thionine Dichlorophenol-indophenol -440 -360 -320 -302 -289 -252 -225 -184 -87 -8 +11 +27 +64 +217 (mM) 5.00 2.50 2.50 2.50 0.10 0.10 2.50 2.50 0.10 0.10 0.10 0.06 0.05 0.10 Relative activity (%) 30 117 0 100" 62 23 83 91 125 70 96 76 76 225

The reaction rate with carbamoylmethylviologen (2.5 mM) is defined as 100 %. Some electron acceptors are soluble rather sparingly. It was not determined whether the concentrations were saturating. Other redox mediators and their half wave potentials are listed in (63). If the reduction is conducted with benzylviologen (E' = -330 to -360 mV (6)) as the mediator at pH 6 the 2-oxo carboxylates will be completely reduced since the equilibrium constant for the reduction of pyruvate as an example is 8*10^. At pH 8.5 with anthraquinone-2,6-disulphonate (E' = -184 mV) the equilibrium constant of this reaction is about 6 orders of magnitude smaller than with benzylviologen and dehydrogenations of (i^)-2-hydroxy carboxylates can be conducted quantitatively when the reduced quinone (AQ-2,5-DS-H2) is effectively reoxidized for instance by Reaction [22]: DMSO + AQ-2,6-DS-H2 ' DMS + H2O + AQ-2,6-DS [22]

The pair dimethyl-sulphoxide/dimethyl-sulphide (DMSO/DMS) has an E'"= +160 mV. The AG of Reaction [22] is -25.1 kJ*mor^ at pH 8.5 and 25 C corresponding to a A T

855

= 2.5*10'*. The use of anthraqumone-2,6-disulphonate as mediator is easily possible since P. mirabilis and P. vulgaris possess a DMSO reductase (Scheme 4). Its activity depends on the growth conditions (Table 18), (47,62). (i) Preparation of pyruvate from (R)-lactate as an example This reaction may not be very interesting for a research laboratory. The procedure was developed for industrial use. But there are aspects which may be interesting for the production of other 2-oxo carboxylates. From racemates of 2-hydroxy carboxylates the (i^)-enantiomer can be dehydrogenated leaving the (iS)-enantiomer. Pyruvate is an interesting building block since its 3 carbon atoms represent 3 different reactive groups accessible to various reactions. On an industrial scale (i?)-lactate is much cheaper than pyruvate. Abstracts of numerous patents published in recent years indicate that most biocatalytic pyruvate preparations show space time yields of less than 0.5 mol*l ^d"\ Only two of 18 procedures achieved values near 1. Based on experiment 7 of Table 15 we showed that up to 100 g wet packed cells oi Proteus can be applied per litre in concentrations of 0.65 M (i^)-lactate which was converted to 94 % in about 1 h to pyruvate corresponding to about 300 fold higher space time yields as those reported before. Often the productivity numbers of published procedures cannot be calculated, because the amount of cells used is not indicated. The concentration of formed pyruvate ranges from 12-590 mM. The highest published concentrations could be reached by the here described methods, too. A single enzyme from the microbial cell is sufficient for the dehydrogenation of lactate to pyruvate, if the electron mediator is regenerated by a nonenzymic method, e. g., by an electrochemical process (62). The success of pyruvate production from lactate depends also on the stability of pyruvate in the presence of Proteus mirabilis or P. vulgaris cells. In fact the cells degrade pyruvate rather effectively if the enzyme pyruvate:formate-lyase (EC 2.3.1.54) is active. Since it is known that for the activation of this enzyme ferrous ions are necessary (64) we blocked the ferrous ions by 5 mM EDTA. Under these conditions pyruvate is stable for more than 100 h (62). Another problem was to find a stable and cheap mediator and an effective regeneration system for the oxidized mediator. Table 14 shows the activity of different mediators. Under various aspects anthraquinone-2,6-disulphonate was especially usefiil. It is completely stable under the reaction conditions and can easily be reisolated if necessary. It works not only very well with HVOR but also with dimethyl-sulphoxide reductase present in Proteus mirabilis or P. vulgaris (Scheme 4). Suspensions of cells were prepared by adding 1 g wet packed cells to 1 ml of 0.1 M Tris/HCl buffer, pH 8.5, which was previously boiled and cooled under an atmosphere of nitrogen. The reactions were started by the addition of this cell suspension to the reaction mixture.

856

TABLE 15
Various methods of pyruvate formation from (R)-lactate. The procedures are applicable to other (R)-2-hydroxy carboxylates, too (62).

dry
Cells No.
1 2 3 4

Volume

Mediator (mmol)

weight
(g)

Final electron (R)- Conver- Space time acceptor lactate sion yield (mmol) (mmol) ( % ) (moltl-'*d-') * Fumarate DMSO N-MMNO AQDS ' Fumarate DMSOf DMSO N-MMNO'
15 26 17" 27.5 32.5 35 13 26 36.4 17 25 32.5 32.5 >99 99 >99 99 >99 >99 94 95 96 >97 10.2 9.1 17.2 8.0 13.3 11.5 14.7 9.9 7.5 11.0

PN (mmol*kg-' (dry cells)*h')

2 1200 18900 50200 23300 28100 24000 30410 (1.0 h) 20550 (1.5 h) 15650 (2.0 h) 32200

P. vulgaris P. vulgaris P. vulgaris P. vulgaris 5 P. mirabilis 6 P. mirabilis 7 P. mirabilis

8 P. mirabilis

0.09
0.72 0.18 0.36 0.18 0.17 1.0

50b 50 70 70 50b 50 50

CAVd AQDS' AQDS' AQDS" AQDS" AQDS" AQDS"

0.15 0.15 0.35 17 0.15 0.15 0.15

0.18

70

AQDS" 0.35

45

42

Space time yield based on 1 g P. VuIguris cells (dry weight). In 0.1 or 0.3 M TriskICI-buffer, pH 8.5. ' Due to the solubility of AQDS higher concentrations are not suitable. Carbamoylmethylviologen. Anthraquinone-2,6-disulphonate. Dimethyl-sulphoxide. N-MethylmorpholineNoxide.

I f not mentioned otherwise, the reactions were conducted in deionized water containing 5 mM EDTA. The pH was kept constant by
adding 2 or 4 Msodium hydroxide. P. vulgaris cells usedf o r experiment I were grown on glucose. All others on lactate.

857

Practical working conditions for the preparation of pyruvate with dimethylsulphoxide (DMSO) as electron acceptor A volume of 50 ml contained 26.0 mmol (/^)-lactate, 0.15 mmol anthraquinone-2,6disulphonate, 0.25 mmol EDTA, 26.0 mmol DMSO and 3.7 g wet packed cells of P. vulgaris at 40 C. The pH 8.5 in the slowly stirred suspension was kept constant with 2 M sodiimi hydroxide. The dimethyl-sulphide formed from DMSO (Scheme 4; Reaction [22]) was removed actually completely by a slow stream of nitrogen gas. The boiling point of the dimethyl-sulphide is 38 C, and its solubility in water is rather low. The formed dimethyl-sulphide was condensed in a cold trap. The same procedure was used with N-methyl-morpholine-N-oxide as electron acceptor instead of dimethyl-sulphoxide. However, the formed amine does not leave the system. Formation of pyruvate with stoichiometric amounts of anthraquinone-2,6-disulphonate as electron acceptor A volume of 70 ml contained 17 mmol (i^)-lactate, 17 mmol anthraquinone-2,6disulphonate, 0.35 mmol EDTA and 1.8 g wet packed cells of P. vulgaris at 40 C. The pH 8.5 was kept constant with 4 M sodium hydroxide. After the reaction 12 mmol reduced anthraquinone-2,6-disulphonate (70 %) was isolated by centrifiigation at 4 ''C. For the isolation of pyruvate the reaction mixture was acidified with perchloric acid to pH < 2, centrifiiged, and the supernatant continuously extracted with diethyl ether. After the ether was evaporated the pyruvic acid was isolated as sodium pyruvate (84). A series of various other experiments are shown in Table 15. Experiment 7 resulted in a space time yield of 294 mol*l "^d"^ with 94 % conversion in 1 h. It was conducted in deionized water without any added buffer. That means crude pyruvate solutions are obtained after the mediator, EDTA and cell components had been eliminated. The pH value in the experiments without buffer was kept constant by automatically adding small amounts of 2 or 4 M sodium hydroxide or 1 M hydrochloric acid if an N-oxide was used as an electron acceptor. For fiirther discussions of the various experiments together with those not mentioned here see (62). (ii) Selective dehydrogenation of aldonates and aldarates with R-conJigurated acarbon atom to 2-oxo carboxylates Some methods are known for the preparation of 2-glyculosonates (2-oxoaldonates) (65,66,67). The catalytic dehydrogenation of a-carbon atoms of aldonates from the hexose series to 2-glyculosonates shows a pronounced time optimum and up to 5-6 byproducts (68). A fermentative process is described by which a Pseudomonas species converts glucose to D-araZ>/>20-hex-2-ulosonate (2-oxo-D-gluconate) in a 0.32 M solution, which was converted to iso-vitamin C (70). As recently shown by the group of Wong (66) with the synthesis of 3-deoxy-D-/waA2o-2-octulosonic acid (KDO), 2glyculosonates can also be prepared by aldolase catalysed reactions. Important is the

858

preparation of L-xy/o-hex-2-ulosonate (2-oxo-L-gulonate), which is converted to Lascorbic acid. We prepared pent- and hex-2-ulosonates according to Scheme 4 (61). The apparent K^ values of the substrates are mostly < 1 mM (Table 16). They were determined with crude extract of P. mirabilis to which the substrates were added as salts at pH 8.5. The apparent Fmax values are 2-13 % of that for (i?)-lactate dehydrogenation (47,62). The absolute values are still rather high when compared with redox enzyme activities of many other microorganisms for rather simple substrates. Two examples with P. mirabilis cells grown on racemic lactate and dimethyl-sulphoxide will be briefly described. TABLE 16 Dehydrogenations of aldonates and aldarates with resting cells of Proteus mirabilis. These cells contained 2-hydroxy carboxylate viologen oxidoreductase (HVOR) with a specific activity of 5.1 U*mg'^ protein for the dehydrogenation of (i?)-lactate (61). Substrate D-Gluconate D-Gulonate D-Galactonate L-Mannonate Lactobionate 6-Phospho-D-gluconate L-Arabinonate D-Ribonate D-Xylonate D-Glucarate Galactarate L-Arabinuronate AQDSox
C A V

(mM) 0.98 0.64 0.48 0.92 0.66 0.64 2.03 0.30 1.27 1.68 0.42 1.46 0.19 0.025 0.042 0.66

^m

V ' max (U.mg-') 0.20 0.15 0.25 0.20 0.15 0.20 0.30 0.65 0.15 0.40 0.10 0.15 0.50' 0.25 0.35 0.45

Conversion ( % ) 96 97 99 98 99 99 98 99 99 99 79

Yield'' (%) 85 95 98 88 70 98 65 71 78 91 70

Productivity number" 760 740 650 210 480 250 280 690 270 270 140

BV"" DMSO'

The apparent ^m values were determined with crude extracts of P. mirabilis at 38 C and pH 8.5. The data were calculated according to Eadie and Hofstee (69). The substrates were tested in the presence of 6 mM anthraquinone-2.6-disulphonate (AQDS). ^ Yield as isolated product. * " Kinetic data for the dimethyl-sulphoxide reductase were determined with 0.6 mM reduced anthraquinone2.6-disulphonate. The ^m values for the mediators were determined with 50 mM D-arabino-hex-lulosonate as substrate. ^ mmol*kg"^(biocatalyst)*h'\ mediators were determined with 50 mM D-araZ>/>70-hex-2-ulosonate.

859

D-Arabino-hex-2-ulosonate sodium salt monohydrate Ten mmol sodium D-gluconate, 15 mmol dimethyl-sulphoxide, 0.05 mmol anthraquinone-2,6-disulphonate, 0.25 mmol EDTA and 5*10"^ mmol tetracycline were dissolved in 50 ml deoxygenated, deionized water, and 2.0 g wet packed cells of P. mirabilis cells were added. The pH of the buffer-free solution was held constant at 9.0 during the reaction by a pH-controUing system delivering 2 M sodium hydroxide. The mixture was stirred under an atmosphere of nitrogen gas at 38 C. The course of the reaction was monitored by HPLC. At the end of the reaction ('-98 % conversion) the pH of the mixture was brought to 3.5 with perchloric acid, the protein precipitate was removed by centrifiigation, the supernatant was treated with active charcoal and filtered. The free acid was isolated by ion exchange chromatography on a 10*210 mm Dowex-50W (20-50 mesh H^ form) column. The pale yellow solution was then brought to pH 8.0 with sodium hydroxide and lyophilised. The residue was taken up in 20 ml methanol containing 2 % water and stirred for 1 h at room temperature. The sparingly soluble sodium salt was collected by filtration and washed with cold methanol and acetone. The resulting white amorphous hygroscopic product (8.8 mmol, 88 % from D-gluconate) was dried and stored over potassium hydroxide at 4 C. The NMR spectrum in ^H20 is identical with that of an authentic sample from Aldrich. A small portion was converted to methyl 2,3,4,5-tetra-0-acetyl-D-araZ7/>2o-hex-2-ulosonate (71). Starting from D-gulonic-y-lactone the salt was formed and a 0.5 M solution converted to D-Jcy/o-hex-2-ulosonate sodium salt monohydrate in the same manner as described for the preparation of sodium D-amZ?/>7o-hex-2-ulosonate. Part of it was converted to methyl-D-xy/o-hex-2-ulosonate, and this fiirther to D-//zr^o-hex-2-enono-l,4-lactone (Dascorbic acid) as described (72). The ^H and ^^C-NMR spectra in ^H20 are identical to those of an authentic sample of L-ascorbic acid. 3.3 Growth oi Proteus mirabilis (DSM 30 118) or Proteus vulgaris (DSM30115) (16) Proteus spp. were grown on a medium containing in gJ'^ 5.0 tryptone (Oxoid), 5.0 yeast extract (Difco), 5.1 K2HPO4, 1.0 HCOONa. In mg*r^ were added: 25 MgS04 *7H20, 170 NH4CI, 40 CaCl2*2H20, 13.7 Na2Mo04*2H20, 0.4 MnS04*H20, 0.4 FeS04*7H20, 0.4 /7-aminobenzoic acid, 0.26 Na2Se03*5H20, 0.02 biotin. As carbon source were added 7.2 g sodium fK,5y)-lactate containing 32 % (R)- and 68 % fS^-lactate per litre. External electron acceptor was 50-60 mM dimethyl-sulphoxide. The initial pH was adjusted to 7.5. Growth was strictly anaerobic under an atmosphere of nitrogen gas at37C. Cells were harvested by centrifiigation, washed and suspended in 10 mM Tris/HCl buffer, pH 7.5. Crude extract was prepared by a French press at 130 Mpa. It was centrifiiged at 25 000 g for 10 min (4 C) to remove cell debris. The enzyme assays were carried out at 37 C. For enzyme activities see Table 17 and for additional details (47).

860

The enzymes necessary for the reduction of 2-oxo carboxylates apphed in form of resting Proteus cells are rather stable under operational conditions. They were used repeatedly or for up to 600 h. They can also be immobilised (47, 73). TABLE 17 Activities of hydroxy carboxylate viologen oxidoreductase (HVOR) and dimethylsulphoxide reductase in P, vulgaris grown on glucose or (7^,5)-lactate with or without different electron acceptors (47). Growth condition HVOR as (i?)-lacWet DMSO^ tate weight reductase dehydrogenase of cells (U mg"' protein) (U. mg'' protein) (g-r') 2.3 3.9 3.5 4.2 <1.0 2.5 2.1 1.6 2.9 2.2 1.2 2.5 1.4 1.4 <1.0 2.6 1.6 0.8 0.6 n.d. 3.8 4.1 3.6 1.6 0.7 <0.01 1.4 8.0 0.9 n.d." 0.3 0.3 0.7 0.5 n.d. 0.7 0.5 0.9 0.5 0.4 <0.01 0.7 0.6 1.1 n.d.

Glucose Glucose + HCOa' Glucose + DMSO Glucose + DMSO + HCOs" (i?,5)-Lactate (7?,5)-Lactate + DMSO (S)-Lactate + DMSO (i^)-Lactate + DMSO (i^,5)-Lactate + TMANO^ (i?,5)-Lactate + N-MMNO' (i?,S)-Lactate + nitrate (i?,S)-Lactate + ftimarate (i^,*S)-Lactate + pyruvate (i?,iS)-Lactate + pyridine N-oxide (i?,iS)-Lactate + tetramethylene sulphoxide

^ DMSO: dimethyl-sulphoxide, ^ TMANO: trimethylamine N-oxide, * " N-MMNO: 7V-methylmorpholine N-oxide, * ^ n.d.: not determined. The specific enzyme activities (U*mg'^ protein) of the crude extract of P. vulgaris were tested with reduced benzylviologen for dimethyl-sulphoxide reductase and oxidized benzylviologen for (R)-2-hydroxy carboxylate viologen oxidoreductase dehydrogenating (R)-lactate.

861

TABLE 18 Enzyme activities of (Ryi-hydroxy carboxylate viologen oxidoreductase (HVOR), dimethyl-sulphoxide reductase, formate reductase and hydrogenase in crude extracts of P. vulgaris and P. mirabilis (47). Substrate for enzyme tests (i^)-Lactate Pyruvate ^ Diethyl-sulphoxide Dimethyl-sulphoxide Ethylmethyl-sulphoxide (S)-Methionine-sulphoxide Tetramethylene-sulphoxide A^-Methylmorpholine N-oxide Pyridine N-oxide Trimethylamine N-oxide Formate ^ Proton (Hydrogenase) ^'^ P. vulgaris ^ (U*mg'^ protein) 2.7 11.1 0.2 0.7 0.6 1.3 1.6 2.4 4.0 3.6 8.5 0.5 P. mirabilis ^ (U*mg"^ protein) 3.5 16.2 0.6 1.9 1.5 4.1 3.7 5.3 8.3 7.7 18.4 1.0

^ The (i?,*S)-lactate for the growth of P. vulgaris was {R) : (5) = 32 : 68 and for P. mirabilis 56 : 44. ^ Measured at pH 7.0. " Reduced methyl viologen (SSTS = 9.0 mM'^cm'^) was used as electron donor. The organisms were grown on (R,S)4actate with dimethyl-sulphoxide. Reductase activities were tested with reduced benzylviologen. If not indicated otherwise all reductions were carried out at pH 8,5 since it was intended to couple them with the dehydrogenation of (R)-lactate. 4. REDUCTION OF CARBOXYLATES AND DEHYDROGENATIONS OF ALCOHOLS WITH CLOSTRIDIUM THERMOACETICUM A previously unknown enzyme activity reducing non-activated carboxylates in Clostridia has been found by our group (74-77). Although this activity is present in several anaerobic bacteria and archaea (77a), its physiological role is unknown. The reaction is remarkable because the reduction of carboxylic acids in aqueous solution is not possible with chemical reducing agents. These agents reduce the protons of water rather than an acylate. The truly reversible aldehyde oxidoreductases from Clostridium thermoaceticum and one from C. formicoaceticum depend strictly on tungsten. The tungsten is complexed to a pterin cofactor which is identical or at least similar to the pterin moiety of the molybdenum cofactor present in most molybdenum containing enzymes (77,78). The pH optima for carboxylate reductions with the purified enzyme from C. thermoaceticum and CAV^* (Reaction [23]) shift to lower values with lower pK values of the substrates. However, at pH 4.0 and lower the enzyme is not stable enough for kinetic measurements. Probably the non-dissociated acids are the real substrates of the tungsten containing aldehyde oxidoreductase of C thermoaceticum. That means the non-dissociated form is bound to the enzyme, or an acylate bound to the enzyme is protonated before it is

862

reduced. The redox potential of a non-negatively charged species, i. e., an non-dissociated carboxyhc acid, is much less negative than that of a carboxylate. This fact may explain why the enzyme from C. thermoaceticum is able to reduce carboxylates with a redox potential of about -580 mV (E"" = -581 mV for acetate/ethanal at pH 7) (79) at the expense of reduced carbamoylmethylviologen with a redox potential of only E'= -302 mV (Table 1). The tungsten containing aldehyde oxidoreductase of C, formicoaceticum is rather different from that of C thermoaceticum. This holds for the amino acid sequence of the N-terminus, the pH dependence of the carboxylate reduction and the redox potential of the artificial mediators necessary for reducing carboxylates. The pH optimum of 6.0 for the carboxylate reduction is independent of the pK value of the acids. This was shown for propionate, 4-fluorobenzoate, benzoate, and 4-methoxy-benzoate. Reduced carbamoylmethylviologen is not able to transfer electrons to this enzyme. Reduced benzylviologen, methylviologen and l,r-2,2'-tetramethylviologen show relative reduction rates of 12, 30 and 100 %, respectively. The E'-values of these viologens are -340, -440 and -550 mV (Table 1). In addition to the tungsten dependent enzyme C. formicoaceticum forms a molybdenum containing aldehyde oxidoreductase, too. This enzyme reduces carboxylates only with the tetramethylviologen mentioned above (80). The purified aldehyde oxidoreductase from C thermoaceticum reduces carboxylates to the aldehydes only (Reaction [23]). No alcohols were present among the products of these reductions (77). The same is probably true for the enzyme from C. formicoaceticum. Before preparative reductions of carboxylates with cells will be described some hints about the purified enzyme will be given (75-77). Besides the purification and partial structural characterisation we conducted some kinetic measurements (77). In addition to the carboxylate reduction the dehydrogenation of aldehydes was studied. There is a broad substrate specificity of the enzyme from C. thermoaceticum for aliphatic and aromatic aldehydes. The K^ values for ethanal, propanal and butanal are in the region of 0.0060.01 mM. The K^ values for acetate and propionate are about 5 and 6 mM that means 3 orders of magnitude larger. The ratio of ^cat / ^m for aldehydes and the corresponding carboxylates is about lO'^-lO^. The K^ values of aromatic aldehydes are < 0.02 mM. An exception is 4-hydroxybenzaldehyde. 4-Hydroxybenzoate the corresponding carboxylate has an extremely high K^n value, too. Table 19 shows fiirther examples of carboxylates being reduced. Additional structural and kinetic data of the tungsten and molybdenum containing aldehyde oxidoreductases from C. formicoaceticum are described (78,81). When the aldehyde oxidoreductase of C. thermoaceticum reduces the non-dissociated acids bound to the enzyme, esters, which are not charged, could also be substrates. However, esters such as methyl propionate are no substrates at all. Lactones seem to be reduced only after the rate-limiting opening of the ring (Table 19). 4.1 Reductions of non-activated carboxylates to alcohols Table 19 shows the productivity numbers for the reduction of various carboxylates to alcohols with resting cells of C. thermoaceticum and carbon monoxide as an electron donor. Four consecutive Reactions [7a] and [23]-[25] catalysed by four enzymes present

863

in C. thermoaceticum lead to the observed mono- and di-alcohols. CO-Dehydrogenase reduces at the expense of two carbon monoxide molecules four molecules V^^ to V^* (Reaction [7a]). These are consumed by Reactions [23]-[24] RCOOH NADP" RCHO + + 2V^- + 2V"- + 2H^ H" H^ ^^=^ ^ ^ ^ ^^^
AldOR

RCHO +

2V^^ +

H2O

[23] [24]

NADPH + 2V"" RCH2OH + NADP^

+ NADPH +

[25]

For the term AMAPOR see Sections 1.2 and 5 (6,82,83). According to Reaction [23] 2 mol carbon monoxide deliver 4 electrons that are necessary for the reduction of a carboxylate to the corresponding alcohol. Reaction [26] summarises these reactions. 2C0 + RCOOH + H2O ^^==^ 2CO2 + RCH2OH [26]

Under an atmosphere of carbon monoxide cells of C thermoaceticum reduce propionate (pK 4.87) at pH 5.5 at an optimal rate and lactate (pK 3.86) at pH 4.5 (not shown). For the reduction of propionate with reduced carbamoyhnethylviologen the pH optimum of the purified enzyme was 4.65. At pH 5.5 the purified enzyme reduced propionate at about 20 % of the maximal rate (77). In cuvettes only the initial rate of Reaction [23] is measured. Within a microorganism Reactions [7a] and [23]-[25] take place in a consecutive manner. The pH optimum of this reaction sequence is different fi-om that of Reaction [23] alone. For instance the pH optimum of carbon monoxide dehydrogenase is 8.4 (85). At pH 5.5, carbon monoxide dehydrogenase and carboxylate reductase showed similar activities in cells grown according to Section 5.3. At pH 4.5 CO-dehydrogenase activity was limiting. At this pH the solutions of reductions with whole cells were not blue, because Reaction [7a] which forms V^* is slower than Reactions [23] and [24] in consuming V^*. At pH 7.0 the aldehyde oxidoreductase does not any longer reduce carboxylates to aldehydes but the enoate reductasefi^omC. tyrobutyricum is active (Section 2). Starting fi-om from a- and/or ^-substituted enoates the chiral saturated acids can afterwards be reduced fiirther with carbon monoxide and C thermoaceticum to the corresponding chiral alcohols. An isolation of the chiral acid is not necessary. After reducing the 2enoate (Reaction [9]) the pH has to be shifted to pH 5.0-5.5. Cells of C. thermoaceticum are added and the chiral carboxylate is reduced with carbon monoxide (74,77). The enoate reducing system of C thermoaceticum shows a low activity and seems not to be as stereospecific as that of C. tyrobutyricum (unpublished). Lactones (Table 19) were slowly reduced to di-alcohols. The rate limiting step in this reaction was probably the hydrolysis of the lactone ring, which was slow at pH 5.5. 2Hydroxypyridine-5-carboxylate was converted to 3-hydroxymethylpyridine. That means the 2-hydroxy group was reductively eliminated. Racemates of chiral substrates carrying a chiral carbon atom in a-position were reduced, too, but in no case could marked stereospecificity be found. Reactions with (K,5j-2-(4-chlorophenoxy)-propanoate were stopped after 50 % reduction. Both enantiomers of the 2-(4-clilorophenoxy)-propan-l-ol

864

TABLE 19 Productivity numbers and relative rates for the reduction of various carboxylates by C. thermoaceticum at the expense of carbon monoxide. The substrates (33 mM) were supplied as their sodium salts in 0.3 M potassium phosphate buffer, pH 5.5. One mM methylviologen was used as mediator. The productivity numbers are calculated for one pair of electrons consumed after a reaction time of one hour.
~~~

Substrate Acetate Propanoate Butanoate Pentanoate 3-Methylbutanoate (R,S)-2-Methylbutanoate 2-Methyl-(E)-2-butenoate 2-Methyl-(E)-2-butenoate (R,S)-2-Methylpentanoate (R,S)-3-Methyl-pentanoate (R)-Lactate (S)-Lactate 4-Methoxyphenylacetate (R,S)-2-phenylpropanoate (R,S)-2-phenoxypropanoate (R,S)-2-(2-chloro-phenoxy)-propanoate (R,S)-2-(4-chloro-phenoxy)-propanoate (R,S)-2-(2,4-dichloro-phenoxy)-propanoate (R,S)-2-(2,4,5-trichloro-phenoxy)-propanoate Benzoate 4-Hydroxybenzoate 4-Methoxybenzoate

Product Ethanol Propanol Butanol Pentanol 3-Methylbutan-l-ol (R,S)-ZMethylbutan-1-01 2-Methyl-(E)-2-buten- 1-01 and (R,S)-2-Methylbutan-l-ol (R,S)-2-Methylpentan-1-01 (R,S)-3-Methylpentanl-ol 1,2-Propandiola 1,2-Propandiola 2-(4-Methoxyphenyl)-ethanol (R,S)-2-phenylpropan-l-ol (R,S)-2-phenoxypropannl-ol (R, S)-2-(2-chloro-phenoxy)-propan1-01 (R, S)-2-(4-chloro-phenoxy)-propan- 1-01 (R,S)-2-(2,4-dichloro-phenoxy)-propanl-ol (R,S)-2-(2,4,5-trichloro-phenoxy)-propanl-ol Benzyl alcohol 4-Hydroxybenzyl alcohol 4-Methoxybenzyl alcohol

Productivity number 630 1140 1180 1110 840 1030 685 1255 870 990 115" 80" 880 1025 0 730 580 470 150 725 150 1300

4-Methylbenzoate 4-Fluorobenzoate 4-Chlorobenzoate Pyndine-2-carboxylate Pyndine-3-carboxylate Pyndine-4-carboxylate 6-Hydroxypyridine-3-carboxylate 6-Chloropyridine-3-carboxylate Succinate Glutarate Hexane dicarboxylate (R,S)-Methylsuccinate 3-Methylglutarate (R,S)-3-Methylhexane dicarboxylate y-Butyrolactone 6-valerolactone E-caprolactone (R,S)-4-Methyl-6-caprolactone
a

4-Methylbenzyl alcohol 4-Fluorobenzyl alcohol 4-Chlorobenzyl alcohol 2-Hydroxymethylpyridine 3-Hydroxymethylpyridine 4-Hydroxymethylpyridine 3-Hydroxymethylpyridine 3-Hydroxymethyl-6-chloropyridme Butane- 1,4-diol Pentane- 1,5-diol Hexane- 1,6-diol (R,S)-2-Methylbutane-1,4-diol 3-Methylpentane-1,5-diol (R,S)-3-Methylhexane-1,6-diol Butane- 1,4-diol Pentane- 1,5-diol Hexane- 1,6-diol (R,S)-3-Methylhexane-1,6-diol

625 675 575 550 360 580 60 340 1355 1125 1220 300 315 1160 5 150 25 30

This rate increases at pH 5.0. The enantiomeric excess of the product was not determined. The product formed is 3hydroxymethylpyridine instead of 3-hydroxymethyl6-hydroxypyridine due to GUMS-analysis. After one hour depending on the substrate 25-75 % of the formed diol are present in form of the lactone. The lactones react rather slowly. After a reaction time of 19 hours.

865

866

had been formed in about equal amounts. As shown earher, (R)- and (*S)-lactate were reduced to 1,2-propandiol with similar rates (74). Reductions of carboxylates up to at least 400 mM are possible. During the reduction the pH of such solutions with 100-400 mM carboxylate may drop considerably. This is probably due to the reduction of carbon dioxide to formate at the expense of carbon monoxide. Mechanistically carbon monoxide dehydrogenase (Reaction [7a]) delivers electrons from carbon monoxide to formate dehydrogenase which adds them to carbon dioxide yielding formate (Reaction [27]). Carbon dioxide is formed by oxidation of carbon monoxide (see above). CO2 + 2e + 2H^ HCOO' + H^ [27]

The pH of such solutions has to be kept constant by adding sodium hydroxide with a pH controlling system. Reduction of 6-chloropyridine-3-carboxylate to 3-hydroxymethyl-6-chloropyhdme With chemical reagents this reduction causes problems because the bound chlorine is labile and may get lost. The pH optimum for the microbial reduction with methylviologen as electron mediator was 5.0, leading to a productivity number of 190 in an electrochemical cell (in analogy to Section 6). The optimum for the working potential was -750 mV versus SCE (saturated calomel electrode) (Table 20). The electromicrobial reduction leads also to the undesired by-products pyridine-3-carboxylate and 3hydroxymethylpyridine. These were even the main products when tetramethylviologen was used as a mediator, with a working potential of -840 mV versus SCE. The lower the pH, and the more negative the working potential, the higher was the amount of the chlorine free by-products. So a compromise had to be found between optimal productivity and minimal formation of the by-product by increasing the pH to 5.6 and applying a working potential of -750 mV versus SCE. The product/by-product ratio was 3.4 under these conditions. Better results were obtained by the microbial reduction of 6-chloropyridine 3-carboxylate using carbon monoxide. The product/by-product ratio was about 80, if a carbon monoxide pressure of 20 bar was applied. In another experiment ethylene glycol diethyl ether was used as a second phase in order to transfer the product to the organic solvent (Table 20) (86). A solution of 30 ml 0.1 M potassium phosphate buffer, pH 5.6, containing 270 mM 6chloropyridine-3-carboxylate and 8 g wet packed cells of C. thermoaceticum was stirred under an atmosphere of about 1.1 bar CO. In another experiment 30 ml ethylene glycol diethyl ether was used as the second phase. Before the reaction was started, carbon monoxide was flushed through the solution. For the experiment with 20 bar carbon monoxide a glass flask with a magnetic stirrer containing the above indicated ingredients was put in an 200 ml autoclave.

867

TABLE 20 Electromicrobial and microbial reduction of 6-chloropyridine-3-carboxylate. The productivity numbers (PN) are given after 7 and 24 h for the uptake of 4 electrons. The organic phase was 30 ml ethylene glycol diethyl ether. Working potential or CO pressure - 750 mV versus SCE - 840 mV versus SCE 1.1 bar {+ organic phase) 20 bar (+ organic phase) 20 bar (- organic phase) Mediator Ratio product/by-product ^ (mM) PN(7h) PN(24h) (7h) (24 h)

MV(5) 150 TMV(5) 40 MV(4) 200 MV(4) 240 MV(4) n.d.

130 20 100 150 130

n.d. n.d.

3 . 4
0.03

24 82
n.d.

10 80 80

^ Product: 3-hydroxymethyl-6-chloropyridine. By-product: 3-hydroxymethylpyridine 4.2 lectromicrobial dehydrogenations of primary alcohols C. thermoaceticum was investigated for the dehydrogenation of primary alcohols with the application of different electron mediators (86). The final electron acceptor was an anode and the reaction proceeded in aqueous media. Unexpectedly the mere choice of the artificial electron mediator determined whether aldehydes or acids were formed. When cells of C. thermoaceticum were used, some mediators did not react with aldehyde oxidoreductase. If aldehyde was the final product, an aldehyde scavenger had to be applied, otherwise the enzymes were inhibited. Table 21 gives a summary of the results of the dehydrogenation of propanol. With anthraquinone-2-sulphonate as mediator besides n-propanol -butanol, 2-methylpropanol, fK,S^-2-methylbutanol, benzyl alcohol, and allyl alcohol were converted to acids showing productivity numbers between 400 and 1200. The dehydrogenation of fjR,iS^-2-methylbutanol showed no enantioselectivity. 3Aminopropanol, ('jR,iS>)-2-aniinobutanol and 5-aminopentanol as well as -octanol and ethylene glycol could not be dehydrogenated. The dehydrogenation of a primary alcohol to the aldehyde seems to depend on the E''' of the mediator and its reactivity with the aldehyde oxidoreductase. The more positive the E' of the mediator, the lower is its reactivity with the enzyme. If thionine or methylene blue is applied, having the most positive E' values among the applied mediators, only the aldehyde is formed. If resorufin was used, with an E' between that of the phenothiazine-dye-type mediators (E' >0 mV) and the mediators used for acid production (E' < -180 mV), the aldehyde formation was only slightly preferred over acid formation. Carbamoylmethylviologen and anthraquinone sulphonates showed only acid production; even when an aldehyde scavenger was applied, only small amounts of aldehyde were formed (86).

868

TABLE 21 Electromicrobial dehydrogenation of propanol, using different electron mediators. Mediators (mM) 1 Thionine 1 Thionine' 1 Methylene Blue ' 1 Thionine" Resorufin 0.25 3 AQ-2-S AQ-2-S 3 AQ-2,6-DS 3 CAV 3 E"' Hydrazine (mM) (mV) + 60 + 60 + 11 + 60 -51 -225 -225 -184 -302 100 100 100 0 100 100 0 0 0 After 1 h reaction After 20 h reaction PNald. PNacid PN aid. PN acid 1200 1200 2500 1200 n.d. n.d. <50 <50 <50 <50 <50 <50 <50 n.d. n.d. 1500 1250 2500 400 1400 1500 330 730 300 <50 <50 <50 <50 <50 <50 <50 420 1300 1500 1200 1650

The buffer also contained 6 mM FeEDTA. A sample of 50 ml 0.1 M Tris/HCl buffer contained 50 mM propanol and 0.2 g wet packed cells ofC. thermoaceticum. The reaction temperature was 40 ^C and the working potential differed depending on the applied mediator. Using carbamoylmethylviologen as mediator the pH was 8.0; with the other mediators it was 7.0. The applied dyes, which have low solubility in water, can be used in an electrochemical cell only in connection with a better water-soluble co-mediator like 6 mM Fe-EDTA. This co-mediator can readily be reoxidized at an anode and reacts quickly with the reduced dyes. 5. USE OF ARTIFICIAL MEDL\TOR ACCEPTING PYRIDINE NUCLEOTIDE OXIDOREDUCTASES (AMAPORs) FOR THE REGENERATION OF PYRIDINE NUCLEOTIDES The role and the reactions of AMAPORs for the regeneration of pyridine nucleotides are generally introduced in Section 2.1. Many different systems have been suggested for the regeneration of (mostly) one of the coenzymes NAD^, NADH, NADP^ or NADPH. Only a few publications which appeared after the review articles of the Whitesides group (87-89) shall be mentioned (90,91). For the photochemical and electrochemical regeneration of nicotinamide cofactors see (92,93). Many experiences exist for the regeneration of NADH by use of an NAD^-dependent formate dehydrogenase from a Candida yeast (94) which catalyses Reaction [28]. NAD(P)^ + HCOO NAD(P)H + CO2 [28]

For the production of this enzyme a continuous computer controlled production and isolation procedure on a pilot scale has been developed (95). Carbon dioxide as the product of the electron donor formate, leaves the solution and does not interfere with the purification of the product. An important progress is a formate dehydrogenase obtained by engineering of an enzyme from the methylotrophic bacterium Pseudomonas sp. 101

869

which accepts NAD^ and NADP^. StabiHty measurements show no decrease of activity over a period of 7 days incubation at a temperature of 25 C (96). Usually formate does not inhibit other oxidoreductases. The disadvantage of most other systems for NADPH regeneration is the formation of a by-product in stoichiometric amounts which does not leave the system. An example is 2-oxoglutarate from .S-glutamate and glutamate dehydrogenase. These problems and others are discussed in the above mentioned reviews. Our findings and experiments on AMAPORs are described in a series of papers (6,7, 82,83,97-100). For some time we called these activities viologen accepting pyridine nucleotide oxidoreductases (VAPORs). They are present in many aerobic and anaerobic microorganisms (7,97). Surprisingly high activities are present in mitochondria from beef heart or yeasts (100). Since we observed that these enzymes accept also artificial mediators such as cobalt complexes (101-104), anthraquinones, thiazine dyes and others we changed the name of such enzyme activities into artificial mediator accepting pyridine nucleotide oxidoreductases AMAPORs (82). They reversibly transfer electrons between various artificial electron mediators and a pyridine nucleotide. The thermophilic Bacillus DSM 406 (16) and other related species (Table 22) contain an AMAPOR which reduces NAD^ and NADP^ at the expense of reduced methylviologen. The enzyme from the species DSM 406 was purified and studied fiirther. Some kinetic data are given in Table 23. The seven indicated K, and six K\ values for this enzyme show that it is suitable for the regeneration of all four forms of pyridine nucleotides. The stability in presence of oxidized and reduced methylviologen at 35 C or 60 C is satisfying for preparative work (98). May be that this enzyme reacts with more artificial electron mediators than viologens. That was not studied by us. The NADH dehydrogenation with CAV^^ shows its pH optimum at 10. The activity at lower pH values is sufficient for preparative work. For the reduction of NAD^ with MV^* the pH optimum is about 6.5. The astonishingly high AMAPOR activities present in crude extract of C. thermoaceticum are summarised in Table 24 (82). In the form of crude extract the rather oxygen insensitive activities are useful for the regeneration of all four forms of pyridine nucleotides on a preparative scale. Reductions via NADH or NADPH dependent reductases can be conducted with reduced methylviologen according to Reaction [29] and [30]. 2MV^' + NAD(P)^ )C=X + + M A P O R 2MV^^ H^ A H^ + NAD(P)H H-)CXH [29] [30]

NAD(P)H +

^ NAD(P)^ -f

In crude cell extracts of C. thermoaceticum the specific activity of AMAPORs for NADP^ reduction with reduced MV is extraordinarily high and more than twice of that for NAD^. NADH and NADPH dehydrogenation for the regeneration of NAD^ and NADP^ is achieved with the same enzyme activities and anthraquinone-2,6-disulphonate (Reaction [31a]). The activities are about the same as for carbamoylmethylviologen (CAV) (Table 24).

870

TABLE 22 Specific activities of AMAPOR in crude cell extracts of different thermophilic bacilli measured at 30 T (98). Strain Bacillus Bacillus Bacillus Bacillus stearothermophilus sphaericus 461 sp. DMS 405 sp. DMS 406 Specific Strain activity ^ 0.09 0.27 0.14 0.25 5acz7/w5sp. DMS411 Bacillus sp. DMS 465 Bacillus sp. DMS 466 Bacillus sp. DMS 730 Specific activity ^ 0.18 0.40 0.57 0.18

^Reoxidation of 2 jimol MV^**mg"^ proteimmin'^ with NAD^. Table 23 Kinetic parameters of AMAPOR from Bacillus spec. 406. For the formation of reduced pyridine nucleotides MV^' and for their reoxidation CAV^^ were used (98). A^m-values (mM) MV NAD" NADP"^ CAV"' CAV^^ NADH NADPH 0.24 0.06 1.82 0.52'' 0.29 0.22 1.43 Product NADH NAD^ NADPH NADH Rel. rate (%)" /Tj-values (mM) MV** NADH NADPH CAV"* NAD^ NADP* 100 50 33 1.8 19 13.5

50 37

no"

100

^ 100 % corresponds to 58 U for the purified enzyme. ^ For the reoxidation of NADH. * " For the reoxidation of NADPH. ^ At the pH optimum for the reoxidation of NADH the rate is about 260% of that of the NADH formation with MV^* at pH 7.0. In crude extract of C. formicoaceticum the activity for the reduction of NAD"^ with MV^* is about 6 U*mg"^ and that for NADP^ 3.5 U*mg"^ protein. The dehydrogenation of NADH and NADPH proceeds with CAV^^ as acceptor with a specific activity of 14 and 8 U*mg"* protein (unpubhshed). For the AMAPORs from C thermoaceticum and C. formicoaceticum the K^ values for the artificial electron mediators and those for pyridine nucleotides are in a reasonable range for preparative transformations. Table 24 shows some ^m values for enzymes present in C. thermoaceticum.

871

TABLE 24 Kinetic data of AMAPOR activities in crude extracts of Clostridium thermoaceticum at 37 "C. Specific activity (U.mg'' protein) 3.9 9.8 1.6 2.0 1.6 1.7 Mediator (mM) 0.38 0.44 0.35 0.25 0.7 1-2
^m

Mediator MV"* MV"* CAV^^ CAV** AQDSox AQDSox

Pyridine nucleotide NAD^ NADP* NADH NADPH NADH NADPH

Pyridine nucleotide (mM) 0.88 0.20 n.d. 0.02 0.07 0.12

pHOptimum 6.5 6.5 8.5 8.5 8.5 8.5

We demonstrated the application of reactions with AMAPOR activities from C thermoaceticum in electrochemical cells and in other forms for the preparative reduction of various substrates (82,83,86). One NAD^/NADH dependent AMAPOR from C. thermoaceticum has been purified and partially characterized (86a). 5.1 NAD^ and NADP^ regeneration with AMAPOR from Clostridium thermoaceticum and anthraquinone-2,6-disulphonate using oxygen as final electron acceptor

In contrast to viologens reduced anthraquinone-2,6-disulphonate formed by Reaction [31a] can be reoxidized in a non-enzymicly catalysed reaction with oxygen as final electron acceptor (Reaction [31b]). The formed hydrogen peroxide can be split by the extremely cheap catalase (Reaction [31c]). The sum of Reactions [3la]-[31c] leads to Reaction [31]. NAD(P)H + H^ + 0.5 O2 NAD(P)^ +
H2O

[31]

This NADP* regeneration consists of the three consecutive Reactions [31a]-[31c]. The reduction of anthraquinone-2,6-disulphonate at the expense of NAD(P)H catalysed from AMAPORs in form of crude cell extract of C. thermoaceticum, the reoxidation of the reduced mediator in a spontaneous reaction with oxygen (112) and the splitting of the hydrogen peroxide by catalase. NAD(P)H + AQ-2,6-DSox + H ' ; = ^ NAD(P)^ + AQ-2,6-DSred
H2O: 2'-'2

AQ-2,6-DSred
H2O: 2-'2
0.5 O2

[31a] [31b] [31c]

O2

AQ-2,6-DSo
H2O

872

TABLE 25 Dehydrogenation of glucose-6-phosphate (G-6-P) to 6-phosphogluconate using AMAPORs from C. thermoacetjcum, glucose-6-phosphate dehydrogenase (G-6-P DH), anthraquinone-2,6-disulphonate and oxygen for NADP^ regeneration (82). G-6-P (mM) 20 20 20 100 300 AMAPOR U 23 23 23 46 69 G-6-P DH" U 28 28 28 28 42 Catalase SOD" kU kU 0 130 130 130 150 0 0 2.2 0 0 Yield (%) 63 92 92 84 41 Reaction time (h) 5 5 5 23 23 Mass balance (%) n.d. 95 95 88 60 Number of cycles forNADP* 130 180 180 810 830

^ EC 1.11.1.6,^ SuperoxidedismutaseEC 1.15.1.1 A total volume of 40 ml 0.1 M Tris/HCl buffer, pH 7.5, at 33 ^C, contained in addition to the indicated substrate concentrations and enzyme activities 1 mM anthraquinone2,6-disulphonate, 3.3 mMMgCh and 0.1 mMor 0.15 mMNADP\ Preparation of 6-phosphogluconate and (2S,3R)-isocitrate under regeneration ofNADP^ (82) For the preparation of 6-phosphogluconate from glucose-6-phosphate with commercially available glucose-6-phosphate dehydrogenase from yeast the results are summarised in Table 25. Electrochemical experiments using the anode as the electron acceptor are shown in Section 6. Without catalase the yield of 6-phosphogluconate was only 63 % after 5 h and almost the same after 71 h (not shown for 71 h). Hydrogen peroxide formed during the regeneration of antliraquinone-2,6-disulphonate with oxygen (Reaction [31b]) seems to be the reason. The presence of catalase considerably increased the yield. The addition of superoxide dismutase together with catalase did not improve the results. With higher substrate concentrations NADP^ cycle numbers of above 800 were obtained. Recently NAD^ regeneration with a cycle number of less than 20 was described for the formation of 6-phosphogluconate with an NAD^ depending dehydrogenase (105). Using pyruvate and (iS)-lactate dehydrogenase for NAD^ regeneration led to cycle numbers of about 1000, but this system is not suitable for NADP^ regeneration (88). Another problem of all NADP(H) containing systems is the low stability of NADP(H) in the presence of high concentrations of phosphorylated compounds such as glucose-6phosphate and 6-phosphogluconate (87,89). The synthesis of (2iS',3i^)-isocitrate from (2/^,3S;25,3i?)-isocitrate by enantioselective oxidative decarboxylation of (2/?,3iS)-isocitrate to 2-oxoglutarate is shown in Table 26. The latter compound can easily be separated from the remaining (2iS',3/?)-isocitrate by the different solubilities of the barium salts of these acids in water. (2iS',37^)-Isocitrate is not commercially available and might be an interesting chiral building block. A cycle number (i)

873

of 1250 without a by-product was observed for NADP^ regeneration. This is a satisfying value compared to methods mentioned before. The originally (2iS',3/^)-isocitrate present in the applied racemate completely reappeared on HPLC. The isolated crystalline mono potassium salt of isocitrate gave the expected optical rotation of [a]2o^= -20.4 and the correct elemental analysis. In a control assay with (2i?,35)-isocitrate dehydrogenase (EC 1.1.1.42) the (2i^,35)-enantiomer could not be detected. TABLE 26 Oxidative decarboxylation of (2i^,3tS)-isocitrate from (2i?,3*S';2S',3i?)-isocitrate leading to (2iS',3i^)-isocitrate with NADP^ regeneration using isocitrate dehydrogenase (IC-DH, EC 1.1.1.42), AMAPORs in form of crude extracts of C thermoaceticum, anthraquinone-2,6-disulphonate and oxygen. The reaction mixture contained --^140000 U catalase. rac. threo isocitrate (mM) 50 360 AMAPOR (U)
23 70

IC-DH (U) 22 45

Yield (%) 100 100

Reaction time (h)

4 33

Number of cycles forNADP^ regeneration 260 1250

A total volume of 40 ml 0.1 M Tris/HCl buffer, pH 7A, at 33 ^C, contained 1 mM anthraquinone-2,6-disulphonate, 3.3 mM MgCh, 0.1 mM NADP^ and the indicated concentrations of (2R, 3S;2S, 3R)-isocitrate. (ii) Dehydrogenation of the (S)-enantiomer from racemates of 3-hydroxycarboxylates with NADP^ regeneration for preparation of (i^)-3hydroxycarboxylates For the enantioselective dehydrogenation of the (S^-enantiomer from a racemic mixture of 3-hydroxybutyrate three different methods were used to regenerate NADP^ (Table 27) (83). The first method worked with catalytic concentrations of NADP^ and anthraquinone-2.6-disulphonate. NADPH was reoxidized by oxidized antliraquinone-2.6disulphonate catalysed by AMAPOR (Reaction [31a]). The reduced anthraquinone-2.6disulphonate was electrochemically reoxidized. In experiment 2 a method described by the Whitesides group (106) was applied for NADP^ regeneration. Oxidized anthraquinone-2.6-disulphonate could also be used in stoichiometric concentrations (exp. 3). In such a case its electrochemical reoxidation was not necessary. Obviously in experiment 1 the product isolation is especially simple. Using the purified (5)-3-hydroxybutyrate oxidoreductase from C tyrobutyricum (107) together with an electromicrobial NADP^ regeneration system with AMAPOR of C. thermoaceticum crude extracts and anthraquinone-2.6-disulphonate, the (iS)-enantiomer of 1.6 mmol (/?,5)-3-hydroxybutyrate was dehydrogenated (exp. 1, Table 27). The remaining (i?)-3-hydroxybutyrate showed 98 % ee. Application of the NADP^-regenera-

874

tion system described by Chenault and Whitesides (87) with the purified (iS)-3hydroxybutyrate oxidoreductase also led to (i^)-3-hydroxybutyrate with 98 % ee but in the presence of 1 equivalent 2-oxoglutarate. In the microbial dehydrogenation (exp. 3) 0.8 g C. tyrobutyricum and 0.3 g C. thermoaceticum cells together with 110 mM anthraquinone-2.6-disulphonate were used. The (.SJ-enantiomer from 4.0 mmol racemic 3-hydroxybutyrate was enantioselectively dehydrogenated. Part of the 3-oxobutyrate formed was converted into acetone and CO2. It was proven that a crude extract of C. tyrobutyricum is not able to transfer electrons to the mediator anthraquinone-2.6-disulphonate, and that C. thermoaceticum lacks (iS)-3-hydroxycarboxylate oxidoreductase. TABLE 27 Enantioselective dehydrogenation of the (5)-enantiomer of (i?,iS)-3-hydroxybutyrate to a mixture of (i^)-3-hydroxybutyrate, 3-oxobutyrate and acetone. NADP^ was regenerated in three different ways (83). No. 1 Substrate concentr. (mM) 40 Amount of Reaction Yield* Enantiome- Pyridine nucleotide substrate time ric excess regeneration system (mmol) (h) (%) (%) 1.6 16 95 98 Electromicrobial NADP^ regeneration with C. thermoaceticum 2-Oxoglutarate/glutamate dehydrogenase AQDS(!10mM),NADP" (1 mM), C. thermoaceticum, C. tyrobutyricum

2 3

40 200

1.6 4.0

16 30

95 90

98 96

Yield of (i?)-enantiomer.

5.2 NADH and NADPH regeneration with crude extract of Clostridium thermoaceticum and other cells Using the purified fS^-3-hydroxycarboxylate oxidoreductase (107) and two forms of NADPH regeneration led to the chiral 3-hydroxy carboxylates shown in Table 28 (83). All products of the bioreduction procedures showed ee values greater than 98 %. On the basis of the optical rotation value reported (108) the synthesized 3-hydroxybutyrate was the (5)-enantiomer. It was assumed that the configuration of the other prepared 3hydroxycarboxylates was the same. As checked with racemic mixtures of the derivatives of the four 3-hydroxy acids mentioned in Table 28, the applied chiral gas/hquid chromatography columns separated the enantiomers. For details see (83).

875

TABLE 28 Preparation of various (iS)-3-hydroxy-carboxylates by reducing 130 mM solutions of the corresponding 3-oxo carboxylates with purified (iS)-3-hydroxy carboxylate oxidoreductasefi*omC tyrobutyricum (109) and the regeneration^^ of NADPH (83). Product 3-Hydroxybutyrate 3-Hydroxybutyrate 3-Hydroxyvalerate 3-Hydroxyvalerate 3-Hydroxycaproate 3-Hydroxycaproate 3 -Hydroxyisocaproate 3-Hydroxyisocaproate Enantiomeric excess ( % ) >99 >99 >99 >99 >98 >98 >99 >99 Yield (%) 98 98 98 98 95 95 80 95 Pyridine nucleotide regeneration system Electrochemical cell/AMAPOR FDH/formate Electrochemical cell/AMAPOR FDH/formate Electrochemical cell/AMAPOR FDH/formate Electrochemical cell/AMAPOR FDH/formate

NADPH was regenerated under anaerobic conditions by crude extracts of C. thermoaceticum containing formate dehydrogenase (FDH) as well as artificial mediator accepting pyridine nucleotide oxidoreductases (AMAPORs) and formate as electron donor. For electromicrobial redox reactions see Section 6. Also the microbial reduction of 3-oxobutyrate with cells of C. tyrobutyricum occurred enantioselectively (Table 29). The (5)-3-hydroxybutyrate showed ee values above 96 %. Without addition of NADP^ to C tyrobutyricum cells 3-oxobutyrate was reduced very slowly (exp. 1). The addition of 1 mM NADP^ to broken cells of C. tyrobutyricum led to an almost 16 fold productivity number (exp. 2). This is the simplest method. By addition of cells of C thermoaceticum the quantitative reduction of 200 mM 3-oxobutyrate could be performed at the expense of hydrogen gas with a productivity number of 1520 (exp. 3). The acceleration fi'om experiment 2 to 3 is caused by the higher AMAPOR activities in the reaction mixture. Cells of C. tyrobutyricum possess 0.80 U*mg'^ protein NADP(H)-dependent AMAPOR activity (97), whereas in cells of C. thermoaceticum this activity is about 8-9 U*mg'^ protein (82). Further examples of the combination of enriched or even purified enzymes together with a crude extract of C. thermoaceticum in the presence of added small concentrations of pyridine nucleotide are shown in fiirther experiments. The increased concentration of NADP^ in the reaction system when additional 0.06 g wet packed cells of C. thermoaceticum were used resulted in a productivity number of 890 (exp. 4). This indicates that the amount of NADP^ in cells of C. thermoaceticum was sufficient for a reasonable reduction rate. We determined about 50 ^g NADP^ per g C. thermoaceticum cells. The conditions applied in experiments 3 and 4 were also usefiil for the reduction of 400 mM solutions of 3-oxobutyrate (exp. 5 and 6). Using formate instead of hydrogen gas as electron donor, under conditions otherwise identical to those used in experiment 4, decreased the productivity number to 420 (exp.7). Starting with 10 mmol 3-oxobutyrate in a 200 mM concentration, obtained

876

by hydrolysis of the ester, led in the presence of 0.3 mM NADP^ with C. tyrobutyricum to a productivity number of 350 (exp. 8). This seems to be the most economic procedure, since ethyl 3-oxobutyrate is much cheaper than the lithium salt of 3-oxobutyrate (83). Table 29 Preparation of (/S)-3-hydroxybutyrate from 3-oxobutyrate by resting cells of C. tyrobutyricum and various additions for the regeneration of the pyridine nucleotide NADPH. For methods A, B and C see text. Substrate No. concentr. (mM) 1 2 200 200 200 Reaction PN time * (h) mmol*kg^h-^ 72 30 37 590 1520 Yield Electron donor (%) 15 88 95
H2 H2

Pyridine nucleotide regeneration system MV (1 mM)'' MV (1 mM), NADP"^ (1 mM), method A MV (1 mM)^ NADP* (ImM), 60 mg C. thermoaceticum MV (1 mM)^ 60 mg C thermoaceticum MV (1 mM)^ NADP^ (ImM), 60 mg C thermoaceticum MV (1 niM)\ 60 mg C. thermoaceticum

H,

4 5

200 400

25 24

890 890

90 90

H2 H2

6 7

400 200

48 40

450 420

80 82

H2

Formate Formate (250 mM), 900 mg C. tyrobutyricum, 600 mg C. thermoaceticum, method B H2 MV (1 mM), NADP^ (0.3 mM), 3000 mg C tyrobutyricum, method C

200

48

350

80

^ Time for quantitative reduction.

Variationof method A.

With purified (5)-3-hydroxybutyrate oxidoreductase yields of 80-98 % for reductions and dehydrogenations are quite acceptable (Tables 28,29). The use of formate as an electron donor together with crude extract of C thermoaceticum is simple and effective. NADH regeneration systems A-C mentioned in Table 29 (83) Method A: A solution containing 1.6 ml 100 mM Tris/HCl buffer, pH 8.0, 0.09 g wet packed cells of C tyrobutyricum, 1 mM NADP^, 1 mM methylviologen and 50 jug tetracycline was placed in a 25 ml glass vessel combined with a mercury filled Warburg

877

manometer. The reduction was started by adding 200 mM 3-oxo-butyrate, produced by hydrolysis of 200 mM ethyl 3-oxo-butyrate by 50 U esterase to the mixture and shaking it under an atmosphere of hydrogen gas at 35 C. The progress of reduction was indicated by the decreasing hydrogen pressure. Method B: A solution containing 25 ml 0.1 M Tris/HCl buffer, pH 8.0, 0.9 g wet packed cells of C. tyrobutyhcum, 0.6 g wet packed cells of C thermoaceticum, 1 mM NADP^, 250 mM formate, 0.5 mg tetracycline and 200 mM 3-oxo-butyrate, by hydrolysis of 200 mM ethyl 3-oxobutyrate by 100 U esterase, was placed in a 50 ml glass vessel at 35 C under an atmosphere of nitrogen gas. The mixture was magnetically stirred. Method C: A solution containing 50 ml 0.1 M Tris/HCl buffer, pH 8.0, 3.0 g wet packed cells of C tyrobutyricum, 0.3 mM NADP^, 1.5 mg tetracycline and 200 mM 3oxobutyrate, produced as mentioned above by hydrolysis of 200 mM ethyl 3-oxobutyrate by 100 U esterase, was placed in a 500 ml glass vessel under an atmosphere of hydrogen gas at 35 C. The reduction started after adding 1 mM methylviologen and shaking. The progress of the reduction was followed by measuring the decreasing dihydrogen pressure. 5.3 Growth of Clostridium thermoaceticum and Clostridium formicoaceticum The cells of C. thermoaceticum DSM 521 (16) were grown in volumes up to 300 1 at 65 C according to (82a) with the following change and additional supplements: sodium thioglycolate was omitted, 10 g NaHCOs, 0.1 g Na2S204 and 0.134 mg NiCl2*6H20 were added per litre growth medium. The yield on wet packed cells was 10-14 g*r^ (76). Cells of C. formicoaceticum DSM 92 (16) were grown on DSM medium 14 (16, p. 280) with some modifications (81). The medium contained the following trace elements additionally or in differing amounts: 100 ^M Fe(NH4)(S04)2, 100 ^iM C0CI2, 10 ^iM Na2W04, 10 ^MNa2Mo04*2H20, 1 iaMNa2Se03, l^MNiCl2, and 280 ^MNa2S204. A modified medium containing 100 mM fiimarate instead of NaHCOs at a pH value between 8.0-8.5 delivered cells with high activities of fiimarate reductase and fimiarate hydratase. The cells were grown in a range from 0.2-300 1, harvested at the beginning of the stationary phase (A578 = 4.5) and stored at -18 C under nitrogen.

6 . FURTHER EXAMPLES OF ELECTROMICROBIAL AND ELECTROENZYMIC REDOX REACTIONS

Enoate reductase, 2-hydroxy carboxylate viologen oxidoreductase (HVOR) and AMAPORs (Section 5) are enzymes able to accept reversibly single electrons from artificial mediators such as viologens and others. These mediators transfer electrons from or to electrodes. Therefore by the presence of the aforementioned enzyme activities biocatalytic redox reactions can be carried out in electrochemical cells. As already mentioned in Section 1.2 AMAPORs catalysing Reactions [8] and/or [8a] are rather ubiquitous. Electromicrobial reductions can also be carried out with yeasts (Section 1,2). Since the potential of the working electrode can be chosen at will, reductions as well as

878

dehydrogenations can be performed if suitable mediators are applied. We demonstrated that in various papers (6-8,10). For reductions in aqueous solutions cathodes with a high overpotential for hydrogen formation must be applied in order to reduce only the artificial mediator. This can be checked by means of cyclovoltammetry (110). Moreover the artificial mediator must not react spontaneously with the substrate. Gold, silver, carbon and mercury are suitable cathode materials when working in a neutral pH range and at working potentials higher than -450 mV versus SCE (saturated calomel electrode). In case of more negative working potentials, lead, bismuth antimony and tin cathodes become also suitable. The electrochemical cell is a standard three electrode arrangement with the reference electrode as the third electrode. Schematic drawings of electrochemical cells used are depicted in (7,8) together with more detailed information. When reductions are performed, oxygen is formed at the anode which may oxidize the reduced artificial mediator forming highly reactive species of oxygen which in turn destroy other components of the catholyte. Therefore catholyte and anolyte must be separated by a diaphragm, which has to meet several requirements: (i) It has to allow proton transfer from the anolyte where protons are formed to the catholyte where protons are consumed (Scheme 2a). (ii) It has to be sufficiently conductive, (iii) It has to prevent oxygen from passing through. Nafion ion exchange membranes with a thickness of 0.5 mm have proofed to be suitable. In addition anaerobic conditions are maintained by flushing buffer and cathode compartment of an electrochemical cell with an inert gas. For dehydrogenations the working electrode must be inert to the positive potentials applied, therefore noble metals have to be used in order to avoid the eventually negative influence of heavy metal cations on enzymes. Also carbon electrodes are very suitable working electrodes since on oxidation no inhibiting heavy metal cations are formed. For optimisation purposes of the described redox systems an electrochemical cell may be especially useful, since the current is a measure of the reaction rate. For a reaction consuming two moles of electrons per mol of substrate a current of 3.2 mA reduces 1 jimol substrate per minute. The influence of all measures taken to optimise the system as varying pH, concentrations, temperature etc. can be followed by recording the current. It is easy to supply 10^-10"* U of enzyme activity contained in wet packed cells of a microorganism or especially when the enzyme is already enriched in 100 ml electrolyte. Under these conditions, the over all reaction rate in the electrochemical cell is often limited by the reduction of the artificial mediator. Sufficiently large electrodes and efficient stirring are helpfiil measures to avoid such limitations. When a microorganism is used for the catalysis of a pyridine nucleotide dependent redox reaction the reaction rate may be limited by the concentration of the pyridine nucleotide. If broken cells are used the concentrations of the necessary nucleotide such as NAD"^ or NADP^ can be added (see Table 29 for an example). If the reaction rate is limited by AMAPOR activity crude extracts of C. thermoaceticum or that of another microorganism can be added. An example for such an optimisation is shown in Fig. 4 (97). This experiment was performed in order to demonstrate what is going on. As examples for preparative purposes see Fig. 4-6 and Tables 30, 31.

879

mA 1.5 1.0 0.5 7 Time [h] Fig. 4. Combination of Candida utilis and Alcaligenes eutrophus cells in an electrochemical cell for the reduction of hydroxyacetone. The C. utilis cells contained 0.63 U of a carbonyl group reductase and the A. eutrophus cells 0.62 U AMAPOR. The cells were suspended in 40 ml 0.1 M Tris buffer, pH 7.0, containing 3.3 mM methylviologen. The applied cathode potential was -700 mV versus SCE. A: Addition of 1.4 mg disrupted cells (dry weight) of C. utilis; B: Addition of 32 jjmol NAD^; C: Addition of 400 jjmol: hydroxyacetone; D: Addition of 0.65 mg disrupted cells (dry weight) of A. eutrophus. The C. utilis cell extract contained about 0.12 U AMAPOR for NADHformation and that of A. eutrophus < 0.003 U hydroxyacetone reductase. 1 Two typical examples for an electroenzymic and an electromicrobial reduction of 6 mmol (')-2-metliylcinnamate and 24.6 mmol 2-oxo-5-methylpentanoate, respectively, are given in Fig. 5 and 6(111). Examples for electroenzymic dehydrogenations combined with electromicrobial regeneration of pyridine nucleotides with C. thermoaceticum are presented in Tables 30 and 31. A graphite working electrode (35-40 cm^, Sigraflex 72010 from SIGRI Electrographite, Germany) was applied. The counter electrode compartment contained a platinum electrode dipped in 3 ml 3.0 M H2SO4. Details are given in Tables 30 and 31. In Section 5 Table 25 the preparation of 6-phospogluconate from glucose-6-phosphate is described using oxygen as the final acceptor. For HVOR oxidized methylviologen is a positive effector but reduced methylviologen becomes strongly inhibiting already in concentrations <0.1 mM, therefore the electrochemical reaction (Reaction [1]) must always be the limiting reaction (48). For the reduction of 2-0X0 carboxylates the rates increase with the decreasing ratio MV^*/MV^^. Benzylviologen does not show these effects. In Fig. 6 the current does not drop to the the starting value but to -50 mA when all phenylpyruvate is reduced after -12 h. At this rate hydrogen gas is formed via hydrogenase also present in P. vulgaris since the concentration of MV^* was <1/10 the K^ of the hydrogenase until the HVOR reaction stops. Using cells of P. vulgaris grown on lactate instead of glucose productivity numbers of up to 450 000 have been achieved (unpublished). 3 4 5 6

880

imA

40 30 20 10

1 1
1
i

10

12 * Time [h]

Fig. 5. Electroenzymic reduction of {E)-2'methylcinnamate. The cathode compartment of an electrochemical cell contained 85 ml 0.1 M potassium phosphate buffer pH 7, 6.0 mmol 2-methylcinnamate and 0.28 mmol methylviologen. The working potential was set to -760 mM versus SCE and after the reduction of the methylviologen the reaction was started by adding 15 U enoate reductase. A maximum current of -40 mA was recorded. The drop of the current to almost zero was indicative for the complete conversion of the substrate to {R)-2-methyl-3-phenylpropanoate. Fig. 6 demonstrates the preparative electromicrobial reduction of of 2-oxo-4-methylpentanoate to (i^)-2-hydroxy-4-methylpentanoate. ^mA

^^Time[h] Fig. 6. Scan of the current during the electromicrobial reduction of phenylpyruvate. The cathode compartment contained 200 ml 0.1 Mpotassium phosphate buffer, pH 7.0, 20 mmol phenylpyruvate and 3 mM methylviologen. The working potential was set to -760 mV versus SCE. After adding 0.075 g wet packed cells of Proteus vulgaris and starting to stir at a rate of ^400 rpm a current of ^35 mA was obtained. The amount of P. vulgaris was too much since the electrochemical reaction Reaction [1]) was limiting (48) (catholyte not blue). Therefore at A the starting concentration of 3 mM methylviologen was doubled to 6 mM. According to HPLC, 96 % of the expected quantity of (R)-phenyllactate was formed after 12 h. The productivity number was approximately 125 000.

881

Table 30 Oxidative decarboxylation of 6-phosphogluconate to ribulose-5-phosphate with 6phosphogluconate-dehydrogenase and electromicrobial NADP^ regeneration with partially purified AMAPOR. Forty ml 0.1 M Tris/HCl buffer, pH 7.2, contained 20 mM 6-phosphogluconate, 3 mM CAV, 0.5 mM NADP^, 3.3 mM MgCl2 and 6-phosphogluconatedehydrogenase (15 U). The reaction temperature was 30 C and the working potential was -200 mV versus SCE. NADP^ regenerating system C. thermoaceticum^ C. thermoaceticunf AMAPOR^ AMAPOR (U) 20 7 20 Yield (%) 80 80 98 Reaction time

(h)
2.3 n.d. 2.5

^ Used as crude extract. ^ Partially enriched by heat treatment of crude extract at 61 C for 30 min, ammonium sulphate precipitation (45 % saturation), resolubilisation of the precipitated protein in 50 mM TEA-maleate buffer, pH 7.5, and chromatography on a Sepharose G 200 column. Table 31 Electromicrobial NADP^ regeneration for the oxidative decarboxylation of (2R,3S)isocitrate fi-om racemic isocitrate leading to (2iS,3i?)-isocitrate, using different mediators. Forty ml 0.1 M Tris/HCl buffer, pH 7.4, contained the indicated concentration of racemic isocitrate, 3 mM mediator, 0.5 mM NADP^, 3.3 mM MgCl2, 0.1-0.3 g wet packed cells of C thermoaceticum and 20-40 U isocitrate dehydrogenase EC 1.1.1.42 fi-om porcine heart. The reaction temperature was 37 C, and the working potential was -200 mV versus SCE. Substrate concentration (mM) 400 50 50 Mediator CAV CAV AQ-2,6-DS After I h n.d. 15 000 17 000 Productivity number After the end Reaction time of reaction (h) 2 600 13 000 14 000 37.3 3.8 3.6

The relatively low productivity number in the experiment with 400 mM substrate is probably due to an inhibition of one or both enzymes by isocitrate .

882

ACKNOWLEDGEMENTS We gratefully acknowledge financial support by Deutsche Forschungsgemeinschaft (SFB 145), EG Programmes BAP 250 (D) and BRIDGE BIOT-CT-90-0157, Fonds der Chemischen Industrie, by BASF and other chemical companies. The extraordinary engagement of co-workers mentioned in the references and of the technical staff is thankfully appreciated.

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J. Caldeira, R. Feicht, H. White, M. Teixeira, J. J. G. Moura, H. Simon and I. Moura, J. Biol. Chem., 271 (1996) 18743-18748. J. Bader, H. Giinther, E. Schleicher, H. Simon, S. Pohl and W. Mannheim, Arch. Microbiol., 125 (1980) 159-165. J. Bader and H. Simon, Arch. Microbiol., 127 (1980) 279-287. H. Sedhnaier, W. Tischer, P. Rauschenbach and H. Simon, FEBS Letters , 100 (1979) 129-132. H. Hashimoto, B. Rambeck, H. Giinther, A. Mannschreck and H. Simon, HoppeSeyler's Z. Physiol. Chem., 356 (1975) 1203-1208. L. Angermaier and H. Simon, Hoppe Seyler's Z. Physiol. Chem., 364 (1983) 961975. R. Leinberger, W. E. Hull, H. Simon and J. Retey, Eur. J. Biochem., 117 (1981) 311-318. A. R. Battersby, A. L. Gutman, C. J. R. Fookes, H. Gunther and H. Simon, J. Chem. Soc. Chem. Comm., (1981) 645-647. A. Gabler, W. Boland, U. Preiss and H. Simon, Helv. Chim. Acta, 74 (1991) 17731789. M. Veith, M. Lorenz, W. Boland, H. Simon,and K. Dettner, Tetrahedron, 50 (1994) 6859-6874. P. Egerer and H. Simon, Biochim. Biophys. Acta, 703 (1982) 158-170. R. Eck and H. Simon, Tetrahedron, 50 (1994) 13631-13640. H. Brunner, W. Zettlmeier, in Handbook of Enantioselective Catalysis with Transition Metal Compounds, VCH Weinheim, Weinheim - New York. A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert and A. Tijani, J. Am. Chem. Soc, 116 (1994) 4062-4066. E. Krezdom, S. Hocherl and H. Simon, Hoppe-Seyler's Z. Physiol. Chem., 358 (1977)945-948. R. Eck and H. Simon, Tetrahedron, 50 (1994) 13641-13654. L. Angermaier, J. Bader and H. Simon, Hoppe-Seyler's Z. Physiol. Chem., 362 (1981)33-38. J. Bader, M.-A. Kim and H. Simon, Hoppe-Seyler's Z. Physiol. Chem., 362 (1981) 809-820. P. Egerer and H. Simon, Biotechnol. Lett., 4 (1982) 501-506. G. Gorgen, W. Boland, U. Preiss, and H. Simon, Helv. Chim. Acta, 72 (1989) 917928. M.-J. Kim and G. M. Whitesides, J. Am. Chem. Soc, 110 (1988) 2959-2964. M. A. Luyten, D. Bur, H. Wynn, W. Parris, M. Gold, J. D. Friesen and J. B. Jones, J. Am. Chem. Soc, 111 (1989) 6800-6804 and literature cited there. A. Schummer, H. Yu and H. Simon, Tetrahedron, 47 (1991) 9019-9034. H. Yu and H. Simon, Tetrahedron, 47 (1991) 9035-9052. D. Bonnaffe and H. Simon, Tetrahedron, 48 (1992) 9695-9706. T. Trautwein, F. Krauss, F. Lottspeich and H. Simon, Eur. J. Biochem., 222 (1994) 1025-1032. C. Schinschel and H. Simon, Appl. Microbiol. Biotechnol., 38 (1993) 531-536. H. Gunther, S. Neumann and H. Simon, J. Biotechnol., 5 (1987) 53-65. R. Eck and H. Simon, Tetrahedron Asym., 5 (1994) 1419-1422. M. Reimer, J. Am. Chem. Soc, 53 (1931) 3147-3149. E. Friedmann, Helv. Chim. Acta, 14 (1931) 783-793. T. Anke, G. Schramm, B. Schwalge, B. Steffan and W. StegUch, Liebigs Ann. Chem., (1984) 1616-1625. M. Rambaud, M. Bakasse, G. Duguay and J. ViUieras, Synthesis, (1988) 564-566. G. M. Ksander, J. E. McMurry and M. Johnson, J. Org. Chem., 42 (1977) 11801185.

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A. Takeda, S. Wada, M. Fujii and H. Tanaka, Bull. Chem. Soc. Jpn., 43 (1970), 2997-2998. 56 S. Tsuboi, H. Furutani, M. Utaka amd A. Takeda, Tetrahedron Lett., 28 (1987), 2709-2712. 57 J.-L. Luche, J. Am. Chem. Soc, 100 (1978), 2226-2227. 58 S. Neumann and H. Simon, FEES Letters, 167 (1984) 29-32. 59 H. Simon, H. Giinther, J. Bader and S. Neumann, in : Enzymes in OrganicSynthesis, Ciba Foundation Symposium, Pitman, London, 111 (1985) 97-111. 60 G. Gubitz and S. Mihellyes, Chromatographia, 19 (1984) 257-259. 61 C. Schinschel and H. Simon, Bioorg. & Med. Chem., 2, (1994) 483-491. 62 C. Schinschel and H. Simon, J. Biotechnol., 31 (1993) 191-203. 63 M. L. Fultz and R. A. Durst, Anal. Chem. Acta, 140 (1982) 1-18. 64 J. Knappe and G. Sawers, FEMS Microbiol. Rev., 75 (1990) 383-398. 65 O. Theander, in: W. Pigman and D. Horton (eds.) The Carbohydrates. Chemistry and Biochemistry Vol. IB., Academic Press, New York, 1980, pp. 1013-1085. 66 T. Sugai, G. J. Shen, Y. Ichikawa and C. H. Wong; J. Am. Chem. Soc, 115 (1993) 413-421. 67 H. Roper, VCH Verlagsgesellschaft Weinheim 1991 267-288, in: Carbohydrates as Organic Raw Materials, ed. F. W. Lichtenthaler. 68 P. C. C. Smits, EP-A-0 152 498 (Int. CI. C0H7/027(1984)) Chem. Abstr., 103 (1985) 160805q. 69 (a) G. S. Eadie, J. Biol. Chem., 146 (1942) 85; (b) B. H. J. Hofstee, J. Biol. Chem., 199(1952)357-364. 70 V. F. Pfeifer, C. Vojnovich, E. N. Heger, G. E. N. Nelson and W. C. Haynes, Ind. Eng. Chem., 50 (1958) 1009-1012. 71 M. A. Ghalambor, E. M. Levine and E. C. Heath, J. Biol. Chem., 241 (1966), 32073215. 72 K. Gatzi and T. Reichstein, Helv. Chim. Acta, 21 (1938) 456-463. 73 G. Karsten and H. Simon, Appl. Microbiol. Biotechnol., 38 (1993) 441-446. 74 H. Simon, H. White, H. Lebertz and I. Thanos, Angew. Chem. Int. Ed. Engl., 26 (1987)785-787. 75 H. White, G. Strobl, R. Feicht and H. Simon, Eur.J. Biochem., 184 (1989) 89-96. 76 G. Strobl, R. Feicht, H. White, F. Lottspeich and H. Simon, Biol. Chem. HoppeSeyler, 373 (1992) 123-132. 77 C. Ruber, H. Skopan, R. Feicht, H. White and H. Simon, Arch. Microbiol., 164 (1995)110-118. 77a H. White and H. Simon, Arch. Microbiol., 158 (1992) 81-84. 78 C. Ruber, J. Caldeira, J. A. Jongejan and H. Simon, Arch. Microbiol., 162 (1994) 303-309. 79 P. A. Loach in: G. D. Fasman (Ed.), Handbook of Biochemistry and Molecular Biology: Physical and Chemical Data (3'^* Edition). CRC Press, Cleveland, 1976, pp. 122-130. 80 H. White, C. Huber, R. Feicht and H. Simon, Arch. Microbiol., 159 (1993) 244-249. 81 H. White, R. Feicht, C. Huber, F. Lottspeich and H. Simon, Biol. Chem. HoppeSeyler, 372 (1991) 999-1005. 82 M. Schulz, M. Bayer, H. White, H. Giinther and H. Simon, Biocatalysis, 10 (1994) 25-36. 82a L. G. Ljungdahl and J. R. Andreesen, Methods Enzymology, 53 (1978) 360-372. 83 M. Bayer, M. Schulz, H. Giinther and H. Simon, Appl. Microbiol. Biotechnol., 42 (1994)543-547. 84 E. V. Price and L. Levintov, Biochemical Preparations, 2 (1952) 22-24. 85 S. W. Ragsdale, J. E. Clark, L. G. Ljungdahl, L. L. Lundie and H. L. Drake, J. Biol. Chem., 258 (1983) 2364-2369.

55

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86 86a 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112

M. Schulz, H. Leichmaim, H. Giinther and H. Simon, Appl. Microbiol. BiotechnoL, 42 (1995) 916-922. M. Bayer, K. Walter and H. Simon, Eur. J. Biochem., 239 (1996) 686-691 H. K. Chenault and G. M. Whitesides, Appl. Biochem. Biotech., 14 (1987) 147-197. H. K. Chenault and G. M. Whitesides, Bioorganic. Chem., 17 (1989) 400-409. H. K. Chenault, E. S. Simon and G. M. Whitesides, Biotech. Genetic Eng. Rev., 6 (1988)221-270. J. Peters and M.-R. Kula, Biotechnol. Appl. Biochem., 13 (1991) 363-370. D. Westerhausen, S. Herrmann, W. Hummel and E. Steckhan, Angew. Chem. Int. Ed. Engl., 31 (1992) 1529-1531. I. Wilhier and D. Mandler, Enzyme Microb. Technol., 11 (1989), 467-483. A.-E. Biade, C. Bourdillon, J.-M. Laval, G. Mairesse and J. Moiroux, J. Am. Chem. Soc, 114(1992)893-897. U. Kragl, D. Vasic-Racki and C. Wandrey, Chem.-Ing.-Tech., 64 (1992) 499-509. D. Weuster-Botz, H. Paschold, B. Striegel, H. Gieren, M.-R. Kula and C. Wandrey, Chem. Eng. Technol, 17 (1994) 131-137. K. Seelbach, B. Riebel, W. Hummel, M.-R. Kula, V. I. Tishkov, A. M. Egorov, C. Wandrey and U. Kragl, Tetrahedron Lett., 37 (1996) 1377-1380. J. Bader, H. Giinther, S. Nagata, S.; H.-J. Schutz, M.-L. Link and H. Simon, J. Biotechnol, 1(1984)95-109. S. Nagata, R. Feicht, W. Bette, H. Giinther and H. Simon, Appl. Microbiol. Biotechnol, 26 (1987) 263-267. H. Giinther and H. Simon, Appl. Microbiol. Biotechnol, 26 (1987) 9-12. S. Nagata, H. Giinther, J. Bader and H. Simon, FEBS Letters, 210 (1987) 66-70. H. Giinther, A. S. Paxinos, M. Schulz, C. van Dijk and H. Simon, Angew. Chem. Int. Ed. Engl, 29 (1990) 1053-1055. A. S. Paxinos, H. Giinther, D. J. M. Schmedding and H. Simon, Bioelectrochem. Bioenerg., 25 (1991) 425-436. H. Giinther, C. Frank and H. Simon, in: D. Behrens (ed.), DECHEMA Biotechnology Conferences 4, VCH, Weinheim, 1990, pp. 107-110. H. Giinther, A. S. Paxinos, M. Schulz and H. Simon, in: D. Behrens (ed.), DECHEMA Biotechnology Conferences 4, VCH, Weinheim, 1990, pp. 281-285. O. Miyawaki and T. Yano, Enzyme Microb. Technol, 14 (1992) 474-478. C.-H. Wong, A. PoUak, S. D. McCurry, J. M. Sue, J. R. Knowles and G. M. Whitesides, Methods Enzymol, 89 (1982) 108-121. M. Bayer, H. Giinther and H. Simon, Appl. Microbiol Biotechnol, 42 (1994) 4045. A. Kramer and H. P. Pfander, Helv. Chim. Acta, 65 (1982) 293-301. M. Bayer, H. Giinther and H. Simon, Arch. Microbiol, 163 (1995) 310-312. J. C. Hoogvliet, L. C. Lievense, C. van Dijk and C. Veeger, Eur. J. Biochem., 174 (1988)273-280. H. Simon, and H. Giinther, in: W. Crueger, K. Esser, P. Praeve, M. Schlingmann, R. Thauer and F. Wagner (Eds.), Jahrbuch der Biotechnologie 1986/87, Carl Hanser Verlag, Miinchen, pp. 359-367. H. E. J. Hendriks,B. F. M. Kuster and G. B. Marin, Carbohydr. Res., 214 (1991) 7185.

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Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 20 1998 Elsevier Science B.V. All rights reserved.

887

Microcystins and Nodularins Hepatotoxic Cyclic Peptides of Cyanobacterial Origin

Luis Moroder and Sabine Rudolph-Bohner Max-Planck-Institut fur Biochemie, Am Klopferspitz 18a, D-82152 Martinsried Germany

The harmfull effects of cyanobacteria (blue-green algae) that grow worldwide in eutrophic fresh and brackish water as well as in marine environments, were originally noted more than a century ago, but only recently was it shown that these organisms produce a variety of bioactive compounds. Among these the microcystins are one important group of cyanobacterial toxins that are involved in poisoning of animals and in human health problems around the world. The microcystins are cyclic heptapeptides characterized by a common invariable structure containing a few variable sections, and all are potent toxins that inhibit the action of type-1 and type-2A protein phosphatases, two of the major serine!threonine specific protein phosphatases in eukaryotic cells, and thus are potent liver tumour promoters. While there is ample information as to the toxicity of these cyanobacterial peptides, their mechanism of action at molecular level as well as their three-dimensional structure in solution and in the enzymebound state have only recently been disclosed. Because of their profound cellular effects, their use as pharmacological probes for enzyme functions may facilitate the understanding of a large diversity of physiological processes that are under the control of reversible phosphorylation. Similarly, knowledge of their mode of action may possibly lead to the design of new classes of phosphatase inhibitors as potential anti-tumor agents, anti-inflammatories and immunosuppressants.

1.

Introduction

Reversible phosphorylation of proteins on serine, threonine and tyrosine residues by protein kinases and phosphatases represents the principal mechanism of signal transduction events that control a multitude of cellular processes (see ref. 1 and 2 for detained reviews). Phosphorylation is a posttranslational chemical modification that is used by prokaryotic and eukaryotic cells to define the properties of a large

888

variety of proteins including enzymes, receptors, ion channels and regulatory and structural proteins.

A^P

Protein kinase

^P^

Protein

Phosphoprotein

Phosphoprotein Phosphatase

^ Q

Fig. 1. Reversible protein phosphorylation From the thermodynamic point of view, phosphorylation and dephosphorylation are both favorable reactions which occur efficiently in the presence of the right catalysts, i.e. of protein kinases or protein phosphatases. Protein kinases are phosphotransferases which catalyse the transfer of the y-phosphoryl group of ATP to the side-chain hydroxyl group of serine, threonine and tyrosine in the presence of Mg2+. Protein phosphatases are phosphotransferases which catalyse the transfer of the phosphoryl group from the side-chain of an amino acid residue to water molecules (Fig. 1). Protein kinases recognize specific substrates and much is known and understood about their mode of regulation in vivo. Conversely, the broad substrate specificity of the protein phosphatases suggests the need of particular mechanisms to restrict the actions of these enzymes. It is therefore likely that higher orders of protein structure are involved in dictating substrate specificity for the phosphatases, since the activities of both protein kinases and phosphatases acting on a particular target molecule are tightly regulated (3). Protein phosphatases, unlike protein kinases, belong to several protein/gene families. They were classified on the basis of their substrate specificity, dependence on metal ions, and sensitivity to inhibitory agents (see Table 1). The activities of the type 1 and type 2A protein phosphatases (PP-1 and PP-2A) are independent of metal ions (4,5). The catalytic subunit of protein phosphatase-1 is bound to the regulatory

889

targeting proteins that determine the subcellular localization and activity of the enzyme (6). Protein phosphatase-2A is inactivated by phosphorylation of tyrosine residues on the molecule (7). The type 2B protein phosphatase (PP-2B), also known as calcineurin, consists of a catalytic subunit (A-subunit) and a regulatory subunit (B-subunit). It is dependent on Ca^^-calmodulin complex for complete activation (3).

Table 1. Classification of the phosphatases PP-1/PP-2A/PP-2B Family of Serine/Threonine Phosphatases - all are sensitive to okadaic acid - PP-1\ dephosphorylate preferentially the p subunit of phosphorylase kinase - inhibited by inhibitor 2 and by the phosphorylated form of inhibitor 1 - PP-2'. dephosphorylate preferentially the a subunit of phosphorylase kinase - insensitive to inhibitor 2 and the phosphorylated form of inhibitor 1 - PP-2 A: divalent cations are not required for activation - PP-2B (calcineurin): activated by Ca^"^ PP-2C Family of Serine/Threonine Phosphatases insensitive to okadaic acid activated by Mg2+ PTP Family of Tyrosine Phosphatases with transmembrane domains without transmembrane domains with dual specificity, i.e. dephosphorylation of serine/threonine and tyrosine

Over 40 protein tyrosine phosphatases have been characterized so far. They possess a catalytic domain and a range of other domains that appear to be essential for subcellular localization and regulation of enzymatic activity (4).

2.

Natural Inhibitors of Phosphatases

In many protein kinases, particularly those which are under the control of second messengers, the regulatory domain contains a pseudo-substrate sequence which binds to the catalytic site and thus prevents access of external substrates to the catalytic site. Binding of the second messengers to the regulatory domain relieves this

890

internal inhibitory effect. For other protein kinases phosphorylation of the catalytic domain is required. This phosphorylation can be either constitutive (autophosphorylation) or provided by a regulatory kinase. Conversely, little is known, so far, about the regulation of protein phosphatases by endogenous modulators. However, a large number of natural toxins (see Table 2) has been identified as powerful and specific inhibitors of the type 1, 2A and 2B family of serine/threonine phosphatases (Fig. 2) (8).

stimuli, e. g. Pliorbol Esters, cAMP, cGMP

^ . /

^ fee^H

ATP V^

Protein Ser/Thr Kinases

0-po:

( (rhr)-OH

Protein Phosphatases 1 and 2A

toxins, e. g. microcystins

Fig. 2. Inhibition of enzymatic dephosphorylation of serine- and threonine-0phosphate residues in proteins by toxins. Among these natural inhibitors of most diverse chemical structure there are two functional classes (9). First, there are the endogenous inhibitors 1 and 2 (heat-stable proteins) that regulate phosphatases within eukaryotic cells (10-12). The second group are secondary metabolites of bacteria, fungi, plants, dinoflagellates and insects whose natural roles may be in signalling, attack or defense interactions among the various organisms (Fig. 3). Unknowingly, the scientific study of natural substances that inhibit protein phosphatases dates back over one hundred years (13) with early reports on toxins produced by cyanobacteria (blue-green algae). In the last decade it could be shown that cyanobacteria produce a variety of bioactive compounds (4) among which microcystins represent the most important and dangerous group of cyanobacterial toxins (15). Since the signalling pathways based on phosphorylation/dephosphorylation play a key role in essential in vivo regulatory mechanisms, such as hormone action and cell growth control (2,16-17), inhibiton of the enzymes involved by exogeneous substances, present in food and water supply, may represent serious hazards not only to livestock, wild animals, birds and fish, but also to human health.

891 Microcystin-LR

Hs^H^
HNv^/N
NHo

^ r

HCH3H
COOH'

CHo CH

Nodularin
COOH

HX

^^

Okadaic acid

Tautomycin

892

Calyculin-A
OH

H3C

A "
CH3

OH OH

OCH3

Cyclosporin A
CH3
CH3 H

^'^IH^

\H3CHO

H^^HCHa

..

H3C Ri = CH(OH)CH(CH3)CH2CH=CHCH3

CH3

FK506

OCH, CH3 CH3 ^ ^ - - - O H

893

Cantharidin

<5^
Endothall

Fig. 3. Chemical structures of exogenous natural inhibitors of type 1, 2A and 2B serine/threonine-protein phosphatases.

Table. 2. Properties of serine/threonine-protein phosphatase inhibitors Inhibitor phosphatases 1 and 2A - okadaic acid - acanthifolicin - dinophysistoxin - tautomycin - microcystin - nodularins - mutoporins - calyculin A - cantharidin - endothall - inhibitors 1 and 2 phosphatases 2B - cyclosporin - FK506 cyclic peptide macrocycHc lactone inhibition as cyclosporin/ cyclophilin complex inhibition as FKBP/FK506 complex Chemical Structure polyether carboxylic acids Potency PP-2A>PP-1PP-2B

polyketide cyclic peptides

PP-1>PP-2APP-2B PP2A~PP-1PP-2B

phosphorylated polyketide terpenoid terpenoid heat-stable proteins

PP2A~PP-1PP-2B PP2A>PP-1PP-2B PP2A>PP-1PP-2B PP-1

894

Such exogenous inhibitors, however, may also be of great benefit as was found to be the case for the cycHc peptide cyclosporin A and the macrolide FK506 from fungal origin, which are excellent inhibitors of calcineurin, the protein phosphatase 2B (18,19). Both are presently used as potent immunosuppressants in human medicine for the prevention of graft rejection. Cyclosporin A and FK506 interact with the endogenous proteins (immunophilins) cyclophilin and FK506-binding protein (FKBP), respectively, and the resulting complexes bind to the activated form of calcineurin and block its phosphatase activity with an IC50 < 10 nM. The physiological relevance of these pharmacological effects is unknown since no endogenous equivalent of cyclosporin or FK506 has yet been identified.

3,

Microcystins and Nodularins

Cyanobacteria grow in nutrient-enriched fresh and brackish waters as well as in marine environments around the world (20,21). The ability of the common bloomforming genera of cyanobacteria to produce low molecular weight hepatotoxins is well documented (22-24), although individual genera can include both toxic and nontoxic species. These toxins have been implicated worldwide in poisonings of domestic livestock, pets, and wildlife after the animals have consumed toxin-containing water and/or cyanobacterial cells from lakes, ponds and farmdugouts (25-28). Accidental ingestion of the toxins may also compromise human health (23,29-31). Cyanobacteria known to produce hepatotoxins include species of Microcystis (32-36), Anabaena (37-40), Nostoc (41,42), Oscillatoria (43,44) and the brackish water Nodiilaria spumigena (45,46). These cyanobacteria produce a wide range of toxins including neurotoxic alkaloids, lipopolysaccharides, phenolic compounds and most importantly, the cyclic hepatotoxic peptides microcystins and nodularins. Since both microcystins and nodularins were recently discovered even in shellfish (47) and tropical fish species (48), and a nodularin variant was isolated in Papua New Guinea also from the tropical marine sponge Theonella swinhoei (49), marine prokaryotes are apparently producing identical toxins as the cyanobacteria. However, since this nodularin variant was isolated from a marine sponge it may well be produced by a microbial symbiont. 3.1. Chemical Structure of Microcystins and Nodularins

Microcystins constitute a large family of cyclic heptapeptides with a high degree of homology in the amino acid sequence. As shown in Fig. 4, they are composed of DAla in position 1, two variable L-amino acids at positions 2 and 4, the p-linked Deryr/zro-P-methylaspartic acid (MeAsp) in position 3, the novel C20 p-amino acid (2S,3S,85,9S) - 3 - amino - 9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid

895

D-iso-Glu H COOH O

7 Mdhaor O ^^^ CH2KJ' D-Ala

H3C

HCH3

H >R

H3(f)=0 HN

4Y

3 D-Me-iso-Asp or D-iso-Asp

Fig. 4. Chemical structure of microcystins D-iso-Glu H COOH CHI 3 N' Mdhb CH.

H3C

HCH3

VVV'
f H 5
HN NH

Arg

H CO

COOH

D-Me-iso-Asp

HgN^

Fig. 5. Chemical structure of nodularins

896

(Adda) in position 5 followed by D-glutamic acid (D-Glu) y-linked to N-methyldehydroalanine (Mdha) (50-52). The main structural variations of the more than 50 variants isolated so far, are related to mutations at the two L-amino acids labeled with X and Y in Fig. 4 (53); correspondingly, microcystin variants are named according to the residues X and Y (54). Among all the variants identified so far the most abundant and, correspondingly, the most studied is the microcystin-LR. Nodularins which are produced by Nodularia spumigena in brackish water habitats (52,55,56) may be considered as natural analogs of microcystins. In fact, the chemical structure of nodularins is that of a cyclic pentapeptide (Fig. 5) containing the residues 3-7 of microcystin, i.e. the C20 amino acid Adda, the two D-amino acids Diso-G\M and D-z^o-MeAsp, and the most common residue L-arginine in the variable position Y, whereas the Mdha residue is replaced by the homologous Nmethyldehydro-a-aminobutyric acid (Mdhb) (52,57). It lacks therefore the D-Ala^-LLeu^ dipeptide of microcystines. A variant was isolated from the marine sponge Theonella swinhoei in Papua New Guinea (49) where the variable residue Y (Arg) is replaced by the hydrophobic L-Val; this [L-Val]5-nodularin was trivially named mutoporin. 3.2. Biological Activities of Microcystins and Nodularins

As mentioned before, microcystins are lethal to a diverse group of animals including dogs, livestock, wild mammals, birds and fish, and intoxications in humans were reported. In rats and mice death occurs approximately 1-3 hr after i.p. injection of the lethal dose of microcystin-LR (37,58,59) and nodularin (56) (LD50 of 50-100 |ig/kg). The toxin causes disruption of the liver leading to death possibly due to liver failure and hemorrhagic shock (59). Histologic lesions of acute microcystin toxicosis progress from "rouding up" of hepatocytes with loss of normal cell-to-cell adhesions, to disruption of hepatic cords, loss of sinusoidal integrity, and death of hepatocytes. These changes in hepatic architecture result in severe intrahepatic hemorrhage. Hepatocytes are thus the target cells in vivo due, at least in part, to a specific uptake of the amphipathic toxin via a multispecific organic anion transporter (60-62). The alterations in the morphology of hepatocytes have been attributed to marked disorganization of intermediate filaments (63) and actin microfilaments (64-66). These cytoskeletal effects are thought to be initiated by the microcystin-induced inhibition of cellular phosphatases. In fact, microcystins and nodularins are the most potent and specific inhibitors of the Ser/Thrprotein phosphatases type 1 and 2A in vitro (67-69), as shown in Table 3, and in vivo (70). The cyclic peptides bind to the same site of the protein phosphatases as okadaic acid, since they inhibit [3H]-okadaic acid binding with similar IC50 values (67,69).

897

Protein phosphatase inhibition has been correlated with the onset of acute microcystininduced hepatotoxicosis in mice (70) and with microfilament reorganization and cell deformation in isolated hepatocytes (65). Inhibition of these enzymes causes hyperphosphorylation of numerous cytosolic and cytoskeletal proteins in isolated hepatocytes exposed to microcystin (63,65,71). It has recently been shown that at higher concentrations similar morphological effects are produced also in nonhepatocytes (72). Table 3. Binding affinities of natural inhibitors of protein phosphatases 1 and 2A Inhibitor okadaic acid tautomycin calyculin-A microcystin-LR mutoporin inhibitor 1 inhibitor 2 ICso (nM) for type 1 protein phosphatase 20 0.2 0.5-2 0.15 0.6 0.45 0.8 ICso (nM) for type 2A protein phosphatase 0.2 1.0 0.1-1 0.15 0.6 -

Like the diarrethic shellfish toxin okadaic acid (73), microcystins and nodularins function as potent liver tumour promoters (71,74-76) and therefore they represent a very serious health risk for humans (77). This tumour promotion activity has been associated with the hyperphosphorylation of cytokeratin (71). 3.3. Structure-Activity Relationship of Microcystins and Nodularins

Since a large number of microcystins has been already isolated and chemically characterized, mutations and modifications in the structure have allowed the identification of essential pharmacophores. The variable L-amino acid residues X and Y are most commonly Leu and Arg, respectively. But microcystin variants with both positions occupied by the basic Arg residue or by hydrophobic residues like Leu and Ala or Leu and Tyr are also produced by various Microcystis strains. While substitution of the Arg residue in position Y with hydrophobic residues or with Met(O) is without significant effect on the toxicity, replacement of the Leu residue in position X with Arg or Met(O) leads to significantly reduced toxicity (53). Variants with

898

homotyrosine or homoisoleucine in position X retain fiill activity, whereas the related Ala, Phe or Trp mutants show a 3- to 4-fold reduced potency. Additional variants containing 1,2,3,4-tetrahydrotyrosine, homotyrosine and homophenylalanine in position X and aminoisobutyric acid and homoarginine in Y have been isolated and structurally characterized, but their toxicity was not reported (53). Additional common differences include demethylation of the amino acid residues 3 and/or 7 (41,78) whereby the dehydroalanine^-variant was found to be 5fold less toxic than the related methylated microcystin (39). Replacement of the Mdha'7 residue with the precursor amino acid residue N-methyl-L-Ser is again minimally affecting the toxicity (34), but the variant with lanthionine in this position shows very weak toxicity probably due to the bulky modification (79). This indicates that the dehydro-amino acid residue itself is unimportant, a fact which is further supported by the observation that dihydro-microcystins, obtained by reduction of Mdha with sodium boron hydride, are fully active both as the stereoisomeric mixture or as isolated isomers, i.e. microcystin-L-Ala^ and microcystin-D-Ala^ (80). The stereochemistry of the Adda residue seems to be essential for the activity and toxicity of microcystins (41,78), since altering the configuration of the double bond from (4E,6E) to (4',6Z) leads to loss of toxicity (78,81). Hydrogenation or ozonolysis of the diene system also gives rise to non-toxic derivatives (82). Conversely, some other variations of the Adda residue are without effect on the toxic properties; e.g. by replacing the methoxy group at the Adda C-9 position with the acetoxy group the toxicity is fully retained (40). A hydroxy variant at the same position of the Adda residue has also been isolated and toxicity was fully retained (34). The amino acid Adda itself is a non-toxic substance (83,84) and similarly biologically inactive are linear microcystin- and nodularin-related peptides (85). From structure-function studies it is also known that esterification of the acarboxyl group of the D-z^o-Glu^ residue generates nontoxic compounds (34,53), probably as a result of the lack of inhibition of the protein phosphatases. In this context it is interesting to note that the methyl ester of okadaic acid is inactive as well (86). The identical hepatotoxicity and binding affinity for protein phosphatases of microcystins and nodularins clearly show that the dipeptide D-Alai-L-Leu(X)2 is unimportant although the D-Ala unit is almost invariant. In fact, only one mutant with D-Ser in this position has been identified so far (40). However, as mentioned above, the cyclic forms of the penta- and hexapeptides are essential. Considerably less variants have been reported for nodularin, but the structurefunction relationships appear to be similar to those of the microcystin series of toxins. Again the [6Z-Adda3]-variant is essentially inactive, whereas the demethylated Addaanalog and the dihydronodularins were found to be as active as the parent compound

899

(53). Interestingly, substitution of the L-Arg residue in nodularin with L-Val (trivially named mutoporin) leads to biological properties which are somewhat different from those of other nodularins. This variant exerts cytotoxicity against tumour cell lines (49), a property not shown by nodularin. Derivatization of the Arg residue in nodularin with acetylacetone to produce the dimethylpyrimidyl-analog led to similar results as the new compound was found to be cytotoxic to L1210 cells (53). Probably this cytotoxicity is also exerted by the microcystin mutants with both the X and Y position occupied by hydrophobic residues. In summary, the toxicity of microcystins and nodularins require that the peptides are in the cyclic form, that the y-linked D-Glu residue contains a free a-carboxyl group, and that the Adda residue has a double bond 6E configuration. Biosynthesis of Microcystins and Nodularins Extensive studies have been performed to disclose the biosynthetic pathway of microcystin and their lower mass analogs, the nodularins (53,85). One of the major questions was the origin of the Adda residue. The methyl substitution pattem was indicative of incorporation of either propionate or acetate followed by methylation via S-adenosylmethionine. Although both propionate and methionine were found to be incorporated, the pattem of labelled metabolites was clearly indicative of an acetateplus-methionine sequence for CI through C8. The remainder of Adda presumably derives from phenylalanine via phenylacetic acid. The other subunits are for the most part derived from predictable pathways. According to the biosynthetic intermediates isolated the assembly of the linear penta- and octapeptides occurs with the Adda unit as N-terminal residue and Arg as C-terminus. Cyclization apparently represents the last step, since conversion of N-methyl-serine and -threonine to Mdha and Mdhb, respectively, occurs in earlier steps. 3.5. Synthetic Approaches for Microcystin and Nodularin 3.4

Various syntheses have been reported so far for the p-amino acid Adda (83,8791). In most of these synthesis the E^E-dienic system was prepared by the Julia-Wittigtype chemistry which, however, did not allow for the complete control of the stereochemistry of the double bonds (83,87-89). More recently an alternative synthesis has been proposed (91) in which the fragments C1-C5 and C6-C10 were joint together under Stille conditions (92). Starting from the suitably protected P-methyl-aspartic acid (1) its reduction to the aldehyde and conversion to the trans vinyl iodide followed by stannylation with hexamethyldistannane in the presence of freshly prepared Pd(PPh3)4 led to the trans vinylstannane 2 (Fig. 6). The commercially available (S)-phenyllactic acid (3) was converted to the Weinreb amide which was methylated at the secondary alcohol function and then converted to the propargylic ketone (4). 5j/t-stereoselective

900

reduction of the carbonyl group produced the propargyUc alcohol which was converted to the bromoallene. This intermediate was alkylated with the organocopper reagent MeCuCNLi to afford the alkylalkyne 5 which was subjected to hydrozirconation followed by quenching with iodine to install the halogen at the less hindered side of the triple bond and thus, to define the geometry of the double bond in compound 6 for the Stille coupling with compound 2, Saponification of the methyl ester afforded the NBoc protected Adda amino acid with the correct E,E stereochemistry for its use in the synthesis of nodularin or microcystin.

NHBOC ,0H

NHBOC 'SnBu3

MeO

MeO
Me

2+6

HO2C. Me Me

Fig. 6. Synthesis of N-Boc-Adda-OH, according to D'Aniello et al. (91), as suitably protected intermediate for the preparation of nodularin or microcystin.

901

Synthesis of (i-alkylaspartates have been reported previously (93-96), but in the very elegant synthesis of mutoporin Valentekovich and Schreiber (89) used D-Thr as a chiral building block which was converted to a y-lactone in five steps through an intermediate tosylaziridine. The y-lactone served then to produce both the backbone portion (C1-C4) of the Adda residue and a differentially protected p-MeAsp. Assembly of the different units to the pentapeptide with N-methyl-D-threonine as precursor for Mdhb was performed by standard procedures of peptide chemistry and final cyclization via the pentafluorophenylester led at high dilution to the desired protected mutoporin. Interestingly, saponification of the ester groups with Ba(0H)2 led concomitantly in unexpected an manner to the quantitative dehydration of the Nmethyl-threonine.
O COOH ^MBHA resin

1. MesI 2.HF

COOH NH2

DBU

Fig. 7. Synthesis of the microcystin fragment Ac-D-Y-Glu-Mdha-D-Ala-Leu-NH2 by solid phase peptide synthesis (100).

902

Although the dehydroalanine is not essential for the biological activities of mycrocystin, the synthesis of the most abundant variant-LR requires incorporation of dehydroalanine. The synthesis of a,P-dehydroamino acids or dehydroamino acidcontaining peptides has been extensively studied (97-99), mainly due to the isolation of numerous biologically active a,P-dehydropeptides from natural, particularly microbial sources. Dehydroamino acid-containing peptides have unique chemical and stereochemical properties which affect both the chemical reactivity and the conformation of the peptides. The methods reported so far are all based on p-elimination of suitable derivatives of serine, threonine or cysteine. Recently the sulfonium salt approach (98,97) has been applied even in the solid phase synthesis of the tripeptide derivative of microcystine Ac-D-Y-Glu-Mdha-D-Ala-Leu-NH2 following the route shown in Fig. 7 (100), but P-elimination was found to occur at extents only slightly higher than 50%.
OCH,

base

CH2 1 1 H2N-C-COOH

Fig. 8. Synthesis of dehydroalanine or dehydroalanine- containing peptides via baseinduced p-elimination of the Se-(4-methoxybenzyl)-selenocysteine residue (101). We have shown that treatment of Se-(4-methoxybenzyl)-selenocysteine or related peptides with DBU in dimethylformamide produces in quantitative manner the related dehydroalanine-compounds as shown in Fig. 8 (101). As this method can be applied to the Fmoc/tBu strategy of solid phase peptide synthesis (102), if Fmoc removal is carried out with due precautions, it should represent a very efficient synthetic approach to microcystins. Recently, syntheses of cyclic peptides modelled on the microcystin and nodularin ring were reported with the dehydroamino acid replaced by Ala and the Adda residue by various a- and p-amino acids which, however, were lacking largesize hydrophobic side-chains (103). Correspondingly, the binding affinities for type 2A protein phosphatase were only in the mmolar range (104). Moreover, the synthesis of a nodularin analog has been reported with the Adda residue replaced by P-alanine or 3hydroxymethyl-P-alanine, Mdhb by sarcosine and MeAsp by Asp (105). The bioactivity of this compound, however, was not reported.

903

4,

Inhibition of Protein Phosphatases by Microcystin and Nodularin

Since microcystins and nodularins (67-69) were recognized as very potent inhibitors of the type 1 and type 2A protein phosphatases, progress in understanding the mechanism of phosphatase inhibition by these toxins was expected from the knowledge of their three-dimensional structures in the free and enzyme-bound state. The cyclic structure and the incorporation of the Mdha or Mdhb residues impose remarkable constraints to the conformational space of these toxins, although one cannot exclude significant conformational changes upon binding of the peptides to phosphatases as was observed for cyclosporin-A upon binding to cyclophilin (106,107). 4.1. Three-Dimensional Structure of Microcystins in Solution

Conformational analysis of microcystin using NMR spectroscopy and distance geometry or molecular dynamics calculations has been performed in DMSO (108110), DMSO/water (110) and water (111). The biological relevance of the examination of preferred conformations of peptides in DMSO has been discussed (112). Since the receptors for these molecules are composed of both hydrophiUc and hydrophobic portions, DMSO should mimic these properties more properly than does water. Interestingly, the preferred conformations of microcystin in these three media show large similarities regarding the ring portion of the molecule. From NMR data and distance geometry calculations of microcystin-LR in DMSO (108) three families of structures were derived that exhibit a common general feature consisting of a compact planar array of the peptide backbone of Adda^-D-z.y^^-Glu^-Mdha^ ring portion (Fig. 9). In family A the D-Ala^ residue lies in this plane with Leu^-D-Me-Asp^ protruding from the plane and with Arg"^ located at the edge of the plane. In family B the Arg"^ residue is located in the plane and Ala^ at the edge, while in family C Arg"^ becomes part of the protrusion and Leu^ moves to the edge at the opposite side. Thus, the three families exhibit saddle-type structures which differ mainly in small movements of the residues that are shifted out of the plane formed by the residues 5 to 7. This saddle-shaped conformation of the peptide backbone, that was determined by us for microcystin-LR in DMSO, is very similar to the structure derived from NMR experiments in DMSO and molecular dynamics calculations (110). Small differences were revealed in the preferred conformation of this microcystin in DMSO/water which derive from changes of the backbone dihedral angles in the vicinity of the amide bond between Mdha^ and AlaUllO). As discussed above, nodularin corresponds in its chemical structure to residues 3-7 of microcystin LR with concomitant replacement of the Mdha residue with Mdhb,

904

I
Mdha

microcystin-LR

Mdha

Fig. 9. Superposition of the most convergent microcystin-LR structures subdivided in the three conformational families A, B and C.

905

thus lacking the D-Ala^-Leu^ dipeptide portion of the microcystins. Since microcystinLR and nodularin exhibit identical hepatotoxocities and binding affinities to protein phosphatases 1 and 2A, this sequential insert in the microcystin structure should become a conformational exon to maintain the correct topological array of the rest of the ring structure which has to be responsible for the selective recognition by the receptor molecules. This hypothesis was experimentally confirmed by the NMR and distance geometry analysis of the nodularin variant mutoporin in aqueous solution (111). As well portrayed in Fig. 9, in our distance geometry-derived structures of microcystine-LR the Adda side-chain retains sufficient conformational space for relatively large movements despite the restricted rotational freedom imparted by the double bonds. In family A the Adda side-chain is bent over the ring structure and in family B it is directed away from the ring, an effect even more pronounced in family C. The latter position as well as the relativeflexibilityof the terminal portion of the sidechain compares well with the microcystin-LR structure determined by Trogen et al (110) in DMSO and in DMSO/water. Moreover, this hydrophobic side-chain is at some distance from the sequentially adjacent Arg side-chain. In order to analyze the effect of natural substitutions on the preferred conformation of microcystins we have determined the 3D-structure of microcystin-LY (Fig. 10) in which the variable residue Arg is replaced by the hydrophobic Tyr unit (113).
Mdha

Fig. 10. Superposition of the 10 microcystin-LY structures with the smallest distance violations.

906

Although th4 Arg-->Tyr replacement is without significant effect on the toxicity (LD50 = 90 |ig/kg in the rat against 50 |ig/kg for microcystin-LR) (114), incorporation of the Tyr residue adjacent to the Adda unit leads to a surprisingly restricted conformational space for the Adda side-chain most probably as a result of a hydrophobic collapse-type interaction (108). This strong interaction leads to movements in the peptide backbone ring structure which adopts a boat-type array significantly different from the saddle-like array in the LR variant. By examining the structures of the two microcystins as derived from the distance geometry calculations, many of the NOES could not be described using the standard method of applying the NOEs to one conformation. Distance violations approaching 1.0 A were observed, particularly for the residues located around the Mdha residue. The constraint that this residue introduces into the cyclic peptide is significant, and it could very well be the source of dynamics, fast on the NMR timescale. With this in mind, we undertook the calculation of these two inhibitors of the protein phosphatases 1 and 2A using the ensemble approach. The possibility of molecular motions fast on the NMR time-scale must always be kept in mind during structure determination using restraints derived from NMR data. The experimental observations (e.g. NOEs, coupling constants) in the case of such averaging are clearly averaged quantities. Therefore, the restraints will be consistent with the average stmcture, a structure that may not exist in solution or even be physically possible. There are a number of examples in the literature of such dynamics taking place (115-126). Different computational approaches to address fast molecular motion have been proposed (127-131). The approach utilized in our study (109) is very similar to the time-averaged method, but utilizes a large number of the molecules to simulate, and the experimental restraints are applied not to each individual structure but to the entire ensemble as an average, i.e. the penalty function is applied only when the average over the ensemble of structures varies from the experimentally determined value (127,132,133). In theory, the results from the time-average and ensemble methods must be identical, although some differences arising from the practical application of the methods, have been observed (134,135). For the LY variant a rather small conformational family was detected and a clustering of the different members of the ensemble for the residues from Leu^ to Adda^. These residues are therefore well determined and conformational dynamics are not taking place in this portion of the molecule. In contrast, the residues of the other half of the molecule, D-Z^-o-Glu^-Mdha^-D-Ala^ show that dynamics occur. This is especially evident for the Mdha residue, where there are large populations at 0,T values of both +30%-30' and -30\-f-30\ This exchange between these two conformers is necessary to reproduce the NOEs about this residue. It is important to state, that

907

although each member of the ensemble is not planar, the average O,^ values about this residue is 0%0* (i.e. planar). This would suggest that the constraint of the system, induced from the cyclization, forces the Mdha residue out of planarity. The ranges of dynamics of the residues surrounding Mdha'7 are smaller. Therefore, the "flip-flop" process of the Mdha causes some distortions of the adjacent amino acids. The results of the microcystin-LR indicate much more significant dynamics than in the case of the LY analog. The results for the Mdha residue are similar to those observed for the LY analog; there are two large families at approximately -40%-40' and +40%+40\ However, in addition, there is a significant number of conformers that adopt a ^ dihedral angle of 180". The "flip-flop" of the Mdha has a large effect on the conformational features of the preceeding residue and the two following residues, namely D-z^o-Glu^, D-Ala^ and Leu^. The Glu residue adopts a significant number of conformations, but shows a tight clustering of conformations about the central value of -150%+80\ Both of the residues after Mdha adopt two conformational families. The D-Ala has great variance in the O dihedral angle as to be expected (it is adjacent to Mdha) and almost no variation of the ^ torsion. Similar results are observed for the Leu2 residue. The remaining residues show only one significant population, although covering a wide range of dihedral angles, often of 30. Clearly the microcystin-LR is less well determined than the conformation observed for the LY analog. Taking into account the results of these ensemble calculations the backbone structure of microcystin-LR reveals a restricted conformational space in part of the ring backbone and significant flexibility in the rest, i.e. mainly involving the residues Mdha'7, D-Ala^ and Leu^. Interestingly, by comparing the 3D-structures of the variant LR in DMSO and in DMSO/water the conformational differences are related to this sequence portion (110). 4.2. Molecular Dynamics Simulation of Nodularin and Okadaic Acid

From structure-function studies it is known that esterification of the a-carboxyl group of D'iso-G\u^ of microcystin generates untoxic compounds, probably as a result of the lack of inhibition of the protein phosphatases (34,53) and that the methyl ester of okadaic acid is inactive as well (86). Correspondingly, this carboxylic function seems to play an essential role. In order to account for the almost identical potency of microcystins and okadaic acid, we have proposed a location of the carboxyl function of the two diverse compounds at the same position and a wrapping of the okadaic polyether chain around part of the microcystin ring and alignment of its hydrophobic tail with the Adda residue side-chain (108). Recently the computer generated minimum energy conformations of okadaic acid and calyculin have been reported (136) and compared to the minimum energy

908

conformations of nodularin and microcystin-LR (137). In this study a ring structure is proposed for okadaic acid which involves an intramolecular hydrogen bond between the CI carboxyl, attached to the first tetrahydropyran ring, and the C24 hydroxyl group attached to the fourth tetrahydropyran ring. The rest of the molecule would simulate in extended manner the side chain of the Adda residue. The result of our energy minimization for okadaic acid is shown in Fig. 11 (109). A chain reversal is observed in the C-terminal portion of the molecule, probably due to a hydrophobic collapse (138), whilst the rest of the molecule adopts an extended and flexible form.

Fig. 11. Stereoview of the lowest energy conformation of okadaic acid as calculated by free molecular dynamics simulation. Free molecular dynamics simulation performed by Trogen et al. (110) on microcystin led to surprisingly similar results as those obtained with NMR-derived restraints, a fact which confirms the high preference of this cyclic heptapeptide for a defined overall conformation. Since the cyclic pentapeptide stmcture of nodularin should contain even stronger inherent restraints, its lowest energy conformation was derived by us from molecular dynamics simulations (109). This conformation, shown in Fig. 12, displays a backbone array surprisingly similar to that of microcystin-LR, i.e. again a saddle structure, but it is less puckered because of excision of the D-Ala^-Leu^ dipeptide portion of the microcystin ring. Again the Adda residue points away from the ring distal from the Arg side-chain. The overall structure is very similar to the distance geometry-derived solution stmcture of mutoporin in water presented by Bagu et al.

909

(111). Most interestingly, replacement of the Arg by Val was not found to induce a hydrophobic collapse between the Adda and the adjacent Val residue as we have observed to occur for the microcystin-LY variant.

Fig. 12. Stereoview of the lowest energy conformation of nodularin as calculated by free molecular dynamics simulations. The search for structural similarities between microcystin, nodularin and okadaic acid, which apparently all bind to the protein phosphatases at the identical sites, led us to calculate the Connolly surfaces mapped with lipophilic potentials. The compounds show a typical lipid-like character with a large peptide headgroup in the case of microcystin and nodularin and a phospholipid-like headgroup in the case of okadaic acid. The largest degree of similarity is observed between microcystin LR and nodularin with their mushroom-like structures that consist of a slightly bended hydrophobic stalk and a hydrophilic head of similar cross area. The structure of okadaic acid forms again a stalk of dimensions similar to those of microcystin LR and nodularin. A stronger bending of the upper part, possibly induced by the protein binding cleft, would allow for a display of the smaller hydrophilic headgroup in a manner similar to the toxic peptides. Finally, microcystin LY has a significantly larger stalk due to the parallel array of the Adda and Tyr side chains in a hydrophobic collapse-type interaction. If the size of this hydrophobic finger in the enzyme-bound state is conditioned by the size of the binding cleft of the protein phosphatases, disruption of the hydrophobic interaction between the Adda and Tyr side-chain is required for binding. The resulting large

910

enthalpic cost has then be compensated by the enthalpy of binding via additional interactions of the hydrophobic Tyr residue, since the toxicity and thus, most probably, even the binding of this microcystin variant to the protein phosphatase 1 and 2A is very similar to that of microcystin-LR. On the basis of these data a possible picture of the enzyme inhibitor complex was derived which foresees an insertion of the sticky finger of these inhibitor structures into the protein cavity of defined dimensions and a display of the a-carboxyl function of Glu^ in juxtaposition for decisive hydrogen bondings or electrostatic interactions (108,109). However, since the Adda residue itself (83,84) or linear microcystin-related precursor peptides are not toxic (85), it is reasonable to assume that the remainder of the peptide (the planar ring portion) plays an important role in the recognition or in maintaining the proper orientation for the Adda residue. The synergic effect of the head and tail of this structures is also confirmed by the very low inhibitory potency of cyclic nodularin-based peptides lacking the hydrophobic side-chain of the Adda residue (104). 4.3. Three-Dimensional Structure of Microcystin in the Enzyme-Bound State

The crystal structure of the catalytic subunit of mammalian protein phosphatase1 complexed with microcystin-LR has recently been determined at 2.1 A resolution (139). The metalloenzyme exhibits a fold unrelated to the known structures of catalytic subunits of tyrosine phosphatases. The two metal ions are positioned in a central |3-a-|3 -a-p scaffold at the active site, from which three surface grooves protrude as potential binding sites for substrates and inhibitors. The C-terminus of the catalytic subunit is located at the end of one of these grooves, so that regulatory sequences following this domain may possibly modulate the function. This fold is expected to be closely preserved in the protein phosphatases 2A and 2B. The X-ray structure of the microcystin/enzyme complex reveals an interaction of the toxin with three distinct regions of the surface: i) the metal binding site, ii) the hydrophobic groove that runs between an a-helix and a loop where a cluster of hydrophobic residues, conserved in protein phosphatase 2A and 2B, is exposed to the surface, and iii) the edge of the C-terminal groove near the active site.The hydrophobic Adda side-chain is tightly packed into the hydrophobic groove, the a-carboxyl group of the y-linked D-Glu^ and the adjacent carbonyl group of the Adda residue form hydrogen bonds with two metal-ligand bound water molecules. The carboxyl group of Mc-isO'Asip^ is hydrogen-bonded with Arg-96 and Tyr-134 and the Leu^ side chain is closely packed to Tyr-272. Moreover, a covalent linkage of microcystin via the thiol addition of Cys-273 to the Mdha'^ residue was observed. This covalent hnkage of microcystin was observed previously (140), but it is not essential for inhibition of the

Fig. 13. Stereoview of the microcystin-LR structure as determined by X-ray crystallographic analysis of the protein phosphatase- l/microcystin complex.

911

912

enzyme by microcystin and nodularin as shown by the high toxicity of the dihydrocompounds (80) and of the precursor peptide, the N-methylated L-Ser-variant (34). Additionally, mutagenesis of the cysteine residue (141) or blockade of the Mdha residue in microcystin (140) was not found to affect the inhibition potency. The peptide backbone structure of the enzyme-bound microcystin, shown in Fig. 13, is almost identical to the family B of structures described by us for microcystin in DMSO (107) with Leu^-D-Me-Z^o-Asp^ puckering out of the plane and with Ala^ at the edge and Arg^ in the plane formed by Adda^-D-z^o-Glu^-Mdha^. The Adda residue protrudes from the plane distal from the Arg residue. The strong hydrophobic interaction of the Leu^ residue with Tyr-272 compares well with the observed significantly reduced toxicity of the microcystin variants with hydrophilic residues in the position X (53). Conversely, the residue Y (most abundantly occupied with Arg) is apparently not involved in the binding. Besides the flexibility observed for the sidechains of the Adda (particularly in the terminal portion) and Arg residues, the conformation of the microcystin in solution is retained in the enzyme-bound state. Correspondingly, the entropic cost in the bimolecular recognition and binding process is significantly reduced, thus favoring the observed tight binding.

5.

Conclusion

The surprising similarity of the 3D structures of microcystin in solution and in the enzyme-bound state represents an additional example of how nature evolved highly potent inhibitors for receptor molecules exploiting rigid structures to overcome the entropic penality when two molecules are to associate in tight complexes. This principle is in the present-day dmg research increasingly applied for the peptidomimetic design of small rigid cyclic stmctures containing the pharmacophores responsible for receptor recognition and binding in the correct spatial array. On the other side, the chemically diverse families of protein phosphatase inhibitors discovered in a serendipitous manner in fresh and brackish water as well as in marine environments once more support the view that marine world is an immense source of libraries of unknown compounds (142). Natural products provide most of the world's population with their pharmacopea and represent the source of leading structures for a significant proportion of synthetic pharmaceuticals (143). The success of natural products as drugs, and the fact that the biological resources from which they originate remain underexploited, continues to provide a significant impetus to the dmg discovery process. In this context one has to remember that estimates of macrofauna diversity range from half a million to ten million species and marine microorganisms (viri, monerans and protists) in the range 1 million to 200 million species (143). Among these species already venomous cone snails have generated via a combinatorial library strategy thousands of highly bioactive venom peptides of remarkable specificity and

913

affinity for cell-surface receptors and ion channels (144), which may be used in the future not only as tools for understanding physiological processes, but they may also provide important lessons in designing combinatorial libraries for drug development.
The authors would like to thank Hans-Jurgen Musiol for valuable discussions and Norbert Schaschke for his help in the preparation of the manuscript. The coordinates of the X-ray structure of microcystin bound to protein phosphatase-1 were retrieved from the Brookhaven database (lFJM.pdb).

6.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

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914

20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

Reynolds, C.S. and Walsby, A.E. (1975) Biol. Rev. 50, 437-481. Skulberg, O.M., Codd, G.A. and Carmichael, W.W. (1984) Ambio. 13, 244247. Carmichael, W.W. (1986) in: Namral Toxins - Characterization, Pharmacology and Therapeutics (Ownby, C.L. and Odell, G.V., eds.) pp. 3-16, Academic Press, London. Lawton, L.A. and Codd, G.A. (1991) J. Inst. Environ. Man. 5,460-465. Codd, G.A. and Beattie, K.A. (1991) Public Health Lab. Ser. Microbiol. Digest. 8, 82-86. Beasley, V.R., Coppock, W.R., Simon, J., Ely, R., Buck, W.B., Corley, R.A., Carison, D.M. and Gorham, P.R. (1983) J. Am. Vet. Med. Assoc. 182, 413414. Edler, L., Femo, S., Lind, M.G., Lundberg, R. and Nilsson, P.O. (1985) Ophelia 24, 103-109. Soil, M.D. and Williams, M.C. (1985) J. South Afr. Vet. Assoc. 56, 49-51. Galey, F.D., Beasley, V.R., Carmichael, W.W., Hooser, S.B., Haschek-Hock, W.M., Lovell, R.A., Poppenga, R.M. and Knight, M.W. (1986) J. Toxicol. Toxin Rev. 5, 256. Dillenberg, H.O. and Dehnel, M.K. (1960) Can. Med. Assoc. J. 83, 11511154. Falconer, I.R., Beresford, A.M. and Runnegar, M.T.C. (1983) Med. J. Austral 1,511-514. Bourke, A.T.C., Hawes, R.B., Neilson, A. and Stallman, N.D. (1983) Toxicon (Suppl.) 3, 45-48. Botes, D.P., Wessels, P.L., Kruger, H., Runnegar, M.T.C.,Santikam, S., Smith, R.J., Bama, J.C.J, and Williams, D.H. (1985) J. Chem. Soc. Perkin Trans. 1,2747-2748. Watanabe, M.F., Oishi, S., Watanabe, W. and Watanabe, M. (1986) J. Phycol. 22, 552-556. Namikoshi, M. Rinehart, K.L., Sakai, R., Scotts, R.R., Dahlem, A.M., Beasley, V.R., Carmichael, W.W. and Evans, W.R. (1992) J. Org. Chem. 57, 866-872. Sivonen, K., Namikoshi, M., Evans, W.R., Gromov, B.V., Carmichael, W.W. and Rinehart, K.L. (1992) Toxicon 30, 1481-1485. Kotak, B.G., Kenefick, S.L., Fritz, D.L., Rousseaux, C.G., Prepas, E.E. and Hrudey, S.E. (1993) Water Res. 27,495-506. Krishnamurthy, T., Carmichael, W.W. and Sarver, E.W. (1986) Toxicon, 24, 865-873. Harada, K.-L, Ogawa, K., Kimura, Y., Murata, H., Suzuki, M., Thom, P.M., Evans, W.R. Carmichael, W.W. (1991) Chem. Res. Toxicol. 4, 535-540.

915

39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

Namikoshi, M., Sivonen, K., Evans, W.R., Carmichael, W.W., Routhiainen, L., Luukainen, R. and Rinehart, K.L. (1992) Chem. Res. Toxicol. 5, 661-666. Sivonen, K., Namikoshi, M. Evans, W.R., Carmichael, W.W., Sun, F., Routhiainen, L., Luukainen, R. and Rinehart, K.L. (1992) Appl. Ennviron. Microbiol. 58, 2495-2500. Namikoshi, M., Rinehart, K.L., Sakai, R., Sivonen, K. and Carmichael, W.W. (1990) J. Org. Chem. 55, 6135-6139. Sivonen, K., Carmichael, W.W., Namikoshi, M., Rinehart, K.L., Dahlem, A.M. and Niemela, S.I. (1990) Appl. Environ. Microbiol. 56, 2650-2657. Meriluoto, J.A.O., Sandstrom, A., Eriksson, J.E., Remaud, G., Craig, A.G. and Chattopadhyaya, J. (1989) Toxicon 27,1021-1034. Bruno, M., Gucci, P.M.B., Pierdominici, E., Sestili, P., loppolo. A., Sechi, N. and Volterra, L. (1992) Toxicon 30,1307-1311. Carmichael, W.W., Eschedor, J.T., Patterson, G.M. and Moore, R.E. (1988) Appl. Environ. Microbiol. 54, 2257-2263. Sivonen, K., Kononen, K., Carmichael, W.W., Dahlem, A.M., Rinehart, K.L., Kiviranta, J. and Niemela, S.I. (1989) Appl. Environ. Microbiol. 55, 22072231. Chen, D.Z.X., Roland, M.P., Smillie, M.A., Klix, H., Ptak, C , Andersen, R.J. and Holmes, C.F.B. (1993) Toxicon 31,1407-1414. Todd, E.C.D and Holmes, C.F.B. (1993) in: Toxic Phytoplankton from the Sea (Smayda, T.J. and Shimizu, Y., eds) pp. 341-346, Elsevier Science Publ, Amsterdam. DeSilva, E.D., Williams, D.E., Andersenn, R.J., Klix, H., Holmes, C.F.B. and Allen, T.M. (1992) Tetrahedron Lett. 33,1561-1564. Botes, D.P., Tuinman, A.A., Wessels, P.L., Viljoen, C.C., Kruger, H., Williams, D.H., Santikam, S., Smith, R.J. and Hammond, S.J. (1984) J. Chem. Soc. Perkin Trans. 1, 2311-2318. Carmichael; W.W., He, J.-W., Eschedor, J., He, Z.-R. and Juan, Y.M. (1988) Toxicon 26, 1213-1217. Rinehart, K.L., Harada, K.L, Namikoshi, M., Chen, C, Harvis, C.A., Munro, M.H.G., Blunt, J.W., Mulligan, P.E., Beasley, V.R., Dahlem, A.M. and Carmichael, W.W. (1988) L Am. Chem. Soc. 110, 8557-8558. Rinehart, K.L., Namikoshi, M. and Choi, B.W. (1994) J. Appl. Phycol. 6, 159176. Carmichael, W.W., Beasley, V.R., Bunner, D.L., Eloff, J.N., Falcomer, L, Gorham, P., Harada, K.L, Krishnamurthy, T., Yu, M.-J., Moore, R.F., Rinehart, K.L., Runnegar, M., Skulberg, O.M. and Watanabe, M. (1988) Toxicon 26, 971-973.

916

55

56 57 58 59 60 61 62 63 64 65 66 67 68 69

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921

CUMULATIVE GENERAL SUBJECT INDEX

VOLUMES 1-20
Abamectin 12:9 (3^20) Abeataxan 20:80,106 25-(10->9) Abeo-26(S->\5) abeO'9^,l4^,\5a-o\ean-5ene-3(3,29-diol 5:744,748,750 9(10->19) Abeo-diene steroidal alkaloids 2:205,206 11(15^1) Abeataxan 20:80,100,101 Abies koreana 20:619 Abies mariestii 20:619 Abiesen 20:283 Abieta-8,11,13-triene from Salvia limbata 20:673 Abietane 9:297 Abietane diterpenoids 20:660-680 Abietatriene from abietic acid 14:676,677 taxodione from 14:676,677 ^Abieta-8(14),13(15)-dien-16,12-olide (jolkiolide E) 9:283,284,290 Ent-AhiQimt derivatives 9:265,283-288 Abietatriene 2:402,403 Abietatriene-6-one 14:669,670,673,674,676 Abietatriene-7-one Baeyer-Villiger oxidation of 14:685,687-689 from dehydroabietic acid 14:685,687-689 taxodione from 14:685,687-689 Abietatriene-diol 14:675,676 Abietic acid in (+)-confertifolin synthesis 4:405-416 in (+)-isodrimenin synthesis 4:405-408 in (-)-warburganal synthesis 4:416 taxodione from 14:672-674,676,677,689-692 Abnormal Beckmann rearrangement 16:133 Abramov reaction 6:353 A brus fruticulosus 15:26 Abrus precatorius 7:152,15:25 Abrusgenic acid 7:152 Abruslactone A abrusgenic acid from 7:152 from Abrus precatorius 7:152 Abrusosides A-D from Abrus precatorius 15:25 structure elucidation of 6:559 synthesis of 10:167 Absinthin from Artemisia absinthium 7:215 from Artemisia sieversiana 7:215 Absolute configuration by C D . procedure 9:27 by Horeau procedure 9:25,26 by Nakanishi's method 2:89 in 24-(P-hydorxyethyl)-in 24-(carboxy-methyl) steroids 15:79-81 in 24-ethyl-26-hydroxysteroids 15:84 in 24-hydroxymethyl steroids 15:79 in 24-hydroxysteroids 15:76,77 in 24-methyl-25,26-dihydroxy-steroids 15:84-86 in 24-methyl-26-hydroxy and 24-methyl-26-oic steroidal side-chains 15:81 -84 m 26-hydroxysteroids 15:77,78 of(+)-aristoserratine 11:296 of(+)-monomoriwei 6:449,450 of(-)-hobartine 11:290 of(-)-peduncularine 11:284 of 3 a, 13-dihydroxy-11 -epiapotrichothecenes 13:520 of amphotericin B 6:231 ofaureol 9:31 of benzo [a] pyrene oxide 7:8,14 ofcarotenoids 7:321 of decaprenoxanthin 7:355 of liverwort sesquiterpenoids 18:607-646 of Mosher's esters 13:77 ofpenems 4:435 of phoracantholide I, J 6:546 ofquinocarcin 10:126 ofR, 5-4-hydroxycyclopentenones 6:315 of sclerosporin 6:549-551 of sigmosceptrellins A-C 9:16 ofsolenopsinB 6:430 of sugars saponins 15:190 oftaxol 11:3,7 ofthienamycin 4:433,436 ofurdamycinA 11:134 Acacetine 226 Acacia astringens 7:427 Acacia nilotica I'All Acacia tomentosa 1:427 Acalycigorigia inermis 5:370 Acalycigorigia sp. 5:368,369 Acanthaceae 7:190,193 Acanthacerebroside A 18:481 Acanthaglycosides A,D,F from Acanthasterplanci 7:288 Acanthaster planci acanthaglycosides A-D,F from 7:288 marthasteroside A from 7:288 thomasteroside A from 7:288 Acanthicifoline 7:191 Acanthifolicin 5:384 Acanthella klethra 20:525 Acanthodris nanaimoensis 19:139 Acanthomyops claviger 6:454 A canthoscelides obtectus 10:160 A canthus ebracteatus 7:176 Acanthus illicifolius 7:176,179,181,182,189-191,193 Acarbose asa-amylase inhibitor 13:3 as a-glucosidase inhibitors 7:47 as antihyperglycemic drug 10:505 as antihyperlipoproteinaemic drug 10:505 enzymatic degradation of 10:506 from A ctinoplanes species 10:503 synthesis of 13:49-60 total synthesis of 10:507 Acarviosine 10:503,504,506 Accedine 5:125

922
Accedinine 5:125 Accedinisine 5:125 Acemicoense 17:358,367-368 Aceraceae 17:358,366-367 Acemikoense 17:375 Acerogenin A 17:367,375,20:276 Acerogenin A biosynthesis of 17:375 Acerogenine-E 17:368 Aceroside I 17:367 AcerosidelV 17:367 Aceroside V 17:367 Aceroside VII 17:358 Aceroside XI 17:368 Acesulfame-K 15:4 Acetal 6:336 Acetal derivatives 6:335,336 mechanism of formation 6:335,336 of 3-methylthio-2-oxopropanals 6:335,336 synthesis of 6:335,336 Acetal exchange 1:453 Acetal-ketal formation 4:699 Acetalization 1:584 /ra5-Acetalization 4:325,326,331,338,339,495 Acetals as chiral auxiliaries 4:327 from (R*,R*)-2,4-pentanediol 14:484 from dimethyl tartrate 14:478 Lewis acid-mediated 14:484 nucleophilic substitution reaction 14:484 reductive cleavage 1:591-595 with dialkylboron bromide and cuprate 14:478 2-Acetamido-1,6 anhydro-2-deoxy-derivative 6:388,389 6-Acetamido-2,3,4-tri-0-allyl-6-deoxy-a-glucoheptopyranosiduronic acid 11:434,435 2-Acetamido-2-deoxy-D-glucopyranose 6:351 2-Acetamido-2-deoxy-D-glucopyranosides 6:389 2-Acetamido-2-deoxy-D-glucose oxazoline derivative of 6:399 2-Acetamido-2-deoxyglucomannans 5:286,287 6-Acetamido-6-deoxy-castanospermine from (+)-castanospermine 12:345,346 synthesis of 12:345,346 p-Acetamidophenyl-1,4,4'-dithiocellotrioside 8:351 /7-Acetamidophenyl-1,4-dithiocellobioside 8:350,351 Acetate-induced decomposition 14:170 Acetoacetic acid ethyl ester 10:410 A cetobacter suboxydans 17:636-637 Acetobromoglucose 10:366,367 P-Acetochloromannose 8:321,322 Acetogenic cyclic peroxides 9:18 Acetogenins 9:385,391,392,395,397-399,403;18:193227;19:81 (-)-Acetomycin absolute stereochemistry of 10:443,444 antimicrobial activity of 10:443 antitumor activity of 10:444,447 biosynthesis of 10:443 Claisen rearrangement by 10:443-448 from Streptomyces ramulosus 10:443 synthesis of 10:443-448 4-ep/- Acetomycin 10:445 (+)-5 -epi-Acetomycin antitumor activity of 10:447 Acetonation 6:279,280 Acetonide 14:160;19:489 Acetonylbutanolides 17:273 Acetophenone 2:169,170 Acetophenone phenylhydroazone 9:581 (+)-exo-5-Acetoxy camphor 4:646 synthesis of 4:656 3-Acetoxy monomethyl phthalates 14:5 19-Acetoxy-11 -methoxytabersonine 2:375 16-Acetoxy-12-O-acetyl-horminone 15:169,170,173 (15/?)-15-Acetoxy-15,20-dihydrocatharanthine 14:815 20-Acetoxy-15,20-dihydrocatharanthine 4:32 (1 S,4R)-4-Acetoxy-2-cyclopenten-1 -ol in prostaglandin synthesis 1:686 16-Acetoxy-7,8-epoxy-3,12-dolabelladien-13-one 20:491 (+)-l- Acetoxy-2-epipinoresinol 5:538-540 la-Acetoxy-20aF-hydroxy-24a,25a-epoxywitha-5-ene22,26-oHde-4p-0-glucopyranoside 20:191 1 P-Acetoxy-8P-hydroxyeudesm-4( 15), 7-diene-8-12olide 20:660 1 - Acetoxy-2-methylbutadiene [2+2] cycloaddition of 12:150,151 with chlorosulfonyl isocyanate 12:150,151 (15'S)-15'-Acetoxy-20'-deoxy vinblastine from (1SR)-15-acetoxy-15,20-dihydro catharanthine 14:815,816 22-Acetoxy-23,24-dinorchola-l,4,6-trien-3-one 11:398 4-Acetoxy-3 [ 1 '-/eA^butyldimethyl-sily loxy) ethyl] -2azetidinone 4:448 205'-Acetoxy-3p-16-dihydroxylanost-7-en-18-oic acid18,16-lactone 7:269 endo-2-AcQ\.oxyA{exo\ 5-dimethylbicyclo [3,3,1] nonan-9-one 6:65,66 from 4,5-cw-dimethylbicyclo [4.3.0] non-9-en-one synthesis of 6:66 3-Acetoxy-4-hydroxybenzaldehyde 8:166,167 2-Acetoxy-5,6-dihydro-2H-pyrans regioselective alkylation of 10:342 stereoselective alkylation of 10:342 6-Acetoxy-5 -hexadecanolides synthesis of 3:157-160 (+)-l- Acetoxy-6-epipmoresinol 5:538-540 16-Acetoxy-7-0-acetyl-horminone from Rabdosia lophanthoides var. gerardiana 15:173 16-Acetoxy-7a-methoxyroyleanone from Rabdosia lophanthoides var. gerardiana 15:173 from Rabdosia stracheyi 15:175 2-Acetoxy-8,13-dihydroxy-ll-e;?/ APO 13:522 12- Acetoxy-8,13-dihydroxy-l l-e/7/-apotrichothec-9ene 9:20 Acetoxy-abieta-triene 14:675,676 4-Acetoxy-P-lactam from Z)-a//o-threonine 12:160 from 6-aminopenicillanic acid 12:160 from I-aspartic acid 12:160 from Z,-threonine 12:161,162

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synthesis of 12:160-162 with ester enolate 12:163,164 with imide enolate 12:164-168 with other nucleophiles 12:170-172 with thiol ester enolates 12:168-170 (+)-(^ram-4'-Acetoxy-cinnamoyl)epilupinine from Lupinus hirsutus 15:521 (+)-15-Acetoxy-e^isocopal-12-en-16-al synthesis of 6:119-122 16a-Acetoxy-holosta-7-en-3b-ol 7:277 16P- Acetoxy-holosta-7,24-dien-3P-ol 7:275 235-Acetoxy-holosta-7,25-dien-3p-ol 7:273 (+)-31 -Acetoxy-Na-benzoylbuxidienine 18-Acetoxy-Na-deacety lisoretuline 1:38-39 5 - Acetoxy arctigenin monoacetate 18:601 6'-Acetoxyavarol 15:301 6'-Acetoxyavarone 15:301 1 -Acetoxybutadiene 1:571 25-Acetoxycholesta-1,4,6-trien-3 -one 11:385 2a-Acetoxycholestanone 18:888 2p-Acetoxycholestanone 18:888 Acetoxycrenulide synthesis of 16:703 (+)-Acetoxycrenulide 18:22-28 20-Acetoxydihydrocatharanthine from catharanthine 14:857,858 vinblastine from 14:857,858 vincristine from 14:857,858 19(/?)-Acetoxydihydrogelse virine from Gelsemium rankinii 15:479 from G. sempervirens 15:479 5 - Acetoxydimethy Imatairesinol 18:602 la-Acetoxyergosteryl acetate synthesis of 11:381-383,388-393 a-Acetoxy fiiranone 12:14 3 -Acetoxy guaiazulene 14:321 235-Acetoxyholost-7-en-3p-ol 7:273 1-Acetoxyisocomene 3:6,60 e/-3a-Acetoxyisopimar-15-en-8a-ol ^^C-nmrof 15:170 from Rabdosia parvifolia 15:173 'H-nmrof 15:169 6-Acetoxymethyl-2,6-dimethyl-9-methoxy tricyclo [5.3.0^'^] undec-9-en-8,ll-dione 8:163 5-Acetoxymethyltrachelogenin 18:602 5-Acetoxymethyltrachelogenin monoacetate 18:602 13-Acetoxymodhephene 3:6,61 18-Acetoxynorfluorocurarine 1:38-39 (+)-l- Acetoxypinoresinol 5:523,533,538,544 (+)-l- Acetoxypinoresinol-4"-0-methyl ether 5:523,533-535 (+)-l- Acetoxypinoresinol-4"-0-methyl ether-4'-p-Dglucoside 5:523 (+)-l- Acetoxypinoresinol-4'-P-D-glucoside 5:523 3-Acetoxypyrrol-2(5H] -one 13:117,118 (+)-12-Acetoxysinularene from Clavularia inflata 6:11 synthesis of 6:77,78 ()-5-e/?/-Acetoxy sinularene synthesis 6:78 (+)-16a-Acetoxytabersonine 2:186 5-Acetoxytrachelogenin diacetate 18:601 7-Acetyhorminone from Salvia candidissima 20:660 A^-Acetyl cysteamine 13:496 Acetyl pyrazine 13:320 N-Acetyl a-amino acids asymmetric hydrolysis 1:678,679 P-Acetyl alcohol 14:462 Acetylamino-1,2-dihydroacronycine 20:800 A'-Acetyl amphotericin B methyl ester amphoteronolide B methyl ester from 6:264,265 3:5:9:11-di-0-isopropylidene derivative from 6:264-266 hexaenal from 6:264,265 macrolide from 6:264-268 Acetyl CoA mevalonic acid from 7:322 3-Acetyl deoxynivalenol 13:520,521,536 A^-Acetyl glucosamine 7:31,47,49 P-(l-3 )-A^-Acetyl glucosaminyltransferase 10:484 Acetyl group 4:322,249 Acetyl-horminone 20:670 A^-Acetyl isomuramic acid 6:386,387 TV-Acetyl isomuranic acid lactones circular dichroism spectra of 6:390 O-Acetyl isophotosantonic lactone 14:357 Acetylandromedol 20:27 A^-Acetyl muramic acid alkaline degradation of 6:387 benzyl a-glycoside of 6:390,391 T>{{R)] configuration of 6:387 lactonisation of 6:389,390 synthesis of 6:387,388 X-ray analysis of 6:387 A^-Acetyl muramic acid 7:31,47,49 A^-Acetyl muramic acid lactones 6:389-396 A^-Acetyl muramic acid methyl ester a-benzylglycosides of 6:395 reaction of 6:387 A^-Acetyl muramoylamide derivatives ofMurNAcS-lactones 6:393 N-Acetyl neuraminic acid (NANA) 13:207-210 O-Acetyl normacusine B 13:386 Acetyl oleanolic acid from I-arabinopyranosyl-3P-acetyloleanolate 7:154 1-O-Acetyl oxetanose from cw-2-buten-l,4-diol 10:598,599 glycosidation of 10:603 1-P-isomerof 10:598,599 via nonphotochemical reaction 10:597,598 synthesis of 10:597-604 O-Acetyl preperakine 13:387 0-Acetyl villamine 13:396 2-0-Acetyl-(5)-(+)mandelic acid 13:468,469 1 -5-Acetyl-1 -thiohex-2-enopyranoside regioselective alkylation of 10:342 stereoselective alkylation of 10:342 Na-Acetyl-11 -hydroxyaspidospermatidine 1:40 Na-Acetyl-11,12-dihydroxyaspidospermati-ine 1:40 6-0-Acetyl-2,3,4-tri-O-benzyl-D-glucono-1,5-lactone 12:335 3-Acetyl-2,6-dimethylpyridin-4-one 13:545

924
3 - Acety 1-2-oxazolone from 2-oxazolidinone 12:411,415 preparation of 12:411,415 3-Acetyl-4,6-dimethylpyridm-2-one 13:545 4-Acetyl-6,8-dihydroxy-5-methyl-3,4-dihydroisocoumarin 15:409 3-Acetyl-(3-D-digitoxose 15:362 A^-Acetyl-P-D-hexosainidase 7:416,417 3-Acetyl-(3-lactam 12:152,161 trans-3 -Acetyl-P-lactam from imine 12:173 Acetyl-coenzyme A 7:112 2-0-Acetyl-D-glucal tetraacetate 10:414 //-Acetyl-D-lividosamine synthesis of 14:188,191 a-A^-Acetyl-s-A^-tosyl-L-lysine methyl ester anodic oxidation of 12:309 (3-N-Acety 1-glucosaminidases 12:346 Acetyl-histamines 15:328 A^-Acetyl-muramyl-(L)-alanyl-(D)-isoglutamine (MPD) 13:210-212 N-Acetyl-muramyl-L-alanyl-D-iso-glutaminyl-S-reA^ butyl-cysteamine 18:927 Nb-Acetyl-Nb-methyltryptamine 9:178 Na-Acetyl-O-methyl strechnosplendine 9:188 3-Acetyl-pyrrolidine-2,4-diones 14:100 17-O-Acetylajmaline 9:183-185 Acetylaminonaphthoquinone 9:437 (-)-A^-Acetylamphetamine synthesis of 14:496,497 Na-Acetylaspidospermatidine 1:40 A^.A/^-Acetylated disaccharide derivative synthesis of 6:401 Acetylation of 5>^ alcohol 19:480 P-Acetylation procedure for acetomycin synthesis 10:447 stereoselective 10:447 2-Acetylbutyrolactone 8:284,285 Acetylcholine receptor 18:863 Acetylcholinesterase 7:18 19-Acetylcorrin 9:600,601 2-Acetylcyclohexanone allylationof 10:412 with allyl acetate 10:412 (+)-Acetyldomesticine 16:519 Acety lenation of acetals 1:611,612 Acetylene mercury catalysed hydrolysis 3:253 reaction with enamines 3:95,96 Acetylene nucleophilicity 1:612 effect on diastereoselectivity 1:612 Acetylene Zipper reaction 8:240,242,469 Acetylene-C-glycosides 10:359 Acetylenes formation formacyl ylides 4:564 formation form carboxyl 4:322, 323 formation from lactones 4:349 Acetylenic a-ketols 6:153 a,P-Acetylenic alcohols 4:493 Acetylenic carotenoids as chemosystematic markers 6:153 biosynthesis of 6:153,154 by chemical conversion 6:142,147 chemical reactions of 6:160 chemosystematics of 6:147 chirality of 6:149 de novo biosynthesis of 6:153 distribution of 6:147 from allenic carotenoids 6:142,147 fimctionof 6:153,154 geometrical isomerism of 6:153 metabolism of 6:153,154 partial synthesis of 6:157-160 spectral data of 6:148,150 stereomutation studies of 6:153,154 steric preference in 6:154 synthesis of 6:157-160 (5)-Y-Acetylenic g-aminobutyric acid (GABA) stereoselective synthesis of 14:473 Acetylenic ketone allylic alcohol from 11:424 asymmetric reduction of 11:424 Acetylenic oxy-Cope rearrangement 8:250 28-Acetylerythrodiol from Salvia tchihatcheffii 20:707 3 -Acety lerythrodiol from Salvia thihatcheffii liS.lOl Acetylexidonin from Rabdosia gaponica var. glaucocalyx 15:171 2'-Acetylglaucarubinone 7:379,380 N-Acetylglucosamine 1:417 P-( 1 -6)-A^-Acetylglucosaminyltransferase in biosynthesis of I-antigens 10:486 iV-Acetylglucosaminyltransferase II 10:500,501 A'^-Acetylglycosides 7:434 (+)-8-Acetylgonoiotril 19:463 3-Acetylgoniotriol 9:394 //-Acetylisocodonocarpine 9:73-75,77 0-Acetylisoretuline 1:38,39 N-Acetyllactosamine (2-acetamido-2-deoxy-4-0-p-Dgalactopyranosyl-a-D-glucose) 10:459,461-467 3-Acetylleptophylline-A 20:486,487 Acetylmelodorenol 9:400,152 A^-AcetyImuramoyl-dipeptide derivatives 6:385 A^-Acetylmuramoyl-dipeptide ester 6:394 A^-Acetylmuramoyl-pentapeptides 6:404,405 7-Acetylneotrichilenone 9:297 A^-Acetylneuraminate lyase from Clostridium perfringes 7:71 Acetylneuraminate pyruvate lyase 11:466,467 A^-Acetylneuraminic acid 10:550 3 P-Acetylolean-12-en-28-al from Salvia tchihatcheffii 20:707 A^-Acetylphenylglycine synthesis of 6:319,320 (+)-Acetylphomalactone antifiingal activity of 19:479 antitumor activity of 19:479 insect antifeedant activity of 19:479 isolation of 19:480 plant growth inhibitory effect of 19:479 synthesis of 19:480 O-Acetylpolyneuridine 5:128 A^-Acetylpipecolate ester 12:309

925
Acetylpipitzol 5:778 O-Acetylretuline 1:38,39 O-Acetylsolasodine 20:489 A^-Acetylsolasodine 20:490 Acetylstrychnovoline 6:523,524 (+)-Acetylthaliporphine 16:519 2-Acetylthiazole (2-ATT) 11:443,444 0-Acetylvallesamine apparicine 5:87,88 ervaticine 5:88 16S-hydroxy-16,22-dihyroapparicine 5:88 pericine 5:88 vallesamine 5:88 0-Acetylvallesamine 9:167,168,171 Acetylvismione D 7:418-420,424 Achantaster planci 15:45 Achillea millefolium 10:151 Achillea nana 10:151 Achillin 7:234 Achiral 2-bromopropionic acid derivatives in Reformatsky reaction 12:166 with 4-acetoxy p-lactam 12:166 Achiral heptanal 12:55 Achiral pyrethroid analogues fromthujone 14:398-401 synthesis of 14:398-401 Achiral thiazolidin-2-thione derivative 12:166 Achiral-a-methoxycycloalkanone chiral co-cyano alcohols from 14:475 with(2/?,4/?)-2,4-bistrimethylsilyl oxime acetates oxypentane 14:475 Aciclovir (9-[2-hydroxyethoxy methyl] guanine) antiviral activity of 10:585 Acid catalyzed arcyrin/arcyrinin model compounds from 12:383 of A^-methylarcyriarubin A 12:383 rearrangement 12:383 Acid chlorides of 2-bromo-3-hydroxybutyric acid 4:473 of 3-hydroxybutyricacid 4:471 Acid-catalysed rearrangement 6:115 of (+)-endo-3 -bromocamphore 16:147 of spiro cyclic lactone 16:225 Acidity ofMT-sulfone 6:329 Acilius sulcatus 5:700 A cinetobacter calcoaceticus 12:103 Acinosolic acids A,B 7:144,145 Aclacinomycine A 4:317,318 Aclacinomycines synthesis of 4:330 Acnistus arborescens 20:241 Acnistus breviflorus 20:234 Aconm 20:22 Aconitin 20:22 Aconitum napellus 20:19 P-Acoradiene 15:261,262 a-Acoradiene 15:262 Acoradienes 5:734 Acoragermacrone synthesis of 8:178 Acorane as sesquiterpene 6:59 a-Acorene 15:260 (-)-Acorenone 16:222 (cf/)-Acorenone B synthesis of 10:315-317 Acosamine synthesis of 4:150 Acrasiomycetes 9:220 Acridin-9-one derivatives 13:348-350,353,361,369, 372-375 synthesis of 13:353-361 Acridone alkaloids 13:347-382 Acridones synthesis of 3:430 ACRL toxins synthesis of 18:178-185 Acromelic acid a potent neurotoxin 19:163 isolation of 19:163 synthesis of 19:163 Acromelic acid A synthesis of 1:329,330 Acronychia baueri 13:347,349;20:789 Acronychia oigophylebeia 13:348,350 oligophylidine from 13:348,350 Acronycin from Acronychia baueri 20:789 structure activity relationship in 20:791-798 Acronycine antitumor activity of 13:365-375 ^om Acronychia baueri 13:347,349 dimerization of 2:127 ()-Acrorenone B synthesis of 16:223 Acronycine azine 20:791 A croscyphus sphaerophoides 5:310 Acrylamide reagents 4:45,18:320 Acrylate of (5)-ethyl lactate 8:142 titanium tetrachloride reaction 8:142 Acrylic acid hydrogenation of 12:154 stereoselectivity of 12:154 Acrylonitrile 14:551 Aery lonitrile reagents 18:318 Actamycin 9:248,250 Acteoside 5:507 Actinidia polygama Miq. 16:290,291 Actinidine synthesis of 4:614,615 (+)-Actinobolin absolute stereochemistry of 16:3 antineoplastic activity of 16:3 dental cariostatic activity of 16:3 from Streptomyces griseoviridus Var 16:3 immunosuppressive activity of 16:3 microbial antitumor antibiotics 16:3 total synthesis of 16:3-26 Actinogyra muelenbergii 5:311-313 Actinomadura melliaura AT 2433-Ai and A2 from 12:366,368 AT2433-BiandB2from 12:366,368

926

Actinomadura sp. 5:55 Actinomadura sp. SF-2370 K-252a (SF-2370) from 12:366,368 Actinomycetales 19:559 Actinomycetes 5:601,606,77-145 ActinomycinD 20:514 Actinoplanes coloradoensis 17:283 Actinopyga agassizi holothurins from 7:267,269 Actinopyga echinites echinoside A&B from 7:269 Actinopyga mauritiana 7:281 Actinorhodin from4,10-dihydro-3H-naphtho [2,3-c] pyran-10one 11:127,128 synthesis of 11:127,128 Actinostatin 1 7:281 Activating group methoxycarbonyl as 6:540 Active oligosaccharides enzymatic synthesis of 10:479,480 Acuminatopyrone 13:544,545 Acumycin 5:613 Acute leukemia in children 14:805 vinblastine for 14:805 vincristine for 14:805 Acyclic amino acids synthesis of 13:512-516 Acyclic [2,3]-Wittig rearrangements 8:196 Acyclic a,a-dialkylated esters preparation of 10:411 Acyclic amino alcohols from 2-oxazolidinones 12:428-430 Acyclic P-hydroxy ketones asymmetric reduction of 14:183,184 Acyclic bastadins synthesis of 10:634,635 Acyclic compound pyrrolidine derivative from 14:555 with I-proline 14:555 Acyclic lactone 11:345 Acyclic TV-Boc-aminoalcohols from 2-oxazolidinone 12:428-430 hydrolytic cleavage of 12:428-430 5-Acyl meldrum acid 10:60 Acyl migration 6:122 Acyl nitro Diels-Alder reaction 1:281,282 Acyl ylides conversion to acetylenes 4:564 1 -Acyl-1,2-dihydropyridine derivative methylcyanodithioformate reaction with 6:433,434 solenopsin A from 6:433,434 3-Acyl-2-oxazolidinones with 2-exo-methoxy-l-apocamphane carboxylic acid 12:438 3-Acyl-2-oxazolone /A'a5-5-bromo-4-methoxy adduct from 12:418 rm5-5-phenyl-seleno-4-methoxy adduct from 12:418 with yV-bromosuccinimide 12:418 with phenylselenyl chloride 12:418

3-Acyl-4-methoxy-2-oxazolidmone iV-deprotection of 12:427,428 l-Acyl-5-benzylpyrrol-2(5//)-ones 13:110,111 N^-Acyl-CC-1065 structure-activity 3:376-379 synthesis of 3:373-376 a-Acylamino radical 12:446 a-Acylamino radical cyclization 1:256,292;12:471 2-Acylamino-2-deoxysugars 14:218 Acylase group 6:551 Acylated amidines 5:574 Acylated flavonol-glycosides 17:142 Acylated guanidines 5:574 Acylating agents enantioselective 14:508 Acylation ofhexaenal 6:264,267 selective 6:283,284 with A^,A^-diisopropylcarbamoyl chloride 10:15 intramolecular 16:18 with Cbz-L-alanine 16:18 with ethy Ichloroformate 16:19 A'-Acylaziridines 13:150 Acylenamines cyclization ot reythrinans 3:460 Acylglycerol 12:392 0-Acylglycosyl bromides 14:172 A^-Acyliminium ion construction of erythrinans 3:458,459 cationic 7i-cyclization of 12:287 intramolecular arylation of 12:447-452 Acyliminium ion cyclization 1:244;12:305,320,335 A^-Acyliminium ion-polyene cyclization 12:464 A^-Acyliminium ion-vinylsilane cyclization 12:453 A^-Acyliminium ions (amido-alkylation reagents) 13:473-518 Acylindole alkaloids 5:80,81 1-Acylindoles photoisomerisation of 1:51 2-Acylindoles 1:51 A^-Acyllactams pyrolysisof 6:430,431 [l,3]-Acylmigration 1:51 A'^-Acylmuramoyl-peptides 6:393 Acylnitrosocycloaddition 19:355 Acylnitroso Diels-Alder reaction 1:386,4:606 Acylnitroso group as dienophile in Diels-Alder reaction 4:606 N-Acylnorreticuline 18:74 Acyloin condensation 8:224,225,12:337 19'-Acy loxfiicoxanthins distribution of 6:134,135 Acyloxonium ion 14:203 P-Acyloxy diazo ketones acid-catalyzed 12:27,28 rearrangement of 12:27,28 to 3-fiiranones 12:27,28 3-Acyloxypyrrol -2(5;^-one 13:116,118,120 15P-Acyloxyquassin fromquassin 11:79,80 Acyloxysulfones reductive elimination of 4:522

927
iV-Acylpyrrol-2(5//)-ones 13:110,111 3-Acylpyrrol-2(5//)-ones 13:112,113,141 3-Acylpyrrolidinone 13:121,122,133,139 3-Acylpyrrolin -2,5-diones 13:114,125,129 A^-Acylsphingosines 18:714 Acylstannanes 10:22-24 Acyltetramic acid biosynthesis of 14:105,106 3-Acyltetramic acids 14:97 Adam's catalyst 4:23;12:152;19:18,70,763 Adamantane 9:116 1-Adamantyl phosphoryl derivatives ADDA Unit 9:496-499 from microcystins 9:496 '^O-NMR of 9:116-118 syn Addition 8:296-298,304 Addition reaction of chiral vinyllithium compounds 12:35-62 to a-methyl-substituted aldehyde 12:35-62 1,4-Addition reaction 14:696,697 Addition to allylic A-systems Felkin-Anh model 3:248 Addition-elimination mechanism for 5-enolpyruvylshikimate 3-phosphate synthase 11:185,187 SE'Additions 10:17-25 Additivity hypothesis 6:149 Adenanthin from Rabdosia adenantha 15:171 from Rabdosia nervosa 15:173 Adenine glycosidation of 10:603,605 with oxetanosyl chloride 10:603,605 Adenocarcinoma of colon 1:276 Adenosine 14:286 Adenosine deaminase 10:587 cv^^/c-Adenosine monophosphate (cAMP) phosphodiesterase 1:422,178 Adenosine-3'-monophosphate 2:47,48 Adenosylhomocy Sterne 19:177 S-Adenosylmethionine 11:201,207 S-Adenosylmethionine dependent methyltransferase 11:208 S-Adenosyl-methionine 1:408 5-Adenosylmethionine (SAM) methylation 9:42,599 S- Adenosylmetionine: caffeate 3-O-metyl transferase 5:468 Adipokinetic hormones 9:487,489 Adiposin-1 and 2 inhibitory activity against a-amylases 10:514 synthesis of 10:514,515 Adiposin-D 10:513 Adiposins synthesis of 13:235-246 Adiposins antibacterial activity of 10:514 from Streptomyces calvus 10:513 a-glucosidase inhibitors of 10:513 Adocia species 7,20-diisocyanoadociane 6:86 Adociane ring system 6:86,87 Adociaquinone A-B 17:33 Adrenaline 15:328 P-Adrenergic blocking agents synthesis of 14:473 p-Adrenergic receptors 18:720 Adriamycin 4-demethoxy analogs of 14:474 synthesis of 14:474,475 Adriamycinone 14:4 Adsorption chromatography 9:450-43,460 chromatographic analysis by 9:450-453,460 Aedes aegypti 9:299 Aegiceras comiculatium 7:176-178,180,185,195 Aegicerasfloridium 7:176-178 Aegicerataceae 7:177,183 Aeridoteres tristis hemogloin components of 5:837 A erobacter aerogenes 11:183 Aerobiosis 9:568 A eromonas hydrophila 4:197 Aeromonas salmonicida 4:197 Aerothionin 10:632 (+)-Aerugin 19:821 Aesculetin from Fraxinus rhynchophyllus 13:660 Aesculetin 7:224 Aesculin 7:224 Aesculosides A,B 7:142,143 A es cuius glabrus 15:191 Aesculus hippocastanum 7:142,143 Aescuius indica aesculosides A,B from 7:142 triterpenes of 7:142,143 A es cuius saponins 15:191 Affmine 16-e/7/-Affmine 5:124 Affmisine 5:123,126;9:179;13:386,429 Affinity column chromatography 16:114 AflatoxinBi 18:711 Aflatoxin M2 synthesis of 14:651-657 via Norrish type II reaction 14:651-657 (+)-Africanol 14:487,488 from chiral dienyl ether alcohol 14:487,488 synthesis of 14:487,488 Africanol 3:93 ()-Africanol by Claisen rearrangement 6:51 ()-dactylol from 6:37 fromhumulene 6:37 from Lemnalia africana 6:50 1,2-methyl shift in 6:37 synthesis of 6:50 Afrocurarine 1:126 Afzelia bipendensis bipendensis from 9:256 Agaricales 9:203 a-Agaroftiran (+)-intermedeol from 14:453 Agavaceae 7:427 Agave cantala 7:427 Agel-489 13:650

928

Agelas mauritianus agelasphins from 18:460,467 Agelas nakamurai agelasin-B from 6:28 Agelas species agelasins from 6:28 Agelasin-B from Agelas nakamurai 6:28 from kolavenic acid 6:28 synthesis of 6:28 Agelasins from Agelas species 6:28 Agelasphin-9b synthesis of 18:467-469 Agelasphins from Agelas mauritianus 18:460,467 Agelenopsis aperta 19:675 Ageratina adenophora 5:28 Ageratoriparin 20:282 Ageratum fastigiatum 5:728 Agglutination inhibitors 2:308,309 Aggregation pheromone of Gnathotrichus 1:692 Aggreticin platelet aggregating inhibitor 5:597 Aglaopheniapluma 5:353 Aglycone from cyclohexene imides 12:378 ofAT2433-BiandB2 12:377-379 ofstaurosporine 12:379-381 synthesis of 12:377-381 Aglycone 15:362 a2-Agonists 8:396-298 Agratis ipsilon 7:397 Agrobacterium rhizogenes 15:376,377;17:395,421 Agrobacterium sp. 7:76 Agrobacterium tumefaciens 9:386,388 Agroclavine 11:199,200 Agyl glycosides 7:53-58 AHB (3-amino-5-hydroxybenzoic acid) synthesis of 9:434 Ahydrovinblastine synthesis of 4:31,32 AI-77-AtoG 15:390 AI-77-B 15:393,396,397,402,404,412-418 AI-77-G 15:392 AIBN (2,2*-azobisisobutyronitrile) 6:353;19:340;481 AIDS 2:421-426 Aids virus 12:245 Ailanthes altissima 2:370 Ailanthinone 7:379,380,398 Ailanthone 7:394,398 Ailanthus altissima 7:392,394 Ailanthus grandis 7:369,381 Ailantone conversion to sinjulactone C 5:800 Aizoaceae 0-methyljoubertiamine from 4:3-5 mesembrine from 4:3-5 Aizumycin from Streptomyces aizunensis 12:63 Ajmalicine from Corynantheyohimbe 8:283

Ajmalicine from Rauwolfia serpentina 13:660 (-)-Ajmalicine asymmetric synthesis of 14:563,564 from piperidine 14:563,564 ()-Ajmalicine 18:332 Ajmalicine-type alkaloids isoreserpiline 5:74 reserpilme 5:74 serpentine 5:74 tetraydroalstonine 5:74 Ajmaline 9:183-185;13:403,404,424-426;15:469 Ajmalinimine 9:183-186 Ajugalactones 20:248 Ajugol 7:455 Akicenin 5:722,723 Akiferidin 5:722,723 Akiferidinin 5:722,723 Akiferin 5:722,723 Aklavinone 4:317,327-329,333,341,342;11:121-123 Akuammicine 1:35:1:45;5:123;9:190,192;14:751 Akuammicine N-oxide 5:123 ;9:190,192 Akuammicine-Nb-metho salt 1:35 Akuammicine-type alkaloids 5:86 (Z)-Akuammidine 15:466,467 19 Akuammidine 5:24,123,127;9:171 ()-Akuammidine (rhazine) 13:403 Akuammidine-type alkaloids 5:74,76 Akuammigine 9:171 Akuammiline 5:80,126,9:194,195 Akuammiline-type alkalids 5:79,80 ALA (5-aminolevulinic acid) 9:591,593,601,603,606 ALA-dehydrase 9:604 Alane 1:455 L-Alaninals amino sugars from 4:118-127 A^-monoprotected 4:127 ^;A^-diprotected 4:124 synthesis from L-alanine 4:118 D-Alaninals amino sugars from 4:118-127 synthesis from D-alanine 4:118 D-Alanine in synthesis of D-alaninals 4:118 I-Alanine in synthesis of L-alanials 4:118-127 I-serine analogue of 4:127 p- Alaninookadaic acid 5:385,388 I-Alanyl-Z)-isoglutamine benzyl ester 6:398,405 Z-Alanylglycine benzyl ester 6:393,394 Alarm pheromone n-undecane in 6:453,454 Alatol 18:745 9-e/7/-Alatol 18:746 Alatolactone derivatives 7:233 AlbaninFandG 4:618 Albartin 7:224 Albati 17:198 Albazoin 17:19 Albene synthesis of 4:639 Albicanol 17:14 Albicanyl acetate 17:14

929
Albifloranine 9:171 Albomitomycin A from Streptomyces caespitosus 13:434 Aibomycin 9:555 Alcaligenes eutrophus 1:690;4:39;8:299 Alcaligenesfaecalis var.myxogenes 5:314 (+)-Alchomeine 16:439 P-Alcohol 19:248 Alcohol dehydrogenase 17:479 Alcohol inversion 1:456,457,459 Alcohol protection as MEM ether 1:558 Alcohols as chiral building blocks 1:684-688 preparation of optically active 1:6 84-6 8 8 CI(NO) spectrum of 2:4 Alcyonidium gelatinosum 18:695 Aldehyde-ketophosphonate condensation 6:264,265 Aldehydes geminal dialkylation of 8:3,5 CI(NO) spectrum of 2:4 by 1,3-dithiane 6:308 byFAMSO 6:311-313 from carboxylic ester 6:334 synthesis of 6:308,311-313,331 1 -Aldehydofuranosides synthesis by RWG contraction 3:225,226 Alder ene reaction 8:277,278,280 Alderene 1,4-diene 8:278 ()-Aldimine 11:278,279 Aldimine 18:680 Alditols 9:499 1-Aldo-C-glycosides 10:350,351,389 Aldoheptofuranoses Aldohexofuranose derivatives 10:428-432 asymmetric quatemization of 10:428-432 Johnson-Claisen rearrangement of 10:432-436 Aldohexoses 10:414,415 Aldol condensation 13:448,468 P-elimination 12:13 acid-catalyzed 16:216,220 asymmetric induction in 4:328,329 base-catalyzed 16:220 chelation controlled 10:286 crossed 11:296,297 diastereoselective 4:328,329;12:15,16 intermolecular 10:182,183,318-320;11:113,115 internal 1:363-365 intramolecular 10:303,306,318,329,330;16:141, 216,216,221,228,259,260 of silyl enol ether and acetone 11:296,297 offuranone 12:13 stannic chloride catalysed 4:328,329 TiCU catalysed 1:537,538 Aldol coupling reactions 11:435-439 Aldol cyclization 2-amino alchohol by 12:411,414 asymmetric 4:327 chkal acetals in 4:329 chiral synthons for 4:491 of a-sulfmylesters 4:491 -494 of aldehyde 12:174,411,414 of ascorbic acid 4:699-705 ofenolate 160 stereoselective 12:154 with enolsilyl ether 12:174 with isonitrile 12:411,414 with A^-acylimine 12:160 Aldol stereoselectivity 12:72 Aldol type addition 16:656 Aldol type condensation of aldehydes 8:426,427 with 2-trimethylsiloxy-3-methylfuran 8:426,427 Aldol cyclization 6:49,50 in (+)-spatol synthesis 6:40,41 Aldol reaction intramolecular McMurry approach 13:602 Aldol-type reaction stereocontrolled 12:36 stereoselective 12:166 Aldolase 11:216 Aldolate trapping 4:17,18 Aldolization 6:7,9,10,17 Aldols by kinetic deprotonation 11:337,338 of2-cyclohexen-l-one 11:337,338 with 4-pentenal 11:337,338 Aldonolactones 7:49,50 P-D-Aldopyranosyl-cyanides synthesis of 10:355 Aldose reductase 9:499-503 Aldose reductase inhibition 6:20 by (+)-dysideapalaunic acid 6:20 (+)-Aldosterone enantioselective synthesis of 16:706-707 (1-^1 )-Aldosyl aldoside 1 -thiodisaccharides 8:317-322 (l->2)-Aldosylketoside 1-thiodisaccharides 8:322-326 Alectoria sarmentosa 5:310,311 Alectoria sulcata 5:310,311 Alexa leiopetala (+)-castanospermine from 12:332 (+)-6-e/7/-castanosperime 12:342 (15',65',7/?,87?,8a/?)-tetrahydroxyindolizidine from 12:332 Alexa leiopetale (+)-castanospermine from 11:267 Alexandrium fundyense 18:703 Alexandrium ostenfeldii 18:703 Alexandrium tamarebnsuis 1:703 Alexandrium tamarensis 17:4;18:703 Alexine 7:13,14,10:567,568 Alflavene biosynthesis of 4:618,619 Algae 9:321 Alicyclic polyketide nonaromatic 12:16 Alioline '^C-NMR spectrum of 5:165 COSY.45 spectrum of 5:163,164 *H-NMR spectrum of 5:163 NOE measurements 5:164 UV spectrum of 5:163 Aliphatic acceptors in Michael reaction 4:705,706 Aliphatic isocyanides synthesis of 12:113,114

930
Aliumvineale 15:196 Alkali metals in prenylation methods 4:394,395 Alkaline degradation ofN-acetyl muramic acid 6:387 Alkaline protease 9:412 Alkaloid AG-1 1:127 Alkaloid production in Zenk's medium 2:373,374 Alkaloids P-carboline 17:89 cinchona 7:444 cyclopentanoid monoterpene 7:443,444 from aspidosperma family 2:376,378 from Capparis decidua 9:73-75,77 from corynanthe family 2:376,378 from iboga family 2:378,379 from Prosopis juliflora 9:70-73 from Schweinfurthiapapilionacease 9:25,26,28 fromstrychnos 2:379 indole 7:443,444 indolizidine 6:422,442,443,445-451 ipecacuanha 7:444 isoquinoline 17:89 molluscicidal activity of 7:427 of Strychnos dinklagei 6:503-536 of Tetraponera 6:451 -454 piperidine 6:422-434 production of 17:404,409,411-412 purine 17:89 pyridine 17:89 pyrrolidine 6:434-444 pyrrolizidine 6:422,442,443,445 pyrroloquinoline 7:444 semi-synthesis of 17:631 synthesis of 14:632-639 synthesis of 16:415-452 Alkane-2,6-diones reductive aminocyclization of 6:433,434 Alkanol 7:231 Alkavinone enantioselective synthesis 1:596,597 Alkenals 2:10 Alkene 2-amino alcohol by 12:411,413 asymmetric hydration of 13:451 asymmetric hydroboration of 13:451,452 n-Alkenoic acids 2:9 oxyamination of 12:411,413 photochemical additions to 1:642 A^'^Alkene 12:22 o-Alkenyl dehydroglycosides 3:245 6-Alkenyl-4-oxapyran-2-ones 10:340 by enolate Claisen rearrangement of 10:340 Claisen rearrangement of 3:245 hydroboration of cw-Alkenes 8:471,472 thermolytic cyclization of 6:429 c-Alkenes 8:471,472 hydroboration of 8:471,472 Alkenols 2:10 (Z)-Alkenones 19:122 Alkenoylcyanide acceptors in Michael reaction 4:709-711 Alkenyl acetates 2:10 Alkenyl azides thermolytic cyclization of 6:429 0-Alkenyl dehydroglycosides Claisen rearrangement of 3:245 (Z)-//-Alkenylinitrone 19:29 Alkenyl phenols molluscicidal activity of 7:427 6-Alkenyl-4-oxapyran-2-ones by enolate Claisen rearrangement 10:340 (3-l-Alkenyl-9-borabicyclo [3.3.1] nonanes 10:156,160 Alkenylcopper-phosphine complex 8:189 Alkenylhydroquinones 9:321,329 Alkenylpyrazines 5:239-246 2-Alkenyltropolones [4+2] cycloadditions of 5:799,800 [6+4] cycloadditions of 5:799,800 A^-Alkenylurethanes 19:29 Alkhanin 7:231 Alkoxides 2-amino alcohol by 12:411,413 Michael addition of 12:411,413 to nitro olefin 12:411,413 2-e;co-Alkoxy derivatives by reduction 12:417 of ketopinic acid 12:417 with L-selectride 12:417 2-e Jo-Alkoxy derivatives P-Alkoxy diazo ketones 12:27,28 P-Alkoxy ketones from chiral acetal 14:481 pure alcohols from 14:481 2-Alkoxy ketones 14:647 3-[ 15)]-2-exo-Alkoxy-1 -apocamhaneearbonyl]2-oxazolones (45',55)-isomer from 12:420,421 methoxybromination of 12:420,421 methoxyselenylation of 12:421,422 (4/?,5/?)-4-methoxy-5-phenylseleno-2oxazolidinones from 12:421,422 reversed p facial selection in 12:420-422 3-[( 1 S)-2-exo-Alkoxy-1 -apocamphane-carbonyl]-2oxazolone to dialkyl azocarboxylates 12:424,425 a-Alkoxy-a-arylacetates synthesis of 6:331 a-Alkoxy-a-arylacetates esters synthesis of 6:328 2-Alkoxy-butadienes in Diels-Alder reactions 4:581 Alkoxyacrylate by methanolysis 14:563,564 1-Alkoxyalkyl-a-glucosides 7:51 Alkoxyalkyl-P-glucosides 7:51 Alkoxyallenes diastereoselective synthesis of 1:627 (y-Alkoxyallyl) stannanes 11:442,443 (a-Alkoxyallyl)-boronic ester from pinacol (1 -bromoallyl) boronate 11:424 P-Alkoxyboranes elimination 4:116

931
a-Alkoxydimethylhydrazones 2-amino alcohol by 12:411,413 nucleophilic addition of 12:411,413 organolithium reagents to 12:411,413 a-Alkoxymethoxy methyl ketone addition of 12:29,30 3-butenyl magnesium bromide 12:29,30 chelation-controUed 12:29,30 4-Alkoxypyridine as catalyst 4:270 a-Alkoxysulfoxide from monochlorinated sulfoxide 6:310 3-Alkylpthalide alkylation of 5:827,828 hydrogenolysis of 5:827,828 Alkyl 1-thiogalactosides synthesis of 8:342 Alkyl 1-thioglycoside 8:347 Alkyl 1-thioxylosides 8:315 Alkyl 4-thiodisaccharide 8:332,333 a-Alkyl a-amino acids 10:411 Alkyl P-D-galactoside 8:316 5ec-Alkyl boronic ester 11:409,411,412 Alkyl C-glycosides from glycosyl fluorides 10:368 Alkyl ketones 14:645 Alkyl maltotrioside 8:346,347 Alkyl pyrazines mass spectroscopy of 5:259 Alkyl quinones 5:821 2- Alkyl-1,4-naphthoquinones 5:823,824 2-Alkyl-l-piperidine 6:424 in Solenopsis species 6:422 4-Alkyl-2-buten-4-olides 3:166,167 4-Alkyl-2-oxazolidinones from 4-methoxy-2-oxazolidinones 12:426 A^-Alkyl-4-hydroxy-2-pyrrolidinones from p-oxoamides 14:650,651 synthesis of 14:650,651 ^A-a5-2-Alkyl-5-hydroxypiperidines 13:486 2-Alkyl-6-methyl pyridine from 2,6-dimethylpyridine 6:425 synthesis of 6:424-426 3-Alkyl-8-hydroxy-3,4-dihydroisocoumarins 15:386 a-Alkyl-a-amino acid asymmetric synthesis of 13:95-99 a-Alkyl-a-mino acid derivatives 13:80 Alkyl-P-Z)-glucopyranosides 7:52 Alkyl-p-D-glucosides 7:104,105 Alkyl-P-glucosides 7:50,51 l-iV-Alkyl-deoxynojirimycins 7:46 Alkyl-substituted azulenes oxidation potentials of 14:347 Alkyl-sulfoxides synthesis of 4:490,491 Alkyl-type phosphoramides 14:286 N-Alkylated pyrrolidinones photo-induced annulation of 12:293 24-Alkylated thomasterol A 15:48 5-Alkylation 8:214 intramolecular 13:145 O-Alkylation a-D-glucopyranoside 6:385 glucopyranoside 6:388 A^-substituted amides 10:215 of potassium koj ate 12:261 ofw-haloalcohol 8:195 Alkylation asymmetric 11:367 base (LDA) mediated 10:408,409 diastereoselective 14:491-499 enantioselective 10:412 in basic media 4:389-391 intramolecular 16:125;19:486 of(5)-a-terpinylamine 11:283 of 1,5-acetyl-1 -thiohex-2-enopyranosides 10:342 of l-benzyl-2,6-dicyanopiperidine 6:433 of 1-phenyl-1-methyl 6,7 seleno-1-ethyllithium 8:6,7 of 2-acetoxy-5,6-dihydro-2H-pyrans 10:342 ofacetals 1:613-616 ofbenzyllithium 8:6 ofcarbanion 8:176 ofcarvone 10:408,409 ofchiralacetals 12:489-493 ofcyanohydrin 8:16 of cyanohydrin ethers 8:177-179,183 ofdianion 11:284,285 of dimethyl malonate 8:185,186 ofdioxolaneenolates 1:644 ofFAMSO 6:313 offluoromalonate 13:82 ofmethylmalonate 13:79 ofMT-sulfone 6:334 of A^-nitrosopyrrolidine 6:439,441 of silver cyanides 12:113 of sulfur stabilized carbanion 8:16 of trans-2,5-\)\s (methoxymethoxymethyl) pyrrolidme 10:412 of w-haloalkylphenylthioacetate 8:176 of a-methyl-phenylacetic acid 10:412 of a-phenyl-y-lactone 10:410,411 of P-ketoester 8:181,191 palladium-mediated 16:422 regioselective 10:342 stereoselective 10:342,410,411;11:284,285 synthesis of 3:166,167 TiCU catalysed 1:615 via sequential dianion generation 16:371 with l-TMS-2-pentyne 11:284,285 with 2,5-dibromo-2-methyl pentane 8:6,7 with 3-butynyl p-toluene sulphonate 14:559 with allylic halide 8:178 with benzyloxymethyl chloride 6:561 with di-^butyl dicarbonate 14:559 with House procedure 10:308,309 with indole-protected tryptophyl bromide 11:283 with organometallic reagents 1:613-616 y-Alkylation in (+)-sinularene synthesis 6:76,77 C-Alkylations of phenolates ofcyanohydrin 8:195 with prenyl bromide 4:382-386

932
Alkylcatechols 9:328 3-Alkyldihydroisocoumarins 15:386,387 6-(9-Alkylerythromycins 13:162-165 3-Alkylidene oxepanes synthesis of 10:221 6-()-Alkylidene-8-hydroxy-8-methylindolizidines synthesis of 12:295,296 6-(Z)-Alkylidene-8-hydroxy-8-methylindolizidines synthesis of 12:294,295 C-Alkylidenepyraneside alloyohimban 3:406,407 synthesis of 3:220,406 Alkylmalonate fluorination of 13:83 (5)-4-Alkyloxazolidin-2-one derivative 12:164-168 3-Alkylphenols 9:323,329,338,346 5-Alkylresorcinol from Grevillea striata 8:227 Alkylresorcinols 9:328,338 (5)-4-Alkylthiazolidin-2-thione derivative 12:164-168 Alkylxanthates 8:316 Alkyne compound from propargyl alcohol 14:570 trans-o\Qfm from 14:570 Alkynoic acids/esters 2:16 Alkynols 2:14-16 a-Alkynone cyclization 6:45 in (+)-A^^'^^-capanellene synthesis 6:45 P-Alkynyl alcohol 12:24 Aikynyl Grignard reagents reaction with l-methoxycarbonyl pyridinium chloride 6:448 reaction with 2-methylpyridinium salts 6:429 Alkynyl-a-chlorohydrins LAH reductions of 8:247 Alkynylation diastereoselective 1:610-612 Alkynylsilane 14:482 All ^rart5-7,8-renieratene synthesis of 6:156,160 AW-trans (3/?,3/?')-alloxanthin CD spectrum of 6:149 All-trans (35,35')-tetradehydroastaxanthin synthesis of 6:157 AW-trans didehydocarotenoids 6:155 AW-trans geranylgeraniol in taondiol methyl ether synthesis 6:56 AW-trans polyprenols 8:66 All-/A'a5-7,8-didehydroisorenieratene synthesis of 6:156,160 Allaentus zeylanicus 5:752 Allamanda blanchetii 19:776 Allamanda catharica Linn 16:299 Allamandicin antifungal activity of 16:299 antileukemic activity 16:299 antimicrobial activity 16:299 cytotoxic activity 16:299 synthesis of 16:299-301 /7/-Allamandicin synthesis of 16:301 Allamandin synthesis of 16:299-301 Allamcin from Allamanda s^p. 16:299 Allamdin antiftingal activity of 16:299 antileukemic activity of 16:299 cytotoxic activity of 16:299 Allamicin from Allamanda sp. 16:299 Allelochemicals 9:387 Allelopathic activities 20:391 Allene 5:370 Allene epoxide rearrangement of 8:36 Allenic acetylenic carotenoids 6:162-164 Allenic carotenoids biosynthesis of 6:139,142 de novo biosynthesis of 6:133-135 chemical reaction of 6:146,147 chemosystematics of 6:133-135 chiralityof 6:137 distribution of 6:133-135 from zeaxanthin (p,P-carotene-3,3- diol) 6:139 fiinction of 6:142,143 isolation of 133,134 metabolic transformation of 6:142,143,155 metabolism of 6:142,143 stereochemistry of 6:138-142 structure determination of 6:135-13 8 synthesis of 6:143-147 ()-Y-Allenyl-GABA synthesis of 13:514 Allenyltin 12:170,172 Alleochemicals 8:219 Allergenic dermatitis 2:277,280-281 Allergy inhibitors 5:759 (+)-^//o-pumilitoxin 339B synthesis of 16:426 Alloaristoteline (epi-11-aristoteline) ^^C-NMRof 11:314 from Aristotelia australasica 11:317,318 from aristoteline 11:321,322 total synthesis of 11:318-322 (+)-Alloaromadendrane-4,10-diol from Ambrosia peruviana 14:379 ()-Alloaromadendrane-4a, 1 Oa-diol synthesis of 14:379-384 ()-Alloaromadendrane-4p, 1 Oa-diol synthesis of 14:379-384 ()-Alloaromadendrane-4p,10P-diol 14:383 Alloaromadendren-4p-ol 14:381,382 Allocryptopine from canadine methiodide 491,492 synthesis of of 6:491,492 Allocryptopine A^-oxide Meisenheimer rearrangement of 6:494 Z)-Allofuranose C3-P bond analogs of 6:359 D-ribo-hexofiiranose from 6:369 Allohobartine 3-ethyl-allohobartine from 11:318,319

933
5,6,7,8-tetrahydrobenz [b] indolizidine from 11:318,:319 3-trifluoroacetyl-allohobartine from 11:318,319 AUohobartine derivative preparation of 11:316,317 (2/?,35)-Alloisoleucine from (25,3S)-isoieucine 10:277,278 ()-a-Allokainic acid synthesis of 13:508,509 a-AUokainic acid pyrrolidine derivative from 14:556,557,560,561 2-pyrrolidone from 14:560,561 (-)-Allokhusiol synthesis of 10:410 AUomelanin 9:231 D-Allomethylpyranose 15:190 AUomones 8:219,220 AUomuscarine from 2-deoxy-D-erv^/iro-pentose 10:394 from 2-deoxy-L-ervr/2ro-pentose 10:394 L-(+)-Allomuscarine synthesis of 10:394 Allomyces macrogynus 5:276,6:544 Allomyces sp. 5:276 AUopumiliotoxins 19:52,54 (+)-Allopumiliotoxins 19:60,61-63,65 (+)-Allopumiliotoxin 267 A synthesis of 16:486-487 7-epimer of 12:297 synthesis of 12:297 (+)-Allopumiliotoxin 267A,339A and 339B synthesis of 12:298-300;16:485-487 AUopumitiotoxin synthesis of 12:297-300 D-AUosan from dihydrolevoglucosenone 14:278 D-Allose from 2,3,5-tri-O-benzoyl-p-D-ribofiiranosyl cyanide 10:358 3,4,6-substituted derivatives of 10:358 Allosecurinine 14:657 ()-Allosedamine 13:474 AUosedamine 10:677 (-)-Allosedamine 13:475,477 AUoserratenone aristolasicone from 11:316,317 AUosorelline 11:320 Allosteric effector 5:835 (3/?,3/?')-Alloxanthin 6:153 Alloxanthin 6:154,155 (-)-Alloyohimban 10:155 (+)-3-p/-Alloyohimban 18:384 (-)-Alloyohimban 18:384 ()-Alloyohimbane stereoselective 14:710,711 synthesis of 14:710,711 Alloyohimbine synthesis of 3:407,410 Alloyohimbines allylation 3:135,222 chemical initiation 3:22 Pd-(0)-catalysed 3:135 photochemical initiation 3:22 with allyl-tri-n-butylstannane 3:222 p-Allyldiisopinocamphenylborane 19:14 AUyl 2,3 -di-O-benzyl-a-L-rhamnopyranoside thermal glycosidation of 8:365,366 Allyl2,3-0-benzyl-4-0-rerr-butyldimethylsilyl-a-Lrhamnopyranoside 8:368 AUyl 3,4,6-tri-p-D-glucopyranoside thermal glycosidation of 8:365,366 Ally 13,4,6-tri-O-benzyl-a-glucopyranosides thermal glycosidation of 8:365,366 Allyl3,5-0-isopropylidene-2-0-triflyl-P-Dlyxofiiranoside 8:330 Allyl acetates isomerization of 4:49 allylation 4:21 ofo-vanillin 4:21 (/?)-Allyl aclohols formation of 14:500,501 Allyl alcohol pyrrolidine derivative from 14:571 (5)-Allyl alcohols formation of 14:500,501 Allyl aluminium 8:24 Allyl p-C-glycoside by reduction with EtsSiH-BFj 10:386 from gluconolactone 10:386 Allyl C-glycoside byozonolysis 10:361,371,372 71-Allyl complexes 4:398 exo-2-Allyl derivative of6-methoxyepicamphor 4:657,658 Allyl ether isomerization to vinyl ether 1:453 Allyl glycidyl ether cyclization of 10:588,589 oxetane ring formation by 10:588,589 reaction of 10:588,589 with sec-butyllithium 10:588,589 a-Aliyl glycosides hy anti SN^ displacement 10:348 from D glucal triacetate 10:419 stereochemistry of 10:348 Allyl isocyanide from allyl iodide 12:113 from silver cyanide 12:113 Allyl mangenese reagent 4:34,344 7i-Allyl palladium complex 4:500;10:214,215 Tii-Allyl Pd alkylation intramolecular 10:10-13 AUylphenols 20:271 Allyl sulfones addition to enones 3:23 Allyl sulfoxide anions addition to enones 3:21,22 ahiusenone 3:435 alpine-borane reagent 3:267 chu-al 3:21,22 synthesis of 3:435 Allyl tributylstannane 12:425,426 N,N-Allyl,a-methyl benzylamine 8:403-404

934
(R)-5-Allyl-2-oxazolidinone from(4/?,5/?)-5-allyl-4-phenylthio-2-oxazolidinone 12:434 (45,55)-5-Allyl-4-methoxy-2-oxazolidmone (35,45)-cyclohexylstatine from 12:432,433 (35,45)-statine from 12:432,433 (-)-5-Allyl-4-methoxy-2-oxazolidinone 12:419 (4/?,5/?)-5-Allyl-4-methoxy-2-oxazolidmone 12:431, 432 (4/?,5/?)-5-Allyl-4-phenylthio-2-oxazolidinone (^)-5-allyl-2-oxazolidinone from 12:434 Allyl-9-BBN 14:482 5-Allyl-derivatives from 5-bromo compounds 12:425,426 Allylamines 2-amino alcohol by 12:411,414 cyclocarbamations 12:411,414 Allylation diastereoselective 1:604-610 of2-acetylcyclohexanone 10:412 ofFAMSO 6:315,316 with allyl acetate 10:412 Allylation reaction 12:484,14:474 (9-Allylation-Claisen rearrangement 12:269 AUylboration 8:477,478 AUylboronate stereoselective addition to glyceraldehyder 1:311,312 7c-Allylcation complex 3:82,83 Allylcerium 8:24 Allylchromium species coupling with carbonyIs 3:81 medium ring compounds from 3:81 C-Allylfiiranoside 3:215 a-Allylglucosides synthesis of 3:214,215 (S)-Allylglycine 13:512 Allylic polyprenols synthesis of 8:66,67,72 Allylic (alkyl) ketene acetal [3,3] sigmatropic rearrangement of 10:417 Allylic acetates 8:228 Allylic acetoxylation 16:420 Allylic alcohol allylic aldehyde from 12:46,47 amides from 14:722,723 asymmetric cyclopropanation of 14:490,491 biomimetic cyclization of 14:717-720 by Claisen rearrangement 14:722,723 epoxidation of 10:39,40 2,3-epoxy alcohol from 14:570 from (/?,/?)-2,3-butanediol 14:490 from acetylenic ketone 11:424 from D-glucose 10:428-438 from dimethyl-tartrate 11:267,268 Johnson-Claisen rearrangement of 10:428-438 mesylationof 4:172,173 one-carbon homologation 3:238 oxidation of 12:46,47,16:594 preparation of 11:424 Sharpless epoxidation of 14:570

withMnOz 12:46,47 with VO (acac)2-TBHP 10:39,40 Z-Allylic alcohols cw-hydroxylation of 4:203 Allylic p-hydroxysulfoxides stereoselective hydroxylation 4:503,504 Z-Allylic P-ketosulfoxides synthesis of 4:509,510 Allylic bromide from ethyl acetoacetate 12:269 with4-bromo-l-butene 12:269 Allylic bromination 6:207 Allylic C-0 bond cleavage with dissolving lithium/amine reduction 1:557,558 Allylic carbocation asymmetric epoxidation of 4:172-174 Allylic carboxyl group phytochemical removal 3:487 Allylic displacement reactions palladium catalyzed 16:397 Allylic ethers hydroboration 4:116 Allylic glycolate esters freland-Claisen rearrangement of 10:437 Allylic hydroxylation with Se02/tert-butylhydroperoxide 1:535 Allylic hydroxylation 6:200,201 Allylic A^-benzoyl-a-amino acid esters Claisen rearangement of 11:471 Allylic oxidation 3:448;6:126,159,162;8:197,198; 11:11,40,41;12:311;16:420,669 ofperezinone 5:722 with Collins reagent 11:83,84 with manganese dioxide 11:356,357 withSeOz 1:549,550 Allylic radicals reductive elimination 4:525 Allylic rearrangement 4:556,6:159,14:191,16:305, 617,669 Allylic strain 6:122 Allylic strain (nonchelate-controlled mode) 14:553 Allylic sulfoxide rearrangement 1:560,564 Allylic sulfoxides [2,3] sigmatropic rearrangement of 11:326,327 Allylic trichloroacetimidates [3,3] sigmatropic rearrangement of 10:421 Allylmetal additions 8:16 a-Allyloxy anions [2,3]-Wittig rearrangement of 3:248-250 Allylsilane 14:482 Allylstannane 1:247,256,312,313,10:17-25 Allyltin derivatives nucleophilic addition by 11:442,443 AUysilane 1:314 (Allyloxy) methyllithium rearrangement of 8:200 Alnusfirma 17:359,364 Alnus glutinosa 19:246 Alnushirsuta 17:360-361 Alnus japonica 17:360,368 Alnus rubra 17:359 Alnus serrulatoides 17:359-360

935
Alnus species 17:358-359,368,375 Alnusdiol 17:368 Alnuson 17:368 Alnusonol 17:368 Alnusoxide 17:368,371 Aloperine 14:754 Alpha-D3 9:513 Alpha-tocopherol 14:617 Alpinia katsumadai 17:362,375 Alpinia ojficinarum 17:362-363,375 Alpinia oxyphylla 17:362,375,379 Alpinia sieboldiana 17:362 Alpinia species 17:358 Alpinigenine synthesis of 1:213,214 c/5-Alpinigenine synthesis of 1:214-217 Alsophila pometaria 18:681 Alstocraline 13:395 Alstonamide ^H-NMR spectrum of 5:155 mass spectrum of 5:155 UV spectrum of 5:155 *^C-NMR spectrum of 5:140 COSY-45 spectrum of 5:139,140 ' H - N M R spectrum of 5:138-140 mass spectrum of 5:138 Alstonerine frommacroline 13:398 synthesis of 13:383,408,411,415- 423 Alstonia augustifolia 13:422 Alstonia scholaris 5:135,137,138,13:383 Alstonia constricta 1:125,214-217,219,2:369 Alstonia macrophylla 5:135,154-157 Alstonia venenata 1:125 Alstoniline synthesis of 1:129,132,138 Alstonilinol synthesis of 1:128,129 Alstonine 1:125 Alstonisidine 13:383,393,405-407 Alstonisine 13:388,391,399 Alstophylline 13:388,403,405 Alstopicralamine COSY-45 specgrum of 5:156,157 ^H-NMR spectrum of 5:157 mass spectrum of 5:157 Alstopicralamine 9:185,186 Alstovine 1:36 Altemaria solani 598 Altermaria mali 12:400 Altemaria 9:203 Altemaria cinerariae dehydrocurvularin by 11:194 Altemaria kikuchiana 5:598 A Itemaria kikuchiana tanaka 15:385 Altemaria solani altersolanol A from 15:346 Altemaria tannius 9:300 Altersolanol A from Altemaria solani 15:346 Altholactone (goniothalenol) 9:393 (+)-Altholactone 19:468 Altholactone biological activity of 19:498 isolation of 19:498 AltohyrtinA 19:580 D-Altropyranoside 6:359,360 C3-P bond analog of 6:359,360 D-Altrose 4:203 Aluminium hydride selective reduction with 3:474 Alutera scripta 5:390 Alzheimer's diseases (-)-physostigmine for 14:637 AMAPOR activity 20:875,878 Amadori rearrangement 18:680 Amalgam procedure 14:746 Amanita agaricus 9:203 Amantia phalloides 5:496 Amaouciaxantin 10:153 Amarogentin 7:490 Amarolide synthesis of 11:78,79 Amaroswerin 7:490 Amarouciaxanthin A 6:136,142 Amarouciaxanthin B 6:151,152 Amaryllidaceae alkaloids 4:8,12,27;10:411;11:229; 16:444 Amaryllidaceae buphanisine from 4:3,4 crinine from 4:3,4 galanthamine from 4:3,4 haemanthidine from 4:3,4 lycoraminefrom 4:3,4 pretazetting from 4:3,4 Amastatin [(25,3/?)-3 -amino-2-hydroxy-5-methyl hexanoyl-L-valyl-L-valyl-L-asparticacid)] leucine aminopeptides A inhibitor of 12:434 leucine aminopeptidase inhibitor of 12:434 Amata sp. 5:225,252 Amathamide A-G 17:83 Amathamides 17:82,84,88,93,95.97 Amathamides C,D,E and F 18:715 Amathia altemata 17:85 Amathia convoluta 17:75,18:715 Amathia genus 17:82 Amathia wilsoni 17:92,95,97,101,18:693 Amauromis phoenicurus hemoglobin components of 5:83 AMB (aminomethyl bilane) 9:595,596 Ambergris fragrances synthesis of 14:420-425 Amberlite IR-45 15:460 Amberlite IRA-400 12:317 AmerlystA-21 19:131 ()-Ambinine cyclization 14:788-791 from 13-methyltetrahydro-protoberberine 14:790, 14:791 synthesis of 14:788-791 X-ray analysis of 14:791 Ambliofriran analogs 1:666-670 Ambrenolide from Salvia yosgadensis 20:692

936
Ambrosanolide 16:140 Ambrosia maritima lAll Ambrosia peruviana 14:379 (+)-Alloaromadendrane-4,10-diol from 14:379 (-)-Ambrox synthesis of 14:420-425 (-)-ep/-Ambrox synthesis of 14:420-425 Ambrucitin from alkynylyl lithium 10:386 synthesis of 10:386 Amebicidal activity of emetine 6:485 of 1,2-secoemetine derivatives 6:485 Amenanthus retroflexus 7:398 American celastraceae triterpenes from 18:757-764 Amethystoidin A from Rabdosia macrophylla 15:173 Amethystonal '^C-nmrof 15:128 from Rabdosia amethystoides 15:171 *H-nmrof 15:121 Amethystonoic acid ^^C-nmrof 15:128 from Rabdosia amethystoides 15:171 ^H-nmrof 15:121 Amicetin 4:234,240,242 Amicoumacin A, B and C 15:388 Amicoumacins biological activities of 15:410-412 ^mm-Amidation 6:409,412 Amide cyclisation 4:546 Amides CD of 2:171 dehydration with chloromethylene 3:212 Amidic penicillins 12:135 Amidoalkylation intramolecular 10:108 Amidoalkylation reagents (A^-acyliminium ions) 13:473-518 Amidocarbonylation 16:408 Amidocyclization 1:382 ()-Amijitrienol from Dictyota linearis 6:52 synthesis of 6:53 (+)-Amijitrienol by intramolecular cycloalkylation 6:53 by methylenecyclohexane annulation 6:53 synthesis of 6:53 Amination intramolecular 6:429;16:438 Amines formation from ketones 6:429 photosensitized oxidation of 16:604 reductive amination of 6:429 (I-a-Aminoadipoly)-L-cysteinyl-D-valine6(LLD ACV) cephalosporin C from 11:211-213 penicillins from 11:211-213 L-a-Aminouronic acid synthesis of 11:459,460 I-a//o-a-Amino acid synthesis of 11:460,461 Amino acid 16:395-414,604 as chiral synthons 4:625 by a-halo boronic ester 11:417-420 photooxidation of 16:604 synthesis of 11:417-420,13:507-516,16:395-414 a-Aminoacid 12:115,435-438 as chiral building blocks 1:678-684 by hetero Diels-Alder adducts 12:435,436 conversion to amino sugars 4:111-156 synthesis of 12:435-438 Amino acid analysis 9:541 Amino acid composition of avian hemoglobins 5:841,842 Amino acid decarboxylases 10:148 Amino acid derivatives synthesis of 6:318-320 P-Amino acids by hetero-Diels Alder reaction 12:158,159 cyclization by UG1 -reaction 12:116 cyclization of 12:115,116 p-lactamsfrom 12:115 synthesis of 12:155,158,159 a-Amino acids/esters conversion to azomethine ylides 1:331-338 decarboxylation of 1:331-336,337 imines from 1:331 Amino acylase for synthesis of a-amino acids 1:678-680 anti, syn, 5y-Amino alcohol 11:246,247 from L-threitol derivative 11:246,247 2-Amino alcohols by aldol reaction 12:411,414 by cyclocarbamation 12:411,413 by electrophilic addition 12:411,414 by Michael reaction 12:411,413 by nucleophilic addition 12:411,413,414 by oxyamination 12:411,414 by reduction 12:411,414 by ring-opening of oxirane 12:411,413 from 2-oxazolone 12:411 -444 synthesis of 12:411-444 a-Amino aldehydes in [4+2] cycloaddition 4:111 in Diels-Alder reaction 4:120 metalloorganic addition to 4:124 //,//-diprotected 4:124 7V-monoprotected 125 preparation of 4:113,114 A^,0-protected 4:130 a-Amino aldehydes 2-amino alcohol by 12:411,414 nucleophilic addition 12:411,414 Amino analogues 12:398 Amino carbonylation intramolecular 14:568 palladium (2^) catalyzed 14:568 2-Amino-1,2-dihydroacronycine 20:800

937 a-Amino ketones 2-amino alcohol by 12:411,414 reduction of 12:411,414 a-Amino ketones steroid-pyrazine dimers via 18:885-887 Amino sugar antibiotics 12:411 Amino sugars of anthracyclinones 4:350 synthesis from amino acids 4:111-156 synthesis from glycine 4:115-118 synthesis of 13:190-207 4-Amino-r',6"-anhydro-2",3",2',3',6',2,3-hept-0benzyl-4,6- dideoxy-p-maltotriose 10:508,509 2-Amino-l ,3-azulenedicarboxylate 14:339 2-Amino-2,3-di-deoxyhexoses 14:145 2-Amino-2,5,6-trideoxy-5-phosphinyl-L-galactopyranoses synthesis of 6:369 [2-Amino-2-deoxy D-galactopyranosyl] adenmes 4:238 synthesis of 4:238 2-Amino-2-deoxy-3-0-(/?)-[(hydroxyme-thyl)ethyl]a-D-glucopyranose 6:387 (i?)-l-(hydroxymethyl)ethyl 2-glyceryl-ether from 6:387 2- Amino-2-deoxy-D-galacto-D-galactans 5:298 2-Amino-2-deoxy-D-glucose 1:512 2-Amino-2-deoxynucleosides synthesis of 4:525 {2S,3Ry3-Amino-2-hydroxy-4-phenylbutyric acid (AHPBA) synthesis of 12:433,434 (2iS,3/?)-3-Amino-2-hydroxy-5-methylhexanoicacid (AHMHA) leucine aminopeptidase inhibitor of 12:434 synthesis of 12:433,434 3-Amino-3-deoxy-D-mannose 12:314 3 - Amino-3 -deoxyhexopyranosy 1 purines synthesis of 4:240 3-Amino-3-deoxynucleosides synthesis of 4:240 3-Amino-3-deoxysugars synthesis of 4:150 4-Amino-4-deoxy-D-mannose 12:314 5'-Amino-5'-deoxythymidine synthesis of 4:289 3-Amino-5-hydroxybenzoic acid (CAHB) synthesis of 9:434 2-Amino-5-nitrotoluene 13:442 2-Amino-5a -deoxy-a-DL-glucopyranose 13:203 Amino-5a-carba-deoxyhexopyranoses 13:203-207 synthesis of 13:17-21 6-Amino-6-deoxysugars from a-amino acids 4:111,127 6-Amino-6-deoxyuloses synthesis of 4:124 5-Amino-7-methoxy-2,2-dimethylchroman synthesis of 13:358,359 (3i?)-Y-Amino-(3-hydroxybutyricacid biological activity of 12:434 central inhibitory transmitter 12:434 synthesis of 12:434 Amino-epoxides 12:351 Amino-sugar related alkaloids 10:553 Aminoacyl heptoglycosides synthesis of 11:433-435 Aminoalcohol benzyl-protected 11:298,299 with aldehyde 11:298,299 Aminoalkyl glycosides 7:48 5'-Aminoalkyl oligonucleotides synthesis of 4:294,295 Aminoalkylated oligonucleotides 4:306 ()-9-Aminoaporphine 16:516-517 (9-Aminobenzylalcohol 18:164 2-Aminobenzy Itetrahydroisoquinoline 18:73 a-Aminobutyrate analogue of LLD ACV 11:212,213 penam product from 11:212,213 y-Aminobutyric acid condensation of 12:287 synthesis of 13:514 with diethyl acetone dicarboxylate 12:287 9-Aminocamptothecin 13:655 Aminocoumarins 18:978 Aminocyclitol 13:212,14:147 Aminocyclitol fortamine 4:118 Aminocyclitol inhibitors 10:517-524 Aminocyclitol oligosides from glucuronide saponins 7:156-158 Aminodeoxyhexosyl-purines synthesis of 4:238-248 Aminodeoxyhexosyl-pyrimidines synthesis of 4:238-248 2-Aminoethanethiol 8:317 2-Aminoethyl phosphonic acid 2:304-309 2-Aminofluorene 8:377 P-Aminofluorene 8:388 Aminoglycopyranoses P-glactosidase inhibition with 7:47 inhibition constants of 7:47 Aminoglycosides hybrimycine 5:615 mutamicins 5:615 Aminohexose derivatives synthesis of 1:25-27 Aminoketal isolation of 11:298,299 Aminoketone irradiation of 14:657-659 preparation of 14:657-659 5-Aminolevulinic acid (ALA) 9:591,593,601,603,606 Aminolysis mtramolecular 12:279 of disaccharide lactone 6:407 ofMurNAcS-lactones 6:393 Aminomethyl bilane (AMB) 9:597 a-Aminonitriles formation of 14:716-718 via Polonovski reaction 14:716-718 2-Aminonucleosides fiision reactions for 4:238 synthesis of 4:238,239 6-Aminonucleosides 4:248

938
4-Ammooctanal diethyl acetal condensation of 6:445,447 with diethyl-3-oxo-glutarate 6:445,447 withethanal 6:445,447 5-AminooUgonucleotides synthesis of 4:294-292 2-Aminooxetanocin A antiviral activity of 10:619,620 6-Aminopencillanic acid (6-APA) 4-acetoxy-P-lactam from 12:160 Aminopentanal 14:739 Aminopeptidase B 10:629,646,652 Aminophenyl dithiocellotrioside synthesis of 8:349,351 /7-Aminophenyl-l ,4,4'-trithiocellotrioside 8:344,346 p-Aminophenyl-1,4-dithiocellobioside 8:351 20a-Aminopregn-5-en-3p-yl- P-D-glucoside 5:128 2-[3-Aminopropylidene]-l,3-dithiane 12:335 Aminoquinone immunosuppressive effect 5:437 Aminotransferase activity 19:650 Aminotriazole oxidation 4:548 (+)-2-Aminotridecanoic acid enzymatic resolution of 1:684 3-Aminoucleosides synthesis of 4:239-241 4-Aminouncleosides 4:241 -247 5- Aminovalerookadaic acid 5:385,388 Aminyl radical heterocyclization ofchloramines 1:292 Amipurimycin 1:398,404-410,4:246,11:430,433 Amisine 20:234 Amiteol ^om Amitermes excellens 14:450-452 synthesis of 14:456-465 Amitermes evuncifer evuncifer ether from 14:452,463 Amitermes excellens amiteol from 14:450-452 Amitermes messinae evuncifer ether from 14:452 Ammania baccifera sesquiterpenes from 9:65 Ammanol 9:65 (+)-Ammodendrine 15:520 Ammonium D-10-camphor-sulfonate 15:425 Ammonium glycyrrhizin 15:5 Ammonium nitrate 2:412,413 Ammonium sulfate precipitation with 2:392,394,399 Ammonolysis with ammoniacal methanol 16:97,98 Ammophilafernaldi 5:224,232,253 Ammophila nigricans 5:224,232,252 Ammophilaprocera 5:225,232,252 Ammophila urnaria 5:223,224,232,252 Amoebicides 7:398 Amorphane 15:247 c-AMP phosphodiesterase inhibitors synthesis of 3:306-319 Amphibian alkaloids 16:426 Amphidinium species 5:396,19:559 Amphidmolide A ^^CNMRdataof 19:562 NOESY experiments of 19:562 relative stereochemistry of 19:562 Amphidinolides 5:396 Amphidinolide B,C 19:564 absolute stereochemistry of 19:564 X-ray analysis of 19:564 Amphidinolide J biosynthesis studies of 19:561 Amphidinolide M cytotoxicity of 19:566 NMR analysis of 19:566 structure elucidation of 19:566 Amphidinolide O structure of 19:561 Amphidinolide Q cytotoxicity of 19:560 Amphiscolops sp. 5:396 Amphotericin B 2:421,422,446;4:513-520;6:261-306; 10:150;17:245 Amphoteronolide 10:153,166 Amphoteronolide B 4:573;6:261-276 Amphoteronolide B methyl ester 6:264,265 Amsonia elliptica 1:125 Amurensosides A-D from Asterias amurensis 7:298 t-Amyl alcohol 12:156 a-Amylase 7:32-35,10:242,243,504-507,514,13:195; 16:86 P-Amylase 7:33,58,59,10:497;16:86 Amylase 6:551,7:32-36,39 a-Amylase inhibitor acarbose as 13:189 Amylases 10:496-498 Amylases 8:343 Amyloglucosidase 7:13,10:567,357,14:150 Amylopectin 7:6,10:496-498 in starch 7:6 Amylose 5:288,291,292,7:6,10:496,497 Amylostatins 7:20,10:509,510-513 as amylase inhibitor 10:509 from Streptomyces diastaticus subsp. amylostaticus 10:509 synthesis of 10:510,511 synthesis of 13:235-246 Amylostatins GXG inhibitory activity of 10:509 Amylostatins GXGG inhibitory activity of 10:509 Amylostatins GXGGG inhibitory activity of 10:509 Amylostatins XG inhibitory activity of 10:509 synthesis of 10:507-511 Amylostatins XGG inhibitory activity of 10:509 Amylostatins XGGG inhibitory activity of 10:509 Amylosucrase from Neisseria per lava 7:69

939
a-Amyrin from Salvia glutinosa 20:707 from Salvia limbata 20:702 from Salvia montbretii 20:704 from Salvia nemorosa 20:702 from Salviapomifera 20:702 P-Amyrin 7:131-145 triterpenes from 7:131-145 a-Amyrin acetate from Salvia glutinosa 20:707 P-Amyrin linoleate 9:461 P-Amyrin palmitate 9:461 Anabsin 7:239 Anabsinthin 7:239 Anacardiacea 5:824,825,826,7:427,9:315,316,318, 321,323,328 (15:0)-Anacardic acid (2-hydroxy-6-pentadecyl benzoic acid) 9:314,316,345,346,356 Anacardic acids 5:824-831;9:313,315,316,328,330, 331,333-341,346,349,355,358,361-368,370,371 Anacardic aldehyde 9:341 Anacardium giganteum 9:316 Anacardium occidentale 7:427,17:645,34,9:75,316, 318,323,329,9:332,9:335,337,338,340,347 Anacardium semecarpus 9:318 Anacyckus pyrethrum pellitorine from 10:162 Anaerobiosis 9:565,572 Anagasta kueniella 9:322 Anagigantic acid (2-hydroxy-6-undecyl benzoic acid) 9:316 (-)-Anagyrine 15:520 Analgesic 17:633 Anaphylactic bronchoconstiction 12:398 Anas platyrhynchos hemoglobin components of 5:836 Anastrepha suspensa suspensolide from 8:222 Anatoxin 18:697,698 (+)-Anatoxin-A synthesis of 13:493,494 Anchusa officinalis 17:126 Ancistrobrevine B from Ancistrocladus abbreviatus 20:447 Ancistrocerus antilope 5:223,232,253 Ancistrocerus campestris 5:224,252 Ancistrocerus sp. 5:251 Ancistrocladaceae 20:407 Ancistrocladidine 20:408,433,434,437 Ancistrocladine 20,408,419,420,422,423,431 (-)-Ancistrocladine synthesis of 16:447 Ancistrocladus abbreviatus ancistrobrevin B from 20:447 Ancistrocladus alkaloids 20:408,437 Ancistrocladus korupensis 20:442,447 korupensamines A and B 20:442 korupensamines C 20:447 michellamines from 20:442 Ancistrocline 20:408,424,425 Ancistrocongine 20:276 Andrena haemorrhoa 19:129,131-132 Ancymidol as cytochrome P-450 inhibitor 4:621 Andalucin ^om Artemisia lanata 7:214 Anderson-Shapiro reagent 4:652 Andrena ocreata 19:129 Andrena ovatula 19:129 Andrena wilkella 19:129 Andromedotoxin 20:17 Andrena wilkella mandibular gland secretion 1:692 Androgens semi-synthesis of 17:626-627 Andrographis paniculata 5:61^,7:117,17:472 Androsace saxifragifolia saxifragifolins A and B from 15:200 Androst-1,4-diene-3,17-dione 9:411 Androst-4-ene-3,17-dione 9:15-17 Androstanolone 18:885 6,(5a)-Androstene-3,17-dione 8:188 6,(5p)-Androstene-3,17-dione 8:188 Androstenedione from p-sitosterol 9:411 17a-hydroxyprogesteronefrom 9:415 Anemia mexicana antheridiogens from 6:195,202,208 Anemia phyllitidis antheridiogen from 6:194,202 Anethol 13:334-337 trans-AnetholQ 5:473,13:332,15:29 Anethum graveolens 7:108,109 Angasiol acetate 17:6 Angelic acid HETCOR spectrum of 5:778 O-Angeloylperezone '^C-NMR studies on 5:778 transformation of 5:794,795 8a-Angeloyloxy-costunolide 20:471 Angiosperms 9:265 Angiotensin! 9:391,10:629,646,652 12,13-ep/-Anguidine 6:234,236 Anguistidine synthesis of 3:405 Angular triquinanes 13:3-25 Angular triquinane synthesis of 3:14 Angusticraline 13:394 Angustiicine 1:36 Angustine 3:405,5:85,126 Angustine-type alkaloids angustine 5:85 Angustoline synthesis of 3:405 (-)-Anhalonine 2:163 14,15- Anhydro-1,2-dihydrocapuronidine 5:125 l,6-Anhydro-2,4-di-0-benzyl-3-0-(tertbutyl-dimethyl silyl)-P-D- glucose 14:255 l,6-Anhydro-2-azido-4-0-benzyl-2-deoxy-p-Z)glucopyranoside 0-alkylation of 6:388

940
3,6-Anhydro-2-deoxy-D-/v:co-hexose fromgalactal 7:59 1,6-Anhydro-2-0-benzoyl-3,4-di-(9-benzyl-P-Dgalactopyranose 14:256 2,6-Anhydro-2-thio sugar 12:53,54 1,6-Anhydro-3,4-dideoxy-a-D-glycero-hex-3 -enopyranose-2-ulose (levoglucose none) 14:267-281 1,6-Anhydro-4'-0-(3,4-anhydro-a-Dgalactopyranosyl)P-maltose 10:515 2,3-Anhydro-4,6-0-benzylidene-p->-talopyranoside 14:167 1,5-Anhydro-4,6-0-benzylidene-D-ribo-hex-1 -enitol Claisen rearrangement of 10:420 1,6-Anhydro-4-deoxy-L-ribopyranose 14:255 3,4-Anhydro-a-D-altropyranoside 14:170 2,3-Anhydro-a//o-hexopyranoside 14:149 1,6-Anhydro-P,Z)-glucopyranose 6:287,288 3,4-Anhydro-p-D-galactopyranoside 14:170 1,6-Anhydro-p-D-glucose 10:425 1,5-Anhydro-galactitol 7:65 1,6-Anhydro-galactose 7:65 1,5-Anhydro-Z-iditol peracetate preparation of 6:372 Anhydroalstonatine 1:125,126 Anhydroamarouciaxanthin B 6:151,152 Anhydroascorbic acid 4:718 Anhydroaustricin 7:236 Anhydrobartogenic acid from Barringtonia speciosa 7:132 14,15- Anhydrocapuronidine 5:125 2',3'-Anhydrocyclitol glycoside 14:147 Anhydrodeacyltautomycin 18:271,284 Anhydrodiatoxanthin from Euglene viridis 6:150 Anhydrodimerisation 7:136 Anhydrodimers 7:136,137 Anhydroerythromycin A 13:158 Anhydrogrossmisin 7:236 1,2-Anhydrohexopyranose derivative 14:147 Anhydromacrosalhine-methine 13:396,397 r,6'-Anhydromaltose 10:507,510,511 1 ",6"-Anhydromaltotriose 10:507 1,6-Anhydromuramic acid derivative prepration of 6:388 E- Anhydropodorhizol 5:486 Anhydropodorhizol (nemorosin) 5:484-488 1,4-Anhydrosorbitol 12:29,30 16,17-Anhydrotacamine 5:126,9:179 Anhydrotaxininol 12:216 15 (28)- Anhydrothyrisiferyl diacetate 5:363 16' -e/7/-A' ^ '^^-Anhydro vinblastine from catharanthine 14:854,855 Anhydrovinblastine anhydrovincristine from 14:818,819 biosynthesis of 14:820,821 Catharine from 14:812,871,820,821 catharinine from 14:820,821,871 (15'5)-20'-deoxy-15'-hydroxy leurosidine from 14:814,815 deoxyleurosidine from 14:871 20'-deoxyvinblastine from 14:871 from catharanthine 14:820,821,869-872 (15'/?)-15-hydroxycatharinine from 14:813,814, 14:820,821 leurosidine from 14:871 leurosine from 14:811,820,821,871,872 oxidation of 14:813,814 3-oxoanhydrovinblastine from 14:813,814 via Polonovski reaction 14:869-872 vinblastine from 14:820,821,871 3'4'-Anhydrovinblastine 2:370372,386-389,392,401 Anhydrovinblastine synthesis of 5:184 16'-e/7/-Anhydrovinblastine synthesis of 5:184,185 Anhydrovinblastine Nb-oxide 15'a-hydroxyleurosidine from 14:812,813 15'-hydroxy-3'-oxoleurosidine from 14:812,813 5'-nor and 5',6'-seco derivatives of 14:872 3'-oxoanhydrovinblastime from 14:812,813 Polonovski reaction of 14:872 Anhydrovincristine from anhydrovinblastine 14:818,819 Anhydrovobasindiol 5:123,9:171,15:469 19 (Z)-Anhydrovobasinediol 15:466,467,491 Aniba sp. neolignans from 8:159 Aniba canellila 19:117 Aniba neolignans total synthesis of 8:159-163 Anigozanthos 17:372 Anilido as protecting group 4:286 8-Anilino-l-naphthalenesulphonic acid 9:453 Anils phenanthridines from 4:542 Anion exchange for oligonucleotide purification 4:283 in HPLC 282, 283 Anion mediated alkylation of difimctional acyclic terpenoids 8:229 [3,3]Anionic oxy-Claisen 12:93 Anionic oxy-Cope rearrangement eight-membered rings by 3:77,78 Anionic pinacol rearrangement 14:360 Anisole Firedel-Crafts alkylation of 6:61,62 Anisomelic acid synthesis of 10:13-17 Anisomycin 14:568 /)/-/?-Anisylmethylamine 12:152 Ankinomycin 11:136 Annelated benzazecines from isoquinoline derivatives 6:483 synthesis of 6:483 Annelation ofresorcinol 19:227 of substituted phenol 19:227 regiospecific 19:227 Annelation reaction 14:694,695 Annona bullata 9:396,397;18:221 Annona densicoma annonacinfrom 9:395

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Annona muricata 17:277;18:213 Annona squamosa 9:398 Annonaceae 9:391,393,395,396,398,399,402;17:251; 19:498 Annonaceous acetogenins 17:251-286 Annonacin 9:395,396;17:266,272,279 AnnonacinA 17:267 Annonacin-10-one 17:272 AnnoninI 17:252 Annotinine 18:341 /ra5-Annularene cyclisation in (-)-zonarene synthesis 6:15 2p,3P-Annulated oxathiaphospholane 8:126-127 13,16-Annulated oxathiaphospholane 8:126,127 Annulation by Simmons-Smith reaction 6:5 intramolecular 10:407 of 1 methyl-2-tetralone 14:670,671 of a-diazo-P-keto ester 10:407 of cyclohexane ring system 6:5,6,29,30 of cyclopentane ring system 6:6-8,30,31 ofenolate 10:414,415 of methylenecyclohexane 6:21,22,53,54 of piperidone derivative 14:734 Piers annulation 6:21,22 Rh (Il)-mediated 10:407 Robinson annulation 6:17-21,29,30 with 3-methylsilyl-3-butene-2-one 10:414,415 [2+3]Annulation of aldehydes 3:5-58 triquinane synthesis by 3:47,48 annulation methods 3:7 for five-membered rings 3:7 [4+1] Annulation triquinane synthesis by 3:40-45 [4+4]-Annulation Danheiser version 3:78 for 8-membered ring synthesis 3:78-79 intermolecular 3:78 Nickel catalysed intramolecular 3:78 Anochertus sedilloti 5:223-225,238,254 Anodic methoxylation 13:485,494 Anodic oxidation 7:161,163;8:159-172;13:474,475,479 of a-iV-acetyl-E-7V-tosy-L-lysine methyl ester 12:309,310 Anomalous metabolism 7:117 Anomalous ORD 2:160 P,p-Anomer synthesis of 8:326 Anomeric characterisation of disaccharide dipeptides 6:413-416 Anomeric deprotection of disaccharide dipeptides 6:413-416 Anomeric effect 1:448,16:9,11,498 Anomeric oxidation 13:625 a-D-Anomers from 2,3,5-tri-O-benzyl-P-ribosyl fluoride 10:369 stereoselectivity of 10:369 Anopheles 2:11745, 2:295-297 "Ansa-Chain" compounds rifamycinS 12:37 rifamycinW 12:39 Ansachain 5:592 Ansamitocin 9:435 (P-3)-Ansamitocin 9:433,434 Ansamycin 2:424,9:431-445,10:153 Ansamycin lactams 10:149,150 Ansatrienin (mycotrienin) derived from shikimic acid 11:190 from Streptomyces collinus 11:189 from Streptomyces rhishiriensis 11:189 Ansatrienin A 9:434 Ant repellant neoxanthinas 6:142 Antabine biosynthesis of 11:205-207 by nicotine synthase 11:205-207 from Nicotiana sp. 11:205-207 from nicotinic acid 11:205-207 aaAntagonist 8:399,400 Antagonistic activity 20:515 Anthelmintic activity 1:408,5:552 Anthelmintic agents 12:3 Anthelmintics 1:435 Anthelmycin conformation of 4:226 Anthelvencins 5:552,553 Anthemidin 7:233 Anthemis saguramica 10:153,162 Antheridic acid from gibberellin A7 6:197-201 total synthesis of 6:195-201 Antheridiogens biosynthesis of 6:206 from Anemia mexicana 6:195,202 from gibberellms 6:171,194-209 from Lygodiumjaponicum 6:194,204-206 synthesis of 6:194-212 Antheridium-mducing factor 19:303 Anthocerotae (homworts) 2:277 Anthocidaris crassispina ganglioside GM5 from 18:486 Anthocyanidins 7:112,114,723 Anthocyanins 5:646,647,658,7:192,723,731,735 Anthonomus grandis 1:693,7:187,190 Anthopleura elegantissima 2:306,9:493-495 Anthracenes 11:113,277 Anthracenediols 11:125,126 1,99,9'-bianthracene-10,10' (9H,9'H)-diones from 11:125,126 Anthracnose fimgi 9:228,230,240 Anthracycline synthesis of 14:271 Anthracycline antibiotics antitumor activity of 14:492 asymmetric synthesis of 14:492,493 synthesis of 1:498-514 Anthracyclinone intermediates synthesis of 1:627-629 Anthracyclinones biological activity 4:318 cardiotoxicity 4:318 resolution of 4:318

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synthesis of 3:448,449 total synthesis 4:317-336 Anthranilate synthase 11:187,188 Anthranilic acid by anthranilate synthase 11:187,188 from chorismic acid 11:187,188 Anthraquinone 9:400,403,11:124 Anthraquinone glutarates 6,11 -naphthacenequinones from 11:122,123 with acetoacetate dianion 11:122,123 Anthraquinone mitoxanthrone 14:21 Anthraquinones 3:433,434;7:418-420,427;13:662,663 Anthraquinone sulphonates 20:867 Anthraquinone-2,6-disulphonate 20:857 Anthraquinones 20:277 Anthraserpine 9:174 Anthricin from /i nthricus sylvestris 18:555 Anthricus sylvestins anthricin from 18:555 Anthrobacter citreus 20:234 Anthrobacter simplex 20:234 Anthrobacter ureafaciens 16:87 Anthrones decarboxylation of 11:121 Anthrotaxis s^^. 3:456 1-Anthroylnitrile fluorescent ester from 5:816 ^//addition 8:298 Anti-AIDS agent (+)-castanospermine \\'261 Anti-Bcnzo [a] pyrene diol epoxide DNA reaction with 7:9 Anti-Bredt compound 13:447 Anti-Cram product 16:337,473 Anti-digoxin antibodies 15:374 Anti-feedant activity 2:277 Anti-fertility action ofplumbagin 2:229-231 of Plumbago zeylanica 2:229,231 of isoshinanolone 2:229-231 Anti-hepatitis B agents 20:527 Anti-HIV-activity 19:511,748 Anti-HIV-assay 20:535,536 Anti-HIV-screening 13:665 Anti-i-antibody 10:480 Anti-inflammatory activity 13:647 Anti-inflammatory agent 7:397,14:315 Anti-inflammatory agents Anti-leukemic activity 1:305 Anti-malarial agents 20:516-521 Anti-Markovinkov product hydride reduction of 16:337 Anti-microbial activity of sesquiterpenes 2:287,288 y4//-orientation 14:753 .4^/-products formation of(5)-ethyl-3-hydroxybutyrate 4:439 Anti-stress activity 20:646 Antibacterial activity 20:245,712 cis Anti-trans-anti stereochemistry of steroid 8:188 Anti-tubercular activity 5:752,753 Anti-tubercular agents 5:751 Anti-tumor activity 1:275,316-320-408 Anti-tumor agent 1:180,268,269 Anti-tumor antibiotics synthesis of 1:498-721 Anti-tumor metabolites 1:239 Anti-venom alkaloid oxidation 1:239 Anti-vitamin activity of 25-aza-vitamin D3 9:519 Antiallergic activity 18:674 Antiallergic effect ofK-252a 12:398 of staurosporine 12:398 Antibacterial activity of 3',4'-dideoxykanamycin 14:145 ofacteoside 5:512 of p-hydroxyacteoside 5:512 of benz [a] anthracene antibiotics 11:134 ofcelastrol 5:747 offorsythiaside 5:512 ofphenylpropanoids 5:512 ofsaframycins 10:78 of staurosporine 12:398 ofsuspensaside 5:512 oftetrazomine 10:117 ofthienamycin 12:147 Antibacterial agent aplasmomycin 5:377 aurantinins 5:601 chimeramycin 5:613 Antibacterial macrolide 5:613,747 Antibiotic activity of2-isocephems 12:192 of 2-iso-oxacephems 12:192 ofsemivioxanthin 11:130 ofthienamycin 12:188 Antibiotic activity of macrolide 17:283 Antibiotic potency of imipenem 4:432 of 1-P-methylthienamycin analogue 4:432 Antibiotic T-1384 5:549 Antibiotics ansamycin 9:431-445 bio-organic chemistry of 9:431-445 biosynthesis of 11:207-213 from microorganisms 5:589 isoquinolinequinones 10:77-145 mitomycin 9:431-445 relative configuration of 6:261 shikimic acid derived 11:182-191 sugar components of 11:213-222 Antibiotics A 26771 B by Penicillium turbatum 11:194 Antibodies 2:345-348,7:29 Anticancer activity DNA-damaging natural products with 20:457-500 ofvinblastine 14:805 of vincristine 14:805 Anticancer agents 19:511 Anticancer compounds 13:347-382

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Anticandidal activity 20:485 Anticaries activity 18:673 Anticholinergic agents 17:395 Anticoccidium agent 4:591 Antidiabetic agents 7:47 Antidote for scorpion sting 5:751 for snake bite 5:751 Antidysenteric agent 5:758 Antiedema activity of staurosporine 12:384 Antifeedant 17:153,234,237 Antifeedant activity of(-)-specionin 10:425 Antifeedant assays 18:771 -774 Antifeedants 7:395-397 Antifertility activity 5:754 Antifouling 17:93,98 Antifungal agents 17:239 activity of 17:378 macrolide 17:16 sesquiterpene dialdehydes 17:233 Antifungal activity of alga 5:342 ofcoelenterate 5:342,368 ofcordigol 7:408 ofcordigone 7:408 offlavolol 3-methyl ether 7:414 offlavonoids 7:413 of garcigerrin 7:423 ofhydroquinoneuncinatone 7:408 of mollusk 5:342 ofnanaomycins 11:127 ofnaphthoxirene 7:423 ofpterocarpans 7:414 of semi vioxanthin 11:130 of sesquiterpenes 2:287 of sponge 5:342,368 of tunicate 5:342 ofurdamycin 11:134 ofxanthones 7:410 Antifungal agents 4:513 Antifungal antibiotic cerulenin 5:613 irumamycin 5:597 phhoamycin 5:607 Antifungal compounds 7:406,408,415 Antifungal flavones 7:413 O-Antigen from Salmonella anatum 6:262 synthesis of 6:262 I-Antigenic determinant 10:483 O-Antigenic polysaccharide from Pseudomonas aeruginosa 14:236 from Salmonella newington 14:233 from Shigella flexnert 14:233 Antigenic specificity 4:197 I Antigens 10:457-461 II Antigens 10:457,461 Antihormones 20:515 Antihepatotoxic activity 17:377 Antiherpes activity 5:565 Antihyperglycemic activity 18:672;19:351 Antihypertensive activity of Forsythia suspensa 5:513 ofK-252a 12:398 of staurosporine 12:384 of suspensaside 5:513 Antihypoxic activity 18:373 Antiinflammatory activity 5:367;17:137,376;18:775 Antiinflammatory agent 5:753 Antiinflammatory drug 17:130 Antiinflammatory effects ofK-252a 12:398 of staurosporine 12:398 Antileukemic activity 4:232;7:382-387,390;17:348 Antimalarial activity ofacetylvismioneD 7:424 ofartemisinin 7:424 of 3-geranyloxy-6-methyl-1,8-dihydroxy anthraquinone 7:424 of 3-geranyloxy-6-methyl-1,8-dihydroxyanthrone 7:424 of quassinoids 7:391-394 of quinine 7:424 ofvismioneD 7:20 Antimalarial agents 8:391 -394,351 Antimetastatic effect of 16:93 Antimicrobial activity against Candida albicans 5:752 against Clostridium difficile 5:601 against Clostridium perfringens 5:601 against Proteus mirabilis 5:752 against Proteus vulgaris 5:752 against Staphylococcus aureus 5:752 of(-)-acetomycm 10:443 of amphibian venoms 15:327-339 ofcryptolepine 5:752 ofdimertriterpenes 18:776-778 ofmedrrhodine A a n d B 5:618 oftriterpenes 18:776-778 Antimicrobial agent 5:753 Antimitotic activity oflignans 5:461 of gigantecin 9:396 Antimycine A antifungal agent 16:694 Antimycoplasmal activity ofnanaomycins 11:127 Antimetastatic agents 19:351 Antineoplastic activity 4:29 Antineoplastic glycoproteins 7:285 Antioxidant 4:495;9:371,372 Antiperiplanar orientation 14:457 Antiphlogistic 17:451 Antipredation 17:93 Antiplasmodial activity 19:587 Antiplasmodial agents 20:525 Antiproliferative activity 7:419,422,245,515;16:93 Antiproliferative effect against HL-60 cells 12:393 against T cells 12:393 BALB/C mouse 3T3 cells 12:393 bovine brain cortex capillary 12:393

944
cis-platin 12:390 endothelial cells 12:393 human breast cancer 2R-75 cells 12:393 human myeloid progenitor cells 12:393 in walker rat carcinoma cell 12:390 L2CB lymphocytes 12:393 mouse isolated microglia 12:393 NIH/3T3 fibroblasts 12:393 of anticancer drug 12:390 ofstaurosporine 12:393 Antipyretic activity 18:775 Antiquorin 9:280 Antirachitic factors 17:623 Antirride 7:465,466 Antirrinoside 7:455,477 Antisense oligonucleotides 257-294 RNA 13:257-294 synthesis of 13:264-281 Antisera 15:368 Antisweet activity of gymnemic acid 18:671,672 Antituberculous activity 20:712 Antitumor 17:17 Antitumor activity of(+)-5-epi-acetomycin 10:447 of(-)-acetomycin 10:444,447 ofacronycine 13:365-382 of benz[a] anthracene antibiotics 11:134 of cyanocycline A 10:103 ofdidemnins 10:254-257 ofdiphyllin 5:462 ofglyfoline 13:375-380 of indolo [2,3-a] carbazole alkaloids 12:390-396 ofK-252a 12:394,395 oflignans 5:461 of naphthocy anidine 10:104 ofnogalamycin 4:335 ofpristimerin 5:747 ofquinocarcin 10:117 ofrebeccamycin 12:394 ofsaframycins 10:78 ofstaurosporine 12:390-394 oftaxol 12:180 oftetrazomine 10:117 ofUCN-01,UCN-02 12:395 ofurdamycin 11:134 ofstaurosporme 5:275 Antitumor agents 3:301,383;9:383,385 Antitumor antibiotic 5:592,593;19:118 Antitumor bioassay 9:383,386,401 Antitumor polyethers 5:377 Antitussive 17:633 Antivu-al activities Herpes simplex virus 17:146 HIV-2 17:146 of(-)-aristeromycm 10:609 of (+)-C-2'-ara-fluoroguanosine 10:609 of 2-amino oxetanocm-A 10:620,621 of3'-azido-3'-deoxythymidine 10:585 of aciclovir (9-[2-hydroxyethoxy)methyl] guanine 10:585 of carbocyclic oxetanocin A and G 10:620,621 ofcarbovir 10:608,609 of D-2'-deoxycarbocyclic guanosine 10:608,609 ofdidenmins 10:253,254 offlavonoids 17:145 of imidazole analogues 5:566 oflignans 5:461 of marine organisms 5:359,364 ofmycalamide A 5:366 of spermidme 5:563 of oleanolic acid derivatives 17:135 of oxetanocin A 10:608,619,620 of oxetanocin G 10:619,620 of quinovic acid derivatives 17:134 of Theonella sp. 5:364 Antiviral agents 19:351,511 Antiviral protein 13:655 Ants chemical defense in 6:421-465 pipeidine alkaloids in 6:422-434 pyrrolidine venom alkaloids in 6:434-444 Apaenogaster rudis 5:254,255 Apergillus oryzae 18:807 monohexosylceramides from 18:807 Aphaenogaster longiceps 5:252 Aphelasterias japonica 15:69 Aphelasteroside A and B 15:68 Aphidicolin 14:583 Aphomia melleus 15:387 Aphomiaoniki 15:383 Aphomia sociella 15:384 Apidae 6:421 Apigenin 5:654,712;7:206,226;9:390 from Salvia mentbretii 20:712 from Salvia nemorosa 20:712 from Salvia sclarea 20:712 from Salvia yosgadensis 20:712 Apigenin-4'-methyl ether from Salvia yosgadensis 20:712 Apigenin-6,4'-dimethyl ether from Salvia yosgadensis 20 :712 Apigenin-7,4'-dimethyl ether from Salvia yosgadensis 20:712 Apigenin-7-methyl ether from Salvia yosgadensis 20:712 Apigravin from 8-methoxyumbelliferone 4:378,381 D-Apiofuranosyl 15:7 Apioglycyrrhizin 15:26 Apiosyl glucosides 5:643 Apium graveolens Aplasmomycin biosynthesis of 11:207-209 by phosphoenol pyruvate 11:207-209 from glycerol 11:207-209 hypothetical mechanism of 11:209 ionophoric antibiotic 14:499 from Streptomyces griseus 19:587 Aplasmomycin B 19:587 Aplasmomycin C 19:587 ApliditesA-G 19:617 Aplidium californicum 10:248;18:716 Aplidium cavernosa 10:248

945
Aplidium constellatum 10:248 Aplidium sp. 5:440,617;10:244,248 Aplinia species 17:358 Aplydilactone 17:6 Aplykurodin A 17:5 Aplyronines A-C cytotoxic activities of 19:609 Aplysia brasiliana 6:6;9:249;18:625 Aplysia dactylomela 5:368;6:35;17:7,8,430 Aplysia faciata 17:6 Aplysia Juliana 17:6 Aplysia kurodai 6:24,56;17:4,6 Aplysia punctata 17:9 Aplysia sp. 5:368 Aplysiapyranoid A-D 17:5 Aplysiatoxins 18:294,549 Aplysilla glacialis 17:14,15 Aplysilla rosea 6:107 Aplysilla sulphurea 17:11 12-ep/-Aplysillin 17:12 Aplysillin 6:107,109 (+)Aplysin-20 synthesis of 1:672 (-)-Aplysin-20 from Aplysia kurodai 6:24 from Laurencia species 6:24 synthesis of 6:24,25 Aplysina fistularis 17:103 Aplysinopsine cytotoxic activity of 5:410 (-)-Aplysistatin antineoplastic agent 16:705 synthesis of 16:705 Aplysulphurin 9:7,8 P-Apo-8'-carotenal 20:752-750,760 Apo-8'-lycopenal 20:592,593 12'-Apo-(3-caroten-12'-al 20:606 8'-Apo-P-caroten-8-al 20:605 8'-Apo-P-caroten-8-oate 20:605 Apo-P-carotenoids synthesis of 20:605-607 Apo-euphanes (apo-tirucallanes) 9:297,307 Apo-tirucallanes (apo-euphanes) 9:297,307 Apoaromadendrone 14:362 Apocarotenal 20:582 P-Cso-Apocarotenal 20:275 Apocynaceae 6:506,520,416,383,748 Apodinine 5:127 Apoenzyme 9:593,595;17:487 P-Apolignans synthesis of 17:339 Aporphine alkaloids synthesis of 16:503-546 Aporphine alkaloids ring expansion in 6:469 Aporphinoids 3:437-444 1 l-Ep/'-Apotrichothecence from Fusarium sporotrichiodes 13:522 Apotrichothecene rearrangement 6:237,238 Apotrichothecenes 6:213,244,245,249,250;13:519,520 (+)-Apoverbenone 19:189 Apovincamine synthesis of 14:635,636 ()-Apovincamine synthesis of 18:331 (+)-Apovincamine 5:127 Apparicine 5:87,88,125;6:503-506,520,521;9:171,173 Apparicme-derived alkaloids 6:503-506,520 Apparicine-type alkaloids 5:87,88 Apsena pubescens 15:384 APT spectrum : of artemisinin 5:26 ofberberine 5:42,43 of 10-demethoxykopsidasinine 5:52 ofeupatorenone 5:29 ofhortensisn 5:15 of 10-hydroxy-11 -methoxydracaenone 5:19 oflarreantin 5:11 ofnirurine 5:51 ofprionitin 5:31 ofquassinoids 5:39 ofsalvinolone 5:34 of sanguinarine 5:45 Apuleia leiocarpa 5:679,680 Apuleidm 5:679 Apulein 5:680 Apuleisin 5:680 Aquafoliacese 9:402 Aquillochin 5:5,6,8 Aquillochin diacetate APT spectrum of 5:7 ^^C-NMR spectrum of 5:9 ' H - N M R spectrum of 5:9 selective INEPT spectrum of 5:9 Arabinose conversion to nogalamycinone 4:355,356 Arabidopsis thaliana 18:721 I-Arabinitol synthesis of 4:506,507 D-Arabinitol phosphorus analogs of 6:355 D-Arabino-2-hexulopyranose 15:190 D-Arabino-hexofiiranose Ce-P bond analogs of 6:376 Z)-Arabinoftiranose phosphorus analogs of 6:352,335 Arabinofuranose nucleoside from mannofuranose 10:388 Arabinogalactin 15:36 Arabinoglucoronopyranosides of oleanolicacid 7:435 L-Arabinopyranosyl 15:7 I-Arabinopyranosyl 3p-acetyl oleanolate acetyl oleanolic acid from 7:155 methyl I-arabinopyranose from 7:155 L-Arabinopyranosyl unit 15:21 Arabinose 7:136,139 I-Arabinose 7:144,181,294,298;11:7,8 P-D-Arabinose derivatives from 1,2,5,6-di-O-isopropylidene-P-Daltrohexofiiranose 10:431-433 Johnson-Claisen rearrangement of 10:432,433

946
Arabinoside gaudichaudioside A from Baccharis gaudichaudiana 15:21 Arabofuranosides 5:657 Araboglycyrrhizin 15:26 Arabopyranosides 5:657 Arabsin 7:231 Aracaceae 9:321 Arachidonamide 9:582 Arachidonic acid metabolism 20:514 Arachidonic acid 9:368,559,561,564,565,568,569,572, 575,582;13:304 from rat alveolar macrophages 12:394 Arachidonic acid methyl ester CI(NO) mass spectrum of 2:12 Arachniodes exilis 15:33 Arachniodes sporadosora 15:33 Araliaceae 7:427,435 Araliopsis tabouensis 2:121 Aranciamycinones by asymmetric epoxidation 4:345 Araneosol 7:226 Araucaria cookii 17:36 Araucaria cunninghamii 17:36 Arbacia lixula 15:104 Arbaciapunctulata 7:303 Arbiglobin 7:234 (+)-Arborescin synthesis of 14:365,366 (+)-l,10-e/7/-Arborescin 14:365,366 Arborescin derivatives 7:234 Arbusculin A-D 7:231,232 ArbusculinE 7:234 Arbusculone from Artemisia arbuscula 7:208 Arbuzov reaction 12:341;14:126;18:236 Arcanose 4:255 Arcapillin 7:226 Archaster typicus 7:304-306;15:74,84 Arctigenin 5:522 Arctigenin 4'-0-glucoside 5:490,491 Arctigenin monoacetate 18:601 Arctiin 5:475,476,489-491,522 Arctium lappa 5:497 Arcyia Z^w-indolymaleimides hypothetical biogenesis of 12:374 Arcyria denudata arcyriaflavin-B from 12:366,370 arcyriaflavin-C from 12:366,370 arcyriarubin A from 12:366,370 arcyriarubin B from 12:366,372 arcyriarubin C from 12:366,372 arcyriaverdin C from 12:366,372 arcyoxepin A from 12:367,373 arcyroxepin B from 12:367,373 arcyroxindole A from 12:367,372 arcyroxocin B from 12:367,372 dihydroarcyriarubin B from 12:366,370 Arcyria denudata 5:55 Arcyria feruginea arcyriarubin C from 12:366,372 Arcyria natans arcyriacyanin A from 12:366,372 arcyriaflavin-A from 12:366,370 arcyrioxocin A from 12:367,472 dihydroarcyriacyanin A from 12:367,372 Arcyria sp. arcyrinAfrom 12:367,373 arcyrinBfrom 12:367,373 Arcyriacyanin A from Arcyria natans 12:366,372 synthesis of 12:382,383 Arcyriaflavin B 5:55,56 ArcyriaflavinC 1:3;5:55,56 Arcyriaflavin-A from Arcyria nutans 12:366,370,372 synthesis of 12:376-379 Arcyriaflavin-B from Arcyria denudata 12:366,370,372 from Metatrichia verparium 12:366,370,372 synthesis of 1:19;12:379 Arcyriaflavin-C from Arcyria denudata 12:366,370,372 from Metatrichia vesparium 12:366,370,372 Arcyriaflavin-D from Dictydiaethalium plumbeum 12:366,370, 12:372 Arcyriarubin A f[om Arcyria denudata 12:366,372 from A^-methylarcyriarubin A 12:375,376 synthesis of 12:375,376 Arcyriarubin B from Arcyria denudata 12:366,372 synthesis of 12:375,376 Arcyriarubin C 1:3 from Arcyria denudata 12:366,372 from Arcyria ferruginea 12:366,372 Arcyriaverdin C from Arcyria denudata 12:366,372 Arcyrin A from Arcyria sp. 12:367,373 Arcyrin arcyrinin model compounds from A^-methylarcyriarubin A 12:383 synthesis of 12:383 Arcyrinin B from Arcyria sp. 12:367,373 Arcyrioxocin A from Arcyria denudata 12:367,372 from Arcyria nutans 12:367,372 Arcyroxepin A 1:3 ArcyroxepmA 12:367,373 from Arcyria denudata 12:367,373 Arcyroxepm B from Arcyria denudata 12:367,373 Arcyroxindole A from Arcyria denudata 12:367,373 Arcyroxocin B from Arcyria denudata 12:367,372 Ardeola ibis hemoglobin components of 5:837

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Ardisiajaponica 13:660;17:117,127 Areca catechu arecoline from 13:660 Arecoline from Areca catechu 13:660 Arelia cordota 20:690 Arenaria kansuensis 18:721 Arenarol 5:458;15:315 Arenarone cytotoxic activity of 5:438 Arenecarbene 3:324,325 Arene-metal 7c-complexes 20:310-312 Arene-olefin metaphotocycloaddition 3:14 Arenes microbial oxidation of 18:430-432 Arenesulphonyl-5-(pyridine-2-yl)-tetrazolides 13:275 ()-Argemonine from methanodibenzazocine 6:471 synthesis of 6:471 Argentation chromatography 9:450,460,464,465 Argentation TLC 9:333,338,343 Argentilactone 19:463,494 Argentiolide A 7:211,231 Argentiolide B 7:230 Argiotoxin-638 655 Arglanin 7:232,234 Argogorytesfargei 5:225,250,253 Argogorytes mystaceus 5:225,231,252,253 Arguticin 9:66 Arguticinin 5:202,203 ;9:66 Arguticinin Argutin 9:66 Argutinin 5:203 Argutinin 5:203 ;9:66 Argylioside 7:443 Aricine 9:174 Ariensin synthesis of 17:318 Arigoni's enzymatic method 18:171 Aristea ecklonii 2:224 (-)-Aristeromycin antivu-al activity of 10:609 synthesis of 8:148 Aristeromycm 8:140 Aristlane 18:607 (+)-Aristocarbinol from (+)-20-hydroxy-hobartine 11:323 Aristocarbinol 9:172 (+)-AristofiTiticosine absolute configuration of 11:325 from Aristoteliafruticosa 11:324 synthesis of 11:323-325 Aristolarine from (+)-20-hydroxyhobartine 11:323 (+)-Aristolasene from (+)-20-hydroxyhobartine 11:323 Aristolasicol (aristotelin-19-ol) 9:172;11:305,312 Aristolasicolone fromhobartin-19-ol 11:305 Aristolasicone 9:172 Aristolasicone (aristotelin-19-one) '^C-NMRof 11:314 *H-NMR spectra of 11:313 from Aristotelia australasica 11:312 fromhobartin-19-ol 11:305 from serratenone 11:312 preparation of 11:312 retrosynthetic analysis of 11:306,315 synthesis of 11:315-317 X-ray crystal analysis of 11:315 (+)-Aristolochene biosynthesis of 15:250 Aristolochia argentina 19:494 Aristolone 20:464 (-)-Aristomakine cw-hexalin structure of 11:302,303 from (-) aristomakinine 11:301,302 from anti-aristotelin-15-ol 11:301,302 from Aristotelia serrata 11:301 IRandNMRof 11:301,302 nOe-difference experiments of 11:303,304 relative configuration of 11:301-303 (-)-Aristomakinine (-) aristomakine from 11:301,302 from flr/-aristotelin-15-ol 11:301,302 from Aristotelia serrata 11:301 IRandNMRof 11:301 relative configuration of 11:301-303 Aristone 11:277 (+)-Aristoserratenine absolute stereochemistry of 11:293 from Aristotelia australasica 11:293 from Aristotelia serrata 11:293 3 -ep/-Aristoserratenine from Aristotelia australasica 11:293 IR mass and ^H-NMR spectra of 11:293 Aristoserratine 9:171 (+)-Aristoserratine (aristotelin-15-one) absolute configuration of 11:296 from Aristotelia serrata 11:296 from peduncularistine (18,19-dehydroaristotelin15-one) 11:296 retrosynthetic analysis of 11:296 synthesis of 11:296-300 X-ray crystallography of 11:296 Aristotelia alkaloid (-)-peduncularine synthesis of 13:491,492 Aristotelia alkaloids biosynthesis of 11:278,279 nomenclature of 11:331 numbering system of 11:331 synthesis of 11:277-334 Aristotelia australasica allo-aristoteline {epi-11 -aristoteline) from 11:317 aristolasicone from 11:312 (+)-aristoserratenine from 11:293 3-e/7/-aristoserratenine from 11:293 Aristoteliafruticosa (+)-aristofruticosine from 11:324 (+)-fruticosonine from 11:278 Aristotelia serrata (-)-aristomakine from 11:301 (-)-aristomakinine from 11:301 (+)-aristoserratenine from 11:293 (+)-aristoserratine from 11:296 (-)-hobartine from 11:278

948
g-^H-Aristoteline 11:311 a//-Aristotelin-15-ol (-)-aristomakine from 11:301,302 (-)-aristomakinine from 11:301,302 Grob-fragmentation of 11:301,302 oxidation of 11:299,300 with DMSO/acetic anhydride 11:299,300 (+)-Aristoteline alloaristoteline from 11:321,322 biosynthesis of 11:278,279 '^C-NMRof 11:314 from (-)-hobartine 11:292-295 from (+).makomakine 11:292-295 synthesis of 11:280-283 X-ray crystal analysis of 11:278 Aristotelinine fromhobartin-19-ol 11:305 Aristotelone 11:321,322 Aritason 20:13 Arjimic acid glycosides of 7:133,134 from Terminalia alata 7:134 Arjunosides I-IV from Terminalia arjuna 7:133 Arlatin 7:234 Armefolin 7:232 Armexifolin 7:232 Armillaria mellea 5:289,290 Armin 7:232 Army worm {Spodoptera frugiperda) 14:451 Amdt-Eistert reaction 13:79,93 Amdt-Eistert homologation 1:237;13:116 Amicenone 3:6,60 Aromadendrane 14:355;15:227;18:607 (+)-4-ep/-Aromadendrene 14:359,362 Aromatic acetylenes 7:222 Aromatic p-carbolines from Nitraria komarovii 14:762 Aromatic chirality method for OH configuration 2:224 Aromatic chromophore Aromatic chromophores 2:171,172;12:46,47 Aromatic compounds oxidation of 6:509 Aromatic erythrinan alkaloids synthesis of 3:456-479 Aromatic isocyanides synthesis of 12:113,114 Aromatic natural products biomimetic synthesis of 11:113-149 v/a polyketides 11:113-149 Aromatic phosphoramidates 14:286 Aromatization 7:360-363;ll:114-119 Array processor 2:113 Arrow poisons 12:233 Arscotin 7:224 Artabortrine 20:480,481 Artabotrys zeylanicus dioxoaporphines of 20:480 Artabsin 7:234 Artabsinolide A-D 7:234 Artabsinolide B 7:209,210,234 Artanin 7:204,205,224 Artanomalolide 7:239 Artausin 7:234 Arteannuin B from Artemisia annua 7:217 Arteannuinic acid 7:238 Arteanoflavone 7:226 Arteanomalactone 7:230 Artecanin hydrate 7:234 Artedouglasia oxides 9:531-533 Artedouglasia oxides A-D 7:217,218 Artefransin 7:234 Arteglasin A,B 7:234 Artelin 7:225 Artemetin 7:206,226 Artemia salina 9:385,387 Artemidin 7:203,223 Arteminisin '^0-NMR spectrum of 17:591 Artemisia abrotanum 7:205,218,240 coumarin-sesquiterpene ethers in 7:205 Artemisia absinthium 7:215,219,220,240 absinthinfrom 7:215 Artemisia alcohol 9:530 Artemisia annua artemisinin from 13:657;20:518 arteannuin B from 7:217 candinane derivatives from 7:217 Artemisia anomala 7:215,240 aurantimide acetate from 7:220 simiarenol from 7:218 Artemisia aragonensis (A. herb alba) 7:212 Artemisia arbuscula 7:208 arbusculone from 7:208 Artemisia argyi 7:218 simiarenol from 7:218 Artemisia aucheri 7:208,241 Artemisia austriaca 7:241 C-methylflavone m 7:207 Artemisia californica 20:4 Artemisia cantabrica 7:216,242 Artemisia capillaris 7:220,242 Artemisia carvifolia 7:206,242 Artemisia compacta 7:205,243 Artemisia douglasiana 7:203,204,217,218,243 Artemisia dracunculus 7:220,243 Artemisia feddei filifolide A from 7:208 filifolone from 7:208 Artemisiafragrans 7:208,244 Artemisia glutinosa 7:220,244 Artemisia gypsacea 7:211,245 Artemisia herba alba (A. aragonensis) 7:212,217, 7:245 Artemisia herba-alba 17:475 Artemisia hispanica elemanolide from 7:216 2a-hydroxyartemorin from 7:211 tamaulipin A from 7:211 Artemisia inculta 7:217,245 Artemisia iridentata ssp. rothrockii 7:208,252 Artemisiajudaica 7:211,216,217,246

949
Artemisia 536 Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia Artemisia ketone 7:100,101,202,203,208,221;9:530, klotzchiana 7:214,246 koidzumii 7:218,246 laciflora 7:203,218,246 laciniata 7:215,216,246;9:529,531,533-535 lanata 7:214,246 latifolia 1'2\ 9,247 leucodes 7:215,247 longloba 7:218,247 ludoviciana 7:203,247 maritima 7:217,427;13:660 marschalliana 7:220,248 molinieri 7:218,248 monosperma 7:204,220,248 moorcroftiana 9:529,530,534 pallens 7:217,249 fallens 9:531 palustris 7:207,220,249 pectinata 7:214,216,249 persica 7:217,249 roxburghiana 7:219,250 rupestris 7:218,250 rutifolia 7:215,250 salsolodes 9:529-531,533,534 santolina 7:212,250 santonicum 7:212,250 schmidtiana

eudesm-1 l-en-4-ols from 14:450 neointermedeol from 14:450 Artemisia selengensis 7:203,204,215,251 Artemisia S!^. 7:201-263;9:529-536 Artemisia szowitziana 7:216,251 Artemisia toumefortiana 7:212,252 Artemisia umbelliformis 7:215,253 Artemisia valentina 7:213,218 Artemisia vulgaris 7:120,208,215,218,253 Artemisia xanthochroa 7:215,253 Artemisinin 5:24-27,518;7:238,424 from Artemisia annua 13:657 Artemisitene 7:238 Artemorin 7:209,210,230 Artenolide 7:239 Artesieversin 7:239 Artesin 7:212,213 ll-e/7/-Artesin 7:213 Artesovin from Artemisia szowitziana 7:216 Artevasin 7:230 Arthritis 17:137 Arthrobacter globiformis 9:418 Arthrobacter simplex 9:418,427,428 Arthropod alkaloids from Solenopsis sp. 11:231 Arthropod ectoparasites 12:7 Arthropoda 19:627 Arthropods agents active against 1:435 Artidae family 19:125 Artificial electron mediators 20:821-824 Artocarpus nobilis 2:231 Amgomycin 19:118

Aryl P-C-glycosides by condensation with tribenzyloxy benzene 10:377 by Lewis acid assisted condensation of aryl ether 10:375 Aryl C-glycosides from ribofiiranosyl chloride 10:362,363 a-Aryl enamine substrates 18:327 P-Aryl enamine substrates 18:333 Aryl ethano-bridge 11:295 Aryl ethers ^^O-NMR spectrum of 17:586 N-(Arylidene) benzyl amines 1:343 2-azaallyl anions from 1:343 isomerization of 1:343 Arylhalides 4:541,544,545,547 Aryl maltotrioside 8:343,344 Aryl methyl ketone chiral acetal of 14:473 asymmetric cyanation of 14:473 cw-3-A^-Aryl sufonamido bomeol 4:661,662 4-Aryl-1,2,3,4-tetrahydroisoquinoline derivatives synthesis of 12:451 l-Aryl-2-methyl cyclohexane 8:9 l-Aryl-2-methylcyclopentane 8:9 4-Aryl-2-oxazolidiones from 4-methoxy-2-oxazolidinones 12:428 2-Aryl-3-methyl-4-benzyltetrahydrofiirans 17:331 (3-Aryl-p-methylacrylates 12:462 Ary 1-C-glycos ides by condensation 11:139-142 intramolecular 11:139-142 via polyketides 11:13 9-142 regioselecti vity of 11:142 stereochemistry of 11:142 synthesis of 11:139-142 4a-Aryl-cw-decahydroisoquinolin 6-formate 12:462 Arylcycloalkanes 8:6 4a-Aiyldecahydroisoquinolines diastereoselective synthesis of 12:456-463 4a-Aryldecahydroisoquinolines 18:81 Aryldihydronaphthalenes 17:337 N-Arylethylhydroindoles 3:457 3-Arylisoquinoline alkaloid synthesis of 14:796-799 4a-Arylisoquinoline ring system synthesis of 12:457,458 Arybiaphthalenes 5:493;17:332 2-Arylpropanoic acids synthesis of 6:322,323 4-Aryltetralin-type lignan synthesis of 18:586-588 Aryltetralins 17:341,343 Arynes generation of 3:418-421,422-454 natural products via 3:517-454 nucleophilic additions of 3:418,421-437 pericyclic reactions 3:418-437 structure-reactivity 3:417,418 Asadaninl&II 17:369 5-Asarinin 5:753,754 Asatone 8:168

950
Asbcisicacid 2:164 Ascaridol 20:13 Ascidia nigra 10:241 Ascidiacyclamide 4:91-93;5:419,420;10:242 Ascididemin from Didemnum sp. 10:244,245 from Eudistoma sp. 10:244,245 Asclepiadaceae 5:751;18:649 Asclepias curassavica 5:249 Asclepiasfruticosa 5:248,249 Ascobolusfurfuraceus 5:279 Ascomycetes 9:202,203 Ascomycotina 9:202 I-Ascorbic acid 13:70 Ascorbic acid 2,3-0-alkandiyl derivatives 4:720 aldol reaction 4:699-705 biological significance 4:725 deoxygenation 4:715-718 esterification by 4:723 etherification 4:718-720 Mannich reaction 4:715 metal complexes 4:720-722 Michael reaction 4:705-715 oxidation of 4:723 platinum derivatives 4:720-722 structure of 4:723,734 synthesis of 17:636 tautomeric forms 4:724,725 Asebotoxin 20:17 Ashurbin 7:233 Asiaticoside 15:213 Asimicin triacetate 17:262 Asimicin 9:391,392,396 Asimicin triacetate 9:391 Asimina tiloba 9:391 Asinger condensation 12:127,129 Asltonia macrophylla 13:383,422 Asltonia muelleriana 13:383,399,422 Asocainol 6:478 Asparagine-linked oligosaccharides biosynthesis of 10:499-502 Asparagopsis sandfordiana marine sterols from 9:83-85 Asparagus cochinchinensis 17:116-117,130.132 Asparagus curillus 7:427 Asparagus piumosus 7:427 Asparagus species 17:130 Asparenomycines in carbapenems 4:434 L-Aspartic acid 4-acetoxy-p-lactam from 12:160 I-Aspartic acid 6:263;13:63 Asparticacid 6:298,299 A^-Aspartyl-pseudodisaccharides 13:218 Asperdiol 10:18 activity against lymphocytic leukemia 8:15 growth inhibition of KB, PS and LE Cell lines 8:15 Asperentin 15:382,385-387 Aspergillic acid 13:321 Aspergillosis 2:422,425 Aspergillus acylase 1:678 Aspergillus alleaceus 20:792 Aspergillus awamor i 2:322,341,353 Aspergillus brevipus 12:400 Aspergillus caespitosus 19:480 Aspergillus duricaulis 15:343,345 Aspergillusflavus 2:446;5:296;9:300;15:386,245; 18:711 Aspergillusfumigatus 5:295-298,322,326;7:65;9:300; 12:400;18:469,807,809 Aspergillus melleus 15:383 Aspergillus nidulans 5:295,296 Aspergillus niger a-L-rhamnosidase from 7:70 P-glucosides from 7:51,52,55,56,65-67 cycloisomerase from 8:296 glucoamylase from 7:62 isozyme I from 2:322,341 lactone from 8:300 Aspergillus ochraceus ochratoxins from 15:387 Aspergillus ochraceus wilhelm 15:384 Aspergillus orizae 13:304 Aspergillus oryzae 1:697,117;2:322,341;5:295; 6:551,552 Aspergillus parasiticus averufmby 11:194 Aspergillus terreus 19:168 Aspergillus sp. 5:276,278,294,301,325, 5:326,328,368,370 Aspergillus spp. 2:323;9:203,300 glucoamylase from 2:322 Aspergillus stellatus (+)-asteltoxin from 10:439 Aspergillus terreus 5:296,730;15:385 Aspergillus -versicolor 18:807,809 Aspergillus wentii 7:56,64;9:300 Asperline 15:350,351;19:463 Asperuloside 7:439,455,469,470,479,480;16:298 Asperulosidol 7:467,468 Asphaenogaster rudis 5:226,243-245 Aspiculamycin 4:242 Aspidospermatan type alkaloids 1:31,32 Aspidosperma indole alkaloids 13:70,93 Aspidosperma alkaloids synthesis of 19:89-116 Aspidosperma alkaloids 4:27,275,411 Aspidosperma cyclindocarpon 19:112 Aspidosperma marogravianum 1:124 Aspidosperma oblongum 1:124,125 Aspidosperma type amarylidaceae alkaloids 11:229 Aspidosperma 19:114-115 Aspidospermatan-type alkaloids 5:71,86,87,135 Aspidospermatidine 1:40 Aspidospermatine 1:40 (-)-Aspidospermidine 19:143 Aspidospermidine 13:93 ;14:632-636 Aspidospermidine A^-14,15-methyl-14,15-oxido 5:126 Aspidospermidines 4:57-68 Aspidospermidose 5:165-167 Aspidospermine alkaloid 18:338 Aspochalasans 13:108,131,134

951
Aspochalasin B 13:142,143 Aspochalasin C 13:108,131,134 Aspochalasins 15:355 Aspteric acid 5:729,730,732,733 Astaxanthin 6:153;20:577,578,588,607 (35,35')-Astaxanthm 6:158 (3/?,3/?)-Astaxanthin 7:321,361,362 (35,3'5)-Astaxanthin 7:361,362 Asteltoxin from Aspergillus stellatus 16:670 (+)-Asteltoxin 10:439-442 absolute stereochemistry of 10:439,440 Claisen rearrangement by 10:439-442 from Aspergillus stellatus 10:439 synthesis of 10:439-442 Aster saponin A 15:209 Aster saponin H 15:210 Aster saponin U 15:211 Asteraceae 7:411,413,427 Asteria pectinifera 1:307 Asteriarubin 6:162 from Asterias rubens 6:161 Asterias amurensis 7:286-298,303;15:44 Asterias amurensis vesicolor asterosaponin-1 from 7:287 thomasteroside A from 7:287 versicosides (A-C) from 7:287 Asteriasforbesi 7:288;15:58,69 Asterias rubens 6:151,152,156,161;7:288,294,304,306; 15:48 Asterias vulgaris 7:288,291,304;15:59 Asterinapectinifera 7:289;15:44,48,55 Asterinic acid 6:161 Asterogenol (20/?-5a-pregn-9(l l)-ene-3p,6a,20-triol) 7:288,291 Asteroidea 7:265,285-307;15:43-45 Asterone 15:45 Asterone (3p,6a-dihydroxy- 5a-pregn-9(l l)-en-20one) 7:290,291 (+)-Asterosaponin 7:285,288,290,291,294, 7:303,304 Asterosaponin 1 (forbeside C) 7:287,288,293 Asterosaponin A and B from Asterias amurensis 7:286,303 Asterosaponin D1-D3 biosynthesis of 7:299,302,303 from Distolasterias nipon 7:299 Asterosaponin Pi from Oreaster reticulatus 7:297,300 Asterosaponins 15:45-58 Asterosides A-D 7:287,293 Astichoposide C 7:273,281,282 from Astichopus multifidus 1:273 Astichopus multifidus 7:272,273,281 astichoposide C from 7:273 Astragalus 13:660 Astragalus emoryanus (-)-swainsonine from 12:313 Astragalus lentiginosis 7:11,486 Astragalus lentiginosus (-)-swainsonine from 12:313 Astragalus mister 19:118 Astragalus sp. 7:23 Astringent 5:751,754 Astrocytes by staurosporine 12:393 tumor promotor in 12:393 Astropecten aurantiacus 15:104;15:61 Astropecten indicus 5:214;7:299 Astropecten latespinosus 7:288;15:48 Astropectenpolyacanthus 7:306;18:725 Astropecten scoparilis 15:68 Asukamycin 11:189 Asymmetric alkylation 11:367 catalytic epoxidation 11:431,432 catalytic osmylation 11:431,432 cycloaddition 11:358 dihydroxylation of 11:423,424 of /raAM-stilbene 11:423,424 Asymmetric cyclization 10:611,631-633 Asymmetric [3+2] dipolar cycloaddition 13:500 Asymmetric 1,3-dipolar cycloaddition 1:371-375 Asymmetric additions to prochiral carbonyl groups 4:332 to prochiral naphthalene rings 4:332 Asymmetric aldol condensation 12:162;13:63 Asymmetric alkylation of methylmalonic acid 10:411 of (-)-pheny Imenthy 1 ester 10:411 Asymmetric allylboration 8:477,478 Asymmetric aza-annulation reaction 18:378,379 Asymmetric bromolactonization with acetals from tartaric amides 4:338,339 with N-bromoacetamide 4:338,339 with chiral acetals 4:338,339 with unsaturated (5)-proline amides 4:336,337 Asymmetric carbocyclization in (-)-2/?,65,85,95)-2,8-dibromo-9- hydroxy-achamigrene synthesis 6:62,63 Asymmetric cyclization biomimetic 14:506,507 of chiral acetal 14:506,507 Asymmetric cyclopropanation with methyl carbenoid 14:488 Asymmetric Diels-Alder 8:139-157 chiral auxiliaries 4:607 prostaglandin synthesis 4:607 p-santalene synthesis 4:607 tetramycin synthesis 4:607 using chiral boron reagent 4:609 Asymmetric Diels-Alder technology 13:602 Asymmetric dihyroxylation ll:60;19:269-270,274, 278,284 Asymmetric dimethylation 10:412-415 Asymmetric epoxidation of()-N-benzyloxycarbonyl-3-hydroxy-4ofallylic alcohol 10:561 ofallylicalkohols 12:323 of allylic alcohols 4:172-174 pentenylamine 12:281 ofswainsonine 10:561 Asymmetric esterification 9:25

952
Asymmetric hydration 13:71 ofalkenes 13:71 Asymmetric hydroboration 8:473,474,478;13:71,72 Asymmetric hydrogenation 12:162;16:411 Asymmetric hydrogenation BINAP-Ru-catalyzed 4:439 of p-keto esters 4:439 Asymmetric hydrolysis by esterases 1:684,685 by lipases 1:684,685 of N-acetyl a-amino acids 1:678,679 Asymmetric hydrosilylation intramolecular 13:72 Asymmetric hydroxylation ofpentadienols 9:572 Asymmetric induction 10:412;12:153,156;14:471, 507,508,524,553 1,2-Asymmetric induction 11:231 -238 1,3-Asymmetric induction 14:529,552 1,4-Asymmetric induction 12:156 1,5-Asymmetric induction 14:499 1,6-Asymmetric induction 14:530 1,4-Asymmetric induction Cram's cyclic model of 4:203,495 in (-)-piperitone 6:15 in aza-annulation reaction 18:373-386 in dienolate addition 3:47 in diyl trapping 3:20 in Ireland-Claisen rearrangement 3:237 reversion using sulfoxides 4:511 self-immolative 3:237 withchiral auxiliaries 4:499-517 Asymmetric ketoester cyclization 4:328-330 Asymmetric metallation of chiral arylaldehyde acetal chromium tricarbonyl complexes 14:511 Asymmetric Michael addition in estrone synthesis 4:501,502 Asymmetric osmylation 19:269 Asymmetric oxidation of prochiral sulfides 14:517,518 of sulfide 4:489 sulfoxides from 14:517,518 with chiral sulfamyloxaziridines 4:489 with chiral titanium complexes 4:489 Asymmetric quatemization by Claisen rearrangement 10:426-428 by consecutive alkylation 10:405,406 of aldohexofuranose derivatives 10:428-432 ofa-carbonof y-lactones 10:405 Asymmetric reduction with Baker's yeast 1:689 Asymmetric reduction by Baker's yeast 10:410 of acetoacetic acid ethyl ether 10:410 of acetylenic ketone 11:424 of acyclic p-hydroxy ketones 14:183,184 of P-keto esters 14:533,534 withlpczBH 8:476 Asymmetric reductions 4:339-345,448 Asymmetric synthesis by diastereofacial selection 13:62-70 by enantiofacial selection 13:70-73 by enantiotopic discrimination 13:60-62 of(-)-ajmalicine 14:563,564 of(-)-sibirine 14:539-544 of (+)-(5,5)-solenopsin A 6:431,432 of (+)-castanospermine 12:346 of(+)-elaeokanineA 12:351,352 of (+)-elaeokanine C 12:351,352 of(/?)-muscone 14:490 of (/?/5)-l,6-dioxaspiro [4.5] decane 14:523,524 of (/2/5)-l,7-dioxaspiro [5.5]-undecane 14:521-526 of [m, n, 1] propellanes 14:490 of 2-deoxy-D-flra6/>jo-hexose 14:176,177 of3-deoxy-D-r/6o-hexose 14:176 of 4-acetoxy-3 -[ 1 '-(/eA^buty Idimethy 1-silyloxy) ethyl]-azetidinone 4:448 of 4-deoxy-D-/vjco-hexopyranose 14:176 of 5,1-linked naphthylisoquinoline alkaloids 20:420-438 of 5,8-linked naphthylisoqumoline alkaloids 20:442-451 of 7,1-linked naphthylisoquinoline alkaloids 20:438-441 of anthracycline antibiotic 14:492,493 of azetidinone 4:448 ofbuphanisine 4:14,15 of chiral alkaloids 10:671-689 of chiral building blocks 14:551-581 of chiral isoquinolines 10:671 ofchh-alpiperidines 10:671 ofcrinine 4:14,15 ofdesoxydaunomycinone 14:23 of indolizidine alkaloids 6:442,443 of monomorine I 6:449,450 of pyrrolidine alkaloids 6:442,443 of pyrrolizidine alkaloids 6:442,443 of /?,5'-4-hydroxycyclopentenones 6:315 ofsolamin 18:202-206 of talaromycin A and B 14:531-539 propane-1,3-diols by 13:53-105 via chiral organoboranes 8:465-478 with chiral sulfur reagents 10:671-689 Asymmetric transformation crystallization-induced 13:77 of malonic acid derivative 13:88 Asymmetric catalysts hydrogenation 17:323 synthesis of 17:479 Asymmetrization of a-symmetric ketones 11:241,242 AT2433-A, from Actinomadura melliaura 12:366,368 AT2433-A2 from Actinomadura melliaura 12:366,368 AT2433-Bi from Actinomadura melliaura 12:366,368 AT2433-B2 from Actinomadura melliaura 12:366,368 Atalantia ceylanica l,5-dihydroxy-3-methoxy-10-methylacridin-9-one from 13:348,350

953
1 l-hydroxynoracronycine from 13:348,349, 13:356 11-0-methylatalphilidine from 13:348,349 A^-methylatalphyllinine from 13:348,349 Atalantia monophylla atalphyllidine from 13:348,349 atalphylline from 13:350 atalphyllinine from 13:349 A^-methylatalphylline from 13:350 Atalfoline from Citrus bnxifolia 13:350 Atalphyllidine from Atalantia monophylla 13:348 Atalphylline from Atalantia monophylla 13:350 Atalphyllinine from Atalantia monophylla 13:348,349 A telopus chiriquiensis 18:724 Athanasin from Athanasia L. 16:666 Atherosclerosis 11:335;12:399 Atherospermidine 20:480,481 Atisense RNA gene expression by 13:257-261 natural regulation of 13:257-261 ^Atis-16-ene-3,14-dione 9:68,269,276,277,279,290 /-Atisane diterpenoids 9:267-281 /-Atisanes 9:267-283 Atisine synthesis of 3:435 Atisu-ene synthesis of 10:180 Atomic orbital coefficients in Diels-Alder reactions 4:586 ATPase 7:282 Atractylis gummifera 20:8 Atractyloside 20:8 Atropa belladona 20:135 AtropagQnvLS 17:395 Atropisomerization 11:49,50 Atropisomers 11:49,50 2-ATT (2-acetylthiazole) 11:443, 11:444 Atta cepholotes 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Atta sexdens rubropilosa 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Atta sexdens sexdens 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Attatexana 5:234,125 Atta-ur-Rahman synthesis of()-16-hydroxydihydrocleavamine 14:850 of ()-16-methoxycarbonyldihydrocleavamine 14:850 of()-coronaridine 14:850 of()-dihydrocatharanthine 14:850 of()-isovincadifformine 14:850 of()-a-dihydrocleavamines 14:850 of()-p-dihydrocleavamines 14:850 ofanhydrovinblastine 14:857 ofvinblastine 14:850-859 ofvincristine 14:850-859 Attanuatoside C 7:295,296,300 Attenuatodside from Hacelia attenuata 7:295 Attenuatoside A-1 7:295-297,299,300 Attenuatoside A-II 7:295,296,300 Attenuatoside B-I 7:295,296,300 Attenuatoside B-II 7:295,296,300 Attenuatoside C irom Hacelia attenuata 15:61 Aucubigenin 7:478 Aucubin 7:440,455,465,472,473,476,478,479,480, 481-483 6-e/7/-Aucubin 7:472,473 Auguidine 6:225,226,229 Augustilobine A&B 9:171 Aulacohorafemoralis chinensis 18:771 (+)-Auranthioclavine synthesis of 16:438 Aurantiamide acetate from Artemisia anomala 7:220 Aurantinin 5:601,603 AurantininA 5:601,604-607 Aurantinin B 5:601,603-606 Aurapten from Limonia acidissima 20:497 Aureobasidium pullulans 5:307,308,314 Aureobasidium sp. 5:307 Aureol 5:430,431,437,438,444;9:31,32;15:300,314 Aureolic acid antitumor antibiotics 3:173-206 Aureolic acid, 3:173-175 Aureothin 5:551 Auricularia auricula-judae 5:290,316,318,319,733 Auricularia sp. 5:287,317,320 Aurones 7:192 (-)-Austalide B from Aspergillus ustus 18:32 Austalides A-F 18:32,37 Australine amyloglucosidase inhibitor of 10:567 from Castanospermum australe 10:567 oligosaccharide chain inhibitor 10:567 Austrocedru chilensis 19:405 Australine a-glucosidease inhibition by 7:11 amyloglucosidase inhibition by 7:13 from Castanospermum australe 7:13 glucosidases I,II inhibition by 7:13 Autoimmunodeficiency syndrome 18:908 Automated synthesis of oligonucleotides 13:257-294 ofoligodeoxyribonucleotides 4:280 reaction cycle 4:281 Automatic DNA synthesizer 4:304 Autooxidation of 1-methylazulene 14:335,336 of benzylic positions 16:571 ofguaiazulene 14:316-319 ofphenylhydrazine 9:581 Autoxicity selection by 7:116,117 Auxins effect on root culture growth 17:424

954
indoleacetic acid as 7:90 naphthaleneacetic acid as 7:90 Avarol 5:430,431,438,439;9:30,31 ;15:238,252 Avarol monoacetate 15:300 Avarone 5:430,431,434,438,439;15:301,314 Avenasativa 9:220 Avenaciolide 3:259,260;19:485 Avencins Ai,A2,Bi,B2 7:136,137 Avenestergenins Ai,A2,Bi,B2 7:136,137 Average mass 2:26 Avermectin 12:13 Avermectin absolute configuration of 12:6 biological activity of 12:709 biosynthesis of 12:6,7 from Streptomyces avermitilis 12:3 isolation of 12:3-6 stereochemistry of 12:6 structure elucidation of 12:3-6 structure-activity relationship of 12:8 synthesis of 12:9-33 Avermectin A 12:3 Avermectin Aia Dainshefsky synthesis of 12:12,13,15 fromD-robosa 12:12,13 from Streptymyces avermitilis 12:6 Avermectin B 12:3 Avermectin Bi insecticidal activity of 12:9 Avermectin B la synthesis of 1:463-465 Avermectin Bia aglycon White synthesis of 12:15,27,28 Avermectin Bip, B2a and B23 10:177;12:6 conversion to avermectin Bia 1:442,443 synthesis of 1:443-445,468,469 Avermectins from lithium acetylide 10:386 mechanism of action 1:43 5 structures of 1:438 synthetic approaches to 1:435-495 synthesis of 10:386 Avermectins A2a 12:6 from Streptomyces avermitilis 12:6 Avermectins Bia 12:6,12-15,22-24 from Streptomyces avermitilis 12:6 Hanessian's synthesis of 12:12-15 Ley synthesis of 12:22-24 X-ray analysis of 12:6 Averufm biosynthesis of 11:194 in Aspergillus parasiticus 11:194 Avermectin Avian hemoglobin alkaline denaturation 5:841 allosteric regulator binding sites 5:849 amino acid composition 5:841 carbon dioxide transport 5:853 electrophoretic mobilities 5:839-841 heme binding sites 5:869 heterogeneity in 5:856 inositol pentaphosphates in 5:857 oxygen affinity 5:856 oxygen uptake 5:853 physiology 5:854-859 primary structure 5:844-850 structure of 5:835-850 Avicennia alba 7:176,181,182,189,195 Avicennia germinas 7:175 Avicennia marina 7:176,180,183,184,194,195 Avicennia officinalis 7:176,181,182,189,195 Avicennia resinifera 7:193 Avicennia sp. 7:176 Avicennia tomentosa 7:189 Avicenniaceae 7:175 Avicenol 4:372,373 Avicine 14:770 Avicularia 17:193 Avidin 18:919 Avidinphosphatase assay 4:284 Axamide-1 from Axinella cannabina 6:5 synthesis of 6:5,6 Axenomycin 19:555 Axial 2-lithiotetrahydropyrans 10:380 by reduction with lithium di-/err-butylbiphenylide 10:380 from 2-(phenylthio)-tetrahydropyrans 10:380 Axial C-glycopyranosides 10:365,366,382 Axillarin 7:26 Axillaroside 7:26 Axinella canabina axamide-1 from 6:5 axisonitrile-1 from 6:5 Axisonitrile-1 from Axinella cannabina 6:5 synthesis of 6:5,6 Ayani 7:226,411-413 Aza spu-ocycle 10:215,216 Aza-adamantane skeleton 11:295 Aza-annulation of enamine related substrate 18:315-386 Aza-annulation reaction asymmetric induction in 18:373-386 Aza-Claisen rearrangement 16:467 Aza-Cope reaction 16:481 Aza-Cope rearrangement Mannich directed 1:68,69 Aza-Cope-Mannich strategy 16:435 Aza-Diels-Alder approaches 16:456 25-Aza-vitamin D3 anti-vitamin activity of 9:519 Aza-[2,3]-Wittig rearrangement 19:22,45,50 Aza-Wittig reaction 1:168,169 3-Aza[5] (1,7) naphthalenophanes synthesis of 6:477 U-Azaacronycine 20:792 2-Azaallyl anions by deprotonation of imines 1:344-347 by C-Si of C-Sn bond cleavages 1:344-351,353 from imines 1:344-347 from N-lithioimidazolidmes 1:344,349-351 from N-metalloaziridines 1:344,348,349

955
generation of 1:348,350 geometry of 1:348,350 Azaallylic anions with aryl halides 4:547 7-Azabicyclo[2.2.1] heptane 19:66 endo-1'Az2ibicyc\o[2.2.1 ] heptanol 19:71 Azabicyclo[2.2.1]heptanone 19:71 8-Azabicyclo [3.2.1] octan-3-one asymmetric cleavage of 14:573,574 N-protected 14:573,574 9-Azabicyclo [3.3.1] nonan-3-one 14:571-574 trimethylsilyl enolate 14:572,573 with chiral lithium amide 14:571-574 2-Azabicyclo [3.3.1] nonane 11:280 1-Azabicyclo [4.3.0] nonane (octahydroindolizine) 11:229 Azabicyclo ketone system asymmetric cleavage of 14:571-574 cis-a, a'-disubstituted piperdine and pyrrolidines by 14:571-574 3 - Azacephalosporine 12:137 Azadiene Diels-Alder 3:311 1-Azadiene Diels-Alder cycloadditions 16:457 2-Azadienes metalloenamines from 4:7,10-14,17 Azadirachta indica 9:293-311 ;13:644;15:384 Azadirachtin 7:397;9:93,94,96,103-105,297 Azadirachtol 9:308 Azadirol 9:297,298,300,306,308 Azadirone 9:302,304-306 Azafluoranthenes 1:167,169 Azafulvene 9:596 Azafulvene bilane 9:593,595 2-Azahexatriene thermal cyclization of 3:395 Azalides 13:161,162 Azasteroids 4:540 Azasugars 14:179 Azepine ester 19:99 3-Azetidinol from Chara globularis 18:677 Azetidinone 13:87 Azetidinone 4:437,441,448,450,452-454,457,458, 461-466;8:264 1 -Azetidinone acetic acid 12:138 Azetidione derivatives Mori synthesis of 13:500 Azetidone 5:412-414 Azidation reaction asymmetric 19:311 Azides dipolar cycloaddition 3:49 thermolytic cyclization of 6:429 l-Azido-l,2,3-trideoxy-D-arabino-oct-4-ulose 12:350 8-Azido-1 -p-menthene reduction of 11:288 6-Azido-2,4-di-0-benzyl-3,6-di-deoxy-a-D-ribohexopyranosyl chloride 14:145 2-Azido-2-deoxy derivative ofD-glucose 6:388 of muramic acid 6:387,388,402,403 2-Azido-2-deoxy-Z)-glucose derivative 6:388 3'-Azido-3'-deoxythymidine (AZT) antiviral activity of 10:585 3-Azido-3-deoxy-1,2-O-isopropylidene-a-Dglucofliranose 12:325 3-Azido-3-deoxy-/w>'o-inositol2,4,5-trisphosphate 18:411 4-Azido-4-deoxy-D-mannose 12:316 6-Azido-6-deoxy-D-arabino hexulose 10:536 Azido-6-deoxy-L-xv/o-hexulose 10:536 2-Azido-Z)-arabino-hexofuranoses 5-deoxy-5-(phenylphosphinyl) Z,-fucosamine from 6:369 from Z)-ribo-hexafiironose 6:363 Azido-ene reaction 16:473 Azido-olefin cyclization 13:447,448 2-Azidobenzaldehyde 13:448 Azidobutenolides 13:448 a-Azidocinnamates 1:165 Azidodeoxy-/w>'o-inositol 18:411 Azidonitration 1:420,421;10:465 Aziridine from (5)-phenylglycinol 10:138,139 azomethine ylides from 1:328-331 fused 1:189,197 nucleophilic opening 1:201,202 photochemical opening 1:328 synthesis of 1:189,197 thermal opening 1:328 Aziridinometosene Aziridinyltriol Azithromycin 13:161,162,183 Azobisisobutyronitrile (AIBN) 10:204,208 Azocine synthesis of 8:210 Azodicarbonyldipiperidine 19:225 a-Azohydroperoxide 9:580 Azomethine ylide cycoadditions by aziridine thermolysis 1:329,330 intramolecular 1:329,330 Azomethine ylides by 1,2-H shifts 1:331-332 formation of 1:324-344 generation of 1:324,339 preparation by aziridine opening 1:328-331 preparation by desilylation 1:324-328 preparation from a-amino acids 1:331-338 Azomonas macrocytogenes 19:814 4-Azoniaspiro [3,3] heptane-2,6 diol from Chara globularis 18:677 Azospirillum lipoferum 4:197 Azotobactins 19:812 Azoverdin 19:811 Azulenequinones 14:314 Azulenes autooxidation of 14:332 electrochemical oxidation of 14:325 oxidation of 14:332-334 Azulenic hydrocarbons oxidation of 14:313-354

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B-prostaglandins synthesis of 16:367 B/C-/ra5-morphinan diastereoselective synthesis of 12:464-471 Babylonia japonica 11:724 BaccatinI 11:4,9;12:179 Baccatin III 11:3,4,179,180;12:179,180;20:81 Baccharis articulata 15:22 Baccharis gaudichaudiana arabinoside gaudichaudioside A from 15:21 Baccharis timer a I'All Bacillarophyceae 6:13 Bacillus antharacis 12:400 Bacillus aurantinus 5:601 Bacillus cereus 7:413 Bacillus megaterium 10:585;12:104 Bacillus pumilis 7:70,308,390 Bacillus sp.TA 12:104 Bacillus sp. 12:103 Bacillus subtilis 5:302,304,368,418,308,353;8:353; 10:117,104,400,345,692,290,556,559;18:778 Bacillus thiaminolyticus baciphelacin from 15:390 Baciphelacin 15:388,390,409,410 Bacitracin 9:413 Backbone rearrangements 7:159,161 -166 Baconipyrones A-D 17:25 Bacteria siderophores from 9:537-557 Bacterial cell wall 6:385,395,397,406 Bacterial growth inhibitors 17:101 Bacterial polysaccharides I-glycero-D-mannoheptose in 4:195 Bacteriorhodopsin 4:526,720,823 Bacterioruberin 7:355-357;20:599 Bacterium pseudomonas 9:322 Bacteroides fragilis 14:107 Bactobolin antibacterial activity of 16:3 antitumor antibiotic 16:3 from Pseudomonas yoshitomiensis Y-12278 16:3 total synthesis of 16:3-26 (-)-Bactobolin 16:22 Baeyer-Villiger rearrangement 4:647,667,139,153; 8:154,597,598 Baeyer-Villiger ring expansion 13:601 Bai-yun-shen baiyuoside from 1:666 Baiyumine A from Citrus grandis 13:348,349 Baiyumine B f^om Citrus grandis 13:350 (+)-Baiyunol synthesis of 1:666-669 thermal glycosidation of 8:362 Baiyunoside synthesis of 1:666-670 from Phlomis betonicoides 15:20 Bakankoside from Strychnos vacacoua 6:503 Baker's conditions 12:46,47 Baker's yeast 4:324,325,340,341,158,263,542,543, 552,553,410;6:13;10:410;13:58,59,309,307;20:573,59 3,818,820 Baker's yeast reduction 13:662,176 Balacnol 5:744,747-749, 7:149,150,152 Balaenonol 5:744,747-749,149,150,152 Balanitaceae 7:426,427 Balanites aegyptiaca 7:426 Balanophonin from Balanophor a japonica 20:642 Balanophora japonica balanophonin from 20:642 BALB/3T3 staurosporine activity against 12:400 Balchanolide 7:230 Baldrinal 7:458,459 Baldwin's rule 14:792,793 Baleabuxidine 2:205 Baleabuxoxazine-C 2:205 Balsamodendron mukul 5:695 Baluchistamine B 20:270 Bamboo shoots GAigfrom 6:187 Bamicetin 4:241,243-245 Ban condensation 1:135 Banerjee and Carrasco synthesis oftaxodione 14:695-699 Banksia grandis 19:246 Bannucine 5:167-169;9:185,186 BAP (6-benzylaminopurine) ascytokinin 7:90,94 Barbilophzia hatcheri 5:730 Barbilophzia lycopodioides 5:730 Barley endosperm assay 6:181 Barnacle settlement inhibitors 17:103 Barrett's approaches for oxahydrindene subunit 12:9-11 ofavermectins 12:9-11 Barrigenic acid from Barringtonia acutangula 7:132 Barrollier reagent 19:755 Ri-Barrigenol 21,22-di-O-angelate 7:139,141 Barringtogenic acid from Barringtonia racemosa 7:132 Barringtonia acutangula barrigenic acid from 7:132 barringtonic acid from 7:132 barrinic acid from 7:132 tangulic acid from 7:132 Barringtonia racemosa barringtogenic acid from 7:132 Barringtonia sp. triterpenes of 7:132,133 Barringtonia speciosa anhydrobartogenic acid from 7:132 bartogenic acid from 7:132 19-e/7/-bartogenic acid from 7:132 Barringtonic acid from Barringtonia acutangula 7:132 Barrigenic acid from Barringtonia acutangula I'AZl Barrollier reagent 19:755

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Bartlett demethylation 8:119 Bartlett pear ester 10:152 Bartogenic acid from Barringtonia speciosa 7:132 19-6/7/-Bartogenic acid from Barrintgonia speciosa 7:132 Barton oxidation 9-BBN (9-borabicyclo-[3.3.1] nonane) 13:72 Barton radical decarboxylation 18:75,340 Barton reaction 14:160 Barton reduction 12:303 Barton's modification 19:135 Barton's procedure 6:282-288,607 Barton's protocol in free radical deoxygenation 6:21 Barton's reaction 6:228,230,231 Barton-type deoxygenation 20:71 Base promoted cyclisations ofarylhalides 4:541 Base-catalyzed equilibration 14:460 Base-induced rearrangement 12:91 mechanism of 14:372-374 of hydroazulene mesylates 14:22-25 of hydronaphthalene-1,4-diol monosulfonate esters 14:356 of hydronaphthalene tosylates 14:368-370 Basidiomycetes fruiting body formation 1:680 glycosphingolipids of 18:813,814 Basidiomycetes 9:220,317 Basidomycotina 9:202 Bastadin-6 10:630,636-638 Bastadins 10:630,632,633-638 Bastaxanthin 6:150;10:153 Bastaxanthins C,B,D.E,F 9-BBN 6:20 reaction with p-fiiranone 6:20 Batrachotoxins (steroids) 11:244 Batramiaflavone 20:283 Bavachalcone synthesis of 4:378,379 Bayberry 13:660 Bayogenin molluscicidal activity of 7:432 Bazzanene 9:212,213,308,309,520,521 Bazzanenone 10:308,309 Bazzania tridens tridensone from 18:639 BBE (berberine bridge enzyme) 11:204 9-BBN reduction with 4:116,117 trans-BC'X'mg fusion 12:205 stereochemistry of 12:205 BE-13793C 12:366,370,396 antitumor activity of 12:396 from Streptoverticillium mobaraeens 12:366, 12:370 topoisomerase I and II inhibitors of 12:370 Beaucage sulfiirizating agent 13:269 Beckman fragmentation ofanti-oxime 19:486 of erythromycin -9-oxime 13:160,161 ofoxacyclopentanonering 16:221 ofoxime 16:240,330 ofoxime 19:14,498 Beewax 19:246 Beer's law 15:423 Beet armyworm 12:397 Begonia plebeha 19:764 Belemnitella species 13:330 Bellus rearrangement 8:205 Bench-top bioassays 9:383-409 Benz [a] anthracene 11:113 Benz [a] anthracene antibiotics antibacterial activity of 11:134 antitumor activity of 11:134 synthesis of 11:134-144 Benz [a] anthraquinone 11:113 Benz-annulation reaction 1:505,506 Benzal malonates inhibitory activity of 9:224-227 synthesis of 9:224-227 Benzaldehyde acetal chromium tricarbonyl complex 14:477 from (2/?,3/?)-2,3-butanediol 14:477 with trimethyl aluminum and titanium tetrachloride 14:477 Benzamido-2-deoxy-P-D-glucopyranosyl)7-(2theophylline 4:238 3-Benzazepine derivative 6:474,484 Benzazepines 1:169 3-Benzazocine 6:469,471 synthesis of 6:469 2-Benzazocine A^-oxide derivative 6:472 Benzazocines 1:192,193 ;6:468-471,442 3-Benzazomne derivative 6:475,476 Benzene thiol 11:358 1,2-Benzenedithiol 11:357 Benzenesulfenylacetonitrile condensation of 12:287 1,2,4,5-Benzenetetracarboxylate 11:124 5y-and aw^/'-indenofluorenone from 11:124 N^-Benzensulfonyl CPI synthesis of 3:323,325,326 Benzidine 7:457 Benzilic-type rearrangement 3:226 Benzimidazoles 12:3 Benzofriranes 20:282 Benzo [a] pyrene benzo [a] pyrene oxides from 7:8 carcinogenicity of 7:8 Benzo [a] pyrene oxides absolute configuration of 7:8 from benzo [a] pyrene 7:8 Benzo [a] pyrene-(-)-7/?,8/?-dihydrodiol 7:8,9 Benzo [a] pyrene-7/?,85'-dihydrodiol-95,10i?epoxide 7:8,9 8,13-Benzo [a]naphthacene quinone from naphthacene glutarate 11:123 Benzo [c] phenanthridine alkaloids biomimetic synthesis of 14:769-803 biosynthesis of 14:771-773 from protoberberines 14:769-803 oxygenative conversion of 14:779-784

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Benzo [c] phenanthridine alkaloids 1:187,542 Benzo[c] phenanthridines 5:42 Benzo[c]naphta [\,2-E] azonine derivative 6:481 Benzochromones 18:978 Benzocyclobutanol 14:685 Benzocyclobutanone synthesis of 14:685 via (2 +2) cycloaddition 14:685 Benzocyclobutenes 3:434-437 2,6-Benzodiazecine derivative 6:486,487 2,5-Benzodiazonin-3-one from keto-imine intermediate 6:480,481 synthesis of 6:480,481 Benzodioxan 8:399,401 1,6,5-Benzodioxazonine from 1,5-benzoxazocineA^-oxide 6:472 4-Benzoloxy-P-lactam from epoxy amide 12:161,162 //^reo(45,55)-4-Benzylamino-5-hydroxy-2-methyl6-phenylhex-l-ene 12:478,479 synthesis of 12:478,479 Benzomorphans 2,6-bridge 3-benzazocine in 6:471 Benzophenanthridine alkaloids synthesis of 3:492,446 Benzoprostacyclins synthesis of 16:386 Benzoquinones 20:273 Benzoquinone derivatives 7:183,184 1,4-Benzoquinones enantiospecific reactions of 16:547-570 stereospecific reactions of 16:547-570 Benzoquinones 5:774-778 [l]Benzothieno [3,2-d] azonine derivative synthesis of 6:476 [l]Benzothiero analogues of hexahydrodibenz [d,g] azecines 6:492 synthesis of 6:492 2,7-Benzoxazacycloundecine derivatives from papavarine 6:495 synthesis of 6:495 X-ray analysis of 6:495 Benzoxazecine from isoquinoline derivatives 6:483 synthesis of 6:483 l//-2,6-Benzoxazecine derivatives 6:486 2//-3,6-Benzoxazecine derivatives 6:486 2,3-Benzoxazepine derivative from c/5-(+)-laudanosme A^-oxide 6:468 2,4-Benzoxazocine 6:469 2,4-Benzoxazocine derivative by ring expansion 6:469 Benzoxazocine derivatives by ring construction 6:468-471 by ring destruction 6:468-471 by ring interconversion 6:468-471 from a-narcotine A^-oxide 6:468 synthesis of 6:468-471 1,5-Benzoxazocine N-oxide 1,6,5-benzodioxazonine from 6:472 thermolysis of 6:472

Benzoxazolidone derivative boron enolate of 12:164,166 CMlkylationby 12:164,166 stereoslective 12:164,166 Benzoxazolin-2-one 7:191,192 2,3-Benzoxazonine from 2-benzazocine A^-oxide derivative 6:472 2,5-Benzoxazonine carbocation intermediate in 6:473 derivatives of 6:476,47 photosolvolysis of 6:475,476 synthesis of 6:473 X-ray analysis of 6:476,477 Benzoxicins 5:798;10:210 N-Benzoyl Cig-phytosphingosine 18:461 A^-Benzoyl phytosphingosine 18:462 3-Benzoyl propionic acid 10:406 4-O-Benzoyl-1,2-cyanoethylidene-a-L-rhamnose 14:242 Benzoyl-1,2:5,6-di-0-isopropylidene-a-Z)-3-Oglucofuranose 6:285,286 (+)-N-Benzoyl-16-acetoxycycloxobuxidine-F 2:200,201 A^-Benzoyl-iso-serinate 12:223,225 Benzoylation 1:415,417,289,290,341 N-Benzoylbaleabuxidine-F 2:205 N-Benzoylbuxidienine 2:205 A^-Benzoylcarbamate cyclization of 14:569 from 2,3-epoxy alcohol 14:569 2-oxazolidinone from 14:569 N-6-Benzoyldeoxyadenosine derivatives 4:278 N-BenzoyIdihydrocyclomicrophylline-F 2:207 5-(l-Benzoylindol-3-ylmethyl)-pyrrolidmone 13:130, 131 0-Benzoylnormacusine 13:386 N-Benzoyhiortropane 1:379,380 synthesis of 1:379,380 1 -Benzoyloxy-3-[(3-guaiazulenyl) methyl]-5-isopropyl8-methylazulene 14:324 iV-Benzoylpyrrolidinone 13:121 A^-Benzoylpyrrolinone synthesis of 8:212,213 Benzyl (-)-P-D-gentosaminide synthesis of 14:50-57 A^-Benzylipiperidine 19:35 (/?)-(+)-Benzyl l-(2-methoxy)-naphthyl sulfoxide 10:684,685 a-Benzyl 1-asparaginate 12:121 (S)-Benzyl 2,3-epoxypropyl ether 10:410,411 from D-mannitol 10:410,411 Benzyl 2-0-methanesulfonyl-b-D-arabinopyranoside 14:50 Benzyl 5-amino-5-deoxy-2,3-0-isopropylidene-a-Dmannofuranoside 10:541 a-Benzyl glycosides of A^-acetylmuramic acid methyl ester 6:395,399 ofMurMAc5-lactones 6:390-395 reactions of 6:390-395 A^-Benzyl lactam (CGP-42700) 12:388 Benzyl sulfmylcarbamate 1:23

959
Benzyl tolyl sulfone 11:349 1 -Benzyl-1,2,3,4-tetrahydro-isoquinolone alkaloids 10:683-685 Benzyl-2,3-anhydro-p-D-ribopyranoside 14:50 4,0-Benzyl-2,3-0-6w (methoxy methyl)-L-threitol 11:233 4-0-Benzyl-2,3-0-isopropylidenetlireose 10:128-130 1 -Benzyl-2,6-dicyanopiperidine alkylation of 6:433 decyanation of 6:433 2,6-dialkylpiperidines from 6:433 6-0-(2-0-Benzyl-3 -deoxy-3 -ethoxy carbonyl-amino4,6-0-isopropylidene-a-D-glucopyranosyl)-A^, A^'diethoxycarbonyl-2-deoxystreptamino 14:145 Benzy 1-3 -oxohexanoate with 3-(l-Ai-pyrroliniumyl) propanal 12:293 Benzyl-4,6-(9-benzylidene-3-deoxy-p-D-r/6ohexopyranoside 14:11,12 synthesis of 14:11,12 Benzyl-5-deoxy-5-(ethyl phosphinothioyl) 3-0compounds 6:374,375 (+)-8-0-Benzyl-6-deoxy-castanospermine 12:346 6-Benzyl-9-(3,4-anhydro-a-l-talopyranosyl)a-denine 4:233,234 A^-Benzyl-L-glutamic acid 12:312 A^-Benzyl-/7-toluensulfonamide 12:323 6-Benzylamino-9-(2-acetamido-2-deoxy-p-Dglucopyra-nosyl) purine 4:238 6-Benzylaminopurine (BAP) 4:227,2387:90,94,95 0-Benzylation 12:327 Benzylation 6:268-270,287,288 A^-Benzylation 7:41-43 of 1,4-dideoxy-1,4-imino-I-allitol 7:41 -43 Benzylbenzoate 9:399 O-Benzyldiscretine fagaronine from 14:776,777 Benzylic hydroperoxide rearrangement 3:316-319 3,5-0-Benzylidenation 12:52,53 of (95)-9-dihydroerythronolide A 12:52,53 Benzylidene glycal 10:344 4,6-0-Benzylidene-a-D-glucopyranoside 14:157 3-Benzylidene camphor 4:663,664 2,4-0-Benzylidene-D-threose 6:354 (l/?)-l-[(dimethoxy) phosphinyl]-Z)-threitol from 6:354 N-Benzylideneaniline 10:679,680 Benzylisoquinoline alkaloids 6:472 Benzylisoquinoline derivatives dibenz[<3(,/]azonine derivatives from 6:477,478,480 Benzylisoquinolines synthesis of 3:422 Benzyllithium alkylation of 8:6 2-Benzyloxy glucals 10:346 (3R,4R)-^A-bis (Benzyloxy) succinic anhydride 12:295 (-)-9-Benzyloxy-9-demethyl-7-methoxynogarene 14:82 () A'^-Benzyloxycarbonyl-3 -hydroxy-4-pentenylamine 12:281 Sharpless kinetic resolution of 12:281 Benzyloxycarbonylation 12:478 A^-Benzyloxycarony 1-1 -proline methyl ester 12:295 exo-15-Benzyloxyhobartine 11:299,300 15-Benzyloxyhobartine derivative 11:298,299 Benzyloxymethyl chloride 6:561 a-(2-Benzyloxypropionyl)-butyrolactone 8:287 5-Benzylpyrrol-2(5H)-ones 13:113 Benzyltetrahydroisoquinoline 18:72,76 1 -Benzyltetrahydroisoquinoline system intramolecular oxidative coupling of 6:480 protostephanine from 6:480 rearrangement of 6:480 A^-Benzyltrifluoroacetamide 14:553,554 Benzyne 16:47 Benzyne cyclisation 4:541-551 Benzyne reaction 16:514 Berbamunin 20:292 Berberidaceae 7:416 Berberideine 20:265 Berberine 1:212;13:660 8,14-cycloberbine from 1:211 ^^C-NMR spectrum 5:44 ' H - N M R spectrum of 5:40 APT spectrum of 5:42,43 biosynthesis of 11:201-204 from Berber is sp. 7:88 from Berberis vulgaris 13:660 INEPT spectrum of 5:43,44 Berberme bridge enzyme (BBE) 11:204 Berberis cell cultures j atorrhizine from 11:201 -204 Berberis koetineana 11:202 Berberis sip. 7:88 berberine from 7:88 Berberis stolomifera 20:292 Berberis vulgaris 13:660 Berdy database 19:759 Bergapten from Limonia acidissima 20:497 (+)-P-cw-Bergamotene 16:235 cw-Bergamotene 16:235,236 Bergenin ^omArdisajaponica 13:660 regioselective hydroboration of 13:135 exo-Bervicomin 19:126 Bestatin 12:412,493,434 Beta vulgaris 15:3;20:721,731,740 Betaenone 4:620,621 biosynthesis of 4:620,621 Betaenone B 4:601,602,621,17:475 Betaenone C biomimetic synthesis of 4:620 synthesis of 4:602-604 Betaine 1:89,752,539,92 Betalaines 20:724,740 Betanidine 20:724-740 Betanine 20:724,731 Betula pendula 17:361,366 Betula platyphylla 17:361 5e/M/a species 17:358.361 Betulaceae 17:358,359,364,366 Betulin 7:189,293 Betulinic acid 7:189,507 Betuloside 20:116 Beyerane 15:252

960 BFs rearrangement 5:782,783 BFs-mediated method 11:117 Bharingine 5:174,175 Bhilawainol 9:318 Bhimberine 9:170,172,173 5,5'-Bi(l,3-di-bromoazulene) 14:334 7,7'-Bi(3-bromoazulene)-l,r (7H,7H>dione 14:342 9,9'-Bianthracene-10,10' (9H, 9'H) diones from 1,9-anthracenediols 11:125,126 Bicarbocyclic bridged systems 6:65-74 Bicarbocyclic fused system 6:5-38 Bicarbocyclic lactone 6:80 Bicyclic (3-lactam by Diels-Alder reaction 12:172,173 from cyclic imines carboxylic acid 12:117 from2H-4H, 1,3-dioxin derivatives 12:160,161 synthesis of 12:172,173 Bicyclic C-glycosides from 2-0-Acety 1-3,4,6-(9-benzy 1-a-D-glycosyl bromide 10:338 Bicyclic cis/trans oxazinolactams 11:260,261 Bicyclic cw-glycols 8:245,246 Bicyclic diterpene 8:220 Bicyclic enone taxodione from 14:678,679. from monocyclic ketones 10:311-313 Bicyclic gephyrotoxins (indolizidines) 11:244 Bicyclic keto ester 14:509 Bicyclic keto-acid 12:283 Bicyclic lactones 12:150 Bicyclic olefin 11:371 Bicyclic triene 6:79 Bicyclo [2.2.1] heptanes 8:415 absolute stereochemistry of 8:415 synthesis of 8:415 Bicyclo [2.2.2] octane ()-sanadaol from 6:70,71 by double Michael addition 8:422 from Li-cyclohexadienolates 8:422 from a,P-unsaturated esters 8:422 synthesis of 8:412-422 Bicyclo [2.2.2] octane ring 8:166 Bicyclo [3.1.0] hexan-2-one ()-sinularene from 6:79 Bicyclo [3.2.0] heptanone bicyclo [6.3.0] undecanone from 6:36 Bicyclo [3.2.1] octadione synthesis of 8:161,162 Bicyclo [3.2.1] octane 8:420,421,40;12:22 Bicyclo [3.2.1] octanone 6:78,79 Bicyclo [3.2.1] octenes from bicyclo [3.3.0] octanones 10:317,318 Bicyclo [3.2.1] system 12:86 Bicyclo [3.2.1]hemithioacetal 8:205 Bicyclo [3.2.2] nonadienone 1:567 Bicyclo [3.2.2] piperazinedione synthesis of 12:71 Bicyclo [3.2.2] system 12:85 Bicyclo [3.3.0] octane spiro [4.5] decane from 10:315 cw-Bicyclo [3.3.0] octanes 13:4 Bicyclo [3.3.0] octanones 10:310,311,317,318 Bicyclo [3.3.1] nonane 6:65-69,224 Bicyclo [3.3.1] nonanes conformation of 3:95 fragmentation of 3:74 Bicyclo [3.3.1] nonyl transition state 4:447;10:317, 318 Bicyclo [4.2.2] mesylate 12:80 Bicyclo [4.2.2] ring system 12:64,65 Bicyclo [4.3.0] non-l-en-3-one 10:310 Bicyclo [4.3.0] nonane (hydroindane) 11:230 Bicyclo [4.3.0] nonane group 6:5-11 Bicyclo [4.3.1] dec-2-en-7-one by Grobfragmentation6:69 by intramolecular [2 + 2] photocyclo-addition 6:69 synthesis of 6:69 Bicyclo [4.3.1] decane group 6:69-72 Bicyclo [4.3.1] decanone nakafiiran-9 from 6:70 synthesis by four carbon polar annulation 6:17,21 Bicyclo [4.4.0] decane 6:10,235 Bicyclo [4.4.1] undecane 6:72-74,234 Bicyclo [4.4.1] undecane group 6:72-74 Bicyclo [4.4.1] undecanone 12:238,244 Bicyclo [5.1.0] ontanone 12:243 Bicyclo [5.2.2] piperazmedione synthesis of 12:84,85 Bicyclo [5.3.0] decane group 6:11,12 Bicyclo [5.3.1] undecane unit 12:179 Bicyclo [5.4.0] undecane group 6:29-33 Bicyclo [5.4.0] undecanone 12:249 Bicyclo [6.2.1] undecane 12:193 Bicyclo [6.3.0] undecane group 6:33-38 Bicyclo [6.3.0] undecane skeleton 1:568 Bicyclo [6.3.0] undecanone from bicyclo [3.2.0] heptanone 6:36 poitediol from 6:36 Bicyclo [6.4.0] dodecyl structures 12:212 9-Bicycloboranonane 13:135 Bicyclohumulenone 2:278,279 Bicyclohumulenone from Plagischila acanthophylla subsp. japonica 8:183 synthesis of 8:183-186 Bicyclomycin antibiotic activity of 12:63 antimicrobial activity of 12:41 biosynthesis of 12:64,65 from Streptomyces sapporonensis 12:63 relative configuration of 12:64 stereochemistry of 12:64 synthetic studies of 12:65-95 toxicity of 12:63 X-Ray analysis of 12:64 from vicinal tricarbonyl 8:274 Bicyrtes ventralis 5:223,224,253 Biczamycin 12:63 Bidesmosidic saponins 7:429,432 Biellmann coupling 10:6-10 Biflavonoids 5:468,756-758

961 Biflorin from Eremophila latrobel 15:258 synthesis of 3:450,451 Biflustra perfragilis 17:81,89,91 Bifiircanol 20:26 Bifur carta bifurcata 18:713 Bignoniaceae 7:406 Biogenesis ofD:A-friedo-oleananes 7:150-152 of phenolic triterpenes 7:150-152 of triterpene quinone-methides 7:150-152 3,3'-Biguaiazulene 14:315,319 5,5'-Biguaiazulene-3,3' (5H,5'H)-dione 14:320 Bijvoet difference method 13:434 Bile alcohols 17:207,212 Bilirubin 10:153 Billheimer method 9:464 Bilobol synthesis of 9:354 Bimolecular [67i+47t] tropone diene cycloaddition of 12:241 Binandkatsuim A 20:276 ^-BINAL-H 16:377 (5)-BINAP 19:29 (BINAP) 13:72 BINAP-Ru-catalyst in asymmetric hydrogenation 4:439 Binary indole alkaloids 5:140-151 Bio-organic chemistry ofansamycin 9:431-445 of antibiotics 9:431 -445 of mitomycin 9:431-445 Bioactive conformations ofhormones 18:819-866 Bioactive O-heterocyclic compounds 20:494 Bioactive metabolite of gtnus Phomopsis 15:341-356 Bioactive natural products chkal synthesis of 13:84-99 synthesis of 13:473-518 Bioactive polyketides 18:193-227 Bioactive steroids from Pseudobersana mossanibicensis 20:276 Bioactivities 17:253 Bioassay 20:464 KB Bioassay 2:404,405,9:230,231,238,220-222 Bioconversion using Morus alba cell 17:470 Biofilms 17:100 Biogeneration of flavors 13:295-345 Biogenesis by intramolecular Diels-Alder reaction 4:616,618 Diels-Alder reaction in 4:615-617,620 of ()-16-hydroxy-a//o-ibogamine 6:503 ofacorene 3:30 ofalflavene 4:618,619 ofapparicine 6:520 ofbetaenone 4:620,621 ofbetaenoneB 4:621 ofcadlinolide A 9:9 ofcatharanthine 4:616 of cedranoid sesquiterpenes 3:29 ofchaetoglobocins 4:620 ofchlorothricholide 4:620 ofcompactin 4:620 of cyclostachine 4:618,619 ofcytochalasin 4:620 ofellipticine 6:520 of guggulu steroids 5:709-713 ofheliocideB 4:618,619 of ikarugamycin 4:620 ofilicicolinH 4:620 ofircinianin 4:618,619 ofmevinolin 4:620 ofngouniensine 6:503 ofnodusmicin 4:620 ofpyoverdins 9:552,553 of strellidimine 6:516 oftabersonine 4:616 ofthienamycin 4:620,621 oftubotaiwine 6:503 ofxenocoumacins 15:406-408 ofzoanthaminone 9:11 Biogenetic precursor ofallamandicin 16:301 ofplumericin 16:301 Biogenic amines 15:328 Bioinsecticides 15:381 Biological activities chiralityin 7:3-28 isolation of 4:243 of(+)-compactin 11:335,336 of(+)-mevinolin 11:335,336 of (-)-selin-l l-en-4a-ol 14:450,451 ofamicoumacins 15:410-412 ofavermectins 12:7-9 ofbaciphelacin 15:409,410 of Z)M-indolyl maleimides 12:384-399,133,91 of erythromycin 13:155-185 of indolo [2,3-a] carbazole alkaloids 12:384-399 of intermedeol 14:450,451 of ivermectin 12:8,9 of macrolactone 155-185 ofmicrocystins 20:896,897 of natural products 7:3-29 ofneointermedeol 14:450,451 ofnocamycin 14:110 ofnodularins 20:896,897 of PI turnover inhibitors 15:461,462 of polyene macrolides 6:261 of self-inhibitors 9:222,238 ofspatanediterpenoids 6:39 ofspatol 6:39 ofsphingolipids 18:459,460 of staturosporine 12:399 ofstreptolydigin 14:108,109 oftaxanes 11:4-6 oftaxodione 14:667 of tetramic acid 14:107-110 of tyrosine kinase inhibitors 15:447,449 ofxenocoumacins 15:408,409 Biological Diels-Alder reaction 17:451

962 Biological investigations of S'a/v/a species 20:659-715 Biological properties ofdidemnins 10:241-302 oflipo-gastrin 18:857-863 oflipo-CCK 18:857-863 Biological raw materials 17:601 Biological stereoselectivity 7:8-10 Biologically active compounds 17:153 Biomethylation 9:47 Biomimetic cationic polyene cyclization 12:456 Biomimetic cyclization of allylic alcohol 14:681-684 Biomimetic olefin cyclization 1:671-673 Biomimetic reaction 9:570,328 Biomimetic studies of oligopeptides 10:629-669 Biomimetic synthesis 20:408-410 of aromatic natural products 11:113-149 of(-)-hobartine 11:287-291 of bisindole alkaloids 13:404-407 from protoberberines 14:769-803 of benzo [c] phenanthridine alkaloids 14:769-803 oflupinamine 14:739-741 of g/7/-lupinamine 14:739-741 ofnitramine 14:748-750 ofnitraramine 14:755,756 ofnitrarine 14:761,762 ofbetaenoneC 4:620 ofdiplodiatoxin 4:620 ofmycotoxin 4:620 ofsolanapyrone A 4:620 of polycyclic terpenoids 6:23 of taondiol methyl ether 6:56 into pentacyclic alkaloids 11:292-295 of tetracyclic alkaloids 11:292-295 ofmacroline 13:398 Biomimetic polyene cyclisations 7:131 Biomphalaria glabrata 7:432-435 Biopolymers 17:481 Bioquercetin 7:226 Bioregulators studies with 2:377-386 chiral synthesis of 6:537-566 BIOSIS 19:758 Biosynthesis [2,3-a] quinolizine and its N-oxide 14:759 by aminoethyl phenyl ethers 2:378 enzymes for 2:365 from tetrahydrocorysamine 14:796 of 3,4'-anhydrovinblastine 2:372 of()-eremolactone 15:272 of(+)-aristolochene 15:250 of(+)-aristoteline 11:278,279 of(+)-isoeremolactone 15:272,273 of(-)-acetomycin 10:443 of (15 /?)-15-hydroxy catharinine 14:820,821 of(5)-nicotine 11:205-207 of 1,2,3,4,6,7,12,12b-octahydroindolo of 5-0-desosaminylprotylonolide 5:614,618 ofactinorhodin 5:617 ofacyltetramicacid 14:105,106 ofajmalicine 2:376 ofamylopectm 14:148 ofanhydrovinblastine 14:820,821 ofantabine 11:205-207 of antibiotics 11:207-213 ofaplasmomycin 11:207-209 ofarctiin 5:476 of Aristotelia alkaloids 11:278,279 of asparagine-linked oligosaccharides 10:499-502 ofaurantinin A 5:604-607 ofavermectins 12:6,7 ofaverufin 11:194 ofp-lactams 11:207-213 of benzo [c] phenanthridine alkaloids 14:771-773 ofbicyclomycin 12:64,65 ofbisabolanes 8:45 of branching in lactosaminoglycans 10:484,485 of carbohydrates 8:64 of Catharine 14:820,821 ofcatharinine 14:820,821 ofcathenamine 1:90-91 of cephalosporin-C 11:211,212 of cephalosporins 11:211-213 ofchimeramycins 5:614 of cholesterol 1:655 ofcholicacid 17:207 of cinnamic acids 5:468 of cis and trans sabinene 11:221,222 ofcorydalic acid methyl ester 14:796 ofdaunomycinone 11:123 of dihydrokomarovinine 14:763,764 ofelasnin 5:590 ofenniatins 13:535 ofepilupmme 14:738,739 of ergot alkaloids 11:199-207 of Forsythia lignans 5:489-492 ofglucoamylase 2:348-360 of glycogen 14:148 of glycolipids 1:417 of glycoprotein 1:417;14:148 ofglycosphingolipids 10:503 oflgD 10:539 ofIgM 10:539 of indole alkaloids 1:31,34,89-92 of indolocarbazole alkaloid 1:6 of ipomeamarone 15:249 of irumamycin 5:597,598,600,601 ofisonitrarine 14:760 ofkomarovidine 14:763,764 ofkomarovine 14:763,764 ofkomarovinine 14:763,764 ofkuwanon 17:465 of lactose 14:148 ofleurosine 14:820,821 ofleurosine 2:372 of lignans 5:459,474,477 of lignin 5:462-466 oflupinine 14:738,739 ofmellein 15:406 ofmicrocystins 20:899 ofmonolignols 5:467-469,607

963
of morphine 18:51-55 ofmyxopyronin 5:606 of naphthyridinomycins 10:104-106 of natural products 2:365 ofnazlinin 14:759 ofnitramidine 14:760 ofnitraramine 14:754,755 ofnitrarine 14:760,765 ofnodularins 20:899 oformosanine 14:738,739 of penicillins 11:211-213 ofpentalenolactone 13:30 ofphillyrin 5:476 of Podophyllum lignans 5:477-489 ofpolyketides 11:191-207 ofrebeccamycin 12:374 ofribostamycin 11:216-219 ofsaframycinA 10:80 ofschoberidine 14:760 ofschoberine 14:757,758 of seconday metabolites 20:291-293 of shikimic acid 11:182-191 of sinapyl alcohol 5:470 ofsparteine 14:738,739 ofstaurosporine 12:373,374 of strictosidine 1:90,91 of strychnon-type alkaloids 1:31,32 of sugar components of antibiotics 11:213 -222 of terpenoids 2:378 of thienamycin 11:210,211 of thiostrepton 11:209-211 of ubiquinones 8:63 ofvallesiachotamine 1:90,91 ofvindolinine 2:378 ofvineomycins 5:596 of vitamin E 8:63 of yohimbine 2:376 oxidative phenolic coupling in 20:291-293 via hypothetical enamine-aldehyde 14:796 de novo Biosynthesis 17-oxoellipticine 6:521 by cyclopropanone sliding reaction 6:37 from zeaxanthin (P,P-carotene-3,3'- diol) 6:139 of24-propylidenechlosterol 9:37 of acetylenic carotenoids 6:147,155,156 of allenic carotenoids 6:133,134,142 of allenic carotenoids 6:142,143 ofantheridiogens 6:206 ofapotrichothecenes 6:249,250 ofasterosaponins 7:299,302,303 ofbrafouefine 6:521 of C45 carotenoids 7:355-364 of C50 carotenoids 7:354-364 of Cephalotaxus diVi^dXoidiS 6:487 of cyclopropane sterols 9:35-43 of cyclopropene sterols 9:44-47 of eight-membered marine compounds 6:37 officisterol 9:40 offiisarins 6:250 ofgorgosterol 9:45-47 ofhebesterol 9:43 of homoerythrina alkaloids 6:487 ofisobrafouedine 6:521 ofleukotrienes 9:562,576 of lipoxms 9:561,575-578 ofnicasterol 9:43 of norterpene cyclic peroxides 9:23,24 ofpeptidoglycan 6:404 ofpetrosterol 9:41-43 of phenolic lipids 9:341,342 ofprotostephanine 6:480 of sambucinicacid 6:250,251 ofsambucinol 6:249,250 ofsterculicacid 9:45 of sulfidopeptide lipoxins 9:576 oftrichothecene 6:247-259 of vitamin B12 9:591,609 Biosynthetic precursors carotenoid 5,6-epoxides as 6:142 Biosynthetic retroanalysis ofnitraramine 14:754,755 Biosynthetic route of tropane alkaloids 17:314 Biotechnology 13:296,297,299 (+)-Biotin 13:514-516 synthesis of 13:514-516 Biotinylated gastrin 18:920 Biotinylated peptides 18:919 Biotranformations of indole-3-pyruvic acid 12:374 of substrates 2:386 studies of alkaloids 2:386 ofellipticine 6:509 of 24-difluoro-25-hydroxy-vitamin D3 9:517 Bipendensin from Afzelia bipendensis 9:256 Biperezone 20:273 3,3'-Biplumbagin 2:212,214,5:754 ' H - N M R spectrum of 2:227 Bipolaris sorokiniana 4:647;9:238 2,3'- Bipyridyl alkaloids 5:753 Birch reduction ofo-toluidine 11:286 of6-methoxy-l-tetralone 12:235 of4-methoxytoluene 12:22-24 of/7-cresyl methyl ether 6:83,84 BIRD sequence 9:97,98 12,12'- Bis (11-hydroxycoronaridyl) 5:129 3,4- Bis (8-hydroxyquinolin-4-yl)-butyrolactone 5:753 Bis (di-isoamyl) borane reduction 9:366 Bis (EDTA-DISTAMYCIN) phenoxazone 5:570 trans-2,5-B\s (methoxymethoxymethyl) pyrrolidine 10:412 double alkylation of 10:412 Bis (netropsin)-3,6,9,12,15-pentaoxahepta-decanediamideEDTA 5:570 synthesis of 5:570 Bis (trimethylsilyl) ethylene glycol 1,3-dioxolane formation 1:584 reaction with aldehydes 1:584 reaction with ketones 1:584 Bis (trimethylsilyl)-1,2-ethanedithiol 1,3-dithiolanesfrom 1:584

964
reaction with aldehydes 1:584 reaction with ketones 1:584 Bis allylic bromide 8:16 Bis indole alkaloids 2:370371,387,389,390,394,398 3'-Bis(2-cyanoethoxy) phosphoryl group branched RNA from 14:291,292 2'-Bis(2-cyanoethoxy) phosphorylation 14:299,302 Bis(bibenzyls) 2:103,2:113 2,5-Bis(dimethylamino) benzoquinone 13:434 Bis(trimethylsilyl) acetylenes 14:473 Bis(trimethylsilyl) butadiyne 14:473 Bis-(3,7-diisopropyl-l-azulenyl) ketone 14:340 Bis-(EDTA-distamycin) fumaramide 5:569 2,4-Bis-(trimethylsiloxy)-furan 13:451 Bis-diazoketone 6:546,547 intramolecular coupling of 6:546,547 2',4'-Bis-0-(2-methoxy ethoxy methyl)-4-(9-methyl7,8-dihydronogarene 14:87 ()-2',4'-Bis-0-(2-methoxyethoxymethyl)-7,8dihydronogarene 14:83,87 ()-2',4'-Bis-(9-(2-methoxyethoxymethyl)-7-con-0methylnogarol 14:88 Bis-THF acetogenins 17:270 Bis-THF structures 17:258 11(15->1), 11(10^9) Bisabeo taxane 20:80,107 5-Bisabolene 17:609 /?-a-Bisabolene 16:232 Bisabolene diterpenes 15:255-257 Bisabolene isoprenologues 15:277 -5-Bisabolene-8-(/?),(5)-epoxide (-)-(2/?,65',85,95)-2,8-dibromo-9-hydroxy-achamigrene from 6:62,63 glanduliferol from 6:63,64 Bisabololoxide derivatives 7:218 (-)-(R,E)- a-Bisabolone synthesis of 16:231 1-Bisabolones 8:39-44,46,48 Bisabolones absolute configuration of 8:39-59 biosynthesis of 8:44,45 relative configuration of 8:39-59 synthesis of 8:39-59 P-Bisabolon 20:6 Bisacnadinine 20:265 Bisanhydrobacterioruberin 20:601 Bisaryltetrahydrofiirans 17:325 Bisbenzylisoquinoline alkaloids 6:472,657,525 Bisbenzyltetrahydroftirans 17:330 Bisbrusatolyl esters 7:383,384 Bischler - Napieralski reaction 3:460,93,633,790;8:291 Bischler-Napieralski condensation isokomarovine from 14:763 komarovidine from 14:763 oftryptamine 14:763 with quinoline-5-carboxylic acid 14:763 Bischler-Napieralski cyclization 4:20,23,444 Biscyanopropylhenyl siloxane 9:456 Biscyclolobin 20:283 6,10-Bisdeoxyaucubin 7:465,466,474,476,477 Bisdesmosides 15:188 Bisdesmosides 7:155 selective cleavage of 7:155 Bisglutarylidene pentane from triphenylphosphoranylidene glutarimide 14:755 Bishopantholide 7:234 Bishopsolicepolide 7:234 cw-Bishydroxylation 4:162,165,182 Bisindole-type alkaloids (3/?)-ervafolidine 5:120 11 -demethylconoduramine 5:115 12,12'-bis (U-hydroxycoronaridyl) 5:121,129 14,15-dehydrotetrastachyne 5:121 16-decarbomethoxy-19'20'-dihydrovoacamine 5:114 16-decarbomethoxyvoacamine 5:114 19'-hydroxyervafolene 5:120 19'-hydroxyervafoline 5:121 19'-/?-hydroxyervafolidine 5:121 19'5-hydroxy-3-ep/-ervafolidine 5:121 19/?-hydroxytabemaelegantine B 5:117 20'S-19',20'-dihydrotabemamme 5:114 20R-1,2-dihydrocapuvosidine 5:114 205-1,2-dihydrocapuvosidine 5:114 3'-3/2/5-hydroxyvoacamine 5:117 3'-7?/5-hydroxy-7V4-demethylervahanine A 5:115 3'-i?/5-hydroxy-A^4-demethylervahanine B 5:115 3 '-/^'5-hydroxy-A^4-demethyItabemamine 5:114, 5:124 3 '-/?/5-hydroxytabemaelegantine B 5:117 3'-/2/5-hydroxytabemamine 5:114 3 -(2-oxopropyl)-conodurine 5:18 3 -ep/-ervafolidene 5:121 3-ep/-ervafolidine 5:121 3-methoxyltabemacelegantine C 5:118 3-oxo-conodurine 5:116 3 -R/S-hydroxy-16-decarbomethoxyconodurine 5:115 3 -/^5-hydroxyconoduramine 5:117 3-/2/5-hydroxyconodurine 5:118 aceedinine 5:112 aceedinisine 5:112 biomimetic synthesis of 13:404-407 bonafousine 5:122 capuvosine 5:114 conodurine 5:116 dehydroxycapuvosine 5:114 divaricatine 5:118 ervafolene 5:120 ervafolidene 5:121 ervafoline 5:120 ervahanine A 5:115 ervahanineB 5:115 ervahanine C 5:115 gabunamine 5:115 gabunine 5:115 hazuntiphylline 5:120,121 isobonafousine 5:122 isocapuvosine 5:114 moinogagaine 5:119 A'4'-demethylvoacamine 5:115 A'4-demethylcapuvosine 5:114 A'4-demethyltabemamine 5:113

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pandicine 5:118 pseudo-vobparicine 5:119 tabemaelegantinine A-D 5:175,118,129 taberaamine 5:113 tetrastachyne 5:121 tetrastachynine 5:121 voacamidine 5:116 voacamine 5:116 voacamine-7V4-oxide 5:119 vobtusine 5:120 Bisiridoids 7:443 Bisisodiospyrin 20:276 3,3'-Bisjuglone 20:276 Bisketene 4:349 26,27-Bisnorbrassmolide 19:263-265 26,27-Bisnortyphasterol 19:268 2',3'-Bisphosphoramidite 14:293 2,3'-Bisphosphorylated ribonucleoside 14:284-290 Bisstrictidine 5:140,141 7,7-Bistaxodione from Salvia montbretii 20:678 Bistetrahydrofliran 10:439,440 Bistratamide 10:243 Bistratenes A,B 10:243 BivittosideA 1-210,21 \ Bivittoside A,B,C and D 1:270;15:91 Bixaorellana 20:721,733,59 Blaberus discoidalis 9:488,489 Black vomit 1:679,680 Blackcurrant oil 13:659 Blainvillea acmella 5:728 Blakeslea trispora P-carotene from 7:320 trisporic acid from 7:320 BlasticidinH 4:241,243 Blasticidin S absolute configuration 4:242,243 biosynthesis of 4:243 synthesis of 4:243 (+)-Blastmycinone synthesis of 16:694 Blastodadiella emersonii 5:276 Blastocrithidia 2:298 Blastomyces dermatiditis 5:307 Blastomyces sp. 5:325,328 Blastomycin synthesis of 3:253 Blastomycinone synthesis of 3:253,254 Blastomycosis 2:422 Blattella germanica 6:53;9:488,489 Blatta orientalis 9:488,489 Blechert's construction 12:195 Bledius mandibularis 4:494 Bledius spectabilis 4:494 Bleekeria vitiensis 1:125 Bleekerine oxidation 1:125,158 Bleomycin 16:573;20:458 Blestrin 20:280 Blighia welwitschii 15:205 Block-type polysaccharides 14:248 Blood platelet-aggregation 16:373 Blumea malcomii 5:678 Bmy-41950 from Streptomyces staurosporeus 12:366,368 Boariol 18:743,752 A^-BOC (3/?,45)-statine from (3/?,45)-statine 12:480 BOC anhydride method 12:121 BOC fimctionality deblocking with TMSOT 4:91,92 A^-BOC-1-allo-threonine methyl ester 12:430 A^-BOC-2-amino alcohol 12:480 (i?)-A^-BOC-2-amino alcohols 12:435,436 with thionyl chloride 12:435,436 (5)-iV-BOC-amino alcohols 12:481 0-A^-BOC-amino benzaldehyde 18:163 (3/?,4/?,55)-iV-BOC-dolaisoleucine 12:486 A^-BOC-proline 19:54 A^-BOC-L-threonine methyl ester from methyl trans (4S,5/?)-5-methyl 3>-tert butoxycarbonyl-2-oxo-oxazolidme-4carboxylates 12:430 Boekman-Silver synthesis of(-)-p-gorgonene 6:18 Bohadschia argus bivittoside B,C from 7:270 Bohadschia bivittata bivittosides A, B, C and D from 15:91 Bohadschia graffei holothurins A,B from 7:269 holothurin A2 from 7:269 Bohadschia marmorata bivittoside B,C from 7:270 Bohadschia tenuissima bivittoside B,C from 7:270 Bohadschia vitensis bivittoside B,C from 7:270 Bolbostemma paniculatum (tu-bei-Mu) tubeimoside I from 7:143,144 Boletinus cavipes 20:26 Boletus edulis 5:289 Boll weevil pheromone 1:693 Bombesin-induced phospholipase C activity 15:447 Bombyx mori 5:832;19:647 Bonafousine 5:128 Bonanzin 7:226 Bone calcium mobilization (BCM) 9:514 9-Borabicyclo [3.3.1] nonane (9-BBN) 13:72 Borage oil 13:659 Boraginaceae 7:408 Borane-methyl sulfide complex 11:3 60 Boration 9:366-368 Borealosides A-D 15:71 Bormination of camphor 4:629,633,634,656,657 of camphor derivatives 4:629-632,633,634,636, 656-658 Bom-Oppenheimer approximation 2:155 1-Bomeol 10:52 Bomeol 9:530 (+)-Bomyl acetate 4:645,46,648 (+)/(-)-Bomyl diphosphate formation of 11:219-221

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from geranyl and neryl diphosphate 11:219-221 hypothetical mechanism of 11:219-221 Boromycin 5:377,414,11:207,208 Boron enolate of 3(/?)-3-hydroxybutanethioate 13:500 Boronic ester 11:409 Borophycin biosynthesis 19:588 Borrecarpin from Borreria capitata 11:278 Borreria capitata borrecarpin from 11:278 Boschnialactone 8:140,155-157;20:72,74,76;16:701 Bose reaction by 3-hydroxybutyric acid 4:440,441 by ketene-imine cycloaddition 4:440 in azetidinone formation 4:440,441 Botanical juvenile hormones 18:498 Bothriochloa bladhi eudesm-ll-en-4-olsfrom 14:450 (+)-intermedeol from 14:450 neointermedeol from 14:450 Bothriochloa glabra eudesm-1 l-en-4-ols from 14:450 (+)-intermedeol from 14:450 neointermedeol from 14:450 Bothriochloa grasses intermedeol from 14:450,451 neointermedeol from 14:450,451 Bothriochloa insculpta eudesm-1 l-en-4-ols from 14:450 (+)-intermedeol from 14:450 neointermedeol from 14:450 Bothriochloa intermedia eudesm-1 l-en-4-ols from 14:449- 451 intermedeol from 14:450,451 neointermedeol from 14:450,451 Botryosphaeria obtusa 15:383 Botryotiniafuckeliana 12:400 Botrytis 4:246 Botrytis cinerea 5:598 Botrytis fabae 2:434 3 (-)-P-Bourbonene synthesis of 16:702-3 (-)-P-Bourbonene 10:405,406 Bovvardia ternifolia bouvardins from 10:640 Bouvardins from Bovvardia ternifolia 10:640 Bovine insulin molecular ion region 2:45 Bovine serum albumin (BSA) 7:114,115 Brachyponera sennaarensis 5:224,225,254 Brackenridgea zanguebarica 7:408 Bractazonine 6:478,487,270 Bradykinin 9:296,298 from Rana nirgomaculata 9:296 from Rana temporaria 9:296 Brafouedine biosynthesis of 6:521 from strychnos dinklasgei 6:503 spectral data of 6:503-506 Brafouedine 9:172 8-Bramodesoxypicropodophyllin 18:593,596 Branch-point specificity ofglycohydrolase 7:32,33 Branched amino sugars synthesis of 10:421 Branched chain nucleosides synthesis of 4:254-257 Branched decarbonucleotide [CpUpUpA(2'-pGpUpG) pUpCpA] 14:299,302 synthesis of 14:299,302 Branched hexaribonucleotide synthesis of 14:291,292 C-Branched nucleoside analogues stereoselective synthesis of 19:511-547 Branched oligoribonucleotides synthesis of 14:283-303 Branched RNAs synthesis of [A(2'-pX)pX] 14:293 synthesis of [A(2'-pY)pX] 14:293 synthesis of [A(2'-pU)pU 14:293,294 synthesis of [CpUpA(2*-pGpU) pUpC] 14:299,301 synthesis of 14:284-303 via 3'-bis(2-cyanoethoxy) phosphoryl group 14:291, 292 via 2',3'-bisphosphorylated ribonucleoside unit 14:284-290 via phosphoramidite approach 14:293,294 Branched tetrasaccharide synthesis of WA16A11 Branched triribonucleotide synthesis of [A(2'-pA)pA] 14:294,295 synthesis of [A(2'-pG)pC] 14:289,290,297-299 synthesis of [A(2'-pG)pU] 14:290,298-300 synthesis of [A(pG)pC] 14:289,290 synthesis of [araA(2'-pU)pU] 14:294 synthesis of [GpA(2'-pG)pC] 14:295-297 synthesis of [pA(2'-pA)pA] 14:294,295 synthesis of [pppA(2'-pA)pA] 14:294,295 synthesis of [U(2'-pA)pU] 14:296,297 Branched trisaccharide synthesis of 10:476,477 Brasilane sesquiterpene from Laurencia implicata 18:633 from Laurencia obtusa 18:625 Brasilenol by a-dimethylation 6:8 by Wacker oxidation 6:6 from Aplysia brasiliana 6:6,249 from brasilenone 6:7,8 from Laurencia obtusa 6:6 synthesis of 6:6,7,625 ep/-Brasilenol from Aplysia brasiliana 6:6 from Laurencia obtusa 6:6 synthesis of 6:6,7 Brasilenol acetate from Aplysia brasiliana 6:6

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from Laurencia obtusa 6:6 synthesis of 6:6,7 (+)-Brasilenol 6:7,8 stereoselective reduction of 6:7,8 Brasilenone 6:7,8 Brasiliensoside 15:55 Brassica compestris L. 19:246 Brassica napus 18:495,498;19:245 Brassicasterol from canola oil 16:324 Brassinolide plant growth promoter 16:321 from Brassica napus 18:495 biological activity of 19:245,281 chemical structure of 19:245 isolation of 19:245 plant growth promoters 19:245 structure-activity relationship of 19:281 Brassinone 18:500 Brassinosteroids antiecdysteroid activity of 16:321 application of 19:242-287 biological activity of 19:473 biosynthesis of 19:283 construction of side chain of 19:245-287 from Brassica napus 19:473 isolation of 19:473 metabolism of 18:520-533 stereoselective synthesis of 16:321-364 structure novelty of 19:473 synthesis of 19:245-287 Brassinosteroid biosynthesis 18:520 Brassinosteroid metabolites 18:534-546 Braun homogenizer 19:692 Brazilin 20:777,780 Bredereck's reagent 8:262,316 Bredius mandebularis 1:684 Bredius spectabilis 1:684 Bredt'srule 12:72 Brefeldin A 8:140,149 e^Brefeldin A synthesis of 8:149;16:304 Brenzcatechin 15:328 Brettanomyces anomalus 5:283 Brettanomyces bruxellensis 5:283 Brettanomyces dublinensis 5:283 Brettanomycesmyces lambicus 5:283 Brevetoxin synthesis of 10:227-231 Brevetoxin A 10:208 Brevetoxin B 10:201,203-205 (+)-Brevianamides A and B 17:475 Brevibacterium ammoniagenes 20:32 Brevibacterium divaricatum 6:385 exo-Brevicomin enantioselective synthesis of 1:637 ejco-Brevicomin from Dendrocotonus brevicomis 11:413 synthesis of 11:413,414 Brevicomins 13:328 Brevifoliol 20:100 Brickellia veronicaefolia 5:680 Brickellin 5:673-677 2,6-Bridged 3-benzazocines in benzomorphans 6:471 Bridged bicyclo [4.2.2] ring system 12:65 Bridged C-disaccharides 10:367 from a-methylene lactones 10:367 Bridged systems 6:65-87 Bridgehead carbanion alkylation 12:89 a,a-Bridgmg reaction 8:205,206,208-210,212,214 Brine shrimp lethality bioassay of 9:385,387-400 Brine shrimp toxicity of Goniothalamus giganteus 9:395 Broka's synthesis of(-)-pseudopterosin-A 6:74,75 Brominated compounds amides 17:84 diphenylether 17:9 phenols 17:81 phenylether 17:9 Brominated terpenoids 6:24,56 Bromination 3-bromo-levoglucosenone 14:269 chemoselective 19:314 Hoye's 1:672 of (+)-3,3-dibromocamphor 16:135 oflevoglucosenone 14:269 withNBS 19:314 Bromination-dehydrobromination sequence 12:237 Brominative cyclization in brominated terpenoids 6:24 in glanduliferol synthesis 6:63,64 of(8i2/5',9/2/5)-8-brome-9-hydroxy-()-bisabolene 6:62,63 Brominative rearrangement 4-Bromo-azetidmone 4:474 Bromine addition 16:336 Bromlactonisation ofbromolactone 8:301 of (4S)-3-methylmuconolactone 8:300,301 6-Bromo-2-lithio-6-methyl-2-phenyl heptane 8:6,7 2-Bromo-3,3 -diethoxy-1 -propene from 2:36 2-lithio-3,3-diethoxy-l-propene from 12:36 5-Bromo-1,2-dihydroacronycine 20:789 9-Bromo-3-gf/o-methyl camphor acid catalysed rearrangement 4:630,631 reactivity towards bromination 4:629 3-eflfo-Bromo-3-ex:o-methyl camphor 4:657,658 2-Bromo-3-hydroxybutyric acid 4:473-475 /rflr5-5 -Bromo-4-methoxy derivatives as 2-amino alcohol synthon 12:418-421 diastereselectivity of 12:419-421 from 3-acyl-2-oxazolone 12:418,419 from 3(15)-ketopinyl-2-oxazolone 12:419-421 7-Bromo-6,8-dihydroxy-3-propyl-3,4-dihydroisocoumarin 15:386 9-Bromo-6-e^o-methylisofenchone 4:630,631,635 synthesis of 4:630,631 (8i^5',9/?/5-8-Bromo-9-hydroxy-(E)- y-bisa bolene 6:62,63 a-Bromo-a-arylacetic acid synthesis of 6:321

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10-Bromo-a-chamigrene from geranyl acetone 6:60 from Laurencia species 6:60 synthesis of 6:60 (+)-2-Bromo-p-chamigrene from Laurencia pacifica 6:63 1-a-Bromo-desoxypodophyllotoxin 18:598 1 -P-Bromo-desoxypodopliyllotoxin 18:598 3 -Bromo-levoglucosenone from levoglucosenone 14:269 6-Bromo-Nb-methyl-Nb-formyltryptamine 18:691,726 {E)-2> -Bromoacry lates synthesis of 8:150,151 p-Bromoacrylates 8:141 7-/7-Bromoanilino-7-demethoxy mitomycin X-ray crystal structure of 13:434 2-Bromoapotrichothecene 6:234 11-Bromobenzoate of ll-hydroxycanthin-6-one 7:389 X-ray analysis of 7:389 N-ip- Bromobenzoyl) palytoxm 5:391,393 (-)-6-Bromocamphor 16:148 8-Bromocamphor synthesis of 4:640,641 ;16:135 (+)-9-Bromocamphor 16:128 9-Bromocamphor 16:133 (+)-5-Bromocamphor 16:144 (+)-10-Bromocamphor from (+)-3,3-dibromocamphor 4:628,629 {+)-endo-3 -Bromocamphor acid catalyzed rearrangement of 635,643 bromination of 4:656,657 sulphonation of 4:628,633,634 (+)-9-Bromocamphor 4:633-635,657,658 (+)-gflfo-6-Bromocamphor from (+)-a-pinene 4:644 (+)-e:xo-5-Bromocamphor synthesis of 4:646 (+)-3-Bromocamphor-8-sulfonic acid salt 12:279 (Z)-3-Bromo-cinnamate 20:789 Bromocarbenoid procedure 1:263 Bromocarbenoid ring expansion 1:263 Bromochamigrene by spiroannulation 6:60,61 by Wittig reaction 6:61 from cyclohexanone aldehyde 6:61 from Laurencia majuscula 6:60 from phenolic a-diazoketone 6:60,61 synthesis of 6:60-62 Bromoconduritol B epoxide with P-glucosidase 7:38,39 Bromoconduritol F with P-glucosidase 7:38,39 Bromocryptine 13:658 2-Bromocyclohedxanone 12:247 a-Bromocyclohexenones hydroindolenones from 4:18,19 2-Bromocyclopentenone 10:48 8-Bromodesoxypodophyllotoxin 18:593,595 Bromodilactone absolute configuration 8:301 X-ray analysis of 8:301 relative configuration of 8:301 Bromohydrin formation 1:523 Bromolactonization 3:265,336-339,177 Bromomesylate 19:229 O- Bromophenacyl okadaate 5:389 Bromoperoxidase 19:454 /7-Bromophenylboronate derivative 8:19 2'-Bromopodophyllotoxin 18:576 Bromopuupehenone 15:299 2-Bromopyridine 2-pyridine carboxaldehyde from 6:312 Bromorebeccamycin ^om Saccharothrix aerocolonigenes 12:366,368 (-)-Bromothebaine 18:87 Bronchodilators 5:759 in treatment of asthma 5:759 Brook-Rubottom-Hassner oxidation ofenolsilane 12:25,26 Brosimones 17:456 Brosimopsis oblongifolia 17:456 Broussonetia kazinoki 2:233,752 Broussonetiapapyri/era 2:233,752 Broussonetia zeylanica alkaloids of 2:231,246 Broussonetine 2:242,244-246 Broussonetine 5:752 Brown's crotylboration 18:280 Brownioside 15:191 Broxil 17:616 Bruccantin 5:39-41 Brucea antidysenterica quassinoids from 7:374-376 Brucea javanica bruceoside-A from 7:371 bruceoside-B from 7:377 quassinoids from 1'311-2>19 Brucea sumatorana 7:391 Bruceantarin 7:374 Bruceantin 7:369-374,383,386-388,391,392,396,398, 71-73,79-95,654,657 Bruceantin-4,5-epoxide 7:388 Bruceantin-5*-ol 7:388 Bruceantinol 7:374,375,392 4,5-Bruceantinolefin 7:388 Bruceantinoside A-C 7:375-377 BruceinA 7:378,392,394-396 BruceinB 7:392,395,396 Brucein C 7:375,388,394,396 BruceinD 7:377,391,392,397 Bruceolide 7:371,391,392,392 15-[()-non-Z-enoyl]Bruceolide 7:395 Bruceoside-A from Brucea javanica 7:371 Bruceoside-B from Brucea javanica 1'311 Brucine 9:189 Brugierol 7:193,194 Brugine 7:191,192 Bruguiera conjugata 7:193,194 Bruguiera cylindrica 7:176,193,194 Bruguiera exaristata 7:191 Bruguiera gymorhiza 7:176,180-182,188,195

969
Bruguiera parviflora 7:180,195 Bruguiera sexangula 7:176,191 Bruguiera sp. 7:176 Brusatol 7:377,383,387,392,394,397,79,11:80 Brusatolyl ester 7:377,383 Bryonia alba 20:13 Bryonia dioica 15:24;20:13 Bryonoside from Bryonia dioica 15:24 Bryophytes sesquiterpenes of 20:468 Bryophytes 2:277 Bryoside from Bryonia dioica 15:24 Bryostatin as anticancer drugs 19:550,572 biochemical aspects of 19:572 chemistry of 19:572 in clinical trials 19:550 pharmacological aspects of 19:572 Bryostatin A and B 18:716 Bryozoans taxonomy of 17:74 Bryum argenteum I'.lll BSA (Bovine serum albumin) 7:114,115 Buchi's intermediate 1:68 Buchi's synthesis 14:868,869 Buddleja davaidii buddlenol A from 20:644 Buddlenol A from Buddleja davidii 20:644 Bufo regularis 2:310,804 Bufogenins 15:328 Bufotenidin 15:328 Bufotenin 15:328 Bugula dentata 17:88 Bugula neritina 5:394,395,153,75,77,89,92, 18:715,716,573-574,576 Bugula trubinata 17:102 Bugula turrita 17:80 Bugularia dissimilis 17:95,101 "Built-in auxiliary" 14:552 ()-Bulbocapme 16:509 Bulgarane 15:247 (-)-Bulgecinine 16:706-707 Bulgecinine 14:193 Bulinus 7:426,432 Bulinus globosus 7:432,434 Bullatacin 9:396-398,252,266,271-272 Bullatacinone 9:396-398,266,278 Bullatalicin 9:397,398 Bullerasp. 5:291 Bulleyanin 15:119,126,133,171 ()-a-Bulnesene synthesis of 14:364,365 Bulnesol 1:545 (^/)-Bulnesol 10:310,311 ()-Buhiesol 14:364,365 Bungarotoxins 18:698 Buntanin from Citrus grandis 13:350 Bupaluspiniarius 4:566 Buphanisine asymmetric synthesis of 4:14,15 from AmarylHdaceae 4:3,4 synthesis of 4:13-17 Bupleurum fruticosum 17:117,127 Burchellin synthesis of 8:160 Burgess reagent 1:257,16,50,53,601,232,296 Bumell synthesis oftaxodione 14:685,687-689 Bursaphelenchus lignicolus 12:398 Bursehemin 18:554,556 Bursera ariensis 17:317 Bursera microphylla 17:330 Bursera schlechtendalii 18:556 Burseraceae 18:558;17:370 Burseran 17:330 Bush beans 9:393 (Z)-But-2-ene-1,4 diol 6:116 l-But-3-enyl-5-hydroxy-5-methyl-pyrroldin-2-one with//'a5-7-fromyloxy-8a-methylindolizidme 12:289 Butadiene trans- cyclohexenecarboxylic acid from 11:340, 11:341 (5)-Butan-l,2,4-triol from (5)-malic acid ester 6:287,289 Butanal 9:338,339 (2/?,3/?)-2,3-Butanediol olefinic dioxolane acetal from 14:471 (2/?,3/?)-2,3-Butanediol benzaldehyde acetal from 14:477 {R,/?)-2,3-Butanediol [(1S)-1 -chloroalkyl] boronates 11:412 (2R,3R)-2,3-Butanediol acetals/ketals 1:591,593 (/?,/?)-2,3-ButanedioI esters 11:412 (2R,3R)-2,3-Butanediol 1:639 Butanolides 6:295-297 19'-Butanoylfticoxanthine 6:134,135,138-141 Butenolide synthesis of 11:453 biosynthesis of 6:252 from butanolides 6:295,296 from glutamic acid 6:252 synthesis of 6:295,296 Butenylation 12:458 ()-2-Butenyldiisopinocampheylborane 13:135 3-Butenylmagnesium bromide 12:29,30 {S)-trans-y-B\AQnyny\ (GABA) synthesis of 14:473 A^-rer^Butoxycarbonyl-I-alanyl-Z)-isoglutamine methyl ester 6:410 A^-rerr-Butoxycarbonyl-I-alanyl-D-isoglutamine benzyl ester 6:409,410 A^-rer^Butoxycarbonylation 12:478,479 t-Butyl acetate Claisen condensation of 11:127,129 lithiated 11:127,129 with naphthalene glutarate 11:127,129 r-Butyl anthraquinone ^^0-NMR spectrum of 17:561

970

tert-Buty\ ester of disaccharide dipeptides 6:413-415 /-Butyl hydroperoxide 12:323 /er/-Butyl hypochlorite addition to olefins 1:451 cyclization with 1:11,12 tert-Buty\ tin hydride reduction of chlorides 1:443,444,451 reduction of dithiocarbonate 1:452,453 (25',5/?)-cw-5-Butyl-2-heptylpyrrolidine from pyroglutamic acid 6:438-349 synthesis of 6:438-440 c w-5-Butyl-2-heptylpyrrolidine from glutamic acid 6:438 synthesis of 6:438,439 trans-5 -Buty 1-2-hepty Ipyrrolidine from glutamic acid 6:438,439 synthesis of 6:438,439 (25,55)-/ra5-5-Butyl-2-heptylpyrrolidine /-Butyl-5-chloro-3-oxopentanoate 8:268 3 -Buty 1-5 -methy loctahydroindolizidine as (monomorine I) 6:445,447 from 2,6-lutidine 6:445,447 synthesis of 6:445 t-Butyl-A^-chloro-A^-argentocarbamate 12:219 2-Butylamino-tetrahydro P-carboline 14:759 4-/er/-Butylcatechol 14:617 iV-Butyldeox-nojirimycin 10:528 2-/er/-Butyldihydroxyoxazole 2-amino alcohol by 12:411,413 electrophilic addition to 12:411,413 /gr/-Butyldimethyl silyl ether 6:264,268;11:339;12:282 /^//-Butyldimethylsilyl (TBDMS) group 4:299,304 /^//-Butyldimethylsilyl ketene acetal 1:465 /gr/-Butyldimethylsilylation 6:119,120 8-O-r-Butyldimethylsilyldehydrononactate 18:242 /gr/-Butyldimethylsilyldehydropodophyllotoxin 18:565 ()-8-0-/er/-Butyldimethylsilylnonactate 18:242 /gA-Z-Butyldimethylsilylpicropodophyllin 18:564 rgr/-Butyldimethylsilylpodophyllotoxin 18:563 /grZ-Butyldiphenylsilyltrifluoromethanesulfonate 1:707,708 7V-I-Butyldiphenylsilyl-S-benzyl-S-methylsulfoximine 10:686-688 /-Butylformamidines 6:430,431 2-(t-Butylimino)-2-[(diethylamino)]-1,3dimethylperhydro-1,3,2- diazaphosphorine 12:342 Y-Butyrolactone 16:687-726 Butyrolactones 3:252-225 Butyrospermol 9:288,289,301 n-Butyryl CoA in Streptomyces cinnamonensis 11:197 mterconversion of 11:197 stereochemical 11:197 Butyryl-CoA dehydrogenase 20:835 6-0-Butyrylcastanospermine 12:332 (+)-Buxabenzamidienine 2:185,186,204,205 (+)-Buxabenzamidine 2:192 structure of 2:192 Buxamine - A 2:205 Buxaminol-B 2:205 Buxamine-C 2:205

Buxaminol-E 2:205 (+)-Buxaminol - G 2:183,184 (+)-Buxaminone 2:201,202,204 (+)-Buxanaldinme 2:188,2:189 (-)-Buxanoldine 2:187,204 (-)-Buxapapinolamine 2:190191 (+)-Buxaprogestine 2:199 (+)-Buxaquamarine 2:178,2:179,205 Buxatine 2:205 Buxenine-G 2:205 Buxenone 2:207 Buxocyclamine - A 2:207 (+)-Buxupapine 2:189,205 5MXM5 alkaloids 2:175,205 Buxuspapilosa 2:175

C(l)-glycosides 10:383 3-C-(a-cyano-a-ethoxycarbonyl) methylene derivative 10:412 2-C-(formyl) methyl derivative 10:418 3-C-(hydroxymethyl) methylene derivatives 10:428, 429 5-C-(hydroxymethyl) methylene derivatives 10:433, 434 Cacaliahastata 19:149 Caesalpina braziliensis 19:776 Caesalpinia pulcheriime 20:475 Callinectes sapidus 19:647,672 Camellia sinensis 20:735 Campesterol 20:234 Camphor 20:16 (+)-Camphor 19:229;20:586 D-Camphor-10-sulphonic acid 19:139 Camphoric acid 20:586,597 mt/^-Camptothecin 20:465 Camptothecin 20:500 Canadensene from T. canadensis 20:107 Canadensolide 19:463 (-)-Canadensolide 19:485 Canavaline 20:486 Cancer chemotherapeutic agents 20:507-511 Cancer chemotherapy 20:460,461 Candida albicans 19:578;20:712 Candida yeast 20:868 Candida lactone 20:474 Candidissiol from Salvia candidissima 20:680 Cannizzaro reduction 19:536 (-)-rra5-Cannabidiol dimethyl ether 19:187 Cannabifiiran 19:194 Cannabinoid 19:185-244;19:203 Cannabinoid receptor (CBi) 19:186 Cannabinoid skeleton retrosynthetic disconnection of 19:186 Cannbidiol synthesis of 19:205 Cannabis sativa as an intoxicant 19:186 Cantharellus cinnabarinus 20:721 Canthaxanthin 20:576,725,749

971
Capsanthin 20:726,733,757 Capsicum annuum 20:586 Capsicum frutescens 20:135 Capsorubin 20:568,586,726,77 (+)-C-2'-ara-fluoroguanosine antiviral activity of 10:609 C-acetylenic hexopyranose 10:374 3-C-Alkyl-enitols 10:344,345 C-alkylation 10:412 Carbamoylmethylviologen 20:867,869 Carbonylation palladium catalyzed 19:189,195 20-Carboxaldehyde 19:471 Carboxyatractyloside 20:8 Carcinogenesis 20:512,513 Carcinus maenas 19:628 (+)-/ra5-Carene epoxide 19:204 Carissa edulis 20:619 P,P-Carotene 20:561,564,571,572,576,584,604,607 (6'R)-P,8-Carotene 20:584 a-Carotene 20:584,721,725 P-Carotene 20:720,721,725,732,735,746-748,760 y-Carotene 20:721,725 Carotenoids 20:561,725,732,745 (+)-Carvone 20:69,70 C-aryl glycoside stereoselective synthesis of 10:370 C-arylglycals by palladium catalyzed coupling 10:344 synthesis of 10:344 (+)-Carvone 20:69,70 Caryophyllene oxide from Salvia sclarea 20:660 Cassane skeleton 19:395 Cassia leptophylla 20:486,487 Castanea crenata 19:246 Catalytic hydrogenation 19:77 Catalytic reduction 19:76,91 Catharanthus roseus 19:246 Cavinton 19:89 C-C bond formation 6:307-349 A^-Cedrene 19:136 Celastrus paniculatus 20:521 Celuxpipens 19:481 Cephalomannine 20:81 ()-Cephalotaxine 19:141 Cephalotaxus s^QCiQS 19:141 Cepharadione A and B 20:481 Cerberalignan A 20:273 a-D-C-glucopyranoside 10:383 C-glucopyranosides 10:346 a-C-glucosides 10:365 a-C-glycopyranoside from phenyl 4,6-di-O-benzy 1-2,3-dideoxy-Derythro-h.Q\-2- enopyranoside 10:354 regioselective synthesis of 10:354,355 stereoselective synthesis of 10:354,355 1-C-glycopyranosides 10:344 C-glycopyranosides by Diels-Alder cycloaddition 10:351 C-glycopyranosyl-a-aminoacids synthesis of 11:470-472 C-glycosidation 10:345 C-glycosidation regioselective 11:140 stereoselective 11:140 C-glycosides aluminated heterocycles 10:369 by coupling of glycopyranosyl-fluoride and enol silylether 10:340 by Lewis acids assisted condensation 10:370 by manganese pentacarbonyl complex 10:364 by Michael addition 10:353 by radical addition of 10:375,376 by radical allylation 10:380 by reduction with EtaSiH/BFs 10:388 by silylation addition 10:379 by Wittig condensation 10:392 by Wittig reaction 10:391 from 2,3,4-tri-O-benzyl-1,6-anhydro-D-glucose 10:377,378 from acylated glycos-2-ulosyl bromide 10:363 from anhydro-glycosides 10:377,378 from carbohydrate lactones 10:385 from glycosylhalides 10:355 from hex-l-enopyran-3-ulose 10:353 from O-acylglycosides 10:370 from phenyl thioglycosides 10:380 from pyranosyl 0-methyl glycosides 10:379 from sugars 10:388-394 from tetra-O-benzyl fluoroglucose 10:368 from a-fiiranosyl glycosides 10:379 reaction with R (PhS) CuLi 10:352 stereocontroUed synthesis of 10:378 stereoselective synthesis of 10:352,376 synthesis of 10:337-403 with P-configuration 10:420 P-C-glycosides by Lewis acid assisted condensation 10:370,371 by reaction of tri--butyl stannyltriflate 10:381 from acetobromo glucose 10:364 from peracetyl glucal 10:347 from phosphonate sulfone 10:391 from tetra-O-acetyl-a-D-glucopyranosyl bromide 10:362 from p-tri--butyltin glycosides 10:384 withEt30BF4 10:338 with LiAlH(0Et)3 10:338 a-C-glycosides by condensation of methylallyl tri--butylstannane 10:381 by condensation with ftiran 10:377 by reaction of acyl ester 10:371 from pyridyl thioglycoside 10:382 from a-tri--butyltin glycoside 10:384 stereoselectivity of 10:371 with allyltrimethylsilane 10:371 P-Z)-C-glycosides from 3,4,6-tri-0-t-butyldimethylsilyl-2-deoxy D-glucopyranosyl phenylsulfone 10:383,384 C-glycosidic naphthalenediol (+)-urdamycinone from 11:142 C-glycosyl compounds by catalytic siloxymethylation of 0-acylglycosides

972

10:373,374 by reaction with HSi R3/CO/Co2(CO)8 10:373,374 C-glycosyl-oxirans from acetobromoglucose 10:361 C-glycosylarenes by reaction of benzoylated 0-alkyl glycosides 10:380 C-glycosylation of aromatic ring 10:387 of heterocyclic ring 10:387 C-glycosylcyanides from acylated bromosugars 10:355 synthesis of 10:355 Charybdis japonica 637 Chemical classification ofwithanolides 20:136-139 Chenopodium ambrosioides 20:12 Chenopodium anthelminticum 20:12 Chiloscyph-2,7-dione 20:473 Chiloscyph-2,7,9-trione 20:473 Chiloscyphus rivularis 20:472 Chiloscypone 20:473 Chiococca alba 175 Chiral synthons by selective redox reaction 20:817-881 Chlidanthine 20:359 Chlorination 19:61 (23/?)-6a-Chloro-5P, 17a-dihydroxy-12P-methoxy-1 oxo-12,22-epoxy-ergosta-2,24-diene-23,26-olides 20:242 (Z)-3-Chloro-butenoate 20:830 (Z)-3-Chloro-cinnamate 20:830 9-Chloroacronycin 20:792 Chlorophylls 20:760-762 Chlorophylls a,b,c 20:728 6-Chloropyridine-3 -carboxy late to 3-hydroxymethyl-6-chloropyridine 20:864 Chloroquine 20:517,518 Chlorotrimethylsilane 19:445 Chlorowithanolides 20:223 Cholest-5-ene-24-one-3 P,7a-diol 20:477 Cholest-5-ene-24-one-3 P,7P-diol 20:477 Cholest-5-ene-3 p,7a,diol-1 -oxo from Salvia glutinosa 20:707 5a-Cholestane 20:248 Chosenia arbutifolia neolignans from 20:640 sesquilignans from 20:640 Chromenes 20:282 Chrysanthemum golden 20:246 CIDMS/MS 19:643 Cinachyra sp. 19:581 Cinachyrolide A 19:580 Cinnamicacid 20:271 Cu-sitiol from Salvia montbretii 20:712 Cistrus hirusutum 19:246 Citral 20:5 Citranaxanthin 20:606,607,757 P-Citraurin 20:757-759 (/?)-(+)-Citronellal 19:215 (/?)-Citronellol 19:43

Citrullus colocynthis 20:13 CitrusinB 20:697 Cladosporium herbarum 20:245 Claisen condensation 19:35;20:740 Claisen disconnection 19:228 Claisen rearrangement 19:229;20:66,67 Clavulones 19:551 Cleistanthane skeleton 19:395 Clematis hexapetala 19:125 Clematis sinensis 20:539,540 Clemmensen-type deoxygenation 19:18 Clerodendron inerme 20:539,540 C-linked glycosyl acetylenes from glycosylhalides 10:358 Clitocybe acromelalga 19:163 Clivia miniata 20:351 3-C-methyl-3-deoxy-2-ulose derivative 10:414,415 C-methy 1-C-acetoxymethyl derivative 10:415 C-methylated hexopyranose 10:414,415 C-nitromethylene derivative 10:412 3C-nucleosides 10:337,338,355,358,388-394 Clostridiumformicoaceticum 20:821,824,861 -862,867, 869,870,871,873-879,881 Clostridium kluyveri 20:821, 824,831,834 Clostridium thermoaceticum 20:821,824,861-863,867, 869,870,871 Clostridium tyrobutyricum 20:821, 824,829,830,834839,863,873-877 Cochineal 20:729,734,768-771 Coelenterates 19:549 Coffein 20:6 Coleus forskohlii 19:137 Collins oxidation 19:320,334,467 Collision-induced dissociation (CID) 19:643 Colon 26 carcinoma 19:609 Colourants 20:719-783 Complete freunds adjuvant (CFA) 19:702 Compositae 19:149,19:389 a-Conidendrin fromTaxusmariei 20:108 (-)-a-Conidendrin 20:620 Cooxidants 19:270 Corey reagent 19:452 Cortex eucommia 20:646 Corticosteroids 20:531 Corynebacterium poinsettiae 20:594 Costunolide 20:471,472 Cotton effect 19:259 Coumarins 20:283,497 3P-0-c-Coumroylmonogynol A from Salvia montbretii 20:704 3p-0-/raAw-/7-Coumroylmonogynol A from Salvia montbretii 20:704 Coupling reaction 20:566 C-prostaglandins synthesis of 16:367-368 CPT-11 20:458 C-pyranosides synthesis of 10:340 Cram's product 19:471,476 Cram selectivity 19:473 Cram's chelation model 19:320,482

973 Crescentia cujeta furanoaphthoquinones from 20:494 p-C-ribofuranoside 10:376 Crinine 20:325,20:351,20:353,20:369,20:384 Crinitol from Cystoseira crinita 20:25 from marine algae 20:25-37 from Sargassum tortile 20:26,20:27 Crinum oliganthum 20:234 mesembrenol from 20:234 Cristacarpin 20:496,20:497 Crocetin 20:726 Crocetindialdehyde 20:568,20:572 Crotalaria species 19:499 Crotonoil 20:19 Croton tiglium 20:19 Crotonate 20:836 Crustacea 19:627 Crustecdysone 19:463,627 Cryptanol from Sahia candidissima 20:661 Cryptocarya caloneura 19:481 Cryptojaponol from Salvia napifolia 20:670 Cryptolestes ferrugineus 19:154 Cryptomeriajaponica 19:246 a-Cryptoxanthin 20:727 Crysoeriol from Salvia candidissima 20:712 C-S bond 6:307,308 heterolytic dissociation of 6:307,308 homolytic dissociation of 6:307,308 C-sucrose 11:469,470 synthesis of 11:469,470 ^^C-INADEQUATE 9:143-146 ^^C-NMR incremental effects of 9:275-280 of a-pipitzol benzoate 5:787 of(+)-l-acetoxypinoresinol 5:533,534 of(+)-l-fraxiresinol 5:535 of(+)-l-hydroxypinoresinol 5:534 of(+)-ejp/-pinoresinol 5:526 of(+)-pinoresinol 5:526 of 10-demethoxykopsidasinine 5:52,54 of 11-O-methylcaesalpin 5:24 of 13-6/7/-11 -0-methylcaesalpine 5:24 of2'-hydroxyflavone 5:4 of2'-methoxyflavone 5:14 of4-hydroxy-sapriparaquinone 5:36 of6-isocedrol 5:789 ofacteoside 5:507 of alloaristoteline 11:314 ofaquillochindiacetate 5:9 ofarguticinin 5:203 ofargutinin 5:203 of aristolasicone (aristotelin-19-one) 11:314 ofaristoteline 11:314 ofartemisinin 5:24 ofberberine 5:42,44 ofbruceantin 5:39 of cadabicine methyl ether 5:210 of caratuberside A 5:212,213 ofcaratubersideB 5:213 ofcedranolides 5:785 ofcedrene 5:789 of colchicine 5:47-49 of cyanocycline A 10:106,107 ofdecitol 4:183 of dendropanoxide derivatives 2:102 ofdenticulatin 5:21,212 ofeupatorenone 5:30 offlavone 5:14 offorsythiaside 5:509 ofgalactomannan 5:303 ofginamallene 5:369,370 ofglucan 5:311 ofguaiacinA 5:200 ofguaiacinB 5:202 ofguaianinA2 5:198 ofguaianinB 5:199 ofguaianinC 5:199 ofguaianinE 5:199 ofheptitol 4:177 ofholacanthone 5:39,40 ofhortensin 5:15 ofindicoside A 5:214 of indocosideB 5:215 ofisoaquillochindiacetate 5:9 ofisobrucein A 5:39,40 ofisopedimcularine 11:284 ofjuliflorinin 5:211 ofl-arabinitol 4:181,182 of lareantin 5:10 of Z,-glycero-D-mannoheptose 4:219 oflycopene 7:342 ofmanzamineA 5:349-351 ofmanzamineB 5:349,350 ofmanzamineC 5:349,350 ofmanzamineF 5:351 ofmatairesinol 5:506 ofnimrine 5:51 ofnortrachelogenin 5:531 of nortrachelogenin methyl ether 5:531 ofodonitinin 5:208 ofodonticinin 5:209 of oligomers of I-glycero-D-mannohptose 4:219 ofonnamideA 5:365 of perezinone derivatives 5:74-78 of permethylated (we5o)-pentitols 4:182 ofpicrasinB 5:39 ofpinnatifidone 5:216,217 of pluchecinin 5:205 of polysaccharides 5:297,298 ofprionitin 5:31-32 of puUulan 5:288,289 ofquinocarcin 10:118 ofquinocarcinol 10:118 ofsaframycinA-D,F,G 10:82 ofsalvinolon 5:33-35 of sanguinarine 5:45 ofsaprorthoqumone 5:37 ofstaurosporine 5:61 ofstaurosporineaglycone 5:61 of suspensaside 5:509,510 ofzeaxanthin 7:342,345,346,351

974
ofa-chaparrinone 5:39,40 ofa-pipitzol 5:786,787 of P-hydroxyacteoside 5:509 ofP-Iumicolchicine 5:47-49 ofx-lumicolchicine 5:47-49 ^^C-Trichodiene 13:520 *^C-oxepane synthesis of 10:212,213 ^*C-phytosphingosine enantioselective synthesis of 18:485,486 C2-P bond analogs ofD-erythritol 6:357,358 ofD-fructofuranose 6:357,358 ofZ)-glucopyranoside 6:357,358 ofD-ribohexitol 6:357,358 C3-P bond analogs of D-allofliranose 359 ofZ)-altropyranoside 6:359,360 ofD-glucofuranose 6:359,360 of A^-glyceraldehyde 6:359 ofZ)-xylofuranose 6:359 C4-alkylations ofp-lactams 12:159-172 with ester enolates 12:163,164 with imide enolates 12:164-168 with other nucleophiles 12:170-172 with thiolester enolates 12:168-170 C4-P bond analogs ofD-erythropentose 6:360,363,364 of A^-glycero-pentopyranose 6:360,361 ofZ)-talopyranose 6:360 ofl-talopranoside 6:360 C5-P bond analogs ofD-erythropentofiiranose 6:365,366 ofD-ribofumose 6:365,366,368 ofZ)-xylofuranose 6:365-367,375 of D-xylo-hexofliranose 6:365,366,372 Ce-P bond analogs ofZ)-arabino-hexofuranose 6:376 ofD-erythro-hexofiiranose 6:376 ofZ)-galactopyranose 6:376 ofD-glucofiu-anose 6:376 ofD-glucopyranose 6:376 ofD-ribo-hexofuranoside 6:376 ofD-ribo-hexofiiranose 6:376 Cg-polyketide 12:290 Ca^^ binding ofgastin 18:851-857 ofCCK 18:851-857 Cabreuvaoil 17:609 Cacospongia 6:11 5'-d (CACTAG (8-Oxo) TCAC) 8:390,391 Cacticin 7:226 Cadaba farinosa sesquiterpenes from 9:64,65 Cadabicilone 9:64,65 Cadabicine 9:73 Cadabicine methyl ether 5:209,210 CM-Cadalane 6:548,459 Cadalene 14:319 Cadambine tetraacetate 9:171 -173 Cadaverine 14:739 Cadinane synthesis of 4:584,585 by [2+2] cycloadditions 6:15 from Artemisia annua 7:217 Cadinane sesquiterpenes 15:278 Cadinolide A biogenesis of 9:9 from Cadlina luteomarginata 9:6 X-ray crystal structure of 9:7-9 Cadlina luteomarginata 9:6 CadlinolideA 17:15 CaesalpinJ 5:17 Caesalpinia sappan 5:17 Caffeic acid 5:467,469,474,479,111,119,579,36 Calabar bean alkaloids synthesis of 14:636-638 Calamanenenes biosynthesis of 15:251 l/?,45-Calamanenes 15:260 (+)-Calamenene 15:244,247 from Eremophila drummondii 15:244 Calamenenes {\RM) 15:259 CalcicolinA 15:119,126,133,171 Calcidiol (25-hydroxyvitamin D3) 11:3 80 (-)-Calcimycin synthesis of 16:712-713 Calciol (vitamin D3) 11:3 80 Calcitriol 9:520,521,43 Calcitriol lactone synthesis of 1:604,607 Calcium alginate 7:92 Calcium chloride 2:414 Calcium effects ofstaurosporine 12:397 Calcium/calmodulin-dependent protein kinase 12:389 Calderiella species macrocyclic lipids from 11:464 Calderol 9:513 Calditol 11:430,464 Galea prunifolia 5:728 Calendula arvensis 17:126 Calendula officinalis lutein from 7:361 Calf intestinal alkaline phosphatase 14:308,309 Calicheamicinone 10:150 Calichemicin 10:153;12:489 California red scale pheromone 4:675,479 Callitristic acid from Rabdosia kunmingensis 15:172 Callosobruclus analis 9:299 Callus culture growth within 2:366 Calmidazolium protein kinase inhibitor of 12:387 Calmodulin 1:4,399 Calmodulin inhibitory activity 2:282,284 Calomyrmex sp. 5:223,224,230,253 Calonectrin deoxynivalenol from 6:230,21 Calonectrin 9:206 Caloscyphafulgens p,y-carotene from 7:338

975
Calpurina aurea 1:421 Calvin photosynthesis 13:330 Calycanthoside 7:224 Calycopterin 5:757 Calycotomine 12:449 CalycuIinA 18:269 Calyculins 5:395,396 Calysterol 9:38,39,44,45 Calyx nicaeensis calysterol from 9:38 dihydrocalysterol from 9:37,44 (23/?,24/?)-23,24-methylenecholesterol from 9:37 nicasterol from 9:37 Calyxpodatypa 9:38,45 Camellidin I&II 15:202 CAMELSPIN 6:140 (-)-Camoensidine 15:520 Camomile 13:660 Campestanyl ferulate 9:474 Campesterol 9:454,129,520 Campesteryl linoleate 9:461 Camphanate method 6:153 (15)-Camphanic acid 14:179 l(SH-)-Camphanic chloride 18:607,613,627 (-)-Campherenol 4:675 Campherenone enantiospecific synthesis of 16:136 (-)-Campherenone 4:675 (-)-a -Campholenic acid 16:125,127,148 (+)-Camphor 10:408,123-124 (-)-Camphor 10:52,123-124 flf-Camphor 11:6,7 Camphor 16:123,124 (+)-Camphor radioimmunoassay of 7:114,115 Camphor 7:95;9:530,536 Camphor enol trimethyl sily ether 4:656,657,665 (-)-Camphor-lO-sulfonate 16:125 Camphor-10-sulphonic acid 4:628,632 Camphor-10-sulphonyl bromide thermolysis of 4:628,629 w-and /7-Camphorene from Eremophila cuneifolia 15:227 Camphorene 5:127,696 (-)-Camphorquinone 4:660,661,666,149 Camphorquinone rearrangement 16:150 (-)-Camphorsulfonic acid 12:417 (+)-10-Camphorsulfonic acid 15:425 Camphorsulfonic acid 6:221,205,68 Campnospermanol 9:323,329 Campnospermum auriculata 9:323 Camptothecin synthesis of 12:283 from Camptotheca acuminata 13:654 as anticancer agent 13:654 ()-Camptothecin 18:333,349,355 Camptothecine 5:84,85,127 Camptothecine-type alkaloids 5:84,85 Canabichromene synthesis of 4:398,399 fj^om Cannabis sativa 4:398 (/?)-(+)-Canadine 10:678 ()-Canadine 6:489,490 Canadine methiodide allocryptopine from 6:491,492 cis (/raAM)-Canadine A^-oxide nitrone from 6:474,475 /rar5-Canadine iV-oxide 6:474,488,489 cleavage product of 6:488,489 photolysis of 6:474 Cancer 17:137 Cancer chemotherapy by substituted benzo [c] phenanthridines 4:544 Candicin 15:328 Candida albicans 2:422,428,438-440,292,5:323,324, 342,356,369,282,400,233;7:282 Candida bogoriensis 5:294 Candida curvata 5:292 Candida cylindracea 12:337;18:429 Candida cylindracea lipase (CCL) 1:658,55,57 Candida guillermondii 2:422 Candida humicola 5:292 Candida krusei 12:400 Candida lipolytica 5:292,308 Candida lusitana 5:292 Candida lusitaniae 5:283 Candida obtusas 5:283,292 Candidaparapsilosis 5:292,323,324 Candida patens 2:441 Candida pseudotropicalis 12:400 Candida rugosa 1:694,306 Candida sp. 5:291,292,328 Candida tropicalis 2:422,400 Candida utilis 7:69,302,235 Candidiasis 2:332,425,432 Candidoses polyene macrolides in 6:261 Canella winter ana 2:441 Canellaceae 7:427;17:234 Canellal 2:447,448 Cangorinin 18:760 CangorosinB 18:665 Canin 7:234 Canine-hysteria 7:6 Cannabis 1:1 (-)-Caimabisativine synthesis of 16:492-493 (-)-Cannibidiol 16:131 Canophyllol 5:744,748,750 Cantabradienoic acid ^om Artemisia cantabrica 7:216,238 Cantharellus cibarius 5:289 Canthin-6-one 7:389,390,394 Cantleyinde derived alkaloids 6:527 Cantleyine from Strychnos muxvomica 6:503,527,529 Cantleyine series 6:522 5-Camphanic acid 16:478 5-Campothecin asymmetric synthesis of 16:431 Capellene-8p,10a-diol 3:63 Capillanol 7:222 Capillarm 7:202,203,223 Capillene 7:202-204,222

976
Capnella imbricata A^^'^^-capnellene from 13:34 capnellanes from 6:42 precapnelladiene from 6:33 Capnellanes from Capnella imbricata 6:42 from (-)-A^^'^^-capnellene 6:42 synthesis of 4:588 Capnellen-3p,8p,10a-triol 3:63,64 (+).A^(i2).Capnellene 10:407 Capnellene synthesis of 3:11,13,19,20,22 A*^^^>-Capnellene synthesis of 3:20 A^^'^^-Capnellene 3:7 (.).A9(i2).capnellene capnellanes from 6:42 (+).A9(i2).capnellene by a-alkaynone cyclization 6:45 by [2+2] cycloaddition reaction 6:43,44 by [4+2] cycloaddition reaction 6:43,44 by cyclopropane sliding reaction 6:48 by Diels-Alder reaction 6:46 by intramolecular alkylation 6:42,43 by intramolecular diyl trapping reaction 6:46 by intramolecular reductive coupling 6:48 by intramolecular type I Mg ene reaction 6:45,46 by methylenation 6:46,47 by 1,2-methyl shift 6:48 by Nazarov cyclization 6:43 by photochemical annulation 6:48 by three-carbon annulation 6:42 Dreiding synthesis of 6:45 from P-diketone 6:48 fromhumulene 6:48 Grubb synthesis of 6:46,47 Liu-Kulkami synthesis of 6:43,44 Oppolzer-Batting synthesis of 6:45,46 Stille synthesis of 6:47 synthesis of 6:42,43 with Tebbe reagent 6:46,47 A^^'^^-Capnellene 34,35 synthesis of 13:34,35 from Capnella imbricata 13:34,35 A^^'^^-Capnellene- 3p,8p,10a -triol 3:7 A^^'^^-Capnellene- 3p,8p,10p-14-tetrol 3:7 A^^^^^-Capnellene- 5a,8p,10a-triol 3:7 Capnellene-2p,8p,10a-triol 3:64 Capnellene-3p,8p,10a-14- tetriol 3:64 Capnellene-5a,8p, 10a-triol 3:64 A^*^-Capnellene-8P,10a-diol 3:7 A^^^^-Capnellene 2p,8P,10a-tril 3:7 Capnellenols by aldol cyclization 6:49,50 by three-carbon annulations 6:49,50 synthesis of 6:48-50 Capparis decidua alkaloids from 9:73-75,77 Capparisine 9:73 Capping reaction in oligonucleotide synthesis 4:279,280 Capraria biflora 15:259 Capreomycin 2:424 Caprifoliaceae 7:427 Capsaicin from Capsicum sp. 7:93 Capsicum annum 13:320 Capsicum sp. capsaicin from 7:93 Capsular polysaccharide from Streptococcus pneumoniae 14:233 (+)-Capuronidine 5:126 Capuronine 5:124 20/?-Capuvosidine 5:125 Capuvosine 5:129 Caralluma tuberculata saponins from 5:212;9:62-64 Carapaabovaa 7:189 Caratuberside A 5:212,213 Caratuberside A-D 9:62-64 Caratuberside B 5:213 Carausius morosus 9:492 5a-Carba -a-D-glucopyranosylamine cw-2,3,4 trihydroxy-5(hydroxymethyl) 1 -cyclohexylamine] 13:195 5a-Carba-a-D-galactopyranose 13:187,191 5a-Carba-a-D-glucopyranose 13:188,215,219 5a-Carba-a-D-glucosamine 13:210,212 5a-Carba-a-D-mannopyranose 13:216 5a-Carba-a-DL-galactopyranose pentaacetate 13:188 5a-Carba-P-DL-mannopyranose derivative 13:191 Carba-disaccharides synthesis of 13:219-221 5a-Carba-DL-hexopyranose 13:187 5a-Carba-glycosylamines synthesis of 13:195-204 5a-Carba-hexopyranoses synthesis of 13:190-207 5-Carba-levoglucosenone 1,4-exo-aductsof 14:279 3-deoxy derivative of 14:279 synthesis of 14:279 Carba-sugars (pseudo-sugars) synthesis of 13:187-255 Carbacepham 8:262 Carbacephems synthesis of 12:121 Carbacyclins 16:388 5-0-Carbamoylpolyoxamic acid synthesis of 1:401 -404 Carbanions 1:351-353 Carbanion 16:30 Carbanion reagents 11:439-443 Carbanion rearrangement 16:620 Carbapenam alkaloid synthesis of 16:708-709 Carbapenams synthesis of 8:262,263 Carbapenem as asparenomycins 4:434 as carpetimycins 4:434 as KA-antibiotics 4:434 as nor-thienamycin 4:434

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as OA-antibiotics 4:434 as pharmacophore 4:434 as pluradomycins 4:434 by Merk procedure 4:453 precursors synthesis 4:469 Carbapenem antibiotics 13:495-507 Carbapenem derivatives 12:122 (+)-6a-Carbaprostaglandin I2 synthesis of 1:698,699 Carbazole imide preparation of 12:388 protein kinase inhibitor of 12:388 Carbazolequinone alkaloid 1:163 Carbene complexes 16:406 Carbene insertion reaction 4:436,438 Carbene-diene cyclization 3:29 Carbene-olefm cyclization 3:325 Carbenoid displacement 1:259 Carbenoid insertion 13:501-503 ()-P-Carbethoxyacroylyl chloride 14:560 Carbethoxycyclohexanone isonitramine from 14:745 nitramine from 14:746 Carbinolamides 4:57 Carbinolamine 4:57,269,270 Carboalumination with MesAl, ZrCpzCb 1:454,455,459 Carboalkoxylation palladium-mediated 12:251 AT-Carboamoyl-Gly-IA human insulin HPLC of pepsin digest 2:38,39 peptides by LSIMS 2:38-41 structure of 2:37-39 A^-Carbobenzyloxyphenylalanine Amdt-Eistert homologation of 13:116 N-Carbobenzyloxyslaframine 12:308 Carbocation intermediate in 2,5-benzoxazonines syntheses 6:474 Carbocupration reaction asymmetric induction in 14:507,508 diastereoselective 14:507,508 of C2-homochiral cyclopropenes 14:507,508 Carbocycles from palladium (+2) complexes 8:272 Carbocyclic nucleoside antibiotic activity of 8:148 antitumor activity of 8:148 antiviral activity of 8:148 Carbocyclic oxetanocin A,G antiviral activity of 10:620,621 synthesis of 10:611-616 Carbocyclic oxetanocins synthesis of 10:608-619 Carbocyclic spiro compounds asymmetric synthesis of 14:544-546 6-Carboethoxyolivetol with geranyl bromide 4:386,387 Carbohydrate *^0-NMR spectrum of 17:542 as chiral building blocks 4:349,359 from a-haloboronic ester 11:420-422 quantitative analysis of 2:336-340 semi-synthesis 17:636-640 synthesis of 11:420-422 Carbohydrate derivative synthesis of 14:659-664 via Norrish type II reaction 14:659-664 Carbohydrate lactones C-glycosides from 10:385 Carbohydrate transportmg proteins 7:29 Carbohydrate-molybdate complexes 15:426-435 P-Carboline alkaloids 2:369,90 P-Carboline derivative 8:285 a-Carbolines 5:414,415,417,245 P-Carbolines 5:417,418 (+)-Carbomenthone Robinson annulation of 6:547,548 2-Carbomethoxycycloheptanone with 4-bromobutyraldehyde dimethyl acetate 12:241 f//-Carbomethoxydihydrocleavamine 14:806,807,850853 16-Carbomethoxydihydrocleavamine synthesis of 5:182,183 Carbomethoxylation 4:36,38 ofketone 4:36,38 16-Carbomethoxyvelbanamine synthesis of 14:831,832 CarbomycinB 10:170 Carbomycins 11:164 Carbon versus oxygen alkylation regioselectivity of 4:367 Carbon-bridged system 12:87 Carbon-tin bond conversion to carbon-silicon bond 1:352,353 Carbonolide A synthesis of 11:165,166 Carbonolide B 11:162-166 Carbonolides stereoselective synthesis of 11:163-172 synthesis of 11:158-172 Carbonyl coupling reaction titanium induced 8:16-18 Carbonyl reduction diastereoselective 1:622 ofp-ketoacetals 1:622 1,2-Carbonyl transposition 3:474,485 1,3-A^-Carbonyl-3'-deoxygentamycin X2 14:146;16:432 Carbonylation Pd(0)-catalyzed 10:29,396,416 N,N'-Carbonyldiimidazole 1:268 A',7\^-Carbonyldiimidazole 4:327 1,1 '-Carbonyldiimidazole 8:90 Carbopalladation 16:374 (-)-Carbovir antiviral activity of 10:608,609 2S-Carboxy-3/?,4/?,55-trihydroxypiperidine absolute configuration of 10:549 from Baphia racemosa 10:549 relative configuration of 10:549 3-Carboxy-cw, cw-muconate cycloisomerisation 8:305 3-Carboxy-cw, cw-muconic acid 8:295,296,306

978

Carboxypachymaran antitumor activity of 5:317 3-Carboxycoumarin 18:978 (45)-3-Carboxylactone 8:297 Carboxylation (25)-methylmalonyl CoA by 11:195 of propionyl CoA 11:195 Carboxylic acid anhydride variation of Claisen condensation 4:375 Carboxylic acid silyl esters with silylated phosphonium ylides 4:564 Carboxylic acids 2:4 Carboxylic esters into aldehydes 6:334 synthesis of 6:326327 5-Carboxymellein 15:383 d5,cw-3-Carboxymuconic acid syn addition of 8:297 cyclisation of 8:295,296 cycloisomerisation of 8:297 from Neurospora crassa 8:297 8:3 Carboxymuconolactone 8:295-297 4-Carboxymuconolactone 8:295,296 Carboxypeptidase 9:489 Carbylamine reaction isocyanides by 12:113 Carcinogenesis 9:583 Carcinogenesis research 15:439 Carcinogenic activity of fumonisins 13:532 Carcinogenicity of benzo [1] pyrene 7:8,9 Carcinomycin 1: 498 Cardanols 9:313-315,323,326,330,332,333,335-338, 340,341,349,352,358,363,368-371 Cardenolide from thujone-derived synthone 14:440-444 synthesis of 14:440-444 from Digitalis 15:361,367 Cardiac depressant 5:750 Cardiac glycosides 9:293 Cardiotonic constituent 17:33 Cardiotonic peptides 5:403 Cardnol methylether byazonolysis 9:338 Cardol monoene 9:319,354 synthesis of 9:354 Cardols 9:315,318,324,328,332,333,335-339,341,347, 349,358,359,368,370 Cardwellia sublimis 9:320 Careaborin 7:189 (+)-Carene 12:243 (+)-Carissone synthesis of 14:406-413 Carmenin 7:236 Carminomycin 4:317 Carminomycinone 14:20 (5)-(-)-Camegine 10:677,679 (/?)-(+)-Camegine 10:677,679,682 Carolisterol A-C from Styracaster caroli 15:76 Carotadiol esters 5:125.121

Carotan lactone 5:725,726 Carotane sesquiterpene biosynthesis of 5:730-732 chemistry of 734 spectroscopic studies of 5:734-737 synthesis of 5:732-733 P-Carotene 4:559,560;7:20,98,318,319,334-342,344; 17:611,612,708 Y-Carotene 7:327-329,333,334,338 (9Z,9'Z)-y-Carotene from(15Z,9Z)-phytofluene 7:332 (9Z,7'Z,9'Z)-neurosporene from 7:332 5-Carotene 7:333,334,337,352 8-Carotene (65,6'5)-s,E carotene 7:338 from Ulua lactuca 7:338 (l/?,r/?)-P-Carotene 7:344 Carotenoid 5,6-epoxides 6:142 Carotenoid biosynthesis 7:317-367 Carotenoid intermediate 4:676 Carotenoid sulfates from carotenols 6:150 partial synthesis 6:150 Carotenoids 4:559;5:370,11,133-169,150,73;7:321, 318-321,329;9:559,583 C4o-Carotenoids 6:110,135,136,143,144 CsoCarotenoids biosynthesis of 7:39-48 stereochemistry of 7:39-44 C45Carotenoids biosynthesis of 7:39-48 stereochemistry of 7:39-44 Carotenols carotenoid sulfates from 6:150 Carotenoproteins 6:161,162,317 (+)-Carotol 14:356 Carotol 5:721,725,731,732,734,737 Carotoltriol 5:730 Carpalasionin from Rabdosia rugosa 15:174 Carpanone from [4+2] cycloaddition 8:168 total synthesis of 8:168 synthesis of 4:617,618 Carpetimycins 4:434,135;12:135 Carpetimycins 4:434 Carpinus cordata 17:369 Carpinus species 17:369 Carrol conditions 6:122 Carrol-Claisen rearrangement 6:417 Carrol rearrangement 10:58,60 Carthamus lanatus eudesm-1 l-en-4-ols from 14:450 intermedeol from 14:450,451 R-(+)-/7-Carvomenthene from/?-(+)-limonene 8:49 D-Carvone 10:43,46,47 (-)-Carvone (spearmint) 6:66,67,549-551,157,156,623; 14:517 Carvone 7:114,115;16:123 5-(+)-Carvone 16:155 /?-(-)-Carvone 16:155

979
(+)-Carvone 7:6,732,608;14:517 D-Carvone epoxide Homer-Emmons reaction of 10:43 Lythgoe aldehyde from 10:46 Caryophyllane 18:607 Caryophyllene synthesis of 3:74,84-89,110 Caryopteris clandonensis 4:612 a-Caryopterone synthesis of 4:396,398,400-402 Caryoptoside 7:470 Casbene 8:16,17,25,181 Cashew nut {Anacardium occidentale) 9:15,316,327 Cashew phenols 9:314,332-334,338,341,368,372 Cassameridine 2:436 Cassia siamea 1:174,3 85 Cassine 18:741 Cassine balae (Elaeodendron balae) 5:743,744,747; 7:149,150 friedo-olenenes from 7:149,150 triterpene quinone methides from 7:149,150 Cassipourea gerrardii 7:192 Cassipourea gummiflura 7:192 Cassipourine 7:192 Cassumins A, B, and C 17:365-367 (+)-Cassythicine 16:509 Castanopsis saponins 15:191 (+)-Castanosperime 6-acetamido-6-deoxy-castanospermine from 12:345 absolute configuration of 12:332 allergic encephalomyelitis activity of 12:332 asymmetric synthesis of 12:346 castanospermine A^-oxide 12:352 chemoenzymatic synthesis of 12:337,338 enzyme-catalyzed acylation of 12:346 from Alexa leiopetala 12:332 from Castanospermum australa 12:332 inhibitory activity of 12:332 insect antifeedant activity of 12:332 O-acyl derivatives of 12:346 plant growth regulating activity of 12:332 relative configuration of 12:332 stereoselective synthesis of 12:353,354 synthesis of 12:321,332-342 X-Ray crystallography of 12:332 (+)-6-e/7/-Castanosperime 12:276,342-344 absolute configuration of 12:342 from Alexa leiopetala 12:342 from Castanospermum australa 12:342 from L-gulonolactone 12:342 synthesis of 12:342-344 1 -ep/-Castanospermine synthesis of 1:280,281 Castanospermine absolute configuration of 10:553,656 almond emulsin P-glucosidase inhibitor of 10:553 as anti-aids agent 11:267 Baeyer-Villiger oxidation of 10:557,558 by chh-al allylic alcohol 11:267 enantiospecific total synthesis of 10:553 from Alexa leidpetala 10:553 from Alexa leiopetale 11:267 from Castanospermum australe 10:553 from Castanospermum australe 11:267 glucosidase I inhibitor of 10:527 glucosidase II mhibitor of 10:527 glucosidase inhibitor of 11:267 glucosidases I,II by 7:11-16 lysosomal a-and p-glucosidases inhibitor of 10:553 maltaseby 7:12 stereoselective 11:267 stereoselective synthesis of 10:557,558 sucraseby 7:12 synthesis of 1:279-281;10:531,533 synthesis of 11:267-271 Wittig-Homer condensation of 10:557,558 a-glucosidase inhibition by 7:12 p-glucosidases inhibition by 7:12 (-)-1 -ep/-Castanospermine synthesis of 12:333-337,344 (-)-Castanospermine (-)-6-e/7/-Castanospermine 12:342 from D-gluconolactone 12:342 (-)-8-e/7/-Castanospermine 6-e/7/-Castanospermine 7:12-15 from Castanospermum australe 7:12 from D-galactose 12:344 from I-gulonolactone 7:12 synthesis of 7:12;12:342 a-glucosidases inhibition by 7:12 e/7/-Castanospermine 7:44 Castanospermine australe australine from 10:567 Castanospermine iV-oxide from (+)-castanospermine 12:352 Castanospermine stereomers 12:342 Castanospermum austale (+)-6-e/7/-castanosperime from 12:342,343 (+)-castanospermine from 11:267 (15,65',7^,8/?,8a/?)-tetrahydroxyindolizidinefrom 12:332 6-e/7/-castanospermine from 7:13 australine from 7:13 castanospermine from 12:332 Castasteron 18:495,503,522 Castasterone from Castaneas^. 16:668 from cyclasterol 16:324 synthesis of 16:322 Castelanolide synthesis of 11:74-76 Castelanone fromchaparrin 11:80,81 Casticin 7:226,411-413 Castor fiber 5:221 Casuareinondiol 17:371 Casuarianjunghuhniana 17:371 Casuarianaceae 17:371 Catalase 9:578 6,3'-g/7/-Catalpol 7:484 Catalpol 440,483,484-486 Catalysts 4:302 Catalytic asymmetric aldol reaction 18:485

980

Catalytic deuteriation 9:476 Catalytic epoxidation 11:431,432 Catalytic hydrogenation with raney nickel 6:425 with rhodium 6:424 Catalytic hydrogenolysis 12:293,163 Catalytic osmylation 11:431,432 Catalytic receptors 18:694 Catalyzed rearrangement 16:512 Catechin 2:232,233,752,192,144 (+)-Catechm 7:192 a-Catechin 7:192,193 Catechol 14:678 Catechol borane reduction 13:562 Catechol monomethyl ethers 5:449,451 Catechol-O-methyl-transferase 5:449 Catecholamines 8:395 Catecholates 9:537 Catecholborane 11:43,44;12:157,158 Catechols 5:447,456,318,325,328,578,579 Caterpillar bioassays 13:536 Catharanthine 2:370373,381,383,385,390,392,398,39, 400,401,402 15',20'-anhydrovinblastine from 14:820,821, 869-873 biosynthesis of 4:66 biosynthetic precursor of 4:31 catalytic hydrogenation of 14:809,810 coupling with vindoline 4:31,32 dihydrocatharanthine from 14:809,810 enzyme catalyzed coupling of 14:820,821 from Catharanthus rosens 13:663 from catharanthus roseus 14:855 vinblastine from 14:854-859 vincristine from 14:854-859 with vindoline 14:820,821 Catharanthine iV-oxide 2:371,816,187;3:857,859 (16 'S^anhydrovinblastine from 14:857,859,816, 817 Catharanthus roseus alkaloid production 2:370-391 alkaloids of 7:416 catharanthine from 13:663;14:855 growth inhibitory activity of 7:416 leurosine from 14:860 vinblastine from 8:283;14:805 vincristine from 8:283;14:805 vindoline from 14:805 Catharine 2:370372,387,390-398 biosynthesis of 14:820,821 from anhydrovinblastine 14:812,820,821,871 from leurosine 14:812 Catharinine 1:90,91 biosynthesis of 14:820,821 from anhydrovinblastine 14:820,821,871 from 20'-deoxyleurosidine 14:812 synthesis of 14:847 ()-Cathenamine 13:490,491 Cationic cyclization ()-chelamine by 14:793-795

()-chelidonine by 14:793-795 sanguinarine by 14:793-795 Cationic cyclopentannelation reactions 14:583-630 Cationic it-cyclization of A^-acyliminium ion 12:287 Cationic polyene polymerization 1:565 Caudicifolin X-ray crystal analysis of 9:288 Caudinoside A from Parachaudina ransonetii 7:278 Caulerpa racemosa 18:689,714 Caulerpalean algae 18:688 Caulocyctis cephalornithos 15:386 Cavemosine synthesis 3:164-166 ep/-Cavemosine synthesis of 3:164-166 ()-Cavinton 18:331 a,p-CBT (cembratriene-4,6-diols) 10:3,4 //-Cbz-(S)-leucinal 12:489 Cbz-L-alanine 16:9 CC-1065 absolute stereochemistry 3:305 antitumor activity of 3:310,302 CDPIdimer 3:331,356-360 DNA sequence selectivity 3:304 formal synthesis of 1:180,184 isolation of 3:301 mechanism of action 3:303,304 molecular mechanic simulation 3:338-351 structure of 3:301 structure-activity relationship 3:338-351 synthesis of 3:331,356-460 synthesis of analogs 3:352 synthetic studies towards 3:301-383 total synthesis of 3:333-337 toxicology 3:302 X-ray crystal structure 3:305 CCK hormone 18:834 CCK-10,-12,-13 18:838 CCK-4,-5,-8,-18,-25,-33,-39, and-58 18:825 CCK-A antagonist 18:863 CCK-A receptor 18:819,825,827,836,857,862-865 CCK-analog [Thr,Nle]-CCK-9 18:836 CCK-B antagonist 18:863 CCK-B receptor 18:824,827,836,839,840,857,858,864 CCK-peptides 18:825,827,836,852,854,857,859,860 CCK-radioligand 18:861 CD correlation of 19*-hexanoylfiicoxanthin 6:137 ofperidinin 6:137 with grasshopper ketones 6:137 CD Cotton effects 17:44 CD excition chirality method 17:35,36,51,53 CD procedure absolute stereochemistry by 9:27 CD spectral analysis of ()-epiperiplanol-B benzoate 6:539 CDPI trimer synthesis of 3:361,362 Ce (OAc)3-BF30Et2 10:572 Cebocephaly 7:21

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Cecrop/a juvenile hormone synthesis of 3:271 Cedrane synthesis of 3:14,29 Cedrane ring system 1:568 Cedranio sesquiterpenes 3:29 biogenesis of 3:29 Cedranolides 5:778-792 5-Cedranone 5:791-792 8,14-Cedranoxide retrosynthesis of 8:163 synthesis of 8:163,164 total synthesis of 8:163-165 a-Cedrene 15:270,609 2-e/7/-a-Cedrene isoprenologue 15:270 Cedrene isoprenologues 15:269-271 (3-Cedrene-14-ol 8:164,165 Cedrol 5:782,788,790 Cefoxitin 6:322 Celangulin from Celastrus angulatus 18:771 Celapanol 18:744 Celastraceae 18:739-778 Celastrol 5:744-746,757,776 Celastrus 18:741,753 Celastrus angulatus 18:771 Celastrus paniculatus 5:743,744,747 Celestraceae 7:150 Celestrol 7:146,147,150-152 Cell cultures organogenesis of 7:94-96 totipotency of 7:94-96 Cellariapilosa 17:95,101 Cellaria species 17:89,92 Cello-oligosaccharides 7:33 Cellobiohydrolases II from Trichoderma reesei 8:351 Cellobiohyrolases I from Trichoderma reesei 8:351 Cellobiose 7:51,58,71,436,349 hydrolysis of 8:349 a-Cellobiose from cellobioside hydrolase II 7:58 Cellobiose analogues 7:64-66 P-Cellobioside 7:52 a-Cellobiose from 7:58 Cellobioside hydrolase II P-cellobiose from 7:58 P-Cellobiosyl fluoride 7:58 Cellulases 7:32-37,39,59,349,340,344,352 Cellulomonas dehydrogenans decapenoxanthin from 7:69 Cellulose 5:275,276,32,268,14:268 a-Cellulose 7:195 Cellulose 1,4-p-cellobiosidase 7:3 DEAE-CQ\MOSQ chromatography 2:392,393,394 Celmisia petriei 7:138 7-p-Celobiosyltheophylline synthesis of 4:226 Celorbicol 18:743 Cembradiene hydroxy ether 15:253 Cembrane 15:253,22,28 Cembrane diterpene biological activity of 8:15 synthesis of 8:15-3;10:3-42 Cembranoids anticancer activity of 8:15 synthesis 8:16,17 (7)-Cembranolides 10:16 c-Cembratriene 15:275 Cembratriene-4,6-diols (a,P-CBT) 3:4 Cembrene 8:16,25 Cembrene A 5:701,702,220,221,255;8:220;12:181 (-) Cembrene-A 5:701,702 3Z-Cembrene-A 8:221 Centaur X3 7:202,203,221 Centaureasp. 5:659 Centaureidin 7:226 (3/?,75)-Centrolobm 17:366 (3/?,7i?)-Centrolobin 17:367 Centrolobium paraense 17:367 Centrolobium robustum 17:367 Centrolobium sclerophyllum 17:367 Centrolobium species 17:358,366 Centrolobium tomentosum 17:367 (-)-Centrolobol 17:358,361 (-)-(/?)-Centrolobol 17:361 Centrolobol 17:367 Cephalodiscus gilchristi 18:875,876,901,902 Cephalomannine 11:4,5,61 ;12:179,180 Cephalosporin-C biosynthesis of 11:211,212 from5-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (LLD-ACV) 11:211,212 from penicillins 11:211,212 Cephalosporins biosynthesis of 11:211 -213 semi-synthesis of 17:617-619 chemical shifts of 4:442 Cephalosporium acremonium 11:211,619 Cephalosporium caerulens 5:613 Cephalostatin synthesis of 3:432 from phenethylisoquinoline derivative 6:487 ()-Cephalotaxine 18:319 Cephalotaxus alkaloids biosynthesis of 6:487 Cephalotaxus spp. 3:455,483,484 Cephalothin 6:322 Cephalothrix linearis 18:725 Cepham derivatives synthesis of 12:131-133 Ceramides synthesis of 4:564,565 Ceratitis capitata 2,5-dimethyl-3-ethyl-pyrazines of 5:223 Ceratocystis brunnea 5:306 Ceratocystisfimbrata 5:305,306,351 Ceratocystis minor 15:385 Ceratocystis paradoxa 5:306,307 Ceratocystis sp. 5:296,305,309,325 Ceratocystis stenocerus 5:305 Ceratocystis ulmi 5:305 Cerbera mangmas 7:176

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Cerbera odollum 7:195 Cerbinal antifungal activity of 16:302-304 from Cerbera manghas L. 16:302 synthesis of 16:302-304 Cercospora beticola 15:351 Cercospora taiwanensis 15:383 Cereale secale 9:328 Cerebroside synthesis of 1:680,681 Cerebrotendinous xanthomatosis 17:207 Ceric ammonium nitrate 4:322,323,331,332 Ceric chloride 1:552 Ceridimine 5:123 Ceriops decentra 7:192 Cmop5 sp. 7:176 Ceriops tagal 7:176,180,195 Cerium (III) chloride 14:753 Cerium ammonium nitrate (CAN) 14:780 Cerium carbanion 1:552 Ceroplasteric acid 1:563-564 (+)-Ceroplastol I 18:20-22 Cerotoma trifurcata 9:392 Cerulenin 5:600,609,613-615 Cesium fluoride 1:563,564 Cestode (tapeworm) 12:7 Cetraria islandica 5:309,310,322 Cetraria richardsonii 5:310,311 Ceylanicine 5:146,147 Ceylanine 5:147-149 CGP-41251 cyclic AMP-dependent protein kinase inbitor 12:388 S6 kinase inhibitor of 12:388 tyrosine specific protein kinase inhibitor of 12:388 a-Chaconine 7:190-192,194,195 Chaetoglobocins 4:620 Chaetoglobosin D 13:108 Chaetoglobosins 13:108,150,355 Chaetomium 5:730,203 Chagas disease 2:293,302 Chain elongation of D-mannopyranose system 4:199 Chalcomoracin 17:465 biosynthesis of 17:465 Chalcone 13:450-452 Chalcone derivatives in Artemisiapalustris 7:207 Chalcones moUuscicidal activity of 7:427 Chalogens 9:109-126 Chamberlin 12:445 (+)-(3-Chamigradiene 6:63 Chamigrane 9:344,59 Chamigrene precursor 6:30 P-Chamydosporol toxicity of 13:543 Chan-Brownbridge procedure in (-)-pseudopterosin-A synthesis 6:74,75 Channel-linked receptors 18:694 Chanoclavine I 11:199,200 Chaparrin 7:381,394,80,81 (i,/-Chaparrinone synthesis of 11:105,106 Chaparrinone 5:38-41,380-381,392,395-396 Chara globularis charamin from 18:677 3-azelidmol from 18:677 4-azoniaspu'o [3,3] heptane-2,6-diol 18:677 Charamin from Chara globularis 18:677 Charania lampas glycosidase of 7:286,288 Charatoxins 18:697 Charge exchange ionization by 2:3 Charonia lampas 15:58,88 Charonia sauliae 7:306,724 Chartella papyracea 17:85,86,89,92,692 Chartellamide A & B 17:86 Chartelline A,B & C 17:86 Chaulmoogric acid 8:140 ()-Chelamidine fromberberine 14:796 synthesis of 14:796 ()-Chelamine from coptisine 14:793-795 stereochemistry of 14:793,794 synthesis of 14:793-795 through cationic cyclization 14:793-795 Chelaner antarcticus pyrrolidine venom alkaloids in 6:436 pyrrolizidme alkaloids in 6:445 Chelate model 11:268,269 Chelating transition state models 12:167 a-and p-Chelation 11:234 Chelation 12:149,150 Chelation controlled aldol condensation 10:286 Chelation controlled Grignard reaction 1:266 Chelation-controlled addition 14:50 Chelation-controUed Sakurai reaction 12:333 Chelation directed addition 3:271 Chelerithrine synthesis of 3:429 Chelerythrine fromberberine 14:773-775,796 from oxychelerythrine 14:774,775 synthesis of 14:773-775,796 through enamide-aldehyde cyclization 14:774,775 ()-Chelidonine biosynthesis of 14:770,771 from coptisine 14:793-795 synthesis of 14:793-795 through cationic cyclization 14:793-795 Chelidonine synthesis of 3:435 Cheliferoside from Lathasterias nanimensis chelifera 15:59 Chelilutine from 7-O-demethyl dihydro chelerythrine 14:780,781 synthesis of 14:780,781

983
Chelirubine biosynthesis of 14:779 from protoberberines 14:111,11^ from sanguinarine 14:779 synthesis of 14:777,778 Chelynotus semperi 17:23 Chemical defense in ants 6:421-465 Chemical ionisation (C.I.) 9:466,470,477 Chemical manganese dioxide (CMD) 4:85 Chemical-induced edema 12:398 Chemoenzymatic synthesis of(+)-castanospermine 12:337,338 Chemoprevention 13:666 Chemoselective epoxidation 14:366 Chemoselective hydroxylation ofbicyclictriene 6:79 Chemoselective reduction with lithium tri -^er/-butoxyaluminohydride 10:85 Chemosy stematics ofacetyleniccarotenoids 6:147 of allenic carotenoids 6:133-135 Chemosystematic markers acetylenic carotenoids 6:155 Chemotaxonomy 18:701 Chemotrypsin 9:500 Chenodeoxycholic acid 17:207 Chenopodiaceae 9:402 Chenopodium album 7:398 Chenopodium quinoe 9:402 Cherylline synthesis of 4:544 Chilomonas Paramecium 2:294 (+)-Chiloscypholone 18:624 Chiloscyphone from Chiloscyphus polyanthos 18:609 Chiloscyphuspolyanthos 2:278,279;18:609 Chimeramycin 5:613,614 Chimeramycins A&B 5:614 Chinicacid 4:561,525 synthesis of 4:561,562 Chippiine 5:128 Chiral 1,3-dioxane 14:480 Chiral 1,4-dihydropyridine isonitramine from 14:744 Chiral 1-acylpyridinium salt 12:351 Chiral 2-amino alcohol synthesis of 12:415,416 Chiral 4-hydroxyoxazolidin-2-ones 12:450 Chiral a,p-ethylenic acetals from C2-symmetric diols 14:479 with phenyl or alkenyl copper-BFs reagents 14:479 Chiral a,p-unsaturated acetals from {R, Ryi+yN, N, N', A^'-tetramethyl tartaric acid diamide 14:478,479 with organo-aluminum reagents 14:478,479 Chiral a-aldoxime-ether acetal organocerium reagents to 14:496 Chiral a-amino acetals Lewis acid-mediated reaction of 14:483 with silicon-containing nucleophiles 14:483 Chiral a-keto acetals chiral tertiary alcohol from 14:491,492 from (-)-(2/?,3/?)-2,3-butanediol 14:491 from (-)-(25,35)-1,4-dimethoxy-2,3-butanediol 14:491 Chiral a-methyl-substituted aldehyde coupling reaction of 12:35,36 with chu-al vinyl halide 12:35,36 Chiral acetals asymmetric cyclization 14:506,507 asymmetric synthesis from 14:496-516 bromination of 14:505,506 diastereoselective 14:505,506 for asymmetric bromolactonizations 4:338,339 from (-)-(25',35)-l ,4-dimethoxy-2,3-butanediol 14:496 from (2/?,4i?)-pentanediol 14:473 from (25',45)-pentanediol 14:481 from l,3-diphenylpropane-l,3-diol 14:480 from C2-symmetric diols 14:469-516 from dialkyl tartarate 14:505,506 from perillene 14:506,507 nucleophilic additions of 4:330-332 preparation of 4:324 with methallylsilane 14:481 with trimethylsilyl cyanide 14:473 Chiral acetylenic acetals chiral alkoxy-allenes from 14:471 with Grignard reagent 14:480 Chiral acrylates 8:416 Chu-al acyclic P-keto acetals 14:501 from (-)-(2/?,3/?)-2,3-butanediol 14:501 LiAlH4-reduction of 14:501 Chiral alcohols 14:470 Chiral alkaloids asymmetric synthesis of 10:671-689 Chu-al alkoxy-allenes from chiral acetylenic acetals 14:480 synthesis of 14:480 Chiral alkyl (l,3-butadien-2-yl) methanols 14:474 Chiral allylboronates synthesis of 11:423,424 Chiral allylic alcohols 4:160-161 Chiral amide bases [2,3] Wittig ring contraction with 10:31-33 Chiral amines from chiral imine 14:496 Chiral aryl Grignard reagents diastereoselective addition of 14:508,509 Chiral arylaldehyde acetal chromium tricarbonyl complexes asymmetric metallation of 14:511 Chiral auxiliaries acetals as 4:327 asymmetric induction with 4:327-345 binaphthyl diols as 4:335 by (/?)-(+)-a-methyl benzylamine 4:324 by l-(-)-methyl ester 4:323 chiral diamides as 4:335 glycosides as 4:327

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in asymmetric Diels-Alder reaction 4:345 in Diels-Alder reactions 4:334-336 oxazolines as 4:327,332,333 preparation of 12:416-418 prolines as 4:327 stereo-differentiating reactions 4:327 sugar as 4:334-336 thiazolidine derived 14:735 Chiral P-lactams synthesis of 12:121 Chiral boron reagent from B (0CH3)-(/?,/?)-(+) tartaric acid 4:609 in asymmetric Diels-Alder 4:609 Chiral building blocks from malonic acid derivatives 13:73-84 monofluorinated 13:81 preparation of 4:349-359,73-84 asymmetric synthesis of 14:551-581 via intramolecular Michael reaction 14:551-567 Chiral carbapenems 12:121 Chiral catalysts 17:479 Chiral chromatography 18:411 Chiral cyclized hemiacetal from chiral vinyl ether 14:487 Chiral cycloalkanone acetal chiral vinyl ether alcohols from 14:486 from (-)-(2/?,4/?)-2,4-pentane diol 14:486 Chiral cyclopropanation chiral pyrethroid analogues 14:401-405 ofthujone 14:401-405 Chu-al dienophiles a-hydroxcarboxylic acid derivatives 8:140 cycloaddition of 14:503 isoquinolinium salt with 14:503 Chiral dienyl ether alcohol (+)-africanol from 14:487,488 cyclopropanation of 14:487,488 Chiral dioxane acetals asymmetric nucleophilic cleavage of 14:476 diastereoselective cross-aldol reaction 14:472 from (25',45)-2,4-pentanediol 14:471 from (2/?,4/?)-pentanediol 14:477,478 with organometallic reagents 14:476 with Reformatsky reagents 14:477,478 Chiral enamine asymmetric 14:553 intramolecular Michael reaction of 14:553 Chiral enol ethers asymmetric 14:489 C-N bond formation 14:489 Chiral enone acetal 14:510 Chiral epoxidizing agent diastereofacial selectivity of 4:172,173 chiral lactones 4:493 from a,(3-acetylenic alcohols 4:493 from keto acids 4:493 preparation of 493 Chiral ester 14:552

Chiral fragments ofamphotericineB 6:282 synthesis of 6:282 Chiral imine [2+2] cycloaddition of 12:161 from ethyl (5)-lactate 12:161 addition of organometallic reagents 14:496 chiral amine from 14:496 Chu-al imine acetal with lithium enolate 14:497,498 Chiral inducer 1:73 Chu-al induction with Schoellkopf reagent 10:653,655 Chu-al induction 18:480 Chiral isoquinolines synthesis of 10:671 Chiral Lewis acids 8:140 Chiral A^-acylated 2-oxazolone 2-amino alcohol synthon from 12:419 electrophilic addition of 12:419 from camphor-derived carboxylic acid 12:419 with bromine and phenyl selenyl chloride 12:419 withDPPOx 12:419 Chu-al N-glycosyl nitrones 1:370,371 Chiral nitroolefmation ofenolates 14:631-644 Chiral ortho ester from diethyl (Z,)-tartrate 14:508 Chiral ortho ester vinyl ethers 14:503 Chiral oxazolines 4:333 Chiral piperidines synthesis of 10:671 Chiral precursor aspartic acid as 6:2989,299 (5)-3-hydroxybutyrate as 6:300,301 (/?)-methyl-p-tolylsulfoxide 6:301,302 Chiral pyrethroid analogues fromthujone 14:398-405 synthesis of 14:398-405 via chiral cyclopropanation 14:401-405 Chiral reduction 1:482 Chiral reproduction 4:346 Chiral sesquiterpenes synthesis of 14:406-425 via Robinson annulation reaction 14:406-425 Chiral shift reagent 4:326 Chiral steroid analogues synthesis of 14:431-444 Chiral steroidal acetal from (2i?,4/?)-(-)-pentanediol 14:481,482 from (25,45)-(+)-pentanediol 14:481,482 with organometallic reagent 14:481,482 Chiral sulfamyloxaziridines asymmetric oxidation with 4:489 oxidation of sulfides with 4:489 Chiral sulfoxides 10:671-685 to 3,4-dihydro-6,7-dimethoxyisoquinoline 10:679-685 Chiral sulfoximines intramolecular addition to 10:671-679

985
to 3,4-dihydro-6,7-dimethoxyisoquinoline 10:679-685 Chiral sulfur reagents asymmetric synthesis with 10:671-689 Chiral sulphoxide (-)-sibirine from 14:747 Chiral synthesis of amino acid 12:477 of 1 -(a-hydroxyalkyl)-1,2,3,4-tetrahydroiso quinolines 12:450 of bioactive natural products 13:84-99 ofbioregulators 6:537-566 ofsemiochemicals 6:537-566 Chiral synthon with yeast 1:482 for 2-aminoalcohols 12:416-425 Chiral tartaric amides /ra5-acetalization of 4:338,339 Chiral template effect 12:489,500 "Chiral templates" 14:267-281 Chiral tertiary alcohols asymmetric synthesis of 14:491,492 from chiral a-keto acetals 14:491,492 Chiral titanium complexes asymmetric oxidation with 4:489 oxidation of sulfides with 4:489 Chiral vinyl ether alcohols from chiral cycloalkanone acetals 14:486 synthesis of 14:486 Chiral vinyl halide coupling reaction of 12:35,36 with chu-al a-methyl-substituted aldehyde 12:35,36 Chiral vinyl sulfoxides intramolecular addition to 10:671-679 Chkal vinyllithium compounds addition reaction of 12:35-62 Chiral w-cyano alcohols from achiral a-methoxycycloalkanone oxime acetates 14:475 synthesis of 14:475 via Beckmann fragmentation reaction 14:475 Chiral ylide from Z,-malic acid 4:125 Chu-al-o-quinodimethanes asymmetric intramolecular 14:502,503 Diels-Alder reaction of 14:502,503 with C2-symmetric acetals 14:502,503 Chirality absorption of polarized light 2:159,160 classification of 2:162-164 polarization of 2:158,159 of acetylenic carotenoids 6:17,20,30,31 ofalleniccarotenoids 6:5 and pheromone activity 7:6 in biological activity 7:3-28 of natural products 7:3-28 C/?/>o-inositol a-glucosidases inhibition by 7:9 P-glucosidases inhibition by 7:9 invertase binding with 7:10(+)-C/z/>o-inositol 7:37,38 from conduritol P epoxide 7:38 Chiron approach Sharpless oxidation 17:211 Chu-ons 14:179 Chiroptical properties in natural product structure determination 2:153-173 Chirotopicity 7:5 Chitanase 5:289 Chitin 5:280,287,289,291 Chitin synthetase 1:399 Chito-oligosaccharides 7:33 Chitobiose derivative 6:398,404,413 Chitosan 4:720,276 Chitosome 5:276 Chitranone 2:212-215,754,755 Chlamydia trachomatis 13:183 a-Chlamydosporol toxicity of 13:543 Chlamydosporol 13:543-545 o-Chloranil 1:131,132 oxidation with 1:131,132 a-Chlorinating reagent 6:310 of sulfoxides 6:310 Chlorination 6:310,340 trans -5-Chloro-l-menthen-8-ol 11:307,308 3'-Chloro-2'hydroxy arguticinine 5:207 3-Chloro-2-hydroxy-arguticinin 9:66 3-Chloro-3-deoxy-<af//o-derivative 14:163 l-Chloro-35-dimethoxy benzene 13:360 2-Chloro-5-nitropyridine 12:309 Chloro-8-hydroxy-l,2-methylene-3-[(l,3,5)-5methyl-1,3,5-heptatrienyl)] octahydroindolizidine 12:301 (15',2/?,35,75',85,8a/?)-7-from indolizomycin 12:301 5-Chloro-8-quinolyl 4:286 6-Chloro-D-tryptophan 15:35 4-Chloro-A'^ oxepenes synthesis of 10:216 Chloro-/rw-(triphenyphosphine) rhodium decarbonylation with 5:802 Chloroacetoxylation Pd(II)-catalysed 16:443 (a-Chloroalkyl) boronic esters synthesis of 11:409,410 Chloroamine 11:307,308 A'-Chloroamines from A^-chlorosuccinimide 6:437 Hofftnann-Loeffler photocyclization of 6:437 Chlorobactene 7:339,361-363 Chlorobiaceae 7:361 (a-Chlorocrotyl) boronic ester (methoxycrotyl) boronic ester from 11:424 from allylic alcohol 11:424 a-Chlorocyclopentene carboxylate esters Favorskii rearrangement of 8:225 7-Chlorodehydronoraporphme 16:516 (+)-P-Chlorodisopinocamphenyl borane 698 Chloroformate ester-induced reaction ring destruction by 6:477,486 Chlorogenic acid 15:36

986
3 -Chloroguaiazulene 14:331 Chlorohydrins 1:451 Chloroklotzchin from Artemisia klotzchiana 1'2\^ Chloromercuric method in synthesis of 6-deoxynucleosides 4:233 (Chloromethyl) zinc reagent 14:490 2-Chloromethyl-4-nitrophenyl-phosphorodichloridate 8:73 2- Chloromethylbenzoate 5:827,828 Chloromethylene dimethylforminium chloride 3:212 6- Chloromethylsalicylate 5:828 m-Chloroperbenzoic acid 2:90-103 o-Chlorophenyl group 4:269 Zj/5-2-Chloropheny Ihydrazones 12:3 79 Chlorophyceae 6:134,147 Chlorophyll 7:98 3-Chloroplumbagin 2:212,214,754 Chloropromazine 12:387 (5)-(i?)-Z-Chloropropionic acid with methyl 2-acetamido-4,6-0-benzylid-ene-2deoxy-a-Z)-glucopyranoside 6:386 Chloropseudomonas ethylica 7:363 Chloropuupehenone 15:299 Chloroquine 13:656 Chloroquine diphosphate 7:393 Chlorosuccinimide 12:487 NA^-Chlorosuccinimide DMSO reaction with 6:310 monochlorinated sulfoxide from 6:310 iV-chloroamines from 6:437 Chlorosulfonyl isocyanate cycloaddition with 4:475,477 1 -acetoxy-2-methylbutadiene with 12:150,151 [2+2] cycloaddition of 4:475;12:150,151 Chlorothricholide biogenesis of 4:620 enantioselective synthesis of 10:409 from D-glyceraldehyde acetonide 10:409 Chlorothricin 2-deoxy-D-rhamnoside moiety of 11:215 2,6-dideoxyhexose moiety of 11:213,214 [2+2] Chromophore 12:196 Chloroindolenine approach to vinblastine analogues 4:31 Chocolate spot disease 4:590 Choisya ternata 6:509 (-)-Chokol A asymmetric cyclopropanation of 14:490 synthesis of 14:490 (-)-Chokol A synthesis of 1:632,635 Cholecalciferol (vitamin D3) 9:509-528 Cholecystokinin (CCK) 18:824 5,a-Cholest-14-dne-3p,6a,24-triol 7:288 Cholest-5-en-3P-ol (cholesterol) 9:5,37,447,449, 9:454,461,462 Cholest-5-ene-3a,4p,21-triol 3,21- disulphate from Ophiura sarsi 15:98 Cholest-7-enyl linolenate 9:470 Cholesta-5,7-diene la,3p,25 triol synthesis of 11:390-393,395 5a-Cholesta-9(l l),24(25)-dien-3p,6a 20,22tetraol aglycone 15:49 5a-Cholestan-3-one octant rule in 2:168 5a-Cholestan-3p,6a,8,15a,16p,25-hexaol from Prot or easier nodosus 15:71 Cholestane tetrol synthesis of 17:213-215 5P-Cholestane-3a,4a, 11P, 12p,21 -pentaol 3,21-disulphate 15:96 5P-Cholestane-3a,4a,l lp,21-tetraol 3,21-di-sulphate 15:96 (25/?) 5P-Cholestane-3a,6p, 15a, 16P,26-pentaol 15:75 i25R) 5a-Cholestane-3p,5,6P,15a,16p 26-hexaol 15:75 (245) 5a-Cholestane-3 p,6a,8,15 p,24-pentaol-aglycone 15:61,68 Cholestanepentols 17:214 Cholestanol 6:261, 8:365,366,553,207 rhamnosidation of 8:365,366 thermal glycosidation of 8:365,366 5a/5P Cholestanols steryl palmitates of 9:454 Cholestanyl palmitate 9:454 Cholesterol rhanmosidation of 8:366 thermal glycosidation of 8:364 biosynthesis of 1:655 catabolism to pregnenolone 5:709,711 Cholesterol (cholest-5-en-3P-ol) 9:5,37,447,449,454, 461,462,464,470 Cholesterol-(7-dehydrocholesterin) 9:510,512,521 Cholesteryl 3,4,6,-tri-O-acetyl-P-jD- glucopyranoside 8:363,365,366 Cholesteryl acetate 9:464,465 Cholesteryl arachidonte 9:454,459,461,467 Cholesteryl butyrate 9:464,465 Cholesteryl caproate 9:464,465 Cholesteryl caprylate 9:465 Cholesteryl elaidate 9:457 Cholesteryl esters 9:450,453,457,462,466-478 Cholesteryl laurate 9:465 Cholesteryl linoleate 9:456,461,464,467 Cholesteryl linolenate 9:456,464,467 Cholesteryl myristate 9:460,465 Cholesteryl oleate 9:456,457,464,467 Cholesteryl palmitate 9:454-456,459,461,464,465,467, 472,477 Cholesteryl palmitoelaidate 9:457 Cholesteryl palmitoleate 9:456,457,467 Cholesteryl stearate 9:456,461,465 Cholic acid biosynthesis of 17:219,221 Choline 5:752 Cholinesterase 7:18 Chondodendrum tomentosum 13:631 Chondria armata 11:21 Chondria oppositidada 6:40 cycloeudesmol from 6:40 Chondrilla sp. 18:718 Chondrillin 5:353,354,718 Chondrococcus hornemanni 5:343 Chondrosia collectrix 18:719

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Choriaster granulatus 7:299 Choriocarcinoma vinblastine for 14:805 vincristine for 14:805 Chorismate mutase prephenic acid from 11:188,189 Chorismic acid anthranilic acid from 11:187 from 5-enolpyruvylshikimate 3-phosphate 11:187, 188 phenylalanine from 11:188 tyrosine from 11:188 6-Choro-9-(3-deoxy-p-D-xylo-hexopyranosyl) adenine 4:232 Chroman enantioselective synthesis of 1:644,645 Chromanes fromisoprene 4:391 from phenols 4:394 in prenylation methods 4:394-396 synthesis of 4:374 Chromanones 9:450 Chromatiaceae 7:361 Chromatogaphic analysis by adsorption chromatrography 9:450-453 by gas chromatography 9:453-460 of steryl esters 9:447-486 Chromatogaster scutellaris cenom 6:455-458 Chromazonarol 15:291,298 g/-Chromazonarol 15:291,299 Chromenes 2:126,368,369,372,373,376,409,410; 13:356,358 Chromium (II) reagents 3:81 Chromodoris cavae 9:4,13 Chromodoris funarea 17:9,10 Chromodoris lachii 17:13 Chromodoris macfarlandi 17:11 Chromodoris maridadilus 6:69 Chromodoris norrisi 17:12 Chromodoris species 17:12,14 Chromodorolide A 9:4;17:13 Chromodorolide B 17:13 Chromogenic substrates 7:53 Chromomycin 17:37 Chromomycin A3 3:173 chromomycinone 3:173 cinchonidine 3:385 Chromomycins 4:245 Chromones 17:574 Chromones 9:113-116 Chromonocoumarins 7:415 e/7/-8-Chromozonarol antimicrobial activity of 5:437 Chryosplenoside A 5:682 Chiysanthellin 15:209 Chiysanthellin B 15:210 Chrysanthemumfrutescens 9:317 Chrysanthemum sp. 7:427 cw-Chrysanthemic acid synthesis of 16:702 rraw^-Chrysanthemy 1 alcohol 7:100,101 Chrysanthemyl alcohol 7:126 cw-Chrysanthenol 9:530 c/5-Chrysanthenyl acetate 9:530,536 Chrysartemin B 7:235 Chrysochromulina species 6:135 Chiysoeriol 7:226 Chrysoeriol-7-O-p-coumaroyl glucoside 5:623 Chrysomelidial from Plagiodera versicolora 16:291 synthesis of 16:291-293 Chrysomma sinensis hemoglobin components of 5:837 Chrysomycin 10:347 Chrysophyceae 6:134,135 Chrysoplenium pseudofauriei 5:678 Chrysosplenium americanum 5:682 Chrysospleniumflagelliferum 5:682 Chrysosplenium grayanum 5:682 Chrysosplenol-D antimicrobial activity of 7:413 Chrysosplenoside E 5:682 Chrysosplin 5:682 Chugaev reaction 4:45 Chukrasia tabularis 9:105 a-Chymotrypsin 2:35 Chymotrypsin (CT) 13:56 Chytridiomycetes 9:202 Cicer arietinum 18:719 Cichoriin inhibitor of dehydropeptidase (DHP-1) 12:145 Cilastatin 4:432 Cinchomeronic anhydride 6:510,511 Cmchona alkaloids 7:444,62 1,8-Cineol 9:530,536;15:225,227 Cinnamate 4-hydroxylase 5:467,468 Cinnamates 9:530,536 Cinnamic acid 5:459,467-470,473,479 ()-Cinnamic acid 5:467 Cinnamolide 2:287,288,414 (+)-Cinnamolide ()-polygodial from 6:28 Cinnamomm osmophloeum 15:29 Cinnamomum sieboldii 15:33 Cinnamonium camphola (-)-dimethylmatairesinol 18:558 10-Cinnamoyl baccatin III 11:61 Cinnamoyl ester of crassin antileukemic activity of 8:15 Cinnamoyl-CoA reductase 5:470 CinnamtanninB-1 15:33 CinnamtanninD-1 15:33 Cinnamyl alcohol dehdrogenase 5:470 Cmnamyl alcohols 5:459,463,467,469-471,473,474, 495,497 Cioclapta species 17:16 Ciona intestinalis 5:405,408,249 Circular dichroic power 17:48 Circular dichroism 2:153,159-61,165,166,169-173, 226,227,137,140,149,264,390,539,542;15:193,194; 423-438 Circular dichroism method (octant rule) 14:743 Circularly polarized light 2:154 Cirsilinol 7:226 Cirsimaritin 7:226

988
Citbrasine from Citrus sinensis 13:350 Citeromyces matritensis 5:283 Citeromyces sp. 5:280 Citpressine I from Citrus depressa 13:350 Citpressine II from Citrus grandis 13:350 Citracridone I,II from Citrus depressa 13:348,349 Citral 13:332 Citramalic acid 8:305 (-)-Citreoviridin 10:439 Citreoviridine 18:176 Citric acid in mangrove plants 7:180 Citric acid cycle 9:554 Citrobacter 12:63 a-Citromycinone 14:14 y-Citromycinone synthesis of 14:8-10 Citronellal 8:47 7?-(+)-Citronellal 8:43-46,57,258,266 R (+)-Citronellic acid 16:344 S-Citronellal 17:610 S'-Citronellate 15:229 (-)-Citronellene 17:605 (+)-Citronellol 1:451 ;2:167,168,17,605 (5)-(-)-Citronellol 11:343,344,367 5-(-)-Citronellol 16:192 (3/?H+)-Citronellol 13:122,123 (R)-Citronellol 18:26 Citronellol 7:105,125 Citropten 18:979 Citrullus colocynthis 5:750 Citrus buxifolia atalfoline from 13:350 Citrus aurantium 15:5 Citrus decumna 13:348,349 Citrus depressa citracridones I,II from 13:348 citpressine I from 13: Citrus grandis baiyumine A from 13:348,349 baiyumine B from 13:350 butanine from 13:350 citpressin II from 13:350 grandisines I,II from 13:350 grandisinine from 13:350 honyumine from 13:348,349 prenyl-citpressine from 13:350 Citrus junos junosidine from 13:348,349 Citrus natsudaidai natsucitrines I,II from 13:350 Citrus paradisi eudesm-ll-en-4-ols from 14:450 (+)-intermedeol from 14:450 Citrus sinensis citbrasine from 13:350 citrusinines I,II from 13:348,350 Citrus sp. 5:651 Citrus unshiu 18:682 Citrusinines 1,11348,350 from Citrus sinensis 13:348,350 Civet acid enantioselective synthesis of 1:637,638 Civetone acyloin condensation of 8:224 from Viverra civetta 8:219 Wittig reaction of 8:223,224 Ciwujianosides 15:191 Cladinose 13:155,156,158,159,162 L-Cladinose nucleosides 4:256 Cladonia alpestris 5:310,313 Cladonia confusa 5:310,313 Cladonia crispata 5:310 Cladonia mitis 5:310 Cladonia rangiferina 5:310 Cladonia sp. 5:310 Cladonia squamosa 5:310 Cladophorafascicularis 5:367 Cladosporin ll:193;15:382,385-387 Cladosporin cladosporiodes 11:193;15:386,193 Cladosporium cucumerium 7:406,409,411,413; 15:64, 415,421,433,64 Cladosporium herbarum 5:302 Cladosporium sp. 5:301,325,328,370 Cladosporium suaveolens 13:309-311,313,315 Cladosporium wemeckii 5:301 Cladosporum herbanum 7:119 Cladrastis lutea 5:678,683 Claisen rearrangement 13:29,30,135,142,358,417, 437,438,443,613 Claisen condensation 1:174,49,410,243,99,100 -Claisen condensation, dual of dicarboxylic acid derivatives 11:114 with acetoacetate dianion 11:114 Claisen cyclization 9:341 Claisen ester enolate rearrangement 10:339 Claisen reaction in poitediol synthesis 6:36 Claisen rearrangement 1:172,173,563,180,181,230, 251,43,45,78,91,471,243,457,459;8:180;11:471; 16:260,340,439,471,623,627,703,712 [3,3]-Claisen rearrangement applications of 10:416-426 asymmetric quatemization with 10:426-428 carboxylic acid anhydride variation of 4:375 Eschenmoser modification 3:230 ester enolate procedure 3:236,240,241 in ()-9-isocyanopupukeanane synthesis 6:82,83 in ()-africanol synthesis 6:5 in ()-sinularene synthesis 6:78,79 in lactone synthesis 3:252-255 indolo [2,3-a] quinolizidines by 14:722-724 internal asymmetric induction 3:234 Ireland modification 3:77,228 modified 3:228 of 1,5-anhydro-4,6-0-benzylidene-D-r/^o-hex-1 enitol 10:420 of allyl ester 14:738 ofallyl phenyl ethers 4:368 of carbohydrate derivatives 10:416-426

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of carbohydrates 3:226 ofchiralallylic alcohols 10:418 of cw-2,5-disubstituted dihydrofuran 10:423,424 of dihydropyran derivative 10:425 ofE (3-hydroxy-l -propenyl)-P-D-glucopyranose tetraacetate 10:422 of N,0-ketene acetals 3:232 of oxygen substituted systems 3:237-248 of silyl ketene acetals 422,423 of vinyl ether derivative 10:420 ofvinyl ketene acetals 10:234,235 ofxanthones 4:368,370-372 ortholactone procedure 3:236 regioselectivity of 4:368,368 Clardy synthesis ofpacifigorgion 6:10 Clarithromycin 13:164,183 Classical Nazarov reaction 14:612 Classification 6:546 by sporulation 6:546 offimgi 6:546 of macroline -related alkaloids 13:384-396 of Rabdosia diterpenoids 15:112 of Strychnos alkaloids 1:32 Clatha palustris lAll Clathriapyramida 6:351 Clathridine 17:18 ClathridineB 17:18 Clausantalene intermediate 4:675 Clausarin synthesis of 4:374,375 Clausena harmandiana 9:400 Clausena heptaphylla 2:118 Clausena indica 2:118 Clausena pentaphylla 2:118 Clauson-Kaas reaction 4:703 Clavalanine 16:708 Clavelina picta 10:249 Clavepictines A,B 10:249 Claviceps eurotium 9:203 Clavicepsfusiformis 5:278 Claviceps purpurea 13:631 Claviceps sp. 5:278;11:200 Clavicipitales 9:203 Clavularia inflata (+)-12-acetoxysinularene from 6:77 Cleavage of olefins witht-BuOOHg/HsIOfi 1:445 withMo(CO)6 1:445 Cleavamine synthesis of 14:810 Cleavamine-type alkaloids capuronine 5:103 (+)-20/?-15,20-dihydrocleavamine 5:103 145,20/?-velbanamine 5:103 Cleistopholis patens 2:340 Clemensen reduction 12:279,697,698,240;15:197,198 (+)-Clemeolide 18:28-32 Cleome icosandra 18:28 Cleome viscosa 18:28 Cleomiscosin A 5:5;7:377 Cw-Clerodane-type diterpene 2:280 Clerodendrum uncinatum 1:408,417,423 Clionacelata 5:411 Clionamide 5:411 Clitocybe geotropa 18:813,814 Clitocybe nebularis 18:813,814 Clofazimine 2:424 Cloning 7:114-117 Clostridium 13:303 Clostridium difficile 5:601 Clostridium perfringens 5:601,71,81,86,87,16:108 Clostridium tetanomorphim 9:598,601 Clostridium themoaceticum 9:606 CMB 4:368,369,372,373 CNBR-induced reaction 6-A12-Arl^A16AllAUA%6, 488,489,491,492,495,496 CNS activity 5:520 Cobalamin 9:605,606 Cobalamin cofactor 11:210 Cobalt-stablized carbocations in macrocyclization 3:83,84 coculolidene 3:456,488 synthesis of 3:477,478,488,489 Cobinamide 9:605,606 Cobyrininc acid 9:591,592,597-601,603,605,606 Cocaine 13:631 Cocarcinogen 1:547 Coccidiomycosis 2:422 Coccinelline from tetrahydropyridinium salts 6:447 Coccw/M5spp. 3:456,478 Cocculus trilobus 3:488 (/?) Coclaurin 20:292 Codeine 13:631;18:47,74,87,91 Codeinone synthesis of 10:180 Codonocarpine 9:73 Codonopsis 13:660 Coenzyme A 11:191 Coenzyme A thioester coenzyme B12-dependent rearrangement 11:197 CoetsoidinA 15:137,145,154,171 CoetsoidmB 15:117,124,131,171 CoetsoidinC 15:137,145,154,171 CoetsoidinD 15:137,145,154,171 CoetsoidinE 15:137,145,154,171 CoetsoidinF 15:138,146,155,171 CoetsoidinG 15:138,146,155,171 Coffee bean 2:116 (-ytrans-Cognac lactone from levoglucosenone 14:272,273 synthesis of 14:272,273 Colaphellus lower ingi 18:771 Colaptes auantus 5:836 ll-e/7/-Colartin 7:213,232 Colchicine 3:287-299,5,179;12:179 (75)-Colchicine 3:287-299;13:652 Colchicine 5:46-49,798,799 Colchicum autumnale 5:46 Coleomycetes 9:203 Coleus forskolii forskoline from 13:659 Coleus sp. 7:96,118

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Collectotrichum lagenarium 16:302 Collelochlorin B synthesis of 4:397,398 Colletotrichum dematium 9:230,238,239 Colletotrichum gloeosporiodes f. ^p.yussiaea 9:288, 229,231-235,238-241 Colletotrichum gloeosporioides (Glomerella cingulaa) 9:228,230,232,238-240 Colletotrichum gloeosporioides/. sp. aeschynomene 9:230,238,239 Colletotrichum graminicola 9:230,238,239 Colletotrichum lagenarium 12:400 Colletotrichum lindemuthianum 9:230,239 Colletotrichum malvalum 9:230,231,238,239 Colletotrichum species 9:228,230,239,247 CoUidine 6:385,396,399,400 5-Collidine 6:549,550 Collin's reagent 16:16 Collins ally lie oxidation 6:27 in (-)-dictyolene synthesis 6:27 Collins oxidation 1:312,313,315,316,16,83,84,210; 6:16;11:83,84 Collins reagent 6:115,350,317,335 CoUins-Wege intermediate in ()-sinularene synthesis 6:78,79 Collinusin synthesis of 17:340 Collisella limatula 17:26 Collision activation 2:4 Collision induced fragmentatin 2:43 Collision-induced decomposition (CID) 9:468,489, 494,496 Collision-induced-dissociation (CID) 18:195 Collisional activated decomposition spectrum (CAD) 5:634 Collisional activation (CA) spectra 5:633 Colneleic acid 9:569,570 COLOC 9:147,151,152,268,274,287,515 Colocynthis vulgris 5:743,744,750 Coloradocin 17:284,286,304-306 Columbamine 11:201-204,656 Comantheria briareus 7:266 Comantheria perplexa 7:266 polyketide sulfates of 7:266 Comanthula pectinata polyketide sulfates of 7:266 Comanthus parvicirrus 7:266 Commiphora mukul 5:695,700,701 Comosine synthesis of 3:484-486 (+)-Compactin biological activity of 11:335,336 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor of 11:335,336 total synthesis of 11:335-377 Compactin biogenesis of 4:620 synthesis of 6:303;13:555-615 Compactinervine 1:36 COMPARE 17:495 Competitive inhibitors 7:40,56,69,70

Comphor derivatives synthesis from camphor-10-sulphonic acid 4:628, 632 Comphor-2,8-homoenol 4:638,641,655 Complestatin 10:629,630,667 Complicatic acid 3:7,64 Compositae 7:104,119,120,185,317,328 Comutagenic effect of estrogens 5:477 7-Con-O-methyhiogarol 4:318,357 Concephalenol 2:213 Concinndiol from Laurencia concinna 6:24 synthesis of 6:24,25 Conduritol B epoxide (1,2-anhydro-myo-mositol) a-glucosidases inhibition by 7:37 P-glucosidases inhibition by 7:37 c/z/ro-inositol from 7:38 invertase bmding with 7:38 Conduritol C cw-epoxide P-galactosidase inhibition by 7:38 Conduritol C trans-epoxide 7:37,38 a-galactosidase inhibition by 7:38 with a-Z,-fiicosidase 7:38 Conduritol epoxides 7:37 Conduritols 14:179 Condyfolan-type Strychnos alkaloids 1:33 Condyfoline synthesis of 1:45,46 Condylocarpine 1:40,41,45 (+)-Condylocarpine 5:126 Condylocarpine-A'4-oxide 5:125 Condylocarpine-type alkaloids (+)-tubotaiwine 5:88,89 condylocarpine 5:88,89 condylocarpine-A^4-oxide 5:89 tubotaiwine-A'4-oxide 5:89 (+)-Confertifolin (+)-euryfiiran from 6:28 from 1-abieticacid 4:405-415 from D-podocarpic acid 4:405-407 from Drimys species 4:404 from Drimys winteri Forst 4:418 frommanool 4:424,425 in (-)-warburganal synthesis 4:418 synthesis of 4:405-419 Confertin synthesis of 1:547 l,2-5y-2,3-a//-Configuraiton 12:35,36,41,43,48 Configuration ofguggultetrol 5:704,706 5>;-Configuration 14:753 arabino' Configuration 5:704 ^[(^)]-Configuration of A^-acetyl muramic acid 6:387 Conformational control in macrolactonization 11:152-158 Conformational effects 12:115 Congocidine alkaline degradation 5:549 ()-P-Conhydrine 13:483 (+)-Coniceine 16:466

991
5-Coniceine synthesis of 1:288,291 absolute configuration of 11:229,230 fi-om (+)-coniine 11:229,230 ()-5-Coniceine synthesis of 13:486,488 Conidia 9:228,230,233,238,240,241 Coniferae 7:99 Coniferaldehyde 5:471 (E)' Coniferaldehyde 5:472,475 Coniferm 5:471 Coniferyl alcohol 5:463,464,466,467,471,472,475,495497 (E)- Coniferyl alcohol 5:472 (Z)- Coniferyl alcohol 5:472 (+)-Coniine 12:280;16:475,476 synthesis of 16:475-476 5-coniceine from 11:229,230 ()-Coniine 13:478 1,4-Conjugate addition ofelectrophile 10:405,406 to a,P-unsaturated carbocyclic aldimines 10:405, 406 Conjugate addition 3:8;14:510 Conjugated dienes synthesis of 8:278 Conjugated ketones octant rule for 2:168 Conjugation-deconjugation epimerization 12:14 Conocephalenol 9:249,252,255;18:625,632 Conocephalum conicum 2:273,277,278;9:249 Conoduramine 5:123 Conodurine 5:123 Conopeum seuratum 17:79 Conopharyngine 5:128 Conopharyngine (10,11-dimethoxy-coronaridine) 9:174,176,177 Conopharyngine hydroxyindolenine 5:128,195 Conopharyngine oxindole 5:128 Conopharyngine pseudoindoxy 1 5:128,129 co-Conotoxin GVIA 18:722 Controlled crisscross annulation 13:442 Convergent lactone synthon synthesis of 13:604 Convolvulanic acid A and B 15:342 Convolvulol 15:342 Convolvulus arvensis 15:341 Convorvolus microphyllus 13:312 Convulsions 5:745 Conyza odentophylla (Pluchea arguta) sesquiterpenes from 9:65-68 Coomassie 9:453 Cooke's dianion 13:594 (+)-Copacamphor 4:675 Copaene 8:33-36;17:608 a-Copaene 8:33-36 Cope elimination 3:470,471,468,494,110 Cope reaction 13:109 Cope rearrangement 1:566,567,182,236,416;3:47,98, 372,139,190,191,249;7:216;10:236 Cope ring enlargement 12:193 Copper (I) catalyzed Grignard additions 10:180 Copper (I) trifluoromethane-sulfonate benzene complex 1:271,272 Copper acetylide 4:396,398 Copper catalyzed Grignard reaction 11:81,82 Coprinus mcrorhizus var. microsporus 5:288 Coprotoxins 18:698 Copsychus saularis hemoglobin components of 5:837 Coptisine conversion to ochrobirine and corydaine. 1:289-291 ()-chelamine from 14:793-795 ()-chelidonine from 14:793-795 sangumarine from 14:793-795 Cora islandica 5:313 Corapavonia 5:313 Cora silandica synthesis of 5:128 Coracias benghulensis hemoglobin components of 5:837 Coracina novachollandiae 5:837 hemoglobin components of 5:837 Corals 18:716 Corchorus acutangulus 18:650 23-hydroxy longispmogenin from 18:650 3P, 16p,23,28-tetrahydroxyolean-12-ene from 18:650 Cordia goetzei 7:408,409 Cordiceps ophioglossoides 5:279,318,320 Cordiceps sinensis 5:279 Cordigol 7:408,409 Cordigone 7:408,409 Cordycepin from3-deoxy-2,5-di-0-(p-nitro-benzoyl)-P-Derythro'pentosyl bromide 10:357,358 synthesis of 10:357,358 Cordycepin (3'-deoxyadenosine) from adenosine 10:593 Coreopsis parvifolia 5:800 Corepoxylone 18:195 Corey's oxazaborolidine catalysts 18:182 Corey epoxide 13:568 Corey method 11:154,157 Corey procedure 6:562 Corey reagent 14:268 Corey's lactone 7:480-482 Corey-Kim oxidation 12:338 Corey-Mukaiyama method 1:271 Corey-Myers synthesis 6:195 Corey-Nicolaou method 12:52,53 Coriaria nepalensis 13:311 Coriolic acid synthesis of 1:528,533 (5)-Coriolic acid 13:311 Coriolin synthesis of 3:17,18,20,40,43 synthesis of 4:588 Coriolin B 3:7,65 Coriolins 13:6 Com syrup 2:355 Comaceae 7:427 Cornitermes ovatus 15:3 84 Cornitermes pugnax 15:3 84

992
Comoside 16:616 Cornusflorida 7:421 Corona virus 5:360 Coronafacic acid synthesis of 4:590,591,596,597 fif/-Coronaridine synthesis of 14:847,850-853 Coronaridine 5:127,171 Coronaridine hydroxyindolenine 5:127 Coronaridine-type alkaloids (-)-heyneanine 5:98 (-)-ibogamine 5:93,97 (+)-heyneanine 5:94 (+)-ibogamine 5:97 lO-hydroxycoronaridine 5:98 10-hydroxyheyneanine 5:99 11-hydroxycoronaridine 5:98 ll-hydroxyheyneanine 5:99 18-hydroxycoronaridine 5:98 18-hydroxyvoacangine 5:100 19-e/7/-heyneanine 5:98 19-e/7/-iboxygaineR 5:97 19-e/?/-iboxygaline 19(R) 5:98 19-e/7/-voacfistine 5:100 19-0X0-voacangine 5:99 19/?-hydroxyconopharyngine 5:101 195-3,19-oxidovoacangine 5:99 195'-hydroxyconopharyngine 5:101 19S-iboxygaine 5:97 3-(2-oxopropyl-)-coronaridine 5:100 3,19/?-oxide-coronaridine 5:94,98 3 -//?/5-hydroxy conopharyngine hydroxyindolenine 5:101 3 -cyano-voacangine 5:100 3-ethoxy coronaridine 5:99 3-hydroxycoronaridine 5:98 3 -hydroxymethylvoacangine 5:100 3 -hydroxyvoacangine 5:100 3 -ketopropy 1-19/?-heyneanine 5:100 3 -oxo-conopharyngine 5:100 3-oxo-coronaridine 5:97 3-oxo-coronaridine hydroxyindolenine 5:99 3-oxo-heyneanine 5:99 3-0X0-voacangine 5:99 3-oxo-voacristine 5:100 3/2/5'-hydroxyconpharyngine 5:101 3/?-hydroxy-19/?-heyneanine 5:94 3 -/^-hydroxyconopharyngine hydroxyindolenine 5:101 3-/?-hydroxyisovoacangine 5:99 35-3p-hydroxyethylcoronaridine 5:99 3iS'-hydroxy-19/?-heyneanine 5:94 35-hydroxyvoacangine 5:100 5-oxo-coronaridine 5:98 6-oxo-coronaridine 5:98 6/?-3,6-oxidovoacangine A'4-oxide 5:100 catharanthine 5:97 conopharyngine 5:100 conopharyngine hydroxyindolenine 5:101 coronaridme 5:97 coronaridine hydroxyindolenine 5:98 ibogaine 5:97 ibogaine hydroxyindolenine 5:97 iboxygaine hydroxyindolenine 5:97 isovoacangine 5:99 isovoacristine 5:100 tabemanthine 5:97 voacangine 5:99 voacangine hydroxyindolenine 5:100 voacristine 5:100 voacristine hydroxyindolenine 5:100 Coronatine 4:690 Corphinoids 9:592 Corphins 9:597,605 Corpora cardiaca 2:90,93,94,99,106,112;9:487,490 ep/-Corrossolin synthesis of 18:200,201 Corrossolone hemi-synthesis of 18:219,221 from Annona muricata 18:219 Corticium caeruleum 18:712 Corticoid hormones 9:411-430 A^^^'^-Corticoids 9:426,427 Corticosteroids 17:627-631 Corvus splendens 5:837 Corydaine synthesis of 1:199-201,221 ()-Corydalic acid methyl ester biosynthesis of 14:796 from corysamine 14:796-799 from tetrahydrocorysamine 14:796 synthesis of 14:796-799 via hypothetical enamine 14:796 Corydaline synthesis of 3:445;14:790 Corydalisol from protopine N-oxide 6:494 Corydamine 4:547 Corymbellus aureus 6:135 Corynan-17-oic acid methyl ester ()-Z-geissoschizol from 14:722-724 ()-3-e/7/-Z-geissoschizol from 14:722-724 using trimethyl orthoacetate 14:725 stereoselective 14:725 using dimethyl acetamide dimethyl acetal 14:722724 Corynane-strychanane series 6:503,520 Corynanthe yohimbe ajmalicine 8:283 yohimbine 8:283 Corynanthe-type alkaloids 15:378 ()-Corynantheal 18:332 Corynanthean 5:112,113 Corynanthean-type alkaloids 5:71,150-163 ()-Corynantheidol 14:709,710 synthesis of 14:709,710 Corynebacterium bovis 12:400 Corynebacterium glutammicum 13:320 Corynebacterium poinsettiae 1:357 Corynoline 14:770 ()-Corynoline from corysamine 14:785-787 oxidation of 14:788,789

993
synthesis of 14:785-787 through enamine-aldehyde cycHzation 14:785-788 Corynoline-type alkaloids 4:455 Corysamine ()-corydalic acid methyl ester from 14:796-799 ()-corynoline from 14:785-787 ()-isocorynoline from 14:785-787 ()-ll-epicorynoline from 14:785-787 ()-ll-epiisocorynoline from 14:785-787 Corytuberine 18:58 Cosciansterias tenuispina cosicinasteroside D from 7:298 Coscinasterias tenuispina 15:46,51,52 Coscinasteroside A-C 15:53 Coscinasteroside D 7:298,302,53 Coscinasteroside E-F 15:53 ()-Costaclavine 18:336 Costaticella hasta harmanfrom 18:726 pavettine from 18:726 Costaticella hastata 17:90 Costunolide by transannular [2,3]-Wittig rearrangement 8:195-198 synthesis of 8:195-198 Costunolide 7:230 Cosynthetase 9:596 Cotton curve 6:542 Cotton effect 2:160,161,169,170,172,173,286,140, 255,551,434,435,623 Cottonogenic derivatives 2:166 Coulomb interactions 2:165 Coulomb's law 2:164,173 4- Coumarate 3-hydroxylase 5:468,469 l,4-Coumarate:CoAligase 5:470 (i:)-4- Coumaric acid 5:467,469,470 Coumaric acid 9:279 Coumarin 9:529 Coumarin-hemiterpene ethers 7:205 Coumarin-sesquiterpene ethers in Artemisia abrotanum 7:269 Coumarinolignan derivatives 5:9 Coumarinolignan isomer 5:5,6 Coumarinolignans 5:3,5,8,9,495,496 Coumarins 4:3,5,8,9,367,372,375,377,389,391,399,400, 495,496,505,517-521,202,204-206,220,224,225, 574-575,971-1080 Coumaryl alcohol 5:463,467 4Coupling constants of 18-e/7/-dialdehydes 6:128,129 Cp2ZrCl2. AgC104 aryl C-glycosides from 10:370 CPI precursor synthesis of 3:371,372 CPI-CDPI2 3:362,367-370 CPMAS spectra 5:776 of6-hydroxyperezone 5:776 Cram i\,2-syn) coupling product 12:42,43,45,48,50,55 Cram (l,2-5>'A7)-selective coupling reaction of chiralvinyl halide 12:35,36 with A chiral-a-methySubstituted aldehyde 12:35, 36 Cram addition ofenolates 16:345 of2-lithiofiirans 16:346 Cram rule selectivity 1:608 Cram's cyclic model 4:201,491 of 1,2-asymmetric induction 4:201 Cram's rule 14:482;16:350 Cram-selective aldol-lactonization 14:115 Cramer reaction 8:77,80 Crassin antitumor activity 8:15,19 synthesis of 8:19-30 titanium-induced coupling 8:19-30 (+)-Crassin 8:29,30 Crassin acetate antibiotic activity 8:15 ' H - N M R spectrum of 8:20 mass spectrometry of 8:20 X-ray analysis of 8:20 synthesis of 10:6,7 Crassin alcohol 10:7 Crataeva nurvals 5:209 Crematogaster ants 6:454,455 Crematogaster deformis mellein 15:383 Crematogaster lineolata 6:454 Crematogaster scutellaris 6:422,453,455 Crepidamine 12:277,285:12:287 Crepidme 12:285 from Dendrobium crepidatum 12:285 X-ray diffraction studies of 12:285 /7-Cresyl methyl ether Birch reduction of 6:83,84 ()-9-pupukanone synthesis from 6:83,84 Cribricellina cribraria 17:79,89-90 Cribrocalina vasculum dihydrocalysterol from 9:37 petrosterol from 9:37 Criegee rearrangement 14:128 Crimmins synthesis 12:11,12 Crinine asymmetric synthesis 4:14,15 from Amaryllidaceae 4:3,4 synthesis of 4:13-17 Crinoidea 7:266,100-103 Crinosterol 16:322,332,334 Crinum asiaticum 18:687 Crispatine synthesis of 1:272,273 Crithidia deanei polysaccharides in 2:296-298 Crithidiafasciculata 2:295-297,577 Crithidia guilhermei 18:791,792 Crithidia harmosa 2:298 Crithidia luciliae 2:298,791,792 Crithidia oncopelti 791 Croalbinecine 1:230,238,484,485 Crobarbatine acetate synthesis of 1:271,272 Crocosimioside H 15:191

994
Cross coupling reactions 16:417 intramolecular 10:163 Pd-catalyzed 10:161,162 with (Z)-tributylvinyl-stannanes 10:162 Cross relaxation rates 2:60,61 Cross-aldol reaction of (7/?,8aiS)-8-hydroxy-8-methyl-7-oxoindolizidine 12:297 Cross-aldolisation 12:289,298 Cross-Claisen condensation 11:114 Cross-conjugated hydronaphthalene dienones photochemical rearrangement of 14:356 C2-symmetric diols 14:469-518 chiral acetals from 14:469-518 C2-symmetric ketene acetal 14:505 asymmetric cycloaddition of 14:505 to 3-formyl chromone 14:505 Crossasterpapposa 7:298,299;15:61,69 Crossasteroside A from Crossaster papposus 15:61 Crossasteroside Pi and P2 15:69 Crossasterosides A-D 7:299,301 Crossed Aldol reaction asymmetric induction in 4:328,329 Crossed Cannizzaro reaction 4:17,135 Crossed Wittig reaction 4:570 Crossed-Aldol condensation diastereoselective 1:596-603 Johnson-Yamamoto mechanism 1:600 Crossopteryx febrifuga 7:417,425 Crotepoxide synthesis of 4:612 Croton 9:265 Croton macrostachys 4:612 Croton oil 12:392 Croton tiglium 12:233 trans-CroXoxvam\6& 8:156 cw-Crotonamide 8:156,157 Crotonates 8:410-412,427 /mw-Crotonates 8:141,147,155 ,157 cw-Crotonates synthesis of 8:155-157 (^-Crotonic acid 11:340,341,359 (Z)-Crotonic acid 11:340,341,359 Crotonyl boronate addition 1:527 Crotyl halide in zinc dust 12:172 with 4-acetoxy P-lactam 12:172 Crotylborane reagent 12:36 Crotylboration 8:477 (-)-(E)-Crotyldiisopinocamphenyl borane 18:280,281 [i]-Crotylpotassium 8:477 [Z]-Crotylpotassium 8:477 "Crown ether effect" 11:234 Crown gall tumors 9:386 Crustacyanin 6:161 Cryoenzymology 7:31 Cryomixture 18:836 Crypsirina vagabunder 5:837 Cryptaustoline 3:423 Cryptaustoline iodide 6:482

Crypthecodinium cohnii 9:47 Cryptocarya pleurosperma 1:365 Cryptococcosis 2:422,433 Cryptococcus albidus 4-thioxylobiose from 8:336,352 Cryptococcus albidus 5:292,328 Cryptococcusflavescens 5:294 Cryptococcus laurentii 5:292,294,328 Cryptococcus neoformans 2:428,446,292,322,5:326328,400,408 Cryptococcus si^. 5:291,292,294,328 p-Cryptoeutreptiellanone 6:150,151 Cryptolepine 1:127 Cryptolepine 5:751,752 Cryptolepis sanguinolenta 5:751 Cryptolestesferrugineus 8:227 Cryptoleuridine 1:365 Cryptomeriajaponica 2:402 Cryptonoline iodide 6:482 Cryptophyceae 6:134.155 Cryptopleurine synthesis of 1:365-367 Crystallization- induced asymmetric transformation 13:76 Crystamidine 3:476 CrytowoUine 3:423 (CT) Chymotrypsin Culmoriuns 13:519,536,537 from Fusarium culmorum 13:536 synergistic effects 13:536 toxicity 13:536 Cu (I)-catalysed 3:8 Cuanzin 8:283,284,289,293 antiarrhytmic activity of 8:283 antihypertensive activity of 8:283 from Voacanga chalotiana 8:283 synthesis of 8:283-293 Cuauhtemone 9:66 Cubitene by a-thiocarbanion-epoxide 8:230 from Cubitermes umbratus 8:230 synthesis of 8:230 Cubitermes sp defence secretion of 8:220 Cubitermes umbratus cubitene from 8:230 Cubugene 8:221 Cuculus micropterus hemoglobin components of 5:837 Cuculus varius vahl hemoglobin components of 5:837 Cucumaria echinata 15:94 Cucumariafraudatrix cucumariosides Gi, Ci and C2 from 15:87,92 Cucumaria frondos a frondogenmfrom 7:277 Cucumaria japonica cucumarioside A2-2 from 7:275;15:87 Cucumaria lefevrei 15:92 Cucumariidae 7:275,277,280 Cucumarioside A2-2 7:275,276,15:87 Cucumarioside Cj & C2 7:275,276 Cucumarioside G, 7:275,277,281

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Cucumarioside G2 from Eupentactafraudatrix 15:89 Cucumariosides Gi, Ci and C2 from Cucumariafraudatrix 15:87,92 Cucurbitane 5:744,750 Cucurbic acid 6:557 Cucurbitaceae 5:743,744,750 Cucurbitacin B glycoside of 5:750 Cucurbitacin D 5:750 Cucurbitacin E glycoside of 5:750 Cucurbitacin I 5:744,751 Cucurbitacin J 5:744,751 Cucurbitacin L glycoside of 5:750 Cucurbitacin 20:4,13 Cul-tributylphosphine complex tandem Michael addition with 4:556,557 Culcia novaeguinea 7:298,15:69 Culcitoside Ci 15:69 Culcitoside C4-C8 15:71 Culcitosides CpCa cumambrinA,B 7:235 cyclases 7:96,109,110 diterpene synthetase 7:109,110 from Culcita novaeguinea 7:298 sesquiterpene synthetase 7:109,110 Culex pipiens fatigans 3:157 Cullmorum 6:219,220;9:206,207,215,216 Culmorone 6:219,220,536 Culture medium effect on prod, of polyphenols 17:432 CumambrinA,B 7:235 Cumarins 9:113-116 27-/7-cumaroxy-ursolic acid 20:6 Cunningham 19:627 Cunninghamella echinulata 20:792 Cunninghamella elegans 20:214 Cumulated ylides 4:658 Cupalaurenol 5:368,7 Cupalaurenol acetate 5:368,7 Cuparene 8:12 ((i,/)-Cuparene synthesis of 8:3,6 Cuparene-related sesquiterpenes 17:7 (+)-a-Cuparenone 10:407 (-)-a-Cuparenone 10:407 {d, /)-P-Cuparenone reduction of 8:6 synthesis of 8:3 {d, /)-a-Cuparenone reduction of 8:6 synthesis of 8:3,4 Cuprate 1:456,457,459,460 Cupressaceae 18:558,19:627 Curan-type Strychnos alkaloids 1:33 Curare alkaloids 20:269 Curculigo latifolia 15:36 Curculin from Curculigo latifolia 15:36 Curcuma longa 8:52,13:660,17:363,373,377,379, 20:734 CwrcM/wa species 17:358 Curcuma tinctoria 17:357 Curcuma xanthorrhiza 17:364 a- Curcumene 5:803-805,20:6 (+)-Y-Curcumene 8:39 Curcumenes 5:777-71^ Curcumin 13:660,357,363,374,379,17:374,20:729, 734,772 Curcuphenol 5:804 (+)-Curcuquinone 8:39 Curcuquinone synthesis of 5:770,771 transformations of 5:694 Curtius reaction 12:448,458 Curtius degradation 19:145 Curtius rearrangement 1:51,6,309,637,638,19:68,79 Curtius-type reaction 13:95 Curvularia lunata 9:412,417,418 Cuspareine synthesis of 3:393 Cussonia barteri 7:427 Cussonia spicata 7:427,435 Cyanide versus isocyanide formation 3:207 Cyanin chloride 20:738 Cyanobacterial origin 20:887-913 Cyano j3-C-glycosides 10:372 4-5'-Cyano derivative 8:335,336 Cyano trapping 1:105 a-Cyanopiperidine 19:35-36 l,2-0-Cyano(p-methoxy)benzylidene-a-D-galactose 14:252 2-Cyano-l,l-dimthylethyl 4:285 2-Cyano-6-oxazolo-piperidine 12:351 2-Cyano-azadiene Diels-Alder reaction 16:458 Cyanobacterial hepatotoxins 9:496-499 a-Cyanobenzyl alkyl ether synthesis of 14:473 Cyanoborohydride 8:205 3-Cyanocephem derivative synthesis of 12:137 Cyanocobalamin 9:598,603,606 Cyanocycline A antitumor activity of 10:103 synthesis of 10:108-115 Cyanocycline F 10:104 2-Cyanoethyl group 4:285 bis-(2-Cyanoethyl) phosphorochloridate 8:74 Cyanogen bromide fragmentation of glucoamylase 2:34 Cyanogenetic glycoside 15:226 Cyanohydrin cyclization of 8:198 synthesis of 8:225,226 Cyanohydrin ether alkylationof 8:177 cyclization of 8:178 Cyanomorpholino sugar 14:21 Cyanonaphthyridinomycm 10:103,104

996
Cyanophthalides daunomycinone synthesis 4:321,332 Cyanophyceae 6:134 Cyanophyta 10:250 Cyanopropylsiloxane 9:456 Cyanosiloxane 9:454,456 (-)-1 -Cyanovinyl (1' 5)-camphanate 14:179 (+)-1 -Cyanovinyl (1 '/?)-camphanate from (1' /?)-camphanic acid 14:179 1-Cyanovinyl (l/?)-camphanate 12:340 1 -Cyanovinyl (15,5^,7i)-3-ethyl-2-oxo-6,8-dioxa-33-azabicyclo [3.2.1] octan-7-exo-carboxylate 12:340 3-Cyanovoacangine 5:124 Cyantions of acetals diastereoselective 1:612,613 Cyathocaline 20:485 Cybister tripunctatus 5:700 Cyclachaenin 5:728,729 Cyclaradine 8:148 Cyclase synthesis of 8:298 from sweet marjoram {Marjoram hortensis) 11:222 diterpene synthetase 7:109,110 sesquiterpene synthetase 7:109,110 Cyclea atjehensis 20:552 Cyclea barbata 20:522 Cyclic amino acids synthesis of 13:507-512 Cyclic AMP 7:387 Cyclic AMP phosphyodiesterase 5:512,513,520 Cyclic p-keto esters reduction with yeast 1:697-701 Cyclic dienes 8:141 Cyclic ene-dione acceptors 4:709,711 in Michael reaction 4:707-709 Cyclic enones 14:502 [2+2] photocycloaddition of 14:502 with chiral a,p-unsaturated acetals 14:502 Cyclic hexadepsipeptides 13:533 Cyclic ketones synthesis of 6:313-315,332,333 Cyclic peroxides 5:353-355 Cyclic steroidal glycosides 15:59,60 Cyclic sulfides 8:205 Cyclic systems synthesis by modifications of 6:33-38 de novo synthesis of 6:33 Cyclic-Cram diastereoselectivity 12:297 Cyclitol derivatives 7:156,157 Cyclic halo ether compounds from marine origin 19:411-461 synthesis of 19:411-461 Cyclindrocarine 19:112 Cyclitols 13:6 Cyclization (+)-(47?)-a-terpinyl from 11:221,222 acyliminium-mediated 10:125 amide iminium ion 10:87 asymmetric 10:631-633 azido-olefin 13:447,448 bicyclic keto ester from 14:509 by C-C bond formation 10:218-231 by C-0 bond formation 10:202 by diphenyl phosphoryl azide 10:641,644,652, 10:656,657 by sodium bistrimethylsilylamide 6:540 catalytic 8:278 Dieckmann 13:445 ene 8:279 enzymatically controlled 11:287 in silver (I) triflate 12:81 intramolecular 10:631-633 intramolecular 11:253,254 intramolecular 12:156 iodotrimethylsilane mediated 11:109 Lewis acid mediated 10:87 ligase catalyzed 14:304,305 mechanism of 6:314,315 mechanism of 7:335-338,358-360 of (-)-(3i?)-linalyldiphosphate 11:221,222 of(Z,)-glutamicacid 6:438-440 of acyclic nucleoside derivative 10:588,592 ofallylglycidyl ether 10:588,589 of a-mono-alkoxy lated piperazinediones 12:90 of cyanohydrin ethers 8:194 of epoxy alcohol 10:599,600 ofepoxyallylic ether 10:590,591 of glucose 11:219 ofhexapeptide 10:289,290 oflycopene 7:334-354 ofneurosporene 7:334-354 ofnitroketone 6:447,448 of oligoribonucleotides 14:304,305 of vinyl sulfoxides 10:673-676 of vinyl sulfoximines 10:679 of a-diazo p-keto ester acetals 14:509 oxetane ring formation by 10:588,589 oxetanocin A synthesis by 10:588-592 palladium catalysed 1:258 reductive 8:278 regioselectivity of 6:540 Rh (Il)-catalyzed 14:509 stereochemistry of 7:338-354 stereoselective 10:110 stereoselectivity of 6:540 transannular 13:440 via SN^ displacement 11:253,254 with copper (II) perchlorate 12:85 with diphenyl phosphoryl azide 10:289,290 with Nicolaou reagent 10:121,122 with pyridinium chlorochromate 11:93,94 Cyclization of ketoesters 4:328-330 Cyclization reaction [2+2] cycloadditions 6:15,43,44 diastereoselective 14:506,507 in (+)-A^^'^^ capnellene synthesis 6:43,44 in cadinane synthesis 6:15 in elemane synthesis 6:15 in germacrane synthesis 6:15 of6-octen-l-al 14:506,507 Rh(I) catalyzed 14:506,507

997
Cyclized branched oligoribonucleotides 14:486,489 (-)-Cyclizidine absolute configuration of 12:306 biological activity 12:305,306 from Streptomyces species 12:305 Cyclo-( 1 -3)-[3-galactooligosaccharides 14:237 Cyclo-( 1 -6)-p-galactooligosaccharides 14:237 9p,19-Cyclo-l 1-0X0 steroidal alkaloids 2:205,206 9p,19-Cyclo-20-oxo-(16-17) steroidal alkaloids 2:207 9p,19-Cyclo-A(6^7) steroidal alkaloids 2:207 7,20-Cyclo-er-kaurane skeleton 15:167 7,20-Cyclo-e/ir-kaurenoids 15:112 Cyclo-L-rhamnohexaose synthesis of 8:359-370 Cyclo-octanoid terpenes synthesis of 6:33-36 1,3-Cycloaddition 1:448,449 [2+2]-Cycloaddition 1:263,343;4:475;8:207,45,185; ll:15-20,45-47;12:l 16,150-152,160,161,173,193,416; 15:266;16:127,470,732,733 carbocyclic oxetanocins synthesis by 10:610-616 enantioselective 10:610-616 in homoerythrinan synthesis 3:481,478 ofallene 16:127 photochemical 16:125,469 with dichloroketene 13:6,36 synthesis of quinoline skeleton 3:385-397 [2+2]-Cycloaddition-fragmentation 12:194,195 [2+3]-Cycloaddition 4-oxo-erythrinans by 3:469 [3+2]-Cycloaddition 8:402,19:66,78,80,174,367 of 2-azaallyl fragments 1:324 ofazomethine 8:402 ofazomethineylide 19:80 intramolecular 19:367 stereospecific 19:367 [3+2]-Cycloaddition reaction 12:155 ofnitrone 12:155 to benzyl crotonate 12:155 [3+4]-Cycloaddition 1:378,522,523 [47t+27t]-Cycloadditions 1:566-571 mtramolecular tropone-olefin 1:568 inverse electron demand 1:566 with tropone as diene 1:566-571 [4+2]-Cycloaddition 1:282,323,420,465,8:207,45,185; 11:11,13,14,16,260-267;16:4,444,493,732;19:108109,148,221,227 acid catalyzed 4:4 base catalyzed 8,9,11,12,22,23 cycloaldolization 4:4,11,17,18,22,23 diasteroselective 12:424,425 high pressure Eu (fod)3-mediated 4:121,143 in (+)-A-^^*^^ capnellene synthesis 6:43,44 in lincosamine synthesis 4:154 in purpurosamine C synthesis 4:115 of2-alkenyltropolones 5:799 of 3-[( 1 S)-2-exo-alkoxy-1 -apocamphanecarbonyl]-2oxazolones 12:424,425 of a-amino aldehydes 4:111 of kojic acid 5:799 reverse stereoselectivity of 4:122 to dialkyl azodicarboxylates 12:424,425 transannular 5:796,797 [4+4]-Cycloaddition 11:17 [5+2]-Cycloaddition 8:160-163,16:552,553;12:260,261 [67c+47i]-Cycloaddition 12:238 [6+3]-Cycloaddition 1:569 [6+4] -Cycloaddition intramolecular 1:571 of cyclopentadiene with tropone 1:570 of dienes to tropone 1:569-571 of2-alkenyltropolones 5:799,800 [8+2]-Cycloaddition 1:568 Cycloaddition 16:7,47 1,3-dipolar 1:247-250 asymmetric 1:371-375;11:300 by 3-hydroxy-1 -arylthiobutene 4:477 by chlorosulfonyl isocyanate 4:475 -exo-transition state 1:370,371 enolate induced 1:502-503 intramolecular [3+2] 1:247-250 intramolecular [4+1] 1:247-250 intramolecular nitrile oxide [INOC] 1:477,480,481 ionic 5:793 lanthanide catalyzed 1:413,415 MgBr2 mediated 1:474 Ni (O)-catalysed intramolecular 3:78,79 of (N-acryloyl) boman-10,2-sultam 11:307,308 ofalkene 11:468 of levoglucosenone 14:270,271 of olefinic ketone 1:693 photochemical [2+2] 1:548 stereoselection 1:370,371 TicU-catalyzed 11:307,308 with bisketene 4:349 with cyclopentadiene 11:307,308 with ethoxycarbonyl formontrile oxide 11:468 with unactivated olefins 1:338 Cycloaddition processes 12:250-261 for tigliane rmg system 12:250-261 Cycloaddition reaction 14:502-505,747,19:226 diastereoselective 14:502-505 with 1-trimethyl silyloxybutadiene 14:747 ofquinonemonoketals 5:796,797 Cycloadduct chiral synthon of 2-amino alcohol from 12:425 rrfl5-4-methoxy-2-oxazolidinone from 12:425 [5+2]-Cycloadducts 16:555-559 [4+2]-Cycloadducts 16:732 Cycloalkane 8:3-14 Cycloaraneosene synthesis of 3:97-99 Cycloart-24-en-3-one 9:288,289 Cycloart-24-en-3p-ol 9:288,289 Cycloartane 9:267 Cycloartene triterpenes 10:151 Cycloartenol 17:622 Cycloartenyl linoleate 9:461 Cycloartenyl palmitate 9:461 8,14-Cycloberbines 1:188,189,192-197 Cyclobullatine-A 2:207 [2+2] Cyclobutane formation 10:611,613

998
Cyclobutanes protic acid rearrangement of 16:553 rearrangements of 16:554 Cyclobutanol 14:647 Cyclobutanone oxaspiropentane rearrangement by 10:618 Cyclobutanone-ring expansion 3:23,24 (-)--Cyclobuxaphylamine 2:197,198 (-)-Z-Cyclobuxaphylamine 2:198,199 Cyclobuxomicreine 2:207 Cyclobuxophylline 2:207 Cyclobuxophylline-O 2:207 Cyclobuxosuffrine 2:207 (+)-Cyclobuxotriene 2:194,195 (-)-Cyclobuxoviricine 2:193,194,204 Cyclobuxoviricine 2:207 Cyclobuxoviridine 2:207 (+)-3,5-Cyclocamphanone 4:646 Cyclocarbamations 12:411,414 Cyclocarbonate group 6:285,286 (245',255)-24,26-Cyclocholesterol from Spheciospongia vagabunda 9:37 Cyclocholesterol 9:41 P-Cyclocitral 14:430,431,20:570 (/?)-(-)-Cyclocitral pallescensin-1 from 6:31 (3-Cyclocitrol condensation of 14:673-676 taxodione from 14:673-676 with 3-isopropyl-4-methoxy-benzyl chloride 14:673-676 (-)-Cyclocolorenone 14:360 Cyclocondensation and//zreo-selectivity 4:130,145 Lewis acid catalyzed 11:446-451 Mg Br2-catalyzed 11:451 MgBr2 catalyzed 1:415,417 with Ce(OAc)3-BF3.0Et2 1:420,421 with Danishefsky's diene 4:122,130 withEuFOD 1:420,421 with X-serinal 4:122 with A',O-protected a-amino aldehyde 4:130 with silyloxydienes 4:113 Cw-p-Cyclocostunolide 2:280,281 Cyclocurcumin 17:363 (,Z)-2,6-Cyclodecadiene 8:177 (,^-2,6-Cyclodecadiene 8:177 Cyclodecadienone by [3+3]-Oxy-Cope rearrangement 8:247 by Diels-Alder reaction 8:249 photocycloaddition 8:250 Cyclodepsipeptides 5:419,10:251,252,263 Cyclodextrins 7:34 a-Cyclodextrin 13:328 synthesis 8:367 methyl analog of 8:367 synthesis of 8:367,368 p-Cyclodextrin Cyclodimerization withDEPC 4:92,93 of tetrahydroisoquinoline precursors 6:495 Cycloeucalenol obtusifiiluol from 9:39 Cycloeudesmol from Chondria oppositiclate 6:40 isocycloeudesmol relation to 6:41 (+)-a-selinene conversion to 6:40 synthesis of 6:41 Cyclofriedo-oleanone X-ray analysis of 7:152 from Euphorbia nerifolia 7:152-154 Cyclofiinctionalization ofethylurethanes 6:427,428 with phenylselenyl chloride 6:427,428 Cyclogibberellane 6:207 9,15-Cyclogibberellin 6:206 Cycloglycofoline 13:348,349,370-372 cw-Cyclogonionenin 18:222 ^ram-Cyclogonionenin 18:222 Cycloheptanone 8:35 Cycloheptene-6,7-dicarboxylate 9:226 Cycloheptenone enolate in perforenone synthesis 6:29,30 Robinson annulation of 6:29,30 Cyclohexadiene 12:11,12 Cyclohexadienones 5:343-346 Cyclohexane ring system annulaton of 6:5,6,29,30 Cyclohexanecarboxylic acid 11:190 from shikimic acid 11:190 cw-l,2-Cyclohexanediol 10:324,325 trans-1,2-Cyclohexanediol 10:324,325 1,2-Cyclohexanediones ^w-Fischer indolization of 12:376,377 Cyclohexanhexaol (inositol) 7:37 Cyclohexanol 11:343 Cyclohexanone 8:36 aromatization of 14:637,638 by chiral lithium amides 571,572 kmetic deprotonation of 14:571,572 prochiral 4-substituted 14:571,572 Cyclohexanone aldehyde 6:61 bromochamigerene from 6:61 spiroannulation of 6:61 spiro[5.5] undecenone derivativwe from 6:61 Cyclohexanone cyanohydrin 12:211 2-Cyclohexen-1 -one aldolsfrom 11:337,338 kinetic deprotonation 11:337,338 with 4-pentenal 11:337,338 1 -Cyclohexene carboxy 1 CoA 11:190,191 Cyclohexene derivatives synthesis of 4:581 Cyclohexene imides arcyriaflavin A from 12:378 6w-2-chlorophenylhydrazones from 12:379 N-methylarcyriaflavin A from 12:378 1 -Cyclohexenecarboxylic acid 11:191 trans -Cyclohexenecarboxylic acid by Diels-Alder addition 11:340,341 from ()-crotonic acid 11:340,341 from butadiene 11:340,341

999
deprotonation of 14:658 with lithium diisopropyl amide 14:658 w-Cyclohexyl fatty acid from thermophilic bacteria 11:190 1 -Cyclohexyl-3-(2-morpholinoethyl) carbodiimide Cyclohexylamine 15:4 (35',45)-Cyclohexylstatine 12:432,433 from(45',55)-5-allyl-4-methoxy-2-oxazolidinone 12:432,433 Cyclohexylstatine(35,45)-4-amino-5-cyclohexyl3-hydroxypentanoic acid) 12:432 renin inhibitor of 12:432 w-Cyclohexylundecanoic acid 11:190 Cycloisomerization of cis, cw-3-carboxymuconic acid 8:297 ofenynes 8:277-281,16:418,435 palladium-catalyzed 16:418 Cyclolaurene 17:7 Cyclolaurenol 17:7 Cyclolodecene 6:541 Cyclomalyanine - B 2:207 Cyclomicrobuxeine 2:207 Cyclomicrosine 2:207 Cycloneosamandaridin 9:305 Cycloneosamandion 9:305 Cyclooctenone synthesis of 8:35 L-Cyclooligosaccharide 8:359-370 Cyclooxygenase 5:521,559,571,572,575,578;9:581 Cyclopamine 7:16,17,21,22 Cyclopapilosine - D 2:207 Cyclopenta [c] pyran 7:458,459 Cyclopentadecanones 10:330,331 Cyclopentadiene 2:162,307,308;11:307,308 Cyclopentadiene 8:141-147,150,153 Cyclopentane annulation 13:6,16 Cyclopentane derivatives c-stereochemistry of 8:9 stereoselective synthesis of 8:9 Cyclopentane ring system annulation of 6:6-8,30,31 cw-l,2-Cyclopentanediol 10:324,325 /roTAw-l ,2-Cyclopentanediol 10:324,325 1,2-Cyclopentanediol 8:20 Cyclopentanoid monoterpene alkaloids 7:443,444 Cyclopentanoid natural products 4:581 Cyclopentanoids 8:139 Cyclopentanol formation of 14:647 in 5-alkoxy ketones 14:647 ring expansion of 8:245 Cyclopentanone 1-piperidenines from 6:428,429 Cyclopentanooxazolidine 12:295 Cyclopentendialdehyde 7:465,466 Cyclopentene annulation 13:14 Cyclopentenpolyols 7:475 Cyclopentylamine derivative 8:397 (i)-Cyclopentylglycine 13:510,511 Cyclopeptide 5:405,419-429 cytotoxic activity of 5:419-429 Cyclopeptolides 10:280,281 Cyclopia 7:16 Cyclophellitols 19:351-388 Cycloposine 7:16,17 Cycloprodigiosin 8:272 Cyclopropa [c] pyrrolo [3,2-e] indol-4-(5H)one (CPI) 3:320 synthesis of 3:320 Cyclopropanation diastereoselective 14:489-491 exo 1:252,253 intramolecular 16:222 of allylic alcohol-acetal 14:490,491 of diazo ketones 3:39,40 of ten-membered enones 8:179 of unsaturated acetal 14:490 with Me3S(0)I-NaH 8:186 with oxysulfiirane 8:183 /rflf5-Cyclopropane 8:183,184 cw-Cyclopropane 8:184,185 Cyclopropane aldimine 12:287 Cyclopropane ring opening 1:250-253 Cyclopropane sterols biosynthesis of 9:35-43 Cyclopropane-1,2,3-selenadiazole 9:122,123 Cyclopropanecarbonitrile 12:287 Cyclopropanedicarboxylic acid 10:618 Cyclopropanes 3:288,232,407 Cyclopropanone 8:36 Cyclopropanone sliding reaction 6:37,48 (+).A-^(i2).capnellene from 6:48 in (+)-dactylol formation 6:237 in eight-membered marine compounds 6:37 Cyclopropene sterols biosynthesis of 9:44-47 Cyclopropyl ether 8:34 synthesis of 8:34 Cyclopropyl imine acid catalysed rearrangement 1:250,251,296 Cyclopropyl ketones 2:168,169 Cyclopropyl-carbinol rearrangement 3:23 Cyclopropylphosphonum salts 12:311 Cycloprotobuxine - C 2:207 Cycloprotobuxine - F 2:207 [2+2] Cycloreversion 15:266 Cycloreversion 4:609 Cyclosarkomycin 8:149-152 Ru04-oxidation of 8:149 ozonolysisof 8:149,150 synthesis of 8:149-152 (-)-(2S,3R)-Cyclosarkomycin 8:150,152 Cycloserine 2:422 Cyclospongiaqumone-I 15:299 Cyclospongiaquinone-II 15:299 Cyclosporin A 10:256-258,299,20:894 Cyclosporine 5:128 Cyclostachine 4:618,619 biosynthesis of 4:618,619 Cyclosterol 16:324 Cyclotetrapeptides 10:250 Cyclotaxanes 20:3,11,80,100 Cycloundecenone 8:214 synthesis of 8:214

1000

Cyclovirobuxeine - A 2:207 Cyclovirobuxeine-B 2:207 Cyclovirobuxine-D 2:207 Cyclovitamin D3 10:70 Cycopentannulation 1:551,552 Cytotoxic T-lymphocytes 18:921 Cyclindrocarpidine 5:128 P-Cylodextrin 13:332 Cymbopogonflexuosus eudesm-1 l-en-4-ols from 14:450 intermedeol from 14:450,451 Cynara scholaris 13:660 Cymol 20:13,16 Cynarin 13:660 Cypenamine 8:474 Cyperaceae 9:391 (+)-6-e/7/-a-Cyperone 10:408 p-Cyperone fromthujone 14:406-413 synthesis of 14:406-413 trienonefrom 14:406-413 (-)-7-e/?/-Cyperone from (-)-carvone 14:452,453 (+)-intermedeol from 14:452,453 paradisiol from 14:453 Wolff-Kishner reduction of 14:452,453 D-Cysteinolic acid 15:76 Cyptanol from Salvia napiflia 20:670 Cystodytes dellechiajei 10:250 Cystodytins A-C 10:250 Cystophora torulosa 9:322 Cystoseira balaerica 20:35 Cystoseira crinita 20:25,28,35 Cystoseira elegans 18:712,713 Cystoseira spinosa (var. squarrosa) 9:321 Cytarabine (ARA-C) as anticancer agent 5:403 Cytidine diphosphate diacylglycerols 18:433 Cytisine 2:62,63 (-)-Cytisine 15:522 Cytisus scoparius (-)-3,13a-dihydroxylupanine from 15:525 Cytochalasans synthesis of 13:107-153 biogenesis of 4:620 Cytochalasin (B) bis-tetrahydropyranylether 13:116 Cytochalasin B synthesis of 10:166;13:116-118,120 Cytochalasin C synthesis of 13:148,149 Cytochalasin D synthesis of 13:107-139 Cytochalasin E 13:107,114 Cytochalasin G synthesis of 13:130,131 Cytochalasin H synthesis of 13:125-129,134 Cytochalasin H and J 15:353 Cytochalasin K 13:107

Cytochalasins synthesis of 8:213 Cytochalasins N, O, P, Q, R and S 15:353 Cytochrome 7:105 Cytochrome P 13:450 168 Cytochrome P-450 catalyzing aromatic hydroxylation 5:456 Cytochrome P-450 inhibitor 4:621 Cytochrome P-450 monooxygenases 5:448,19:629 Cytochrome P-450 O-hydroxylases 5:455 Cytochrome P450 17:475 Cytochromes 18:914 Cytokinins 4:227-229,7:89,90,94,20:531 6-benzylaminopurine (BAP) as 7:90 2,4-dichlorophenoxyacetic acid as 7:90 kinetin (6-frirfiiryl amino purine) as 7:90 Cytopathogenicity 15:76 Cytopathic "activity" 20:442 Cytosolic inositol (tris) phosphate 18:857 Cytosine 19:516 Cytostatic activity 18:775-778,20:796 Cytotoxic agents 19:601 Cytotoxic against human neurablastoma NB-1 cells 12:390 staurosporine 12:390 Cytotoxic activity of 9-methoxycamptothecine 5:84 of Acalycgorgia 5:368,369 of alga 5:342,346 ofcamptotheeine 5:84 ofcoclenterate 5:342 of cyclic peptides 4:101,102 of moUusk 5:342 of sponge 5:342-346,353 oftunicate 5:342 of ulithiacyclamide 4:101 Cytotoxic agent 2:404,293-303,653 savinin 13:653 from Nerium oleander 9:293-303 Cytotoxic hydrophilic taxol derivatives 12:221 Cytotoxic peptides 4:83,110 Cytotoxicity of p-alaninookadaicacid 5:388 of y-aminobutyrokadaic acid 5:388 of 5-aminovalcrookadaic acid 5:388 ofamphidinolideB 5:396 of glycookadaic acid 5:384,385 of halichondrin B 5:378,380 of halichondrm C 5:380 ofhomohalichondrin A 5:380 ofhomohalichondrinB 5:380 of norhalichondrin A 5:378,380,383,384 ofokadaicacid 5:384,385,389 of taurookadaic acidf 5:388 of tumour necrosis factor 5:387 Cytovaricin 5:607 Cyttaria hariotti 5:278

P-Z)-glucuronidase 16:77,81, 16:108 D(+)-tryptophan 13:408,409,416,417,427

1001

D-2'-deoxycarbocyclic guanosine antiviral activity of 10:608,609 D-a-aminouronic acid synthesis of 11:459,460 D-a//o-a-amino acid synthesis of 11:460,461 D-flf//o-threonine 4-acetoxy-P-lactam from 12:160 D-arabino-hex-l-ulosonate 20:857,859 D-arabino-hex-l-ulosonate sodium salt monohydrates 20:859 D-arabitol 9:288 P-D-Desosaminyl methymycin 11:151 D-ery/Zzro-p-methylaspartic acid 9:496 a-D-glucopyranose 13:188,215 a-D-glucopyranosyl chloride allylation of 10:362 stereoselectivity of 10:362 D-glucosamine mitomycin from 13:203,210,211,435 D-glucose 11:156,158,18-20 D-glyceraldehyde derived allylic alcohols Johnson-Claisen rearrangement of 10:436,437 D-glycero-D-guloheptose from D-glucose 10:419 D-glycero-D-manno-hcptopyranose 11:429 D-glycero-D-talo-hQptito\ (volemitol) 11:457 D'gtycero-D-talo-L-talo- undecose pentaacetonide synthesis of 11:455-458 D-gluonic-y-lactone 20:859 D-isoascorbic acid 12:304,13:488 D-mannitol 13:70,18:443 D-mannonic-5-lactam by microbial oxidation 10:538 with Gluconobacter suboxydans 10:538 D-mannono-nitriles catalytic hemihydrogenation of 10:463 Nef reaction of 10:464 a-D-mannopyranoside 13:216 3 -(0)-a-D-mannopyranosyl-5a-carba-a-Dmannopyranose 13:216,217 D-mannose derivative 10:413 di-C-alkylation of 10:413 D-myo-inositol 18:391 D-pipecolic acid 12:280 D-prostaglandins synthesis of 16:368 (3-D-ribofiiranosyl cyanide 10:356 D-ribose 10:337 D-^/2/"eo-hex-2-enone-1,4-lactone 20:859 D-xv/o-hex-2-ulosonate sodium salt monohydrate 20:859 D:A-friedo-olean-3,21-dione 7:147,148 D:A-friedo-oleananes biogenesis of 7:150-152 from Kokoona zeylanica 7:147-149 D:B-friedo-oleanane 7:150 ID INADEQUATE spectra 9:145 2D INADEQUATE spectra 9:143-146 2D-C0L0C 9:147,151,152

Dacetyllaurencin enzymatic synthesis of 19:453 Dacrydium cuprassinum 13:19-22 Dacrydium cupressinum 3:117 Dacrydium intermedium 20:619 Dactomelynes 19:411 Dactylol synthesis of 3:91-93 from Aplysia dactylomela 6:35 relation to poitediol 6:35 synthesis of 6:36,37 (+)-Dactylol cyclopropanone sliding reaction in 6:37 from (+)-africanol 6:37 from tricarbocyclic epoxide 6:37 Dactylomelol 17:8 Dactylopius coccus 20:734 (-)-Dactylosponol 15:297 (-)-Dactylospontriol 15:297 (-)-Dactylynes 19:411 Dactylynes 19:411 Dacus cucumis 2,5-dimethyl-3-,6-dimetyl pyrazines of 5:225 Dacus cucurbitae 2,5-dimethyl-3-methylpyrazines of 5:225 methylpyrazines of 5:222 Dacus dorsalis 2,5-dimethyl-3-methylpyrazines of 5:222 Dacus occfipitalis 2,5-dimethyl-3-ethylpyrazines of 5:222,223 Dacus oleae 4:571,222;14:521,19:131 DAHP {2)-diQOxy-D-arabino -heptulosonate 7phosphate) 11:183,184 Dakin reaction 9:341 /ra5-2,5-Dalkylpyrrolidines in Monomorium species 6:434 in thief ants 6:443 synthesis of 6:443,444 Damaliscus dorcas 19:122 P-Damascenone from Rosa damascena 14:425 from safronitrile 14:430,431 fromthujone 14:431,432 synthesis of 14:430,431 a-Damascenone 13:328 y-Damascenone from Rosa damascena 14:425 Damascones (rose oil ketones) synthesis of 14:425-431 Damiana 13:660 Dammaran-20(5)-ol oxidation with/w-CPBA 2:91 Dammarane derivatives 2:91-93 Dammarane triterpenoids 2:91-93 a-Damscone from Rosa damascena 14:425 Damsin 1:546 Danaidone from Danaus gilippus 8:223 Danaus gilippus danaidone from 8:223 Dandrolasin 17:13

1002

Danishefsky's diene 1:460,474;4:122,130,132;8:207; 13:565;14:18,636-638;16:474,496,654 Danishefsky synthesis 12:12,13,15 of mitomycins 13:443 ofaveraiectin Ala 12:12,13,15 Danishefsky's pyran synthesis 1:460,407 3-Dansylamino piperidone 9:549 Dansylation 9:547,549 Dapetes 198 Daphna genkwa yuanhuacine from 13:660 Daphnane 12:246 Daphne mezereum 20:22 Daphnetoxin 20:22 Daphnetin 7:224 Daphniphyllium alkaloid synthesis of 16:441 Dartiscin 5:682 Darzens-Nenitzescu condensation 19:235 DAST 19:341 Darzens reaction 17:612 Dasycarpidone 1:34,56-58 Dasytricha 2:294 Datisca cannabina 5:678,682 Datiscanin 5:682 Datiscetin 5:678 Datiscoside 5:682 Datura %QnviS 17:395 Datumetilin 20:181 Datura stramonium 20:135 Datura tatura daturataturin A and B from 20:194 Datura innoxia 11:204 Daturalactone A 20:194,242,246 Daturalactone B 20:194,223,241,246 Daturalactone C 20:180,241 Daturalactones 20:180 Daturilin 20:181 Daturadiol 7:164,166 (+)-Daucene 14:356 (-)-Daucene 5:732,734,226 (-)-Daucol 14:356 Daucol 5:721,725,730-732,736,737 Daucus carota 5:721,730 Daucyl-d, 1-alaninate hydrobromide 5:721 Daunomycin 1:498,371-319,412,474,475,493 ;14:474, 475 Daunomycinone synthesis of l:500-502;4:321,322,349;14:24-42 biosynthesis of 11:123 from aklavinone 11:123 synthesis from amino acids 4:345-349 synthesis from hydroxy acids 4:345-349 Daunorubicin 4:317,318,355;14:3;20:458 L-Davmosamine synthesis of 1:510-513 Daunosamine 4:150;14:4 synthesis of 4:150 3-ep/-Daunosamine synthesis of 4:149 Daunosamine analogues of adenine 4:240,241

ofcytosine 4:240,241 of puromycin 240,241 of thymine 4:240,241 Daurinol synthesis of 17:335 Davana ether 9:533 Davanone 3:58,217,218;7:217;9:531 -533 DawodensinA 15:117,124,131,171 (DBU) Diazabicyclo[5.4.0]undec- 7-ene 6:126; 127; 13:424,425 DCC-HOSu procedure 6:407,409 DDQ (2,3-dichloro-4,5-dicyanobenzoquinone) 11:156, 165 DDQ 8-10,14,18 De-isopropylidenation 4:200,201 De-A^-protection via hydrogenolysis 11:270 De-0-Acetylation 14:230,232 De-0-benzylation 12:37,38,52 4-Deacetoxy T-2 toxin 9:210 9- Deacetoxy-14,15-deepoxyxeniculin 5:369,370 Deacetoxy-3'-chloro-2'-hydroxyarg;uticinin 5:207 ^H-NMR spectrum of 5:207 Deacetoxy-3 -chloro-2-hydroxy-arguticinin 9:66 e/7/-12-Deacetoxyaplysillm 17:12 12Deacetoxycephalosporin C C-3-hydroxylation of 11:211,212 Deacetoxylakuanmiiline 9:194,195 10-DeacetylbaccatinIII 12:217 10-Deacetyldaphylloside 7:469,470 Na-Deacetylaspidospermatine 1:40 Deacetylation 1:10 10-Deacetylbaccatin III 11:3,5,61 from Taxus baccata 11:61 Deacetyldeformoakuammiline 9:194,195 N-Deacetylisoretuline 1:38,39,9:183,188 Deacetylretuline 1:38,39 10-Deacetyltaxol 20:81 7-e/7/-10-Deacetyltaxol 20:81 10-Deacetyltaxol 11:61 Deacetylvindoline hydrazide 14:808,863 coupling of 14:808 with 20[3-dihydrocleavamine 14:808 9-Deacetylxenicin 5:370 Deacylgymnemic acid 18:655,656,661 Deamination 1:681 of (/?)-2-aminohexadecanoic acid 1:681 Dean-Stark water separator 19:219 Deazaflavin F420 20:840 Dearomatization 4:333 Debaryomyces castelli 5:283 Debaryomyces hansenii 5:282,283 Debaryomyces kloeckeri 5:283 Debaryomyces phaffi 5:283 Debaryomyces subglobosus 5:283 Debenzylation 11:253,254;19:110,115 Debenzylidenation by Hanessian procedure 12:347 Deboronation 11:412,413 Debromination 4:336,337 Debromoaplysiatoxin 18:295,297,19:219 (2,4Z)-2,4-Decadienal 10:151

1003

(2,4)-2,4-Decadienal 10:151,155 ^ra5-Decahydro-5,8a-dimethyl-1,6-naphthalenedione derivatives 10:461 (+)-rra5-Decahydroquinoline 219A 19:4,7 Decahydroisoquinolines 12:446 Y-Decanolide 13:32,310,313,315,328,332 (R)-Y-Decanolide 13:308,309,315,329 (5)-y-Decanolide 13:311,312 5-Decanolide 13:312,315 Decapeptides 9:487-489 Decaprenoxanthin absolute configuration, of 7:355;20:596,597 from Cellulomonas dehydrogenans 7:357 Decarboalkoxylative cyclization alkaline 14:720-722 indolo-[2,3-a] quinolizidines from 14:720-722 stereochemical course of 14:720-722 Decarbomethoxy-15,20,16,17-tetrahydrosecodine 5:124 16- Decarbomethoxy-19',20'-20'-ep/-voacamine 5:128 16- Decarbomethoxy-19',20'-dihydrovoacamine 5:124 16'-Decarbomethoxy-20'-deoxy-vinblastine 4:30,31 Decarbomethoxycatharanthine 14:870,871 Decarbomethoxydeacetylvinblastinemonohydrazide from deacetylvindoline hydrazide 14:863 velbanamine from 14:863 Decarbomethoxylation with MgCb/DMSO 3:473 with CaCb/DMSO 3:475 16/?-Decarbomethoxytacamine 5:125 165-Decarbomethoxytacamine 5:126 16/?, 16'-Decarbomethoxytetrahydrosecamine 5:141,142 165,16'-Decarbomethoxytetrahydrosecamine 5:142,143 16-Decarbomethoxyvoacamine 5:125 Decarbonylation Rh (I)-catalysed 3:308,309 with Wilkinson's catalyst 11:263 with chloro-rrw-(triphenyphosphine) rhodium 5:802 Decarbonylation -iminium ion cyclization 4:38,39 Decarboxylase 8:298 Decarboxylation of p-keto ester 16:371 ofanthrones 11:121 of 2-methyl-3-buten-2-yl acetate 11:130 Pd-catalyzed 11:143,144 of vinylogous b-keto acid 14:678-681 10-Decarboxyquinocarcin antitumor activity of 19:338 cytotoxic activity of 19:338 Decarboxylative condensation 11:195 Decarine synthesis of 3:429 11-Dechlororebeccamycin from Saccharothrix aerocolonigenes 12:366,368 L-Decilonitre 19:118 Decilorubicin 19:118 Decinnamoyl taxinine J 11:5 Decipiances 15:263-269 Decitol 4:183 Deconjugation 1:464,465 Deconjugative alkylation 4:38

Decyanation 6:431-433 Dedrogyl 9:513 Deepoxyneoxanthin 6:136,143,144 20-Deethyl-20-epivincadififormine 19:109,112 20-Deethyl-3-oxo-20-epivincadifformine 19:110-111 20-Deethyl-3-oxotabersonine 19:112 20-Deethyl-3-oxovincadifformine 19:110-111 20-Deethyl-3-thiooxotabersonine 19:112 16-Deethylapovincamine 19:112 20-Deethyltabersonine 19:112 Deethylibophyllidine 9:190 20-Deethylvmcadifformine 19:109,111-112 20-Deethyltubifolidine synthesis of 1:66 Defluorination of2-fluroestradiol 5:477,453,455 Degalactosylation 7:55 Degradation ofaureol 9:31,32 of ear/o-sigmosceptrellin-A 9:28,29 ofgeraniol 7:104,105,116 ofnerol 7:105 ofa-pinene 7:106 Dehomologation 12:95 Dehydration with Burgess reagent 10:124 of ^-monosubsituted formamides 12:113 Dehydrioiridodial 16:290 Dehydro abietic acid abietatriene-7-one from 14:685,687-689 18,19-Dehydro-alloaristoteline alloaristoteline from 11:319,320 ()-Dehydroancistrocladine 20:419,420,426 10-Dehydro-lO-deacetyl-l \{\5-\yabeo baccatin III 20:107 19,20-Dehydroyohimbine synthesis of 3:412,415 19,20-Dehydro-lO-methoxytalcarpine 13:388 (+)-14,15- Dehydro-16-e/?/-vincamine 5:126 22-Dehydro-24-norcholesterol 9:41 26-Dehydro-25-epiaplysterol from Petrosiaficiformis 9:40 9,11 -Dehydro-3-deoxy-2-oxa-25-hydroxy-vitamin-D3 9:515 9,1 l-Dehydro-3-deoxy-a-nor-2-oxa-25-hydroxyvitaminDs 9:515 Dehydro-9,10-aristoteline 9:172 y-Dehydro-a-amino acid synthesis of 11:471,472 Dehydro-arachidonic acids 9:568 1,4-Dehydro-P-lactam 12:159,160,167,172,173 Dehydroabietane 2:402,404 Dehydroabietic acid from Rabdosia nervosa 15:173 1,2-Dehydroacetyh-etuline 1:38,39 (-)-A^-Dehydroalbine from Lupinus termis 15:524 Dehydroamino acids 16:410 1,2-Dehydroaspidospermidme 2:370;14:635,636 Dehydrobromination 11:341,342 Dehydrobruceantin 7:374 Dehydrobruceantol 7:374

1004

Dehydrobrucein-B 7:374 (-)-5,6-Dehydrocamphor 16:144 (+)-5,6-Dehydrocamphor 4:644 7-Dehydrocholesterin (chlolesterol) 9:510,511 7-Dehydrocholesterin reductase 9:512 7-Dehydrocholesterol 5:406 22-Dehydrocholesterol 9:47 7-Dehydrocholesterol (provitamin D3) 9:511,521 7-Dehydrocholesterol-reductase 9:511 18,19-Dehydrocobyrinic acid 9:601 Dehydroconiferyl alcohol 5:497 (-)-Dehydrocostus 14:368 Dehydrocostus lactone synthesis of 1:556,559 Dehydrocurvularin by Alternaria cinerariae 11:193,194 Dehydrocyanation 10:120,121 Dehydrocyclospongia quinone-I 15:299 1,2-Dehydrodeacetyl retuline 9:195 Dehydrodesoxypodophyllotoxin 18:553,555 1,2,3,4-Dehydrodesoxypodophyllotoxin 18:557,561 3,4-Dehydrodesoxypodophyllotoxin 18:588 Dehydrodiconiferyl alcohol 5:465,467,497 24-Dehydroechinoside A from Actinopyga agassizi 7:270 (-)-10,11 -Dehydroepingaione 15:237 3-Dehydroecdysone 19:634 19,20- Dehydroervatamine 5:124 Dehydrofalcarmone 7:202,222 2-Dehydroferruginol 2:402 Dehydrogeissoschizine 15:486-488 Dehydrogenation in CI(NO) mass spectra 2:3,4 of amines 4:54 with CMD 4:85 withDDQ 1:8,9,59 with other oxidants 4:85 with palladium black catalyzed 14:763 with p-toluene sulfinyl chloride 4:54 with selenium reagents 14:440 with sulfur catalysis 14:763 13,18-Dehydroglaucarubinone 7:381 22-Dehydrohalitylosides D,D from Sphaerodiscus placenta 7:298 Dehydroipomeamarone 15:249 Dehydroiridodial from Actinidia polygama Miq. 16:290 Dehydrou-idodiol 3:136 Dehydrologanin 16:294 (+)-5,6-Dehydrolupanine from Thermopsis chinensis 15:523 11,12-Dehydromakomakine (+)-makomakine from 11:281,282 Dehydromatricaria ester 7:202,203,221 (-)-A^-Dehydromultiflorine from Lupinus termis 15:525 R-(+)-10,11 -Dehydromyoporene 15:229 (-)-Dehydromyoporone 15:229 (-)-10,11 -Dehydrongaione 15:237 (E)-8-e/7/-2,3-Dehydrononactate 18:236 (6S,8R)-(E)-2,3-Dehydrononactate 18:237 Dehydronorglaucine 16:508

Dehydroophioxanthin 15:100 Dehydrooxoperezinone 5:771,773 Dehydropeptidase-1 (DHP-1) 12:145 D-r/60-Dehydrophytosphingosines 18:465 Dehydropodophyllotoxin 18:554 Dehydropreakuammicine 1:31 (+)-20/?-1,2- Dehydropseudoaspidospermidine 5:124 (-)205-l,2- Dehydropseudoaspidospermidine 5:124 3-Dehydroquinate from Z-dQOxy-D-arabino- heptulosonate 7phosphate 11:184-186 3-Dehydroquinate synthase 11:184,219 1,2-Dehydroreticuline 18:53 1,2-Dehydroreticuline reductase 18:53 1,2-Dehydroreticuliniumion 18:53 6,7-Dehydroroyleanone from Rabdosia lophanthoides var. gerardiana 15:173 from Rabdosia stracheyi 15:175 Dehydrosalvilimbinol from Salvia limbata 20:683 2,3-Dehydrosalvipisone 20:712 Dehydroscoulerine by S'-tetrahydroprotoberberine oxidase 11:204 from scoulerine 11:204,205 Dehydrosecodine epipandoline from 14:832 pandolinefrom 14:832 3-Dehydroshikimate 11:184,185 Dehydroshowdomycin by Wittig reaction 10:393 synthesis of 10:393 25-Dehydrostichlorogenol 7:272 Dehydrosulfinylation 6:342 19,20-Dehydrotalcarpine synthesis 13:411,427,428 3 -Dehydroteasteron from Distylium racemosum 18:500 from Triticum aestivum 18:500 synthesis of 18:512,513 25-ep/-4-Dehydro-2,3,25,27-tetrahydrophysalinA 20:189 14,15- Dehydrotetrastachynine 5:129 Dehydroxdycapuvosine 5:124 Dehydroxyisocapuvosine 5:124 19,20-Dehydroyohimbines 3:399,411,412 Dehyrocivetone 8:224 Deketalization 14:678,679 Deklamin 9:513 Delayed COSY spectra 9:151,152 Delesseria sanguinea A'.lXl Delesserine synthesis of 4:712,713 Delphinidin 5:646 Delphinin chloride 20:738 Delphinium species 20:19 Demania toxica 5:393 a-Demascone 19:137 DeMayo reaction 3:74,75,102,103 Demercuration with sodium borohydride 1:671,672 4-Demethoxy anthracyclinones 14:10

1005

4-Demethoxy daunomycinone 14:17 4-Demethoxy-l-O-methyl daunomycinone 14:5 6-Demethoxy acronycine 20:795 Na-Demethoxy-11 -methoxy-( 19/?-hydroxygelselselegine 15:513 4-Demethoxy-6-desoxyadriamycinones 14:8 4-Demethoxy-7-deoxydaunomycinone 1:507,508 7-Demethoxy-7-deoxydaunomycinone 4:342,343 4-Demethoxy-7-0-methyl daunomycinone 14:5 4-Demethoxy-9-deacetyl-9-(hydroxymethyl) daunomycinone 14:12 4-Demethoxyadriamycin 4:317 16'-Demethoxycarbony 1-16'-ep/-deoxyvinblastine 14:850-852 synthesis of 14:850-852 Demethoxycarbonylation by Welch procedure 10:308,309 Demethoxycarbonyldeoxyvinblastine 5:183,184 synthesis of 5:183,184 12-Demethoxycylindrocarpidine 5:124 (-)-12-Demethoxy-A'( 1 )-acetylcyclindrocarine 19:112 12-Demethoxy-A'^( 1 )-acety Icyclindrocarine 19:115 (+)-Demethoxy aspidospermine 19:143 Demethy Icryptoj aponol from Salvia montbretii 20:666 4-Demethoxydaunomycin synthesis of 1:501,505-510;4:319,320,323,324,334, 335 (+)-4-Demethoxydaunomycinone synthesis of 4:319,320 Demethoxydeoxodihydrocolchicine synthesis of 3:290 (+)-3 -Demethoxyerythratidinone synthesis of 8:270-272 3-Demethoxyerythratidinone synthesis of 3:479 1 -Demethoxyfeudomycinone enantioselective synthesis of 4:346,347 Ng-Demethoxyhumantenirine 15:494,495 10-Demethoxykopsidasinine 5:52-54;9:186-189 Demethoxykopsidasinine 9:188,189 Na-Demethoxyrankinidine from Gelsemium elegans 15:496 12- Demethoxytabemulosine 5:127 (-)-Nb-Demethyl alstogustine N-oxide 9:190 7-(9-Demethyl chelerythrine 14:783 7-O-Demethyl dihydrochelerythrine 14:780,781 Demethyl frutescin 9:317 7-O-Demethyl oxychelerythrine 7,8-demethylene sanguinarine from 14:783,784 A^-methyl decarine from 14:783,784 Demethyl zeylasteone 7:147,148 Demethyl zeylasteral 7:147-149 N- Demethyl-16-ep/-accedine 5:127 3'-N-Demethyl-2',4'-bis-0-(2-methoxyethoxy methyl)-7-con-0-methylnogarol 14:88 3 '-N-Demethy l-2'-4-bis-0-(2-methoxy ethoxy methyl)-7,8 dihydronogarene 14:87 (-)-9-Demethyl-7,9-dimethoxynogarene 14:82 9-Demethyl-9-hydroxy-7-methoxynogarene 14:82 ^a-Demethyl-Na-formylleurosine 14:818,819

A^b-Demethylalstophylline oxmdole 5:159-161 Nb-Demethylalstophylline oxindole 9:196,197 (+)-Demethylaspidospermidine 5:127 Demethy lation 1:8,9 A'4-DemethyIcapuvosine 5:124 11 - Demethylconoduramine 5:129 4- Demethyldesoxypodophyllotoxin 5:480-484,488 Demethyldihydrokamebacetal A 15:135 (-)-Nb-Demethylechitamme 9:183,184 5-Demethylene bicyclomycin synthesis of 12:75,76 7,8-Demethylene sanguinarine 14:783,784 5-Demethylene-6-deoxy bicyclomycin synthesis of 12:75,76 Demethylenepodophyllotoxin dimethyl ether 18:597 23 -Demethy Igorgosterol from Gorgoniaflabellum 9:37 from Gorgonia ventilina 9:37 O-Demethylpalosine 5:127 Demethylpeceyline 5:149-151 4'- Demethylpodophyllotoxin 5:475,477,479, 5:480-482,488,493 ()-6-Demethylstatine synthesis of 13:514 A'4-Demethyltabemamine 5:123 A'4- DemethyIvoacamine 5:128 Demethylyatein 5:488 Demethylzelasteral 5:744-746 Demethylzeylastrone 5:744-746 22/?,255-Demissidine 7:19-21 Demissidine 7:23 Dendrobates histrionicus (+)-indolizidine from 11:294 Dendrobates pumilio Panamanian population of 19:4 pumiliotoxin B from 12:294 Dendrobates speciosus A^-oxides of allopumiliotoxin 267 A from 12:294 AT-oxides of pumiliotoxin 323 A from 12:294 Dendrobates tricolor pumiliotoxin 251 D from 12:294 Dendrobatid alkaloids synthesis of 11:244-267 biology of 10:3 chemistry of 19:3 pharmacology of 19:3 synthesis of 19:3-88 Dendrobatid specionsus indolizidines from 11:266 Dendrobatid toxin synthesis of 1:286,287 Dendrobatidae 11:244,294 Dendrobatide 12:294 (-)-Dendrobine synthesis of 16:435 Dendrobium crepidatum crepidamine from 12:285 crepidinefrom 12:285 dendrocrepine from 12:285 Dendrocotonus brevicomis exo-brevicomin from 11:413

1006

Dendrocrepine 12:277,285,286 Dendrodoa grossularia 5:412;10:245 Dendrodoine cytotoxic activity of 5:412 Dendrodoris grandiflora 17:28 Dendrodoris limbata 17:28 Dendroibatidae 19:3 Dendroid-test method 13:233,234 Dendrolasin cyclizationof 1:666 Dendropanax trifidus dendropanoxide from 2:98-103 Dendropanoxide 2:98-103,164,165 Dendryphiella salina 10:152 Dendiyphiellin A 10:149,152 Densitometry 9:453 DentatinA 7:232 DentatinB 7:230 Denticulatin 5:211,212 Dentroctonus brevicomin 19:126 Denticulatin A and B antimicrobial activity of 17:24 Denudatin antifeeding activity of 8:160 synthesis of 8:160 Deoxmannojirimycin 10:527 13 -Deoxo-13 a-acetyloxy-1 -deoxy-nor-taxine B 20:80 13 -Deoxo-13 a-acety loxy-1 -deoxytaxine B 20:80 13-Deoxo-13a-acetyloxytaxineB 20:80 6-Deoxo-24-epicastasterone 18:503,514 6-Deoxo-28-norcastasterone 18:507 9(/?)-9-Deoxo-9-dimethyl-aminoerythromycin A 13:182 6-Deoxocastasteron 18:503 (-)-Deoxoprosopine 12:475 (+)-Deoxoprosopinine 13:482 Deoxoscalarin 17:10 2-Deoxycrustecdysone 19:466 11-Deoxy anthracyclinone 14:49 2-Deoxy ^-arabino pyranosyl cyanides 10:354 2-Deoxy P-glucose 7:59 11-Deoxy daimomycinone 14:472 (-)-7-Deoxy daunomycinone synthesis of 14:493,494 Deoxy PDE-I synthesis of 3:355 Deoxy PDE-II synthesis of 3:355 3 -Deoxy-1,2,5,6-di-0-isopropylidene-3 -C-methyl-aD-glucofuranose 10:435,436 3-Deoxy-1,2:5,6-di-0-isopropylidene-a-D-r/Z?ohexofuranose 14:154,155,157,166-171 3-Deoxy-1,2:5,6-di-0-isopropylidene-D-xv/ohexofuranose 14:172 2-Deoxy-1 -hydroxysugars 11:141 9,11-Deoxy-11-methyl-prostaglandins 7:481 (15/?')-20'-Deoxy-15'-hydroxyleurosidine acetylderivative of 14:814,815 from 20'-deoxy-15'oxoleurosidine 14:814,815 3-Deoxy-D-manno-2-octulosonic acid 20:857 (155')-20'-Deoxy-15 '-hydroxyleurosidine acetyl derivative of 14:814,815

20'-deoxyleurosidine from 14:814,815 20'-deoxy-15'-oxoleurosidine from 14:814,815 from anhydrovinblastine 14:814,815 Moffat oxidation of 14:814,815 thioxobenzoate derivative of 14:814,815 20'-Deoxy-15'-oxoleurosidine (15'/?)-20'-deoxy-15'-hydroxyleurosidine from 14: 814,815 20'-deoxy-15 '-oxovinblastine from 14:814,815 from (15'S)-20'-deoxy-15'-hydroxy leurosidine 14:814,815 20'-Deoxy-15'-oxovinblastine from 20'-deoxy-15'-oxoleurosidine 14:814,815 (15'R)-15'-hydroxy-20'-deoxyvinblastine from 14:814,815 12-Deoxy-16-e/7/-acetoxyscalarafiiran synthesis of 6:122,123 3-Deoxy-la-25-dihydroxy vitamin D3 synthesis of 10:70 2-Deoxy-2-desmethlenebicyclomycin synthesis of 12:87 2-Deoxy-2-fluoro-P-D-glucopyranoside as P-glucosidase inhibitor 7:64 2-deoxy-2-fluoroglucosyl fluorides 7:64 3-Deoxy-2-oxa-25-hydroxy-vitamin D3 9:515,516 2-Deoxy-2-phosphinyl-Z)-tetritol 6:357 2-Deoxy-24-epibrassinolide 18:507 Deoxy-3 -C-hydroxymethyl-P-D-glucopyranosyl) 9-(3 adenine 4:255 3-Deoxy-3-fluoro-D-wyo-inositol 18:439 3-Deoxy-3-fluoro-sucrose 7:69 11 -Deoxy-4-demethoxydaunomycinone 1:501 4-Deoxy-4-phosphinyl-Z)-ribofiu'anoses 6:363-365 5-Deoxy-5-(alkylphosphinyl)-D-xylopyranoses 6:368 5 -Deoxy-5 -(ethyIphosphinyl)-L-idopyranoses 6:3 73 5-Deoxy-5-(hydroxyphosphinyl)-D-glucopyranoses 6:370,371 5-Deoxy-5-(hydroxyphosphinyl)-)-mannopyranoses 6:374 5-Deoxy-5-(phenylphosphinyl))-Z)-xylopyranoses 6:368 5-Deoxy-5-(phenylphosphinyl)-I-fucosamine from 2-azido-Z)-arabino-hexofiiranose 6:369 6-Deoxy-5-enohexopyranoside Ferrier reaction of 10:510 S-hydroxycyclohexan derivative 10:510 5-Deoxy-5-phosphinothioyl-Z)-xylopyranoes 6:374,375 5-Deoxy-5-phosphiny 1-D-glucopyranoses 6:369-372 5-Deoxy-5-phosphinyl-Z)-mannopyranoses 6:373,374 5-Deoxy-5-phosphinyl-Z)-ribopyranoses 6:368 5-Deoxy-5-phosphinyl-Z)-xylopyranoses 6:374,375 5-Deoxy-5-phosphinyl-I-idopyranoses 6:373 6-Deoxy-6-[(ethoxy) alkyl phosphinyl]-Z)-glucopyranose 6:377 (+)-1 -Deoxy-6-8-Di-e/7/-castanospermine 12:350 (+)-1 -Deoxy-6-8a-Di-ep/-castanospermine 12:350 5-ep/-2-Deoxymakisterone A 19:468 (-)-6-Deoxy-6-fluorocastonospermine 1-Deoxynojirimycin 12:332 1 -(3-Deoxy-|3-threo-pentoftiranosyl) uracil 19:515

1007

(+)-7-Deoxy-6-ep/-castanospermine 12:276 (-)-1 -Deoxy-6-e/7/-castanospennine 12:350 6-Deoxy-6-fluoro-sucrose as competitive inhibitors 7:69 1 -Deoxy-8-ep/-ivangustin from Artemisiapectinata 1'2\A 3 -Deoxy-a-D-ara^mo-hexopyranoside derivative 14:156 3 -Deoxy-a-D-ara^/wo-hexopyranosy 1-3 -deoxy-aD-flA-a^wo-hexopyranoside 14:148 3-Deoxy-a-D-arafZ>/o-hexopyranosyl-a-Dglucopyranoside 14:148 6-Deoxy-a-D-galactohexopyranosy 1 bromide 14:151 [2-Deoxy-a-D-glyc-2-enopyranosyl] arenes 10:352, 353 Deoxygenation of^erZ-alcohol 19:516 radical 516 withAIBN 19:516 withBujSnH 19:516 9-Deoxygoniopypyrone 19:463,19:497 1 -(2-Deoxy-a-D-ribo-hexopyranosyl) cytosine cw-principle 4:586,587 endo-m\Q 4:587 in biogenesis 4:615-617 intermolecular 4:587-595 intramolecular 4:595-603 inverse electron demand 4:579,580,604,605 lysergic acid by 504,605 manaomycin A by 4:591-593,609 mechanism of 4:579,580 monomorine I by 4:606 nanaomycin d by 4:591-593 nepetalactone by 4:604,605 ofacylnitroso 4:606 oxazoles in 4:604 palitantinby 4:588-590 prostaglandin by 4:607 pumiliotoxin by 4:584,585 regiochemistry of 4:584-586 retro 4:609-615 solanapyrone 4:598,599 stereochemistry of 4:586,587 stereochemistry of cycloaddition 4:122,123 terramycin 4:609 tetrazinesin 4:604 triazines in 4:604 triquinanes by 4:588 vemolepinby 4:584,585 volume of activation 4:112 with heterodiene systems 4:583 with ketenacetals 4:357 with modified cyclohexadienes 4:583 with N-sulfinyl dienophile 4:356 with o-quinon dimethane 4:583,584 with a-amino aldehydes 4:120 P-santalene by 4:607,608 2-Deoxy-a-D-/'/^o-hexopyranosyl-2-deoxy-a-Dr/6o-hexopyranoside 14:148 2-Deoxy-a-D-r/^o-hexopyranosyl-a-Dglucopyranoside 14:148

3-Deoxy-a-D-jcy/o-hexopyranoside 14:169 2-Deoxy-a-glucose 7:59,60 9-(6-Deoxy-a-Z,-idopyranosyl) adenine synthesis of 4:233 9-(6-Deoxy-a-I-talo-pyranosyl) adenine synthesis of 4:233 3 -Deoxy-a-L-xy/o-hexopyranoside 14:182 3'-Deoxy-aminoglycoside antibiotic 14:144-147 l-(2-Deoxy-P-arabino-hexopyranosyl) thymine 4:230 synthesis of 4:230 9-(6-Deoxy-(3-D-allopyranosyl) adenine synthesis of 4:233 7-(2-Deoxy-P-D-arabino-hexopyranosyl) theophylline synthesis of 4:230 3-Deoxy-P-D-furanurono-6,1 -lactone 14:506 9-(6-Deoxy-P-)-glucopyranosyl) adenine 4:233 synthesis of 4:233 2-Deoxy-P-D-lyxo-hexopyranose 4:230 Deoxy-p-D-xy/o-hexopyranoside derivative 14:164 47-(3-Deoxy-P-Z)-xylo-hexopyranosyl) theophylline 4:232 3-Deoxy-p-L-hexofuranoside 14:182 2-Deoxy-P-r/Z>o-hexopyranose 4:231 2-Deoxy-p-r/6o-pyranosyl cyanides 10:354 6- Deoxy-P-ribohexopyranos-3-ulose 5:602 1-Deoxy-castanosperine 12:347 (-)-6-Deoxy-castanospermine 12:346 4-Deoxy-D,L-jcv/o-hexopyranose synthesis of 14:178 6-Deoxy-D-fl[/rro-heptopyranoses 11:429 6-Deoxy-D-altroheptose synthesis of 4:195 3-Deoxy-D-ara6/>70-heptulosonate-7-phosphate (DAHP) synthase 11:183,184 3 -Deoxy-D-arra6/>io-hexopyranose 14:148 3 -Deoxy-D-ara6mo-hexose 14:143 2-DQO\y-D-arabino-\\QxosQ asymmetric synthesis of 14:176,177 4-Deoxy-D-<a[ra6/oo-hexose 14:143 l-Deoxy-D-galacto-heptulose 7:60 2-Deoxy-D-glucose 15:435 3-Deoxy-D-g(vcero -D-gflr/acro-2-nonulosonic acid 11:429,467 4-Deoxy-D-/vJco-hexopyranose asymmetric synthesis of 14:176 3-Deoxy-D-/>ao-hexose 14:143 4-Deoxy-D-/j^o-hexose synthesis of 14:158 2-Deoxyphysalolactone 20:223 3-Deoxy-D-/wflo-2-octulosonic acid 11:429,440, 11:441,464 6-Deoxy-D-/wflo-heptopyranoses 11:429 6-Deoxy-Z)-mannoheptose 4:195 3-Deoxy-D-r/Z)o-hexofuranose 14:159 3-Deoxy-D-r/6o-hexofuranoside 14:164 synthesis of 14:164 3-Deoxy-D-n7)o-hexopyranose 14:148 4-Deoxy-D-r/Z>o-hexopyranoside 14:164 synthesis of 14:164 4-Deoxy-D-r/6o-hexose 14:143,174

1008

3 -Deoxy-D-r/Z^o-hexose asymmetric synthesis of 14:176,177 3-Deoxy-D-/*/Z)o-hexose derivative synthesis of 14:163 2-Deoxy-D-riboftiranose 6:361 3 -Deoxy-D-jcy/o-hexopyranose derivative from methyl P-D-galactopyranoside 14:164,165 3 -Deoxy-D-xy/o-hexose 14:143 4-Deoxy-D-xv/o-hexose 14:143,147 4-Deoxy-Y-rhodomycinone synthesis from mannose 4:354 synthesis of 4:352 2-Deoxy-galactose 7:59 1-Deoxy-galactostatin 10:543 3-Deoxy-hexoaldoses 14:144 4-Deoxy-hexoaldoses 14:144 3-Deoxy-hexoses synthesis of 14:143-200 4-Deoxy-hexoses synthesis of 14:143-200 4-Deoxy-/>a:o-hexose 14:175 3-Deoxy-magellanol 18:745 4-Deoxy-magellanol 18:745 6-Deoxy-magellanol 18:745 3-Deoxy-maytol 18:745 (+)-12-Deoxy-scalaradial by Diels-Alder reaction 6:58 synthesis of 6:58,125-129 2-Deoxy-scyllo-inosose 2-deoxystreptamine from 11:217-219 5-Deoxy-stansioside 7:462,463 14-Deoxy-stypodiol from stypodiolmethyl ether 6:55 synthesis of 6:55 14-Deoxy-taondiol methyl ether from (+)-manool 6:55 synthesis of 6:55 Deoxytedanolide antitumor activity of 19:558 isolation of 19:558 Deoxytrimethylbrazilone (B) 20:777 Deoxy-vj/-santonm 7:212 2'-Deoxyadenosine 10:592,593 3'-Deoxyadenosine (cordycepin) 10:592,593 11-Deoxyadriamycin 1:498 11 -Deoxyanthracycline 14:48 10-Deoxyaucubin 7:481 Deoxybouvardm synthesis of 10:640-642 Deoxybouvardin methyl ether synthesis of 10:640-642 15-Deoxybruceolide bruceantin from 11:79,80,85,86 (+)-6-Deoxycastanospermine 12:337,338 synthesis of 12:337,338 Deoxycholate 9:565 11-Deoxydanucomycinone synthesis of 3:448,449 10-Deoxydaphylloside 7:470,471 11-Deoxydaunomycin 1:498

11-Deoxydaunomycinone chu-al synthesis 4:329,330 enantioselective synthesis of 1:596 synthesis of 1:500,501 synthesis of 4:327 7-Deoxydaunomycinone synthesis of 3:449,450 3-Deoxydebromoaplysiatoxm 18:295 9-Deoxyerythromycin A 13:175,176 Deoxygalactostatm 7:41 Deoxygenation withPBrs 1:391,392 ofD-glucose 11:219 by zinc-copper couple 4:424 by zinc-dust 4:424 of ascorbic acid 4:420-423 12,13 -Deoxygenation ofverrucarol 6:234 Deoxygeniposide 7:470 5-Deoxygoniopypyrone 9:394 2'-Deoxyguanosine 8:377,378 Deoxyguanosine 8:388-392 2-Deoxyhexopyranosyl purimidines 4:229-232 2-Deoxyhexopyranosyl purines 4:229-232 (6-Deoxyhexopyranosyl) adenines 4:232,233 Deoxyiodo-nucleosides 4:225 14-Deoxyisoamijiol 10:182 3'-Deoxykanamycin A synthesis of 14:144,145 3'-Deoxykanamycin C 14:186 (+)-5-Deoxykievitone 4:378,379 20'-Deoxyleurosidine catharinine from 14:812 from anhydro vinblastine 14:871 oxidation of 14:812 3'-oxo-20'-deoxyleurosidine from 14:812 vmcristine derivative from 14:818,819 20'-Deoxyleurosidine-N-oxide 5',6'-seco derivatives of 14:872,873 6-gp/-7-Deoxylincosamine 11:446 3-Deoxymaltose derivative from 3-chloro-3-deoxy-fl//o derivative 14:163 Deoxymannoj irimycin chemico-enzymatic synthesis of 541 from Lonchocarpus costaricensis 10:538 from. Lonchocarpus sericeus 10:538 from Omphalea dianadra L 10:539 from Streptomyces lavendulae 10:539 golgi a-mannodiase I,II inhibitor of 10:539 golgi a-mannosidase I mhibitor of 10:539 intramolecular aminomercuration of 10:540 synthesis of 10:528-538,540-542 a-mannosidase inhibitor of 10:539 p-mannosidase inhibitor of 10:539 ()-Deoxymannojirimycm 18:347 Deoxymannoj irimycin a-mannosidase inhibition by 7:15,41,42 5-Deoxymyricanon 17:371 18-Deoxynargenicm synthesis of 17:298,301 Deoxynivalenol 13:519,538

1009

4-Deoxynivalenol 6:221,224,225,243 Deoxynivalenol 6:230,231,237,240-242 Deoxynivalenol (vomitoxin) 9:204-207,215,216 7-Deoxynogarol 14:47,78,79 (+)-7-Deoxynogarol 14:68-72 9-ep/-7-Deoxynogarol 14:78 1-Deoxynojirimycin 11:267 Deoxynoj irimycin 7:14,15,41,42 I -Deoxynojirimycin (1,5-dideoxy-1,5-imino-Dglucitol 12:332 Deoxynucleoside-3 -phosphorothioamidates 13:271 Deoxynucleosides 8:373 3 -Deoxynucleosides synthesis of 4:232 6-Deoxynucleosides synthesis of 4:232 II -Deoxyprostanoids 1:63 9,640 2-Deoxyribose 6:337,337 3-Deoxyrosaranolide synthesis of 11:164 4-Deoxysiastatin B 16:98 2-Deoxystreptamine from 2-deoxy-scyllo-inosose 11:217,218 (-)-8-Deoxyswainsonine 12:304,332 3-Deoxytetranguloi 11:135 4-Deoxytromidioside 7:302 20'-Deoxyvinblastine 14:863,864,871 16*-ep/-Deoxyvinblastine 14:870,871 16'-e/7/-20'-epz-Deoxyvinblastine from 15,205-dihydrocatharanthine N-oxide 14:870,871 DEPC cyclodimerization with 4:92,93 Dephenyl thiolation 14:306 Deplancheine 1:118 ()-Deplancheine 18:333 Deprotection of oligonucleotides 4:282,283 of triethyl silyl group 4:533 with tetra-A^-butylammonium fluoride 6:119-122 Deprotection of alcohol with TMSCl/Nal 1:558 Deprotonation LDA-mediated 10:425 of allylic ester 10:425 of 3-C-methyl-3-deoxy-2-ulose derivative 10:414, 415 withA^-lithio-2,2,6,6-tetramethyl-piperidine 10:414,415 asymmetric 11:241,242 azabicyclic ketone 11:241,242 Depsides 9:317,328 Depsipeptides 9:213;10:250,251,256,259,263,267,284, 295-298 6,3'-e/7/-Derivative 7:483 Dermasterias imbricata 2,4-di-0-methyl-p-D-quinovopyranosyl-( 1 2 ) - 5 O- sulphate-P-D-fucofiiranosyl from 15:66 imbricatine from 7:306 Dermocanarin I 20:277 Derris araripensis 7:177,193

Derhsnicou 7:177,193 Derris sericea 7:177,193 Derris trifoliata 7:176-178 Derris ulignosa 7:181,182 Derris urucu 7:177,193 Des-(25-28)-thymosin al 8:433,434 Des-iV-methyhioracridones 13:352 Des-A^-methylnoracronycine synthesis of 13:370,371 Des-O-methyllasiodiplodin 9:288,289 (+)-Desacetoxymatricarin 14:357,358 Na-Desacetyl-17-0-acetyl-18-hydroxyisoretuline 1:38,39 Na-Desacetyl-18-hydroxyisoretuline 1:3 8,39 Desacetylakuammiline 5:126 Desacetyltacralme 5:126 Desalanyl-iV-acetylactinobolin synthesis of 16:11 Desaturation reactions 7:327-331,360 16/?-Descarbomethoxytacamine 9:179,180 165-Descarbomethoxytacamme 9:179,180 Descobalto-cobyrinic acid 9:598 15-Desenecioylbruceoside-A 7:373 Desepoxy-4,5-didehydromethylenomycin A 14:593 Desepoxymethyl enomycin A 14:602 Deserpidine from Rauwolfia serpentina 3:399,403,412-415; 8:283;9:171;13:631;19:748 synthesis of 3:412-415 Desethyl ebumamonine enamine 17-oxy-20-desethyl-A^^^^^-didehydroeburnamoninefrom 14:729 20'-Desethyl-20'-deoxyvinblastine 4:32;14:861 20'-Desethyl-20'-deoxyvincovaline 14:861 Desethylflavocarpine synthesis of 1:137 Desethylibophyllidine 5:126 Desformyl desoxy pyoverdin D 9:550 Desformyl pyoverdin D 9:550 Desglucosylstevioside from Rubus suavissimus 15:18 Desilylation with HF-pyridine 8:263 of N-(trimethylsilyl) methyl iminium ions 1:325, 328 with cesium fluoride 1:249 Deslanoside 15:361,362 Desmethoxycuanzine from 2-acetylbutyrolactone 8:284,285 synthesis from 8:284-292 A^-Desmethylacronycine 20:793 Desmethyl quatemine 9:185,186 Ci8-Desmethylcytochalasin D synthesis of 8:212-217 5- Desmethylnobiletin 5:654 Desmia sp. (red alga) 5:343 Desmotroposantonin 7:237 Desorption chemical ionization (DCI) 5:632 Desorption techniques 13:652 Desosamine 5:615,616,13:155,156,159 Desoxoalstonerine 13:402,403 Desoxodehydrolaserpitine 5:725,727

1010

Desoxy-16-buxidienine 2:205 18-Desoxy-Wieland-Gumlich aldehyde 1:36 11-Desoxyanthracyclines 14:22 3'-Dexoyadenosine 19:515 Desoxyasperdiol by directed hydromagnesiation 10:29,30 synthesis of 10:29,30 Desoxybenzoin robustic acid from 4:382,384 isorobustic acid from 4:382,384 11-Desoxydaunomycinone asymmetric synthesis of 14:23 7-Desoxydaunomycinone 14:5,6 6-Desoxydaunomycinone 14:7 Desoxynivalenol (vomitoxin) 9:206,207,217 218 13-Desoxyphomenone from Hansfordia pulvinata 6:552 Desoxypicropodophyllin 18:552,553,555,596 ()-Desoxypodophyllotoxin 18:586,588,590 Desoxypodophyllotoxin 5:480,481,483-485,487-489 Dess-Martin oxidation 19:370-371 Dess-Martin periodinate 19:357 Destabilizing effect 12:72 Destomicacid 4:130 Desulfonylation 19:77;11:349 Desulphurization 3:472,307-309,484,167;14:167,680, 681 withAIBN 19:527 withBusSnH 19:527 (+,-)-DET 6:263,269,271,278 Dethioacetalization 12:348 Detoxin 12:412 DetoxinBi 12:412 Detoxin B3 12:412 Detritylation 4:276-279,282,284 Deuterated glycerol asymmetric synthesis of 11:422,423 3 -Deuterio-4-methyIpyrocatechol 8:309 Deuteriosuccinic acid 8:72 27-Deuterocholesterol 5:774 Deuteromycotina 9:202 Deutziol 9:455 Dexamethasone guggulsterones from 5:713,714,602,605,608, 1-Dexoynojirimycin 10:543-546,549 antihyperglycemic activity of 10:526 antiviral activity of 10:529 by enzymatic aldol condensation 10:535,536 from B. polymyxa 10:524 from B. subtilis 10:524 from B. amyloliquefaciens 10:524 from Bacillus 10:524 from Morns bombycis 10:524 from nojirimycin 10:524,525 from Omphalea diandra 10:524 from Streptomyces lavendulae 10:524 from Streptomyces lavendulae subsp. trehalostaticus 10:524 glycosidase inhibitors 10:525 intramolecular aminomercuration of 10:532 intramolecular reductive amination of 10:530

synthesis of 10:529-538 e/iflfo-Dextranse 7:35,36 Dextransucrase from Streptococcus sanguis 7:69 Dextrinase 10:504 a-Dextrins catalytic hemihydrogenation 10:463 G/Mcoo-nitriles 10:463,464 DNef reaction of 10:464 Di-C-alkylation 10:413 of D-mannose derivative 10:413 Di(4,4'-hexyloxy-carbonylphenyl) ether 20:709 6,6-Di-C-methyl heptopyranose derivative 10:414 3,3-Di-C-methyl-2-ulose 10:415 2,2-Di-C-methyl-3-deoxy-4-ulose 10:414,415 2,2-Di-C-methyl-3-ulose 10:415 4,4-Di-C-methyl-4-deoxy-D-glycero-hexo-pyranoside2-ulose 10:414,415 //,;V-Di-cyclohexylcarbodiimide (DCC) 8:76 2,3-Di-ep/-mannostatin A 19:356 8,13-Di-e/7/-manoyloxide 20:691 Di-e/7/-7-con-0-methyhiogarol 14:75,76,78 (+)-1,8a-Di-epi-castanospermine synthesis of 12:335,336,345 (+)-6,7-Di-epi-castanospermine synthesis of 12:337,338,345 (-)-1,6-Di-epi-castanospermine synthesis of 12:342-344 12,18-Di-epi-scalaradial (-)-1 -8a-Di-g/7/-slaframine synthesis of 12:312 (-)-1,8-Di-epi-swainsonine from (5)-glutamic acid 12:325 from methyl 3-acetamido-2-0-acetyl-3-deoxy4,6-di-O-mesyl-a-D-glucopyranoside 12:326,327 (+)-2,8-Di-epi-swainsonine 12:325 (-)-8,8a-Di-epi-swainsonine divergent synthesis of 12:330 from 2,3-0-isopropylidene-L-erythrose 12:330,331 inhibitory activity of 12:331,332 synthesis of 12:329-332 (-)-2,8a-Di-g/7/-swainsonine 12:325,331 1,6-Di-epicastanospermine from I-gulonolactone 7:12 synthesis of 7:12 roc-l,2-Di-fattyacyl-3-mercaptoglycerol 18:841 Di-/-menthol (acetoxymethylene) malonate 13:66 Di-myristoylphosphatidylcholine (DMPC) 18:839 3,4-Di-O-acetyl-1,2:5,6-di-0-cyclohexylidene-/wyoinositol 18:426 2,3-Di-O-acetyl-1,6-anhydro-3-0-trifluoromethylsulfonyl-p-D-galactopyranoside 8:331,341 Di-0-acetyl-2,3-dideoxy-P-D-threo-hex-2-1 -(4,6enopyranosyl) uracil synthesis of 4:236,237 4,6-Di-0-acetyl-3-deoxy-D-glucal 14:146 N,0-Diacetylsolasodine 20:490 3,4-Di-0-acetyl-6-0-trityl-1,2-cyanoethylidene-a-Dgalactose 14:241 -

1011 3,4-Di-0-acetyl-6-0-trity 1-1,2-O-cyanoethy lideneP-D-mannose 14:240,246 (+)-2',4'-Di-(9-acetyl-7,8-dihydronogarene 14:67,68 (+)-2',4'-Di-0-acetyl-7,9-di-e/7/-7-con-0-methylnogarol 14:75 (+)-2',4'-Di-<9-acetyl-7-con-0-methylnogarol 14:75 (+)-2',4*-Di-0-acetyl-7-methoxynogarene 14:80 (+)-2',4'-Di-0-acetyl-9-benzyloxy-9-demethyl-9methoxynogarene 14:82 (+)-2',4'-Di-0-acetyl-9-demethyl-7,9-dimethoxynogarene 14:82 (+)-2',4'-Di-0-acetyl-9-demethyl-7-methoxynogarene 14:80 (-)-2',4*-Di-0-acetyl-9-demethyl-9-hydroxy-7methoxynogarene 14:82 (+)-2',4'-Di-0-acetyl-9-g/7/-7-deoxynogarol 14:71 2',4'-Di-0-acetyl-con-nogarol 14:74 3,6-Di-0-acyl-4-deoxy-P-D-g/vcero-hex-3enopyranosyl-2-ulose 10:353 3,4-Di-0-benzoyl-2-0-trityl-a-L-rhamnopyranoside 14:242 1,4-Di-0-benzoyl-/wyo-inositol 18:421 6,7-Di-O-benzoylcastonospermine hydrochloride 12:345 D-and L-2,4-Di-(9-benzyl-/wyo-inositol 18:427 1,6-Di-O-benzyl-A^-acetyl-muramic acid methyl ester 6:388,389 4,6-Di-0-benzylidene-2,3-0-paratoluenesulfonyla-D- glucopyranoside 14:154 4,6:4',6'-Di-0-benzylidene-a-a'-trehalose 14:149 1,2:3,4-Di-0-cyclohexylidene-/w>'o-inositol 18:428 3:5,9:11 -Di-0-isoproplidene derivative 6:264,265 1,2:5-Di-0-isopropyliden-D-glucofuranose 14:159 Di-O-isopropylidena-a-D-glucofuranose 1,2:5,66:282,283 Di-0-isopropylidene-(+)-valienamine 10:507 4,7:5,6-Di-0-isopropylidene-(l,4,6/5)-4,5,6trihydroxy-3-hydroxymethyl-2-cyclohexenylamine 10:511,512 1,2:5,6-Di-(9-isopropylidene-3-6>-p-toluenesulfonyl- Dglucofiiranose 14:171 l,2:5,6-Di-0-isopropylidene-3-0-trifluoro-methylsulfonyl-a-D-allofuranose 8:329 1,2:3,4-Di-0-Isopropylidene-6-0-/7-tolylsulfonyl-a-Z)galactopyranose 8:339,340 l,2:3,4-Di-0-isopropylidene-a-D-galactopyranose 10:476 l,2:5,6-Di-0-isopropylidene-a-D-glucofuranose 14:152 2,3:5,6-Di-0-isopropylidene-a-D-mannofuranoside 10:541 2,3:4,5-Di-0-isopropylidene-p-D- fructopyranose 12:350 (+)-1 -deoxy-6-8a-Di-e/7/-castanospermine from 12:350 (-)-l-deoxy-e/7/-castanospermine from 12:350 1,2:5,6-Di-0-isopropylidene-D-glucofuranose 14:168 1,2:4,6-Di-0-isopropylidene-D-hexofiiranose fromD-allose 14:160 fromD-altrose 14:160 from D-galactose 14:160 fromD-glucose 14:160 fromD-gulose 14:160 fromD-idose 14:160 fromD-mamiose 14:160 fromD-talose 14:160 Di-O-isopropylideneglucoftiranose S-methyl dithiocarbonate 14:157 22,24-Di-O-methyl soya-sapogenol B from soyasaponin I 7:157,158 3-0-Di-O-methyl xylose 7:298 2,4-Di-0-methyl-P-D-quinovopyranosyl-(l2)-5-0sulphate-P-D-fucofiiranosyl from Dermasterias imbricata 15:66 Di-palmitoylphosphatidylcholine (DPPC) 18:839 Di-substituted azulenes oxidation of 14:336-338 2,6-Di-/er/-butyl-4-methylphenol 9:579 Di-/raAw-polyscis-prenols 8:66 Di-rr<ar5-polycis-a-saturated prenols (dolichols) 8:66 Diacetone glucose 10:412 2,15-Diacetoxy-13-hydroxy-11 -epi APO 13:522 3-(2',3'-Diacetoxy-2'-methyl-butyryl)-cauhtemone 7:185 1 a,3 P-Diacetoxy-23,24-dinorchol-5-en-22-ol 11:388-390 la,3 P-Diacetoxy-23,24-dinorchola-5,7-dien-22-al synthesis of 11:398-402 1 a,3 p-Diacetoxy-23,24-dinorchola-5,7-dien-22-ol synthesis of 11:398-402 2a,7a-Diacetoxy-6p-isovaleroxylabda-8,13-dien-15-ol 17:27 2,13-Diacetoxy-8-hydroxy-11 -epi APO 13:522 Diacetoxyavarol 15:300 1 a,3 P-Diacetoxychola-5,7-dien-24-al synthesis of 11:398-402 la,3P-Diacetoxychola-5,7-dien-24-ol synthesis of 11:398-402 la,3P-Diacetoxychola-5-en-24-ol 11:388-390 (-)-15a, 16a-Diacetoxyspongian 6:108,109 Diacetylirumamycin ozonolysis of 5:599 Diacetyl dimethylbartogenate 7:132,133 3,13-Diacetyl GA3-7-aldehyde 8:128,129 3,13-Diacetyl-GA3 phenacyl ester synthesis of 8:133,134 Diacetylajmaline 9:183,184 Diacetylenicfl//o-xanthin6:150,153 C4o-Diacetylenic carotenoids 6:149 Diacetylsandwichine 9:183-185 Diacetylsarpagine 9:174 1,3-Diacyloxypropanes 13:53,54 Diadematidae 7:283 Dialdehyde 8:18,19 18-ep/-Dialdehydes 6:129 Dialkoxy anils 4:544 a, p-Dialkoxy ketone 11:235 2,6-Dialkoxy ketones 14:647 3,4-Dialkoxyfurans Diels-Alder cycloaddition 12:19,20 with alkyl coumalates 12:19,20 Dialkyl azodicarboxylates [4+4] cycloaddition of 12:424,425

1012

to 3-[( 1 S)-2-ex:o-alkoxy-1 -apocamphanecarbonyl]2-oxazolones 12:424,425 Dialkyl ethers 2:4 Dialkyl tartrates 14:489 2,6-Dialkyl-2-cyanopiperidines 6:431,432 /rflr5-2,5-Dialkyl-3,4-dehydropyrrolmes synthesis of 6:441 cis a,a'-Dialkylated p,P'-heterosubstituted oxepanes 10:214 cis-a,a'-Dialkylated p,p'-heterosubstituted oxocanes 10:214 rrarAM-2,5-Dialkylated pyrrolidine 11:256,257 Dialkylation 6:332,341 Dialkyiboranes 9:366 2,6-Dialkylpiperidines from l-benzyl-2,6-dicyanopiperidine 6:433 synthesis of 6:424-434 cw-Dialkylpiperidine 19:34 cw-2,6-DiallQ'lpiperidines 6:431,432 fra5-2,6-Dialkylpiperidines 6:431,432 2,5-Dialkylpyrrolidine ant alkaloids enantioselective synthesis of 6:443 2,5 -Dialky Ipyrrolidines by reductive amination 6:437,438 in Monomorium species 6:436 in thief ants 6:434 synthesis of 6:437,438 2,5-Dialkylresorcinol 9:322 Diallenic carotenoids 6:135,136 Diallyl cuprate 12:425,426 (E,E)-Diallylic ether synthesis of 8:196 Diamagnetic-y-gauche effect 9:119 2,4-Diaminobutyric acid 9:547,548,553 2,3-Diaminoglucosyl analogs 6:406,407 /g5o-Diaminopimelic acid 6:404 Diaminopimelic acid-diaminopimehc acid (DAP-DAP) linkage 12:95 Diaminopimely-D-alanine 12:96 1,6:3,4-Dianhydro-p-D,L-fl//o-hexopyranose 14:184 3,4:l',6'-Dianhydromaltose 10:511,512 from 2,3,2',3'-tetra-0-acetyl-1 ',6'-anhydro-6-deoxy4-0-/7-tolylsulfonyl-P-maltose 10:511 1,4:3,6-Dianhydromannitol Dpp-bromobenzoate 2:164 Dianiiinophosphoric chloride 18:397 Dianiiinophosphoric esters 18:397 Dianilinophosphoryl chloride 14:286 Dianion alkylationof 11:284,285 condensation of 12:9,10 from4-[rer/-butyldiphenylsilyl)oxy]-2-(tributylstannyl)-()-2-buten-l-ol 12:9,10, ofFAMSO 6:323-325 stereoselective 11:284,285 with l-TMS-2-pentyne 11:284,285 with a,p-epoxy cyclohexanone derivative 12:9,10 Dianion aldol condensation 12:69 Diastereoconversion 12:479 Dianthus sp. acylated anthocyanins 5:659 malic acid in 5:659

Diaperoecia californica 17:90,92 Diapocarotenoids 7:317;20:602 Diaporte helianthi 15:345 Diarylbutanes 17:349 Diarylcyclobutanes 17:348 Diarylether 17:388 Diarylheptanoids 20:276 Diarylheptanoids activity of 17:375 biosynthesis of 17:373 dienone 17:372 Diasesartemin 7:219 Diastereolselective alkylations 1:613-616 Diastereolselectivecyclopropanations ofa,p-unsaturatedacetals 1:629-632 Diastereodifferentiatingisomerization 4-hydroxy-2-cyclopentenone acetal from 14:510 of meso-3,4-epoxycyclopentanone 14:510 Diastereofacial selection 13:62-70 Diastereofacial selectivity ofchiralepoxidizing agent 4:172,173 Diastereomeric aminonitrile 10:126,127 Diastereomeric camphanates 6:152 Diastereomeric resolution 1:585-588 Diastereomers 13:280-282 Diastereoselection 10:215 1,2-Diastereoselection 4:443,448,451,472,474 Diastereoselective acetylenation 611,612 Diastereoselective addition of chiral aryl Grignard reagents 14:508,509 to carbonyl compounds 14:508,509 of Grignard reagents 1:621 toketals 1:621 Diastereoselective alkylation 17:324 Diastereoselective cyanation 14:473 Diastereoselective cyclizations 1:590,591 Diastereoselective cyclopropanation 6:544,545 Diastereoselective eliminative cleavages 1:618,619 Diastereoselective halolactonization 1:620,627-629 Diastereoselective Michael addition 6:86,87,286 Diastereoselective reduction Johnson-Yamamoto rationale 1:595 ofcarbonyls 1:622 Diastereoselective synthesis of(3/?,4/?)-stame 12:479-481 of 2(a-hydroxyalkyl) piperidines 12:453 of 4a-aryldecahydroisoquinolines 12:456-463 of 6-hydroxy-4a-phenyldecahydro 12:457 ofB/C-/rflf5-morphinan 12:464-471 ofoctahydroisoquinolines 12:457 of piperidine derivatives 12:471 of pyrrolidine derivatives 12:471 Diastereoselective synthesis ofmethylphosphonate 13:276-278 ofphosphorothioate 13:276 Diastereoselectivity 11:359 Diastereotopic groups 17:481 Diastereoselectivity 16:372 Diatoxanthin 20:579,580 1,5-Diazabicyclo [4.3.0] non-5-ene 11:353 Diazabicyclo [5,4.0] undecene 12:466 1,8-Diazabicyclo [5.3.0] undec-7-ene 11:341,342

1013

1,8-Diazabicyclo [5.4.0] imdec-7-ene 11:359 3,8-Diazabicyclo[3,2,1 ] octane synthesis of 10:135-137 Diazabicyclo[5.4.0]undec-7-ene (DBU) 424,425 Diazidation 10:465 Diazines 3:20 a-Diazo P-keto ester acetal 14:509 2-Diazo-3 -oxopentanoic acid derivatives 12:172 with 4-acetoxy p-lactam 12:172 3,8-Diazobicyclo [3,2,1] octane 10:107,117 a-Diazoketone 19:18 Diazoketone cyclization 1:492 from adenosine 10:593-595 preparation of 10:593-595 Wolff rearrangement of 10:593-595 Diazoketone insertion copper mediated 1:555,556,564 cyclization 1:492 Diazomethane 1:404,405,439 esterification 1:404,405 methylation with 1:435 ring expansion with 3:12 sugar aglycone linkage cleavage by 7:155,156 Diazotization 3:325,226 Diazotized aniline 19:89 DIBAH reduction 6:428;14:634;19:172 (DIBAL-H) reduction of a,P-unsaturated ester 10:428,429 DIBAL 1:177;14:529,530;19:318 reduction with 6:285,286,293,294,288,299,549,550 DIBAL reduction 11:432,457;13:456,464,465;20:67 Dibenz [b,d] oxocin derivative 15:34,35 Dibenz [b,g] azecine derivative 6:492,493 Dibenz [c,g] azacycloundecine 6:496 Dibenz [c,g] azonine derivartive 6:474,475 Dibenz [d,f\ azonine derivatives from benzylisoquinoline derivatives 6:477,478,480 from 1-halogenobenzylisoquinoline 6:482 from neoproaporphine intermediates 6:480 from neospirene intermediates 6:480 synthesis of 6:477,478,480,482 Dibenz[b,fl azecine derivative 6:492,493 Dibenzazecine 6:487-493 Dibenzindolizidine 3:425 Dibenzo [d,fl azecines 3:481 Dibenzo [d,fl azonines 3:468,469 Dibenzo oxazacycloundecine derivatives 6:494 Dibenzoate fromcw-2-buten-l,4-diol 10:597 fromD-glucose 10:597 Dibenzocyclooctanes 20:276 Dibenzocyclooctadienes 17:346 Dibenzopyrrocoline alkaloids 6:482 Dibenzoquinolizine hexahydrodibenz[f/,g] azecmes from 6:492,493 Dibenzoyl-P-D-ribopyranose condensation of 10:589,590 A'; A^-Dibenzyl benzoyl acetamides photolysis of 14:650,651

(45',5/?)-3,5-Dibenzyl-4-isobutenyloxazolidin-2-one 12:480 Dibenzylazodicarboxylate (DBAD) 12:157 Dibenzylbutanes 17:315 Dibenzylbutyrolactones 5:485-490,320 ^m-Dibenzylideneacetone dipalladium 8:277,278 (-)-(25',35)-1,4-Dibenzyloxy-2,3-butanediol unsaturated acetal from 14:490 (25,6/?,8/?,9/?)2,8-Diboromo-p-chamigrene from(8/?,9/?)-8-bromo-9-hydroxcy-()-Y-bisabolene 6:62,63 synthesis of 6:62,63 endo-3,9-Dibromo-4-bromomethy 1 camphor reactivity towards bromination 4:629 7-5y-9-Dibromo-6-endomethylisofenchone synthesis of 4:630,631 (-)-(2/?,65,85',95)-2,8-Dibromo-9-hydroxy-achamigrene by asymmetric carbocyclization 6:62,63 from (:)-a-bisabolene-8(/?),9(5)- epoxide 6:62,63 from Laurencia nipponica 6:63 synthesis of 6:62,63 (+)-3,9-Dibromocamphor 16:138 (+)-9,10-Dibromocamphor 16:138 (+)-3,3-Dibromocamphor 4:628,629,638,639;16:144 (+)-10-bromocamphorfrom 4:638,639 (+)-ef/o-3,9-Dibromocamphor 4:634,635,643 acid catalysed rearrangement 4:635,643 reactivity towards bromination 4:629,630 (+)-9,10-Dibromocamphor C(3)-methylation of 4:657,658 2,6-Dibromophenol 17:81 2-(2',4'-Dibromophenoxy)-4,6-dibroanisole anti-inflammatory activity of 5:367 Dibutyltin oxide for stannoxane preparation 1:274 1,2-Dibutyroyl inositol 18:409 a-Dicarbonyls synthesis of 8:262 P-Dicarbonyl 10:343-348 Dicarbonyl coupling by Mukaiyama procedure 3:99 intramolecular 11:345,364-467 with TiCla/LAH 3:80,81 with TiCyZn-Cu 3:80,81 Dicyclic carotenoids 6:147,148 Dichamanetin 9:399,400 1,3-Dichloro-1,1,3,3-tetraisopropyldisiloxane 18:409 2,3-Dichloro-4,5-dicyanobenzoquinone(DDQ) 11:156,165 Dichlorocarbene addition 10:413 Dichloroketene [2+2]cycloaddition with 13:6 (Dichloromethyl) boronic ester synthesis of 11:409,410 (Dichloromethyl) lithium 11:410 Dichloromethylenation 3:223 Dichloromethylphosphine 13:276 2,4-Dichlorophenoxyacetic acid 7:90,97,111 Dichomme 5:126,183 Dichomine-type alkaloids 5:106 Dichroafebrifuga 20:522

1014

Dicrotaline 1:271 Dicrotonic acid 7:143,144 Dictamine 3:385,386 Dictindiol 9:79,80,87 Dictinol 9:79,87 Dictintriol 9:79,80,87 Dictydiaethalium plumbeum arcyriaflavin-D from 12:366,370 Dictyoceratida 6:107,111 ;19:568 Dictyoceratidae scalaradial from 6:58 12-ep/-scalaradial from 6:58 12,18-di-ep/-scalaradialfrom 6:58 Dictyoceratidaquinone 15:300 Dictyoceratin-A 5:432,433,292,293 Dictyochromenol 15:294 Dictyodendrilla cavernosa 18:718 Dictyodial 5:370 (-)-Dictyolene by Collins allylic oxidation 6:27 from Dictyota acutiloba 6:27 from 6-ep/-a-santonin 6:27 synthesis of 6:27 Dictyols 17:97 Dictyopteris divaricata dictyopterone from 6:16 p-dictyopterol from 6:16,18 (-)-zonarene from 6:15 Dictyopteris undulata isozonarol from 6:17 zonarolfrom 6:17 Dictyopteris zonaroides (-)-zonarene from 6:15 P-Dictyopterol by Peterson olefmation 6:18,19 by van de Walle approach 6:16 from Dictyopteris divaricata 6:16,18 synthesis of 6:16,18,19 (3-Dictyopterol precursor from a-phenylselenide 6:16 synthesis of 6:16 Dictyopterone by van de Walle approach 6:16 from Dictyopteris divaricata 6:16 synthesis of 6:16 Dictyostatin 19:557 Dictyostelium 9:220 Dictyostelium discoideum 5:275,384 Dictyota 9:78,79,86 Dictyota acutiloba (-)-dictyolene from 6:27 Dictyota crenulata 5:370,70;6:70 Dictyota dichotoma 9:86,88 Dictyota divaricata 6:52 Dictyota indicia 9:78-81 Dictyota linearis (+)-amijitienol from 6:52 dolasta-1 (15)-7,9-trien-14-olfrom 6:52 isoamijiol from 6:53 Dictyota spinulosa 5:370

Dictyotaceae dolastanes from 6:52 marine diterpenes from 6:52 1,2-Dicyclohexyl-1,2-ethanediol 11:423 (5, S)-1,2-Dicyclohexyl-1,2-ethanediol dichloromethy 1 boronate from chiral 1,2-dipheny 1 ethanediol 11:423,424 (a-methyl crotyl) boronic ester from 11:423,424 Dicyclohexylborane 4:116,117 Dicyclohexylcarbodiimide 12:328 Dicyclohexylideethane synthesis of 4:521 Dicyclohexylidene-wyo-inositol 18:403 1,2:4,5-Dicyclohexylidene-/wyo-inositol 18:401 Dideacetoxy argutin 9:66 E-2,3-Didehydroaspartic acid 15:347 E-2,3-Didehydroisoleucine 15:347 7,8-Didehydroisorenieratene 6:155,156 3,4-Didehydroproline 15:347 15,15-Didehydromimulaxanthin 20:580 3,4-Didehydrovaline 15:347 11,11 '-Didehydroxy-7,7-dihydroxytaxodione from Salvia montbretii 20:680 Didemethoxycarbonyltetrahydrosecamine 5:141 Dideminine B from Trididemnum species 12:455 Didemnenones A,B 10:244,245 Didenmidae 10:250 Didemnin 12:412 Didemnin X 10:250-257 Didemnin A 10:251-256,258-262,265,266,268-272, 275,276,281,285,291 Didemnin A 4:84,102-106,421,422 Didemnin-B (isodidemnin-I) 10:251-258,262,263,266272,276,277,281,285,291 Didenmin B synthesis of 4:103-106 antitumor activity of 5:421 antiviral activity of 5:421 immunosuppressive activity of 5:421 Didemnin C 4:103-106,276,281,285,291;5:421;10:251, 254,271,272,281,285,291,292 Didemnin D 5:422 Didemnin E 5:422,250-257,299 Didemnin F 5:426-428 Didemnin G 5:427 Didemnin group 4:83 Didemnin Y 10:250-257 Didemnins antitumor activity of 5:421,254-257 antiviral activity of 5:421,253,254 biological properties of 10:241-302 cytotoxic activity of 5:421 immunosuppressive activity of 10:257,258 synthesis of 10:241-302 Didemnum chartcium 17:22 Didemnum species 10:244 Didemnum voeltzkowi 10:244 1,5-Dideoxy-1,5-imino-D-glycero-D-allo-heptitol 11:461,462 synthesis of 11:461,462

1015

Dideoxy C-glycoside 10:389 1,4-Dideoxy-1,4-immo-I-allitol A^-benzylation of 7:41-43 A^-methylation of 7:41-43 1,5-Dideoxy-1,5-imino-D-glucitol from D-glucose 12:332 synthesis of 12:332 1,5-Dideoxy-1,5-imino-Z-fucitol 7:41,42 2,2-Dideoxy-2,3'-diphthalimido-p,P- trehalose 6:400 3,6-Dideoxy-3,6-imino-1,2-O-isopropylidene-a-D7,1 l-Dideoxy-4-demethoxydaunomycinone 4:338 4,5-Dideoxy-4-phoshinyl-Z,-lyxofuranoses 6:362,363 2,4-Dideoxy-4-phosphinyl-Z)-erythro-pento-furanoses 6:361,362 2,4-Dideoxy-4-phosphinyl-L-threo-peto-furanoses 6:361,362 4,5-Dideoxy-4-phosphinyul-D-ribofuranoses 6:362, 6:363 5,6-Dideoxy-5-(phenylphosphinyl)-I-idopyranoses 6:372 4,20-Dideoxy-5-hydroxyphorbol derivative 2:267 5,6-Dideoxy-5-phosphinyl-D-idopyranoses 6:372 10-(2,6-Dideoxy-P-arabino-hexopyranosyl) cytosine 4:234 9-(2,3-Dideoxy-Z)-erythro-hexopyranosyl)-adenine 4:235 5,6-Dideoxy-Z)-glucopyranoses 6:366,367 5,6-Dideoxy->-idopyranoses 6:366,367 3,13-Dideoxy-evoninol 18:746 1,2-Dideoxy-galactose 7:65 2,3-Dideoxy-hex-2-enopyranoside 10:418 2,3-Dideoxy-maytol 18:745 3,4-Dideoxy-maytol 18:745 4,6-Dideoxy-sucrose 7:42 4,4'-Dideoxy-trehalose derivative from 4,4'-diiodide 14:165 from trehalose 14:165 2,3-Dideoxyascorbic acid 4:715-718 7,11 -Dideoxydaunomycinone 1:503,504 7,9-Dideoxydaunomycinone 1:505 (S,S)-3,4-Dideoxyhexitol 11:251-259 2,6-Dideoxyhexoses by TDP glucose oxidoreductase 11:214,215 from glucose 11:214,215 in Streptomyces violaceoruber 11:214 7,9- 3',4'-Dideoxykanamycin B 14:145 1,6-Dideoxynojirimycin derivatives 7:42 Dideoxynucleosides 4:234 4,6-Dideoxynucleosides 4:234 2,3-Dideoxypyranosyl-purines 4:235 (-)-(9/?)-7,l l-Didesoxy-13-deoxodaunomycinone 14:8 Didrovaltrate from Valeriana wallichii D.C. 16:295 synthesis of 16:296-297 Dieckmann condensation 3:289,338,339,191;8:192, 284,293 of ethyl 2-[l-(2-ethoxycarbonylmethyl) piperidinyl]proponoate 12:284 of ethyl 4-[l-(2-ethoxycarbonyl pyrrolidinyl)] butyrate 12:293

Dieckmann cyclization 1:340,183;10:328,408,410,411; 12:126,147,279,308,445;13:546,25,26,117,131-133, 17;14:34,35 Diels Alder dimerization 2:122,128 Diels -Alder reaction asymmetric 12:26,27 cycloaddition 16:7,219,245,422 facial selectivity in 10:351 intermolecular 12:19,20,380 intramolecular 10:409;12:19,20,380;16:4,24,456 inverse electron demand 16:433 Lewis-acid catalyzed 12:26,27 of 3,4-dialkoxyfurans amides 12:19,20 of amine 16:474 ofbutadiene 11:340,341 of dimethyl acetylenedicarboxylate 12:379,380 of enantiomeric tetraenic acid derivative 10:409 ofenedione 16:28,34 oflevoglucosenone 14:270,271 of A^-furftiryl-P-chloroacryl amides 12:19,20 of pyranose diene 10:351 ofstyrene 16:555 precursor of 16:5,261 transition state of 16:5 with ()-crotonic acid 11:340,341 with bis (nitrophenyl) butadiene 12:379,380 with Danishefsky diene 16:10 endo Diels-Alder adduct m ()-precapnelladiene synthesis 6:33,34 Diels-Alder adduct 6:84,85,125,340,451;4:388,389 Diels-Alder chemistry of bicyclic intermediate 16:9 Diels-Alder equivalents 3:4 Diels-Alder reactions 20:769,770 "ortho'' adduct formation 4:584 (+)-capnellene by 4:588 (+)-coriolin by 4:588 (+)-hirsutene by 4:588 acybiitroso 1:386 adduct 1:8,9,15 asadiene 3:311,437-441 asymmetric 4:334-336,596-598,606-609 asymmetric intramolecular 14:502,503 atomic orbital coefficients in 4:585,586 betaenoneBby 4:601,602 cadinane by 584,585 cholesterol by 4:587 coronafacic acid 4:590,591,596,597 diastereoelectivity of 4:441 dienesin 4:581-584 dienophiles in 4:584 diplodiatoxin by 4:500-602 effect of Lewis acids 4:586 Eu (fod)3-mediated 4:121,122,143 exo versus endo transition state 1:373-374 for bicyclic compounds 8:410 frenolicinby 4:591,592,594,609 gephyrotoxin 223AB by 4:606 hetero 1:478 heterodienes in 4:583 heterodienophiles 4:112,583 high pressure 4:112,121,122

1016

imino 1:288,289;4:604,605 iminodienophile in 4:604,605 in anthracyclinone synthesis 1:502,503 in synthesis of quinolines 3:387-397 intermolecular 19:464 intramolecular 1:71,347,478,479;3:79,80; 8:403-406;10:51,52,155,156;ll:ll,92,93, 99-108;12:253;13:108-115,l 17-141,144,149; 14:735;19:11,464 intramolecular imino 1:385-382 intramolecular nitroso 1:379-381,383 inverse electron demand 3:311 Lewis acid catalyzed 8:141 nitraramine by 14:751-754 non-catalyzed reaction 8:142 N-sulfinyl cycloaddition 22,23 odd carbon equivalent 3:419 of 1,3-butadiene 19:68 ofchiral 1 ;3-dieneacylnitroso 19:11 of chiral o-quinodimethanes 14:502,503 of daunosamine derivative 10:375 ofenal 19:66 offuran 19:366 offurandienes 12:253 of imines 3:55 ofisoprene 19:226 of methyl-()-3-acetoxyacrylate 11:306,307 of A^-carbomethoxy pyrrole 19:77 of A^-substituted pyrroles 19:77,226 of optically active nitroolefin 19:144 oforthoqumodimethane 11:92,93 ofperezone 5:768 ofpyridyldienophile 19:75 regioselecti vity 12:16,17 retro-Diels-Alder reaction 14:821,822 stereoselectivity 12:16,17 stereospecific 19:6 with 2-azaallyl aniions 1:347 withacetal 14:502,503 with butadiene 11:356,357 with Danishefsky diene 19:144,208 with doubly activated butadienes 3:465 withisoprene 11:306,307 with ketoester 19:226 with methyl vinyl ketone 19:208 with nitroso compounds 1:359-392;12:16,17, 250,253,416 with p-quinonediimide 3:322-323 Diels-Alder sequence asymmetric 11:359 in ()-A^^'^^ capnellene synthesis 6:46 in ()-12-deoxy-scalaradial 6:58 Diemenensin A antibacterial activity of 17:24 Diemenensin B 17:24 Diene chromophore 11:369 Diene dimerization 3:107 Ni(0)-catalysed 3:107 (Z,)-Diene ester 12:46,47 Diene glycoside asymmetric Diels-Alder 4:334 Diene isomerization 1:447,448

7,9(1 l)-Dieneseychellogenm 15:91 Diene synthesis 6:308 Diene-carbenoid addition 3:49 a-Dienes cyclopenthesis from 3:38,39 p-Dienes synthesis of 3:38,39 Dienes 4:525 formation by reductive elimination 4:525 1,3-Dienes cyclization of 8:278,280 palladium catalyzed 8:280 Dienic acid synthesis of 3:38,39,41 Z,Z-l,4-Dienicmacrolides 8:240 Dienol disilyl ehters Lewis acid cataylzed 12:172 with 4-acetoxy-P-lactam 12:172 Dienone-phenol rearrangement 2:253,615,625,628; 19:406 Dienophiles from L-ascorbic acid derivatives 12:17 synthesis of 12:17 in Diels-Alder reactions 4:583 3-Dienoyl tetramic acid 14:109 Dienoylpyrrol-2(5//)-one 13:120-123 a,P Y, 6-Dienoyltetramic acids 14:104 3,8-Diepialexine 7:14 3,24-Diepibrassinolide 18:530 3,24-Diepibrassmolide-3P-laurate 18:533 3,24-Diepibrassinolide-3 P-myristate 18:533 3,24-Diepibrassinolide-3p-paknitate 18:533 3,24-Diepicastasteron 18:496,530 Diepomuricanin A 18:212,219 (R,R)-Diepoxide buildmg block 11:251,252 (S,S)-Diepoxide building block 11:251,252 2,3-Diepoxy-D-arabino-hept-2-enono-1,4-lactone 11:457 trans-3,3 -Diethoxy-1,2-cyclobutane dicarboxylate 10:613,614 Diethoxyphosphono acetate 9:525 Diethyl (I)-tarrate chiral ortho esters from 14:508 (+)-monomorine I from 6:44 Diethyl [2-^H2,2-"C] succinate 11:196 Diethyl 2,2'-bi-l-benzoate 11:125 Diethyl aluminum 2,2,6,6-tetramethyl piperidine 10:48 Diethyl amino (di-/-butoxy) phosphine 14:305 Diethyl phosphorocyanidate (DEPC) 4:83 Diethyl phthalate 9-0X0-3 -fluorenelacetate from 11:124 (/?,/?)-Diethyl tartrate 11:346 Diethy 1-3 -oxo-glutarate condensation of 6:445 with 4-aminooctanal diethyl acetal 6:45 witethanol 6:445 Diethylaluminum cyanide 3:213 Diethylnitrosamine 12:399 (+)-Diethyltartarate 6:264,268 I-(+)-Diethyltartrate 11:99,132,139 Difficidin 5:606,607 Difforlemenine 9:181

1017

24-Difluoro-25-hy(iroxy-vitamin D3 biotransformation of 9:517 10,10-Difluoroarachidonic acid 9:551 2,4-Difluoroestradiol 5:451-453 Digalactosyl 1-tliio analog ofp,p-trehalose 8:317 synthesis of 8:317 Digeminine A from Tridedemnum species 12:477 Diginatigenin 15:362 Diginatin 15:362 Digitalis 2:402,439 Digitalis glycosides from Digitalis lanata 13:631 Digitalis lanata 15:367,315,317 Digitalis purpurea steroidal lactones from 14:439 digitoxinfrom 5:505 Digitonin 2:54 Digitoxigenin 14:443-444,362 Digitoxin 5:505,439,362 Diglucuronate 15:26 Diglycosides 7:272,281,298 Digoxigenin 15:362 Digoxin 15:362 Digoxin-protein conjugates 15:366-368 a),co'-Dihalides 4:560-563 l,co-Dihaloalkanes 6:313,314 ketones from 6:313,314 a-Dihalomethylcycloheptanones 8:35 Diheptoses in Aeromonas hydrophila 4:196 in Neisseria meningitidis 4:196,206 in oligosaccharide synthesis 4:204,205 24,24-Dihomo-la,25-dihydroxy vitamin D3 pharmacological activity of 11:385,386 synthesis of 11:385-387 24,24-Dihomo-24-methylcholesta-5,7-diene-1 a,3 P, 25-triol 11:387,388 24,24-Dihomo-25-hydroxycholesterol 11:386 Dihydro (A22,23) avermectin Bja (ivermectin) 1:435 1,2-Dihydro-l-arylnaphthalene lignans 17:338 14,15- Dihydro-12-methoxyvincamine 5:126 20,21 -Dihydro-19-desoxomacroline 13:403,404 19,20-Dihydro-19-hydroxycondylocarpine 1:40 22,23-Dihydro-1 a,25-dihydroxyvitamin D2 24/?-epimer of 11:395-398 synthesis of 11:395-398 6,7-Dihydro-3-[(3-guauiazulenyl)methylene]-8(3H)guaiazulene 14:344 4,10-Dihydro-3H-naphtho [2,3-c] pyran-10-one (yellow pigment) 11:127-129 ()-nanaomycin from 11:127 synthesis of 11:129 (2/?,3/?)-2,3-Dihydro-5,7,3',4'-tetrahydroxy-6-methoxy3-0-acetylflavonol 15:32 3,4-Dihydro-6,7-dimethoxy-isoquinoline to chu-al sulfoxides 10:679-685 to chiral sulfoximines 10:679-685 3,4-Dihydro-6,7-dimethoxy-isoquinoline-N-oxide 10:684

1,2-Dihydro-6a-santonin (l)-a-santonin from 14:413 9,10-Dihydro-9,10-dihydroxy anthracene from anthraquinone 11:124 5,7,12,14-pentacenediquinone from 11:124 synthesis of 11:124 with acetoacetate dianion 11:124 P-Dihydro-agarofiiran skeleton sesquiterpenes 18:775 Dihydro-P-carboline 8:287,288 3,4-Dihydro-P-carboline 13:489,490 Dihydro-isokomarovine from Nitraria komarovii 14:762 2,3-Dihydro-A^-methylacronycine 13:359 Dihydro-O-methylmacusine B 13:387 Dihydroacarbose by reductive-amination coupling of 10:508,509 synthesis of 10:508,509 Dihydroactinidiolide 3:157,158 Dihydroailanthinone 7:379,380 19,20-Dihydroakuammicine 1:32-35,54 2,16-Dihydroakuammicine 1:35 Dihydroalloevodionol 4:386,387 Dihydroalstonerine 13:398,423,424 20-21 -Dihydroalstonerine 13:420-423 ()-Dihydroanatoxin-A 13:493,494 Dihydroancyriacyanin A from Arcyria nutans 12:367,372 Dihydroanils 4:541,545 ()-18,19-Dihydroantirhine 14:706-708 i)-3-epi-18,19-Dihydroantirhine by alkaline decarboalkoxylative cyclization 14:708 from tetrahydropyridme 14:708 stereoselective 14:707,708 synthesis of 14:707,708 Dihydroarcyriaflavin A 12:377 Dihydroarcyriarubin B Arcyria denudata 12:366,372 Dihydroartemesinin 13:657 19,20-Dihydroaspidospermatine 1:40 Dihydroastaxanthin diacetate 6:154 22,23-Dihydroavermectin (ivermectin) Bi 12:8 from avermectin Bi with Wilkinson's catayst 12:8 22,23-Dihydroavermectin Bi aglycones 1:443 conversion to milbemycins 1:443 Dihydroavermectin B ip 1:470 22,23-Dihydroavermectin Bib aglyconeof 12:17-19 Julia synthesis of 12:17-19 2,3-Dihydro-3(l-aziridinyl) withaferin A 20:245 Dihydrobenzene 12:22-24 Dihydrobenzofiiranols synthesis of 14:651 via photocyclization of ketone 14:651 Dihydrobicyclomycin 12:65,66 [26-^H]-Dihydrocalyesterol 9:44 [28-^H]-Dihydrocalyesterol 9:45 Dihydrocalysterol 9:36-38,41-45 from Calyx nicaeensis 9:37,44 from Cribrocalina vasculum 9:37

1018
from Petrosiaficiformis 9:37 from Petrosia hebes 9:37 205-1,2- Dihydrocapuvosidine 5:129 8,9- Dihydrocarotane sesquiterpene 5:728,729 Dihydrocarotol 5:734 Dihydrocarpalasionin 15:143,152,160,174 (+)-Dihydrocarvone 14:454 5-ep/-paradisiol from 14:454 (-)-Dihydrocarvone 5:721 (R)-Dihydrocarvone 13:546 fif/-Dihydrocatharanthine 14:806,807,850-853 Dihydrocatharanthine 14:809,810 dihydrocatharanthinol from 14:809,810 synthesis of 5:182 15,205-Dihydrocatharanthine N-oxide decarbomethoxycatharanthine from 14:870,871 deoxyvinblastine from 14:870,871 16'-e/7/-deoxyvinblastine from 14:870,871 16'-ep/-20'-e/7/-deoxyvinblastine from 14:870, 14:871 vindoline-N-methylamide from 14:870,871 with vindoline 14:870,871 Dihydrocatharanthinol from dihydrocatharanthine 14:810 3,14-Dihydrocellipticine 5:125 Dihydrocephalostatin 18:902-904 Dihydrochalcones 7:229,30,31 Dihydrochelerythrine fromberberine 14:774,775,796 synthesis of 14:774,775,796 through enamide-aldehyde cyclization 14:774,775 Dihydrochromones 20:282 (-)-Dihydrochrysanthemolactone synthesis of 16:257-258 R-(+)-Dihydrocitronellic acid 15:231 a/p-Dihydrocleavamme 14:806,807,808,850,851,863, 864 Dihydrocleavamine 5:181,182;14:807,808 (-)-205'-15,20- Dihydrocleavamine 5:124 Dihydrocodeinone 18:96,98 Dihydrocompactin 13:580 19,20-Dihydrocondylocarpine 1:34 Dihydrocoptisine 6:491 a-Dihydrocomin 7:461 Dihydrocorphinol 9:602 Dihydrocorynantheol 13:92,93 ()-Dihydrocorynantheol 18:331 Dihydrocostunolide 17:609 Dihydrocoumarin 7:205,206,225 Dihydrocubebin 17:318 (-)- Dihydrocubebin 5:753,754 Dihydrocurcumin 17:363 Dihydrocurecuquinone 5:767 Dihydrocycloakagerine 9:179 2,3-Dihydrodaturalactone B 20:246 ()-(3-A^-Dihydrodesoxycodeine methyl ether 18:65 Dihydrodesoxyotonecine 1:243 11 p, 13-Dihydrodouglanin acetate 7:212,213 3,14-Dihydroellipticine 6:507,516,518,519 Dihydroerysodine synthesis of 3:478 dihydrofiirans 3:55-58 from vinyloxiranes 3:55-58 (95>Dihydroerythronolide A seco acid synthesis of 16:719-721 (5, 5)-l,2-Diphenylethane-l,2-diolfrom 11:423,424 95'-Dihydroerythronolide A synthesis of 16:718-719 (95)-9-Dihydroerythromycin A erthromycin A from 12:53,54 Dihydroerythromycin A 13:173-176 (95)-9-Dihydroerythronolide A erthromycin A from 12:53,54;16:718-719 erthronolide A from 12:48-53 Dihydroflavonoids 7:228 Dihydroflavonols 15:30,31 6,7-Dihydroflavopereu-ine 1:124,142,143,150,153,157, 158 Dihydroflustramine C 18:691,725 Dihydroflustramine C A^-oxide 18:691 Dihydrofolate reductase 7:387 Dihydrofreelingyne 15:235 Dihydrofiimariline 1:198,199,207 Dihydrogambirtannine oxidation to ourouparine 1:158 synthesis of 1:137 Ajor-Dihydroguaiaretic acid 9:578,579 Dihydrohalichondramide 17:16 ()-18,19-Dihydrohunterbumine ()-10-O-methyl-18,19-dihydro hunterbumine from 14:706,707 synthesis of 14:706-708 withCHjNz 14:706,707 Dihydroindolizidine 11:241,243 6,7-Dihydroindolo [2,3-a] quinolizine 1:151 3,4-Dihydroisocoumarins 15:382 Dihydroisocoumarins 9:267,15:5,30,31,381-418 Dihydroisodocarpin 15:141,149,158,174 Dihydroisojacareubin 4:368,370 Dihydroisoosajin monomethyl ether 4:393,394 Dihydrojasmone 19:158,19:160 (+)Dihydronepetalactone 20:71 Dihydrophenanthrenes 20:280 (255) 25,27-Dihydrophysalin A 20:189 2,3-Dihydropiperidine 19:45 Dihydrokalafimgin 11:128 Dihydrokamebakaurin aldehyde triacetate 15:135 Dihydrokikumycin B 5:557,568 Dihydrokomarovinine biosynthesis of 14:763,764 1,2-Dihydrokoumine from Gelsemium elegans 15:476 Dihydrolanosterol 8:365,366 Dihydrolanosterol ester 9:467 Dihydrolevoglucosenone 14:278 (+)-Dihydrolimonene 8:227 2,3 -Dihydrolinderazulene antifungal activity of 5:369 (+)-Dihydrolmonene ozonization of 6:541 (-)-periplanone-B from 6:541,542 Dihydromarthasterone 7:289;15:51

1019

Dihydromevinolin synthesis of 13:575,608,609 3,4-Dihydromilbemycin E from Streptomyces sp. 16:659 Dihydromyoporone 1:604,606 9-Dihydromyoporone 15:229 75,9/?-(-)-9-Dihydromyoporone 15:230 Dihydronepetalactone 16:289 Dihydroneptalactones 7:477 3,6-Dihy(ironicotinic acid 11:206 Dihydronitidine 14:775,776 Dihydronitraraine from (5)-glyceraldehyde 14:765 synthesis of 14:765 Dihydronodularin fromnodularin 9:496 (+)-7,8-Dihydronogarene 14:68 7,8-Dihydronogarene 14:78 Dihydronorfluorocurarine 1:46-48 22-Dihydrooccelasterol 9:41 Dihydroonychine 2:442 Dihydroparfiimidine 1:206-209 Dihydroperaksine 13:387 Dihydroperezine 5:766,767 Dihydroperoxides 9:560 Dihydrophenanthridines 4:541 Dihydrophymaspermones 15:233 (+)-Dihydropindine 16:495 (-)-Dihydropinidine 16:482 Dihydropinidine 1:391,392 (+)-Dihydropmidine 14:572,573 Dihydroprotoberberines Hofmann degradation of 14:771-773 ()-Dihydroprotoemetine 18:330 (+)-20/?-18,19- Dihydropseudovincadifformine 5:124 DihydropseurataF 15:117,124,131,174 Dihydropyran 12:158 Dihydropyran derivative 10:425 Dihydropyranocoumarins 18:984 Dihydropyridines 1:91,92 Dihydropyrrole synthesis of 10:112,113 2,3-Dihydropyrrolo [1,2-a] indole 445,442 (2R,3Ry Dihydroquercetin (toxifolin) 5:496 Dihydroquercetin 3-acetate 4'-(methyl ether) 15:26 (+)-Dihy droquercetin 3 -O-acetate 15:31 Dihydroquinone uncinatone 7:408,423 Dihydrorugosanin 15:142,150,159,174 Dihydrosanguinarine from coptisine 14:793-795 synthesis of 14:793-795 through cationic cyclization 14:793-795 11 a, 13-Dihydrosantamarin 7:213 Dihydroschelhammeridine synthesis of 3:484-486 Dihydrosecurinine 14:657 Dihydroserratenone 11:309 Dihydrosiphonarin A and B 17:25 Dihydrosirohydroochlorin 9:603 Dihydrosphingosine 18:786 Dihydrosecodine 19:90 15,20-Dihydrosecodine 19:91

Dihydrospiniferin-1 derivative by Birch reduction 6:72 by electrocyclic rearrangement 6:72,73 by Jones oxidation 6:72 by Simmons-Smith cyclopropanation 6:72 from6-methoxy-l-tetralone 6:72 Marshal synthesis of 6:72,73 Dihydrostemmdenine acetate 1:49 19,20(-)-l 1,12-Dihydrostepharine 2:254,258 (+)-8,9-Dihydrostepharine 2:254,258 20W-19',20'- Dihydrotabemamine 5:128 Dihydrotachysterol synthesis of 4:521-526 Dihydrothebainone 18:59 ()-Dihydrothebainone 18:70,72,73,77,78 Dihydrothiopyrans 8:207 Dihydrothiopyrone synthesis of 8:207,208 Dihydrotubastrine 5:360 Dihydroudoteal 18:688 3,4-Dihydroumbelliferone 4:400 12,13-Dihydroursolic acid 9:293,294 a-Dihydroverbenol 7:461,462,467,468 la,25-DihydroxyvitaminD3 20:669 Dihydrovincarpine 1:124 2,3-DihydrowithaferinA 20:181,194,214 ent-12a, 16-Dihydroxy-13 [/?]-imar-8( 14)- ene-3,15dione 9:283,284 ent-13 [5], 14[5?l-Dihydroxy-3-oxo-tis-15-en-17-al 9:268,269,276 Ent- \3[S\, 15p-Dihydroxyatis-16-ene-3,14-dione 9:268,269 Ent-13 [5], 18-Dihydroxyatis-16-ene-3,14-ione 9:268,269,276,282 Ent-16a, 17-Dihydroxyatisan-3-one 9:68,269,276, 9:277,168,169,176 Ent-3^,\3[5]-Dihydroxyatis-6-en-14-one 9:268,269, 9:276,280 2a,14-Dihydroxydehydroabietic acid 20:669 la-25-Dihydroxy-(24/?)-fluoro-cholecalciferol 10:57,69 3a, 13-Dihydroxy-11 -e/7/-apotrichotec-9-ene 9:210 3p,13-Dihydroxy-l l-ep/-apotrichotec-9-ene 9:210 2a, 13-Dihydroxy-11-epiapotrichothecene 13:520 2P-13-Dihydroxy-11 -epiapotrichothecene 13:520 10- Dihydroxy-11 -methoxydracaenone 5:17,18,20,22, 556 3,4'-Dihydroxy-2,3'-bipyridine 2:239,753 l,5-Dihydroxy-2,3-dimethoxy-10-methylacridin-9-one from Glycosmis bilocularis 13:348,350,355 synthesis of 13:354,355 (22R,23R,24S)-22,23-Dihydroxy-28-homoergosterol 18:520 (22R,23R,24R)-22,23-Dihydroxy-2a,3a-epoxy-24methyl-5a-cholestan-6-one 18:512 2,13-Dihydroxy-3,l 1-epoxy APO 13:522 (/?)-2,4-Dihydroxy-3,3-dimethyl-butanoic acid 10:442, 10:443 5,3- Dihydroxy-3,6,7,4*,5'-pentamethoxyflavone 5:757 1,5-Dihydroxy-3-methoxy-10-methylacridin-9-one 13:348,350 1,2-Dihydroxy-3-pentadecyl benzene 9:314,318,343

1020

6,8-Dihyciroxy-3-undecyl-3,4-dihydroisocoumarin 15:386 3p,20^-Dihydroxy-30-novolenan-12-en-28- oic acid 7:139,140 3,6-Dihydroxy-4,5,7-trimethylmellein 15:385 2,6-Dihydroxy-4-methoxyacetophenone 4:386,387 3,6-Dihydroxy-5,7-dimethylmellein 15:385 1,3-Dihydroxy-5-alkylbenzenes 9:320,321 l,3-Dihydroxy-5-heneicosyl benzenes 9:343 l,3-Dihydroxy-5-hexyl-2-propyl benezene 9:322 l,3-Dihydroxy-5-nonadecyl benzene 9:343 l,3-Dihydroxy-5-pentyl benzene (olivetol) 9:344 l,3-Dihydroxy-5-tridecyl benzene 9:344 1,3-dihydroxy-5-tridecyl benzene from 9:344 3p,6a-Dihydroxy-5a- pregn-9(l l)-en-20-one (asterone) 7:156,157 3p,6a-Dihydroxy-5a- pregn-9(l l)-en-20-one 15:45 2a,3P Dihydroxy-5a-pregnane-6,20-dione 18:530, 18:534 105,1 l/?-Dihydroxy-5(6),15-rosanedien-7-one 20:474 5,4'- Dihydroxy-6,7,3'-trimethoxyflavone 5:653,655 5,4'- Dihydroxy-6,7,8,3'-tetramethoxyflavone 5:653, 5:655 5,4'- Dihydroxy-6,7,8-trimethoxyflavone 5:653 3,4,'- Dihydroxy-6,7-dimethoxyflavone 5:14,15 5,8- Dihydroxy-6,7-dimethoxyflavone 5:624,627,628, 640 5,4'- Dihydroxy-6,7-dimethoxyflavone 5:653,657 2p,4P-Dihydroxy-6-deoxy-celorbicol 18:744 5,7- Dihydroxy-6-methoxyflavonoid 5:640 5,6- Dihydroxy-7,3',4'-trimethoxyflavone 5:655 5,6- Dihydroxy-7,4'-dimethoxyflavone 5:623,653 5,6- Dihydroxy-7,8,3',4'-tetramethoxyflavone 5:655 5,6- Dihydroxy-7,8,4-trimethoxyflavone 5:629,653 7,8-Dihydroxy-7,8-dihydro-vitamin D2 9:522 7,8-Dihydroxy-7,8-dihydrobenzo [1] pyrene 9:583 5.6- Dihydroxy-7,8-dimethoxyflavone 5:624-629,640 9,10-Dihydroxy-7-methoxynaphtho [2,3-c] pyran-1 (IH)-one (semivioxanthin) antibiotic activity of 11:130 antifiingal activity of 11:130 2a,4P-Dihydroxy-8-epi-celapanol 18:746 5.7- Dihydroxy-8-methoxyflavonoid 5:640 2a,3p-Dihydroxy-B-homo-6a-oxa-5a-pregnane-6,20dione 18:530 3P,29- Dihydroxy-D:p-friedo-olean-5- ene 5:747 1,2-Dihydroxy-hexahydro-3(2H)-indolidinones 12:305 la,25Dihydroxy-vitamin D3 9:12,514,516,519 24/?,25-Dihydroxy-vitamin D3 9:512,514 1,3-Dihydroxyacridin-9-one 13:355,358 9,11-Dihydroxyacronycine 13:366,367 (+)-3,9-Dihydroxyaporphine 16:518 1,3-Dihydroxybenzene 14:655 dichlorination of 14:655 with sulfiiryl chloride 14:655 2,4-Dihydroxybenzoic acid 4:395,398 la,25-Dihydroxycalciferol (calcitriol) 9:20,521 1 a-25-Dihydroxycholecalciferol-26,23 (S)-lactone synthesis of 10:59 7,8-Dihydroxycoumarin 4:372,373 5,6- Dihydroxyflavonoid 5:625-627,629,658 5.8- Dihydroxyflavonoid 5:625,627,628,658

5,8- Dihydroxyflavonols 5:627 28,29-Dihydroxyfriedelan-3-one 7:150 Dihydroxyheliotridane synthesis of 1:246,252,253,52 3,4- Dihydroxyhomoisoflavan 5:21,22 1,2-Dihydroxyindolizidine 12:303-306 (+)-(6/?,75,8a^)-Dihydroxyindolizidine 12:306 6,7-Dihydroxyindolizidine 12:348 from methyl 2-azido-4,6-0-benzylidene-2-deoxya-D-altropyranoside 12:348 synthesis of 12:348 5,7-Dihydroxyisoflavone 4'-0-methylosajm from 4:382,385 4'-0-methylwaranglone from 4:382,385 with 3,3-dimethylallyl bromide 4:382 6,7- Dihydroxylate coumarin 5:516,517,520 cw-Dihydroxylation of A^^-stigmasterol 16:332 ofbrassicaterol 16:332 ofergosterol 16:332 Dihydroxy lation 11:423,424 (-)-3,13a-Dihydroxylupanine 15:523 from Cytisus scoparius 15:523 15 2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) 7:13 2/?,5i?-Dihydroxymethyl-3/?,4/?-dihydroxypyrrolidine absolute configuration of 10:545,546 almond emulsin p-glucosidase inhibitor of 10:545 enantioselective synthesis of 10:546,547 from Derris elliptica 10:545 from Lonchocarpus sericeus 10:545 from Omphalea diandra 10:545 insect trehalase inhibitor of 10:545 relative configuration of 10:545,546 yeast invertase inhibitor of 10:545 yeast a-glucosidase inhibitor of 10:545 P-galactosidases 10:545 p-glucosidases 10:545 3,11-Dihydroxymyristic acid 13:312 (6R,7R)-6,7-Dihydroxynonan-2-one 11:413,414 6,5-Dihydroxyperezone 5:795,796 20/?-18,19-Dihydroxypseudovincadififbrmme 9:190 Dihydroxyserrulatic acid from Eremophila serrulata 15:257 3,11-Dihydroxystaurosporine from Eudistoma sp. 12:366,370 (22R,23R)-22,23-Dihydroxystigmasterol 18:515 Dihydroxythymoquinone 5:776 14,15- Dihydroxyvincadifformine 5:124 1,24-Dihydroxyvitamin D2 9:513 l,25-DihydroxyvitaminD2 9:513 24,25-Dihydroxyvitamin D2 9:513 24,26-Dihydroxyvitamin D2 9:513 25,26-Dihydroxyvitamin D2 9:513 la,25-Dihydroxyvitamin D2 (ercalcitriol) synthesis of 11:393-395 24/?-epimer of 11:393-395 la,24/?-Dihydroxyvitamin D3 synthesis of 11:384,385 la,245-Dihydroxy vitamin D3 synthesis of 11:384,385

1021

la,25-DihydroxyvitaminD3 (calcitriol) 11:379,380, 385,395 synthesis of 11:384,385,388-423 1,7-Dihydroxyxanthone 5:759 2,3- Dihydroxyxanthone 5:759 Dihydroyohimbine 15:487 20/?-l,2- Dihyrocapuvosidine 5:123-125,127,131,129 (+y20R-l5,20- Dihyrocleavamine 5:124 Diindole 12:382,383 3,5-Diiodo-L-tyrosme 10:653,661,667 Diisobutylaliminium hydride 1:523,324,353,4:589,590 Diisobutylaluminium 6:115 Diisobutylaluminum hydride-A^-butyllithium "ATE" complex 14:595 7,20-Diisocyanoadociane by intramolecular [4+2] cycloaddition 6:86,87 by stereospecific intramolecular Diels-Alder cycloaddition 6:86,87 byvinylation 6:86,87 by Wittig coupling 6:86,87 enantioselective synthesis of 6:86,87 from ^fi^oc/a species 6:86 from(l/?,25,5/?)-(-)menthol 6:86 (+)-Diisopinocamphenylborane 20:587 Diisopropyl (bromomethyl) boronate 11:425 synthesis of 11:425 A^,A^-Diisopropyl carbamoyl chloride 10:15 Diisopropyl ethanediol esters insect pheromones II from 11:415-417 Diisopropyl tartrate 12:282,19:445 3,7-Diisopropyl-l-azulenecarbaldehyde 14:337,340 Diisopropy lamine 12:113 Diisopropylamine borane 4:437 in stereoselective reduction 4:437 Diisopropylethanediol (DIPED) 11:415 (S, 5)-Diisopropylethanediol methyl boronate 11:415, 416 (/?,/?)-Diisopropylethanediol propylboronate 11:415 Diisopropylethylamine 12:46,47 N,N-Diisopropylphosphoramidites 18:398 p-Diketone in (+)-A^^*^^-capnellene synthesis 6:48 photochemical annulation of 6:48 a-Diketone synthesis of 8:165,166 1,3-Diketoneenolates 3:74,75 1,4-Diketones 2,5-dialkyl pyrrolidines from 6:437,438 reductive amination of 6:437,438 2,2'-Diketospirilloxanthin 20:594 Diketopiperazine 10:638,96,97,321 Dilactone synthesis of 6:301,303 Dilaspiralactone 4:712 retro Diels-Alder reaction 8:150 Dilignan 5:497,498 Dilignols 5:464-466 Dilithium (cyano) dimethyl cuprate 11:361 Dilithium (cyano) divinyl cuprate 11:360,361 Dimeric triterpenes 18:764-709 Dimethylsodium 4:322,323 Dimethomorph 9:226

10,11 -Dimethoxyacronycine 20:792,20:798 (2R)-5,6-Dimethoxydehyroiso-a-lapachone 20:494 1,3-10,11 -Dimethoxy indolines 9:185,186 1R-1 -Dimethoxy phosphenyl-)-threitol 6:355 (+)-(2i?,3/?)-1,4-Dimethoxy-2,3-butanediol 14:499, 14:500 2,4-Dimethoxy-3-methyl-phenol 13:437,438 2,6-Dimethoxy-4-hydroxyacetophenone 4:386,387 Dimethoxy-5-(7-hydroxyheptyl) benzene 9:345 2,12-Dimethoxy-6,7,8,9-tetrahydro-5-//-dibenz [d,J] azonine-3,ll-diol 6:478 synthesis of 6:478 Dimethoxyabieta-8,11,13-triene demethoxylation of 14:676,677 totaxodione 14:676,677 transformation of 14:676,677 Dimethoxyabietatriene 14:697,698 5,7-Dimethoxyanthracene 11:120 Dimethoxyanthracene Claisen condensation of 11:126 5,5'-dipentacene 14,14' (5H,5'H) dione from 11:126 with methyl acetoacetate dianion 11:126 with Pb (0Ac)2 11:126 Dimethoxybenzaldehyde 9:343,354 Dimethoxybenzene 14:670-674,681,682 1,3-Dimethoxybenzene 4:389 3,5-Dimethoxybenzoic acid 9:344 3,5-Dimethoxybenzoyl chloride 9:344 A^-(2,4-Dimethoxybenzyl) tu-andamycin 14:138 (-)-/ra5-2-(3,4-Dimethoxybenzyl)-3-(3,4-methylenedioxybenzyl)-Y-butyrolactone 18:556 4,4-Dimethoxybutyronitrile 6:319 1,1 l-Dimethoxycanthin-6-one 7:389,390 10-11 -Dimethoxycoronaridine (conopharyngine) 9:174, 176,177 Dimethoxyethane (DME) 8:16,166 5,7- Dimethoxyflavone 5:652,413 3,5-Dimethoxyfluorobenzene 9:346 a,a-Dimethoxylation 3:474 Dimethoxyolivetol 19:187 1,8-Dimethoxynaphthalene glutarate 11:120 3,4-Dimethoxyphenethyl alchol 12:448 3,4-Dimethoxyphenol 8:170 anodic oxidation of 8:170 (3,4-Dimethoxyphenyl) methyl methyl ketone from veratraldehyde 6:334 methyl-DOPA from 6:334 8-(3,5-Dimethoxyphenyl) octan-1 -ol synthesis of 9:339 2-(3',4'-Dimethoxyphenyl)-l,3-thian 12:466 3,4-Dimethoxyphenylpropionic acid 12:448 2,5-Dimethoxytetrahydrofiiran 19:18,19 2,6-Dimethoxytoluene 13:437,438,448 Dimethoxytrityloxyethylsulfonylethyl 4:285 Dimethyl (methylthio) sulfonium triflate (DMTST) 10:467 Dimethyl 2-amino-1,3 -azulenedicarboxylate 14:339 Dimethyl 2-amino-6-formyl-1,3-azulenedicarboxylate 14:339 2-Dimethylamino-1,2-dihydroacronycine 20:800 Dimethyl 3,5,10,13-tetraoxotetra decanedioate 11:116

1022 Dimethyl 6-substituted 3,5,9,1 l-tetraoxododecanedioatell:118 3,5-Dimethyl benzylalcohol 9:225 7,12-Dimethylbenz (a) anthracene 20:508 2,2-Dimethyl chromanes 9:115,116 Dimethyl ketal 11:347 Dimethyl A^-boc-^/^reo-P-hydroxy-L-glutamate 12:431, 432 Dimethyl phosphorochloridite 18:399-402 Dimethyl polysiloxane 9:454,456 (/?, /?)-2,5-Dimethyl pyrrolidine 14:555,556 Dimethyl sulfoxide (DMSO) oxidation 10:413,414 4,4-Dimethyl thiazolidin-2-thione derivative 12:164, 166 4,6-Dimethyl-l,3-cyclohexadiene 6:83,84 1,2-Dimethy 1-1 -carboxymethyl-2-phenyl cyclopentane 8:13 5,9-Dimethyl-deca-2,4,8-trienoate 20:839 12,7-Dimethyl-1 -1,6-dioxaspiro[4.4]nonanes 19:129 A^.O-Dimethylnorbelladine 20:359 from Pancratium maritimum 20:359 4,4-Dimethyl-1 -mesityl-2-pentyn-1 -one 14:615 CIS 1,2-Dimethyl-l-phenyl cyclopentane 8:8 /raAw-l,2-Dimethy 1-1-phenyl cyclopentane 8:8,9 1,2-Dimethyl-l-phenyl cyclopentane 8:6 ,7 2,8-Dimethyl-l,7-dioxaspiro [5.5] undecane 1:692 6,7- Dimethyl-Ihydroxyxanthone 5:759 4,7-Dimethyl-2-(4,68-trimethy 1-1 -azuleny 1)-1 H-inden1-ones 14:342 3,5-Dimethyl-2-cyclohexan-l-one 6:82,83 ()-9-isocyanopupukeanane from 6:82,83 5,5-Dimethyl-2-cyclpentenone 13:16 4,4-Dimethyl-2-oxazolidone derivative 12:164,166 1,3-Dimethyl-2-oxohexahydropyrimidine 8:316,343 2,5- Dimethyl-3,6-di(l-hydroxyisopentyl) pyrazines 5:226,246,247 2,5- Dimethyl-3,6-di-(l-oxoisopentyl) 5:226,246, 247,266 2,5- Dimethyl-3,6-diisopentylpyrazines 5:225,227, 229,246 2,5- Dimethyl-3,6-dimethylpyrazines 5:225,227,236 2,5- Dimethyl-3-( 1 -hydroxyisopentyl)-6-( 1 -oxoisopent2-enyl)-pyrazines 5:227,247,266 2,5- Dimethyl-3-( 1 -oxoisopentyl)-6-( 1 -hydroxy isopentyl)-pyrazines 5:226,246,247,266 2,5- Dimethyl-3-(1 -oxoisopentyl)-6-( 1 -oxoisopent2-enyl)-pyrazinesm 5:226,247,266 2,5- Dimethyl-3-(2-methylbutyl)-pyrazines 5:224,228, 230,231,243,244,259,260 2.5- Dimethyl-3-alkylpyrazines 5:227 2.6- Dimethyl-3-alkylpyrazines 5:227,237,238 2,5- Dimethyl-3-citronellylpyrazines 5:225,230,239, 246,261 2.5- Dimethyl-3-ethylpyrazines 5:222,225,231-237, 249-251 2.6- Dimethyl-3-ethylpyrazines 5:223,237,238 2.5- Dimethyl-3-isobutylpyrazines 5:223,228,230232,238 2.6- Dimethyl-3-isobutylpyrazines 5:223,237,238 2,5- Dimethyl-3 -isopentyl-6-( 1 -hyd-roxyisopentyl)pyrazine 5:226,246,247,266 2,5- Dimethyl-3-isopentyl-6-(E-isopent-1 -enyl)pyrazines 5:226,245 2,5-Dimethyl-3-isopentyl-6-(isopent-2-enyl)-pyrazines 5:226,245,266 2,5- Dimethyl-3 -isopentyl-6-)Z-isopent-1 -enyl)pyrazines 5:226,245 2.5- Dimethyl-3-isopentylpyrazines 5:223,224,227233,237,238,240,243,244,246,251,259-261 2.6- Dimethyl-3-isopentylpyrazines 5:224,227,237 2,5- Dimethyl-3-methylpyrazines 5:222,228,232-237 2,5- Dimethyl-3-n-allq^lpyrazines 5:232-237 2.5- Dimethyl-3-n-butyl-pyrazines 5:224,232,237,238 2.6- Dimethyl-3-n-hexylpyrazine 5:225,237,238 2.5- Dimethyl-3-n-pentylpyrazines 5:225,228,232,259, 260 2.6- Dimethyl-3-n-pentylpyrazines 5:225,237,238 2.5- Dimethyl-3-n-propylpyrazines 5:223,228,229,232, 233,240 2.6- Dimethyl-3-n-propylpyrazines 5:223,232,237 3,7-Dimethyl-3-phenyl-7-octene 8:10 cyclization of 8:10 2.5- Dimethyl-3-phenylethylpyrazine 5:257 2.6- Dimethyl-3-5ec-butyl-pyrazines 5:223,237,238 2,5- Dimethyl-3-5ec-butyl-pyrazines 5:223,238 (35,4/?)-3,7-Dimethyl-4-hydroxyoct-6-enoic acid 11:414 2,3- Dimethyl-5-isobutylppyrazines 5:223,227,232 2,2-Dimethyl-5-nitromethylpyrrolidin-1 -ol 12:284 3,3-Dimethyl-8-nitro-4-oxy-octahydroindolizidine-5-ol 12:284,285 2,5- Dimethyl--styryl-pyrazines 5:225 2,5-Dimethyl-Z-3-styryl-pyrazines 5:225,239-241, 5:257,262 Dimethylacetamide dimethylacetal 14:722-724 3,3-Dimethylallyl alcohol 7:100 3,3-dimethylallyl bromide 8:70 Dimethylallyl diphosphate 7:323,324,330,348,352 4-(Y,y-Dimethylallyl) tryptophan synthase 11:200 3-0,1 -Dimethylallyl) xanthyletin synthesis 4:374,375,399,400 1 -(3,3-Dimethylallyl)-2-hydroxynaphthalene 4:394 6-(3,3-Dimethyiallyl)-7-hydroxycoumarin 4:385,386 3,3-Dimethylallyldilaurylsulfonium perchlorate 8:40 Dimethylallylindole 2:447 Dimethylaluminium benzenethiolate 14:755 Dimethylaluminium complex 14:750 Dimethylaluminium tert-hxxtyX sulphide 1:271,272 Dimethylaluminum amide 1:288 4-(Dimethylamino) pyridine 12:328,473 2-Dimethylamino-5-methoxy-benzoquinone 13:434 (9/?)-Dimethy lamino-9-deoxyerythromycin A 13:181 Dimethylaminopyridine (DMAP) 11:154 4a-Dimethylation in (+)-brasilenol synthesis 6:8 7,12-Dimethylbenz [A]-anthracene 10:4 4,5- Dimethylbenzo[b]furan 5:277,278 A^,A^-Dimethylbenzylamine 5:827,828 eafo-7,7-Dimethylbicyclo-[3.3.1]-nonane-3-ol-9-one 15:135 Dimethylchlorosulfonium chloride 9:526 2,2-Dimethylchromans 13:367 Dimethylcopper lithium 1:263

1023

4,4-Dimethylcyclopentene 13:36 4,4-Dimethylcyclopentenone 13:9,14 A';A^- Dimethylethanolamine 5:229 Dimethylformylpyrazine 5:240,241 (3R,4S)-N, O-Dimethylisostatine 12:477 (-)-Dimethylmatairesinol 18:558 4,4-Dimethyloxazolidin-2-thione derivative 12:164,166 (2/?,3/?)/(25',35)-2,3-Dimethylpentane-l,2diol-enantiomeric pair 15:86 Dimethylphenylethylpyrazine 5:241 (1 S,R)-1 -Dimethy lphosphinyl-2,3 -O-isopropylidene-Dglycerols 6:353,355 2,5-Dimethylpyrazines 5:222,228,2332-237 6-Dimethylpyridine 6:424-426 2,6-Dimethylpyridine 6:425 Dimethylsulfoxonum methylide 6:550,551 Dimethyltryptamine 2:395 5,8-Dimethyoxy isocoumarin from Artemisia carvifolia 7:206 from soyasaponin I 7:227,228 3,5'-di-0-methyl-myricetin 7:227 3',4'- Dimetoxyflavone 5:653 Dimoracin 20:282 Dimorphecolic acid synthesis of 1:533,534 Dimsyl sodium 6:482,492,493 2,4-Dinitro-phenylhydrazone 8:43,319 few-Dinitrophenylhydrazone derivative ofmyoporone 15:228 Dinklageine from Strychnos dinklagei 6:522 spectral data of 6:524,526 synthesis of 6:526 Dinoflagellates 17:20 Dinophyceae 6:134,135 Dinophysis acuminata 5:384 Dinophysis fortii 17:20 Dinophysistoxin-1 17:19,269 Dinophysistoxin-2 17:20 Dinophy sistoxin-3 17:19 Dinoponera grandis 5:223,224,229,254 Dinor-sesquiterpenes 9:65 Dinorcholenic acid 16:323 26,27-Dinortyphasterol 16:352 Dinosterol 9:47 1,3-Diolmonotosylate 3:73 v/c-Diols 2:173 Dioncophyllaceae 20:407-409,417 Dioncophylline 20:265 Dioncophylline A and C 20:408,418,437,438,440 DIOP 13:72 Dioscoreaceae 17:130 Diosgenin 2:443,444;7:19 Diosmetin from Salvia candidissima 20:712 Diospyros 7:406,423 Diospyros abssinica 7:417 Diospyros canaiculata I'.llA Diospyros kaki Thimb 19:246 Diospyros maritima 2:231,22,754 Diospyros usambarensis 7:427,435 Diospyros zombensis 7:417,427,429 2,9-Dioxabicyclo [3.3.1] nonane 14:108

Dioxacyclohexenone 1:642 Dioxanone 12:15,16 l,6-Dioxaspiri[4,4]nonane 19:128 {R/S) 1,6-Dioxaspiro [4.5] decane asymmetric synthesis of 14:523,524 {R/S) 1,7-Dioxaspiro [5.5]-imdecane asymmetric synthesis of 14:521-526 from Dacus oleae 14:521 from (5)-malic acid 14:521,522 from (-)-menthyl (5)-p-toluene sulfmate 14:522,523 Dioxepane synthesis of 10:218,219 2H,4H,l,3-Dioxin derivative 12:160,161 3,5-Dioxoalkanoates 11:114 Dioxoabieta-8,13-diene 20:670,11,12 Dioxoaporphines 20:480 (Z)-l,4-Dioxodec-7-ene 19:161 Dioxoester 11:117 l,3-Dioxolan-4-ones 1:603,609 1,3-Dioxolanes 1:584 Dioxolanes 1:644 Dioxygenases 9:559 3,2'-Dioxygenated flavonoids 5:673-694 Dioxygenation 9:560,561,566,567,570,573,575 /^-Dioxygenation 9:574,575 5,5'-Dipentacene 14,14'(5H,5'H)-dione 11:126 Diphenols 17:368 Diphenyl ether anti-inflammatory activity of 5:367 Diphenyl phosphane chloride 9:524 Diphenyl phosphorazidate (DPPA) 4:83 (S, S)-1,2-Diphenylethane-1,2-diol 11:423,424 Diphenylphosphoryl azide 10:289,290 ,641,644,645, 652,656,657 Diphosgene 12:113 Diphospha adamantane 9:528 1,3-Diphospha-heterocycles 9:529 Diphylleia cymosa 5:492 Diphyllin 5:461,462,493 Dipiperidine spiroalkaloids biosynthesis of 14:748 hypothetical 14:748 Dipiperidme-P-carbolines 14:759-765 Diplamine 10:244 Diplodia maydis 4:600 synthesis of 4:230 Diplodiatoxme biomimetic synthesis of 4:620 synthesis of 4:600-602 Diplodiosis 4:600 ^Diplophyllolide 2:278,279 Diplophyllin 2:278,279 Diplophyllum albicans 2:278 Diplorhoptrum alkaloids 6:422,423 Diplosoma species 10:244 Dipodascus sp. 12:337 1,3-Dipolar addition 1:230,231,291 Dipolar [3+2]cycloaddition 19:155 Dipolar cycloaddition intramolecular 13:84-86;19:42 intermolecular 19:309 of methyl acrylate 19:309

1024

ofalkenes 16:463 of nitrile oxide 16:464 to 3 -oxidopyrazinium 10:135 1,3-Dipolar cycloaddition 1:227,278,284,285,324-344, 4:435;10:65,66,138,139,215,216,11:238-241,264,283 [3+2]Dipolar cycloaddition 13:500,191 Dipolar cycloaddition 3:223 Dipolar solvents 19:119 Dipole LUMO control 1:363 6,8-Diprenylflavanone from 7-hydroxy-flavanone 4:378,380 in azetidinone synthesis 4:437 6,8-Diprenylnoreugenin 4:382,384 A^,A^-Diprotected I-alaninals 4:124 a-amino aldehydes 4:124 D-(+)-DIPT 19:445,480,490 D-(-)-DIPT 19:490 DIPT 4:172-174,179,186,187 Dipyrromethane 9:592,593 Diquinane diterpenes 13:3-52 sesquiterpenes 13:3-52 sesterterpenes 13:3-52 synthesis of 13:3-52 Diradical trapping 3:20 Direct chemical ionization (DCI) 2:45 Direct cM-hydroxylation 14:183 Direct sample introduction 9:476-478 Directed hydromagnesiation 10:29,30 Directed-aldol condensation 15:15 Dirhodium tetrakis (trifluoroacetate) 10:210 Diribonucleoside 2',3'-cyclic phosphates 14:285 Dirithromycin 13:171,172 Dirman 17:28 7-Dis-O-methylnogarol 14:78 a-l,4Disacccharide 8:369,370 Disaccharide 6:377,29,33,50,53,60,62,70;10:338 Disaccharide acids 6:401,407,412,413 Disaccharide dipeptides 6:395,396,398,406-409,41-416 anomeric characterisation of 6:413,416 anomeric deprotection of 6:413-416 tert butyl ester of 6:413-415 2D COSY spectrum of 6:407,408 synthesis of 6:397,398,406,407 Disaccharide lactone 6:395,396,407 Disaccharide methyl ester synthesis of 6:395,396 Disaccharide thioether 8:342 Disaccharide-L-alanyl-D-isoglutamine benzyl ester 6:410,411 Disaccharides synthesis of 11:469 semi-synthesis of 17:636 C-Disaccharides synthesis of 3:223,224 1,2-Disaccharides synthesis of 8:362 Discadenine 9:220 Disc-diffiision method 20:712 Discodermia calyx 5:396

Discriminative functionalization in hexopyranoses 10:415 ofgeminal dimethyl groups 10:415 Disiamyl borane (bis(3-methyl-2-butyl) borane 14:183 Disiamylborane 4:116,117 Disidea pallescens pallescansin-A from 6:20,23 pallescensin-D from 6:31 pallescensin-F from 6:31 pallescensin-G from 6:31 (+)-Disparlure synthesis of 16:695-696 (+)-Disparlure 19:481 Dissymmetrization enzymatic 19:45 of/we50 compound 19:45 Distamycin 5:551,552 Distamycin analogues synthesis of 5:558-564,567 Distemonanthus benthamianus 5:676-681 Distolasteria nipon 7:299;15:55 Distorted flavonols 5:673-694 Distylium racemosum 18:498,500,512,520,19:247 A^,A^-Disubstituted amides 4:389 2,5-Disubstituted ant pyrrolidines synthesis of 6:441,442 A/;A^-Disubstituted benzyl amines 4:389 in metallation reactions 4:389 3,5-Disubstituted-2-formylpyrrolidme 19:316 2,5-Disubstituted decahydroquinoline 19:3-13 3,5-Disubstituted indolizidines absolute configuration of 11:245 from dendrobatid frogs 11:245 synthesis of 11:245-259 3,5-Disubstituted mdolizidines synthesis of 19:24-37 5,8Disubstituted indolizidines synthesis of 19:38-51 5,8-Disubstituted indolizidines via hetero Diels-Alder approach 11:260-267 synthesis of 11:260-267 cw-2,8-Disubstituted oxocane 10:232 2,8-Disubstituted oxocene synthesis of 10:223 cw-2,5-Disubstituted piperidine 19:36 cw-a, a'-Disubstituted piperidines synthesis of 14:571-574 2,6-Disubstituted piperidines 6:430,431 cis-a, a*-Disubstituted pyrolidine synthesis of 14:571-574 c-2,5-Disubstituted pyrrolidine by ozonolysis 11:241,242 (+)-monomorine I from 11:241,242 2,3-Disubstituted quinolines synthesis of 3:393,394,396 2,4-Disubstituted quinolines synthesis of 3:394,396 4,5-Disubstituted-2-oxazolidinon 12:427,428 from 4-methoxy-2-oxazolidinone 12:427 Disulfide bond 2:28,30 Disulfide-containing peptides 2:36 Diterpene alcohol 5:3,31-37

1025

Diterpene synthetase (cyclase) 7:109,110 Diterpene dibenzoates of Caesalpinia pulcherrima 20:475 Diterpenes 2:402,403,404;5:3,31-37;6:110,7:102,121, 122,187-189;15:252-260;17:8,11-15,27,148;18:756 Diterpenoids 9:78,265,272,283,293,295,297,298,639642;14:639-64;15:111-185;20:660 Dithaiothreitol 4:101 1,3-Dithialane system synthesis of 1:537 1,3-Dithiane 6:307-309,332,338 1,2-Dithietane synthesis of 10:229 1,4-Dithio-P-cellobiose 8:347,349 Dithioacetal S,S-dioxides 6:307-349 Dithioacetal S-oxides 6:307-349 Dithioacetals 11:357 Dithiocarbonate 1:452-453 1,4-Dithiocello-thiocellobioside 8:348,349 1,4-Dithiodisaccharide 8:348,349 Dithioerythritol (DTE) 2:20 4,4'-Dithiomaltotrioside 8:331 Dithiothreitol 2:20,579 Diuretic activity 12:398;17:451 Diveprisine 2:125 Divergent synthesis 12:330 Divinyl cyclopropane rearrangement 12:246, 12:247 cis-1,2-Divinylcyclobutanols 11:45,47 Divinylcyclopropane-cycloheptadiene conversion 3:287 Divinylketone 8:412 Diydronaphthalene synthesis of 8:402,403 DL-2,-(3,4-Dihydroxyphenyl) alanine 6:312 synthesis of 6:312 DL-epiisopodophyllotoxin 18:600 DL-myo-inositol 1,3,4,5-tetrakisphosphate 18:413 DM-CCK sonication 18:844 DMAP (4-dimethylaminopyridine) 11:154,157 DMAPP 7:98,110,11:201,202,19:520 DMAT synthase 11:202 DMDP (2,5-dihydroxymethyl-3,4-dihydroxypyrrolidines 7:13,14 DMSO 6:310,329,330 DNA 7:9 DNA (polymerase) 1283,284 DNA complex 5:575-581 DNA-damaging activity 20:467 DNA-damaging agents 20:460,20:461 DNA-damaging natural products 20:457-500 DNA ligase 4:267 DNA polymerase 4:267 DNA template 4:306 DNA-polymerase 7:387 3-(2',3*-Doacetoxy-2'-methyl-butyryl)cauhtemone 7:141 y'Dodec-(6Z)-enolide 13:315 4-Dodecanolide synthesis of 1:683,684 DNA synthesiser 19:539 (/?)-5-Dodecanolide 13:307

y-Dodecanolides 13:314 Dodecanoylphloroglucinol 5:753,754 6-Dodecynoic acid methyl ester 2:17 Dodonea saponins 15:191 Dodonea viscosa 7:139,427 Doebher-von Miller quinoline synthesis 1:171 DolabelidesA 19:557 Dolabella auricularia 19:557,19:601 Dolabella auricularia 4:87,420,421 P-Dolabrin synthesis of 1:527 Dolaisoleucine synthesis of 12:477,483-486 Dolasta-1 (15),7,9-trien-14-ol by intermolecular [2+1] cycloaddition 6:52 by intermolecular reductive coupling 6:52 by three-carbon annulation 6:52 from Dictyota divaricata 6:52 from Dictyota linearis 6:52 synthesis of 6:52 (+)-Dolasta-l (15),8-dien-14p-ol stereoselective synthesis of 6:54 Dolastane 6:52,54,79,182 Dolastatin 12:10,477,485,486;5:421 Dolastatin 3 cytotoxic activity of 5:420,421 synthesis of 4:87-89 Dolichodenis clarkii 5:224,253 Dolicholide synthesis of 19:258 Dolichos lablab L 19:247 Dolichos kilimandscharicus 7:432,433 Dolichos marginata ssp.erecta 7:413,414 Dolichyl [P-"P] diphosphate 8:107 Dolichyl phosphates 8:73,106 Domesticine synthesis of 3:428 Domoicacid 17:21 DOPA synthesis of 410 DL-Dopa. (DI-3-(3,4-dihydroxyphenyl) alanine) synthesis of 6:312 Dopamine 18:53 Dorimidazole A 17:18 Doris verrucosa 6:15 Dorosophila 19:629 Dorylinae 6:421 Double cyclization reaction 10:121,122 Double dioxygenation 9:560,561 Double indolization 1:8,9 Double Michael addition with extended acceptors 8:414,415 with substituted a,b-unsaturated esters 8:412-414 with 2-trimethylsiloxy-cyclohexadienes 8:417 with a,P-unsaturated ketones 8:418 Double Michael reaction 3:143,144,735 Douglanin 7:232 Dowex 50(H^ resin colunm 19:527 Doxorubicin 12:396,13:378,379,14:3,21 Doxorubicin (adriamycin) 4:317-319 DPPA 4:83 Dracaena loureiri 5:17

1026

Dracaenones APT spectrum of 5:19,20 biosynthesis of 5:20 ^^C-NMR spectrum of 5:20 CSCM ID spectrum of 5:19,20 ^H-NMR spectrum of 5:17-20 INEPT spectrum of 5:19,20 synthesis spectrum of 5:20,21 Dracunculin 7:225 Drechslera gigantea 6:555 Dregamine 5:125 Dregaminol 5:125 Dregaminol methylether 5:127 Dreiding synthesis 6:45 Driman-8,ll-diol 1:663 synthesis of 1:663 Drimane 18:607 Drimane sesquiterpenes 4:303-425 Drimanes 7:100,408,154 Drimanic sesquiterpenes 6:108 Drimanolides 2:280 DrimartolA 7:224 Drimenin 20:469 (-)-Drimenin 6:14-15 Drimenin isomerisation 4:407,408 Drimenol 7:100,103,110,122,123 Drimys species 4:404 Drimys winteri Voxsi 4:418 Droplet countercurrent chromatography Droserone 2:212-215,754,755 Drosophila melanogaster 18:698 DSP values 17:118 Duasmodactyla kurilensis 7:279,91,153 Dubamine synthesis of 3:392,393 DubiosideF 15:211 Duboisia genus 17:395 Duckweed {Lemna minor) 9:383,384,386,387,389,390 Duct cell carcinoma of breast 1:276 Dufour glands 6:421,422,453,454,457,458 Duguetia panamensis 9:402 Dulcitol 5:779 DulcosideA 15:16 Dunalia australis 20:191,194 Dunawithanine A,B from Dunalis australis 20:191 DuocarmycinA 10:248 Dynamic NMR study ofstaurosporine 12:367 Dysazecine from Dysoxylum lenticellare 6:487 synthesis of 6:487,488 Dysidea 6:111,410,433,37 Dysideaavara 5:433,438 Dysidea Jragilis nakaftiran-9 from 6:69 (+)-upialfrom 6:65 Dysidea genus 17:10,11 Dysidea herbacea 4:404 (22/?,23/?)-22,23-methylene cholesterol from 9:37 (+)-Dysideapalaunic aldose reductase inhibition of 6:20

from Dy^/V/ea species 6:20 synthesis of 6:21 Dysoxylum lenticellare 6:487 Dysoxylum spp 3:456 Dyspepsia 5:754 Dytiscus marginalis 5:700

E-(3-hydroxy-1 -propenyl)P-D-glucopyranose tetraacetate 10:422 E. coli 18:921 -co//BFi-ATPase 10:439 -Diene 16:4 (^-/7-Nitro-cinnamate 20:830 E-prostaglandins synthesis of 16:369-374 Ebenaceae 7:406,417,423,429,435 (-)-Ebumamonine 19:143 Ebumamenine 13:94 Ebumamine 1:112,93,94 (+)-Ebumamine synthesis of 14:636 (-)-Ebumamonine synthesis of 16:709-710 Ebumamonine synthesis of 8:266 (-)-Ebumamonine from Vinca minor 8:283 Ebumamonine synthesis of 5:187,189,190,632-636 ()-Ebumamonine from indoloquinolizidine enamine 14:728 synthesis of 14:728 (-)-Ebumamonine 9:180 Ebuman-type alkaloid 5:71,107-110 (-)-Eburunamenine synthesis of 14:636 Ecbeallium elaterium 20:13 Ecdysone 2:169 a-and P-Ecdysone 20:248 Ecdysteroid phosphates 19:641 Ecdysteroids biosynthesis of 19:629-634 Ecdysteroids 19:631 3-ep/-Ecdy steroids 19:634 Ecdysterone 20:114 Echiguanine 15:458-461 Echiguanine A and B 15:459 Echinacea 13:662 Echinaster brasiliensis 15:55 Echinaster luzonicus 7:294 Echinaster sepositus 7:294,298;15:59 Echinasterosides B,,B2 7:298,300 Echmatine N-oxide 1:275 Echinocystic acid 7:434 Echinocystis macrocarpa 7:330 Echinodermata 7:265,266 Echinoderms 7:265-316 Echmoidea 7:265,282-285,43,103,104 Echinolactones A,B from Echinophora lamellosa 7:136

1027
Echinophora lamellosa echinolactones A,B from 7:136 glycyrrhetic acid from 7:136 smilagenin from 7:136 EchinosideA 7:269,271,280 EchinosideB 7:269,271,280 Echinothuridae 7:283 Echitamidine 1:36 20-ep/-Echitamidine 1:36 Echium piantagineum 19:247 Eciton hamatum 5:250 Ecklonia stolonifera 19:553 Ecklonialactone A cytotoxic activity of 19:554 isolation of 19:553 relative stereochemistry of 19:553 Ecklonialactone B 19:553 Ecteinascidia turbinata 10:79 Ecteinascidins 10:248,249 Edgar-Greene-Crabbe' intermediate 14:365 ' Edman degradation 2:33;9:489,499,549,551;19:797 (+)-Edunal 4:385,386 Effect of torsion angle rotation 17:556 Effects of NH^ 17:433 Effusanin A from Rabdosia nervosa 15:173 Effusanin B from Rabdosia langituba 15:173 from Rabdosia ternifolia 15:175 Effusanin E from Rabdosia nervosa 15:173 from Rabdosia ternifolia 15:175 Egg white lysozyme 2:31,32,34,36 Ecklonialactones 19:552 Egregia menziessi 19:554 Ehrlich arcitis 20:245 Ehrlich carcinoma 19:609 Ehrlich products 13:300 Ehrlich's reagent 9:592;19:755 Ehuazulene 14:315 Eicosanoids 1:528 Eicospentaenoic acid biosynthesis of 19:552 4-Eicosphingenin 18:786 Eight-carbon sugars synthesis of 4:163-175 Eight-membered cyclic ethers Eight-membered marine compounds biosynthesis of 6:37 by cyclopropanone slidmg reaction 6:37;210,218220,224-226,234 Eight-membered oxocane 10:202 Eight-membered rings by anionic oxy-Cope rearrangement 3:77 by [4+4] annulation 3:78 by dicarbonyl coupling 3:81 by Michael additions 3:83 by Nicholas reactions 3:83,84 by retroaldolization of enone-ene-photo adducts 3:74,75 by ring contractions 3:76,77 by transannular acylation 3:81,82 from allylchromium-carbonyl coupling 3:81 synthesis of 3:73-111 Eilatin 10:247 Eimeria tenella 17:376 Ekebergia senegalemis 2:117,2:118,120,2:269 Ekeberginine 2:117-120,95 Ekebergolactone A 2:269,270 Ekebergolactone B long range dd correlation spectrum 2:269,270 NOE difference spectra 2:272 2D NOESY spectrum 2:272 Ekesenin 2:117 Elaeocanine synthesis of 12:454 Elaeocarpine 12:277 Elaeocarpus alkaloids general synthetic route to 1:283,284 biogenesis of 12:292 Elaeocarpusin thermolysis of 4:718 Elaeodendrol from Elaeodendron glaucum 7:152 Elaeodendron balae (Cassine balae) 149,150 Elaeodendron glaucum 5:751,\52 (+)-Elaeokanine A synthesis of 1:283,284,286,288,289:12:189;13:487, 488;16:460 (+)-Elaeokanine A asymmetric synthesis of 12:351,352 from (+)-elaeokanine C 12:352 Elaeokanine B synthesis of 1:284,286,289 (+)-Elaeokanine C asymmetric synthesis of 12:277,351,352 (+)-elaeokanine A from 12:352 synthesis of 16:476 Elaeokanine C from Elaeocarpus kaniensis 12:289 from l-(methoxycarbonyl)-2-methoxy pyrroline 12:292 synthesis of l:277,278,282,284-286;12:289-293 Elaeokanine E 12:277 Elaiophylin synthesis of 16:713-714 Elaodendrum 18:741 Elasnin 5:590,591 Elastase 2:35 ofchymotrypsin 5:590 of human granulocyte 5:590 ofpancrea 5:590 oftrypsin 5:590 Elastase inhibitor from Streptomyces noboritoensis KM-2753 5:590 Eldana saccharina 11:414 eldanolide from 3:168;11:414 synthesis of 3:168 (-)-Eldanolide from levoglucosenone 14:272,273 synthesis of 14:272,273 ;16:240,692 Eldanolide from Eldana saccharina 11:414

1028

from (/?)-pinanediol methy Iboronate 11:414 synthesis of 11:414 (+)-Eldanolide synthesis of 16:692 Electophilic addition 2 amino alcolol by 411,413 regioselective 12:418 stereoselective 12:418 to 2-^er^butyldihydroxy 12:411,413 Electric transition dipole moment 2:156 Electrochemical oxidation ofazulenes 14:325 ofguaiazulene 14:325,326 Electrocyclic rearrangement 6:72 Electroenzymic reactions 20:877 Electrolysis 19:35 Electromicrobial dehydrogenation 20:867 Electromicrobial reductions 20:877 Electron impact/field desorption DEI 5:632 7i-Electron SCF-CI-DV MO method 17:39-40,45,47 Electron-demand 17:553 Electron mediators 20:821 -824 1,4-Electrophilic addition 1:487,488 Electrophiles 19:464 Electrophoresis 19:648 Electrophoretic mobility 9:541 Electrophoretic patterns 5:838 Electrophoretic studies 5:836 Electrophorus electricus 18:721 Electrospray ionization 9:487,499,502 Electrospray Ionization Interface (ESI) 19:750 Eleganediol 20:26 Elegansamine from Gelsemium elegans 15:484 Elemane 7:216,168 by [2+2] cycloadditions 6:15 Elemanolide from Artemisia hispanica 7:216 P-Elemol synthesis of 14:406-413 Elemol 15:244 Elenoic acid synthesis of 3:254,255 Elenolide 7:442,477,478 Eletrophoretic mobilities 5:839-841 Eleuterin 4:591,592 Eleutherococcus senticosus Harms {Acanthopanax senticosus) 5:505,514,515,521,523,524,544 Eleutherozoa 7:265,267-316 Eleven-carbon sugars byosmylation 4:188 synthesis of 4:187-190 Elimination 16:366,416 p-Elimination 11:184 5y-Elimination 11:184,188 1,4-Elimination 11:187 P-Elimination antiperiplanar 12:17 of 3-mesyloxy-l-threonate 12:17 stereoselective 12:17 HUnnig base-mediated 14:291,292

Elimination thermal 4:44,45 enantioselective epoxidation 4:29,30,343-345 by molybdenum (VI) oxodiperoxo complexes 4:344,345 by Sharpless procedure 4:29,30 of non-fiinctionalised olefins 4:344,345 Elimination 6:540 P-Elimination reaction 10:593 y-Elimination 19:165 Elimination with KN(SiMe3)2 1:440 Elimination-addition mechanism 14:457 Eliminative cleavages 1:618,619 ELISA 15:363-366 Ellagic 20:276 Ellagetannins 20:276 Ellagitannine 17:360 Elliptically polarized light 2:154 Ellipticin cytotoxic activity of 5:415 EUipticine biogenesis of 6:520 biotransformation of 6:509 from Strychnos dinklagie 6:506 oxidation of 6:509 17-oxoellipticine from 6:508 regiospecific oxidation of 6:508 spectral data of 6:519 synthesis of 6: 447,448,509,512,513 EUipticine derivatives 6:510,511,515,516,520 EUipticine derived alkaloids 6:506-520 Ellipticine-type alkaloids 5:89,90 Ellipticity 2:153,2:160 Elliptinone 2:212,214,754 Elsinan 5:278,754 Elsinoe leucospila 5:278 /?-(+)-Eludanolide 19:134 EMBASE 19:758 Elymoclavine 11:200 Embelin 7:182 Ememogin 15:143,152,160,175 Emetine 13:92 (-)-Emetine synthesis of 14:565 ()-Emetine 18:330 amebicidal activity of 6:485 Emmon's-Homer addition 3:267 Emmons-Homer reaction 13:119 Emodin 9:400 Empidonnax hammondii 5:836 Enamide photocyclization non-oxidative 3:404-406 reductive 3:407-410,414 Enamide-aldehyde cyclization 14:772-779 Enamidines 6:430,431 Enamine formation 1:452 Enamine related substrates 18:315-386 Enamine-aldehyde cyclization ()-corynoline by 14:785-787 ()-ll-epicorynolineby 14:785-787 ()-l 1-epiisocorynoline by 14:785-787 ()-isocorynoline by 14:785-787

1029

Enamines acid-catalyzed 14:791-793 cyclization 14:791-793 reactions with acetylenes 3:95,96 singlet oxygen cleavage of 8:261 P-Enamino imine substrate 18:343,366 P-Enaminoesters cyclization of 14:738 dehydropyrrolizidines from 14:738 Enaminosulfoxides in a-ketoacid derivatives synthesis 6:317,318 Enantio-sigmosceptrellin-A 9:28,29 Enantiofacial selection asymmetric synthesis by 13:70-73 Enantiomeric chiral auxiliary 12:342 Enantioselective epoxidation 6:445,446 fermentative reduction 6:158 hydrolysis 13:54 Michael addition 6:86 oxidation 13:54 reduction 13:54 Sharpless epoxidation 6:287 transesterification 13:53,54 Enantioselective hydrolysis with Candida cylindracea 12:337 with Pseudomonas sp. 12:337 Enantioselective reactions 16:559 Enantioselective reduction 18:288 Enantioselective synthesis of(-Hli?-8aS)-l-hydroxyindolizidine 12:281 of(-)-slaframine 12:311,312 of (-)-Y-rhodomycinone 14:14-17 of (+)-(15,8aS)-1 -hydroxyindolizidine 12:281 of(+)-stoechospermol 6:39,40 of 2,5-dialkylpyprrolidine ant alkaloids 6:443 of 7,20-diisocyanoadociane 6:86,87 of e/7/-lupinamine 14:741,742 of kaurane-type diterpenes 14:546 oflupinamine 14:741,742 ofsolenopsinB 6:429,430 of spirovetivane-type sesquiterpene 14:546 Enantioselective yeast hydrolysis 12:338 Enantiospecific synthesis 4:625;12:313,314,317,318 Enantiotopic discrimination asymmetric synthesis by 13:60-62 Encephalocele 7:20,21 Enders reagent 4:327 Endiyne antibiotic 10:154 Endo and exo-bicyclic compounds 10:138,139 Endo benzyloxy group 12:340 Endo-anhydroverticillol 12:182 Endocrine control 19:628 10-EndOe endOn cyclization 10:219 8-EndOe endon cyclization 10:219 Endomyces spp. 2:323 Endomycopsisfibuliger 5:280,282 Endonuclease 13:290 Endonuclease restriction map 2:354 Endoperoxcides cytotoxic activity of 5:406-408

Endoperoxide rearrangement 4:419,420 Endoperoxide synthase 9:571 Endosymbiosis 6:134 Ene cyclization 1:294,159,17 2',3'-Ene-3'-C-phenylselenone 19:524 Ene reaction of 17(20) Z/pregnenes 10:59 mtramolecular 11:91,108 intramolecular 16:17,246 of acryloyl chloride 16:246 of A^-sulfoxyl imines 16:17 intramolecular 3:21 metallo-variant 3:21 ofmalondialdehyde 6:225,226 Ene-quinone-methide 5:744,747,749 Ene-type reactions 1:616,617 Engelhardtia chrysolepis 15:31 Engler synthesis 14:692-695 Enmein from Rabdosia lophanthoides 15:173 from Rabdosia sculponeata 15:174 Enmenol from Rabdosia japonica 15:172 Enniatins 6:219,220,213,519,533-535;13:533 Enoate triol enantioselective 12:15 from (-)-quinic acid 12:15 synthesis 12:15 Enoates 8:140,141 Enol derivatives of camphor 4:663-667 Enol ether reaction with azetidinone 4:437 enterobacteriaceae 4:196 triheptoses in 4:196 Enol lactone 8:297 Enol silyl C-glycoside 10:342 Enol silyl ether (enolate) 12:160,161,163,164 3-Enol-17,21 -triacetate 9:416-418 Enol-acetate nucleosides synthesis of 4:237 Enolate alkylation 14:738 Enolate Claisen rearrangement 10:340 Enolate formation LDA-mediated 10:410,411 of Y-lactone 10:410,411 5-Enolpyruvylshikimate 3- phosphate synthase 11:185,187 5-Enolpyruvylshikimate 3-phosphate (EPSP) 11:185187 Enone 8:176-178,181,183-186,191;11:344 -Enone 8:177 Z-Enone 8:177 A2,3Enone 12:25 Enone epoxidation 10:36 Enone-alkene photocycloadditions 6:33,34 Enones 10:352-354 Enoyl CoA reductase from Streptomyces collinus 11:191 Entada saponins 15:191,214 Entamoeba histolytica 6:485,398 Entandrophragma 9:102 Entandrophragma utile 9:95

1030
Enterobacter cloacae 12:63 Enterobactin 9:537 Enterococcusfaecalis 10:117,400,20:712 Enterolactone 5:461 Enukokurin 2:262,265 Enyne 8:277-281 Enyne carbocyclization 12:263 Enzymatic activity 20:861,20:878,20:889 Enzyme assays 20:859 Enzymatic aldol condensation 10:535,536:11:216 Enzymatic coupling 2:392,394,396,398,399,401 Enzymatic cyclization 7:100 Enzymatic enantiotopic differentiation 13:624 Enzymatic hydrolysis 6:150;7:268,270;13:54,56,57; 16:291 ofgeniposide 16:291 of diacetylenic a//o-xanthin 6:150 of soya bean flour 9:412,413 Enzymatic oxidation of sulfides 14:517,518 sulfoxides fi-om 14:517,518 Enzymatic reaction 16:108,110,111 Enzymatic reduction 12:338,58 Enzymatic synthesis of oligonucleotides 13:279,280 Enzymatic transesterification 13:55 Enzymatically controlled 11:287 Enzyme 8:347-353 Enzyme activity 2:389,390,2:392,394,396,399 Enzyme catalyzed conversion 2:372 Enzyme catalyzed reactions 7:29 Enzyme inhibitors 8:347-351 ENZYME program 17:493-494,500 Enzyme system of Morus alba 17:470 Enzyme-aided enantioselective acylation 18:428 Enzyme-aided enantioselective hydrolysis 18:426-428 Enzyme-carbohydrate interactions 7:29-86 Enzyme-catalyzed acylation 12:346 Enzyme-catalyzed reactions 9:612,176 Enzyme-inhibitory properties 7:14 Enzymic galactosylation 10:469 Epatorenone 5:28-30 Epchrosine 6:505,521 Epchrosine (19/?,20/?-epoxy-apparicine) 9:172,173 (-)-Epedradine A 9:76 Epeolus cruciger 5:223,224,231,253 Epeolus variegatus 5:223,224,231,253 Ephedra sinica Stapf 5:505 EphedradineA 9:75 /-Ephedrine 18:601 Ephedrine 5:751,752 1-Ephedrine 5:505 ^'-Ephedrine 5:752 3-Epi-aristoserratenine 9:194,185 (+)-Epi-P-necrodol 16:147 Epi-(3-necrodol 16:153 (+)-Epi-P-santalene 16:131 16-Epi--isositsirikine 9:170,171,173 11-Epi-ephedradine A 9:75,76,78 20-Epi-ibophyllidine 9:190,192 4-Epi-isopimaric acid 15:172 (-)-7-Epi-nootkatone 16:239 16-Epi-rhazinaline 9:195 (-)-I-Epi-swamsonine synthesis of 16:675 16-Epi-Z-isositsirikine 9:171 Epiacetylaleuritolic acid 7:144,145 16-Epiafrmine 9:181,182 19-Epiajmalicine 9:171 ()-Epialloyohimbane synthesis of 14:710,711 ()-ll-Epiambinine 14:788-791 (+)-Epibatidine synthesis of 19:69 (-)-Epibatidine synthesis of 19:69 24-Epibrassinolide 19:247 Epicatechin 20:782 ()-A^-8-Epicedrene 19:136-137 Epiaotrichothecene 9:211 Epidermophytony7occo5w/w 20:245 Epidihydrophysalin C 20:189,20:247 from Witharingia cocculolides 20:189 (+)-12-Epiaplysistatin synthesis of 16:705 Epiapotrichothecenes 13:520 Epiaschantin from Hernandia ovigera 18:552 3-Epiaustraline 10:567,568 1-Epiaustraline 10:567,568 2-Epiavermectin Bu derivatives 12:15 24-Epibarassinolide 16:322 24-Epibrassinolide 18:509,511,529,530,533,534 7-Epicarminomycinone 14:20 1 -Epicastanospermine synthesis of 10:556 6-Epicastanospermine 10:567 24-Epicastasteron 18:503,511,514,529,530,533 Epicathenamine 9:171 8-Epichromazonarol 15:291,298 Epicodisterol 9:42 ()-3-Epicorynanthediol synthesis of 14:709,710 ()-l 1-Epicorynoline from corysamine 14:785-787 oxidation of 14:788,789 synthesis of 14:785-787 through enamme-aldehyde cyclization 14:785-788 7-Epidaunomycinone 14:7 Epidermal growth factor 15:441 Epiepoformine synthesis of 4:612,613 Epiepoxydon synthesis of 4:612 Epifrenolicin 4:592,594,595 (+)-l 1-Epigigantenone synthesis of 6:555,556 Epigloeosporone synthesis of 9:241-243 7-Epigloeosporone 9:245 Epiguadalupol from Laurencia snyderae 6:30

1031

from perforenone 6:30 synthesis of 6:30 Epihaemanthamina 20:352 4-Epihenryine A 15:114,121,128,172 19/?-Epiheyneanine 9:171 7-Epithydroxylogonin 20:62 ()-l l-Epiisocorynoline from corysamine 14:785-787 oxidation of 14:788,789 synthesis of 14:785-787 through enamine-aldehyde cyclization 14:785-788 13,14-6w-Epijeunicin 8:15,16 (+)-10-Epijujenol 16:264 synthesis of 16:264 Epilachna varibestis 7:396 (-)-Epilamprolobine from Sophora tomentosa 15:524 ()-Epilamprolobine 18:367 (+)-Epilamprolobine N-oxide from Sophora tomentosa 15:524 7,8-Epilantolactone 10:187 (+)-Epilupinine synthesis of 16:467 ()-Epilupinine synthesis of 13:483,484 Epilupinine diastereoselectivity of 14:732-737 from piperdine acetic acid 14:738 stereochemistry of 14:734 synthesis of 14:732-737 (+)-Epimalyngolide 19:494 Epimagnolin from Hernandia ovigera 18:552 Epimerase 11:195,196 Epimeric 2,3-epoxy brassinosteroids synthesis of 18:512 (22S,23S)-Epimeric 24-epicastasterone 18:509 Epimerization 6:558,559,367 (19/?>Epimisiline 5:173 (195)-Epimisiline 5:173,174 Epimodhephene 13:39 Epimukulol 10:25-29 Epinodosin from Rabdosia gaponica var. glaucocalyx 15:171 from Rabdosia henryi 15:172 from Rabdosia J aponica 15:172 from Rabdosia sculponeata 15:174 Epinodosinol from Rabdosia japonica 15:172 from Rabdosia parvifolia 15:173 8-Epinonactic acid 18:235 (+)-20-Epipandoline 9:190 Epipedobates tricolor 19:66,19:146 (+)-Epiperiplanol-p-benzoate 6:539 Epipinoresinol 20:620 Epipinorisenol 4'-0-glucside 5:490,491,494 Epipodophyllotoxin synthesis of 18:561,597-601 14-Epipseudovincadifformine 19:105,19:107 20-Epipseudovincadifformine 19:105,19:107 ()-5 -Epipumiliotoxin synthesis of 18:340

Episesartemin-B 7:219 (-)-6-Epislaframine 18:386 Epistatine 12:430,431 16-Epitacamine 9:179,180 Epitaondiol 17:8 ()-5-Epitashiromine 18:345,353 22/?-Epitautomycin 18:294 Epithienamycin A,B,E,F 4:434 Epithienamycin C,D 4:434,450 1 -Epivalidamine 13:197,198 Epivincadine synthesis of 14:634,636 Epobenzoxocin system synthesis of 4:358 Epoformine synthesis of 4:612 epoxidation 4:339-354,396,505 asymmetric 4:339-345 Sharpless asymmetric 4:496 stereospecific 4:505 Epomuricenin 17:277 Epomuricenin A 18:212,219 Epoxidase 7:103,104 Epoxidase-epoxide hydratase system 7:107 Epoxidation enantioselective 16:571 hydroxy-directed 19:259 of allylic alcohol 16:342 ofcannabidiol 19:236 ofenol 19:259 of enolsilyl ether 16:332 of ketone 8:182 oflimonene 16:229 of methyl perillate 6:545 ofstigmasterol 16:334 of vinylsilane moiety 16:268 of a,p-unsaturated ketones 16:571 ofa-patchoulene 16:151 regioselective 1:436,439 Sharpless 12:236 Sharpless asymmetric 1:278,279,507,508,510 stereoselective 8:179-182;16:349;19:372 with alkaline hydrogen peroxide 16:349 with t-BuOOH-KH 8:180-182 witht-BuOOH-Ti (OPr-i)^ 3:100,101 withVo(acac)2/t-BuOOH 1:436,439 C (2,3)-P-Epoxidation of allylic alcohols 10:39,40 Sharpless 10:39,40 with VO (acac)2-TBHP 10:39,40 Epoxide 1:277 Epoxide alkylation 14:746 Epoxide hydratases 7:103,104 Epoxide hydrolase 7:8 Epoxide opening acid catalysed 1:439 cuprate mediated 1:536 organo cuprate mediated 1:536 with cuprate 1:456,457 with dimethyl cuprate 1:523 withRedal 1:538 Epoxide rearrangement 6:550,551,136

1032

a-Epoxide reduction 4:418 Epoxide-fliranoid rearrangement 6:162 Epoxides l:681-684;2:4 Epoxidisation system 7:105 Epoxisolancerotetrol 5:736 Ent-Za, 14a-Epoxyabiea-11,13(15)-dien-16,12-olide Golkinolide A) 9:283,284,290 2,3-Epoxy alcohol A'^-benzoylcarbamate from 14:569 pyrrolidine derivative from 14:570 with benzoyl isocyanate 14:569 P,y-Epoxy alcohols 10:412 Epoxy allylic ether cyclization 10:590,591 fromD-ribose 10:590 synthesis of 10:589,590 Epoxy amide 4-benzoy loxy-b-lactam 12:161,162 from L-threonine 12:161,162 5p,6P-Epoxy-l-oxocholist-2-ene-4p -ol 20:245 1,2-Epoxy-S-carotene 20:593 Epoxy peroxide 4:422,423 Epoxy resins 9:370 Epoxy sterol 17:22 Epoxy sulfoxide 6:310 5p,6p-Epoxy-27-hydroxy-1,4-dioxowitha-2,24dienolide 20:234 4p,5p-Epoxy-17p-hydroxyestran-3-one 5:449 (+)-7,8-Epoxy-2-basemen-6-one 16:226 19/?-20/?-Epoxy-apparicine (apparicine) 9:172,173 19',20'-Epoxy-conoduramine 5:128 lp,2p-Epoxy-enone intermediate 5:447 3,20-Epoxy-er-kaurenes 15:136 Epoxy-nucleosides 4:225 5p,6P-Epoxy-1 a, 14a, 17p,20-tetrahydroxy-with-24enolide 20:245 19R,20S-19,20-Epoxyakuammicine (stictine) 9:192 Epoxyalkyl glycosides 7:39 9a, 1 la-Epoxycholest-7-ene 3p,5a,6P-tetrol-6-acetate 5:410 a-Epoxidation 11:383 Epoxidation 11:470 15P,20P-Epoxydihydrocatharanthine 14:811,871,872 leurosinefrom 14:811,871,872 A^-oxide derivative of 14:811 with vmdoline 14:811,871,872 Epoxydilactone 17:608 Epoxydon synthesis of 4:612 Epoxyeleganolone 18:713 2,3a, P-Epoxyenone 14:678-681 24,28-Epoxyergost-5-ene-3P,7a-diol 20:476,20:477 24,28-Epoxyergost-5-ene-3P,7P-diol 20:477 Epoxyguaianolide 14:362 16,23-Epoxyhalosta-7,24-dien-3P-ol 7:277 Epoxyindenone 1:189 Epoxyjaeschkeanadiol 5:724,725,731,732,735 Epoxyketone 15:167 Epoxyketonucleosides synthesis of 4:248 Epoxy lactone 17:10

(S)-l,2-Epoxylycopene 20:593 1,2-Epoxylycopene 20:593 7,20-Epoxyroyleanone 20:670 Epoxysesquipellandrene 8:58 synthesis of 8:58 Epoxyshikoccin 15:163-165,174 Epoxyshikoccin 15:167 22,23-Epoxysteroids 15:48 24,25-Epoxywithanolide D 20:246 6p,7p-Epoxywithanone 20:204 Epstein-Barr virus 10:4;12:234,390,395 Equisetin from F.equiseti 13:545 antibiotic properties 13:545 leukemogenic activity 13:545 stereochemistry of 13:545 synthesis of 13:545-547 Equisetum arvense 18:495,20:247 Erbstatin 15:441 Ercalcidiol (25-hydroxyvitamin D2) 11:381 Ercalciol (vitamin D2) 11:381 Ercalcitriol (1 a,25-hydroxy vitamin D2) 11:381 Eremane diterpenes 15:271-274 (-)-Eremanthin 14:368 Eremanthus glomerulatus 7:427 Eremmophla aureonontata 5:223,225,253 Eremoacetal 15:238 EremofruUanolide 2:280,281 (+)-Eremolactone synthesis of 8:425 from Eremophilafreelingii 15:252,271 from Eremophilafraseh 15:252,271 synthesis of 15:272 Eremophila 15:225-282 Eremophilanolide 20:660 Eremophila abietina 15:227 Eremophila alternifolia 15:225,232 Eremophila caerulea (+)-fenchone from 15:227 oleanolic acid from 15:281 ursolic acid from 15:281 Eremophila clarkei 15:253 Eremophila cuneifolia 15:227,248 Eremophila dalyana 15:225,227 Eremophila decipiens 15:263 Eremophila dempsteri 15:227,254 Eremophila drummondii (+)-calamenene from 15:244 serrulatane from 15:259 (+)-spathulenol from 15:248 Eremophila duttonii 15:225 Eremophila elderi 15:225 Eremophila exilifolia 15:252 Eremophila foliosissima 15:255 Eremophila fraserii 15:248,252,271 Eremophilafreelingii eremolactone from 15:252,271 freelingyne from 15:233 Eremophila georgei 15:269,271 Eremophila gilessi 15:225 Eremophila g/utinosa 15:252 Eremophila granitica 15:254 Eremophila inflate 15:229

1033
Eremophila interstans 15:245,247 Eremophila latrobei 15:229,232,258 biflorinfrom 15:258 Eremophila longifolia 15:225 Eremophila maculata 15:226,229 Eremophila miniata 15:229 Eremophila mitchelli 15:226,281 Eremophila paisley 15:248 Eremophila petrophila 15:252 Eremophila platycalyx 15:281 Eremophila racemosa (+)-spathulenol from 15:248 Eremophila rotundifolia freelingyne from 15:233 Eremophila scoparia 15:227,232,244 Eremophila serrulata 15:257,259 Eremophila spp. (+)-isoeremolactone 8:423 Eremophila virgata 15:245 Eremophila viscida 15:260 Eremophilane sesquiterpenes 6:554-556 Eremophilane-type sesquiterpene 18:639 Eremophilanes 7:214,216,152,227,243 7-epi-Eremophilene 15:250 Eremophilone Claisen rearrangement by 10:436,437 synthesis of 10:436,437 from Eremophila mirchelli 15:238 synthesis of 15:243 stereoselective synthesis of 15:240 Ergocalciferol (vitamin D2) 9:510,521 a-Ergolene synthesis of 4:605,606 Ergonovine from Clavicieps purpurea 13:631 Ergost-5-en-la,3P-diol 11:381 Ergost-5,24 (28)-diene-3p,7a-diol 20:476,20:477 Ergost-5-ene-3 p,7a,24,28-tetraol 20:476 Ergosta-5,24 (28)-diene-3P,7(3-diol 20:477 Ergostane 16:332 Ergosterin (ergosterol) 9:509,510 Ergosterol 5:406,261,322,509 Ergosterol [(24/?)-24-methylcholest-5,7,27-trien-3P-ol] 9:447 Ergosterol esters 9:456 Ergosterol mesylate 18:509 Ergosterol-5,8-peroxide from Artemisia feddei 7:218 Ergot alkaloids biosynthesis of 11:199-207 Ergotamine 13:631 Ergoxanthine 20:282 Eriobotryajaponica 17:115,118-119;19:247 EriocalxmA,B 15:176 Erithrodiol 20:705 Erithrodiol-28-acetate 20:707 Erythrina burana 20:496 Erivanin 7:232 3-e/7/-Ervafolidene 5:129 Ervafolidine 5:129 Ervafoline 5:129,172 Ervahanme 5:123 ErvahanineC 5:129 Ervatamia coronaria 5:135,136,158,171,172 Ervatamine 5:125 20-e/7/-Ervatamine 5:127 Ervatamine-type alkaloids 19,20-dehyroervatamine 5:81 ervatamine 5:80-82 20-e/?/-ervatamine 5:81 isomethuenine 5:81 methuenine 5:81 methuenine-A'4-oxide 5:81 6-oxo-methuenine 5:81 silicine 5:81 6-0x0-16-e/>/-silicine 5:81 20-ep/-silicine 5:81 iso-6-ojco-silicine 5:81 Ervaticine 5:87,88,124,135,136 Ervatinine 5:126,136,137 Ervincidine 13:393 Ervinidinine 9:190 Ervitsine 5:126 Ervitsine-type alkaloids 5:81,82 Envinia herbicola 17:637 Erwinia spQCXQS 4:434 Erybidine synthesis of 6:478 EryocalyxinA 15:171 Eryocalyxin B from Rabdosia eriocalyx 15:171 from Rabdosia eriocalyx var. laxiflora 15:171 Erysodienone synthesis of 3:468 Erysodine 3:455 Erysotinone 3:478 Erysotramidine synthesis of 3:471-476 Erysotrine synthesis of 3:470,474,475 Erytharbine synthesis of 3:476 Erythraline synthesis of 3:474 Erythramine 3:455 Erythratidine 3:455 Erythratidinone 3:455 Erythrina alkaloids 3:455-493 Erythrina arborescens synthesis of 3:455-493 Erythrina berteroana 7:417 Erythrina crysta - galli L. 3:476 Erythrina lithosperma 3:479 Erythrina Xy^Q 11:229 Erythrinan-3-one 6:411,41^ Erythrinane skeleton synthesis of 1:327 D-Erythritol 6:357,358 Erythritol 9:288 rv^/iro compounds 12:415,416 (155',165)-Erythro diasteromer of pumiliotoxin B 12:294 Erythro ethyl p-hydroxy-p-(2- piperidyl) propanoate 12:279

1034

Erythro-l'donino alcohols 12:430,431 Erythro-glycal 10:341 D-Erythro-hexofuranose 6:376 p-Erythroidine 3:455-456 Erythroidine alkaloids synthesis of 3:487,488 Erythromycin 5:613 Erythromycin A 11:196,197 biological activity of 12:48 from (95)-9-dihydroerythronolide A 12:53,54 total synthesis of 12:53,54 X-ray crystal studies of 13:156 Erythromycin A. aglycone 3:233 Erythromycin B 11:196,197 Erythromycin-9-oxime Beckmann rearrangement of 13:160,161 Erythromycylamine 13:170,171 Erythronolide 13:155,156 Erythronolide A 3:233-278,280 synthesis of 11:152,153,157 Erythronolide A enol ether 13:165 Erythronolide A seco-acid synthesis of 11:154-156 Erythronolide B by dioxanone-to-dihydropyrane enolate Claisen rearrangement 10:340 secoacidof 16:660 synthesis of 16:660-661 synthesis 3:278-280 D-Erythropentofliranose 6:365,366 D-Erythropentose 6:360,463,364 Erythroxy Ion monogynum 10:180 Eschenmoser reaction 8:211 Eschenmoser ring contraction 9:601,602 Eschenmoser's salt 4:665,10:164,19:94 Eschenmoser-Claisen rearrangement 10:417,419-421, 427,428 Escherichia coli 4:433;5:367,429,434;7:39,44,46, 50,52,54;9:293,308,537,592,593,596,603,604,606; 8:102;11:182,214;12:63,95-109;13:157,162,164,261, 262,283;17:378;18:709,722,727;18:921;19:601; 20:712 Escherichia coli BFl-ATPase 10:439 Eschweiler-Clarke methylation 10:84,165 Eschweiler-Clarke reaction 1:203,384,385 Esculetin 5:515,517,521,579 Esculin 5:515,521 Eserethole synthesis of 1:326 (-)-Eserethole (-)-physostigmine from 14:637,638 synthesis of 14:636-638 (-)-Esermethole synthesis of 14:639 (-)-Estafiatin 14:358,359 Espeletia gQnus 19:389 Espeletiopsis quacharaca 13:11 Esperamicin synthesis of 489 Esperamycin 10:150,153 Estafiatin 1:546,558,235

Ester enolate Claisen rearrangement. :236,246,259, 3:261-265,267-270,274-276,278-280;14:497 Ester epimerization 1:466 Ester exchange reaction 4:519 Ester type glycoside linkage 7:154,155 Esterase 13:303 Esterification 4:91,92,276,292,391,409,412,413 Estogen-sensitive tissues 5:447 Estradiol synthesis of 3:435 fluorinated derivatives of 5:451 Estragole 13:335 Estreogen 5:477,499,456 Estrogen 2-/4-hydroxylase acticity 5:449 Estrogen 2-hydroxylases 5:449 Estrogen hormones 9:411 Estrogen responsive kidney 5:447 Estrogen-induced cell transformation 5:451 Estrogenh binding site 5:455 Estrogens 17:625-526 Estrone asymmetric synthesis of 4:501,502 synthesis of 3:435 (-)-Estrone 4:675 (+)-Estrone 7:6 Ethambutol 2:424,20:714 1,2-Ethanedithiol 11:357 Ethanoflurene 6:175 Ethanolamine 5:299 Ethanophenanthrene 6:173,174 5 5,lOP-Ethanophenanthridine nucleus 4:4, Etherifiction 4:718-720 Ethionamide 2:424 Ethisolide 3:261,19:485 Ethnoarcheological studies 13:630 Ethnopharmacology 13:640 3-Ethoxy-coronaridine 5:126 Ethoxycarbonyl (methylidene) triphenylphos3 -Ethoxycarbonyl pyrrolidinone 13:131,132 Ethoxycarbonylation 6:541 MIN-(P-Ethoxycarbonylethyl)-5-oxopyrrolidine-2carboxylate 12:308 Ethoxycarbonylmethylenetriphenylphosphorane 12:315 (3 -Ethoxy carbony Ipropy 1) tripheny Iphosphonium bromide 12:318 3-Ethoxycarbonylpyrrol- 2(5H)-ones 13:131,132 5a-Ethoxy-4,5-dihydrojabarosalactone B 20:223 2-(Ethoxycarbonyl)-tryptamine 19:89 19-Ethoxycarbonyl-19-demethylvincadifformine 19:112,115 6w-Ethoxyethyl olivetol 19:225 P-Ethoxypropiophenone 14:648 Ethyl 8'-apo-P-caroten-8'-oate 20:606 Ethyl p-apo-8'-carotenate 20:756 Ethyl-2-(diethoxyphosphonyl) propinoate 20:595 Ethyl (l/?,25)-5,5-ethyienedioxy-2-hydroxycyclohexane-1-carboxylate 6:552,553 Ethyl (2,4)-12-hydroxy-2,4-dodecadienoate 10:152 24-Ethylidenecholesterol 20:234 Ethyl (5)-lactate 12:161

1035

Ethyl 1,6-dithiogentiobioside synthesis of 8:341 Ethyl 2-[l-(2-ethoxycarbonybnethyl) piperidinyl]propanoate 12:284 Ethyl 2-methoxy-6-methyl benzoate synthesis of 9:346,347 Ethyl 3-(5)-hydroxybutyrate 6:263 Ethyl 3-hydroxybutanoate 1:689,690,707 (5)-Ethyl 3-hydroxybutyrate 4:439,440,448,449,452, 453,455,464 Ethyl 4-[l-(2-ethoxycarbonylpyrrolidinyl)] butyrate Dieckmann condensation of 12:293 Ethyl a-bromocrotonate 8:418,419 Ethyl benzamalonate 9:224 Ethyl diazoacetate 14:402 Ethyl fructofuranoside 8:324,325 (5)-Ethyl lactate 8:133,136 Ethyl malonyl CoA 11:194 ()-Ethyl picolate 12:279 Ethyl sorbate 8:410,414,148,149 24-Ethyl thomasterol A 15:48 2-Ethyl-2-hydroxyindolizidine 12:284 2-Ethyl-2-propen-l-ol 14:828 24-Ethyl-24,28-methylene-cholesterol 9:36,37 24-Ethyl-26-hydroxysteroids 15:84 2-Ethyl-3-vinylcyclopentanone enolate 8:192,193 9-Ethyl-4-hydroxy-3 -hydroxy-methyl-1,7-dioxaspiro [5.5]-undecane 14:531 2-Ethyl-5-heptyl-1 -nitrosopyrrolidine 6:439,440 synthesis of 6:439,440 3-Ethyl-5-methylindolizidine 6:450 2-Ethyl-5-pentylpyrrolidme 6:437,444 7-EthyI-7-hydroxyindoIizidine 12:286 3-Ethyl-allohobartine 11:318,319 24-Ethylbrassinone 18:500 (245)-24-Ethylcholest-5,22-dien-3 P-ol (stigmasterol) 9:447 (24/?)-24-Ethylcholest-5-en-3p-ol (sitosterol) 9:447 (+)-3-Ethylcompactin 11:371 (9-Ethylcryptaustoline iodide 6:482 (-)-N-Ethylcytisine from Echinosophora koreensis 15:525 iV-Ethyldeoxynojirimycin 10:527,528 3-Ethylidene-l,3-dihydro-indol-2-one 9:236,237 4,6-(9-Ethylidene-iV-benzoyl-D-glucosamine 18:462 Ethyllithium 14:510 Ethylmalonic acid 13:76 Ethylphenyl acetate 6:323 2-Ethylpropane-l,3 diols 13:88-93 2-Ethylpropanol 14:840,841 Ethylurethanes 6:427,428 Ethylvinyl ketone 6:19 Etoposide 5:461,462,13:364,365,654,20:458 Etzionin 10:247 Eu (fod)3-mediated [4+2] cycloaddition 4:121,122,143 Diels-Alder reaction 4:121,122 Eu(hfc)3 4:326 Eu FODTM cyclocondensation using 1:420,421 Eubacterium saburreum 4:195 Eucalyptol 13:337

Eucalyptus calophylla 19:247 Eucalyptus marinata 19:247 Eucalyptus spathulata (+)-spathulenol from 15:248 Eucannabinolide 17:608 Eucommia ulmoides oliv. 5:505,521-525,530,544 Eucommia ulmoides 20:613,647-648 Eucommiol 7:441,442,472-474 Eudesm-1 l-en-4-ols from Amitermes excellens 14:451 from Artemisia schmidtiana 14:450 from Bothriochloa bladhi 14:450 from Bothriochloa glabra 14:450 from Bothriochloa intermedia 14:449 from Bothriochloa insculpta 14:450 from Carthamus lanatus 14:450 from Citrus paradisi swingle 14:450 from Cymbopogonflexuosus 14:450 from Euginia uniflora 14:450 from Geigeria burkei 14:450 from Humulus lupulus 14:450 from Myrica gale 14:450 from Pisidium guajava 14:450 from Podocarpus dacrydioides 14:450 from Riccardia jackii 14:450 from secretion of termite soldier 14:451 from Senecio amplexicaulus 14:450 from Subulitermes bailey 14:451 from Subulitermes oculatissimus 14:451 from Subulitermes parvellus sp A+B 14:451 from Velocitermes velox 14:451 Eudesmaafraglaucolide 7:232 Eudesman-12,6-olides 7:212,231-233 Eudesman-12,8-olides 7:212,214,233 Eudesmane 7:208,214,168,181,187 Eudesmane alcohol from (-)-a-santonin 14:456-465 synthesis of 14:456-465 Eudesmane sesquiterpenes 2:280 Eudesmanes from Wieland-Miescher ketone 6:18,19 synthesis of 6:18,19 2,3-5eco-Eudesmanes 7:216 4,5-5eco-Eudesmanolide 7:215 Eudesmanolides from Wieland-Miescher ketone 6:18 synthesis of 6:18 (+)-a-Eudesmol synthesis of 14:406-413 P-Eudesmol 15:243,244 neointermedeol from 14:453,454 ozonolysis of 14:453,454 (+)-p-Eudesmol 14:490 synthesis of 1:632;14:490 via asymmetric cyclopropanation 14:490 Eudestomins 8:274 Eudistoma cf. rigid 10:247 Eudistoma glaucus 5:353 Eudistoma olivaceum 5:417,418,246,100 Eudistoma sp. 12:366,370,10:247 Eudistoma 19:660 EudistominA 5:418

1036

Eudistomin C 5:417,418 EudistominD 5:418 Eudistomin E 5:417,418 Eudistomin F 5:418 Eudistomin G 5:418 Eudistomin H 5:418 Eudistomin! 5:418 Eudistomin J 5:418 Eudistomin K 5:417,418 Eudistomin L 5:417-418 Eudistomin M 5:418 Eudistomin N 5:418 Eudistomin O 5:418 Eudistomin P 5:418 Eudistomin Q 5:418 Eudistomin R 5:418 Eudistomin S 5:418 Eudistomin T 5:418 Eudistomins A-Q, S,T 10:246,247 Eudynamis scolopacea 5:837 Eugenol 5:473,474 Euginia uniflora 14:450 Euglena viridis 6:150 Euglenopyceae 6:134,147,150,151 Eukaryotic genes 4:268 Eumenesfraternus 5:224,225,232,253 Eumycota 9:202 Eunicea s^QCiQS 10:9 Eunicia succinea 10:7 Eunicea tourneforti 20:492 Euniolide 10:7 Euodynrusfuscus 5:224,253 Euoniminol 18:747 Euonomynus 18:741 Euonymus 18:753 Eupafoiin 7:226 Eupatin 7:227 Eupatilin 20:712 from Salvia limbata 20:712 from Salvia nemorosa 20:712 Eupatorenone 5:28-30 Eupatorium adenophorum 5:28 Eupatorium maculatum 20:145 Eupatorium trapezoideum 15:247 Eupentactafraudatrise (Cucumaria fraudatrix) 7:275,276 Euphanes (tirucallanes) 9:267,297,302,307 (-)-Euphococcine synthesis of 16:481 Euphorbia 12:233,234 Euphorbia acaulis 9:265,267,288 Euphorbia caudicifolia 9:265 Euphorbia fidjiana 15:385 Euphorbiafidjiana 9:265-292 Euphorbia helioscopia 9:265 Euphorbiajolkinii 9:265 Euphorbia lagascae 9:391 Euphorbia later ifolia 2:262 Euphorbia milii 5:678 Euphorbia nerifolia 7:152-154 Euphorbiapallasii 9:265,288 Euphorbiapoisonii 2:261

Euphorbia species 9:265,267,20:19 Euphorbia triaculeata 9:265 Euphorbiacea 7:477,187,417,265,386,391;17:343,439 Euphorbiacear 12:233 Euplaxaura erecta 14:315 Eupolauridine anticandidal activity of 2:441,442 Euponera sp. 5:224 Euretaster insignis 7:304,94,45 Europhthalma alkaloids 6:422-434 Europine N-oxide 1:275 Europium sp. 5:325 Eurycomalactone 7:393;11:71 Eurycomanol 7:393 Eurycomanone 7:393 Eurycomma longifolia 7:393 (+)-Euryfuran from (+)-confertifoline 6:28 from (+)-manool 28 from Dysidia herbacea 4:404 from Euryspongia species 4:404 from Euryspongia species 6:20 from Hypselodoris calif orensis 6:20 from Hypselodoris porterae 6:20 frommanool 4:422-424 from trimethyl decalone 6:20 synthesis of 6:20,28,116,403,422-424 (-)-Euryfiiran from Hysselodoris califomiensis 4:404 Giom Hysselodoris porterea 4:404 Euryspongia species 4:404 Eustigmatophyceae 6:134 Eutreptiellanone 6:150,151,153 EuxanmodinA 20:277 Euxlophorine A 1:127 Evan's alkylation 19:62 Evan's reduction 18:253 Evan's asymmetric strategy 12:435,436 Evan's chiral auxiliaries 12:435-438 Evan's rearrangement 16:296 Evan's-Cope reaction 12:193 Evan's-Cope ring expansion 12:192 Evans aldol methodology 16:483 Evans asymmetric alkylation 1:455,456,469,604 Evans asymmetric induction procedure 14:534 Evening primrose oil 13:658,659 Everniaprunastri 5:310-312,322 Z-Evemitrose 19:118 Evolution 18:677-728 Evolutionary aspects 9:591-609 ofvitaminB 12 biosynthesis 9:591-609 Evoninol 18:747 Evuncifer ether 14:452,463 from Amitermes evuncifer 14:452,463 from Amitermes excellens 14:452 from Amitermes messinae 14:452 Exact vs. nominal mass 2:44 Exaltolide 19:118 Excelsin 7:398 Excisanin A from Rabdosia excisa 15:171 from Rabdosia inflexa 15:172

1037
from Rabdosia macrocalyx var. jiuhua 15:173 from Rabdosia serra 15:174 Excisanin B from Rabdosia excisa 15:171 from Rabdosia macrocalyx var. jiuhua 15:173 Excisanin C 15:115,121,129,171 Exciton interaction 2:164 Exciton-chirality method 18:748 Excoecaria agalloccha 7:176-178,180,183,195 Exencephaly 7:20,21 Exidonin (rabdosin B) 15:143,152,160,172,173 from Rabdosia henryi 15:172 from Rabdosia japonica 15:172 from Rabdosia longituba 15:173 xo addition 8:160,161 xo orientation 14:753 Exo-P-l,3-glucanase 10:526 Exo-enol tautomer 14:101 5-exo-Trig aryl radical-alkene cyclization 3:327,328 Exons 13:290 3'-Exonuclease 13:288,291 Exonucleases 13:290,291 Expectorant 17:451 Extrachromosomal HBV DNA 20:541,544 Extraction 9:449,450 Ezoalantonin 7:233 Ezomontanin 7:235 EzomycinA-1 4:246,247 EzomycinA-2 4:245,247 Ezomycins synthesis of 1:422,431 oxidation of 6:311 preparation of 6:309-311 Famesal E isomer 8:19 oxidation with Se04/t-BuOOH 8:19 oxidation with BaMn04 8:19 reaction with ethyl 8:l-diethylphosphono-2methylbutanoate 8:18,19 reduction with LiAlH4 8:19 Z isomer 8:19 Famesane sesquiterpenes 17:155 P-Famesene 7:100,101,103,121-123 ,-Famesol 1:656 Famesol 7:108,125,8:222,20:88 (,)-Famesol derivatives 1:657 cis, /ra5-Famesol pyrophospate 5:730,731 (Z,)-Famesols 8:75 (,)-Famesols 8:75,77 Famesyl acetate 8:197,198 (,jE)-Famesyl acetate 1:663 Famesyl diphosphate 7:324 Famesyl pyrophosphate 6:247,248 (,)-Famesylsulfone 1:657 Famochrol 7:224 Fascaplysin 5:411,412 Fascaplysinopsis sp. 5:411 Fasciospongia rimosa 19:568 Fast oligonucleotide deprotection (FOD) 13:266 Fatty acid antileukemic activity of 7:24 biosynthesis of 11:191 by condensation of malony 1 unit 11:191 oxidative degradation of 13:303-306 stereochemical course of 11:191 Favorskii reaction 6:335 Favorskii rearrangement 8:225;10:410;16:242,20:69,70 (+)-Faxu-esinol-l-P-D-glucoside 5:524,538,542,543 FDP aldolase 14:176 Feist's acid 10:618 Felidae 7:7 Felikiol 5:736 Felkin-AHN model 11:234,440,474,643;12:21;19:474 Felkin-ANH conformation 3:255,134 Felkin-ANH transition state 1:402,406,423 Felkin-Nguyen (Anh) 8:213 (+)-Fenchone 16:268 from Eremophila caerulea 15:227 Fenchone 4:649,20:16 Fenestrene (lauren-1-ene) synthesis of 3:117-124 Fenoprofen 6:323 Fercolide 5:723,724 Fercomin 5:723,724,728 Femenol from Artemisia vulgaris 1:218 Ferredoxin-NAD oxidoreductase 20:835 Ferri-pyoverdins 9:553 Ferrichrome 9:551,555 Ferrier reaction 10:347,419,510,433-437 Ferrier rearrangement 13:191,200,201,203,210 Ferrier-type reactions elimination-addition by 3:212,213

F-prostaglandins synthesis of 16:374-378 ^ NMR measurements 11:361 F^ FAB mass spectrometry ofpyoverdins 9:541,545 Fabaceae 7:177,193 FABMS/MS (Tandem Mass Spectrometry) 9:487-507 re-Face selectivity 12:57 7i-Facial selection 12:419-422 in methoxybromination 12:419-422 in methoxyselenylation 12:421,422 reversed 12:419-422 Facial selectivity 10:36 Factors I-III 9:597,600,601,603,604,606 Fagara macrophylla 7:427 y-Fagarine 20:539,540 Fagaridine 14:783 Fagaronine 3:430;14:769,776,777;13:656,769,770, 775-777 Fagomine 7:15,10:543,544 Falcarindiol 7:415 Famciclovir 20:534 FAMSO aldehyde synthesis by 6:311-313 alkylation of 6:313 allylation of 6:315,316 dianion of 6:323-325 methyl methylthiomethyl sulfoxide in 6:309-325 organic synthesis by 6:311-323

1038

filifolone 3:40 synthesis of 3:40 Ferroprotoporphyrin IX 20:518 Ferrous sulphate reduction 4:422,432 Ferruginol 2:402,403 Ferruginol from Salvia candidissima 20:660 from Salvia limbata 20:673 from Salvia montbretii 20:666 from Salvia napifolia 20:670 from Salvia tomentosa 667 Ferruginyl 12-methyl ether from Salviapomifera 20:665,666 Ferruginol 14:668,670,674,689,690 Fertility regulation 13:658 Fertility-regulating agent 13:658 Ferugin 5:725,726 Ferula akitschkensis 5:723 Ferula communis subs.communis 8:57;5:723 Ferula elaeochytris 5:723 Ferula galbaniflua 19:157-158 Ferulajaeschkeana 5:725 Ferula karatavika 1:660 Ferula lancerottensis 5:725,727 Ferula lapidosa 5:723 Ferula linkii 5:725,734 Ferula pallida 5:723 Ferula rubicaulis 19:158 Ferula s^. 5:721,732 Ferula tenuisecta 5:723 Ferula tingitana 5:723 Ferulate 5-hydroxylase 5:468,469 Ferulic acid 5:469,470,474,475,479,495 -Ferulic acid 5:472 Z-Ferulic acid 5:472 Ferulidin acetate 7:236 Feruone 5:724,725 Ferutidin 5:622,623 Ferutin 5:722,723 Ferutinin 5:722,723,731,732 Festigiolide 5:728 ()-Festuclavme 18:386 Fetizon oxidation 4:340,343,370 Fetizon reagent 18:28 Fetizon's convergent synthesis 12:195 Fetizon's intermediate 12:196,198 Fetizon's photochemical route 12:195 Fetizon's reagent 1:508,349,366,570 Feverfew 13:660 Ficisterol biosynthesis of 9:40 Ficus costata 2:231 Ficus diversiformis 2:231 Ficus elastica 8:66 Ficusfergusoni 2:231 Ficus pyrifolia 20:522 Field desorption (FD) 2:46-48,632,645,467,487 Fieser's solution 19:653 Filamentous fungi 9:203 Filifolide A from Artemisia filifolia 7:208 Filifolone from Artemisia filifolia 7:208

Finitin 7:212,232 Finkelstein substitution 6:310 Fire ant 1:682;6:422 Fischer carbene complexes 1:505,506 Fischer indole reaction 14:845 Fischer indole synthesis 1:79,144,152,284;11:285,492 Fischer mdolization 1:15,51,60 ^M-Fischer indolization 12:376,377 Fischer projection 11:422,423 Fischer-Helferich procedure 4:222 Fischer-Kiliani synthesis 4:157-159,175,179 Fisher-Irwin test 9:386 Fitzsimmon cycloaddition 11:447 FK-506 8:273 Flagpole type interaction 14:736 Flammulina velutipes 5:289 Flash pyrolysis 1:250 Flash vacuum pyrolysis 3:27,588 Flash vacuum thermolysis 1:337 Flatulence 5:754 Flavanones 17:143-144,580 Flavans 7:192 Flavobacter dehydrogenans 9:417,418 Flavobacterium 4:432 Flavobacterium sp. 7:330,336,341-345,347-351,358, 360,363 Flavocarpine 1:124,135,153,156 Flavoglaucin 9:313 Flavologlycan polymer 7:193 Flavone 4:377,12,13,622,624,634,737-639,643,651, 653,252 Flavonoid C-glycoside 5,7,4'-/r/-0-methylvitexin 10:362 Flavonoid C-glycosides 5:643 Flavonoid disulphates 5:655 Flavonoid glucuronide 5:643 Flavonoid glycosides 5:632,633,641,645,649,656,658, 664,665 Flavonoid sulphate 5:655,663,664 Flavonoid-6,7-disulphate 5:648 Flavonoids 4:367,5:3,12,467,510,511,621-624,627, 630,632,637,641,642,645,649-652,659-662,666,757, 756,7:202,206,208,220,226-228,411-413,427;9:390, 15:30;17:341;20:283,709 Flavonol 17:117,139-141 Flavonol 3-methyl ethers 7:411,412 Flavonol methyl ethers 7:411,412 Flavonolignans 5,495,596 Flavonols 5:622,624,626,628,634,637,192 Flavonones 5:643 Flavopereirine 1:124,129-136,141-143,145,147,149, 153,155,156 Flavors analysis of 13:322-345 biogeneration of 13:295-345 legislation of 13:337-340 Flavoxanthin 20:727 Flexibacter elegans 9:323 Flexibilene synthesis of 8:16,17 FlexicaulinA 15:117,124,131,171 Flexuiibin 9:314,323,328,329,368 Florisil column chromatography 14:661

1039

Flouro-p-lactone 16:727-744 Fluorene 6:173 Fluorenone 6:176-181 N(2-Fluorenyl) guanidine 8:382,383 Fluorenylguanidine 8:382 Ar-9-Fluorenylmethyloxycarbonyl (fmoc) 4:289 Fluorescence indicator fura-2 18:856 Fluorescence inducing reagents 9:453 4-Fluorestradiol 5:447,448,451-454 Fluorinated analogues 9:517,518 Fluorination 13:81-83 ofalkylmalonate 13:83 of chiral half-esters 13:81 of monalkyl malonic acid 13:81 with 1 -fluoro-2,4,6-trimethylpyridinumtrifluoromethane sulfonate 13:82 4-Fluoro-2-hydroxyestradiol 5:454 4-Fluoro-2-methoxyestradiol-3-methyl ether 5:453 Fluoro-sugars 10:368-370 C-Fluorocurarine 1:36 Fluorocurarine synthesis of 1:41,46-48 8-Fluoroerythromycin A (flurithromycin) synthesis of 13:166 3-Fluoroestr-l,3,5 (10)-trien-17P-ol 5:449 2-Fluoroestradiol 5:447-456 Fluoroestrogen 5:451,453,454 Fluoroglycosides 10:368-370 a-Fluoroketone 5:449 2a-Fluoroketone 5:450 2p-Fluoroketone 5:450 a-Fluoromethylamino acids 10:147,148 Fluoroquinolone antibacterials 2:425 Flurithromycin(8-fluroroerythromycin A) synthesis of 13:166 Fluromalonate 13:82 Flustrafoliacea 17:80,85,87,102,103;18:689,692, 693,708,725 Flustra papyracea 17:86 Flustrabromine 18:691 Flustramide A and B 18:691 Flustramine A,B,C,D and E 18:690,691 Flustramine D-iV-oxide 18:691 Flustramines 17:87 Flustraminol A and B 18:691 FlustrarineB 18:690 Flustriidae 18:690-693 FNE 8:396 FOD (fast oligonucleotide deprotection) 13:267,361,268 Foeniculum vulgare 5:473 Fogomine 10:567 Fogs grandifolia 5:472 Foliacraline 13:394 Fommanosin 13:6 Food mutagens 8:378,388,389 Footprinting 5:580 Forbeside A (versicoside A) 7:288,293 Forbeside B (glycoside B2) 7:288,293 Forbeside C (asterosaponm 1) 7:288,293 Forbesides A-C 7:292 Force field method 9:281 (5)-Formaldehyde di-p-tolyl dithoacetal S-oxide

m (5)-propranolol synthesis 6:346,437 synthesis of 6:343,344 Formaldehyde dimethyl dithioacetal 6:311 Formica 6:454 Formicids 6:421 (+)-N-Formmylcyclomicrobuxeine 2:196,197 Formyation 6:74 FormycinsA 10:356 FormycinsB 10:356,357 iV^-Formyl lactam 12:390,392 Formyl piperzinedione 12:66 Na-Formy 1-12-methoxy echitamidine 1:36 3-Formyl-34a-/rflr5-isoquinolines 12:469 2-Formyl-4,5-diphenyloxazole 14:598 6-Formyl-5-isopropyl-3,7-dimethyl-1 H-inden-1 -one 14:328 4-Formyl-8-hydroxyquinoline 2:232,233 4-Formyl-8-hydroxyquinoline 5:752,753 a-Formyl-a-phenyl acetic acid 10:408 Formylation-diazotransfer procedure 10:594,595 Formylchromane 4:495 Na-Formylechitamidine 1:36 Formylguaiazulene 14:315 3(+)-N-FormyIharappamine 2:177,178 Formyloxy compound 11:298,299 rraAw-7-Formyloxy-8a-methylindolizidine 12:288,289 (+)-Formylpapilicine 2:182,183,204 3-Formylrifamycin SV 12:37 N-Formylvinamidine 2:398 Forosamine 5:614 Foroxymithine 15:449 Forskalinone from Salvia forskahlei 20:672 from Salvia hierosolymitana 20:672 Forskolin 10:183;13:659 Forsythia suspema \ar.fortunei 5:475 Forsythia intermedia 5:489-491,492,494 Forsythia mandshurica Rupr. \ar.japonica Maxim 5:505,514-516,520,523-525,531 Forsythia sp. 5:511-513,521 Forsythia suspensa 5:489,506,522,592,616 Forsythia viridissima Lindley 5:505,506,514,522 Forsythiaside 5:506,509,512-514 Forsythosides A 16:628 Fortimicin 4:118 Forysthide aglycone dimethyl ester synthesis 16:294-295 Fosfonomycin 6:352 Four component condensation 12:11,115,117 Four-carbon polar annulation 6:17,21,29,30 Fourier transform methods 5:3 FPP 7:110,122 Fragmentation-recombination of a,P-unsaturated methoxymethyl ester 10:412 to a-hydroxymethyl unsaturated ester 10:412 Fragranol from Artemisia fragrans 7:208 Fragrant odor of liverworts 2:278 Framework molecular models 17:490 Frank-Condon prmciple 2:157 Fraser-Reid synthesis 12:13,14

1040

Prater method 10:321 Fraxetin 5:497,515-519 Fraxetin dimethyl ether 5:516 Fraxidin 5:516,225 Fraxin 5:515,516,520,521 Fraxin methyl ether 5:516 Fraxinol 5:516,517,519 Fraxinol methyl ether 5:516 Fraxinusjaponica Blume 5:505,514,515,520,521,523525,531 Fraxinus rhyncehophyllns 13:660 (+)-Fraxiresinol 5:524,535-538,542 (+)-6-ep/-Fraxh-esinol 5:542 (+)-Fraxu-esinol dimethyl ether 5:542 Fredericamycin A antitumor agent 16:27 antitumor antibiotic 16:27 synthesis of 16:27-74 Free radical condensation 10:355 Free radical cyclization 3:326 Free radical deoxygenation 6:21 Free sugars 10:389-394 Freelingyne synthesis of 10:167 from Eremophila freelingii 15:233 from E. rotundifolia 15:233 Fremy's salt 9:456,457,10:120,121,14:780,19:653 Frenolicin synthesis of 4:591,592,594,609 Friedal-Crafts acylation 8:16,13:448,18:234 Friedal-Crafts reaction 1:499-501 ;5:485;10:312,313; 11:140,318,319;14:7,670-676,681-684;19:306;20:692 intramolecular 10:312,313,11:140 Friedel-Crafts alkylation 6:61,62,74,75,10:376,18:231 Friedel-Crafts annulation 18:70 Friedel-Crafts products 6:309 Friedel-Crafts reaction Friedelan-3,21-dione 5:744,746 Friedelan-3b-ol 7:167,168 Friedelin derived triterpenes 7:145-153 Friedelin5:744,746;7:147,148,150,161,162,189; 18:770 synthesis of 3:435 Friedlander reaction 3:386 Friedo-oleanenes 7:149,150 from Cassine balae 7:149,150 Fritsch-Buttenberg-Wiechell rearrangement 18:171 Fromia monilis 15:60 Formyl-l,4a-^raAw-isoquinolines 12:469 1Frondogenin 7:277 FrondosideA 15:92 FrondosideB 15:94 Z)-Fructofiiranose 6:352,355,357,358 a-D-Fructofiiranosyl 1 -thio-a-D-glucopyranoside synthesis of 8:323,326 p-D-Fructofuranosyl 1 -thio-a-D-glucopyranoside 8:322,325 D-Fructose 6:355 phosphorous analogues of 6:355 Fructose 7:181 C-Fructosides 3:217 synthesis of 3:217

Fruit lactones 13:297 Frullania dilatata 2:280,607 Frullania nisquallensis 2:280,471 Frullania tamarisci 2:278,280;9:254;18:607,614,623 Frullanolide 2:280,2:281 (-)-Frullanolide 18:607,20:471,472 Frutescin 9:317 (+)-Fruticosonine 11:278,279,286 FrutinoneA-C 7:415 Fuchs synthesis 18:892-895 Fuchsiaefoline 5:128,387 Fucogalactomannans 5:289 9-(P-D-Fucopyranosyl) adenine 4:232 Fucosanthin 7:320,321 Fucose 286-289,292-294,302 a-L-Fucosidase 12:349 Fucosidases 7:41 Fucosterol 5:408,7:124 Fucosyltransferase 10:500,501 Fucoxanthin 6:133-137,139,141,142,146,10:153, 20:583,584 Fucoxanthinol 6:135,136,142,143 Fucus serratus 6:139 Fuerstione 19:405 Fuji oxidation 14:727 (+)-Fukugetin (morelloflavone) 5:758 Fulicaatra 5:837 Fuloplumierin antibacterial activity of 17:19 Fulvine synthesis of 1:272,273 Fulvinic acid synthesis of 1:263 Fulvo derivatives 7:459,460 Fulvoharpagide 7:459,460 Fulvoipolamiide 7:458,459 Fulvou-idoids 7:458 Fulvolamiol 7:459,460 Fulvoplumeirin 7:441,458,459,656 Fumarates 8:142-144 Fumaricacid 7:180 Fumaricine 1:198,199,219 Fumaritridine 1:208,209 Fumaritrine 1:208,209,211,212 Fumarofme 1:207,209-211 Fumonisins 6:219,220,252;9:203,204,214,215;13:530533 Funco oreganus 5:836 Fungal spore 9:219-248 Fungal toxin synthesis of 1:289 Fungi 2:341 Fungi and protozoa 18:785-814 Fungicidal activity 17:243 Fungicidal saponins 7:433 Fungicides 9:226 Funk's convergent Ireland-Claisen macrolactone Furan C-glycosides 10:349 Furane 3:443 Furaneol 13:318,319 Furanoaphthoquinones from Crescentia cujeta 20:494

1041

Furanocoumarins 20:497 Furanoaphthoquinones 20:494 Furanocoumarin 4:388,389,396,398;7:433;9:402; 18:978,979,985;20:497 Furanoid C-glycosides 10:343,344 Furanoid compounds synthesis of 3:55-58 Furanonaphthoquinones 5:16,17 P-Furanone reaction wih 9-BBN 6:20 synthesis of 10:384 Furanosesquiterpenes 15:227-238,197 Furanosyl C-glycosides synthesis of 10:367 Furanoterpenes 5:371,107 Furans 17:324,585 Furanurono-6,1 -lactone 14:180 Furanyl C-glycoside 10:391,392 Furfuryl (:)-2-(sulfonyl) acrylates 12:19 N-Furfliryl acryl amide cycloaddition 12:19 6-Furfiirylaminopurine (kinetin) 7:90 Furfuryllithium 4:141,142 Furo [3,2-C]pyrid-4 (2H)-one 8:286 Furo-indoloquinolizine derivative 8:285 Furobenzazonine derivative 6:473,474 (-)-Furodysin from Z>v5/^ea species 6:28 oxy-Cope rearrangement in 6:28,29 synthesis of 6:28,29 lactone 17:10 Furodysinin ^om Dysidea species 6:28 oxy-Cope rearrangement in 6:28,29 synthesis of 6:28,29 Furofoline II 13:371,372,374 Furoguaiacidin diethyl ether synthesis of 17:325 Furopyridones 8:288,289 Furostane glycosides 17:136 Furostanol glycosides 17:116,135 Furst-Plattner effect 19:357 Furyl alcohol 16:655 2-Furycarbmol 19:464,19:473 23-Furylbrassinolide 19:280 Furyl carbinols 16:639,648,651 2-Furylcarbinols 19:463-509 Furyllithium reagents 11:440 Fusarentin 6,7-dimethyl ether 15:387 Fusarentin 6-methyl ether 15:387 Fusaricacid 6:219,220 Fusarin A,C,D,E,F 13:526,527 FusarinC 9:203,204,214,215 Fusarins biosynthesis of 6:250,252 from Fusarium moniliforme 6:250,252 Fusarium 13:519,524-529 Fusarium acuminatum 13:535 Fusarium acuminatum 9:204,213 Fusarium avenaceum 13:526,535 Fusarium avenaceum 9:204,205,213,214 Fusarium compactum 13:536

Fusarium crookwellense 13:526 fusarin C from 13:526 Fusarium crookwellese 9:205 Fusarium culmorum 13:519,520,526 Fusarium culmorum 4:648,250,204-208,212 Fusarium equisete 9:204 Fusarium equiseti 13:543,545 Fusarium graminearum 9:204-208,216,524,543 Fusarium larvarum 15:381,386 Fusarium lini 18:807 monohexosylceramides from 18:807 Fusarium merismoides 9:204 Fusarium moniliforme 9:203-205,214,215;13:524 Fusarium moniliforms 13:524,526,530 Fusarium nygamai 13:530 Fusarium oxysporum 9:204 Fusarium oxysporum f. sp. cucumerinum 9:238 Fusarium poae 9:204,314,315,526 Fusarium proliferatum 13:530 Fusarium roseum 13:543 Fusarium sambucinum 13:526,543 Fusarium sambucinum 9:204 Fusarium semitectum 9:204 Fusarium solani 9:204 monohexosylceramides from 18:807 Fusarium species 6:219-259,201-218 Fusarium sporotrichioides 13:526 Fusarium sporotrichioides 6:247,204,205,208-213 Fusarium subglutinans 13:530 Fusarium toxins 9:201-208 Fusarium tricinctum 9:205 Fused azacycloundecine systems synthesis of 6:496 cis/trans-Fused decalones 14:460 Fused eight-membered ring systems 6:468-474 Fused eleven-membered ring system 6:494-497 Fused lactone nucleoside synthesis 4:252 Fused nine-membered ring system 6:472-482 Fused ten-membered ring systems 6:483-493 Fusicoccum amygdali 15:385 Fusicoplagins A-D 2:81 Fusioccane 3:93,94 Fusion reactions 4:236,38 Fusion technique 4:222 Fusobacterium nucleatum 4:195 Futoenone synthesis of 8:159 Futoquinol synthesis of 8:169,170

G-protein-coupled receptors (GPCR) 18:822 G-protein-linked receptors 18:694 G-proteins 18:861 (+)-GAi synthesis of 6:178-181 GAi2 6:172,194 GA,2 aldehyde 6:171,172,186 GAi3 72,187 GAi9 biogenesis of 6:188 from bamboo shoots 6:187

1042

GA24from 6:188 GA44from 6:188,189 GA20 fromOAss 6:186 GA24 6:188,189 GA3 methyl ester synthesis of 8:117 GA31 synthesis of 6:191 GA32 synthesis of 6:191-193 GA36 6:172,189 GA37 synthesis of 6:184,185 GA38 synthesis of 6:184,185 GA4 6:172,176,168,202,209 ()-GA4 synthesis of 6:178-181 GA44 6:186,188 GA53 6:186,188 GA69 6:191 GA7 6:172,186,195,201,202,209 GA70 6:191 GA9 6:172,194 GA9 methyl ester 6:204 GABA 1:89 GABA (y-aminobutyric acid) syndesis of 13:514 GABA antagonists 14:657 ()-Gabaculme synthesis 13:509,510 Gabunamine 5:124 Gabunine 5:124 GaINAcyffl->4[NeuAca2->3)Galy^l-4Glcy51->' 1 Cer 5:488 Gajasmin 16:298 P-Galabioside 14:149 Galactal 7:59 p-D-Galactan 5:275,278,279 Galactan 5:276,300 Galactinol 18:396 Galacto-configuration 4:147,148 Z)-Galacto-hexodialdopyranose Witting olefination of 4:163,164 Galactomannan 5:279,286,289,290,292,293,295,301, 302,306-309,312,313,325 D-Galactonic acid 5-lactone 2:163 Z)-Galactopyranose 6:376 Galactopyranose 7:47 Galactopyranosides 5:657 p-D-Galactopyranosides derivatives 7:52-54 4-5-P-D-Galactopyranosyl 8:4-thio-D-galactose 8:335 4-5-P-D-Galactopyranosyl-4-thio-a-D-galactopyranoside 8:335 4-5-p-D-Galactopyranosyl-4-thio-D-glucose 8:335 6-5'-P-D-Galactopyranosyl-6-thio-D-glucose synthesis of 8:338,339 4-O-a-D-Galactopyranosyl-P-D-galactopyranoside 14:149 3-0-P-Z)-Galactopyranosyl-D-galactose 7:137 Z)-Galactose 4:130,197,198,29

I-Galactose 4:197,198 Galactose 7:153,158,294 Galactose oxidase 7:71,72 D-Galactose-molybdate complex 15:4/'9 p-Galactosidase 10:470,471,567,568 a-Galactosidase 7:38,39,567,568 P-Galactosidase ofKcoli 8:315 synthesis of 8:315 inactivation by P-galactoside analogue 7:40 inhibition by aminoglycopyranoses 7:47 mhibition by conduritol C cw-epoxide 7:38 mhibition by conduritol C /rons-epoxide 7:38 inhibition by P-galactosyl amines 7:44 inhibition by nitrophyenylthiogalactoside 7:48 Galactosidases from E CO// 7:39,50,52,65 a-D-Galactosidation of methyl 2-0-benzyl-4,6-0-benzylidene-P-Dgalactopyranosides 14:150 Galactosides 7:48 P-Galactosides 8:315 p-Galactoside analogue 7:39,40 p-Galactoside derivatives 7:52,55 Galactostain 7:41,42,267 from Streptomyces lydicus 10:542 mammalian P-galactosidase inhibitor of 10:542 Galactostatin lactam 10:543,550 p-Galactosyl amines 7:44 P-galactosidase inhibition with 7:44 Galactosyl transferase 10:468,500,501 P-Galactosylation 10:470 a-Galactosylceramides 18:460 P-(l-4)Galactosyltransferase 10:484 D-Galactouronic acid 4:198 Galactouronic acid 6:363 D-Galacturonic acid 7:181 Galpinone 20:276 Galanthamine 4:3,4,13,21;20:325,346,370,385 Galantinic acid 12:487 Galeon 17:371 Galipine 3:385,386 Galium species 4:400 Gallicm 7:230 Gallic Wars 19:140 Galpmone 20:276 Galsky potato disc method 9:386 Gambirtannine 1:100,101 Gamma linoleic acid 13:659 Gamma-elimination 8:420 GanervosinA 15:138,146,155,173 GanervosinB 15:141,173 Ganglioside 18:486,786,788 Ganglioside GM3 16:88 Ganglioside GM4 8:343-344 Ganglioside GM5 18:486 from Anthocidaris crassispina 18:486 Gangliosides 7:307,10:459 Garaniol 20:20,31 Garcigerrin A 7:444,445,457 Garcinia 1:444

1043
Garcinia gerrardii 7:444,445,457 Garcinia mancostana 4:382,384 Garcinia spicata 5:757,758 Garcinia thwaitesii 5:757,758 GarcinoneA 4:382,284 Gardenia cramerii 5:756,757 Gardeniafosbergii 5:756,757 Gardenia jasminoides Ellis 16:298 Gardenias^. 5:756,757 GardeninB 5:654 GardeninD 7:227 Gardenoside 16:298 Gardneria nutans 15:491 Gardnerine from Gardneria nutans 15:491 Gargugamblins 17:370 Gariboldi synthesis 6:20 Garjasmidin 16:298 Garjasmin 16:298,299 Garrya diterpene alkaloids 6:174 Garry ine synthesis of 3:435 Garuga gamblei 17:370, Garuga pinnata 17:370,375-376 Garwga species 17:375 Garugamblin-1 17:386,389 Garugamblin-2 17:386 Garugamblins 17:378 Garuganinlll 17:386 synthesis of 17:386 Garuganins 17:370,378 GASPE spectrum 5:145 Gassman oxindole synthesis 3:320 Gasteromycetes 9:202 St-4 Gastric carcinoma 19:298 Gastrin and CCK 18:824-840 Gastrin family 18:819-866 Gastritis 17:137 Gastrointestinal cancer 1:275 Gaucher's disease 7:39 Gaudichaudioside B 15:22 Gaudichaudioside C 15:22 Gaudichaudioside F 15:22 GB-2a 5:758 GB-I 5:758 GB-Ia 5:758 Gedunin 7:190,191 Ge/ger/a species 20:10 Geigerin 20:10 Geigeria burkei 14:450 Geissman-Waiss lactone 13:484,485 Geissochizol 5:73,126 ()-Geissoschizine 13:490,491 Geissoschizine 1:21,31 ;5:126,520,171 Geissoschizine-type alkaloids 5:71,73 ()-3-e/7/-Z-Geissoschizol 14:722-724 ()-Z-Geissoschizol 722-724 Geissoschizol 9:171 Geissoschizoline 1:34,38,39,41,42,46,48 Geissospermum laeve 1:124 Geissospermum vellosii 1:124 Gel electrophoresis 2:19,114 Geldanamycin 5:592,434 Gelonium multiflorum 9:265 Gelsamydine 15:483-486 Gelsedine 15:481,482 Gelsedine-type alkaloids 15:481-483 Gelselegme 15:483,484 Gelselegine-type oxindole alkaloids 15:483-485 Gelsemamide 15:472,473 Gelsemicine 15:482 Gelsemide 7:441 Gelsemme 15:478,479 Gelsemine N-oxide 15:479 Gelsemine-type oxindole alkaloids 15:478-481,504,505 Gelsemium alkaloids 15:465-515 Gelsemium elegans akuammidine from 15:466 gelsemamide from 15:472,473 humantenine from 15:472 kouminefrom 15:475,476 11-methoxygelsemamide from 15:472,473 16-ep/-voacarpine 15:469 Gelsemium rankinii 15:465 Gelsemium sempervirens 1:125,465-467 Gelsemoxonine 15:481,482 Gelsenicine 15:481,482 Gelsevirine from Gelsemium elegans 15:479 from Gelsemium rankinii 15:479 from Gelsemium sempervirens 15:479 Gene experession control 5:580,581 Gene expression byantisense RNA 13:257-261 natural regulation of 13:257-261 Gene transfer 7:121-123 Genes synthesis of 4:267 Genetic mapping 9:606,607 (+)-Genipin 16:290,20:56 Genipin 7:441 Genkwanin 227 GentamicinCz 4:188 Gentamycin Cia 115 GentamycinX2 14:145 Gentiana sp. 5:651 Gentianaceae 17:421,434 Gentianine 6:528,529,444 Gentianine derived alkaloids 6:528,529 Gentianine series 6:522 Gentiobiose 8:349 Gentiobiose 15:436 Gentiopicroside 7:442 Gentosamine 14:50 Geothelphusa dehaai 19:647 Geothricum penicillatum 13:302 Gephyrotoxin l:23,223,287,288,292,385-389;4:606; 6:449;7:11,10:186,453,16:453 3-Gerandyloxy-6-methyl-1,8-dihydroxyan-throne 7:418-420,424 Geraniaceae 7:120,421 Geranial 13:333,17:433 Geranicacid 20:5 -Geraniol 8:77 Geraniol 7:100,101,104,105,107,108,116,117,125, 19:83;20:5

1044

Z-Geraniol 8:77 Geraniol acetate 10:9,14 Geranium macrorhizum 5:679 Geranium thunbergii 17:421,428,433 Geranyl acetate 15:227 from Eremophila abietina 15:227 Geranyl acetone 6:60 Geranyl bromide 4:386,386,391 Geranyl diphosphate 11:219-221 (+)-bomyl diphosphate from 11:219-221 (l/?)/(15)-[l-'H]Geranyl diphosphate 11:220,221 Geranyl diphosphate 7:324 Geranyl geranyl phosphate 11:4 Geranyl geranyl pyrophosphate 11:24 Geranyl hydroquinone 5:440 Geranyl-geranyl pyrophosphate 5:701 Geranylfamesol 6:111 Geranylgeraniol 15:253,20:26,28,30 (,,)-Geranylgneraniol derivatives 1:662-665 Geranylgeranyl diphosphate 7:321,322,324,325,327, 330,348,351 rrans-Geranyllinalool 20:590 3-Geranyloxyemodin 7:418-420 Gerlach's procedure 6:542,543 Germacradiene 8:59 Germacradienolides 7:210 cis, cw-Germacradienolides 7:210,211 Germacrane 6:15,607 Germacrane 7:209,211,212,214,216 Germacrane lactone 8:195-201 Germacrane-12,8-olides 7:231 Germacranolides 2:280,210,211 GermacreneD 9:531,534 Germacrene isoprenologue 15:278 (-)-Germacrene-D 6:540 Germacrenoid structure 6:538,539 Germacrolides 7:210 Germacrone synthesis of 8:178 Germination 9:219-248 Germination inhibitor 1:684 synthesis of 1:684 Gerrardine 7:192 Gestogens semi-synthesis of 17:623 GF-109203 X 12:389 Ghromenes 7:409,410 8-C-Ghycosylflavones 5:644 CsoGibberelins 6:184-190 Gibberellafujikuroi 8:115,117 Gibberellenic acid from gibberellic acid 6:199 growth effect on root culture 17:425 as gibberellin 6:171,172,181-184 as gibberellin A3 6:171,172 gibberellenic acid from 6:199 total synthesis of 6:181-183 synthesis of 8:116 Gibberellic acid (GA3) 6:181-183,209,100;7:100;8:115120 C20 gibberellins from 6:186-190 from Gibberellafujikuroi 6:172,186 in gibberellic acid 6:171

Gibberellin antheridiogens from 6:171,194-209 partial synthesis of 6:186,194-209 from gibberellic acid 8:115 homonuclear 8:'H-'H-shift 8:117 mass spectrum of 8:117 synthesis of 8:115-137 Gibberellin A7 6:197-201 Gibberellin 0x0 esters 8:128 Gibberellm thioanalogs 8:123-127 Gibberellin-7-aldehydes 8:128 Gibberellin synthesis of 3:435 Gibberellins synthesis of 8:115-135 Gibberellins Ai,A3,A4,A7,A9 7:188 Gibberellins GA4 8:115,119,120 Gibberellins GA55 from lp-azido-3P-hydroxy compound 8:121,122 synthesis of 8:119,121,122 Gibberellins GA57 fromGAs 8:121,122 synthesis of 8:115,121,122 Gibberellms GAgo fromGAs 8:122 synthesis of 8:115,121,122 Gibberellins GA7 fromGAs 8:119 synthesis of 8:115,119,120 Gibberic acid synthesis of 8:117 a//o-Gibberic acid synthesis of 8:117 Gibbons ia elegans 17:94 Gigantecin 17:277;18:221,222 Gigantecin 9:395-397 Gigantenone 6:554-556 (+)-Gigantenone 6:555,556 Gigantetronenin 18:221 Gilman reagent 10:25 Gilvocarcin 10:343,374 Ginamallene 5:369,370 Gmgerenones A, B and C 17:378 Gingerol 9:321,328 Gingko biloba 9:317,321,323,659,660 Gingkolides 13:659 Ginkgol 9:323 Ginkgolic acid 5:826-828,355,436,317 Ginkoaceae 9:317,323 Ginseng 13:660 Ginsenosides 15:191 Gitaloxigenm 15:362 Gitaloxin 15:362 Gitoxigenin 15:362 Gitoxin 15:362 Gizzerosine synthesis of 1:679,780 Glabellin235 (+)-Glabrol synthesis of 4:378,380 Glacialosides A,B from Marthasterias glacialis 7:299 Glaciolide 17:14,15

1045

Glanduliferol 6:63,64 Glaucarubin 7:394,398,660;13:660 Glaucarubinone 7:379,383,392,394,395,396,7:398, 72,79,80,105;11:79,80,105 Glaucarubol 7:394 Glaucarubolone 7:396,398 Glaucasterol (papakusterol) from Pseudothesis species 9:37 from Sarcophyton glaucum 9:37 ()-Glaucine 16:506,514 ^'-Glaucine 16:507 Glaucine synthesis of 3:424,425 Glaucocalactone 15:141,149,158,172 Glaucocalyxin A&B 15:172 Glaucocalyxin C 15:112 Glaucocalyxin D 15:114,121,128,172 Glaucocalyxin E 15:114,121,128,172 (-)-Glechomafiiran 20:660 Gleditsiajaponica 15:195 Gleditsia saponins 15:191 Gleosporium fructigenum 18:715 Globicin 7:235 Globularidin 7:440 (-)-4-e/7/-Globulol 14:359 Glococladium sp. 5:370 Gloeosporium lacticolor 15:351 Gloeosporone synthesis of 10:233 Gloeosporone 9:220,229,234,240-243,245-247 Glomerella cingulata 5:278,415,228,230,240 Glomerellafructigene 9:230,239 Glomerella glycines 9:230,239 Glomerella gossypii 9:230,239 Glomerella species 9:228,230,239 Glomerella tucumanensis 9:230,239 Gloria superba 5:47 D-Glucal 2:162 Glucal triacetate 11:356,357 Glucan 5:276-280,287,288,291,292,295,299,305,307, 308,310-312,316,321 Glucan-polyolalcohol 5:318,319 Glucanase 7:32-36,59,60 a-Glucanase 7:60 eJo-Glucanase (take-amylase) 7:34,35,42 P-D-Glucans 5:287,292,295,307,308,310-312-315,316, 320,321 a-D-Glucans 5:287,307,309,310 ejco-a-Glucans 7:59,60 Glucansucrase 7:69 Gluco-octenitol 7:60,69 Gluco-triflate 14:155 Glucoamylases 2:321-360,49,50,58,62,63;7:34,49; 10:497,504 Glucobioses 7:69 Glucodextranase 7:58 Glucoferulic acid 5:476 Z)-Glucofuranose 6:359,360,369,370,376 Glucogitaloxin 15:362 Glucomannan 5:306 Gluconobacter oxydans 10:530 Gluconolactone 10:386,387

23-0-y^D-Glucopyranosyl-2-epi-25-methyldolichosterone 18:495 23-0-)^D-Glucophyranosyl-25-methyldolichosterone 18:495 2 2-0-y^D-Glucophyranosyl-3,24-diepicastasterone 18:529,53 3 -0-/?-D-Glucophyranosyl-3,24-diepicastasterone 18:529,541 23-0->^D-Glucophyranosyl-brassinolide 18:522 a-D-Glucopyranans 5:307,310,317 Z)-Glucopyranose 6:352,355,370,373,376 Glucopyranose 7:47 a-Glucopyranoside 19:369 P-Glucopyranoside 19:369 a-D-Glucopyranose 1-thiolate derivative 8:318 D-Glucopyranose 3-O-triflate 8:343,344 D-Glucopyranoside 6:357-359 A^-(Glucopyranoside-3-yl)-peptide ester 6:406,407 Glucopyranosides 5:657 Glucopyranosyl 1-deoxynoju-imycin derivatives 7:42 a-D-Glucopyranosyl 1 -thio-a-D-mannopyranoside 8:347 P-D-Glucopyranosyl 1-thio-P-D-glucopyranoside (p,P1-thiotrehalose) 8:317 4-5-a-D-Glucopyranosyl 4-thio-D-glucose 8:331,332 6-5-p-D-Glucopyranosyl 6-thio-D-glucose 8:338,339 Glucopyranosyl fluoride 7:58 a-D-Glucopyranosyl phosphate 14:151,152 6-S-P-D-Glucopyranosyl-6-thio-a-D-glucopyranoside heptaacetate 8:337,338 6-S-P-D-Glucopyranosyl-6-thiocyclomaltoheptaose 8:340 6-5-a-D-Glucopyranosyl-6-thiocyclomaltoheptaose 8:340 a-D-Glucopyranosyl-a-D-mannopyranoside 8:347, 8:348 synthesis of 8:347,348 9-Z)-Glucopyranosyl-adenine 4:224,225 25->^D-Glucopyranosyloxy-24-epi-brassinolide 18:539 26-/?-D-Glucopyranosyloxy-24-epi-brassinolide 18:541 (-)-(/r5-4'-P-D-Glucopyranosyloxy-3'methoxycmnamoyl) lupinine 15:521 from Lupinus luteus 15:521 (-)-(^ra5-4'-P-Glucopyranosyloxycinnamoyl) lupinine from Lupinus luteus 15:521 5'-p-D-Glucopyranosyloxyepijasmonic acid 6:557 P-Glucopyranosylvalienamine 13:233 Glucoronides 5:645 D-Glucosamine 14:186,461 Glucosaminyl-chu-o-inositol phosphate 18:434 Glucose 2:321,332,262,276-278,282-284;7:136,139, 142,181 Glucose isomerase 2:321 Glucose oxidase 7:71,104,105,111,112;19:701 Glucose-6-phosphate 11:216,217 Glucosidase 19:356 a-Glucosidase 10:498,514,526,431,247-250,86-87; 19:369-370 a-Glucosidase inhibitors 7:46,48;10:496;13:235-246 Glucosidase 16:108

1046

2p-Glucosidase 5:471 P-Glucosidase inhibitor 19:369 P-Glucosidase 2:379,352,514,526,567;10:568,249,250; 19:357,365,369 3,8-diepialexine inhibition with 7:14 6-ep/-castanospermine inhibition with 7:12 australine inhibition with 7:15 castanospermine inhibition with 7:12 DMDP inhibition with 7:15 from Aspergillus niger 7:51,52 from Penicillium expansum 7:14 from valienamine 7:46 inhibition by 2-deoxy-2-fluoro-p-D-glucopyranoside 7:36 inhibition by acarbose 7:47 inhibition by conduritol B epoxide 7:38,39 inhibition by nojirimycin heptitol derivative 7:43 inhibition by vaHdamycin 7:47 scyllo-mosiXoX from 7:38,39 with bromoconduritol B epoxide 7:38,39 with bromoconduritol F 7:38,39 Glucosidase II 10:499,526,527 Glucosidase 1 10:526,527 a-Glucosidase I 10:501 a-GIucosidase II 10:501 a-Glucosidase inhibitors Glucosidases 7:41 nojirimycin inhibition by 7:41 Glucosidases I,II 7:12,13 Glucosidation 16:296 a-D-Glucosides 2:330 a-Glucosides 8:226,359,361,366 Glucosidic bond 16:588 Glucosyl chloride (2,3,4,6-tetra-O-benzyl-a-Dglucopyranosyl chloride 8:359-362 9-Glucosyl derivative 4:224 9-Glucosyl derivative of theophylline 4:224 Glucosyl mannoside 8:l-thio-a,a-disaccharide 8:319, 8:320 24-0-P-D-Glucosyl officigenin 7:139,140 Glucosyl ste vioside 15:19 0-Glucosylation 5:516,520,525-532,545 7-0-P-Glucosylisofraxidin 5:515 Glucosyltransferases 2:322 D-Gluctol 6:357,358 p-Glucuronic acid 16:81,84 Glucuronic acid 7:156;15:26,77 D-Glucuronic acid 7:294 Glucuronic acid-based inhibitor 16:115 P-Glucuronidase 16:81,82,84,88,90 Glucuronide linkage 7:156-158 Glucuronide saponins 7:156-158 D-Glucurono-6,3-lactone 18:396,442 D-Glucuronopyranosyl 15:7 Glucuronoxylans 2:300 Glucuroxylomannans 5:294,326,327 (/?)-Glumatic acid 12:322,325 Glutarenghas 9:319 Glutamic acid 2:357;11:419 (5)-Glutamic acid 12:322,325,19:325

L-Glutamic acid 4:148,252,438,439;6:438,439;13:607; 14:633 (Z,)-Glutamic acid 6:438-440 Glutamine 6:409-413 Glutamine synthetase 7:6 Glutamyl peptides 6:409,410 Glutarenghol 9:319 Glutaric acid derivative 11:118 Glutaric anhydride 13:540 Glutaric dialdehyde 14:739 Glutarimide 14:740,749 Glutarimide intermediate 6:410,411 Glutarimide rings 1:313 Glutathione peroxidase 9:109 Glutathione S'-transferease 9:562,576,577 Glutinol 7:150 Glutinopallane 17:154 Glutinosi 17:199 Glutinosin 15:167-170,172 Glycals 4:223,59-62,337-352;10:338-341 Glycan 6:397-404 Glycanases 8:347-351 (5)-Glyceraldehyde 14:765 D,Z,-Glyceraldehyde 6:359 Z,-Glyceraldehyde 16:99 D-Glycero-Z)-galactoheptose 4:195,198,199 D-Glycero-Z)-/wao-heptose 4:195,202,203 Z-Glycero-Z,-/nflo-heptose 4:195,197-202,207,209 Z-G/ycero-D-wflw/io-heptopyranose 11:429 D-Glycero-I-/wflfo-heptose 4:197,198 D,Z,-Glycero-pentopyranose 6:360,361 Glycerol 2:20 (li?,2/?) [l-^Hi, ^H] Glycerol 11:208 Glycerol tri-myristate 2:48,49 Glyceryl p-galactoside 7:65 Glycidol 13:70 Glycine max soyasaponin A3 15:196 Glycine 4:115-118 D-Glycitol 6:355 Glycoalkaloids molluscicidal activity of 7:427 Glycobismine A 13:371,372,374,380 Glycocitrine I,II 13:338,350,357,358,372,373 from Glycosmis citrifolia 13:348,350 Glycocyamidine 5:549 Glycocyamine 5:549 Glycofoline from Glycosmis citrifolia 13:348-351 Glycogen 7:32 Glycogen phosphorylase 7:29,30 Glycohydrolase 7:29-37,40,47,50,58,59,65,69 Glycohydrolase lysozyme 7:31 Glycolamide 16:84 Glycolipid biosynthesis 1:417 Glycolipids 18:785-814,143 N-Glycolyhieurammic acid 18:786 Glycookadaic acid 5:385-386,388,389 Glycopeptide 5:279 Glycopeptide antibiotics 10:657-669 Glycopeptides 13:202 Glycoprotein 5:282-285,12,457,458,461 ;10:462,479, 143

1047 Glycoprotein biosynthesis 1:417 Glycopyranoside analogs 7:14,15 Glycopyranosyl-pyrimidines 4:224 p-Glycosidase 7:27,28,31 Glycosidase 7:36-48,53,55-57,60,72;19:351 a-Glycosidase 7:59 a-Glycosidase inhibitors 10:496 Glycosidase inhibitors 7:40,59 Glycosidases 8:347,351,337-403,470,471;10:495-573, 86;16:86 Glycosidation by mycosamine 6:276,277 by silicon ether 6:262,276,277 in (-)-pseudopterosin-A synthesis 6:74,75 Noyori's 1:671,672 of l-O-acetyl-oxetanose 10:603 of adenine 10:605 ofamphoteronolideB 6:276,277 regioselective 6:262 stereochemistry of 3:197 with oxetanosyl chloride 10:605 with silver triflate/TMU 1:670,671 p-directing 2-bromosugars 3:202 S-Glycosides synthesis of 10:380 Glycoside 7:133,134,136 Glycoside Bz (forbeside B) 7:287,288,293 from Asterias amurensis 1:2S7 P-Glycosides 8:359,361,366 Glycosides 8:359-363,337-403;17:115 6,8-di-C-Glycosides 5:644 0-Glycoside 8:315;10:344,370-380 mtramolecular rearrangement 10:379 stereoselective synthesis of 10:340 Glycosides of polyhydroxysteroids 15:60-72 1,2-cw-Glycosidicbond 14:202 l,2-/A-flAw-Glycosidic bond 14:202,204 Glycosidic linkage 16:93 Glycosmis bilocularis 13:348,350,355 Glycosmis citrifolia cycloglycofoline from 13:348,349 glycocitrine I from 13:348,350 glycofoline from 13:348,349,361 pyranofoline from 13:348,350 Glycosphingolipids biodegradation of 10:503 biosynthesis of 10:503 from denteromycetes 18:806 from zygomycetes 18:806 isolation and purification of 18:786-797 metabolism of 10:502,503 ofbasidiomycetes 18:806 of fungi 18:806 of Trypanosoma cruzi 18:796-802 Glycosyl amines 7:44-47 Glycosylceramidase 19:352 Glycosyl chlorides 8:359-361 C-Glycosyl compounds 3:213-228 Glycosyl cyanide 10:358 Glycosyl fluorides 7:58,59 Glycosylfreeredicals 3:221-223 Glycosyl halides substrates 7:50-59 Glycosyl isocyanides 3:209,210 Glycosyl manganese pentacarbonyl 10:364 Glycosyl phosphates 8:83 Glycosyl pyridinium salts P-glycosidases inhibition by 7:57 glycosidases reaction with 7:55-57 Glycosyl thioformimidates from glycosyl nitriles 10:357 Glycosyl transferases 7:69 4-0-Glycosyl-2-deoxystreptamine 14:144,145 a-Glycosyl-c/i/ro-inositol 18:434 Glycosyl-O-trichloroacetimidate 14:211 7-Glycosyl-purines 4:224 Glycosylalkynes 10:359 C-Glycosylation 1:429,430,513,514 Glycosylation 6:395,397,398,400;10:470,471,472, 474-486 a-Glycosylation 13:217 l,2-c/5-Glycosylation 14:209 l,2-fra5'-Glycosylation 14:209 c-Glycosylation procedures 14:202 Glycosylation reactions 14:201-259 Glycosylcobaltoxime 10:366 6-C-Glycosylflavones 5:644 8-C-Glycosylflavones 5:644 Glycosylhalides 10:355 Glycosyllithium reagents 3:222 Glycosylphosphatidylinositol anchor 18:840 Glycosyltransferase 10:459,461,495-573,115 Glycosyltransferase inhibitors 10:495-573 Glycowithanolides from Withania somnifera 20:247 2-Glyculosonates 20:857 Glycoxylon huberi 15:31 Glycyphylla smilax 15:31 Glycyphyllin 15:31 Glycyrrhetic acid 7:136,138 Glycyrrhiza glabra 15:5 Glycyrrhiza inflata 15:26 Glycyrrhizin 7:142,4,22,25 0-Glycosyl-C-glycosylflavone 5:644 Glyfoline antitumor activity of 13:375-380 from Glycosmis citrifolia 13:348,349,361 synthesis of 13:361-367 Gmelina arborea 17:332 Gnetifolin 20:280 Gnetum ula 9:258,263 Gobius criniger 18:48 Golden hampster 5:747 Golgi a-mannosidase I 10:501 Golgi mannosidase lA 10:559 Golgi mannosidase IB 10:559 Golgi mannosidase II 10:559 Gomaline 5:154 Gomberg-Batchman-Hey reaction 20:310 Gomophia watsoni 15:61 Gomophioside Ai9 15:61 Goniocin 18:193 Goniofufurone 9:394 Goniodiol 19:463 8-e/7/-Goniodiol 19:497

1048

GoniodominA 19:578 antifungal activity 19:578 antifungal metabolite 19:578 (+)-Goniofufurone 19:463 Goniopypyrone 9:394,19:463 Goniothalamicin 9:395 Goniothalamas giganteus 19:498 (i?)-(+)-Goniothalamin 19:463 (6i?)-(+)-Goniothalamin antifungal activity of 19:479 antitumor activity of 19:479 insect antifeedant activity of 19:479 isolation of 19:481 plant growth inhibitory effect of 19:479 synthesis of 19:481 Goniothalamin 9:393;19:463 Goniothalamus giganteus 9:393,395;18:221,222 Goniothalamus sesquipedalis 9:393 Goniothalenol (altholactone) 9:393 Goniotriol 9:393,394 (+)-Goniotriol 19:464 Gonomia kamassi 1:124 Gonystylus keithii 19:764 Gonyaulax tamarensis 17:4 Goodeniaceae 6:522 Gorgonane 18:607 (-)-P-Gorgonene 6:18,27,28 Boekman-Silver synthesis of 6:18 by Robinson annulation 6:18 frommaaliol 6:28 from Pseudopterogorgia americana 6:18,27 synthesis of 6:27,28 Gorgoniaflabellum 9\2>1 23-demethylgorgosterol from 9:37 Gorgonia ventilina 9:37 23-demthylgorgosterol from 9:37 Gorgosterol 9:35-37,45-47 Gorman's synthesis 14:862-864 Gorytes campestris 5:251 Gorytes mystaceu 5:251 Gossypol 13:652,659,251 Gosypetone reaction 5:625 Gougerotin 4:241,242 GPP 7:110,122 Gracilaria edulis 19:570 Gracilaria verrucosa 19:571 Gracula religiosa 5:837 Grahamamycin 4:575,576 Gram-negative bacteria 16:3, 16:652 Gram-positive bacteria 12:48 Gramicidin 10:256 Gramilaurone 13:522 Graminae 9:320,328 Granaticin 11:213-222 2,6-dideoxyhexose moiety of 11:214,215 Grandiflorenic acid 19:389 Grandisines I,II 13:350 Grandisinine 13:350 from Citrus grandis 13:350 (+)-Grandisol 1:643,693,236 synthesis of 1:643,693 Granilin 7:212,233 Granulaterosides A 7:299,301

Granulatoside A 15:63 Grape fruit oil 14:449 (+)-paradisiol from 14:449 Graphium sp. 5:307,309,325 Grapholitha molesta 15:384 Guidongnin 15:142,150,159,174 '^C-nmrof 15:159 from Rabdosia rubescens 15:174 H-nmrof 15:150 Grapholitla molesta 6:557 Grasshopper ketone 6:137,143,144,158 CD correlation with 6:137 synthesis of 6:143,144 Gravelliferone 4:371,372 synthesis of 4:371,372 Graynatoxin 20:17 Grayanotoxins 1:546,547 Grayanotoxin-1 19:397 Green's procedure 6:548 Grevillea banskii 9:319,320 Grevillea hilliana 9:320 Grevilleapteridifolia 9:320 Grevilleapyramidalis 9:319,354 Grevillea robusta 9:320 Grev/7/ea species 9:329 Grevillol 9:320 Griffithine 9:149,150 Grifolafrondosa 5:287 Grifola umberllata 5:287,317 Grifolin 9:313 Grignard addition 10:147,167,180;16:380;19:39,45, 62,541 Grignard coupling 19:45 Grignard cross coupling reaction 14:575 Grignard reaction l:261,262,533;4:330-332,353,354; 6:159,549,550;8:165,166;9:344,345,352,527;11:81,82, 248,249;14:670;18:473,630;20:571,589,592,595,599, 600,604 Grignard reagent 4:160;19:33,35-36,38,513,518;20:569, 585,596,598 Grindelic acid 6:107 Griseofulvin synthesis of 4:581 Griseogenin 7:269 Grob-type fragmentation reaction 19:229 Gromphadorhina portentosa 9:488,489 Grosshemin 1:556,559-563 Grossularine-1 5:414-417 Grossularine-2 5:414-417 Grossularines 10:245 Ground state analogue inhibition 7:40,41 Group transfer polymerization 8:409 Growth inhibition 17:142 Growth-inhibitory activity 7:407,416-419,423 Grubb synthesis 6:46,47 Grundmann ketone 10:54,55,68,69,71 Gryllus bimaculatus 9:492 Guadalupol 6:30 GuaiacinA,B 5:197,200 GuaiacinsA-F 9:51,58,59 Guaiacol 9:467 Guaiacum officinale 5:197,139,319,324;9:51-59

1049

Guaiacylglycerol-p-coniferyl alcohol ether diferulate 20:634 Guaiacylglycerol-P-coniferyl ether 5:464,465 Guaian-12,16-oHdes 7:214,234-236 Guaian-12,8-olides 7:214,236 Guaiane 7:209,214,355,607 Guaiane alcohol 14:375 from Nardostachys jatamansi 14:375 synthesis of 14:375 /rart^-Guaiane sesquiterpenes 6:546,547 Guaiane system 3:44,45 synthesis of 3:44,45 Guaiane-type diterpenes 6:11 Guaianes 17:154 Guanidine alkaloids 20:488 GuaianinA 5:197,198 GuaianinA2 5:197,198 GuaianinB 5:197-199 GuaianinC 5:197,199 GuaianinE 5:199,200 GuaianinsA-L 9:51,52,54-58 Guaianolide from (-) a-santonin 2:280,214,215,548;6:548 Guaiazulene 5:363,369 as an anti-inflammatory agent 14:315 autooxidation of 14:316-319 electrochemical oxidation of 14:325,326 from Euplaxaura erecta 14:315 hydrogen peroxide oxidation of 14:324,325 oxidation of 14:313-349 peracid oxidation of 14:320-324 with NBS and NCS 14:331 Guaiazulene sesquiterpenes 1:545 Guaiazulenequinone 14:315,319,321 6-(3-Guaiazulenyl)-l(6H) guaiazulenenone 14:320 6-(3-Guaiazulenyl)-3(6H)-guaiazulenone 14:328 8-(3-Guaiazulenyl)-3,7-dimethylbenzofulvene-4carbaldehyde 14:343 8-(3-Guaiazulenyl)-5-(1-hydroxy-1-methyl-ethyl)3,7-dimethyl benzofiilvene 14:343 1 -(3-Guaiazulenyl)-6a-isopropyl-2,5-dimethyl- 1,1a, 3,6a- tetrahydrocyclopropa [fj inden-3-one 14:320 Guaiazulenylindenones 14:315 3-(3-Guaiazulenylmethyl)-8(8aH)-guaiazulenone 14:344 Guaiol 14:313 ()-Guaiol 14:356 Guanidinoacetic acid 5:549 Guanosine analong 4:237 Guettarda platypada 17:116,125 Guggullignan-I 5:703 Guggullignan-II 5:703 Z-Guggulsterol 5:699,700 Guggulsterol-I 5:699,700 Guggulsterol-II 5:699,700 Guggulsterol-III 5:699,700 Guggulsterol-IV 5:701 Guggulsterol-V 5:701 Guggulsterol-VI 5:699,700 jE-Guggulsterone 5:699,700 Z-Guggulsterone 5:699,700 Guggulsterones 5:699-701 D-/3/jco-Guggultertrol-18 5:705,706

Guggultetrol synthesis of 5:705,707 D-ara^mo-Guggultetrol 5:704,706 Guggultetrol configurations 5:704,706 Guggultetrol esters 5:704-709 D-A-/Z>o-Guggultetrol-l 8 5:704,706,708 D-xy/o-Guggultetrol-18 5:704,706,708 Guggultetrol-18 5:710 Guggultetrol-20 5:708 D-A;y/o-Guggultetrol-20-ferulate 5:708 Guggulu constituents of 5:695-714 fractionation of 5:697 lignans from 5:703 steroidal compounds from 5:698-703 steroids of 5:709-717 Guggulu steroids biogenesis of 5:709,712 D-jcv/o-Guggulutetrol-18 ferulate 5:708 Gugulipid 5:715,716 Guianin 8:159 synthesis of 8:159 Guttiferae 7:409-411,417,418,420-423,19:768 X-Gulonolactone 6-ep/-castanospermine from 7:12 l,6-di-e/7/-castanospermine from 7:12 I-Gulopyranose analogs 6:373-375 Gum resin 5:700 Gundelia toumefortii 7:427 Gutierrezia grandis 5:680 Gutierrezia microcephala 5:680,681 Gutierrezia texana 5:679 Gutierrezia-xanthocephahum complex 5:676 Gycolicacid 16:84 Gym.galatheanum 6:76-D 6:135 Gyminda 18:741 Gymnema sylvestre 15:36;18:649,650,653,661,671,673 Gymnemagenin 18:649,650 Gymnemanol 18:650,665 Gymnemasides 18:650 Gymnemic acids from Gymnema sylvestre 18:649-676 biological activity of 18:670-674 Gymnestrogenin 18:649,650,656 f![om Gymnema sylvestre 18:649,650,656 Gymnochromes A-D 15:105-107 Gymnocolea inflata 2:280 Gymnocrinus richeri 15:105 Gymnodium breve 19:430 Gymnodinium breve 17:20 Gymnolaemata 17:106 Gymnomitrion obtusum 13:39 Gymnomitrol 13:39-41 Gymnosperma glutinosum 5:679-6 81 Gymnospermae 9:317,321,323 Gymnotroches axillaris 7:192 Gynostemma pentaphyllum 18:662 Gypenosides 18:650 Gypsogenin 17:121 Gyrophora aureolum 6:135 Gyrophora esculenta 5:311,322 Gyrostroma missouriense 15:351,383 Gyroxanthal 6:162,163

1050

Gyroxanthin 6:162-164

H-glycosides from 3:228 Haageanolide 8:195-201 Hacelia attenuata 7:290,295,304-306,61 ;15:61 Haemagglutinin 16:93,102 Haemagglutinin-based inhibitors 16:111 Haemanthamine 20:325,353,356,369,383 Haemanthidine 20:352 Haematoxylin 15:34,20:781,782-784 Haematoxylon campechainum 15:34,20:776 Haemodoraceae 17:372 Haemophilus influenzae 4:195 Hairy root cultures 17:426 Hakamori method 2:336;15:192 Hakamori permethylation 5:199 Hakea amplexicaulis 9:320 Hakea persihana 9:320 Hakea trifurcata 9:320 Halcyon smyrnensis 5:837 Halenaquinol 6:4 Halenaquinol dimethyl ether 17:40 Halenaquinone 17:33 (+)-Halenequmol 17:48-50,55-61 (+)-Halenequinone 17:48-50,55-61 Haliangolides 7:210,211 Haliangolidin 7:230 Halicerebroside A 18:459 Halichondriajaponica 18:475 Halichondria melanodocia 5:387 Halichondria okadai 5:378,379,383,384 Halichondria panicea 17:719 Halichondria species 17:17 Halichondride sesquiterpene isocyanides in 6:79 antitumor activity of 5:378,380 from Halichondria okadai 5:378,380 Halichondrins B,C 5:377-382 Haliclona sp. 5:346,347,459 Halide displacement in glycosidation 1:670,671 with silver triflate/TMU 1:670,671 Halimeda incrassata 18:689 Halimedatuna 689 Halitunal antiviral activity of 16:302 from Halimeda tuna 16:302 Halityle regularis halityloside D and I from 15:61 gomophioside A from 15:61 halitylosides A,B,D,E,F,H,I from 7:297 Halityloside A, I ^om Halityle regularis 15:61 Halitylosides A,B,D,E.F,H,I, from Halityle regularis 7:297 from Nordoa gomophia 7:298 from Nor dona novaecaledonia 7:298 from Sphaerodiscus placenta 7:298 Hallerone 16:616 w-Halo-acids 8:239 (a-Haloalkyl) (alkyl) boronic ester 11:409

(a-Haloalkyl) boronic ester amino acids from 11:417-420 carbohydrates from 11:420-422 from alkenyl boronic esters 11:409,410 synthesis of 11:409,410 w-Haloalkylphenylthioacetate alkylationof 8:176 Haloamidation 14:568 Halobacterium sp. bacterioruberin from 7:355 Halocynthia roretzi halocynthiaxanthin from 6:152 mytiloxanthinone from 6:152 Halocynthiaxanthin 6:142,143,152 from Halocynthia roretzi 6:152 a-Haloester dioxoester from 11:117 Halofantrine 20:516 Haloform reaction in (-)-upial synthesis 6:66,67 Halogen-containing compounds chamigrenes 17:7 monoterpenes 17:9 sesquiterpenes 17:7 Halogenated analogues 12:398 Halogenated quinones anthraquinones from coupling of 4:331,332 Halogenation reaction diastereoselective 14:505,506 a-Halogeno ketones octant rule 2:168 1-Halogenobenzyl isoquinoline derivatives dibenz [d,fl azonine derivatives from 6:482 Halogene-nucleophile 19:438 Halohydrin formation 2-deoxy-1 -hydroxy sugars from 11:141 Halolactonizations ofcycloalkeneketals 1:627-629 a-Halomethylcycloheptanone synthesis of 8:35,36 a-Halomethyltetrahydroeucarvones 8:36 Halopuupehenones from Heteronema 6:23 synthesis of 6:23,24 Halton's synthesis oftaxusin 12:200-203 Halymenia porphyroides marine A^-acylsphingosine from 9:85,86,88 Halyminine 9:85,86,88 (+)-Hamatme 20:422-424 Hanessian reaction 1:511,512 Hanessian'sdeconjugation-epunerization of avermectin Bia derivatives 12:13 Hanessian's epimerization macrocyclization with 12:28 Hanessian's procedure from debenzylidenation 12:347 Hanessian's synthesis of avermeetin B ^ 12:12-15 Hanessian-Nicolau thioacetal Hannoa klaineana 18:726

1051

Hannokinin 17:360 Hannokinol 17:360 Hanphyllin 7:230 Hanseniaspora osmophila 5:283 Hansenula beijerinkii 5:287 Hansenula bimundalis var. americana 5:287 Hansenula capsulata 5:280,284,315 Hansenula ciferii 5:287 Hansenulafabianii 5:287 Hansenula minuta 5:315 Hansenula mrakii 5:287 Hansenula saturnus 5:287 Hansenula sp. 5:281,282,315 mannans from 5:282 Hansenula subpelliculosa 5:282 Hansenula wingei 5:282 Hansfordia pulvinata 'H,*^C-NMR of analogs 6:413-415 ofMurNAc 6:413-415 Hantzsch synthesis racemization during 4:86 (+)-Hapalindole Q 16:131 Hapalindoles from Hapalosiphonfontinalis 11:278 Hapalochlaena maculosa 18:724 Hapalosiphon fontinalis hapalindoles from 11:278 Haplophyllum dauricum 17:335 Harappamine 2:176,177 Hard acids/bases 3:409 Harmaline tautomerism of 5:190 Harman from Costaticella hastata 18:726 Harman 5:353 Harpagide 7:455,459,460-466,477 Haslinger and Michel synthesis oftaxodione 14:689-692 Hasnenula holstii 5:280,285,315 Hastanecine synthesis of 1:245,246,252,253 (+)-Hastanecine 12:472 Hastatoside 7:455 Hatanecine 3:54 Hatch-Slack metabolism 13:330 Hazuntine 9:193 Hazuntinine 5:124 Hazuntiphylline 5:129 HBsAg 20:533 HBsAg secretion 20:539 HBV infection 20:528-530 Heamanthidine from amaryllidaceae 4:3,4 pretazettine from 4:17 synthesis of 4:17-20 Heartworm 1:435 Heathcock's asymmetric aldol reaction 18:283 Hebesterol biosynthesis of 9:43 from Petrosia hebes 9:37 Heck arylation 19:274,19:277 Heck coupling 19:276

Heck reaction 16:367,391,400,412,416,418,427,429, 430,432,435,438,439,447;18:96;19:22,78,279,284 asymmetric 19:22 intramolecular 16:429,430,438,439 of olefin 19:279 palladium-catalyzed 19:78 Pd(0) catalyzed 16:439 silver modifaction of 16:429 with l-octen-3-one 16:391 Heck reaction conditions 19:227,279 Heck vinylation intramolecular 16:432 Hecubine 5:172 Hedamycin 11:136 Hedera helix 7:427,20:6 Hederagenin 7:134,135,429,431-433,9:61,62 molluscicidal activity of 7:432 a,p-Hederin 20:6 Heinsia crinata 151 Heinsiagenin A,B 10:151 Hela-S3 cells 19:557 Heldrichinic acid from Salvia napifolia 20:670 Helenalin 20:10 Helenanes antiinflammatory activity of 16:664 antileukemic activity of 16:664 cyctotoxic activity of 16:664 Helenanolide synthesis of 16:133 Helenanolide intermediate 4:674 Helenium amarum 20:10 Helenium microce 20:10 Helferich-type glycosylation 10:477 Heliathus annuus L. 19:247 Helicacus kanaloanus 15:383 Helichrysum nitens 5: 413 antifimgal flavonoids from 5:651 Helicity rules 2:164,165 Helicobacter pylori 13:183 Helicondria species petrosterol from 9:37 Heliconius pachinus macrolide from 8:222 Heliocidaris erythrogramma 17:95 Heliocide B biosynthesis of 4:618,619 Heliopsis buphthalmoides 17:319 Heliopsis helianthoide 5:728,334 hemoglobin components of 5:836-839 in bird species 5:836-839 Heliopsis longipes 7:427 Heliothis virescens 7:395 (+)-Heliotridane synthesis of 16:444 Heliotridane synthesis of 1:239,243,256,258,54 Heliotridine synthesis of 1:231,232,246 (+)-Heliotridine synthesis of 12:472-474

1052

Heliotrine synthesis of 1:267,268 Heliotropium strygosum 19:145 Heliotropium-ArtQn. 19:145 Helioxanthin synthesis of 17:334 Helix promatia 18:655;19:636 Helmchen's camphor 8:416 (+)-Helminthosporal synthesis of 16:265 Helminthosporal 8:162,163 Helminthosporin teres 2:434 Helminthosporium oryzae 9:237 Helminthosporium sativum 4:23,24 Helvetia gyomitra 9:203 Hemacytometer 9:232 Hemi-synthesis ofacetogenins 18:219-222 ofsolamin 18:219,220 ofreticulatacin 18:219,220 ofcorrossolone 18:220,221 of isodeacetyluvariein 18:221 ofgigantccin 18:221,222 Hemiacetal 7:465 Hemicellulose 7:195 Heminitidulan synthesis of 4:391,392 Hemisphere rule 2:165 Hemolysins 9:317 Hemophilus influenzae 13:162,177,181 (Z)-Heneicos-6-en-l 1-one sex pheromone of 19:124,126 Henricia laeviuscola henricioside from 15:48,55 Henricioside A from Henricia laeviuscola 15:48 Henry condensation 1:408,409 Henry reaction 19:120,165,173 pyperidine-cataly zed 19:165 HenrycineA 15:115,122,129,171,172 '^C-nmrof 15:129 from Rabdosiaflexicaulis 15:171 from Rabdosia henry i 15:172 ^H-nmrof 15:122 Henryin (reniformin A) '^C-nmrof 15:131 from Rabdosia henryi 15:172 from Rabdosia latifolia var. reniformis 15:172 ^H-nmrof 15:124 Heparanase activity in malignant cells 16:90 Hepaticae 9:249 Hepaticae (liverworts) 2:277 Hepatitis B surface antigen 20:537 Hepatitis B virus 20:227,20:528 Hepatoprotective activity 20:116 Hepatotoxic cyclic peptides of cyanobacterial origin 20:887-913 Hepatotoxins cyanobacterial 9:496-499 Hepoxilin 9:576 Hepoxilins (hydro-epoxides) 9:577 Heptaacetyl tunicaminyl uracil 1:420,421,572

Heptacyclic tropone 11:125 1 ,Z-8-Heptadecadiene 2:8 Heptanal 9:338,339 Heptanedioic acid derivative tetraoxoalkanedioates 11:117 Heptanolide from Baeyer-Villiger reaction 10:232 Heptaphylline 2:118,2:119 Heptenes 9:400 Heptitol 4:17 Heptitols 11:429 Heptobioses 4:205,206 Heptodialdopyranose derivative Wittig olefmation of 4:180,181 Heptose region of oligosacchardies synthesis of 4:195-216 Heptuloses 11:429 (+)-Herandulcin synthesis of 16:229 Herbacetin-3,8-dimethyl ether 5:624 Herbacetin-8-methyl ether 3-diglucoside 5:623 Herbasterol antimicrobial activity of 5:410 ichtyotoxic activity of 5:410 Herbicidal antibiotic 5:592,607 Herbicides 7:398,383,384,387 Herbimycin as an antitumor antibiotic 5:592 as herbicidal agent 5:592 from Streptomyces hygroscopicus 5:592 Herbolide A-F,H,I 7:230,233 Hercynolactone 5:729,730 Heritianin 7:185-187 Heritiera littoralis 7:176,177,180,181,185,187,190 Heritol 7:185,187 Heritonin 7:185,187 Hernandia cordigera 5:485,561 5'-methoxypodorhizol from 18:561 Hernandia ovigera 5:485 Hernandia ovigera L, hemandionfrom 18:600 isohemandion from 18:600 isohemandion from 18:600 desoxypicropodophyllin from 18:600 epiaschantin from 18:600 epimagnolin from 18:600 Hernandiapeltata 20:522 Hernandiaceae 18:558 Hemandin synthesis of 18:579-594 Hemandion 18:552,555 from Hernandia ovigera 18:552 65,1W-Hemandulcin 15:14 (+)-Hemandulcin 15:14-16 Hemiarm 18:974,976 Hemiarin 7:204,205,224 Hemiarm (7-methoxycoumarin) 9:113,114 Hemolactone 18:554,565,569,566 from Hernandia ovigera 18:569 Heroin 18:48 Herpes simplex 5:418 Herpes simplex type 12:366 Herpetomonas curzi 2:298

1053
Herpetomonas mmuscarum 2:298,301 Herpetomonas samuelpessoai 2:298 polysaccharides in 2:299-301 Hesperidinase 7:270 Hesperiphona vespertina hemoglobin components of 5:836 ofa-cedrene 5:790 ofartemisinin 5:25,26 of angelic acid 5:778 oftiglicacid 5:778 of 7-hydroxyfrullanolide 9:152 spectra of 8:151,152 Hetero Diels-Alder reaction addition of 16:654 approaches 16:456 asymmetric 11:260-267 diastereoselective 12:424,425 enantioselective 11:260-267 for nepetalactone synthesis 4:604,605 for tylophorine synthesis 4:604,605 gephyrotoxin 223AB by 4:606 gephyrotoxin by 4:606 iminodienophile in 4:604,605 intramolecular 6:449;14:757,758;19:43,223 intramolecular Lewis acid catalysed 1:553 lysergic acid by 4:604,605 monomorine I by 4:606 of2-methoxybutadiene 12:257 oxazoles in 4:604 pyran adduct from 12:257 reaction of 16:439 tetrazines in 4:604 triazines in 4:604 using nitroso dienophiles 1:378 with ethyl glyoxalate 12:257;13:69,490,625,177, 757,758,187 (3-amino acid by 12:158 Hetero-P-glucosidase 10:498 Hetero-Cope rearrangement 8:205 1 p-Heteroatom-substituted carbapenems synthesis of 12:165 Heterocyclic bicyclic substrate 17:497 Heterocyclic compound semi-synthesis of 17:614-622 N-Heterocyclic compounds 12:445 Heterocycloaddition 1:359-392 Heterodienophiles in D-allo-threonimal 4:143 in Diels-Alder reaction 4:563 Heterolytic dissociation 6:307,308 Heterolytic fragmentation 13:575 Heteromercuration of carbamates 1:382 Heteromorpha trifoliata 7:415 Heteronema halopuupehenones from 6:23 puupehenones from 6:23 Heteronuclear correlation spectroscopy 5:4,749 Heteronuclear Multiple Bond (HMBC) Connectivity spectra 9:147-153 ofgriffithine 9:149,150 Heteronuclear Multiple-Quantum Coherence (HMQC) 5:314 Heteronuclear shift correlated spectra 9:127,151 -154, 156-157 Heterophyllae coumarine-hemiterpene ethers in 7:205 Heteropolysaccharides 5:289,290,292,294 Heteropora alas kens is 17:90,92 Heterostilbene photocyclization 3:355 Heterotropa takaoi 17:348 Heterotrophic cell lines 7:205 Heteroxanthin 6:150 Hexaacetate 6:400 of2,2-dideoxy-2,2'-diphtalimido-p,P-trehalose 6:400 Hexabranchus sanguineus 17:16,19:609 Hexacarbonyldicobalt 12:175 3-Hexadecanoyl derivative for Epstein-Barr virus 12:234 m lymphoblastoid cells 12:234 ofingenol 12:234 Hexadecyltrimethylammonium hydroxide (CTAH) 18:832 6-Hexadecyn-l-ol CI(NO) spectrum 2:15 3,4,5,6,18,19-Hexadehydroochropposinine 1:124 (2,4)-2,4-Hexadienoic acid (sorbic acid) 10:149 Hexaenal acylation of 6:264-267 from A^-acetyl amphotericin B methyl 6:264-267 Hexaenoic acid 9:568 Hexaflouroacetylacetonate derivative 16:384 Hexafluoro-25-hydroxy-vitamin D2 derivatives 9:518 Hexaglycosides 7:272,278,281,288-290 Hexahydrobenzofiiran component ofavermectins 12:24 parsons approach for 12:24 (-)-Hexahydrocannabinol 19:215 Hexahydrocurcumin 17:363,368 (5)-Hexahydrocurcumin 17:365 Hexahydrodibenz [d,g] azecines 6:492,493 [1] benzothieno analogues of 6:492 from dibenzothieno analogues of 6:492 synthesis of 6:492,493 (5)-Hexahydromandelic acid 6:291,292 Hexahydronaphthalene portion of compactin 11:340343 Hexahydronaphthalene portion of mevinolin 11:3 43 345 Hexahydroporphinoids 9:603 Hexahydroporphyrins 9:605 Hexahydroproaporphines 2:255 Hexahydropyrrolocarbazole synthesis of 1:72 (+)-a-Hexahydrostepharine 2:256 (+)-P-Hexahydrostepharine 2:256 Hexahydroxydiphenic acid 15:33 3 P, 16P,21 P,22a,23,28-Hexahydroxyolean-12-ene 18:649 Hexalin alcohol asymmetric synthesis 13:601 Hexalone 15:241

1054

Hexamer cyclization reaction of 8:369,370 Hexamethyl phosphoric triamide 11:353 Hexamethyl phosphoric triamide (HMPA) 13:63 Hexamethylphosphoric acid (HMPA) 8:316,318-321, 324,326,330,331,333-336,341-343,346 Hexanortriterpenoid 9:102,297,298 HexanoylCoA 11:194 19'-Hexanoylfucoxanthin CD correlation of 6:137 distribution of 6:134,135 ozonolytic degradation of 6:137 19'-Hexanoyloxyfucoxanthin 6:142,143 19'-Hexanoyloxyisomytiloxanthin 6:142,143,151 19'-Hexanoylparacentrone 6:136 Hexapeptide cyclization of 10:289 Hexaphenylhydrazone 9:580,581 Hexapyranose nucleosides in synthesis of 4:6 deoxynucleosides 4:237 Hexasaccharides 7:31 trans-HGxenal synthesis of 6:282,284 Hexepi-uvaricin synthesis of 18:207-211 Hexitols 7:181 Hexodialdopyranoside derivative Wittig olefination of 4:171 Hexokinase 7:387 Hexopyranose derivatives 10:426-428 Hexopyranose nucleosides synthesis of 4:222-225 Hexopyranose-purines 4:224 Hexopyranosyl-pyrimidines 4:224 (5Z,9Z)-3-Hexyl-5-methylindolizidine synthesis of 6:450,451 Heynea trijuga 2:267 (+)-Heyneanine 5:127 (-)-Heyneanine 5:127 (-)-19S-Heyneanine 5:127 Heyneanine 9:171 Hg(H) mediated Ritter reaction 11:281,282 Hibiscones A-D 7:185,186 Hibiscoquinones A-D 7:185,186 Hibiscus rosa-chinensis 7:180,183,195 Hibiscus tiliaceus 7:185 Hiburipyranone 15:386 High dilution technique 11:153,154 High performance liquid chromatography (HPLC) 2:368,375,393,397,404;5:621,622,624,648-650;9:460464 High pressure technique [4+2] cycloaddition by 4:121 in Diels-Alder reaction 4:112 High-accumulating Imes 7:98-103 Higher plants 7:121-123 gene transfer in 7:121-123 Hikizimycin 1:398,410-417 Hikizimycin 11:430,449 Hikizimycin 9anthelmycin) 4:241,245 Hikosamine 11:449 Hilbert-Johnson reaction 1:399,400;4:223,224,230,239

Himerometra robustipinna 7:266 Himeyoshin 7:233 Himi-ketal formation 2:237,238 Hinckdentine A 17:88 Hincksinoflustra denticulata 17:85,88 (+)-Hinesol 16:239 Hinge-peptide 18:930-958 Hinokinin 18:566 Hinokiol 2:403 Hinokiol 2:403 Hinokitio synthesis of 1:340,341 Hippocasculin from A esculus hippocastanum 7:143 Hippocratea 18:741,754 Hippocratea indica 5:749 Hippocrateaceae 18:740 Hippocrepis balearica 19:117 Hippocrepis comosa 117 Hippodiplosia insculpta 17:90,92 Hippospongia metachromia 5:430 Hippospongia sp. 5:432 Hippospongin 3:157,158 Hippuricacid 9:387 Hiptagamadablota 19:117 Hirama synthesis biomimetic 12:16 of avermectin oxahydrindene subunit 12:15,16 Hirsutene synthesis of 3:7,12,13,17,18,20,22,40,65;4:588; 13:34-37 (+)-Hirsutene 4:588 Hirsuticacid 3:5,7,12,65 (+)-Hirsutine 13:67 Hispidulin 7:227;19:773 Hispidulin-7,4'-disulphate 5:655 Hispidulin-7-sulphate 5:655 Histamin 15:328 Histanecine isolation of 19:149 necinebase 19:149 Histone phosphorylation 7:387 Histoplasma capsulatum 5:307 Histoplasma duboisii 5:307 Histoplasmafarcinosum 5:307 Histoplasma sp. 5:325,328 Histoplasmosis 2:422 (-)-Histrionicotoxin 16:427,432,453,19,14,15-16 Histrionicotoxins 11:244;18:698,19:3,14-17 Hitachimycin 10:153 HIV (human inmiuno deficiency virus) 7:12 HIV whole cell assay 19:757 HIV-assay 19:757 Hiyama reagent 12:36 Hiyama-Ozaki reaction 3:99 HLADH 17:479,481 HLADH-catalyzed reactions 17:483 HMB (hydroxymethylbilane) 9:591,592,595 HMG-Co A reductase HMG-CoA reductase 5:407;7:108,109,111,112;15:450 HMPA 19:415-416 ejco-Hobartm-15-ol 11:299,300

1055

Hobartm-19-ol aristolasicol from 11:305 aristolasicolone from 11:305 aristolasicone from 11:305 aristotelinine from 11:305 oxidation of 11:309 serratenone from 11:305 sorelline from 11:305 synthesis of 11:309 (-)-Hobartine absolute configuration of 11:290 (+)-aristoteline from 11:292-295 biomimetic synthesis of 11:287-291 from Aristotelia serrata 11:278 from (-)-(3-pinene 11:281,282 synthesis of 11:280-283 Hobartine 9:178 Hobartine derivative 11:298,299 19-substituted 11:309,310 synthesis of 11:309,310 Hobartine-aristoteline transformation of 11:292-295 Hodgkin's disease 4:29 vinblastine for 14:805 vincristine for 14:805 Hof&nann's cycloaddition 18:257 Hof&nann degradation 18:51 Hoffmann rearrangement 1:410,411 Hofiftnann-like rearrangement 19:14 Hof&nann-Loeffler photocyclization 6:437 of A^-chloroamines 6:437 Hofmann degradation 6:480,4899:547,548;14:771-773, 793-795 Hofinann elimination 6:481,488;16:53 Hofinann reaction 14:868 Hofinann rearrangement 3:313 Holacanthone 5:38-41 Holacanthone 7:396 Hollocellulose 7:195 Holostane 17:118 Holostanol 7:267,268 Holothuria atra holothurin A from 7:269 holothurin B from 7:269 holothurin Bi from 7:269 Holothuria edulis holothurin A2 from 7:269 Holothuria floridana holothurm Ai from 7:269 holothurin A2 from 7:269 holothurin B, from 7:269 Holothuria grisea holothurin Ai from 7:269 Holothuria leucospilota 15:87 Holothuria leucospilota holothurin A from 7:268 holothurin B from 7:268 holothurm from 7:268 Holothuria lubrica holothurin A from 7:269 holothurm B from 7:269 Holothuria mexicana 7:281 Holothuria pervicax 15:92

Holothuria scabra 1:210 Holothuria squamiera holothurin A from 7:269 holothurin B from 7:269 Holothuria tubulosa 15:104;17:134 Holothuria vagabunda 7:267,268 Holothuriidae 7:268,280 Holothurin 7:267-282,303;15:87 Holothurin A from Holothuria atra 7:268 from Holothuria graeffei 7:269 from Holothuria leucospilota 7:268 from Holothuria lubrica 7:269 from Holothuria squamifera 7:269 LD50 of 7:280 Holothurin Ai from Holothuria floridane 7:269 from Holothuria grisea 7:269 Holothurin A2 from Bohadschia graeffei 7:269 from Holothuria edulis 7:269 from Holothuria floridana 7:269 Holothurin B from Holothuria atra 7:269 from Holothuria graeffei 7:269 from Holothuria leucospilota 7:268 from Holothuria lubrica 7:269 from Holothuria squamifera 7:269 Holothurin Bi from Holothuria atra 7:269 from Holothuria floridana 7:269 Holothurinogenin 7:267,268 Holothuroidea 7:265,267-282;15:43,87-94 Holotoxigenol 1:211,21S HolotoxinA 7:277-279 from Stichopus japonicus 7:277 HolotoxinA2 7:277-279 Holotoxin B from Stichopus japonicus 7:277-279 Holotoxin Bi 7:277-279 Holotoxin C 7:280 Holotoxins A, Ai, B and Bi from Parastichopus californicus 15:87 from Stichopus japonicus 15:87 Holton's taxol synthesis 12:220 Homarus americanus 19:668 Homo sapiens 18:705 Homoaldol reaction 8:156,157 Homoallylic alcohol from epoxide 11:346,347 with vinylmagnesium bromide 11:346,347 Homoallylic coupling 10:118 Homoarginine 9:499 25-Homobrassinolide 16:352,19:253,225 synthesis of 19:258 (+)-Homobuxaquamarme 2:179,2:180,205 (-)-Homocamphor 16:149 (+)-cw-Homocaronic acid 16:221 Homocarotenoids 7:317,318,355-364 25-Homocastasterone fromacetonide 16:337

1056

()-Homochelidonine 14:769,796 from berberine 14:796 synthesis of 14:796 Homochiral auxiliary 1:578 C2-Homochiral cyclopropenes 14:507,508 Homochiral diol auxiliaries 1:579-582 Homochiral ketone auxiliaries 1:579,583,584 Homochiral-3-ketosugar 11:435 Homoconjugated 0X0 compounds 2:170 Cotton effect of 2:170 helicityin 2:170 Homocoriolic acid 13:315 Homocylindrocarpidine 5:127 Homoditerpene 17:22 28-Homodolicholide 16:335 28-Homodolichosterone 16:335 Homoenolate ions from allylic esters 3:217 Homoeriodictyol 7:228 Homoerythrina alkaloids biosynthesis of 6:487 Homoerythrinan alkaloids synthesis of 3:480-486 Homogeranoitrile bromohydrin spirolaureone from 6:64 Homohalichondrins A 5:378,380,382 Homohalichondrins B 5:378,380,382 Homohalichondrins C 5:378,382 Homoisoflavan 5:17,18,20,23,24 Homoisopavine base system synthesis of 6:471 (/?)-(-)-Homolaudanosin Homologation 6:32;11:257,258,462-464;12:82;14:175 Homolycorine 20:325,347,353,468 25-Homolyphasterol 16:352 Homolytic dissociation 6:307,308 a-Homonojirimycin 10:544,545 from Omphalea diandra 10:544 Homonojirimycin 11:267 (+)-a-Homonoj irimycin synthesis of 11:431,432 ()-Homononactate 18:253 Homonuclear 2D J-resolved spectra 9:139,140 Homonuclear correlation spectroscopy (*H-^H COSY) 5:3 Homonuclear Hartmann-Hahn spectroscopy (HOHAHA) 9:146,149,151-153,158,159 ofgrififithine 9:149 Homophthalate Claisen condensation of 11:119 with acetoacetate dinion 11:119 Homophthalic acid amide 11:117 (/?)/(5)-Homoproline 13:507,508 synthesis of 13:507,508 Homopterocarpin 20:730,20:774 Homopumiliotoxins 19:52 Homoricinoleic acid 13:315 Homostatine derivatives 12:477 Homoteasterone from Raphanus sativus 18:507 Homothienamycin synthesis of 8:262

Homotriterpenes 9:267 Honyumine 13:348,349 Hoppe coupling 10:15 Horeau's method 5:146,149;9:25,26,28,402;12:313; 15:76,270,475;20:27 Horeau's partial resolution method 5:371 Horhammerinine 2:375 Horhammmericine 2:375 Horminone from Salvia acetobulosa 20:673 from Salvia candidissima 20:660 from Salvia multicaulis 20:673 from Salvia napifolia 20:670 from Salvia tomentosa 20:667 from Rabdosia lophanthoides var. gerardiana 15:173 Horminone-18-oic acid from Salvia divaricata 20:661 Hormodendrum sp. 5:325 Hormone-like substances 6:538 Hormones 18:819-866;19:627-687 bioactive conformations of 18:819-866 Homer Bestmann oxidation 8:207 Homer reaction 6:285,286 Homer-Emmons condensation 1:410,411;10:13-17,19; 11:432;14:129;16:655;18:288 Homer-Enmions coupling 14:115,123 Homer-Enmions olefmation 10:534,441,442,14:126, 16:460,490,18:288,633 Homer-Emmons reaction 1:448,450;5:828;8:16,209, 270,271;10:43;13:175,210,570;14:593;9:356;18:481,5 86;19:14,45,62;20:567,575,580,585,588,591,595,596, 599,606 Homer-Wadsworth-Emmons condensation 19:529 Homer-Wadsworth-Emmons olefmation 20:567 Homer-Wadsworth-Emmons reaction 12:30;20:72-74 Homer-Wittig olefmation 10:157,159,164,16:673 Homer-Wittig reaction 9:525,6:545,546,19:448 Homer-Wittig reagents 10:164-166,20:720 Homer-Wittig-type reagent 19:452 Horse radish peroxidase (HRP) 5:497,498;6:519; 14:820,821 ;15:366 Horsfieldia iryaghedhi 5:753 Horsfieldin 5:753,754 Hortensin 5:14,15 Hortia arborea 4:400 fiiranocoumarin from 4:398 Hortiolone from fiiranocoumarin 4:396,398 synthesis of 4:396,398 Hoslundal 2:129,2:135 Hoslundia opposita 2:129 Hoslundin 2:129,133,135 Hoslundiol 2:129,134,135 Host-guest complexes 13:328 Hot CNSL bat process 9:330,331 Houk's "inside crowded" model 12:57 Houk's "outside crowded" model 12:58 Houk's concept 11:240 House procedure 10:308,309 House's conditions 12:46,47 Hovenia dulcis 15:36

1057

Hoye's bromination 1:678 Hoye's procedure 6:56,57 HPLC anion exchange 4:283 for oligonucleotide purification 4:283 ofdiastereomers 13:280-282 of tryptic peptides 2:34 reversed phase 4:283 (5Z,8^-3-Hptyl-5-methylpyrrolizidine 6:445,446 from 3-(5-methyl-2-fuiyl) propional-dehyde 6:445,446 HSV-2-Virus antiviral activity against 4:237 by guanosine analog 4:237 Huang-Minion modification 14:684 Huang-Minion reduction 14:674,676,677 Htickel MO method 18:981 Hudson lactone rule 10:262 Huisgen pyrrole synthesis 13:445 Co-3-Human colon carcinoma 19:289 Human growth hormone 4:271 Human I g d Hinge-fi-agment 18:907-958 Human immunodeficiency virus (HIV) 7:12,396 Human leukemia cells 18:269 Human leukocyte elastase inhibitor of 16:727 Human nasopharyngeal KB staurosporine activity against 12:390 Human neuroblastoma NB-1 cells cytotoxic against staurosporine 12:390 Human neuroblastoma nbla-N-5 cells tamoxifen activity against 12:390 Human neuroblastoma SH-SY-5Y cells 12:390 Human neutrophils 12:390 Human neutropil protein kinase C 12:389 Human onchocerciasis ivermectin for 12:9 Human platelets study of protein kinase C in 12:390 by staurosporine 12:390 Human xenografted carcinomas 19:330 Humantenine fi-om Gelsemium elegans 15:472 Humantenine-type oxindole alkaloids 15:472-474 Humantenirine 15:472 Humantenirine (11 -methoxy-rankinidine) 9:196,197 Humicola spp. 2:323 Humulene 3:77,78,6:37,48,13:6 (+)-afi"icanol fi"om 6:37 (+)-A^^'^^-capnellene from 6:48 Humulus hupulus P-famesene fi-om 7:121 eudesm-1 l-en-4-ols from 14:450 (-)-selin-l l-en-4a-ol from 14:450 Hunig's base 6:549,550,10:20,12:333,16:489 Hunsdiecker reaction 10:605 Hunteria indole alkaloids 13:70,93 ()-Huperzine A 18:321,324 Hura crepitans 20:19 Huratoxin 20:19 Hyalbidone 17:400

Hyalodendronpyrium 5:305 Hyalodendron sp. 5:305 Hyalophora oecropia 1:206 Hyattella 19:568 Hybrimycins 5:615 Hyderabadine 5:124,158 Hydnocarpin 5:496 Hydnocarpus wightiana 5:496 Hydr actinia echinata 18:701 Hydrangea macrophylla phyllodulcin from 13:660 Hydrangea macrophylla 15:5,30,387 phylloduclin fi-om 15:30 Hydrangenol 2:288,289,387 Hydrangenol glucoside 2:288,289 a-Hydrastine synthesis of 1:191,192 P-Hydrastine synthesis of 1:191,192 P-Hydrastine A'-oxide 1,2-H shift in 6:468 thermally-induced rearrangement of 6:468 Hydration mercury catalysed 4:332 of acetylenes 4:332 Hydrato-pyrrhoxanthinol 6:151,152 Hydrazine reduction with 1:20 Hydrazone 18:67 1,4-Hydride reduction 12:154 Hydride reduction 14:153,19:372 of sulfonates 14:153 [1,2]-Hydride shift 10:216,222,19:518 Hydride shift 9:45,46 2,6-Hydride shifts 4:626,627,634,643 in camphor derivative 4:634,643 in rearrangement of camphor 4:626,627 Hydride transfer 17:486-487 6,2-Hydride-shift 4:650,651 /ram-Hydrindane synthesis of 10:51 /ra5-Hydrindane 13:24 /ra/w-Hydrindane system 14:552 cw-Hydrindane system 9:526 Hydrindanol 10:55,56 Hydrindanone 9:249-252,10:51,56 in (+)-9-isocyanopupukenanane 6:80 Hydroalanation 10:21,24,29 Hydroangea macrophylla 2:286 cw-Hydroazulene fi-om tropone 12:251 Hydroazulene mesylates 14:376-379 Hydroazulene sesquiterpenes 14:355-387 Hydroazulene skeleton synthesis of 1:553 Hydroazulenes 10:181 Hydroboration 8:470-473,475,478;10:15;ll:83,84;316, 317,319;14:456,681,682;16:472;19:367 highly stereselective 12:151,152 of allylic ethers 4:116 of olefin 12:151,152 of vinylic ethers 4:116

1058

regioselectivity 4:116 stereoselective 19:367 to alcohol 12:151,152 Hydroboration-oxidation 14:773,774 Hydrochalcones 7:192 Hydrocortisone a-acetate 9:17,416 Hydrocortisone 9:411,418-423,428,429 Hydrodictyon reticulatu 19:247 Hydrodictyon reticulatum 18:495,507 Hydrodicyclopenta [a,d] cyclooctane 1:563-565 Hydroformylation 16:409 Hydrogen abstraction 16:41 Hydrogen bonding 17:562 Hydrogen peroxide oxidation 14:324,325 Hydrogen phosphonate method of oligonucleotide synthesis 4:274-276 mechanism of 4:275 1,5-Hydrogen shift 1:327 Hydrogenase activity 20:836 Hydrogenation 2,2>-anti selective 12:35,36 heterogenous 12:36 homogenous 12:35,36 of double bond 19:45,19:307 of ketones 19:27 of methyl acetoacetate 13:72,73 ofpyranone 19:468 ofp-ketoester 19:29 on naphthalene-Cr (C0)3 comples 4:343,344 stereoselective 12:151,152;19:296,19:301 using Adam's catalyst 19:70 A'-Hydrogenase activity 9:420 stereoselective 16:345 of azide group 16:78 Hydrogenocobyrinic acid 9:601 Hydrogenolysis 6:276,426,435,451,168,169,19:6,36,38, 42,104,332,362,367-368,371 Hydrogenomonas eutropha 4:439 Hydroindane (bicyclo [4.3.0] nonane) 11:230 c w-Hydroindanone 19:10 Hydroindolenones from a'-bromocyclohexenones 4:17-19 Hydrolase 5:617,618,13:195,235,17:480 Hydrolysis asymmetric 1:678,679,682 by Candida cylindracea lipase 1:685 by lipases 1:684,685 by pig liver esterase 1:685 by pig pancreatic lipase 1:685 by Pseudomonas fluorescens lipase 1:685 of N-acetyl a-amino acids 1:678,679,684,685 acid-catalyzed 11:361 enantioselective 13:54 photochemical 6:331,333 selective 6:285,286 Hydrolytic cleavage 12:428-430 Hydrolytic fragmentation 12:198 Hydronaphthalene tosylates 14:368-370 Hydronaphthalene-l,10-diol monosulfonate esters Pinacol rearrangement of 14:356 /^-Hydroperoxide 9:574

Hydroperoxide 17:9 Hydroperoxidase activity 20:514 Hydroperoxide dehydrase 9:526,577 Hydroperoxide isomerases 9:577,578 Hydroperoxide lyase 9:577;13:11 Hydroperoxide oxidation 4:559 Hydroperoxides photodecomposition of 16:608 Hydroperoxides cyctotoxic activity of 5:409 reduction with 5:408,409 9/13 -Hydroperoxo-y-linolenic acids 9:582 24-Hydroperoxy-24-vinyl-cholesterol(saringosterol) 10:249 25-Hydroperoxy-2a,3 P, 12p,20S-tetrahydroxydammar23-ene 18:650 5-Hydroperoxy-6,8,l 1,14-eicosatetraenoic acid (5-HPETE), 5:513,514 135-Hydroperoxy-9Z,l l-octadecadienoate 9:563,565 13 /?-Hydroperoxy-9Z, 12-octadecadienoate 9:566 55'-Hydroperoxy-icsatetraenoic acid 9:562 Hydroprene 10:149 Hydroquinone 5:439,440;9:579 Hydroxamates 9:537,580 (5)-Hydroxamic acid 19:11 Hydroxamic acid 1:296;9:549 Ent-17-Hydroxyabieta-8( 14), 13( 15)-dien-16-al 9:83,284 Ent-11 a-Hydroxyabieta-8( 14),3( 15)-dien-16,12-olide 9:283,284-290 Ent-12p-Hydroxymethyl-3-oxo-16-norpimar-8( 14)-ene15,21-carbolactone 9:283,284 Ent-13 [5]-Hydroxy-14-oxo-3,4-seco-atis-16-en-3,4olide 9:268,269,276 Ent-13 [5]-Hydroxy-4,5-oxy-4,5-oxy-4,5-seco-atis-16ene-3,14-dione 9:268,269,276 M3[5]-Hydroxyatis-16-ene-3,14-dione 9:268-276, 9:279,280,286,290 Ent-16-Hydroxy-13 [/?]-pimar-8( 14)-ene-3,15-dione 9:283-287,290 Ent-18-Hydroxyatis-16-ene-3,14-dione 9:268,269,279 r-7a-Hydroxydiplophyllolide 2:278,279 (4S)-Hydroxmethylbutanolide from Z-glutamic acid 6:292 from D-ribonolactone 6:292 from D-ribonolactone 6:292 13-Hydroxy 3a, 11 -epoxy-apotrichothec-9-ene 9:210 a-Hydroxy acids 1:446,447 as chiral building blocks 1:680,681 3-Hydroxy acids as chu-al synthons 4:625 w-Hydroxy acids 8:176,233,234,236 cyclization of 8:234 intramolecular esterification of 8:176 lactonization of 8:233,234,236 Hydroxy amino acids synthesis of 12:431-438 A^-Hydroxy compounds 8:376 (R)-2-Hydroxy carboxylates dehydrogenation of 20:840-842

1059

to 2-oxo-carboxylates 20:840-842,853 preparation of 20:842 Hydroxy dithioketal 10:203,204 Hydroxy epoxides 10:205-207 cw-Hydroxy epoxides 10:207 ^a5-Hydroxy epoxide cyclization of 10:205,206 P-Hydroxy ester from (a-bromoalkyl) boronic ester 11:425 synthesis of 11:425 p-Hydroxy esters as chiral building blocks 1:689-701 2-(l-Hydroxy ethyl)-naptho [2,3-b] furan-4,9-dione 20:494 14-Hydroxy ferruginol from Salvia montbretii 20:666 2-Hydroxy glycal 10:349 P-Hydroxy ketones 1:701-707 Hydroxy ketones syn selectivity of 10:205 P-Hydroxy lactone 12:29,30 10-Hydroxy liriodenine 20:483 2-Hydroxy muconate 10:152 4-Hydroxy A^-(3,7-octaienly) oxazolidin-2-one 12:468 10-Hydroxy octadec-(8E)-enoic acid 13:313 13-Hydroxy octadeca-(9Z,l l)-dienoic acid 13:311 11-Hydroxy palmitic acid 13:312 Hydroxy pyrrolidinone carboxylate 8:269 7p-Hydroxy sandracopimaric acid from Salvia heldrichiana 20:690 25-Hydroxy vitamin D2 10:63,65,66,68,69 synthesis of 10:69 25E, 26-Hydroxy vitamin D2 10:65 (24/?)-la-Hydroxy vitamin D2 10:66 la-Hydroxy vitamin D3 10:43,59,69 synthesis of 10:59,69 25-Hydroxy vitamin D3 10:67 14p-Hydroxywithanone 20:180,20:242 4-Hydroxywithanolide E 20:223 4p-Hydroxy withanolide E 20:214,245 np-HydroxywithanolideK 20:246 16a-Hydroxy-(-)-kauronoic acid 9:397 205-Hydroxy-1,2-dehydropseudoaspidospermidine 5:126 205-Hydroxy-1,2-dehydropseudoaspidospermidine 9:195 4-Hydroxy-l,2-dithiolane 7:193,194 5-Hydroxy-l,4-naphthoquinone 14:49 Hydroxy-1 -arylthiobutenes cycloaddition with 4:477,478 11 -Hydroxy-1 -methoxycanthm-6-one 7:389,390 1 -Hydroxy-1 -methylindolizidines 12:282 4-Hydroxy-1 -0x0-1,2,3,4-tetrahydronaphthalene 11:118 I -Hydroxy-1 -phenylindolizidines 12:282 4-(3-Hydroxy-1 -propenyl) derivatives Johnson-Claisen rearrangement 10:436-438 II -Hydroxy-10-methoxynoracronycine from Citrus decumna 13:348,349

{Zytrans-1 -Hydroxy-10-vinyl-2-cyclodecene synthesis of 8:196 (E)-trans-1 -Hydroxy-10-vmyl-2-cyclodecene synthesis of 8:196 1-Hydroxy-l l-methoxycanthin-6-one 7:389,390 12-Hydroxy-11 -methoxydiaboline 9:189 10-Hydroxy-11 -methoxydracaenone 5:17-20 12-Hydroxy-11 -methoxyhenningsamine 9:27 19-Hydroxy-l 1-methoxytabersonine 2:375 10-Hydroxy-11 -methoxytabersonine 5:128 6-Hydroxy-12-tridecene 9:241,243 Hydroxy-15P-aristoline 9:172 16 (5)-Hydroxy-16,17-dihydroapparicine 6:505,506 1 SS-Hydroxy-16,22-dihydroapparicine 5:124 165-Hydroxy-16,22-dihydroapparicine 9:171,172 3/2/5-Hydroxy-16-decarbomethoxyconodurine 5:125 10-Hych-oxy-16-ep/-affinine 5:124 19(5)-Hydroxy-18,19-dihydrokoumme from Gelsemium elegans 15:476 X-ray analysis of 15:477 19(/?)-Hydroxy-18,19-dihydrokoumine 15:476,477 18-Hydroxy-19(Z)-anhydrovobasinediol 15:500 13-Hydroxy-2,15-diacetoxy-11 -ep/-apotrichothec-9ene 9:210 23-Hydroxy-2,16-dehydroretuline 9:186 (4/?,6/?)-4-Hydroxy-2,2,6-trimethylcyclohexanone 6:143,144,158 synthesis of 6:158 6-Hydroxy-2,2-dimethyl chromene 10:248 (4iS)-4-Hydroxy-2,6,6-trimethyl-2-cyclohexen-1 -one 6:159 synthesis of 6:159 4-Hydroxy-2-cyclopentenone acetal from meso-3,4-epoxycyclopentanone 14:510 (+)-1 -Hydroxy-2-e/?/-pmoresmol 5:538 (35)-3-Hydroxy-2-ethyl-butyronitriles 13:59 3-Hydroxy-2-hydroxymethyl pyrrolidine hydrochloride 14:570 from pyrrolidine derivative 14:570 3-Hydroxy-2-hydroxymethyl-6-substituted piperidines 12:474 (/?)-3-Hydroxy-2-methylpropionate 6:292,293 (5)-5-Hydroxy-2-penten-4-olide 14:273,274 from levoglucosenone 14:273,274 23-Hydroxy-2,16-dehydroretuline 1:38,39 (5)-2-Hydroxy-2,2-dimethylcyclohexanone 3 P-Hydroxy-20 -methoxy-3 0-norolean-12-en-28-oic acid 7:139,140 (15R)-15'-Hydroxy-20'-deoxyvinblastine acetyl derivative of 14:814,815 from 20'deoxy-15'-oxovinblastine 14:814,815 19/?-Hydroxy-20-e/7/-ibophyllidme 5:127 195-Hydroxy-20-ep/-ibophyllidine 5:127 18-Hydroxy-20-ep/-ibophyllidine 9:190 19/?-Hydroxy-20-ep/-ibophyllidine 9:190 195-Hydroxy-20-ep/-ibophyllidine 9:190,192 (+)-19Hydroxy-20-e/?/-pandolme 5:124 19-Hydroxy-20-epipandoline 9:190 25-Hydroxy-24-epicastasterone 18:529 26-Hydroxy-24-epicastasterone 18:529 la-Hydroxy-25-oxa-25-phospha-vitamin D3 9:520

1060

15'-Hydroxy-3 '-oxoleurosidine from anhydrovinblastine N-oxide 14:812,813 13-Hydroxy-3,ll-epoxyAPO 13:522 (20R)-Hydroxy-3,24-diepibrassinolide 18:531 25-Hydroxy-3,24-diepibrassinolide 18:532 (20R)-Hydroxy-3,24-diepicastasteron 18:531,539,542 8-Hydroxy-3,4-dihydroisocoiimarin 15:3 84 7-Hydroxy-3,4-epoxy-laurane (laurol) 9:193,194,199 6-Hydroxy-3,5,9,1 l-tetraoxododecanedioate from a-hydroxyglutarate 11:118 7-Hydroxy-3 -(3 -hydroxy-4-methoxybenzyl) chromane 5:20-22 19'5-Hydroxy-3-e/7/-ervafolidine 5:129 2-Hydroxy-3-methoxyxanthone 5:759 (-)-8-Hydroxy-3 -methyl-3,4-dihydroisocumarin 15:3 83 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase 11:335 7-Hydroxy-3 -oxoindolizidine synthesis of 12:287,288 17-Hydroxy-3 -oxotabersonine reaction with nitrogen nucleophiles 4:58,59 reaction with sulfiir nucleophiles 4:58,59 N-2-Hydroxy-3 -trans-octadecenoyl-1 -O-D-glucosy 1-9methyl-cis-4,8-sphingadienine 18:807 8-Hydroxy-3-undecyl-3,4-dihydroisocoumarin 15:386 3 P-Hydroxy-30-nor-olean-12,20(29)-dien-28-oic-acid 9:51 3-Hydroxy-30-norolean-12,19-dien-28-oicacid 7:139,140 6'-Hydroxy-4'-methoxyavarone 15:301 3P-Hydroxy-4,4,14-trimethylpregna-9(l 1), 16-diene20-one 7:279 3-Hydroxy-4-alkoxy substitution 15:30 ()-5-Hydroxy-4-oxonorvaline()HON 13:512,513 5-Hydroxy-4-oxyindolizidines 12:284 3-Hydroxy-4-pentenyl amines stereoselective cyclization of 14:568 to pyrrolidines 14:568 6-Hydroxy-4a-aryl-cw-decahydroisoquinolines 12:458, 459 synthesis of 12:458,459 6-Hydroxy-4a-aryl-^ra5-decahydroisoquinolines 12:457 6-Hydroxy-4a-phenyldecahydro 12:457 from 6-hydroxy-4a-aryl-/ra5-decahydroisoquinoline 12:457 6'-Hydroxy-5'-acetyl-avarol 15:301 6-Hydroxy-5-methylmellein 9:288,289 5-Hydroxy-5-vinyl-2-cyclopenten-1 -ones 14:625 5-Hydroxy-6,7,3',4',5'-pentamethoxyflavone 5:756,757 5-Hydroxy-6,7,4-trimethoxyflavone 5:653 5-Hydroxy-6,7,8,4'-tetramethoxyflavone 5:653 5-Hydroxy-6,7,8-trimethoxyflavone 5:652 5-Hydroxy-6,7-dimethoxyflavone 5:652 2-Hydroxy-6-(2-oxoheptyl) benzoic acid 9:328 2-Hydroxy-6-[(Z)-heptadec-8-enyl] benzoic acid 9:316 4p-Hydroxy-6-deoxy-6-deoxy-celorbicol 18:743 (+)-l-Hydroxy-6-e/7/-pmoresinol 5:538,540,541 7-Hydroxy-6-methoxycoumarin 9:288,289 2-Hydroxy-6-methylbenzoic acid 9:341,347,350 5-Hydroxy-6-oxo-coronaridine 5:127

2-Hydroxy-6-pentadecylbenzoic acid (15:0-anacardic acid) 9:336,345,346,372 2-Hydroxy-6-tetradecylbenzoic acid 9:317 2-Hydroxy-6-undecylbenzoic acid (anagigantic acid) 9:316 5-Hydroxy-7,8-dimethoxyflavone 5:640 l-Hydroxy-7-methoxyxanthone 5:759 7-Hydroxy-7-methyl-5-oxoindolizidine configuration of 12:289 synthesis of 12:289 7-Hydroxy-7-phenylindolizidines 12:286 8a-Hydroxy-7a(H)-eremophila-1,11 -diene-9-one 15:242 6-Hydroxy-8-methoxyflavonoid 5:640 T-Hydroxy-a,p- unsaturated aldehydes 7:459,460 4P-Hydroxy-alatol 18:747 ()-16-Hydroxy-a//o-ibogamine biogenesis of 6:503 15-Hydroxy-angustilobien A 9:171 a-Hydroxy-P-amino acid synthesis of 12:493 (/?)-a-Hydroxy-P-phenyl propionate (3RAS) statine from 12:479 25-Hydroxy-celapanol 18:744 4P-Hydroxy-celapanol 18:744 4p-Hydroxy-celorbicol 18:743 (-)-(/rfl[5-4'-Hydroxy-cinnamoyl)lupinine from Luplnus luteus 15:521 21a-Hydroxy-D:A-friedo-olean-3-one 7:147,148 4S-Hydroxy-dendrolasin 15:233 Hydroxy-du-ected epoxidation of trifluoracetate salt of 12:300 Hydroxy-epoxides (hepoxilins) 9:577 5-Hydroxy-ferulic acid 5:469,470 a-Hydroxy-isovaleric acid 13:533 (25',3i?)-P-Hydroxy-L-glutamic acid synthesis of 12:431,432 4-Hydroxy-L-proline 13:445 /ra/M-4-Hydroxy-L-proline 13:485 3'-/^5'-Hydroxy-N4-demethylervahanine 5:125 3 '-/^^5'-Hydroxy-N4-demethyItabemamine 5:124 16-Hydroxy-Nb-demethylalstophylline oxindole 9:196, 197 Hydroxy-octadecandienoates 9:566 10-Hydroxy-/7-methoxybenzoate 5:725,726 6p-Hydroxy-pentahydroxy-agarofurano 18:746 1 a-Hydroxy-vitamin D 10:45,49 1 a-Hydroxy-vitamin D3 9:518,519 15-Hydroxy-Z-5,Z-8, Z-11,-13- eicosatetraenic acid methyl ester 2:12 1 -Hydroxyacridin-9-one (A^-methylnoracridin)-9-one 13:348,362,363 11-Hydroxyacronycine 13:357,358,366,367 P-Hydroxyacteoside 5:506,509,511,513,514 2-Hydroxyaklavinone 11:120 12-Hydroxyakuammicine 5:123 12-Hydroxyakuammicine 9:193 a-Hydroxyaldehyde derivatives synthesis of 6:316,317

1061

a-Hydroxyaldehydes synthesis of 6:336,337 P-Hydroxyalkyl selenides from cyclohexanone 2,2,6,6-tetramethyl 8:4 from deoxybenzoine 8:4 2,2,6-trimethyl cyclohexanone 8:4 l-(a-Hydroxyalkyl) isoquinolines 12:449 2-(a-Hydroxyalkyl) piperidines diastereoselective synthesis of 12:453 synthesis of 12:453-456 2-(a-Hydroxyalkyl) pyrroUdines synthesis of 12:473 1 -(a-Hydroxyaikyl)-1,2,3,4-tetrahydroisoquinolines 12:448 1 -(a-Hydroxyalkyl)-1,2,3,4-tetrahydroisoquinolines chiral synthesis of 12:450 a-(a'-Hydroxyalkyl)-N- heterocycles 12:447 5-Hydroxyalkylbutan-4-olides synthesis of 3:160-161 Hydroxyamide 8:231,234 8-Hydroxyanamycins B,0,S,W 9:443 18-Hydroxyanhydrovobasinediol 15:503 9-Hydroxyanthracene from homophthalate 11:119 synthesis of 11:119 4-Hydroxy aporphines 16:510 synthesis of 16:510 2a-Hydroxyartemorin from Artemisia hispanica 7:211 4'-and 5'-Hydroxyasperentin 15:386 6'-Hydroxyavarol 15:301 3 '-Hydroxy avarone 15:301 1 -P-Hydroxybaccatin 111:5 w-Hydroxybenzaldehyde 10:121,125 (+)-5-exo-Hydroxybomeol 4:647,648 (-)-3-ejco-Hydroxybomeol 4:647,648 (-)-5-efi?o-Hydroxybomeol 4:647,648 (-)-6-exo-Hydroxybomeol 4:647,648 (+)-5-ertafo-Hydroxybomeol 4:648 (3/?)-3-Hydroxybutanethioate boron enolate of 13:500 (i?)-3-Hydroxybutanoic acid acetals diasteroselective allylation of 1:610 P-Hydroxybutanoic acid ester 10:410 3-(4-Hydroxybutyl)-5-propylindolizidine absolute stereochemistry of 11:253 biological activity of 11:253 synthesis of 11:253-256 (/?)-3-Hydroxybutyrate 12:154 RK-286C (4-hydroxy-4-demethyl aminostaurosporine) from Streptomyces sp. RK-288 12:366,367 protein kinase C inhibitor of 12:386 (5)-3-Hydroxybutyrate 6:300,301 as chiral precursor 6:300,301 3 -Hydroxybutyrates a//-products formation 4:439 in thienamycin synthesis 4:431 p-lactam formation 4:446 lithio dianions of 4: 441

3-Hydroxybutyric acid 4:431,438,440,465,471,479,480 acid chlorides of 4:471 in thienamicin synthesis of 4:438-440 efi?o-3-Hydroxycamphor 4:660 ex:o-3-Hydroxycamphor 4:660 I l-Hydroxycanthin-6-one 11-bromobenzoateof 7:389,390 lO-Hydroxycanthine-6-one 7:393 a-Hydroxycarboxylic acid derivatives of 8:140 (15/?)-15'-Hydroxy catharinine biosynthesis of 14:820,821 from anhydrovinblastine 14:813,814 fromleurosine 14:813,814 2-Hydroxychrysophanol 9:400,401 25-Hydroxycolecalciferol 9:521 ip-Hydroxycolecalciferol (alfacalcidol) 9:521 5-Hydroxyconiferaldehyde 5:470 3-/2/5'-Hydroxyconoduramine 5:125 3/?-Hydroxyconopharyngine 9:174 19/?-Hydroxyconopharyngine 5:128 195'-Hydroxyconopharyngine 5:128 3-i?/5-Hydroxyconopharyngine 5:128 3-/?-Hydroxyconopharyngme-hydroxyindolenine 5:128 3iS'-Hydroxyconopharyngine-hydroxyindolenine 9:195 19-Hydroxycoronaridine 5:126 3-/?/5-Hydroxycoronaridine 5:126 10-Hydroxycoronaridine 5:127 II -Hydroxycoronaridine 5:127 3/?-Hydroxycoronaridine 9:171 10-Hydroxycoronaridine 9:174 11 -Hydroxycoronaridine 9:174,176,177 10-Hydroxycorynanthediol synthesis of 14:709,710 7-Hydroxycoumarin (umbelliferone) 9:114 (+)-4-Hydroxycrebanine synthesis of 16:510 12-Hydroxyculmorins 13:536 15-Hydroxyculmorins 13:536 5 -Hydroxy culmorins from Fusarium culmorum 13:536 15-Hydroxyculmorons 13:536 3p-Hydroxycycloar-25-en-24-one 9:288,289 21-Hydroxycyclolochnerine 13:389 R, 5'-4-Hydroxycyclopentenones absolute configuration 6:315 asymmetric synthesis 6:315 from A^-tataric acid 6:315 20(S)-Hydroxydamaran-3p-yl acetate oxidation with/w-CPBA 2:91,92 20(5)-Hydroxydammaran-3-oen 2:94 10-Hydroxydeacetylakuammiline 9:195 4-Hydroxydecanoic acid 13:308,315 Hydroxydictyodial 5:370 20-Hydroxydihydrocatharanthinic acid lactone 14:815,816 6-Hydroxydihydrochelerythrine 14:773-775 ()-16-Hydroxydihydrocleavamine synthesis of 14:850-853 16-Hydroxydihydrocleavamine coupling with vindoline 4:29

1062

16-Hyclroxydihydrocleavamine synthesis of 5:183,184 Hydroxydihydroeremophilone 15:239,241 19(5)-Hydroxydihydrogelsemine from Gelsemium elegans 15:479 from Gelsemium rankinii 15:479 19(/?)-Hydroxydihydrogelsemine 15:481 from Gelsemium rankinii 15:481 from Gelsemium sempervirens 15:481 19(/?)-Hydroxydihydrogelsevirine from Gelsemium elegans 15:479 19(5)-Hydroxydihydrogelsevirine 15:479 19(5)-Hydroxydihydrokoumine 15:475 (-)-(10/?)-Hydroxydihydroquinine synthesis of 14:464,465 20-Hydroxydihydrorankinidine X-ray analysis of 15:472,473 10-HydroxyelHpticine anticancer activity of 6:507 from Strychnos dinklagei 6:509 spectral data of 6:518 17-Hydroxyellipticine 6:513-515 from Strychnos dinklagei 6:515 spectral data of 6:515,519 18-Hydroxyellipticine 6:515,516,519 g/o-2-Hydroxyepicamphor 4:660 8a-Hydroxyeremophilone 15:242 19'-Hydroxyervafolen 5:129 1,3,5-^w-(2-Hydroxyethyl) cyanuric acid 12:411,415 2-oxazolidinone from 12:411,415 2-(r-Hydroxyethyl) propenoates 4:479 nuceophilic conjugate addition to 4:479 24-(P-Hydroxyethyl)-and 24-(carboxymethyl) steroids absolute configuration of 15:79-81 (S)-l-(l '-Hydroxyethyl)-/3^carboline 18:726 3-(P-Hydroxyethyl)-coronaridine 9:171 3S-3P-Hydroxyethylcoronaridine 5:126 5-Hydroxyethylmellein 9:288,289 (N-2-Hydroxyethylpiperazine-N'-2-ethane-sulfonic acid) buffer 15:443 Hydroxyferuloyl-CoA 5:470 7-Hydroxyflavanone 4:378,380 3-Hydroxyflavanones 7:192 2'-Hydroxyflavone 5:12-14 5-Hydroxyflavones 5:630 2'-Hydroxyflavonoids 5:640 2'-Hydroxyflavonol-3-methyl ethers 5:640 21 a-Hydroxyfriedela-3-one 5:744,746 7-Hydroxyfrullanolide 9:143-145 fromSpharanthus indicus 9:143 Hydroxygaleon 17:371 18-Hydroxygardnutine 15:502 10-Hydroxygeissoschizol 5:126 10-Hydroxygeissoschizol diacetate 9:174 14-Hydroxygelsedine from Gelsemium elegans 15:482 from Gelsemium sempervirens 15:482 14p-Hydroxygelsedine 9:196 14-Hydroxygelsemicine 15:481 from Gelsemium sempervirens 15:482 14-Hydroxygelsemicine 9:196,197

14-Hydroxygelsenicine 15:481,482 from Gelsemium elegans 15:482 13-Hydroxygibberellms 6:181 preparation of 6:181 12- Hydroxygibberellins 6:190-194 preparation of 6:190-194 (+)-7a-Hydroxyglaucines 16:504 (+)-7p-Hydroxyglaucines 16:504 (+)-7P-Hydroxyglaucines 16:504 (2/?,3/?)-3-Hydroxyglutamic acid synthesis of 12:477 P-Hydroxyglutarate 11:127 naphthalenediol from 11:127 3-Hydroxyglycals 3:228 3-Hydroxyguaiazulene 14:321,324 4p-Hydroxyhemandulcin 15:15 (/?)-2-Hydroxyhexadecanoic acid 1:681 5-Hydroxyhexadecanoic acid synthesis of 1:683,684 2'-Hydroxyhexadecanoyl-1 -O-P-D-glucopyranosyl-9methyl-4,8-D-erytho-sphingadienine 18:814 10-Hydroxyheyeanine 9:174-176 10-Hydroxyheyneanine 5:127 11 -Hydroxyheyneanine 5:127 (+)-20-Hydroxyhobartine (+)-aristocarbinol from 11:323 (+)-aristolasene from 11:323 aristolarine from 11:323 sorellinefrom 11:323 3P-Hydroxyholosta-7,25-dien-16-one 7:275,279 3P-Hydroxyholosta-9(l l),25-dien-16-one 7:277,278 15-Hydroxyhumantenine 15:472,473 7p-Hydroxyhyoscyamine 17:397-399 6P-Hydroxyhyoscyamine 17:398-399 19R-19-Hydroxyibogamme 5:126 19/?-Hydroxyibogamine pseudoindoxyl 5:123 19/?-Hydroxyibophyllidine 5:127 19-Hydroxyibophyllidine 9:190,192 ()-cw-1 -Hydroxyindolizidme synthesis of 12:279,280 1 -Hydroxyindolizidine diastereomers of 12:278,279 (+)-(15,8a5)-1 -Hydroxyindolizidine enantioselective synthesis of 12:281 from Rhizoctonia leguminicola 12:278 (-)-(l/?,8aS)-l-Hydroxyindolizidine 12:278,281 enantioselective synthesis of 12:281 from Astragalus oxyphysus 12:278 from Rhizoctonia leguminicola 12:278 2-Hydroxyindolizidine relative configuration of 12:284 synthesis of 12:283,284 ()-cw-2-Hydroxyindolizidine 12:284 ()-/ra5-2-Hydroxyindolizidine 12:284 6-Hydroxyindolizidine synthesis of 12:285,286 7-Hydroxyindolizidine antitremorine action of 12:286 synthesis of 12:286-289 cw-8-Hydroxyindolizidine 12:293

1063

Sa-Hydroxyindolizidine 12:300-303 l-Hydroxyindolizidine-6-carboxylic aid 12:283 6a-Hydroxyiridomyremcin 7:476 P-Hydroxyisobutyric acid 13:87 (S)-|3-Hydroxyisobutyric acid 18:172 Hydroxyisoindolone 13:114 3-Hydroxyisoleucine 15:347 16-Hydroxyisoretulinal 1:36;9:186 12-Hydroxy isoretulinal 1:36 18-Hydroxyisoretuline 1:38,39 3-/2/5'-Hydroxyisovoacangine 5:127 a-Hydroxyketone synthesis of 6:337;8:224,225;14:458,459 p-Hydroxyketone synthesis of 17:365;14:458,459 Hydroxy! inversion 1:204,205 13-HydroxylofbaccatinIII 12:218 Hydroxyl removal 1:454,456 la-Hydroxylase inhibitors of 9:515 25-Hydroxylase 9:520 Hydroxylated indolizidines 12:275-363 trans-Rydroxylaiion of olefin 1:413,414 withHzOz 1:260 withWOa 1:260 Hydroxylation 5:827 by stereospecific double bond 11:464 cw-Hydroxylation 1:413,415 stereoselective 1:413,415;4:511 stereospecific 4:503,504 Whiteside's procedure 1:668 withBa(CL03)2 1:260 with CUCI2/CU/O2 5:827 with osmium tetroxide 4:508,509 withOS04 1:260 12P-Hydroxylation 13:663 a-Hydroxylation 4:331,333;13:43 cw-Hydroxylation 4:45,145,204,205,344 lincosamine derivative from 4:145 ofacrylates 4:45 of E-allylic alcohol 4:204 of Z-allylic alcohol 4:205 with Os04-chiral base 4:344 o-Hydroxylation of 2-alkylbenzoic acids 5:826 C-3 Hydroxylation 7:359-361 Up-Hydroxylation 9:417 15a-Hydroxyleurosidine from anhydrovinblastine N oxide 14:812,813 (15'^)-15-Hydroxyleurosidine (15'5)-15'-hydroxyleurosidine from 14:814,815 Moffatt oxidation of 14:814,815 (15'5)-15'-Hydroxyleurosidine from (15'/?)-15-hyxyleurosidine 14:814,815 18-Hydroxylochnerine 13:386 23-Hydroxylongispinogenin 18:650,656 from Corchorus acutanguliis 18:650 (+)-12a-Hydroxylupanine 15:524 from Lygos raetam 15:524 (-)-6a-Hydroxylupanine 15:524

6-Hydroxyluteolin 5:654,665 6-Hydroxyluteolin-6,7-disulphate 5:655 6-Hydroxyluteolin-7-0-(6"-caffeoyl)-sophoroside 5:654 6-Hydroxyluteolin-7-sophoroside 5:624 6-Hydroxyluteolin-7-sulphate 5:655 18-g/o-Hydroxymakomakine 11:326,327 (+)-13p-Hydroxymamanine 15:523 from Maackia amurensis 15:523 5-Hydroxymatairesinol 18:601 5-a//o-Hydroxymatairesinol 18:601 (i?)-(-)-5-Hydroxymellein 15:383 3-Hydroxymellein 15:383 4-Hydroxymellein 15:383 cw-(3/?,4/?)-(-)-4-Hydroxymellein 15:383 trans and cw-(35',45)-4-Hydroxymellein 15:531 5-Hydroxymethlmellein 9:288,289 Hydroxymethyl C-glycoside reaction with butyl lithium 10:338 fromglycal 10:338 reactions with tributyltinmethyl iodide 10:338 3-Hydroxymethyl cyclopentanone from 3-oxocyclopentane carboxylic acid 6:558 3-Hydroxymethyl indole in Mannich reaction 4:715 cw-Hydroxymethyl oxocane synthesis of 10:233 24-Hydroxymethyl steroids absolute configuration of 15:79 (/?)-l-(Hydroxymethyl) ethyl 2-glyceryl ether 6:387 from 2-amino-2-deoxy-3 -0-(/?)-[hydroxymethyl) ethyl]-a-Z)-glucopyranose 6:387 (5)-5-(Hydroxymethyl)-2-pyrrolidinone from (5) pyroglutamic acid 11:264 245',22^-24-Hydroxymethyl-(cholesta-5,22-dien3P-ol 15:98 2R-Hydroxymethyl-3/?,45'-dihydroxy-pyrrolidine chemico-enzymatic synthesis 10:549 from Angylocalyx boutiqveanus 10:547 from Arachiodes standishii 10:547 synthesis of 10:548-549 yeast a-glucosidase inhibitor of 10:547 24(5)-Hydroxymethyl-cholesta-5,22()-dien-3p-ols 15:51 4-Hydroxymethyl-iridoids 7:467,468 Hydroxymethylbilane (preurog'en) (HMB) 9:591, 9:592,595 Hydroxymethylglutaryl coenzyme A reductase 13:553 3-Hydroxymethylvoacangine 5:128 11-Hydroxynoracronycine 13:348,349,356-358,366, 367,370 from Atalantia ceylanica 13:348,349,356-358 synthesis of 13:356-358 18-Hydroxynorfluorocurarine 1:3 8,39 4-Hydroxyochratoxin A 15:388 Hydroxyoctadecatrienoic acid synthesis of 1:534-536 (4E,8E)-N-D-2'-Hydroxypalmitoyl-l-0-P-Dglucopyranosyl-9-methyl-4,8-sphingadienine 18:813 6-Hydroxyperezone ^^C-NMR spectrum of 5:766,794,795 transformations of 5:794,795

1064 15-Hydroxyperezone 5:795,796 transformations of 5:795,796 a-Hydroxyphenylacetaldehyde synthesis of 6:316,317 Hydroxyphenylethanol 15:3514(+)-l-Hydroxypinoresinol 5:523,533,537,538, 5:542 (+)-l-Hydroxypinoresinol dimethyl ether 5:533-534, 536 (+)-1 -Hydroxypinoresinol-1 -P-D-glucoside 5:523,538, 542 (+)-1 -Hydroxypinoresinol-4'-P-D-glucoside 5:523 (+)-1 -Hydroxypinoresinol-4'-0-methyl ether 5:523, 533-536 (+)-1 -Hydroxypinoresinol-di-p-D-glucoside 5:523 Hydroxypristimerinene 5:747,749 17a-Hydroxyprogesterone 9:415,416 from androstenedione 9:415 6a-Hydroxypterocarpans sphenostylins B 7:413,414 6a-Hydroxypterocarpans sphenostyUns C 7:413,414 6-Hydroxypyrano [2,3-c] acridin-7-ones (noracronycines) 13:348 3-Hydroxypyrrol-2(5H)-one 13:117,118 3-Hydroxypyrrole-2-carboxylates 8:272 8-Hydroxyquinoline 2:244;5:752;9:540 12-Hydroxyretulinal 1:36 18-Hydroxysacculatal 2:278,279 19-Hydroxysacculatal 2:278,279 (+)-13a-Hydroxysepticine 12:278 5 -Hydroxy siastatin from bovine liver 16:86 23p-Hydroxysolanidine (leptinidine) 7:18,22 13 a-Hydroxy speticine 12:301 12a-Hydroxyspongia-13(16), 14-diene 1:662,663 synthesis of 1:682,683 ()-12a-Hydroxy spongia-13 (16), 14- diene synthesis of 6:111,112,115,116 11-Hydroxystaurosperine from Eudistoma sp. 12:366,370 7-Hydroxystaurosperine from Streptomyces sp. N-126 12:366,368 24-Hydroxysteroids absolute configuration of 15:76,77 26-Hydroxysteroids absolute configuration of 15:77,78 3-Hydroxystigmastan-6-one 9:288,289 (+)-l-Hydroxysyringaresinol 5:524,535-538 3 -Hydroxytabemaelegantine 5:129 19i?-Hydroxytabemaelegantine B 5:129 17-Hydroxytabersonine 4:57,58 195-Hydroxytacamine 5:128;9:179 17-Hydroxytacamonine 5:126;9:180 5-Hydroxytetrahydroharmane 5:125 Hydroxythymoquinone 5:763 3-Hydroxythymoquinone 5:767 6-Hydroxythymoquinone 5:767 20-Hydroxytingenone 5:744,746,747 22-Hydroxytingenone 7:146 Hydroxytingenone 7:149 3a-Hydroxytrichothecene 6:229,247 from 3-ketotrichothecene 6:229 Hydroxytropylium ion 1:568 5-Hydroxytryptamine 5:125;15:328 5-Hydroxytryptophan 6:319 Hydroxyvalidamine 10:518;13:189,195,197 19-Hydroxyvandrikine 9:193 Hydroxyvinamidine 2:389,390,398 14a/14p-Hydroxyvincadifformine 14:831 12-Hydroxyvincadifformine 5:124 15P-Hydroxyvincadifformine 5:169-171 15p-Hydroxyvincadifformine 5:169,170 19-Hydroxyvincamajme 5:155,156 1 a-Hydroxyvitamin D2 11:381-383,385,395,402 Ip-Hydroxyvitamin D2 synthesis of 11:402-404 25-Hydroxyvitamin D2 9:512,513,515,520,521;11:381 24-Hydroxyvitamin D2 9:513 ip-HydroxyvitaminD3 11:402-404 25-Hydroxyvitamin D3 12:401 1 a-Hydroxyvitamin D3 ((1 S)-hydroxycalciol) 11:380, 381,385,395,402 25-Hydroxyvitamin D3 (calcidiol) 11:380,388-393 3 -Hydroxyvoacangine 5:124 2-Hydroxyzanthone 5:759 Hydrozirconation 10:59;13:486 Hydrozyindolizidine 12:293 8(+)-Hygroline 7:192 Hymenomycetes 9:202,203 Hymenoxys turneri 15:32 Hyodeoxycholic acid 16:352 Hyoscyamine from phenyl alanine 11:204,206 (5)-tropic acid moiety of 11:204,206 Hyoscyamine 13:662 6P-Hyoscyamine 13:662 Hyoscyamine 17:398-400,417 anticholinergic agent 17:395 Hyoscyamus albus 17:398 Hyoscyamus gQmxs 17:395 Hyoscyamus niger 13:631 Hypaphorine 5:752 Hypecorine 6:494 Hypercholesterolemia 11:335 a-7c-Hyperconjugation 12:454 Hyperenone-A 5:759 Hyperenone-B 5:759 Hyperforin derivatives 7:420,421 Hypericin retroviral activity of 7:421 from Hypericum perforatum 13:657 Hypericum 7:409 Hypericum annulatum 7:417 Hypericum calycinum I'All Hypericum chinense 1:422 Hypericum japonicum 5:758 Hypericum mysorense 5:758,759 Hypericum perforatum 5:758,656 Hypericum revolutum 7:409,410,417,420-422 Hyperin 7:227 Hyperstable olefins 12:207 Hypertrehalosaemic hormones 9:487 Hyphochytridimycetes 9:202 Hyphomycetes 9:203 Hypnophilin 3:7,65

1065 Hypocholesterolemic agent 13:554 Hypocholesterolemic drug 5:195 Hypoglycemic activity 18:672 Hypoglycemic effects 17:139 Hypolaetin 5:665 Hypolaetin-3'-methyl ether-7-glycosides 5:658 Hypolipaemic drug 5:695 Hypoponera opacior 5:224,230,254 Hypopyhyllanthin synthesis of 17:344 Hyporeales 9:203 Hypotensive activities 17:451 ofcryptolepine 5:752 Hypotensive alkaloid 5:751,752 Hypothetical biogenesis 12:374 of Arcyria bis-indo\y maleimides 12:374 Hypothetical incorporation of methylmalonyl CoA 11:195 with macrolide antibiotic 11:195 with polyether antibiotic 11:195 Hypoxanthine 15:460 Hypoxanthine-guanine-phosphoribosyltransferase 15:371 9-D-Hypoxanthines 4:224,225 Hypselodoris californensis curyfliranfrom 6:20 Hypselodoris godefroyana 6:69 curyfuranfrom 6:20 nakafuran-9 from 6:29 Hypselodoris porterae 6:20 Hyrtios eubamma 6:23 puupehenone from 6:23 Hyrtois 6:111 Hysselodoris califomiensis 4:404 Hysselodoris porterae 4:404 Hyssopus officinalis 7:119 Hytakerol 9:513

195-19-hydroxy-20-ep/-ibophyllidine 5:106 ibophyllidine 5:106 20-e/7/-ibophyllidine 5:106 195-iboxygaine 5:106 19-e/7/-Iboxygaine 5:126 Iboxygaine hydroxy indolenine 5:127 19-e/7/-Iboxygaline 5:127 Iboxyphylline synthesis of 14:847 Ibuprophen 6:322,323 Ichikawa synthesis 616-618 Ichorati 17:200 Ichthyotoxicity 17:24;18:607,716 Icosapolyenoic acids 9:559 Icosatetraenoates 9:566 (5,8,1 l,14Z)-Icosatetraenoic acid 9:560 Icosatetraynoic acid 9:564 8,11,14-Icosatrienoic acid 9:577 Icsatrienoic acid (dihomo-g-linolenic acid) 9:564 Z,-Idopyranose analogs 6:369,370,372,373 IDP-Isomerase 7:324 lejmialides (A-D) 10:247,19:606 Iguesterin 5:747,18:757,776 Ikarugamycin 4:620;10:153,18:10-17 biosynthesis of 4:620 Ilex aquifolium 20:6 //ejc lactone 20:6 Ilex paraguariensis 20:6 Ilex verticillata 9:402 IlicicolinH 4:620 biogenesis of 4:620 Ilimaquinone 5:430;15:291,314 absolute configuration of 5:430 antimicrobial activity of 5:434,437 5-epMlimaquinone 9:31 ;15:315,319 oxidative degradation of 9:31 Illicic acid (vachanic acid) 7:212 Ilybiusfenestratus 5:780 Imbricatine 7:306,307 Imbricatosides A 15:64 Imelutine 1:167 Imidazole 12:152 Imidazolidines 2-azaallyl anions from 1:349-351 Imidazolidinone 8:156 Imidazolo [4,3-a] isoquinoline 12:447 Imidazolone 5:412 cytotoxic activity of 5:413,415 Imide enolates 4-acetoxy-P-lactam with 12:164-168 C4-alkylation with 12:164-168 from propionic acid derivatives 12:164-168 Imidoyl chloride 14:157 Imidoyl phosphate 8:79 synthesis of 8:79 Imine [2+2] cycloaddition of 12:173 azaallyl anions from 1:331 -344 cis reduction of 6:428 deprotonation of 1:331-344 preparation by Standmger reaction 1:352-353 trans reduction of 6:428

Lanthella basta 10:632 bastaxanthins from 6:150 Iberisamara 19:762,20:12 Iboga alkaloids 1:112,93-96,163-165,422 Ibogaine 5:101,126,174 Ibogaine hydroxyindolenine 5:101,126 Ibogaine pseudoindoxyl 5:126 Ibogaline 5:127,174 ofZ-Ibogamine 14:806,807 (-)-Ibogamine 5:124 (+)-Ibogamine 5:125 Ibogamine pseudoindoxyl 5:126 Ibogan-type alkaloids 5:71 Ibophyllidine 5:126,847 synthesis of 14:847 2-e;7/-Ibophyllidine 5:126 Ibophyllidme 9:190,192 Ibophyllidine-A'4-oxide 5:126 Ibophyllidine-type alkaloids desethylibophyllidine 5:100 19-hydroxyibophyllidine 5:106 18-hydroxy-20-epiibophyllidine 5:106 19R-19-hydroxy-20-ep/-ibophyllidine 5:106

1066

trans-3 -acetyl-p-lactam from 12:173 withdiketene 12:173 ylides from 1:331-334 Iminium 'A' 2:390,2:398,402 Iminium'B' 2:390,390 Iminium cyclization 1:243 Iminium ion cyclization to vinylsilanes 1:286,287 Iminium ion-vinylsilane 19:52 Iminium ion-vinylsilane cyclization 12:454 P-Imino carboxylic acid 8:384 2-Imino cyclic ethers synthesis of 10:215 Imino Diels-Alder approach 14:732,733 Imino Diels-Alder reaction 4:36,37,604 y^Imino sulfoxide substrate 18:382 5,8-Imino-7-0-mesyl-2,3,5,8-tetradeoxy-Dglucooctano-1,4-lactone 12:325 Iminodienophile in Diels-Alder reaction 4:604 Iminogalactitol 7:42 Imipenem A^-formimidoly derivative of theienamycin 12:145 Imipenem antibiotic potency of 4:432 PBP-2 affinity for 4:433 thienamycin derivative of 4:431,432 Immobilised cultures 7:92 Immobilized glucoamylase 2:356 Immunoadjuvant monophosphoryl lipid A in 18:918 Immunoadjuvant properties 6:385 Immunoassay screen 19:188 Immunogens 18:909-920 Immunological assays 15:361 Immunomodulation 7:16 byswainsonne 7:16 Immunoprecipitation 7:122 Immunoregulatory agents 19:351 Immunosorbent assay 15:361 Immunosuppressant agents 16:561 Immunosuppressive activity 18:739,921 ofdidemnins 10:257,258 Immunosuppressive therapy 20:528 Incartine from Lycoris incarnata 20:351 2D INADEQUATE spectrum of dammmaran-20 (5) of 2:96,98 of salculaplagin triacetate 2:88 Indanoaziridine 1:189 from isoquinolinium betaine 1:109 Indanomycin 10:348 synthesis of 3:275,276 Indanone 11:115 Indazole dione 2:215,217 Indenobenzazepine biogenesis of 1:218,219 from 8,14-cycloberbines 1:209-211 from spirobenzylisoquinoliens 1:207-208 oxidation of 1:216 reaction with Lewis acids 1:196,197 rearrangement to spirobenzylisoquinoline 1:205,206 synthesis of 1:196,197

synthesis of 1:205,206 trans-XO'CiS'isomQr'izaiion 1:210 a//-Indenofluorenone from 1,2,4,5-benzenetetra carboxylate 11:124 H-NMRof 11:124 5rv-Indenofluorenone from 1,2,4,5-benzenetetra carboxylate 11:124 ^H-NMRof 11:124 Indicarol acetate 9:79,81,87 Indicine 1:269,270,325,326 synthesis of 1:270,325,326 Indicine N-oxide 1:268,270,275,554 as anti tumor agent 1:275 synthesis of 1:268,270 Indicol 9:79,80,87 Indobine 9:178 Indicoside A from Astropecten indicus 15:61 *^C-NMR spectrum of 5:214 FAB mass spectrum of 5:214 *H-NMR spectrum of 5:214 Indicoside B 5:215 Indicoside C 5:215 Indicosides A-C 7:299,301,302 from Astropecten indicus 7:299 Indigo reduction with hydrazine 1:20 Indigofera endecaphylla 19:117 Indigofera swaziensis I'AXl INDO MO method 18:981,985 Indolalkylamines 9:510 Indole [2,3-a] carbazole alkaloid 5:55 Indole alkaloids 1:31-34;2:172,173;5:3,69-134,389, 390,443,444;9:163-199,85;13:70,92,93;10:407,411; 14:703-730 aspidosperma 13:70,92,93 Aspidosperma type 10:407,411 bisynthesis of 1:31-34 carbon 13 NMR of 9:165 CD of 2:172,173 Corynanthe 13:92,93 Cotton effects in 2:172,173 hunteria 13:70,93 Hunteha type 10:407;13:70,93 identification of 9:163-199 mass spectroscopy of 9:165 synthesis of 14:703-730 thin layer chromatography of 9:164 UV spectroscopy of 9:164,173 Indole N-/er/-butyloxycarbonyl 3:309,310 thermolytic deprotection 3:309,310 Indole-2,3 -quinodimethane 1:16,17 Indole-3-pyruvic acid 12:374,375 biotransformation of 12:374 Indole-monoterpene alkaloids from Strychons dinklagei 6:503-522 from Strychnos species 6:503 of corynane strychnane series 6:503-520 Indole acetic acid 7:90,114 Indoles, synthesis of Fischer 1:79,144,152 Smith 1:360,365

1067

Indoline derivatives 9:183-191 Indolizidine-7-one 19:33 Indolizidine 9:72 (+)-(5)-Indolizidine 12:280 (-)-(^)-Indolizidine 11:246-267;12:280 (-)-Indoiizidine 209D synthesis of 16:489 Indolizidine alkaloids 7:11-13,453-502 synthesis of l:360-365;10:556,561;16:453-502 (+)/(-)Indolizidine alkaloids absolute stereochemistry of 11:246 spectral data of 11:246,249,254,255, 11:264 synthesis of 11:246-267 asymmetric synthesis of 6:442,443 in Solenopsis conjurata 6:450 synthesis of 6:442,443,445-451 (-)-(15,2/?,8a5)-Indolizidine-l,2-diol configuration of 12:303 from Rhizoctonia leguminicola 12:303 (-)-swainsonine from 12:303 synthesis of 12:303-305 (15,2/?,8a/?)-Indolizidine-1,2-diol synthesis of 12:303,304 Indolizidinediol 13:488 Indolizidines 19:25,32,38,45-46,48-51 synthesis of 19:42,32 enantioselective synthesis of 19:50 (-)-Indolizidines 205 A synthesis of 16:479 (-)-Indolizidines 235B 16:479 synthesis of 16:479 Indolizidone cross-aldolisation of 12:298 from L-proline thioester 12:297 (+)-Indolizomycin synthesis of 16:461 (-)-Indolizomycin absolute configuration of 12:301 antibiotic activity of 12:301 from Streptomyces gr is line 12:300 from Streptomyces teryimanensis 12:300 reduction of 12:301 synthesis of 12:301-303 ()-Indolizomycin synthesis of 12:301-303 Indolo [2,3-a] carbazole alkaloids 12:365-409 biological activity of 12:384-399 synthesis of 12:375-383 Indolo [2,3-a] carbazoles against Herpes simplex type 12:366,370 cytotoxic against human cancer cell lines 12:370 from Nostoc sphaericum 12:366,370 Indolo [2,3-a] pyrido [a] quinolizine 3:404 IH-Indolo [2,3-a] pyrrolo [3,4-c] carbazole 12:365 Indolo [2,3-a] quinolizine synthesis of 1:142,144,153,155 Indolo [2,3-a] qumolizine alkaloids 8:288 synthesis of 1:123,159 Indoloazacyclodecane 14:862

Indoloazepine 14a and 14p-hydroxyvincadifFormine from 14:831,832 condensation of 14:831 epZ-pandoline from 14:831 pandolinefrom 14:831,832 with 4-ethyl-4,5-epoxy pentanal 14:831 Indolocarbazole alkaloids biosynthesis of 1:6 Indoloquinolizidine 15:497 Indoloquinolizidine aldehydes 1:111 Indoloquinolizidine enamines preparation of 14:727 Indoloquinolizidine iminium salts by Pothiovski reaction 14:715-718 from indolo [2,3-a] quinolizidine Nb oxides 14:715-718 Indoloquinolizidine Nb-metho salts preparation of 14:718,719 stereoselective 14:718,719 Indoloquinolizidine Nb-oxides conformational equilibrium of 14:712 preparation of 14:711-714 stereoselective synthesis 14:711-714 Indolo-[2,3-a] quinolizidine by alkaline decarboxylative cyclization by Claisen rearrangement 14:722-724 preparation of 14:704-706,720-724 Indoloqumolizidines 1:115,116;1:99,100,712 3-Indolyl acetic acid 9:236 6w-Indolyl maleic anhydride 12:381 6w-Indolyl maleimides 12:365,372,375-383 biological activity of 12:384-399 protem kinase activity of 12:389 synthesis of 12:375-383 2-(2-Indolyl)-propionic acid 9:236,237 l-[2-(3-Indolyl)ethyl]-3-methoxy carbonyl 1,4,5,6tetrahydro pyridines 14:720 alkalme decarboalkoxylative cyclization of 14:720 indolo [2,3-a] qumolizidines from 14:720 3 -Indoly l-acetonitrile Ritter reaction of 11:281,282 with (-)-P-pmene 11:281,282 3-Indolylacetaldehyde 11:288 2-Indolylacetaldehyde from N-(p-MPS) indole 11:315,316 preparation of 11:315,316 Indolylmagnesium iodide 1:7 Indomethacm 7:397,20:514 INEPT spectra 2:92,93 of 4-hydroxysapriparaquinone 5:36 ofaquillochin 5:6 ofartemisinin 5:27 ofberberine 5:43,44 of colchicine 5:47 of damaran-20(S)-ol 2:92,93 ofeupatorenone 5:30 oflarreantin 5:10,11 ofprionitm 5:31 ofsalvinolone 5:34,35 ofsanguinarine 5:43 Incremental effects 9:277,278

1068

Inflammatory activity 20:531 InflexaninA 15:112,115 from Rabdosia inflexa 15:172 'H-mm-of 15:122 InflexaninB 15:112,117,124 from Rabdosia inflexa 15:172 ^H-nmrof 15:124 Inflexarabdonin A 15:120 '^C-mm-of 15:133 from Rabdosia inflexa 15:172 *H-mm-of 15:126 Inflexarabdonin B 15:117 '^C-nmrof 15:131 from Rabdosia inflexa 15:172 'H-nmrof 15:124 Inflexarabdonin C 15:114 ^^C-nmrof 15:128 from Rabdosia inflexa 15:172 'H-nmrof 15:121 Inflexarabdonin D 15:120 ^'C-nmrof 15:133 from Rabdosia inflexa 15:172 ^H-nmrof 15:126 Inflexarabdonin E 15:115 '^C-nmrof 15:129 from Rabdosia inflexa 15:172 'H-nmrof 15:122 Inflexarabdonin F 15:120 ^^C-nmrof 15:134 from Rabdosia inflexa 15:172 ^H-nmrof 15:127 Inflexarabdonin G 15:115 '^C-nmrof 15:129 from Rabdosia inflexa 15:172 'H-nmrof 15:122 Inflexarabdonin H 15:115 '^C-nmrof 15:129 from Rabdosia inflexa 15:172 'H-nmrof 15:122 Inflexin 15:112,115 ''C-nmrof 15:129 from Rabdosia inflexa 15:172 ^H-nmrof 15:122 Inflexinol 15:112,117 from Rabdosia inflexa 15:172 'H-nmrof 15:124 Influence of phytohormones 17:408,410 Infiiscaside 2:280,281 Ingenane synthesis of 12:233-245 Ingenane system 1:547 Ingenol 1:546,547,571 ;2:261;12:233-245 ^H-nmr of 12:234 synthesis of 1:547 synthesis of ring system 1:571 synthesis of 12:233-245 X-Ray crystallography of 12:234 Ingol 2:261 Inhibitins 7:119 ofaminoglycopyranoses 7:47 of 1 thio p-Z)-galactopyranosides 7:48 Inhibition 7:47,48;9:581

Inhibitors of enzymes 9:515 of vitamin-D-metobolism 9:515 Inhibitory activity of(+)-castanospermine 12:332 of(-)-swainsonine 12:327 of (-)-(8,8a-di-ep/-swainsonine 12:325 ofbenzalmalonates 9:225-227 Inhibits pisatin 12:399 Inhoffen-Lythgoe diol 1:591,592 synthesis of 1:592 Injection techniques 9:457 Inlet systems 2:45 INOC reaction 1:480,481 /wyo-Inositol 13:190 D-c/z/>o-Inositol 18:439 Inositol (cyclohexanhexaol) 7:37 L-c/7/>o-Inositol 2,3,5-trisphosphate 18:416 Inositol phosphates 18:393-451 Inostamycin 15:453-456,461 Inouye's photochemical route 12:198 Insect antifeedant 2:288 Insect juvenile hormone analogues fromthujone 14:391-397 synthesis of 14:391-397 via P-lactone route 14:395-397 Insect neuropeptides 9:487-493 Insect pheromones via diisopropylethanediol esters 11:415-417 via pinanediol esters 11:412-414 synthesis of 3:270-273,493,494;ll:412-417 Insect repellant 5:757 Insecticidal activity 18:229,704 Insecticides 7:395-397 Insulin bovine 2:23-25 gene synthesis 4:271 isotopic distribution of (MMH^) 2:25 Insulin B chain 2:23-25 Insulin receptor tyrosine specific protein kinase 12:390 Integerrimine 1:272-274 synthesis of 1:272-274 Integerrinecic acid 1:263-266 synthesis of 1:263,264 Integerrinecic acid lactone 1:266,267 synthesis of 1:266,267 Interferon 4:273 gene synthesis 4:273 LPS induction of 4:199 interleukini 4:199 Interferon-a-Pandy 20:531-533 Interferon production by human cell cultures 12:390 protein kinase in 12:390 Interleukini 5:388 Interleukin I induction 4:197 by LPS 4:197 (+)-Intermedeol biological activity of 14:450,451 from a-agaroftiran 14:453 from Bothriochloa bladhi 14:450 from Bothriochloa glabra 14:450

1069
from Bothriochloa intermedia 14:449-451 from Bothriochloa insculpta 14:450 ^om Carthamus lanatus 14:450,451 from Citrus paradisi 14:450 fromCymbopogonflexuosus 14:450,451 from (-)-7-ep/-cyperone 14:452,453 from Senecio amplexicaulus 14:450 f[om Velocitermes velox 14:451,452 synthesis of 14:456-465 total synthesis of 14:452,453 Intermedine 1:269 Intermedine N-oxide 1:270 Intermolecular aldol condensation 10:318-320 Intermolecular cationic [5+2] cycloaddition 8:160,161 Intermolecular cyclization spirosystems construction by 6:59 Intermolecular Diels-Alder reaction 6:549,550 Intermolecular Michael reaction enantioselective 14:552 Intermolecular 0-alkylation 8:198,199 Internal aldolization in (+)-2-isocyanopupukeanane synthesis 6:81 Internal alkylation 6:74 in (+)-9-isocyanopupukeanane synthesis 6:80 Internal Diels-Alder reaction 6:86,87 Intemuclear distance and cross relaxation rates 2:60,61 from NOE rations 2:61 Interproton distances 2:70,71 Intestinal worms 1:435 Intramolecular reaction (2+2) cycloaddition 11:45-47 [4+4] cycloaddition 11:17 1,3-dipolar cycloaddition 11:283-285 aldehyde-ketophosphonate condensation 6:264,265 aldol condensation 11:90,108,113,115 aldol condensation 12:82 aldol condensation 183,303,306,318,329,330 alkylation of 8:176,177 amidoalkylation 10:108 amidomercuration 12:281 aminolysis 12:279 annulation 10:407 asymmetric hydrosilylation 13:72 azido-olefm cyclization 13:447,448 Biellmann coupling 10:6-10 C-C bond formation 12:65 cross coupling reaction 10:163 cross-aldolisation 12:289 cyclization 10:631-633;12:281,327 dicarbonyl coupling 11:345,364-367 Diels-Alder reaction 10:51,52,155,409;11:11,92,93, 99,108;13:108-115,111;14:745 double cyclization 10:83 displacement 12:347 ene reaction 11:91-108 epoxide alkylation 14:746 esterification of 8:176 etherification 12:65 Friedal-Crafts acylation 10:131 Friedal-Crafts reaction 10:312,313 hetero Diels-Alder reaction 6:449 Homer-Emmons condensation 10:13-17 imino Diels-Alder approach 14:732,733 Michael addition 11:312;14:736 Michael reaction 9:435,437;10:51,52;13:180-443 mixed Claisen condensation 12:104 Mukaiyama condensation 10:181,182 N-acyliminium ion cyclization 11:284,285 nitrile oxide cyclization 14:745 nitrone cycloaddition 14:744 0-C bond formation 12:83 Pi-allyl Pd alkylation 10:10-13 photocycloaddition 11:20 photoreduction 12:283 proton transfer 12:102 Pummerer reaction 10:682 rhodium II mediated 10:407 ring contraction 11:42,43 ring-opening 12:83 Sakurai reaction 10:182 5-alkylation 13:145 SE'additions 10:17-25 SN2 cyclization 12:85 SN'-process 11:323 stereoselective cyclization 10:92 translactonization 13:159 rra5-sulfenylation 12:69,72 Ulmann reaction 10:640 Wadsworth-Emmons reaction 12:328 Wittig Homer reaction 11:152,153 Wittig reaction 13:601 Wittig-Homer cyclization 12:292 Wittig-type reaction 12:147 a-diazo-P-keto ester synthesis 10:407 Intramolecular [2+1] cycloaddition 6:52 Intramolecular [2+2] cycloaddition 12:193 Intramolecular [2+2] photoaddition 12:210 Intramolecular [2+2] photocycloaddition 6:69 Intramolecular [4+1] pyrroline annulation 1:250 Intramolecular [4+2] cycloaddition 5:166-168,182 olefin tropolone 5:799 Intramolecular [4+2] cycloaddition in ()-sinularene synthesis 6:85 in 7,20-diisocyanoadociane synthesis 6:86,87 Intramolecular 1,3-dipolar cycloaddition 12:318 Intramolecular acetalization 14:60 Intramolecular acylinitroso Diels-Alder reaction 1:386 Intramolecular addition to chiral sulfoximines 10:3-11 to chiral vinyl sulfoxides 10:3-11 Intramolecular Alder ene reaction 10:222,224 Intramolecular aldol condensation 6:549,550,231; 15:235,269,297 Intramolecular aldol cyclization 6:36,66,67;18:633 in poitediol synthesis 6:36 in (-)-upial synthesis 6:66,77 Intramolecular alkylation 6:42,43;8:225-233,540,558 Intramolecular amidoalkylation 1:246 Intramolecular aminomercuration 10:532,540;12:333 Intramolecular arylation 12:447-452 Intramolecular base-induced rearrangement 14:374 Intramolecular carbenoid displacement 1:259

1070

Intramolecular chelation 14:53 Intramolecular Claisen condensation 18:299 Intramolecular coupling 6:546,547 Intramolecular cyclization nickel-catalyzed 2:282 spirosystems construction by 6:59 in ()-9-isocyanopupukeanane synthesis 6:82,83 Intramolecular cycloalkylation 6:6 in ()-amjitrienol synthesis 6:53 in tricyclic natural products synthesis 6:74 Intramolecular cyclopropanation 6:73,74 Intramolecular Diels-Alder reaction betaenoneBby 4:601,602 betaenone C by 602-604 coronafacic acid by 4:596,597 diplodiatoxin by 4:600-602 endoTulQ 4:18 fused versus bridged product 4:565 in biosynthesis 4:616,621 kinetic selectivity 4:601 solanapyrone A by 4:598 stereoselectivity 4:595,596 Intramolecular displacement reaction 12:311,344 Intramolecular diyl trapping reaction 6:46 Intramolecular double Michael addition 8:418 Intramolecular glycosylation 14:236 Intramolecular heteroene reaction 12:295 Intramolecular Homer-Emmons condensation 12:341 Intramolecular Michael addition in ()-sanadaol (p-crenutal) synthesis 6:70,71 Intramolecular Michael cyclization ofan acyclic compound 14:552 Intramolecular Michael reaction 6:178,184,196 asymmetric 14:551-567 by chiral enamine 14:551-567 enantioselective 14:551-567 Intramolecular oxidative coupling 6:480 Intramolecular 7i-alkylation 6:184,185 Intramolecular photocycloaddition 6:34,35,54 m ()-ep/-precapnelladiene synthesis 6:34,35 in isoamijiol synthesis 6:54 Intramolecular Firmer reaction 15:415 Intramolecular reduction 14:153 Intramolecular reductive amination 12:316 Intramolecular reductive coupling 6:48,52,54 in ()-A^^'^^ capnellene synthesis 6:48 indolasta-1 (15),7,9-trien-14-ol synthesis 6:52 in isoamijiol synthesis 6:54 Intramolecular ring closure reaction 6:492 Intramolecular trans-ketalizsition 10:211 Intramolecular type I-"Mg-ene" reaction 6:45,46,76-78 in ()-A^^^^^ capnellene synthesis 6:45,46 in (+)-sinularene synthesis 6:76,77 Intramolecular Wittig reaction 1:234,235,573 Introns 13:290 Inula cappa 5:678 Inula crithmoides 5:728 Inula nervosa 19:125 Inverse electron demand in Diels-Alder reaction 4:579,580,604 using enamines 4:604

using enols 4:604 using ketone dithioacetal 4:604 Inverse INEPT 9:593 Inversion of alcohol center 1:204,205,456,457,459 Mitsunobu protocol 1:459 Invertase 7:38-69 conduritol B epoxide bmding to 7:38 from Candida utilis 7:69 ew^Invictolide synthesis of 16:711-712 Invictolide 1:681-683 ;3:272,273 Iodine pentoxide 1:51 oxidation of indoles to 2 acylindoles 1:151 Iodine-catalyzed 6:139-141,153,154 stereomutation mixtures 6:139-141,154 isomerization 6:141,153,154 5-Iodo ketones 8:245 4'-Iodo-4'-desoxydoxorubicin 14:21 w-Iodoalkyl-2-phenylthiomethyl-4,6-dimethoxybenzoate 8:176,177 lodobenzene diacetate a-hydroxylation of ketones 4:331 lodocarbonate 11:361 enantiomerically pure oil from 11:346,347 with/7-toluene sulfonic acid monohydrates 11:346,347 8-Iodocoumarin 4:372 lodocoumarin with copper acetylide 4:396,398 lodocyclisation ofalkene 10:391 lodocyclocarbamation 4:126 lodoetherification 10:21,24 lodolactone 8:153,154 lodolactonization 1:526,254,199,204-206;13:208,622 by wi-chloroperbenzoic acid 11:358,359 by iodine 11:358,359 lodomagnesium salt 14:750 lodomethylphenyl sulfide 4:463 alkylation with 4:462 /7-Iodophenyl4-(9-triflygalactopyranosylglucoside 8:343,345 D-Iodopyranoside 19:367 lodosobenzene 14:780 lodotrimethyl silane 1:390;11:528 cyclization with 11:109 Ion-exchange column chromatography 19:519 Ionic cycloaddition 5:793 Ionization energy 2:3 Ionization techniques 2:43-55 (+)-Ionomycin synthesis of 16:715-716 lonomycin 3:58 a-Ionone 20:576,20:584 \|/-Ionone 20:589 (R)-(+)-a-Ionones 20:584 a-Ionone 13:328,330 P-Ionone 17:612 lonophore synthesis of 3:273-277 lonophore activity 4:93

1071

lonophore X-14547 A synthesis of 10:425 lonophores 16:711 lonophoretic activity 18:857 "lonoxide" principal 14:424,425 lophotoxins 18:697,698 Ipalbidine synthesis of 1:283,293,363-365 Ipalbine 1:362 IpczBCl as chiral reducing agent 8:476 IpcBHz as chiral reducing agent 8:475,476 Ipecacuanha alkaloids 7:444,92 Ipolamiide 7:458,459,463,463 Ipolamiidol 7:467 (+)-Ipomeamarone 15:236,237 Ipomeamarone biosynthesis of 15:249 synthesis of 3:57-58 (-)-Ipomearone 15:237 Ipomine 1:362 Ipomoea tissue cultures of 2:369 Ipomoea alba alkaloids of 1:362 Ipomoea muricata 1:362 IPP 7:98,104,107,110 IPP-DMAPP isomerase 7:108,109 5-(+)-Ipsdienol 16:242 Ipsenol synthesis of 10:188 Ircinia wistarii ircinianin from 6:8 wistarin from 6:8 Ircinianin biosynthesis of 4:618,619 from Ircinia wistarii 6:8 from methyl g-oxosenecioate 6:8 synthesis of 6:8 (-)-Ireland alcohol synthesis of 14:119,120 Ireland approach 12:16,17 Ireland-Claisen rearrangement 3:614,268;10:416,417, 424-425,429;18:230,231,259;20:67 in nonactic acid synthesis 3:228 ofallylicglycolate esters 10:437 ofsilylketeneacetal 10:423 Iridium black selective hydrogenation with 6:83,85 Iridodial 7:441,442 Iridodiols 7:442,482 Iridoid boschnialactone 8:133 Iridoid glucoside 6:529,114,439,440,445,457;7:461, 469,472,475 chemistry of 7:455-486 classification 7:454,455 nomenclature 7:451,452 structural characteristics 7:453,454 Iridoid precursor 6:503,529 Iridoids '^C-NMR spectrum of 7:486,487

'H-NMR spectrum of 7:486,487 4-hydroxymethyl-substituted uidoids 7:467 5-hydroxy-substituted iridoids 7:463,464 acid catalysed transformations 7:456-468 acid hydrolysis of 7:462 aglycon 7:458,461,465,486 analgesic activity of 7:490 antidote for a-amanitin poisoning 7:490 antileukemic activity of 7:490 antiphlogistic activity of 7:490 antitumor activity of 7:490 as chiral templates 7:468 biogenesis of 7:488,489 biological activity of 7:490 bisuidoids 7:443 chemistry of 7:439-492 choleretic activity of 7:490 chromatography of 7:488 definition of 7:439 diuretic activity of 7:490 gentiopicroside type 7:443 glycosides 7:439,457,461,468,469,472,475 glycosylation of 7:488 glycosylation with trifluoromethane-sulfonate (TMS-triflate) 7:488 hepatoprotectivity of 7:490 hypotensive activity of 7:490 mterconversion of 7:469 iridodiols 7:442 laxative activity of 7:490 miscellaneous-type 7:442 NaBHt reduction of 7:466 oleuropein type 7:443 partial synthesis of 7:478-486 plumeria-type 7:442 secoiridoids 7:442,443 secologanin type 7:443 sedative activity of 7:490 simple 7:440,441 stability of dihydropyranic ring 7:455 synthesis of 16:289-320 synthesis of 7:487,488 uterine contracting activity of 7:490 valeriana-type 7:442 Iridolactam alkaloids 6:503,529 Iridolactam derivatives 6:522-527 Iridomyrmecin 7:441,442,16:289,20:70,74 Iridomyrmecin derivatives 7:476,477 Iridomyrmex humilis 5:223,225,240,241,245,253 Iridomyrmex nitidus 5:222-224,233,253 Iridomyrmexpurpureus 5:222,224,233,253 2,5-dimethyl-3-ethyl pyrazines of 5:222 Iridomyrmex purpureus sanguineus 5:224,233,253 Iridomyrmex rufoniger sp.gr. 5:223,237,253 Iris germinica 10:152 Iron pentacarbonyl 14:689,690 Iron tricarbonyl derivatives acylationof 1:572 oftropone 1:572 P-Irone 10:152 Irreversible cytotoxicity 15:447 Irreversible inhibitors (suicide substrates) 7:36-40

1072

Irritant terpenoids from liversorts 2:287 Irumamycin 5:467-471 Irumanolidel 5:599 Irumanolide II 5:599 Ismine 20:356,369 ()-e^Iscoent-Isocopal-12-ene-15,16-dial synthesis of 6:119-122 Iso-1-cytochrome 18:915,916 Iso-1-cytochrome C 18:832,838 3-Iso-19-ep/-ajmalicine 1:103,104 (+)-Iso-allamandicin synthesis of 16:301 (+)-Iso-Ambrox synthesis of 14:420-425 Iso-p-peltatin B methyl ether 18:59 2-Iso-oxacephems antibiotic activity of 12:126 synthesis of 12:126,127 (+)-Iso-plumericin synthesis of 16:301 Iso-Withasomine synthesis of 1:343 Isoacronycine (pyrano[3,2-b] acridin-6-one) dervatives 13:348,356 ^-Isoafrol 8:160 Isoagatholactone 1:662,56,57,107,108 synthesis of 1:662 from (+)-labda-8(20), 13-diene-15-oic acid 6:65,57 from Spongia officinalis 6:56,107 (+)-Isoagatholactone from (+)-Isoagatholactone 6:56,57 from ent-mQthy\ isocopolate 6:56,57 synthesis of 6:56,57 (-)-Isoagatholactone synthesis of 6:57 Isoagatmic acid 6:107,108 Isoajmalicine 9:171 5Isoajmaline 9:183,185,403 Isoalatol 18:745 Isoamijiol 6:53,54 Isoamylases 10:498 Isoanacardic acid 9:371 Isoanacardic aldehyde 9:370 Isoannonacin-10-one 17:270 (+)-Isoaplysin-20 synthesis of 1:663,664 Isoaplysin-20 6:56 ()-Isoaplysin-20 6:56,57 Isoaquillochin diacetate 5:7,8 Isoarcapillin 227 Isoavenaciolide 19:485 synthesis of 3:260,261 Isobacteriochlorins 9:591,597,604 Isobalchanolide 7:231 Isobetanidine 20:724,731 (+)-Isoboldine 16:512 ()-Isoboldine 16:509 Isoboldine 18:58 Isobonafousine 5:128 (+)-Isobomyl acetate remote oxidation of 4:645,646

Isobrafouedine 6:172 biosynthesis of 6:521 spectral data of 6:403-506 from Strychmos dinklagei 6:503 Isobrucein 5:38-41 Isobrucein-A 7:396,397,72 Isobrucein-B 7:374,381 Isobrugierol 7:193,194 Isobutyl (2,4)-2,4,8-nonatrienamide 10:151 Isobutyl (2,4,8Z)-2,4,8-decatrienamide 10:151 Isobutyl (2,4,8Z)-2,4,8-eicosatrienamide 10:151 Isobutyl (2,4JE;,8Z,10)-2,4,8,10- dodecatetraenamide 10:152 Isobutyl-methoxy pyrazine 13:320 Isobutylamides molluscicidal activity of 7:427 Isobutyrate 11:197 in Streptomyces cinnamonensis 11:197 monensin A with 11:197 [l-*^C]Isobutyrate 5:608 N-Isobutyrolycycloxobuxine 2:205 N-Isobutyroylcycloxobuxidine-H 2:205 Isobutyryl CoA in Streptomyces cinnamonensis 11:197 interconversion of 11:197 stereochemical 11:197 (245)-24H-Isocalysterol 9:38,44,45 Iso-6-canavaline 20:486 2-/socaproyl-3 R-hydroxymethyl-y-butyro lactone 18:700 Isocarbacyclin enantioselective synthesis of 1:639-641 synthesis of 14:509 (+)-Isocarbacyclin synthesis of 6:315 preparation of 16:388 Isocaryophyllene synthesis of 3:73,74,84-89 6-Isocassine 9:50,53 (23R)-23H-Isocalysterol 9:38 (23S)-23H-Isocalysterol 9:38,45 from Calyx podatypa 9:38 Isocedranes 13:41 Isocedranol 15:270 5-Isocedranone 5:791,792 Isocedrene 13:46 6-Isocedrol 5:789 Isocelorbicol 18:743 2-Isocephems antibiotic activity of 12:126 synthesis of 12:126,127 Isochiloscyphone 18:614 Isochromazonarol 15:299 (2/?,35)-Isocitrate 20:872 Isocodonocarpine 9:53,54,57 Isocoma wrightii modhephene from 13:37 Isocomene 13:4-6 epz-Isocomene 3:41 P-Isocomene 3:6,20 Isocomene synthesis of 3:6,9,15,21,24,60

1073

(+)-Isoconcinndiol from Laurencia snyderae 6:26 ()-14-epMsocopal-12-ene-15,16-dial 6:108,110 (+)-gMsocopal-12-ene-15,16-dial 6:108,110 ()-14-e/7/-eMsocopal-12-ene-15,16-dial 6:111,119, 122 synthesis of 6:119-112 eMsocopalane 6:108 Isocopalane-type diterpenes 6:119-122 ()-Isocorynoline from corysamine 14:785-789 oxidation of 14:785-789 synthesis of 14:785-789 through enamine-aldehyde cyclization 14:785-788 Isocoumarins 7:266,267,270,287,20:283 Isocrepidamine 12:286 Isocrispatine 1:272,273 Isocyanides by alkylation of silver cyanide 12:113 by carbylamine reaction 12:113 by dehydration of N-minosubstituted formamides 12:113 from diphosgene 12:113 from phosgene 12:113 from triphosgene 12:113 Isodendrocrepine 12:286 from dendrocrepine 12:286 9-Isocyanopupukeanane 17:16 ()-9-Isocyanopupukenanane by Claisen rearrangement 6:82-83 by intramolecular cyclization 6:82-83 by internal alkylation 6:80 by selective hydrogenation 6:83 from bicarbocyclic lactone 6:80 from 3,5-dimethyl-2-cyclohexan-l-one 6:82-83 from hydrindanone 6:80 from Phyllidia varicosa 6:79 synthesis of 6:80,81 ()-2-Isocyanopupukenane by internal aldolization 6:81 from becarbocyclic lactone 6:80 from 2-ketopupukenanone 6:82 ^om Phyllidia 6:80 synthesis of 6:80,81 ()-Isocycloeudesmol 6:41,42 by olefin-ketocarbene cyclization reaction 6:41 relation to cycloeudesmol 6:41 from Laurencia nipponica 6:41 synthesis of 6:41,42 Isodactylol synthesis of 3:91-93 Isodactylyne Isodasycarpidone 1:58 synthesis of 1:58 ep/-Isodasycarpidone synthesis of 1:58 Isodeacetyl uvaricin from Annona bullata 18:221 from Uvaria narum 18:221 hemi synthesis of 18:221,222 Isodeoxybouvardin 10:640-642 synthesis of 10:644,645

Isodeoxybouvardin methyl ether 10:640-642 synthesis of 10:644,645 Isodesoxypicropodophyllin 18:588 Isodesoxypodophyllotoxin 5:485 Isodidemnin-1 5:422-426 Isodidemnin-I (didemnin-B) 10:251,253,262,263 Isodihydrofiitoquinol A synthesis of 8:169,170 Isodihydrofiitoquinol B 8:170 Isodihydroirido diol 3:193 Isodihydronepelactone 16:289 Isodiospyrin 7:423 Isodityrosine 10:629-669 synthesis of 10:630 Isodocarpin from Rabdosia ragosa 15:174 Isodomedin 15:174,175 from Rabdosia pseudo-irrorata 15:174 from Rabdosia umbrosa 15:175 from Rabdosia umbrosa var. hakusanensis 15:175 from Rabdosia umbrosa var. latifolia 15:175 Isodomoic acid E3 17:21 Isodonal 15:142,150,159,162,172,173 ^^C-nmrof 15:159 from Rabdosia japonica 15:172 from Rabdosia macrophylla 15:173 ^H-nmrof 15:152 Isodonoiol 15:143,152,160,172 ^^C-nmrof 15:160 from Rabdosia japonica 15:172 *H-nmrof 15:152 IsodopharicinA 15:115,122,129,174 ^^C-nmrof 15:129 from Rabdosia pharicus 15:174 'H-nmrof 15:122 Isodopharicin B 15:115,122,129,174 *^C-nmrof 15:129 from Rabdosia pharicus 15:174 *H-nmrof 15:122 Isodopharicin C 15:115,122,129,174 (+)-Isodrimenin 4:403-415,419 from Drimys species 4:404 from 1-abietic acid 4:405 from dpodocarpic acid 4:405 isomerisation from drimenin 4:407,408 synthesis of 4:405-415 Isodunnianol 20:271 Isodurene disulfonyl dichloride (DDS) 14:288 Isoebumamine synthesis of 14:635,636 (-)-Isoebumamine 9:179 Isoekebergolactone B 2:273 Isoekerbergolactone 9:95 Isoelaeocarpicine synthesis of 1:283 (+)-Isoelaeocarpine 12:277 Isoelectric focusing 2:19,347 Isoeleuterin 4:591 (+)-Isoepicampherenol 4:674 Isoeremolactone 15:210 synthesis of 8:425-428

1074

(+)-Isoeremolactone synthesis of 15:272,273 Isoeremophilone 15:243 Isoergosterol 18:509 Isoerivanin 7:232 Isoetin 5'-glucoside 7:206,207,227 Isoeucommiol 7:472,473,475,485 6-ep/-Isoeucommiol 7:473 Isoeugenol 5:473,497 Isoeuoniminol 18:747 Isoflavan 4:388,389,391,392 Isoflavones synthesis of 4:377,378,381-385,391-394,17:19 Isoflavonoids 7:193 Isoflustramine D 18:691 Isofraxidin 5:515,520,7:117,120,204,224 anticancer activity of 5:521 sedative activity of 5:521 28-Isofucosterol 20:234 Isofiilvine synthesis 1:272,273 Isofutoquinol X-ray crystallography of 8:170 Isofutoquinol B 8:170 Isogingerenone B 17:378 Isoglutamine isomerisation of 6:410 rearrangement to glutamine 6:409-413 Isogmelmol 5:533 Isoguanine 15:460 Isogymnochrome D 15:105-107 Isogymnomitrol 13:41 Isohemandin 18:586 Isohemandion from Heerandia ovigera 18:552 Isohoslundin 2:129,134 Isoiguesterim 18:776 Isoimperatorin 9:402 Isoindolme 8:397-403 as a2 agonists 8:397-403 synthesis of 8:400-402 cw Isoindoline 8:401 /ra/w Isoindoline 8:402,403 Isomdoline alpha-2 antagonists 8:400 Isomdolone 8:212,217 synthesis of 8:212;13:108-115;142 Isoingenol 1:571 Isoingenol synthesis 12:234-245 Isointermediol 20:473 Isoiridomymercin 16:289,20:68,69,74 Isojuliprosine 5:211 Isokaemferide 7:411-413 Isokomarovine from Nitraria komarovii 14:762 from quinoline-5-carboxylic acid 14:763 synthesis of 14:763 via Bischler-Napieralski condensation 14:763 Isolactarane 17:154 Isolancerotriol '^C-NMR spectrum of 5:736 5-isovalerate of 5:736 Isolariciresinol 20:108,620

Isolasalocid A 11:152 Isolaserpitine 5:725 Isolaulimalide 19:568 Isolaurepinnacin 19:411 synthesis of 10:210,213 (25,35)-Isoleucine (2/?,35)-alloisoleucine from 10:277,278 Isolevoglucosenone synthesis of 14:279 Isolexins 5:578 Isolichenan 5:309,310,322 Isolimonen 20:13 6-e/7Msolincosamine 11:446 Isolobophytolide synthesis of 10:10-13 Isolobophytolide antitumor activity 8:15,19-32 from Labophytum crassum 8:20 ^H-NMR spectrum of 8:20 synthesis of 8:19-32 X-ray analysis of 8:20 Isolongifolene 4:639 Isolongirabdiol 15:142 *^C-nmrof 15:159 from Rabdosia longituba 15:172 ^H-nmrof 15:151 Isomagellanol 18:746 Isomaltase 499,504,505,38:7:57 Isomaltose 15:436 Isomaltoside synthesis of 11:469-471 Isomarchantin C 2:283,284 Isomycorhodin 2:140 DEPT spectra 2:142 hetero COSY spectra 2:142,143 sugar residue of 2:143 (+)-Isomedicarpin tuberostan from 4:382,383 synthesis of 4:382,383 Isomelodienone 9:400 Isomenthol 17:605 a-Isomer 10:349 fromenone 10:352 P-Isomer by 1,4-addition of thiolane anion 10:354 D-/>ao-Isomer 5:705,706 Isomerase 17:480 Isomerization 1:189;6:117,126,153-155,157,221,541, 542,556 acid catalyzed 16:236 iodine catalysed 6:141 ofcarbon-carbon double bond 16:371 ofcyclosterol 16:332 ofdiene 1:447,448 of glutamine 6:410 of isoglutamine 6:410 of N-cyclohexylisopropylamine (MMA) 1:532 of olefins 1:413,414 photochemical 413,414 silylatropic 10:111 to catechol 16:615 with camphorsulfonic acid 6:222

1075

with iodine/benzene 1:447,448 with methyl magnesium derivative 1:532 /J.^ Isomerization 6:141 trans, cis Isomerization 6:141,142 CM-Isomerization 6:153,162 Isomers of 2-methyl-l,6-dioxaspiro [4.5] decane 14:526-531 synthesis of 14:526-531 Isomethuenine 5:126 Isomethuenine-A^-oxide 5:126 (+)-Isomintlactone 19:153 preparation of 19:152 Isomitocins mitomycins from 13:445-467 Isomitomycin A 13:434,445,446,453 from Streptomyces caespitosus 13:2 synthesis of 13:460-469 Isomolvizarin 18:193 Isomultiflorenol 7:164,165 Isomuramic acid 6:386 Isomyricanon 17:372 Isonaamidine 17:17 IsonaamineA 17:17,18 A*'^-Isonakafiiran-9 synthesis of 6:70 Isoneriucoumaric acid 9:293-299 Isongaione acetate 15:237 Isoniazid 2:424 7-cw-Isonieratene 6:155,156 Isonimocinolide 9:297-299 Isonitramine 14:742-750 *^C-NMRof 14:742 diastereoselectivity in 14:743-747 enantioselective synthesis of 14:743-747 from L-prolinol 14:743-747 from Nitaria sihricia 14:541 ^H-NMRof 14:742 synthesis of 14:543 Isonitrarine (3-epinitrarine) biosynthesis of 14:760 Isonitrile aldol reaction of 12:411,414 2-amino alcohol by 12:411,414 with aldehyde 12:411,414 Isonitrile 17:14 Isonitrile reduction chemistry 12:211 (-)-Isonootkatone 16:239 Isonoyanine 20:265 Isoopalanoids 6:108 from (+)-labda 8(20),13-diene-15-oic acid 6:57 synthesis of 6:119-122 Isophysodic acid 20:283 Isooxazolidine-4-carboxylic acid 12:156 Isoparvifolinone 5:800,801 formation from parvifoline 5:800,801 ozonolysis 5:800,801 (+)-Isopeduncularme *^C-NMRof 11:285 synthesis of 11:284,285 Isopelletierine 12:284 Isopenicillin 11:211 Isopenicillin-N-synthase 11:212,213

Isopentalenene 3:6,61 Isopentenol 7:104 Isopentenol (tetrahydrogeranylgeraniol) 8:70 Isopententenyl diphosphate famesyl diphosphate from 11:219-222 formation of 11:219-222 from mevalonate 5-diphosphate 11:219-222 geranyl diphosphate from 11:219-222 Isopentenyl diphosphate 7:322-324,330,348,352 Isopentenyl-diphosphate: dimethylallyl diphosphate isomerase 11:201 from Saccharomyces cerevisae 11:201 2-Isopentyl-3-(-4-methylpent-1 -enyl)-5-methylpyrazine 5:265,266 Isophytolaccagenin 7:144,145 Isophytolaccinic acid A 7:144,145 Isopicropodophyllone 5:481,483 e/-Isopimar-15-en-6a,7a,8a-triol ^^C-nmr of 15:170 from Rabdosia parvifolia 15:173 ^H-nmrof 15:169 ewMsopimarane 15:112 Isophysodic acid 20:283 Isopimaric acid from Salvia candidissima 20:690 from Salvia heldrichiana 20:690 from Salvia wiedemanni 20:690 Isopinocampheyl borane 13:71 L-Isopodophyllotoxone 18:600 ()-Isoprene 8:65 Isoprene 4:394 chromanesfrom 4:391,396,398 (Z)-Isoprene 8:65 Isoprene-rule diterpenes 11:4 Isoprenoid biosynthesis 17:471 Isoprenoid metabolites 11:219-222 Isoprenoids synthesis of 16:662-670 Isoprenoids 6:133,185 Isoprenylation by 4-(y,Y-dimethylallyl) tryptophan synthase 11:200 of tryptophan 11:200 Isoprenylphenols 17:451,20:271 biosynthesis of 17:747 2-Isopropenyhiaptho [2,3-b] furan-4,9-dione 20:494 Isopristimerin III 7:149,760 l,2:5,6-Di-0-Isopropylidene-D-glucose vinyl iodide from 12:41 Isopropyl 1-thio-P-D-galactopyranoside 8:315 8-Isopropyl-2,5-dimethyl-l,4-naphthoquinone 14:319 5-Isopropyl-3,7-dimethyl-1 -oxo-1 H-indene-6carbaldehyde 14:319 5-Isopropyl-3,7-dimethyl-lH-inden-l-one 14:328,329 7-Isopropyl-4-methyl-1 -azulenecarbaldehyde 14:319 3-Isopropyl-8-(3,7-diisopropyl-1 -azulenyl) benzofulvene 14:340 Isopropylcatechol taxodionefrom 14:684-686 D-Isopropylidene glycerldehyde 19:166 (/?)-2,3-Isopropyliden glyceraldehyde 12:21,22

1076

O-Isopropylidene protection with 6:269,270 5,6-0-Isopropylidene 1,2-(methoxycarbonyl) ethylidene-a-D- galactofuranose 14:233 1,2-0-Isopropylidene derivative 6:279,280,285,286 from D-xylose 6:269,270 from I-xylose 6:269,270 (R)-2,3-Isopropylidene glyceraldehyde 18:181 1,2-0-Isopropylidene-(-)-swainsonine 12:317 2,3-0-Isopropylidene-1,6-di-O-p-toluenesulfonyi-a-Lsorbofiiranose 10:528 4,5,(9-Isopropylidene-2-methylpent-2-ene-1,4,5-triol Claisen rearrangement of 10:436,437 with triethyl orthoacetate 10:436,437 Isopropylidene-3-deoxy-a,Z)-ribo hexofuranose 1,2-06:282,285 2,3-0-Isopropylidene-D-erythrose 12:318 1,2-0-Isopropylidene-D-glyceraldehyde (1,3dioxolane) 10:437,438 2,3-O-Isopropylidene-D-glyceraldehyde 6:353 2,3-0-Isopropylidene-L-erythrose (-)-8-ep/-swainsonine from 12:330,331 (-)-8a-e/7/-swainsonine from 12:330,331 (-)-8,8a-Di-e/7/-swainsonine from 12:330,331 2,3-Isopropylidene-I-threitol 19:167 1,8-0-Isopropylidenylcastanospermine 12:345 (-)-Isoprosopinine 12:435 (-)-Isoprosopmine A 12:475 Isoptera 19:118 Isotaxiresinol 20:108 Isotaxu'esinol-6-methyl ether 20:107 Isotenulin 20:10 ()-Isopteropodine 13:490,491 (-)-Isopulegol 16:268 Isopulmericin antifimgal activity of 16:299 antileukemic activity of 16:299 cytotoxic activity of 16:299 Isoquercitin 7:227 Isoquinoline 10:185,673,674 Isoquinoline alkaloids 1:168;5:3,42,494,265,266; 13:642 synthesis of 1:187-226 Isoquinoline derivatives 6:495,496 annelated benzazecines from 6:483 benzoxanecines from 6:483 methano-bridged benzoxaxecines from 6:483 Isoquinoline A^-oxides pyrolysis of 6:468 Isoquinoline-derived alkaloids synthesis of 6:467-502 Isoquinolinequinones 10:77-145 antibiotics 10:77-145 from actinomycetes 10:77-145 from marine sponges 10:77-145 naphthyridinomycin type 10:77,103-115 saframycin type 10:77-103 synthesis of 10:77-145 Isoquinolines 17:91 Isoquinolines, synthesis of 1:168 Isoquinolinium betaine 1:189

Isoquinolinium salt cycloaddition of 14:503 with chiral dienophiles 14:503 Isoqumolino-pyrolinedione photochemical reaction of 3:465,466 Isoquinuclidine 1:112 (+)-3-Isorauniticin synthesis of 16:437 3-Isorauniticine 9:171 Isorenieracistene 6:155,156 Isoreserpiline conversiont to bleckerine 1:158 Isoreserpiline 5:128 Isoreserpine 13:410 Isoretronecanol 1:231,233,235-237,241,244,247-251, 253,256,257,259,260,325,326,339 ()-Isoretronecanol synthesis of 13:483,484 Isoretronecanol from dihydrofriran 14:737 synthesis of 14:737 Isoretronecanol 3:54 Isoretronecanolate synthesis of 1:248 Isoretronecic acid synthesis of 1:265,266 Isoretulinal 1:36 Isoretuline 1:38,39 Isorhamnetin 5:652;7:206,227 P-Isorhodomycinone 4:318 by C-prenylation 4:382,384 from desoxybenzoin 4:383,384 Isoriccardin C 2:283,284 (-)-Isoroemerialinone 2:257 Isoridentin 7:230 Isosabandin 7:225 Isosaccharinolactone Isosacculatal 2:278,279 Isosafrol 8:161 ZIsosakuranetin 7:228 Isosalutaridine 18:58 Isosandwichine 9:183,185 Isoschaftoside 7:227 Isoscopoletin 5:515,516 Isoscopoletin-6-D-glucoside 5:515,516 Isoscutellarein 5:624,627,658 Isoscutellarein-4'-methyl ether 7-glycosides 5:658 epMsoshinanolone 2:213,215,216,222-224 Isoshinanolone 2:213,215,216,222,225,227,228 biosynthesis of 2:227,228 CD curve of 2:226,227 chemical interconversion of 2:222,223 configuration of 2:224 ' H - N M R spectrum of 2:227 oxidation with DDQ 2:227 physical data of isomers 2:225 stereoisomers of 2:222 structure and stereochemistry 2:222-225 UV spectra of 2:226 eo-Isoshinanolone 2:222,224 Isoshinanolone 5:754,755 isosilymarin 5:496 isositsu-ikine 2:375,125

1077
16-e/?/-Isositsirikine 5:125 ^-Isositsirikine 9:171 Z-Isositsirikine 9:171 Isositsirikines 9:168 Isosolenopsin A synthesis of 1:389,390 ()-Isosophoramine 18:323 5-ep/-Isospongiaquinone 15:315,318 Isospongiaquinone 15:315,418 Isostatine 10:263,266-269,272-275,278-284 (35,4/?,55)-Isostatine 12:476,477 Isosterism 13:165 Isostigamasterol 18:515 Isotelekin 7:233 Isotetracenone antibiotics 5:596,597 (+)-Isothebaine 16:512 Isothiocyanate 17:14 Isothiouronium salts 8:316 Isothujone 7:95,98,99,101 Isotingenone 18:760 Isotingenone III 18:760 (-)-Isotirucallol biomimetic synthesis of 16:211 Isotope effect 9:96,102-106,475,476 Isotope pattern 2:43,44 Isotopic analysis 13:334-337 Isotopic distribution 2:2,25 Isotope shifts 9:106 Isotricha 2:294 Isotrichodiol 13:524 Isotussilagin synthesis of 1:230,231 Isovaleraldehyde 4:396,398 17-Isowithanolide 20:246 Isoxazolidine 19:42 Istanbuline D from Salvia yosgadensis 20:660 Ixocarpalactone 20:241,242 Ixocarpalactone A 20:185,194,223 Ixocarpalactone B 20:181,194 5-Isovalerate offerutriol 5:725,727 ofisolancerotriol 5:725,727 of lapiferol 5:725 Isovalerate *^C-NMR spectrum of 5:735 oferpoxyisolancerotetrol 5:725,727 of epoxyj aesehkeanandiol 5:735 ofisolancerotetrol 5:725,727 6P-Isovaleroxylabda-8,13-dien-7a, 15-diol 17:27 Isovallesiachotamine 5:125 Isovangustin 7:233 Isovelbanamine fi-om 1-glutamic acid 14:866-867 synthesis of 14:865-867 via thio Claisen rearrangement 14:865-867 Isovincadifformine synthesis of 14:850-853 Isovincoside (strictosidme) 6:520 Isovitexin 7:227 Isovoacangine 5:127 Isovoacangine 9:174 7S-Isovoacristine 5:128 Isoxazolidine synthesis of 1:230,231 P-aminoalcohol from 12:290 hydrogenation of 12:290 Isoxazolines 12:20-22 Isozeylanone 2:212 Isozonarol from Dictyopteris undulata 6:17 Rau synthesis of 6:17 synthesis of 6:17,18 Welch synthesis of 6:17 Isozonarone 15:297 Isozymes 17:481 ^om Phaseolus vulgaris 9:563; Itersonilia tilletiopsis 5:291 Ito cyclization 10:6 Ivaxanthifolia 5:728 (+)-Ivalin 10:405,406 Ivermectin (22,23-dihydroavermectin Bi) biological activity of 12:8,9

(+)-Jaborol 20:181 Jaborosa bergii 20:180 Jaborosalactone A 20:234 Jaborosalactone F 20:223,20:242 Jaborosalactone M 20:181 Jacaranda acutifolia 5:682 Jacaranone 16:616 Jaceidin 7:227 Jaceosidin 7:227 Jaceosidin-7-sulphate 5:655 Jaceosidine-7,4'-disulphate 5:655 Jadiffine 9:172 Jaeschferin 5:722,725 Jaeschkeanadiol 5:722,723,730-332 Janua bioticus 17:100 Jasmin flowers 19:158 Jasmin-flower oil 6:557 Jasminin 7:443 Jasminum officinale 7:218,222,223 Jasminumsp. 7:218,219 cw-Jasmone 9:534,536 Jasminum grandiflorum 19:152,158-159 Jasmonicacid 6:557 Jaspamide (jasplakinolide) anthelmintic activity of 5:429 antifimgal activity of 5:428 insecticidal activity of 5:428 Jaspis 19:580 Jflf5/7w species 5:428,19:613 Jaspisamides A-C cytotoxic macrolides 613 from Jaspis species 19:613 Jatorrhizine by Berberis cell cultures 11:201 -204 formation of 11:201-204 from columbamme 11:201-204 Jatropha gossypilifolia 10:152 Jatrophane 2:262 Jatrophone 10:152,155,156

1078

Jegosapogenol 21 -(2,3-dihydroxy-2-methyl)butanoate)-22-angelate 7:139,141 Jeiranbatanolide 7:235 Jenkins's synthesis 12:185,186 Jervine 7:16,17,21,22 Jeunicin 17:22 JICST-E 19:758 JiuhuaninA 15:130 '^C-nmrof 15:155 from Rabdosia macrocalyx var. jiuhua 15:173 ^H-nmrof 15:146 Johnson synthesis oftaxodione 14:681-684 Johnson-Claisen rearrangement of allylic alcohols 10:428-438 ofaldoheptofiiranoses 10:432-436 of D-glyceraldehyde derived allylic alcohols 10:436,437 of 4-(3-hydroxy-1 -propenyl) derivatives 10:436-438 of L-lyxofuranose derivatives 10:431,432 Jone's oxidation 19:252,19:304,19:320-321 Jones reagent 19:173,19:428 JulichromeQi 20:277 Juniperus communis 20:16 Juniperus sabina 20:16 Juniperus virginiana 20:16 Johnson-Lemieux reaction 3:328 Jone's reagent 14:818 Jones map of amino acid residues 17:539 Jones model 17:507 Jones oxidation 4:456,50,465,470,490-492;16:323,29, 30,595,248,235,514,627,641,72,551,558 Jones reagent 6:17,25,55,78,509,515,461;12:466,508, 613 reaction with stypodiol methyl ether 6:55 Joullie method 10:283 Jourdan-Ullman condensation 13:353-355 Ju-Fang synthesis of(+)-polygodial 6:14 of(-)-polygodial 6:14 of()-polygodial 6:14 Juglone 9:258 Juglone derivative synthesis of 4:396,398 Julandme 1:363 synthesis of 1:365,367 Julia coupling 1:457,458,461-464 Julia olefmation reaction 16:230 Julia reaction 1:454,456 Julia sulfone 1:463 Julia synthesis 9:356 of aglycon of 22,23-dihydroavermectin Bib 12:17-19 Julifu-osine 5:211 Julifloricine 5:211 Julifloridine 5:211;9:70 Juliflorine 5:211 Juliflorinine 5:211 Juliprosine 9:72 Juliprosinene 9:71,72,77

Juliprosopine 9:70 Jung synthesis 12:19,20 Jungermannia infusca 2:280 Juniperus virginiana 15:346 Juniperus communis 5:485 Juniperus foetidissma 8,14-cedranoxide from 8:163 Junosidine from Citrus junos 13:348,349 Junosine from Citrus junos 13:348,349 Jusiaea decurrens 9:214 Justicia procumbens 17:333 Justicia prostata 17:335 (+)-Juvabione synthesis of 16:211 Juvenile hormone (JHI) synthesis of 1:704-707 Juvenile hormone III synthesis of 1:704,705

K-252a("SF-2370") 12:366,368 K-252b from Nocardiopsis sp. K-290 12:366,368 protein kinase C inhibitor of 12:384 K-252c (staurosporinone) from Nocardiopsis sp. K-290 12:366,368,369 protein kinase inhibitor of 12:386 synthesis of 12:379-381 K-252d 12:366,368,369,386 Nocardiopsis sp. K-290 12:366,368 protein kinase mhibitor of 12:386 K-25a 12:366,368,369,384,390,395,396,398,399 antaillergic effect of 12:398 anihypettensive activity of 12:398 antiinflammatory effect of 12:398 antitumor activity of 12:395 effect on nerve growth factor 12:396 from Nocardiopsis sp. K-252a 12:366,368 protem kinase A mhibitor of 12:384 prostaglandin production by 12:399 porcme spleen protein kinases inhibitor of 12:390 protein kinase C inhibitor of 12:384,390 protein kinase G inhibitor of 12:384 K-Selectride reduction with 12:151,152 stereoselectivity 12:151,152 KA-antibiotcs incarbapenem 4:434 Kabalka's procedure 6:547,548 KabiramideC 5:396,397,17 antifungal activity of 5:16 Kadsura s\iQC\QS 17:346 Kadsurenone 16:561 Kaempferol 7:206,227 Kaempferol 3-methyl ether from Salvia yosgadenis 20:712 Kaempferol 3-0-(6"-0-rhamnopyranosyl) galactopyranoside 7-0-glucopyranoside 5:633

1079

a//o-Kainic acid synthesis of 1:328,329,334,335 Kainicacid 12:446 Kairomones 8:219 Kala-azar 2:302 Kalafimgin 4:591,617,618,128 Kalopanax saponins 15:191 Kamebacetal A 15:135,137 from Rabdosia excisa 15:171 from Rabdosia henryi 15:172 from Rabdosia latifolia var. reniformis 15:172 from Rabdosia umbrosa \ar. leucantha 15:175 ^H-nmrof 15:145 Kamebacetal B 15:137 from Rabdosia umbrosa var. leucantha 15:175 'H-nmrof 15:148 Kamebakaurin 15:117 from Rabdosia excisa 15:171 from Rabdosia henryi 15:172 from Rabdosia inflexa 15:172 from Rabdosia longituba 15:173 from Rabdosia serra 15:174 from Rabdosia umbrosa 15:175 from/?, umbrosa war. leucantha 15:175 Kanamycine 20:714 Kamebakaurinin 15:117,125,131,175 '^C-nmrof 15:131 from Rabdosia umbrosa var. leucantha 15:175 ^H-nmrof 15:125 Kamebanin from Rabdosia excisa 15:171 from Rabdosia inflexa 15:172 from Rabdosia umbrosa 15:175 from Rabdosia umbrosa var. hakusanensis 15:175 from Rabdosia umbrosa var. latifolia 15:175 from Rabdosia umbrosa var. leucantha 15:175 Kanamycins 14:144 Kanedelia candel 7:180,181,183,184,194,195 Kanerin 9:293,294 Kanerodione 9:293,294 Kanerol 9:293 Kaneroside 9:293,294 Kansuinine B 2:262,264,266 Kaposis sarcoma 2:421 Karachicine 2:180,181 Karamatsu 20:613 Karatavic acid 1:660,662 from Ferula karatavika 1:660 synthesis of 1:660-662 cw-Karenin 9:295,296 transKzumm 9:295,296 Karpluspople expression 17:552 Karviskione 20:277 Kato's synthesis of^eco-taxane 12:181,182 Katsuki-Sharpless epoxidation 12:324,481 Kauniolide 7:235 (-)-Kaiir-16-en-19-oic acid 9:396,397 ert/-Kauran-16p, 17-diol from Rabdosia glutinosa 15:172 S,9-seco-ent-Kaura.nQ 15:162 Kaurane 9:271

(-)-Kaurane 19:387 Kaurane skeleton 19:387 6,1-seco-ent-Kaurane skeleton 15:136,162 Kaurane-type diterpenes enantioselective synthesis of 14:546 6,1-seco-ent-KauTanQS 15:112 e/-Kaurene 15:16,135 e/-Kaurene glycoside from Stevia rebaudiana 15:16-18 6,7-seco-ent-Kaurenoid diterpenoid 15:136 Kaurene-type diterpenoids 2:280 Kaurenoic acid 6:186 GAi2 aldehyde from 6:171,172 S,9-seco-ent-KsMrQnoids 15:112 e/-Kaurenoids 15:112 Kawin from Piper methysticum 13:660 KB activities 20:81 KDO (3-deoxy-D-manno-2-octulosonic acid) 13:207210 Keck method 11:157 Kedde reagent 19:753 Kelly procedure 10:111 Kemebakaurin 15:135 Kende's synthesis 12:187 Kent method 6:386 Keramamine A antimicrobial activity of 5:419 Keramamine B 5:351,352,419 antimicrobial activity of 5:419 Keratinocytes by staurosporine 12:393 tumor promoter in 12:393 Kermesicacid 20:768 Kerriamycin isotetracenon antibiotic 5:596 Kerriamycin A 5:596 ()-Kessane 14:365 Ketal 8:160 Ketalization 6:73,82,83,85 regioselective 11:41,42 /raws-Ketalization acid catalyzed 4:8,9 Ketalized Diels-Alder type adducts 17:458 Ketamine 18:680 Keten acetals Diels-Alder reaction with 4:357 Ketene complex 16:406 Ketene dithioacetal derivative preparation of 12:156,157 Ketene dithioacetal S,S-diozides 6:733 synthesis of 6:33,334 Ketene silyl acetals 4:463,464 Ketene-imine cycloaddition 4:440,470-472,474 1,2-diastereoselection 4:472 in Bose reaction 4:440,470 Ketenylidene-triphenyIphosphorane 4:569,572 P-Keto acetals addition of organometallic reagents to 14:497-499 diastereoselective 14:497,498 from (+)-(2/?,3/?)-1,4-dimethoxy-2,3-butanediol 14:497-500

1080

from (/?,/?)-2,4-pentanediol 14:497,499 LiAIH4-reduction of 14:499,500 NaBH4-reduction of 14:500 a-Keto acetals from (-)-(25,35)-l ,4-dimethoxy-2,3-butanediol LiAIH4-reduction of 14:500,501 Michael addition of 14:500,501 with methyl addition of 14:510 P-Keto cyclohexanecarboxylates 12:18 trans-^-Keto ester from azetidinone 4:437 P-Keto esters 4:436,439 in asymmetric hydrogenation 4:439 P-Keto thioester reduction of 11:195 4-Keto-5-methyl-/ra5-decalins 9:30 P-Keto-acid 8:384 decarboxylation of 8:297 a-Keto-p,Y-unsaturated acetal addition of Grignard reagents 14:496 5-Keto-imine intermediate benzodiazonin-3-one from 6:480,481 a-Ketoacetals diastereoselective reduction 1:622 3-Ketoadociaquinone A 17:33 a-Ketoamide from aminoketal 11:286 p-Ketoamide asymmetric hydrogenation of 12:162 4-unsubstituted P-lactam from 12:162 a-Ketobutyric acid 13:319 Ketodeoxoscalarin 17:10 3-Ketoepitaondiol 17:8 p-Ketoester 6:429,430;14:652,653 P-Ketoester enolization 14:734 a-Ketoglutaric acid 9:542,543,553 4-Ketoheptanolide 19:422 Ketohexopyranose nucleosides 4:248-253 7-Ketoisodrimenin 20:469 7-Ketoisodrimenin-5-ene 20:469 Z?w-a-Ketol astaxanthin 6:152,153,161 a-Ketol rearrangement 11:53,54 Ketolactam 6:510-513,602 ellipticine derivatives from 6:510,511 Ketologanin 7:470 Ketone formation by epoxide rearrangement 5:782,783 Ketone reduction Luche's conditions 1:415,417 stereoselective 1:415,417 to equatorial alcohol 1:415,417 with axial hydride attack 1:413,415 withNaBH4-CeCl3 1:413,419 Ketonucleosides 4:234,253,19:512 biological activity in 4:253 stereospecific reduction 4:253 Ketonucleosides synthesis of 19:512 3 '-Ketonucleosides 19:513 Ketopelenolide A 7:231

Ketophosphonate 6:275-277 from lithiomethylphosphonate 6:276 macrolidefrom 6:276,277 Ketopinic acid reduction of 12:417 4-subsituted 2-oxazolidinones from 12:416,417 with L-Selectride 12:417 (IS)-Ketopinicacid 12:417 from (-)-camphorsulfonic acid 12:417 (+ytrans-Ketopmic acid 4:640,641 3 -(I5)-Ketopinyl-2-oxazolone methoxybromination of 12:419-422 methoxyselenylation of 12:421,422 /ra5-5-bromo-4-methoxy derivatives from 12:419-421 reversed n facial selection in 12:419-422 Ketoprofen 6:323 3-Ketopropyl-197?-heyneanine 9:171 2-Ketopupukeanone (+)-2-isocyanopupukeanane from 6:82 Ketopyranose nucleosides 4:248 3-Ketoreductase 19:648 Ketoresorcinol 19:226 A-nor-Ketosteroid 2:163 A-seco-6-Ketosteroid Cotton effect of 2:169 Ketosugars Grignard reactions with 4:353,354 p-Ketosulfoxides reaction with enolate anions 4:502 reduction 4:502-504 synthesis of carbohydrates 4:504-512 synthesis of macrolides 4:513-512 3-Ketotrichothecene 3a-hydroxytrichothecene from 6:229 reduction of 6:229 8-Ketotrichothecenes 6:230,231,234,235 Ketotriol asadanin 17:369 Ketourethane 12:303 Khaya grandifoliola 5:700 Khusimone synthesis of 3:32 (+)-Khusimone 4:674 Kidamycin "aglycone" antitumor antibiotics 11:136 0-methyi derivative of 11:137 1 -oxabenz [a] anthracene 11:136 synthesis of 11:135-139 Kigelia africana 7:406 Kijanimicin 19:118 I-Kijanose 19:118 Kikumycin 5:553,554 Kikumycin A Kikumycin B 5:553 Kinetic deprotonation of 2 cyclohexen-1-one 11:337,338, ofenone 11:368 Kinetic isotope effect 7:56,57 Kinetic parameters of cellobiose analogues 7:65,66 of lactose analogues 7:67.68 of methyl p-gentiobioside 7:52

1081

of methyl P-lactoside 7:52,54 of phenyl P-D-glucopyranoside derivatives 7:55,56 Kinetic resolution 1:508,698,3:23,19:478 by Sharpless epoxidation 4:342 of secondary 2-furylcarbinols 19:478 under Sharpless epoxidation conditions 19:478 Kinetin (6-furfurylaminopurine) 7:90 Kinetoplastid flagellates 2:298 polysaccharides as markers 2:298 Kmgiside 16:307 from Lonicera morrowii A. Gray 16:307 Kinoprene 13:667 Kirby reaction 8:76 Kirk-Petrow reaction 10:409 Kishi synthesis 13:436-442,443,457,458,461 of mitomycins 13:4-10,25,26,29 Kishi'srule 1:404,130,163,167,168,171,175;4:178, 181,183,184,188,197,202,203,705 Kishi's-model 4:503,504 Klaineanone synthesis of 11:74-76 Klebsiella 12:63 Klebsiella pneumoniae 5:325,308,308,106,12:400; 20:712 Klemer fragmentation 3:201,202 Klemer-Rhodomeyer reaction 1:510,511 Kloeckera africana 5:283 Kloeckera magna 1:701,283,13 in microbial reduction 6:13 Klityveromices species 13:302 Klyne-Hudson rule 15:207 Knoevenagel condensation 6:67,68,316,320,328,331, 334,53 in 14-e/7/-upial synthesis 6:67,68 Knoevenagel condition 11:140 Knoevenagel cyclisation 9:341 Knoevenagel reaction 13:109 Knoevenagel-type reaction 7:475 Kocienski-Lythgoe condensation 4:602,603 Kocienski-Lythgoe-Julia olefination reaction 11:393-395 Kodo-cytochalasin-1 and2 15:353 Koenigs-Knorr reaction 6:395 Koenigs-Knorr condensation 3:199 modification of 3:199 Koenigs-Knorr coupling (Ag2C03-AgCL04) 1:419,420 Koenigs-Knorr procedure 10:571 Koenigs-Knorr reaction 8:359,363,206,258 Koenigs-Knorr synthesis 10:466 Koga's method ofasymmetrization 11:241,242 of a-symmetric ketones 11:241,242 Kograva toxicity 15:353 Koidzumiol 7:218 Kojic acid 0-alkylation of 12:269 with allylic bromide 12:269 [4+2] cycloaddition of 5:799 from Taxus mairei 20:118 Kokoona zeylanica 5:743-745 D:A-friedo oleananes from 7:147-149

phenolic triterpenes from 7:147-149 triterpene quinone methide from 7:147-149 Kokoondiol 5:744-746,147,148 Kokoonol 7:147,148,147,148; 3,27-diozy derivative 5:745 3,21,27-trioxy derivative 5:745 Kokzeylanol 5:744-746,147,148 Kokzeylanonol 7:147,148 Kolavenic acid agelasin B from 6:28 from Solidago species 6:28 Kolbe reaction 9:371 Komaroine 14:762 from Nitraria komarovii 14:762 Komarovi(di)ne 14:758 Komarovicine from Nitraria komarovii 14:762 from quinoline-8-carboxaldehyde 14:763 komarovidine from 14:763 komarovine from 14:763 synthesis of 14:763 via Pictet-Spengler reaction 14:763 Komarovidine biosynthesis of 14:763,764 from komarovicine 14:763 from Nitraria komarovii 14:762 from quinoline-5-carboxylic acid 14:763 synthesis of 14:763 via Bischler-Napieralski condensation 14:763 Komarovine biosynthesis of 14:763,764 from komarovicine 14:763 from Nitraria komarovii 14:762 Komarovinine biosynthesis of 14:763,764 from Nitraria komarovii 14:762 from quinoline-6-carboxaldehyde \4\163 synthesis of 14:763 via Pictet-Spengler reaction 14:763 Konevenagel-type reaction 11:139 Kopsidasinine 5:53,9:188,189 Korupensamine C 20:449,451 from Ancistrocladus kerupensis 20:447 er-Korupensamine D 20:440 Korupensamines A and B 20:443,451 from Ancistrocladus kerupensis 20:442 Koteconazole 2'A23M^ Koumicin N-oxide 15:466,467 Koumicine 15:466,467 19(E)-Koumidine 15:466,467 from gardnerine 15:469 Koumine from Gelsemium elegans 15:475,476 Koumine Nb-oxide from Gelsemium elegans 15:475 Koumine-type alkaloids 15:475-477,500-503 synthetic studies of 15:500-503 Kouminol 15:475 Kozikowski's retrosynthetic analysis 13:588 Kozikowski approach for avermectin oxahydrindene subunit 12:20-22 Kozikowski's nitrile oxide 12:21,22

1082

Krapcho decarboxylation 18:246 Kraus method 6:225,226 Kraus's method 11:129 Krebs cycle 7:112,117,387 Krebs cycle enzymes 11:197 Krebs tricarboxylic acid cycle 6:252 Krohnke's procedure 6:513 Krohncke reaction 20:602 Kryptogenin 5:774 KT-5720 12:384-386 KT-5822 12:384-386 KT-5926 myosin inhibitor of 12:388 protein kinase mhibitor of 12:385,386 Kuanoniamines A-D 17:23 Kuehne's synthesis of vinblastine 14:831-849 of vincristine 14:831 -849 Kuhn-Roth oxidation 11:210 Kulactone 9:300,305,308 Kurarmine 9:150 Kurilogenin 7:280 from Duasmodactyla kurilensis 7:279 Kuriloside A from Duasmodactyla kurilensis 15:89 Kurospongin 5:371 Kutney's synthesis ofvinblastine 14:806-821 of vincristine 14:806-821 Kuwajima's B-ring cyclization route 12:190 KuwanonG 17:451 biosynthesis of 17:165 optical rotation of 17:464 KuwanonsJ 17:455 I-A;y/o-hex-2-ulosonate 20:858 (+)-Labda-8(20),13-dien-15-oic acid 6:56,57,111,117, 120,125 er-Labdane 15:252 Labdane diterpenoids 1:662 Labdane-type diterpenoids 20:691 Labdanes 10:408 (+)-(13E)-13-Labdene-8,15-diol 1:671,672 Labiatae 7:96,118-120 Labumine synthesis of 1:248,339 Lac-permease 8:353 Lacarol 7:224 LaccaicacidC 20:277 Laccol 9:319 Lachnanthes tinctoria 4:618 Lachnanthocarpone 17:372 Lachnanthocarpone formation 4:618 Lachnates 17:372 Lachnophyllum ester 7:221 Lacinartin 7:204,205,224 Laciniatafuranone 9:532,533 Lactam 0-methylation 1:325,326 P-Lactam 12:115,159-172 by4CC 12:115

from p-amino acids 12:115 C4-alkylation of 12:159-172 Lactam analogues 12:388 Lactam carbonyl selective reduction 3:474 p-Lactam compounds from P-amino acid 12:155-159 synthesis of 12:155-159 Lactam sulfoxide cyclization of 3:109 p-Lactamase 16:727 P-Lactamase stability oftheinamycin 4:431 P-Lactamase TEM-1 inhibitor of 16:728 Lactams 17:573 ^^0-NMR 17:573 P-Lactams 11:706-213 biosynthesis of 11:207-213 5-Lactams 18:315 synthesis of 18:315 p-Lactamase inhibition by thienamycin 12:145 P-Lactamse mhibitor 12:135 Lactarane 17:154 Lactarazulene 14:315 Lactarius camphoratus 17:156 Lactarius chrysorrheus 17:196 Lactarius circellatus 17:197 Lactarius controversus 17:198 Lactarius deceptivus 17:198 Lactarius deliciosus 17:198 Lactarius deterrimus 17:198 Lactarius flavidulus 17:198,201 Lactarius fuliginosus 17:153,201 Lactarius fulvissimus 17:200 Lactarius genus 17:153,156 sesquiterpenes from 17:159 biogenesis of sesquiterpenes from 17:159 Lactarius glaucescens 17:198 Lactarius glutinopallens 17:199 Lactarius glyciosmus 17:199 Lactarius helvus 17:199 Lactarius indigo 17:199 Lactarius lignyotus 17:200 Lactarius mitissimus 17:200 Lactarius necator 17:199 Lactarius pergamenus 17:198 Lactarius picinus 196,201 Lactarius piperatus 17:197,198 Lactarius quietus 17:196 Lactarius rufus 17:199 Lactarius scrobiculatus 17:153,196,197 Lactarius subvellereus 17:198 Lactarius thejogalus 17:200 Lactarius torminosus 17:196,197 Lactarius vellereus 17:153,196,197 Lactarius, metabolites 17:154 Lactase 10:498 Lactate synthesis of 12:223

1083

(i?)-Lactates 8:140 (5)-Lactates 8:140 Lactic acid 2:163 Lactiflorasyne 7:204 from Artemisia lactiflora 7:203 X-ray analysis of 7:203 Lactiflorenol 7:218 from Artemisia lactiflora 7:218 Lacto-7V-biose I 10:459,461,467-471,476 synthesis of 10:474,475 Lacto-AT-biose II [GlcNAcP(l-3) Gal] fromoxazoline 10:474,475 Lacto-iV-wo-octaosyl ceramide 10:461 Lacto-A^-eo-hexaose 10:478,480 by double glycosylation 10:478 Lacto-A^-weo-tetraose 10:462 fromoxazoline 10:478 Lacto-A^-tetraose from Lactobacillus bifidus 10:468 Lactobacillus helveticus 13:319 Lactol 11:140,141 Lactone hydrogenation of 19:469 methylation of 19:469 stereochemistry of 19:469 y-Lactone reduction of 19:470 (45',55)-Lactone 8:296 S'-Lactone 8:298,306 syn addition of 8:306 (4/?)-Lactone anti addition of 8:305,306 /^-Lactone 8:298 Lactone annulation 13:29-31 Lactone Claisen rearrangement 13:544,596 Lactone methyl-isomerase 8:300 Lactone rearrangement fragmentation 3:96 Lactone synthesis 13:615-626 asymmetric synthesis of 13:621,622 Lactone synthon 13:615 synthesis of 13:615 Lactone triflate ring contraction reaction 10:605 to oxetane-2-carboxylate 10:605 Lactone unit construction of 11:345-347 model studies on 11:345-347 of compactm and mevinoline 11:345-347 5-Lactones 10:218 Lactones CD of 2:171 saturated 17:275 synthesis of 3,157,171;10:385-388;14:557,558 unsaturated 17:271 via intramolecular hetero-Diels-Alder reaction 14:557,558 Y-Lactone 17:270 Lactonisation acid-catalyzed 12:157,158 by Gerlach's procedure 6:542,543 of A^-acetyl muramic acid 6:389,390,395

ofw-hydroxy-acids 8:233 with pyridinium acetate 11:84,85 Lactoperoxidase 19:455 Lactoquinomycin 11:128 Lactosamine A^-acetylation of 10:462 catalytic hydrogenation of 10:462 from3-0-|3-D-galactopyranosyl-D-arabinose 10:463 from D-lactal hexaacetate 10:464 from lactose 10:462-466 from monosaccharides 10:466,467 synthesis of 10:461,467,471 Lactosaminoglycan 10:460 Lactose 1:508,509,499 Lactose analogues 7:67,68 Lactosylceramide 18:796 A^-(5)-Lactoyl-(5)-proline 13:482 Lactuca virosa 20:8 Lactucin 20:8 Lactucopicrin 20:8 Ladenburg prism mechanism 7:362,263 Ladybird alkaloid 6:447 Laevigatoside 7:293 from Linckia laevigata 7:290 Laeviuscolosides F,G,H and I 15:64 Laevoglucosan 1:453 Lagerstroemia subcostata Koehne 1:368 Laguncularia racemosa 7:175 Lahoramine synthesis of 1:207 Lahoricine 5:125,158,159 Lahorine 1:207 Lamalbid 7:471 (+)-Lambertic acid 10:407,640-642 synthesis of 14:640-642 Lamellariidae 17:21,22 Lamellarins A-D 17:22 Lamiide acid rearrangement of 7:463 aglycone 7:463 Lamiide aglycone reduction of 7:475 Lamiidol 7:467 Laminarabiose hydrolysis of 8:349 (-)-Laminitol 18:434 Lamiol 7:440,455,459,460,464-466 Lamiol aglycone reduction of 7:475 ()-Lamprolobine 18:367 Lamprometra palmata gyges 7:266 Lanatoside A-E 15:362 Lancerodiol 5:732 /7-methoxybenzoate of 5:724,725 Lancerotriol /7-methoxybenzoate of 5:724,725,731 Lancerotriol ester 5:732 Lankaumycin 4:255 Lanostane 9:267,302 Lanostene triterpenes 10:151 Lanosterol 7:266

1084

Lanosterol ester 9:467 Lansic acid synthesis of 1:658-660 Lansiolic acid synthesis of 1:648-660 Lansioside A,B,C 1:658 Lansium domesticum 1:658 Lanularic acid 2:287,288 Lapidin 5:722,723 Lapidolin 5:722,723 Lapiferine 5:722,723 Lapiferinin 5:722,723 Lapiferol *^C-NMR spectrum of 5:736 isovalerate 5:736 LappaolB 5:497,498 Lardoglyphus konoi pheromoneof 1:696 (-)-lardoIure from 14:487 Lardolure from acarid mite 1:696 synthesis of 1:696 (-)-Lardolure from Lardoglyphus konoi 14:487 synthesis of 14:487 (+)-Lariciresinol 20:620 (+)-Lariciresinol ferulate 20:620 (+)-Lariciresinol p-coumarate 20:620 Larixdecidua 17:332 Larix leptolepis 20:613 Larmor frequency 9:127,131 Larrea divaricata 17:315 Larrea tridentata 5:9 Larreantin 5:9-11 Larus asrgentatus hemoglobin components of 5:837 Larus Philadelphia hemoglobin components of 5:837 Larvotoxic 17:102 Lasallia papulosa 5:311 Lasallia pensylvania 5:311 LasalocidA 11:196 synthesis of 10:424,715 Laser desorption mass spectrometry (LDMS) 5:632,633 Laser desorption 9:487 Laserpitine 5:725,727,734 Laserpitium halleri subsp. halleri 5:728 Laserpitium latifolium 5:725,727 Lasiantheaefruticosa 5:728 Lasidiol angelate 5:728,729 Lasioderma serricorne (cigarette beetle) 1:695,275 serricomin from 14:275 Lasiodiplodia theobromae 6:557,290,477 Lasiodiplodin 9:288,289 Lasiodonin 15:172,173 from Rabdosia gaponica var. glaucocalyx 15:172 from Rabdosia macrophylla 15:173 from Rabdosia parvifolia 15:173 Lasioglossumzephyrum 8:222 Lasiokaurin from Rabdosia henryi 15:172 from Rabdosia japonica 15:172

from Rabdosia longituba 15:172 from Rabdosia macrophylla 15:172 Lasiokaurinol 15:172 Lasius niger 6:454 Lasonolide A cytotoxicity of 19:570 (-)-Lasubine synthesis of 16:477 Lasubine I synthesis of 1:367-370 Lasubine II 1:367 4-e/7/-Lasubine II 1:368 2-e/7/-Lasubine II 1:369 "Latent Michael-acceptor" 12:99 Latrinculia brevis trunculin-A,B from 9:20 Latrunculia apialis 18:716 LatrunculinA 17:13,19:568 Latrunculins 19:550 Latrunculin magnifica 17:14 Laudanine 18:49,73 S'-Laudanosine 16:507 (+)-Laudanosine oxidation of 16:506 ()-Laudanosine methiodide 6:475,476 cw-Laudanosine A^-oxide 2,3-benzoxazepine derivative from 6:468 Meisenheimer rearrangement product from 6:468 ()-Laudanosine A^-oxide preparation of 6:472 themolysis of 6:472 Laulimalide 19:568 Lauraceae 9:402,240,327 Laurane 9:81 Laurediols 19:454 Laureline synthesis of 3:424,425 Laurenan 10:232 Laurencenynes 19:454 Laurencia concinna concinnidiol from 6:24 Laurencia glandulifera glanduliferol from 6:63 (+)-Laurencin 19:412 Laurencia implicata brasilane sesquiterpene from 18:633 Laurencia majuscula bromochamigrene from 6:60 Laurencia nipponica 6:41,63 (-)-(2/?,65,95)-2,8-dibromo-9-hydroxy-achamigrene from 6:63 ()-isocycloeudesomol from 6:41 Laurencia obtusa 5:363;8:625 brasilenol from 6:6 brasilenol acetate from 6:6 brasilenol from 6:6 e/?/-brasitenol from 6:6 Laurencia okamurai 19:454 Laurencia pacifica (+)-2-bromo-P-chamigrene from 6:63 Laurencia perforata 6:29,30,56 Laurenciapinnata 6:9,26

1085
Laurenciapinnatifida 5:216,363,81 -8 marine sesquiterpenes from 9:81-83 Laurencia poitei poitediol from 6:35 Laurencia snyderae 6:6,30 epiguadalupol from 6:30 guadalupol from 6:30 isoconcinndiol from 6:30 Laurencia sp. 5:361-363,368,370 Laurencia specie 6:24,59,60;9:8;10:231 (-)-aplysin-20 from 6:24 10-bromo-a-chamigrene from 6:60 spirobicarbocyclic chamigranes from 6:59 cyclic ethers from 10:213 Laurencia subopposita 6:10 oppositol from 6:9 prepinnaterpene from 6:9 Laurencia venusia 5:361 Laurencin 10:201;19:411 total synthesis of 10:202 absolute stereochemistry of 19:422 EI-HRMS of 19:422 IR spectrum of 19:422 isolation of 19:421 (+)-Laurencin 19:412 Laurenene from Dacrydium cuprassinum 13:19 X-ray crystal analysis of 13:19,20 Laurenene 3:6,25,61,117 Laurenobiolide 7:231 Laurenyne 19:411 (-)-Laurenyne synthesis of 10:225 Laurifine synthesis of 6:477,478 Laurifinine synthesis of 6:477,478 Laurinterol 17:7 Laurol (7-hydroxy-3,4-epoxy-laurane) 9:81,82,87 Laurolenal 2:170 A^-Lauroylvaline synthesis of 6:320 Laurycolactone A 11:71 Lauryl chloride protection with 6:429 A^-Lauryl-6-methyl-2-piperidone pyrolysisof 6:430,431 Lauthisan synthesis of 10:213 (+)-Lauthisan 10:232,19:412,420 synthesis of 10:232;19.412 cis -Lauthisan synthesis of 10:235 Lavandula angustifolia 7:94,95,108,109,118,119,125, 126 Lavandula sp. 7:125 Lavandulol 7:126 Lavendamycin 3:385 synthesis of 3:387 Lavendustin 15:444-447 Lavendustin A and B 15:445 Lawesson's reagent 3:354,355;8:126,127;10:565; 12:301,305,322 LC chromatogram 19:771 LD50 7:280,284,306 Lead tetraacetate oxidation of diol 1:439 oxidation of ring C of yohimbine 1:15 8,439 glucuronide linkage cleavage by 7:156-158 Lead tetraacetate oxidation 5:788 Leaf spot disease 4:601 Lectins 7:129 Ledol 20:17,19 Ledum palustre 20:17 Leech repellent 5:745 Leepacine 5:150-152 Lefevreiosides Ai, A2, C and D 15:96 Legionella pneumophila 13:155 Legislation 13:337-340 Leguminosae 7:413,414,417,427,429,431-434,358,366, 19:118 Leishma braziliensis 2:311 Leishmania 18:791,793,794 Leishmania adleria 2:311,313 immunity against kala-azar 2:313 Leishmania amazonensis 2:298,794 Leishmania donovani glycopetidophosphophingolipid 2:312 polysaccharides of 2:311,312 Leishmania enrietti carbohydrates in 2:314 Leishmania mexicana amazonensis 2:314 carbohydrates in 2:314 Leishmania spp. glycocomplexes of 2:311-314 polysaccharides of 2:311-314 Leishmania tarentolae 2:298,311 carbohydrates in 2:311,314 Leishmania tropica major polysaccharides in 2:314 Leishmaniases 2:293 Lemieuix oxidation 18:171 Lemieuix-Johnson oxidation 4:592,593;10:591-592; 13:613;18:81 Lemieux-Nagabhushan reaction 14:145 Lemieux-von Rudloff oxidation 1:261 -262;6:291,292 Lemmatoxin molluscicidal activity of 7:428 Lemmatoxin-C molluscicidal activity of 7:428 Lemna bioassay 9:386,387,389,390;15:344 Lemna minor (duckweed) 9:383,384,386,387,389,390 Lennoxamine 1:163,164 synthesis of 1:176,177 Lentinan 5:279 antitumor activity of 5:317 Lentinus edodes 5:287,288,316 Leontice leontopetalum 9:153 Lepidine 3:396 Lepidoptera 9:322,772 a,P-Leprosols 9:322,338,345 Leptinel 7:18 Leptinidine (23P-hydroxysolanidine) 7:18,22

1086
Leptochilus acolhuus 5:223,224,253 Leptodactylin 15:328 Leptogenys diminuta (3i?,45)-4-methyl-3-heptanol from 11:415 Leptogorgia virgulata 17:99 Leptomonas collosoma 2:301 Leptomonas samueli 2:298 polysaccharides of 2:301 Leptophyllin-A 20:486,487 Leptophyllin-B 20:486,487 Lesquerella species 13:310 Lethality bioassay of brine shrimp 9:385,387,388,399,400 Letharia vulpina 5:310,311,313 Lethasterias nanimensis chelifera 15:59 Leucadendron 4:712 Leucetta chagosensis 17:17 Leucine aminopeptidase 12:434 Leucine aminopeptidase A 12:434 Leucocyclies formosies 10:151 Leucojum aestivum 20:359 Leucojum vernum 20:359 Leucodopachrome 16:614 Leucodrin 4:712 Leucomitomycin C 13:436 LeucomycinAa 5:611,612 Leucomycins 11:164 Leuconolide Ai 11:163,170 Leuconolide A3 11:163,170 Leuconolides 11:160,163-172 stereoselective synthesis of 11:163-172 Leuconostoc measenteroides 2:350,314,325,69;7:69 Leucophaea maderae 9:488,489 Leucoquinazirine 4:351 Leucospermum 4:712 Leucotriene B4 synthesis of 10:168 (+)-Leucoxylonine 16:505 Leudrin 4:712 LeukameninE 15:175 from Rabdosia umbrosa var. latifolia 15:175 Leukemia 1:275 Leukotrienes 1:528 Leukemia P388 19:558 Leukoencephalmalacia 9:215 Leukopenia 5:135 Leukotrien A4 synthesis of 4:567 14,15 -Leukotriene A4 1:533 Leukotriene A4 5:513 Leukotriene B3 synthesis of 10:159,12:399 Leukotrienes semi-synthesis of 17:642 Leukotrienes 5:513,9:368,559,560 biosynthesis of 9:562,576 Leurocristine from Catharanthus roseus 13:655 Leurosidine 14:813,840-846 enantioseletive synthesis of 14:840-846 from anhydrovinblastine 14:871 oxidation of 14:813 3'-oxoleurosidine from 14:813 Leurosine biosynthesis of 14:820,821 cleavamine from 14:862,863 deacetylvindoline from 14:862,863 20'-deoxyvinblastine from 14:863,864 Na-demethyl-Na-formylleurosine from 14:818,819 from anhydrovmblastine 14:820,821,871,872 from Catharanthus roseus 14:859 from 15p,20(3-epoxydihydrocatharanthine 14:871,872 from leurosine N-oxide 14:864 (15'/?)-l 5'-hydroxycatharinine 14:813,814 oxidation of 14:813,814 3'-oxoleurosine from 14:813,814 21 '-oxoleurosine from 14:813,814 synthesis of 14:811 vinblastine from 14:860 Leurosine conversion to anhydrovinblastine 5:186,189 Leurosine N-oxide leurosine from 14:864 Leurosinone 5:144-146 Levansucrase from Bacillus subtilis 8:353 Levoglucosan 12:44,45 a-methyl aldehyde from 12:45 Levoglucosenone (-)-a//o-yohimbane from 14:267,276,277 (-)-eldanolide from 14:272,273 (-)-/raAw-cognac lactone from 14:272,273 (-H'*a5-whisky lactone from 14:272,273 (-)-5-multistriatin from 14:273,274 (+)-multistriatin from 14:267 (S)-5-hydroxy-2-penten-4-olide from 14:273,274 cycloaddition of 14:270,271 from D-galactose 14:267 Michael addition reaction of 14:271,272 oligomerization of 14:271,272,274 Prelog-Djerassi lactonic acid from 14:267 preparation of 14:268 purpurosamine C from 14:268 reaction of carbonyl group 14:268,269 reaction of double bond 14:269,270 reserpinefrom 14:267 serricomin from 14:267,275 synthesis of 14:267,268 tetrodotoxin from 14:267,276,277 Lewis acid catalysis 11:446-451 Lewis jung carcinoma 19:609 Lexitropsins 5:567,578 Ley synthesis ofavermectinBia 12:22-24 Ley's procedure in ()-polygodial synthesis 6:13 LiangshaninA 15:114 '^C-nmrof 15:128 from Rabdosia Hangshanica 15:172 H-nmrof 15:121 LiangshaninB 15:114

1087

"C-nmrof 15:128 from Rabdosia liangshanica 15:172 'H-nmrof 15:121 LiangshaninC 15:114 *^C-nmrof 15:128 from Rabdosia liangshanica 15:172 *H-nmrof 15:121 LiangshaninD 15:115 from Rabdosia liangshanica 15:172 ^H-mm-of 15:122 LiangshaninE 15:115 ^^C-mnrof 15:129 from Rabdosia liangshanica 15:172 'H-nmrof 15:122 LiangshaninF 15:116 ^^C-mm-of 15:129 from Rabdosia liangshanica 15:172 ^H-mnrof 15:123 LiangshaninG 15:114 '^C-mnrof 15:128 from Rabdosia liangshanica 15:172 'H-nmrof 15:121 Libinia emarginata juvenile hormone from 1:704 Lichenan 5:309-311,322 Lichens 9:317,328 LiC104 as supporting electrolyte 8:166,167 Licoisoflavone synthesis of 4:378,383 y-Licorane synthesis of 3:431 Licoricone synthesis 4:378,383 Lienomycin 6:261 relative configuration of 6:251 Ligand-receptor interactions 19:240 Ligase 17:480 Light circularly polarized 2:154 interactions with molecules 2:155,156 linearly polarized 2:153 Light scanning detection (LSD) 18:195 Lignan podophyllotoxin 13:654 Lignans 5:9,459,503, 753,754,311;17:313,441; 20:108-113,273,613 from Hernandia ovigera 18:551 synthesis of 18:551 biological activity of 5:505,544,545 from A bies sachalinesis 20:613 -620 from Salix sachalinensis 20:627 Lignarenones A,B 10:152,167,171 synthesis of 10:167,171 Lignin 5:309-311,322,461-463,467,472 Ligularone synthesis of 4:615 Liliaceae 6:487,7:427,17:130 Limonen 20:6,13,16 Lilium longifolium teasterone myristate from 18:507 teasterone 3-myristate from 18:495,522 Limatine 1:40

Limatinine 1:40 Limatulone 17:26,27 Limbinol from Salvia limbata 20:683 LimocinA 9:300,302,303 LimocinB 9:300,302,303 Limocinin 9:300,304,305 Limocinol (tirucalla-7,24-dien I6P-0I) 9:300,301 Limocinone 9:300-303 Limonene 20:6,13,16 (+)-Limonene Nazarov cyclization of 10:412 (+)-Limonene oxide 19:205 (+)-Limonene 5:702;15:257 (-)-Limonene 16:211,216 Limonene 16:211,221,260 /?-(+)-Limonene 5:732,733;8:48;16:208 5-(-)-Limonene 6:74,75;16:208,225 (-)-pseudopterosin A from 6:74,75 Limonene-1,2-oxide 16:208,217 Limonia acidissima 20:497 Limonin 9:307 Limonoids 9:307,20:492 from Trichilia emetica 20:492 Linalol 13:332 Linalool 20:587 Lindlar catalyst 19:42,594 Linalyl acetate 17:604 (-)-(3R)-Linalyl diphosphate 11:220 Linarioside 7:440 Linckia guildingi 7:298 Linckia laevigata 7:290,295,46,61 laevigatoside from 7:290 maculatoside from 7:290 marthasteroside Al from 7:290 ophidianoside F from 7:290 thomasteroside A from 7:290 Lincomycin 1:429 Lincosamine 11:429 and galacto configuration 4:147,148 by [4+2] cycloaddition 4:145 fromD-threonine 4:140-143,145,147,148,:140,141 synthesis of 4:140-143,145,147,148 Lincosamine derivative 4:145 by cw-hydroxylation 4:145 Lindelofine synthesis of 1:267 Linderazulene 5:368,369;14:315 Lindlar catalyst 6:79,157,559 triple bond reduction 4:532 Linear conformation ofpolyketide 11:115 Linear triquinane 13:34-46 synthesis of 3:14 Linearly polarized light 2:154 Lineus fuscoviridis 18:725 a-Linked 3'-deoxycyclitol synthesis of 14:147 P-( 1 ^ 1 )-Linked 4,4'-dithiotrisaccharides synthesis of 8:344-346 P (1^6)Linked 6-thiodissacharides synthesis of 8:339

1088

P-(l-6)-Linked disaccharides 6:395,396,403 a-D-Linked glucans 5:288 Linked scan mass spectra 2:43 1-^4 Linked thiodisaccharides 8:329-337 1-^2 Linked thiodisaccharides synthesis of 8:327,328 l->6 Linked thiodisaccharides 8:340 1^3 Linked thiodisaccharides synthesis of 8:329 1^6Linked thiosaccharides 8:338-340 S'-Linked thiotrisaccharides 8:340 Linkiol 5:725,727 Linkitriol /7-methoxybenzoate of 5:725,727 Linoleic acid 13:304,305,311,313,659 Linoleic acid (9,12Z)-octadecadienoic acid 9:560-563, 565-567,573-575,581 Linolenic mmethyl ester 2:11 Lipase 19:48,153 Lipase? 1:687,19:153 Lipase PS 16:703 Lipases 13:9,14 Lipid disorders 5:695 Lipid outoxidation 9:564 Lipid peroxidation inhibitor of 4:495 Lipid storage disease (phytoesterolemia) 9:478 Lipid-linked high-mannose oHgosaccharide (IV) 10:499 Lipo-CCK physical properties of 18:844-848 biological properties of 18:857-863 Lipo-gastrin physical properties of 18:844-848 biological properties of 18:844-848 Lipohilicity 15:355 /?(+)-a-Lipoic acid synthesis of 1:536-538 Lipoic acid synthesis of 1:600,602 Lipopeptidophosphoglycan (LPPG) 2:302-309 Lipophilic derivatives 18:840-851 Lipophilicity 4:369 Lipophosphoglycan (LPG) 2:312 from Leishmania donovani 2:312 Lipoxins 9:559 biosynthesis of 9:561,575-578 Lipoxygenase 13:303,305,311 5-Lipoxygenase 5:513,514,820 Lipoxygenase 5:521,559-589 Lipoxygenase catalysis products of 9:559-589 substrate of 9:559-589 5-Lipoxygenase inhibitory activity 2:282,284,335 Lipoxygenation 9:573 of linoleic acid 13:311 /^-Lipoxygenation 9:574,575 Lipozyme activity 20:845 Lippia nodiflora 5:647,648,655 Lippiasp. 7:427 Lipriadulcis 15:14

Liquid secondary ion mass spectrometry (LIMS) dispersing matrices 2:20 effect of salts 2:24 of bovine insulin 2:23-25 of methiony 1-enkephalin I-.IX-IZ of peptides 2:20-30 spectrometry (LIMS) 2:20-41 Liquid secondary ionization LSI MS 9:487 Liquid sodium amalgam 11:371 Liquid sodium-potassium alloy 11:371 Liriodendron tulipifera 5:476 Liriodenine 2:435-439;9:396,398,20:483 activity in 2:435,437,439 Lirodendrin 5:475,476 Lisianthoside 7:443 Lissoclinamides (1-5) 10:242,243 Lissoclinotoxin A 10:244 Lissoclinum bistratum 10:243 Lissoclinum patella 4:89,93,99,5:419,420,10:242,243 Lissoclinum perforatum 10:244 Lissoclinum vareau 10:243 Lissodendoryx isodactyalis 5:395,13:168,18:715,716 (-)-Listenolide Cj and C2 16:698-699 Lithiated trimethylsilylacetonitrile 1:311,312 Lithiation of 2-methoxy-A^,A^-diethylbenzamide 5:827 of 3-methoxy-A';A^-dimethylbenzylamine 5:828, 5:829 with 5ec-butyllithium 5:827,828 1- Lithio glycals by direct lithiation 10:345 from tributyltm 10:345 2-Lithio-2-phenyl-6-heptene synthesis of 8:7,8 2-Lithio-3,3-diethoxy-1 -propene 12:36,40,43 Lithiodianion-imine condensation 4:433,443-448,450, 464 Lithioglycal 10:346 N-Lithioimidazolidines anionic cycloreversion of 1:349-351 2-azaallyl anions from 1:349-351 Lithium /4,4'-di (tert. butyl) biphenyl (DTBBP) 11:309 Lithium di (a-ethoxyvmyl) cuprate addition of 12:25 BF3 0Et2 promoted 12:25 toA^'^enone 12:25 Lithium isopropylcyclohexylamide (LICA) 10:410 Lithium methylcrotyl aluminate condensation with 6:298,299 Lithium organocuprates 1,4-addition 4:555,556 Lithium organyls 1,2-addition 4:556-558 Lithium \xi-sec butylborohydride (L-Selectride) 11:234 Lithium triethyl borohydride 11:423 reduction with 11:83,84 Lithontriptic 20:79 Lithramine 20:276 Lithospermum erythrorhizon shikoninfrom 7:88 Littorine 17:397

1089
Lituaria australasiae 19:596 Lituarines A-C 19:596 Liu-Kulkami synthesis 6:43,44 Liver cancer 20:528 Liverwort sesquiterpenoids absolute configuration of 18:607-646 Liverworts 1:719,81,273,277-290 Lividomycin A 14:186 Lividomycin B 14:145,186 Z)-Lividosamine 14:144 Z)-and I-Lividosamine synthesis of 14:186-193 I-Lividosamine 14:144 Lobaria retigera (-)-retigeranic acid from 13:22 Lobatosides 15:191 (7E)-LobohedIeoUde 10:13,14 Lobohedleolide 8:15,14,5,13,14 inhibition ofhela cells growth 8:16 of hela cells 8:16 Lobophylum crassum 8:11 isolobophytolide from 8:20 Lochnera (Vinca) rosea 1:125 Lochneram 13:387 Lochnericine 2:375 20-e/7/-Lochneridine 1:32,127 Lochneridine 1:36 Lochneridine 5:172 Lochnerine 9:174,386,429 Loco syndrome 7:71 Locusta 9:489 Locusta migratoria manilensis 18:771 Locusta migratoria migratorides 7:395,18:771 Loganiaceae 6:520,530 pyrido [4,3B] carbazole alkaloids in 6:507 (+)-Loganin synthesis of 16:294 Loganin 6:503,529,7:440,455,470,20:47 strychonovoine from 6:524 Loganin aglycone silyl ether from Strychons nux vomica 16:293 synthesis of 16:293-294 Loganin derivatives 6:524 Lombardo methylenation 6:209 Lombardo reagent methylenation with 11:40,41 Lonchura malabarica hemoglobin components of 5:837 Lonchura malacca hemoglobin components 5:837 Lonchura punctuiata 5:837 hemoglobin components 5:837 Long range heteronuclear COSY spectrum 2:147-151 isomycorhodin 2:150 Long range '^C-*H-COSY spectrum 2:93,95, of 20 (5)-hydroxydammaran-3-one 2:39,94 ofdendropanoxide 2:100 of marchantin A trimethyl ether 2:107,112 of marchantin A trimethyl ether 2:107,112 of sacculaplagin triacetate 2:87 Long range HETCOR 9:147,151,153 Long-chain sugars 14:179 Long-rang 5C/5H COSYspectrum 2:115,261,263, Long-range *^C-'H-shift correlation spectrum ofacteoside 5:507 Long-range C-H couplings in aromatic compounds 2:115-135 (+)-Longibomeol 4:675 (+)-Longicamphor 4:675 Longicaudosides A,B 7:309,94 from Ophiderma longicaudum 7:308 Longifolene 4:675,16:136,608 to isologifolene 4:639 Longifolene 7:110 LongikaurinA 15:138,145 ^^C-nmrof 15:155 from Rabdosia longituba 15:173 from Rabdosia ternifolia 15:175 'H-nmrof 15:156 LongikaurinB 15:139 ^X-nmrof 15:156 from Rabdosia longituba 15:173 'H-nmrof 15:147 LongikaurinD 15:175 from Rabdosia trichocarpa 15:175 LongikaurinG 15:139 *X-nmrof 15:156 from Rabdosia longituba 15:172 ^H-nmrof 15:147 Longilobol from Artemisia longiloba 7:218 Longipinane derivatives 7:218 Longipinen synthesis of 8:33,37 Longipinen-7-ol NOED spectra of 9:534 a-Longipinene synthesis of 8:33,37 p-Longipinene synthesis of 8:33,37 (+)-a Longipinene synthesis of 8:37 (+)-P-Longipinene synthesis of 8:37 Longirabdosin 15:116,123,135,173 from Rabdosia longituba 15:173 'H-nmrof 15:123 Lonicera nigra I'All Lonomycin 19:128 Lophanthoidin A 15:167,168-170 ^^C-nmrof 15:170 from Rabdosia lophanthoides 15:173 ^H-nmrof 15:169 Lophanthoidin B 15:168-170 '^C-nmrof 15:170 from Rabdosia lophanthoides 15:173 'H-nmrof 15:169 Lophanthoidin C 15:168 from Rabdosia lophanthoides 15:173 'H-nmrof 15:169 Lophanthoidin D 15:168 from Rabdosia lophanthoides 15:173 ^H-nmrof 15:169

1090

Lophanthoidin E 15:168-170 "C-nmrof 15:170 from Rabdosia lophanthoides 15:173 *H-nmrof 15:169 Lophanthoidin F 15:168-170 ^^C-nmrof 15:170 from Rabdosia lophanthoides 15:173 *H-nmrof 15:169 Lophozozymus pictor 5:393 Low-valent titanium from reductive elimination 4:521-535 Lotus uliginous 19:117 Low-valent titanium reagent keto aldehydes with 11:3 64 preparation of 11:364 (LPLC) 7:407,408,410,415,418 antigenic specificity of 4:195 6-deoxy-D-mannoheptose in 4:195 interleukin I induction by 4:197 LSPD experiments 2:111 ofmarchantinA 2:108,112 Lucenin2 7:207 Luche reaction 1:474 Luche reduction 14:126,19:372-373 Luche-type reduction with a,(3-unsaturated ketone 4:130 Lucidene 751 Ludalbin 7:232 Ludongnin 15:112 LudongninA 15:112,141 '^C-nmrof 15:158 from Rabdosia rubescens 15:174 from Rabdosia rubescens var. lushiensis 15:174 ^H-nmrof 15:149 Ludongnin B 15:141 '^C-nmrof 15:158 from Rabdosia rubescens 15:174 from Rabdosia rubescens var. lushiensis 15:174 ^H-nmrof 15:149 LudovicinA-C 7:232 Luffariella variabilis 17:10 Luffariella variabilius 18:717 Luffariellin A and B 18:717 LuffariellinA-D 17:10 Luidia maculata 7:303-306,15:46 luidiaglycosides A-D from 7:288 maculatoside from 7:289 marthasterosides from 7:289 thomasteroside A from 7:289 Luidiaglycosides A-D 7:288,289,293 from Luidia maculata 7:288 Lukes-Sorm dilactam 6:441,442,444 T-Lumicolchicine 5:47-49 P-Lumicolehicine 5:47-49 Lumnitzera sp. 7:176 Lupeol 7:189 Lunacarine 3:385,386 Lunaricacid 2:288,289 Lungshengrabdosin 15:120 '^C-nmrof 15:134 from Rabdosia lungshengensis 15:173 ^H-nmrof 15:127 (+)-Lupanine 15:520 (+)-Lupanine N-oxide 15:523

Lupeol 9:267,20:698 from Salvia glutinosa 20:707 from Salvia montbretii 20:704 ^om Salvia pomifera 20:702 Lupin alkaloids 15:519-549 Lupinamine biomimetic synthesis of 14:739,742 enantioselective synthesis of 14:741,742 ep/-Lupinamine biomimetic synthesis of 14:739,742 enantioselective synthesis of 14:741,742 Lupine alkaloids synthesis of 14:731-768 (+)-Lupinine synthesis of 16:462 Lupinine 14:731,732 from dihydropyran 14:737 from piperidine acetic acid 14:738 selectivity of 14:737,738 synthesis of 14:731,737,738 (-)-Lupinine 15:520 ()-Lupinine 18:345,356,370 Lupinus hirsutus 15:521 Lupinus luteus (-)-(trans'4' -P-D-glucopyranosyloxy-cinnamoyl) lupinine from 15:521 (-)-(/ra5-4'-|3-D-glucopyranosyloxy-3'methoxycinnamoyl) lupinine from 15:521 (-)-(/rfl/M-4'-hydroxy-cinnamoyl) lupinine from 15:521 (-y(trans-4' -rhamnosy loxy-ciimamoy 1) lupinine from 15:521 {-)-(trans-4' -rhanmosy loxy-3' -methoxy-cinnamoy 1) lupinine from 15:521 Lupinus termis 15:524,525 (-)-A^-dehydroalbine from 15:524 (-)-A^-dehydromultiflorine from 15:525 Lushanrubescensin 15:120 '^C-nmrof 15:134 from Rabdosia rubescens 15:174 from Rabdosia rubescens var. lushiensis 15:174 'H-nmrof 15:127 Lushanrubescensin B 15:120 '^C-nmrof 15:134 from Rabdosia rubescens var. lushiensis 15:174 ^H-nmrof 15:127 Lushanrubescensin C 15:118 ^^C-nmr of 15:131 from Rabdosia rubescens 15:173 from Rabdosia rubescens var. lushiensis 15:174 'H-nmrof 15:125 Lushanrubescensin D 15:118 '^C-nmrof 15:131 from Rabdosia rubescens var. lushiensis 15:174 *H-nmrof 15:125 Lushanrubescensin E 15:118 '^C-nmrof 15:132 from Rabdosia rubescens var. lushiensis 15:174 H-nmrof 15:125 (-)-Lusitanine 15:522 from Maackia amurensis 15:522 Luteicacid 5:299

1091

Lutein 7:98,320,336,350,351,352,363,20,584,727,733 absolute configuration of 7:360 C-3 hydroxylation of 7:359-361 from Calendula officinalis 7:361 Luteolin 5:497,7:206,207,227 from Salvia limbata 20:712 ^om Salvia montbretti 20:712 from Salvia nemorosa 20:712 from Salvia s dare a 20:712 from Salvia yosgadensis 20:712 Luteorosin 17:12 2,6-Lutidine monomorine I from 6:445,447 2,6-Lutidine 7:154 Luvunga angustifolia suberosine from 20:497 Luzonicoside from Echinaster luzonicus 7:294 Luzonicoside A 15:59,60 Lyase 17:480 Lychnophora sellowii bisabolone from 8:48 Lycoctonin 20:22 Lycopene 7:318,319,321,322,327-354,358;20:561,587, 588,725 Lycopersium esculentum 20:135 Lycorenine 20:351,20:352 Lycorine 20:234,347,351,356,367,368,384 from Narcissus pseudonarcissus 20:233 Lycoris incarnata incartinefrom 20:351 T-Lymphoblast cells 19:556 Lyngbia gracillis 19:586 Lyngbia majuscula 19:492,587 Lyophilization 19:703 (7Z,9Z,7'Z,9'Z)-Lycopene 7:330,335 from (9Z,7Z,9Z)-neurosporene 7:332 Lycopersene 7:325,326 Lycopersicon esculentum 18:523,529,532,533 ()-Lycopodine 18:321 Lycopodium alkaloid 18:3-7 Lycopodium alkaloids 16:456;18:341 Lycopodium magellanicum 18:3 Lycopodium paniculatum 18:3 Lycopsamine 1:269 Lycoramine 4:13 from Amaryllidaceae 4:3,4 retrosynthesis of 4:4,5 synthesis of 4:20-23 y-Lycorane 16:427 a-Lycorane synthesis of 1:337 Lycorenine model synthesis 1:333,334 (+)-Lycoridine 16:429 Lygodium japonicum 1:683 antheridiogen from 6:194,204-206,208 Lygos raetam (-)-6a-hydroxylupanine from 15:524 (+)-12a-hydroxylupanine from 15:524 Lymphatic filariasis 12:9 Lymphocytes 15:369 Lymphocytic leukemia system 18:696 Lymphoid leukemia 4:723

Lyngbya gracilis 17:4 Lyngbya majuscula lyngbyatoxin from 11:278 Lyngbya majuscula 5:411 ;18:294 Lyngbya Xoxm A 5:412 cytotoxic activity of 5:411 Lyngbyatoxin from Lyngbya majuscula 11:278 Lyophilization 11:271 Lyratol 7:208 Lysergic acid 11:201 Lysergic acid synthesis of 4:604,605 Lysicamine 2:436 Lysicamine synthesis of 3:444 Lysocellin 15:455 Lysostaphin 6:398 Lysozyme 2:31,32;7:31,32,49,55,57 transition state analogues of 7:49 Lysozyme mechanism 7:31-36,43,50 Lysozyme reaction 7:49 Lytechinastatin from Lytechinus variegatus 7:285 Lytechinus variegatus 7:285;15:104 lytechinastatin from 7:285 Lythgoe aldehyde from D-carvone epoxide 10:46 Lythgoe-Inhoffen diol 10:49,50 D-Lyxitol synthesis 4:506 D-Lyxo-pentodialdofliranoside Wittig olefmation of 4:176 L-Lyxofiiranose derivative from 1,2-0-isopropylidene-P-L-idofiiranose 10:431 Johnson-Claisen rearrangement of 10:431,432

Maackia amurensis (+)-13 p-hydroxymamanine from 15:522 (-)-lusitanine from 15:521 Maackia tashiroi 15:523 tashu-omine from 15:523 (+)-Maackiain fromchromene 4:385,386 synthesis of 4:385,386 (-)-10-e/7/-Maalienone 14:359 Maaliol (-)-P-gorgonene from 6:28 Mabinlin 15:36 Macarpine from oxychelirubine 14:781-783 from sanguinarine 14:779 synthesis of 14:781-783 v/a chelirubine 14:779 MacbecinI 3:233;10:150,153 Macbecmll 10:153 MacfarlandinA-E 17:11,12 MacLafferty rearrangement 6:443 Macralstonidine 13:383,392,405,406 Macralstonine 13:383,392,405 Macroalgae 19:549

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MacrocalinA 15:112,;19:555 antibiotic activity of 19:556 cytotoxic activity of 19:556 from Rabdosia macrocalyx 15:173 synthesis of 19:556 MacrocalinB 15:138,146,173;19:555 from Rabdosia macrocalyx 15:173 *H-nmrof 15:146 Macrocalyxin A 15:112,143,161 '^C-nmrof 15:173 from Rabdosia macrocalyx 15:173 from/?, macrocalyx war.Jiuhua 15:173 'H-nmrof 15:152 Macrocalyxin B 15:112 from Rabdosia macrocalyx 15:173 Macrocalyxin C 15:112 from Rabdosia macrocalyx 15:173 Macrocalyxin D 15:116,123 *^C-nmrof 15:130 from Rabdosia macrocalyx 15:173 'H-nmrof 15:152 Macrocalyxin E 15:116 ^^C-nmrof 15:130 from Rabdosia macrocalyx 15:173 ^H-nmrof 15:123 Macrocalyxoformin A 15:141,150,158,172-174 '^C-nmrof 15:158 from Rabdosia henryi 15:172 from Rabdosia macrocalyx 15:173 from Rabdosia sculponeata 15:174 ^H-nmrof 15:150 Macrocalyxoformin B 15:141,149 from Rabdosia macrocalyx 15:173 *H-nmrof 15:149 Macrocalyxoformin C 15:141 '^C-nmrof 15:158 from Rabdosia macrocalyx 15:173 ^H-nmrof 15:150 Macrocalyxoformin D 15:142 *^C-nmrof 15:159 from Rabdosia macrocalyx 15:173 'H-nmrof 15:151 Macrocalyxoformin E 15:142 '^C-nmrof 15:159 from Rabdosia macrocalyx 15:173 'H-nmrof 15:151 Macrocarbocyclic rings synthesis by titanium 8:16-18 with TiCls/Zn-Cu 8:16-18 Macrocarpamine 13:393 Macrocycle synthesis of 10:280,281 Macrocycles 8:175-201,219-256 Macrocyclic [2,3]-Wittig rearrangements 8:196 Macrocyclic antibiotic 4:255,574 Macrocyclic cytochalasans synthesis of 13:115-120 Macrocyclic derivative from tetrahydroisoquinoline precursor 6:495 Macrocyclic diarylether glycosides 17:367 Macrocyclic diarylheptanoids synthesis of 17:387 Macrocyclic diterpenes 8:221

Macrocyclic hydrocarbons 8:15-31 Macrocyclic lactones 12:243;17:75 as a defence secretion 8:220 Macrocyclic lipids from Calderiella sp. 11:464 Macrocyclic pyrrolizidine dilactones 1:270-275 Macrocyclic reaction 8:175-201 Macrocyclic sesquiterpene alklaoids 18:753-755 Macrocyclic transannular reaction 8:187-201 conformational control in 11:152-163 of geranyl geranyl pyrophosphate 11:24 with Hanessian's epi-merization 12:28 Macrocyclization 4:591;8:21;11:24,152,158, 163;12:28 by allychromium species 3:81 by dicarbonyl coupling 3:80 by Michael additions 3:83 by Nicholas reactions 3:83,84 by transannular acylation 3:81 for synthesis for 8-membered rings 3:80-84 polymer supported 3:82-83 transition metal mediated 3:80,83 Macrodithiolactones 10:227,228 by macrolactonization 10:227 by sulphurization 10:227,228 from hydroxy acids 10:227 Macrofoulers 17:99 Macroheterocyclization palladium mediated 16:423 Macrolactone biological activity effects on 13:155-185 Macrolactonization 1:445,452,453,461,462,464,465; 8:233-242;9:246,247,290;12:244;13:115,20 A^'^Macrolide 12:13 Macrolides 3:277-281;4:513-520;5:609,356,357,6:272277;9:246,247,290;8:175-201,222;16:658-662 absolute configuration of 5:609 from ketophosphonate 6:276,277 structure determination of 5:609 synthesis 4:513-520;8:175-201 (0-1 hyroxylation of 8:222 (O-hyroxylation of 8:222 P-oxidation of 8:222 Macrolide antibiotics 3:277-281;5:606,609,613;195; 13:155-185,664 acetylspiramycin 5:609 biosynthesis of 11:192 difficidin 5:609 erythromycin 5:609 methylmalonyl CoA with 11:196 oleandomycin 5:609 oxydifficidin 5:609 synthesis of 12:35-62 Macroline alstonerine from 13:398 biomimetic transformation of 13:398 synthesis of 13:383,411,423,424 Macroline-related alkaloids classification of 13:384-394 synthesis of 13:383-432 MACROMODEL 17:494,500,529,540

1093
Macrophiotrix longipeda 7:309 Macrophomisphaseolina 6:555 Macrophyllin B from Rabdosia longituba 15:173 Macrosalhine 13:389 Macrospegatrine 13:391,396 Macrostamine 4:547 Macrotermitinae 8:220 Maculatoside from Linckia laevigata 7:290 from Luidia maculata 7:289 MacusineB 13:387 Maduralide 19:559 Madelimg reaction 1:52 Maderrhodins B 5:617,618 Maesa lanceolate 5:819;17:240 Maesanin 5:819-823 ^^C-NMR spectrum of 5:820 from Maesa lanceolate 5:819 ' H - N M R spectrum of 5:819 reaction with ClCHzOCHa/NaH/DMF 5:822 reaction with KOH/EtOH 5:822 reaction with MCPBA/CH2CI2 5:822 synthesis of Magellanine 18:3-7,665 Magellaninone 18:3-7 Magellanol 18:746 Magic bullet 9:491,492 MagireolA 5:363 MagireolB 5:363 MagireolC 5:363 Magllanesine from oxyberberine 6:470 MagnamycinB 5:613 Magnifera indica 9:321 Magnolia salicifolia 17:348 Magnolia sp. neolignans from 8:159 Magnolialide 7:213 Magnoliophyta 18:740 Magnolioside 7:224 Magnolitae 18:740 MagnomycinB 10:170 Magnus's synthesis of vinblastine analogues 14:821-830 of vincristine analogues 14:821-830 Mahmoodin 9:297,298 Maillard reaction 13:317-319 Majetich synthesis ofperforenone 6:32,33 Maj idea foster i majideagenin from 7:141 triterpenoids of 7:139,141 Majideagenin from Maj idea fosteri 7:141 Majoranolide 9:402 Majorenolide 9:402 Majorynoide 9:402 Majvinine 13:386 MaJcisterone A 19:628 (+)-Makomakine 11:278,279 (+)-aristoteline from 11:292-295 synthesis of 11:280-283 Malabaricanediol 17:611 MALDI 19:751 Maleic acid in mangrove plants 7:180 /w-Maleimidobenzoyl-N-hydroxysuccinimide ester 18:911 N"-Maleoyl-P-alanyl-gastrin-[2-17] derivatives 18:913 (5)-Malic acid 8:140; 365;13:513; 14:521-527 dimethyl ketal from 11:346,347 reduction of 11:404 4,7-dioxaspiro [5.5] undecane from 14:521-526 2-methyl-l,6-dioxaspiro [4.5] decane from 14:526-527 L-Malic acid chiral ylide from 4:125 in mangrove plants 6:263 in mangrove plants 7:206 Malic acid dehydrogenase 7:387 /?-(+)-Malic acid 16:691 (5)-Malic acid ester (5)-butan-l,2,4-triolfrom 6:287,290 Malkanguniol 18:744 Mallory stilbene photocyclization 3:305 Malondialdehyde 9:564 ene reaction of 6:225,226 Malonicacid 13:53,67 in mangrove plants 7:180 Malonic diesters enzymatic hydrolysis of 13:56,57 Malonyl-CoA 9:341;11:194 Malonylsaikosaponins 15:191 Maltase 10:504 castanospermine inhibition with 7:12 Maltase-glucoamylase 10:498 Maltase-glucoamylases (y-amylases) 10:498 Maltby's-generalization 4:200 Malto-oligosaccharides 2:328;7:33,34,39 p-Maltose 7:58 Maltose derivatives 7:62,63 Maltose-1-^^C hydrolysis by glucoamylase 2:332,333 4-0-Maltoside 8:349 3'-5-Maltosyl-glyc-2-enopyranoside maltotriose 8:343, 345 Maltotetraoses from taka amylase 7:34,35 Maltotriose 8:343,344;15:436 a-Maltotrioside 7:35 Malvaceae 5:751;7:185 Malyngolide 3:157,158 Malvin-3,5-diglucoside 20:724 (-)-Mamanine N-oxide from Sophora chrysophylla 15:522 (-)-Malyngolide 19:463 antimicrobial activity of 19:492 isolation of 19:492 Mamanuthaqumone 15:300,315 Mammary carcinoma 1:275

1094

Mammea africana 7:417 Mammea americana coumarins from 4:389,391 {-yMammea B/BB 390,391 synthesis of 4:390,391 Mammea longifolia coumarins from 4:389,391 sarangin B from 4:391 Mandelic acid as chiral auxiliaries 1:603 (/?)-Mandelic acid 19:355 (/?)-Mandelohydroxamic acid 19:355 (5)-Mandelic acid 12:473 (5)-(+)-Mandelic acid 13:468 Mandragora officinarum 13:631 Mandshurin manica bradleyi 5:250 Manduca sexta juvenile hormone from 1:704 Maneonene 17:7 Mangamines 5:346-353 Mangrove plants 7:175-199 Manica bradlyi 5:250 Manica hunteri 5:250 Manica mutica 5:250 Manica rubida 5:235,254 2,5-dimethyl-3-methyl-pyrazines of 5:222 2,5-dimethyl-3-methyl-pyrazines of 5:222 methyl pyrazine of 5:222 Mannans 5:280-285,291,292,299,306,323,324 Mannich base methiodide condensation of 14:406-408 withthujone 14:406-408 Mannich condensation in ()-stoechospermol synthesis 6:39 Mannich reaction 1:244;6:39;9:332;13:473;16:481 intramolecular 14:746 of dimethyl a-ethylmalonate 14:850 with diethylamine 14:850 with vitamin 4:715 Mannich-Aldol condensation 12:293 D-Mannitol 3:225;9:288;14:633;15:426 (45)-hydroxymethyl butanolide from 6:292 dehydration of 3:225 Z)-Mannofiiranose phosphorus analogues of 6:355 Mannoglucogalactan 5:300 Mannojirimycin 7:42;10:538-542,550 from Streptomyces lavendulae 10:538 mannosidase inhibition with 7:41 ()-Mannonolactam 18:347 Mannonolactone 7:49 Mannopyranose 7:47 Z)-Mannopyranose system Ci chain elongation of 4:201 Z)-Mannopyranoside 6:373,374 a-Z)-Mannopyranosyl 1 -thio-a-D-mannopyranosides 8:319,321,347,348 a-D-Mannopyranosyl a-D-mannopyranoside 8:347 a-I-Mannopyranosyl glycosides 7:70 2-a-Mannopyranosyl-1 -phosphatidlyl-Z)-w>'o-inositol 18:449 D-Mannose 4:199,200,354

L-Mannose Wittig methylenation 10:413 Mannose 7:181 Z)-Mannose-6-(Z)-mannosyl phosphate) 5:284,285 D-Mannose-molybdate complex 15:434 a-Mannosidase 19:354,19:356-357 lysosomal 19:487 Mannosidase inhibitor of 19:356 mannojirimycin inhibition by 7:41 Mannosidase II 19:487 a-Mannosidase 2:351;7:13,15; 10:559,560, 567,568;13:247,249,250 deoxymannojirimycin inhibition with 7:11 from soybean 16:86 swamsonine inhibition with 7:11 /?a-l,2-Mannosidase 10:501,559 a-1,3-Mannosidase 10:559 a-l,6-Mannosidase 10:559 a-D-Mannosidase 7:11 P-Mannosidase 7:11,15;10:567,568 a-Mannosidase inhibitor synthesis of 1:331 a-Mannosides 8:359 Mannosidosis 7:11 a-Mannosidosis byswansonine 7:12 Mannostatins 10:523,524 MannostatinA 19:351-352 absolute stereochemistry of 19:352 structure of 19:352 2-ep/-Mannostatin A sulfone 19:356 Mannostatins A & B 10:523,524 a,D-mannosidase inhibitors 10:523 from Streptoverticillium verticillus var. quintum 10:523 Mannosyl chloride (2,3,4,6-tetra-a-(9-benzyl-a-Dmannopyranosyl chloride) thermal glycosidation 8:359-361,366 Mannosylated phosphoinositides 18:393 D-Mannitol 18:157,159 Z)-Mannitol diacetonide 18:157 Manoalide 3:157,158; 18:717 antibacterial activity of 16:666 inflammatory activity of 16:666 inhibitory activity of 16:666 from Luffariella variabilis 16:666 Manool 6:122 in (+)-confertifolin synthesis 4:424,25 in (+)-euryftiran synthesis 4:422-424 m (-)-warburganal synthesis 4:419,420,424,425 from Salvia limbata 20:691 from Salvia sclarea 20:691 ()-Manool 6:28,55-57 e/-methyl isocopolate from 6:56,57 in 14-deoxy-taondiol methyl ether synthesis 6:55 in ()-euryfiiran synthesis 6:28 in ()-isoagatholactone synthesis 6:56,57 Manoyl oxide 20:691 from Salvia candidissima 20:691

1095

ManosononeE 3:446,451 synthesis of 3:450,451 ManosononeF 3:450 synthesis of 3:450 Manosonone I synthesis of 3:450 MansononeH 5:773 ManzamineA 5:346,348,350 Manzamine B 5:346,347,349,350 ManzamineC 5:346,347,350 Manzamine D 5:346,347,350 Manzamine E 5:350 Manzamine F 5:346-353 MaoecrystalA 15:137 ''C-nmrof 15:154 from Rabdosia eriocalyx 15:171 from Rabdosia eriocalyx var. laxiflora 15:171 ^H-nmrof 15:145 MaoecrystalB 15:138,176 ^^C-nmrof 15:155 from Rabdosia eriocalyx 15:171 from Rabdosia eriocalyx var. laxiflora 15:171 ^H-nmrof 15:146 MaoecrystalC 15:138 ^^C-nmrof 15:155 from Rabdosia eriocalyx 15:171 ^H-nmrof 15:146 Maoecrystal D (rabdolongin B) 15:112,138 ^^C-nmrof 15:155 from Rabdosia eriocalyx 15:171 from Rabdosia longituba 15:173 'H-nmrof 15:146 Maoecrystal E 15:139 from Rabdosia eriocalyx 15:171 ^H-nmrof 15:147 Maoecrystal F 15:139 ^^C-nmrof 15:156 from Rabdosia eriocalyx 15:171 *H-nmrof 15:147 Maoecrystal G 15:138 from Rabdosia eriocalyx 15:171 ^H-nmrof 15:146 Maoecrystal! 15:139 ^^C-nmrof 15:156 from Rabdosia eriocalyx 15:171 *H-nmrof 15:147 MaoecrystalJ 15:139 '^C-nmrof 15:156 from Rabdosia eriocalyx 15:171 'H-nmrof 15:147 Maoecrystal K 15:139 *'C-nmrof 15:157 from Rabdosia eriocalyx 15:171 ^H-nmrof 15:148 Maoyerabdosin 15:139 *^C-nmrof 15:156 from Rabdosia japonica 15:172 ^H-nmrof 15:147 Marasmic acid 13:6 Marchantiapaleaceae 2:281 Marchantia palmata 2:283 Marchantia tosana 2:281 MarchantinA 2:108,281,282

Marchantin A trimethyl ether 2:104,105 MarchantinD 2:282 Marchantin E 2:282 Marchantins 2:112,282,283 from liverworts 2:103 from Marchantia paleacea 2:103 from Marchantia polymorpha 2:103 from Marchantia tosana 2:103 structure of 2:109 Marchantins A-C 2:282 Marfat-Helquist aimulation 13:11,12 Margocinin 9:297,299 Margolone 9:297,299 Margosinolide 9:297,298 Margosone 9:297,299 Maridomycins 11:164 Maridonolides 11:160,163-172 stereoselective synthesis of 11:163 -172 Marijuana 19:137 Marine animals novel natural products from 9:3-14 Marine algae crmitolfrom 20:25 Marine arthopodes 19:627 Marine diterpenoids 6:52-54 dolastanesin 6:52 from Dictyotaceae 6:52 from Dictyota indica 9:78-81 Marine invertebrates neuropeptide from 9:493-495 Marine macrolide antifiingal activity of 19:549 antitumor activity of 19:549 antivu-al activity of 19:549 bioactive 19:549-626 cytotoxic activity of 19:549 immunomodulatory activity of 19:549 Marine metabolites 20:283 Marine iV-acyl shingosine from Halymeniaporphyroides 9:85,86,88 Marine prostanoids 1:687 Marine pyranopyrans synthesis of 10:421,422 Marine quinones 15:289-326 Marine sesquiterpenes 15:289-326 from Laurenciapinnatifida 9:81-83 Marine sponges isoquinolinequmone from 10:77-145 Marine sterols 9:35-50 from Asparagopsis sandifordiana 9:83-85 from Myriogloia sciurus 9:83-85 Marinovic extension of Stork's vinyl radical cyclization 12:15 Maritimin 7:232 Maritinone 2:213,215;5:754,755 Marjoram hortensis (sweet marjoram) cyclase from 11:221 Markers ethane as 9:564 in lipid autoxidation 9:564 pentaneas 9:564

1096

Marmesin 20:497 Marschalk condensation 1:595 Marschalk reaction 4:346,347,350,352;14:5,12 Marshall synthesis 6:73 of(-)-dictyolene 6:27 of dihydrospiniferin-l derivative 6:72,73 Marshallia tenufolia 10:442,443 Marthasterias glacialis 7:289,299;15:48,104 glacialosides A,B from 7:299 Marthasterone 7:289 Marthasteroside A 15:47 Marthasteroside Ai 7:293 from Acanthasterplanci 7:288 from Linckia laevigata 7:288 from Nardoa gomophia 7:290 Marthasteroside A2 7:289 Marthasteroside B,C 7:289,293 Martin reagent 13:601 Martin sulfiirane reagent 6:204,205 Maslinicacid 7:134,135 Maslinic lactone 7:135 from Terminalia alata 7:134 Mass spectrometric analysis of steryl esters 9:447-486 Mass spectrometry 5-methylpyrazine 5:265 of 2,5 -dimethyl-3-isopentylpyrazine 5:259,260 of2,5-dimethylpyrazines 5:258 of 2,5-dimethyl-3 -(2-methylbutyl) pyrazines 5:259,260 of 2,5-dimethyl-3,6-dimethylpyrazines 5:258 of 2,5-dimethyl-3-citronellylpyrazine 5:261 of 2,5-dimethyl-3-methylpyrazines 5:258 of2,5-dimethyl-3-n-pentylpyrazine 5:259,260 of 2-isopenty 1-3 -(-4-methy Ipent-1 -eny l)-5 of 2-methy 1-3-isopentry 1-5-(4-methylpent-1of5-methyl-3-(2-methylbutyl)-2-(3-methylof5-methyl-3-(2-methylbutyl)-2(Z)-3-methylpentof 5-methyl-3-(2-methylbutyl-2-(E-3-methylpent-1 enyl)pyrazine 5:263 ofalkylpyrazines 5:258 offlavonoids 5:621,531-648 ofenyl)pyrazine 5:263,265 of methyl pyrazines 5:258,265,267 ofpyrazines 5:258-268 pentyl)pyrazine 5:262-264 Mass spectrometry 9:165,466-478 by direct sample mtroduction 9:466-469 chloesteryl esters analysis by 9:466-478 of indole alkaloids 9:165 Mass spectroscopic ionization techniques 2:43-55 Mflwo/a lactone 3:157,158 Mastigomycotma 9:202 Matairesinol 5:488-493,522,526,530 O-glucosylation of 5:525 O-methylation of 5:525 Matairesinol 4'-0-glucoside 5:489-491 Matairesinol-di-P-D-glucoside 5:522 Matairesinoside 5:522 Matricanin 7:214,215,235 Matrine 14:757 (+)-Matrine 15:520

Matsumoto synthesis oftaxodione 14:670-676 Mauiensine 9:183 Maurapyrone A-D 17:25 Maurenone 17:25,26 Mayo-type sequence 12:198 (+)-Mayolide A synthesis of 16:699-700 Maytansine 4:491-493;9:433;11:5;13:654 synthesis of 4:491-493 Maytansinoids 9:432,435;18:739 Maytensifolia A,B from Maytenus diversifolia 7:152 Maytensifolic acid 7:153 from Maytenis diversifolia 7:152, X-ray analysis of 7:152, Maytensifoliol 7:152 from Maytenus diversifolia 7:152 Maytenus boaria 18:752,775 Maytenus buchanii tissue culture of 7:146 triterpenes of 7:146 Maytenus buxifolia 18:757 Maytenus diversifolia maytensifolic acid from 7:152 maytensifolia A,B from 7:152 maytensifoliol from 7:152 triterpenoids of 7:152 Maytenus genus 18:739,740 Maytenus ovatus 4:492 Maytenus rigida wilfordinfrom 18:771 Maytol 18:747 MC-1 6:135 MC-903 9:516,517 McFayden-Stevens reduction 8:273 McLafferty rearrangement 2:6 McMurry coupling 11:337,354 intramolecular 11:343,363,364 McMurry cyclization 11:27 McMurry reaction 9:250,255 intramolecular 11:337 McMurry reagent 13:601 MCPBA oxidation 8:216 MD (molecular dynamics) 10:269 MDLISIS-Base 18:971 MDP analogs of 6:405 by solid-phase method 6:405 2,3-diaminoglucosyl analogs of 6:385,407 immunadjuvant properties of 6:385 structure of 6:405 MDP(A^-acetylmuramyl-L-alanyl-D-isoglutamine 13:210-212 4-Me-antirrinoside 7:455 Mebadonin from Rabdosia umbrosa 15:175 Mecambrine 2:162 Mechanics 6:316,320 of acetal derivatives formation 6:335,336 of cyclization 6:314,345 Mechanism of C (8) bromination of camphor 4:638,639

1097

of C(9) bromination of camphor 4:633,634 of biomimetic olefin cyclization 1:671-674 of cyclization 7:335-338,358-360 of Diels-Alder reaction 4:579,580 of hydrogen phosphite method 4:277 of Hthio dianion-imine condensation 4:444-447 of phosphite method 4:272 of phosphotriester method 4:270 Mechanism based inhibitors oxposides as 7:36-40 Mechanism-based yeast bioassays 20:461,462,464 Mechanistic aspects of vitamin B12 biosynthesis 9:591-609 Mechanistic considerations diastereoselectivity 55-58 of tandem process 12:55-58 Mederrhodins 5:590 Mederrhodins A 5:617,618 Medicagenic acid 7:432,433 Medicago sativa 15:202,20:734 Medicinal plants 17:421 (+)-Medioresinol 4'-P-D-glucoside 5:524 (+)-Medioresinol dimethyl ether 5:537 (+)-Medioresiol-di-P-D-glucoside 5:54 (+)-Medirorsinol 5:524,536-538 Medium pressure liquid chromatography (MPLC) 9:464 Medium ring ethers biological activity of 10:201 synthesis of 10:201-239 Medorinone 18:338 Meerwein's reagent 8:205;12:289,20:426 Meerwein's salt 12:300,305,320 Meerwein-Pondorf-Verley-Oppenauer reaction intramolecular 14:481 Mefloquine 13:656,20:517,518 Megalobulimus paranaqnensis 2:306 Megalosaccharide 10:459 (-)-Megaphone synthesis of 16:705 Megastigmane 10:152 Mehranine 5:171,172 Meisenheimer rearrangement ofallocryptopineA^-oxide 6:468 of cw-()-laudanosine N-oxide 6:468 [l,2]-oxaza ring formation by 6:472 Melanoma B16 19:289 Melaleuca leucadendron phyllodulcin from 15:387 Melampolides 7:210 from Artemisia gypsacea 1:211 Melanine biosynthesis of 16:613 Melanine pigment physiological role of 16:615 Melannorrhea usitata 9:319 Melanoma 1:275 Melanoma cells 16:90 Melastomacea 9:321,328 Melatonin 19:629 Meldrum's acid 1:516;10:282;13:56,67

Meleagris gallopavo hemoglobin components of 5:836 Melia azedarach 9:502 Meliaceae 6:487;7:185,216,217;9:295,296 Melicopicine 13:351-354,365,368 synthesis of 13:353,354 Melilotic acid 7:205,206 MelionineE 1:125,126 MelionineF 1:127 Melissa officinalis callus cultres of 2:404 (+)-Mellein 15:351 (/?)-(-)-Mellein 15:383 (5)-(+)-Mellein 15:383 Mellein biosynthesis of 15:406 Mellein derivatives 15:383-385 Melodienone 9:400 Melodium fruticosum 10:152 Melodorumfruticosum 9:399 Melon-fly pheromone 3:157-158 Melosmidine 16:505 Melosmine 16:505 Melospiza lincolnii hemoglobin components of 5:837 Melospiza melodia hemoglobin components of 5:837 MEM protection v^^ith 6:558,559 MEM ethers 1:558 deprotection TMSCl/Nal 1:558 for alcohol protection 1:558 MEM-directed organometallic addition 12:201 9-Membered cyclic sulfide 8:205 14-Membered cyclic triene (,,)-triene 8:188 (Z,,)-triene 8:188 15-Membered macrolides acumycin 5:613 mycinamicin 5:613 rosaramicin 5:613 14-Membered macrolides erythromycin 5:613 oleandomycin 5:613 10-Memberedring synthesis of 8:179-186 14-Membered ring by keto-aldehyde coupling 8:26 6-to 8-Membered ring expansion by reactions of enamines with acetylenes 3:95;96 10-Membered rings entry into 1:570 13-Membered thiolactone 8:205 Membranipora membranacea 17:93 Membranipora perfragilis 17:91 Memmeisin 19:773 Menadione 9:391,392,400 Meningitis due to Candida neoformans 2:422 Menippe mercenatia 19:628 Mentella genus 19:4 (+)-/ra5-/7-Mentha-2,8-dien-1 -ol 19:203

1098

Mentha 7:124,126 /7-Menthadienol condensation of 19:187 (-)-Menthyl-(5)-/7-toluenesulfmate 19:14 Mentha longifolia 7:119 Mentha spicata cv. lacinata 7:119 /?-(+)-/7-Menthne 16:261 Menthol 13:332,337 (L)-Menthol 10:684,685 ^-Menthol 14:179 (-)-Menthol 17:605 L-Menthol 13:300 from L-menthone 13:299 L-Menthol from 13:305 Il/?,25',5/?)-(-)-Menthol in 7,20-diisocyanodociane synthesis 6:86,87 L-Menthone 13:299 (-)-Menthyl (+)-(/?)-;7-toluene-sulphinate 10:66 (-)-Menthyl(5)-/7-toluene-sulfmate from p-toluenesulfmic acid sodium salt 14:517,518 with 4-[(tetrahydro-2H-pyran-2yl) oxy] butylmagnesium chloride 14:522,523 1-Menthyl diazoacetate diastereomeric 14:684 hydrazone of 14:684 l-(-)-Menthyl ester as chiral auxiliary 4:437 Menthyl glyoxalate with di-/7-anisylmethyl amine 12:152 (-)-Menthyl A^-amino carbonate 14:684 (-)-(5)-Menthyl /7-toluenesulfinate synthesis of 4:490 Mentzetriol 7:441,442 Mercaptolysis 6:279,280,282-286 Mercaptomethylation 6:323-325 Merck method 12:135 Merck procedure for carbapenem formation 4:453 mercuric salt method 4:22 for nucleoside synthesis 4:22 Mercur talis annua 17:117 Mercuric acetate 1:125 oxidative cyclization 1:133 Mercuric amidation 14:568 Mercury (II) triflate formation of 1:657 Mercury (II) triflate/A'^A'^-dimethylaniline complex 1:657,658 Mercury (II) trifluoromethanesulfonate cationic olefin cyclization 1:656 Mercury group 1:659 replacement by OH group 1:659 Meridianone 7:233 Merulinic acids 9:317 Merulius spQcks 9:317,327,350 Mesembrenol from Crinum oliganthum 20:234 Mesembrenone from Narcissus pallidulus 20:234 (+)-Mesembrine 10:407 synthesis of 16:710

(-)-Mesembrine enantioselective 10:410,411 total synthesis of 10:410,411 ()-Mesembrine synthesis of 13:483,493 Mesembrine from Sceletium species 4:3-5 retrosynthesis of 4:3,4 synthesis of 4:10-12 Mesembryanthmoidigenic acid 7:139,140 etabolically-active cells 7:114-117 cloning of 7:114-117 selection of 7:114-117 Mesitoylated model compounds 17:268 Mesitylene sulfonyl-3-nitro-triazole (MSNT) as condensing agent 4:271 Mesitylene sulfonyl-tetrazol (MSTe) as condensing agent 4:271 N-Mesitylenesulfonyltriazole 18:401 Meso-3,4-epoxycyclopentanone chiral acetal derivatives of 14:510 diastereodifferentiating isomerization of 14:510 4-hydroxy-2-cyclopentenone acetal from 14:510 MesO'Cyclic ketones asymmetrization of 14:486 Mesoponera castanea 5:224-227,229,245,247,254 Mesoponera castaneicolor 5:224-227,229,245,257,254 Mesoponera sp. 5:224-227,245,247,254 Mesotetro 19:363 Mesuaferrea 4:768 coumarinsfrom 4:389,391 Mesua gQmxs 19:768 Metarhizium anisopliae 19:486 Mesua thwaitesii coumarinsfrom 4:389,391 (15,2/?,85,8a/?)-2-0-Mesyl-5-oxo-l,2,8-trihydroxyindolizidine 12:325 Mesylate elimmation 1:477 Mesylation 4:16,126,442;6:9,10,71,76,77,229,289; 6:290,390,548-550;10:322,323;19:147,371 axial 1:415,417 of alcohol 19:494 of allylic alcohols 4:16 of primary alcohol 19:477 l|3-Mesyloxyeudesmanolides 14:365 Mesyloxy oxazolme 18:461 ()-(Z)-Y-Mesyloxy-a,P-enoates 10:411 (),(2)-y-Mesyloxy-a-alkyl-a,p-enoates 1,3-chirality transfer in 10:411 E-selective 10:411 with organocyanocopper trifluoroborane 10:411 3 -Mesy loxy-Z-threonate antiperiplanar 12:17 p-elimination of 12:17 stereoselective 12:17 Metabolic degradation oftriterpenes 7:190,191 Metabolism 18:523-533 ofbrassmosteroids 18:523-533 of24-epibrassinolide 18:523-533 of24-epicastasterome 18:523-533

1099

Metabolism 6:142,143,155,156 of acetylenic carotenoids 6:155,156 ofalleniccarotenoids 6:142,143 ofquassinoids 7:388 of vitamin D 9:511,512 of vitamin D2 9:513 of vitamin D3 9:514,521 Metabolite 17:4 MetachrominD 18:643 Metachromin-A 15:296 Metachromin-B 15:296 Metachromin-C 15:296 Metacycloprodigiosin 8:272 Metal acetates 11:116 Metal complexes of ascorbic acid 4:720-722 Metal enolates 3:409 contact ion pair 14:497 from a,a-disubstituted ethyl ester 14:497 Metal reduction of v/c-phenyl thiobenzoate 6:541,542 with sodium naphthalenide 6:541,542 Metalated arenes 11:140 Metalated sugar 11:140 Metallation with n-butyllithium 5:822,823 Metallation reactions in basic media 4:386-389 A';A^-disubstituted amides with 4:389 A^,A^-disubstituted benzyl amines with 4:389 Metallo-ene reaction 3:21;16:418,437 intramolecular 16:437 A^-Metalloaziridines 2-azaallyl anions from 1:348,349 ring opening of 1:348,349 Metalloenamines 4:5-7,22 from 2-azadienes 4:7,10-14,17 Metalloendopeptidase 9:500 Metalloorganic addition to a-amino aldehydes 4:124 Metarhizium anisopliae (-)-swainsonine from 12:313 Metastable ion measurements 9:467 Metastasis of tumors 19:351 Metastatic cells 16:76 Metatrichia vesparium arcyrialflavin B from 12:366,370 arcyrialflavin C from 12:366,370 P-Methallyltriphenylstannane 12:478 p-Methallytri-n-butylstannane 12:478 Methane sulphonate DBU reaction with 6:126,127 Methanesulfonyl chloride 8:27-30 AT^-Methanesulfonyl CPI 3:325 synthesis of 3:325 Methaniminium methylide 1:336,337 1//-1,5-Methano-2,5-benzoxazonine derivaives from 10p-methyl-5//-oxazolo [2,3-A] isoquinoline derivatives 6:474 synthesis of 6:483

Methano-bridged benzoxazecines from isoquinoline derivatives 6:483 synthesis of 6:483 Methanobacterium thermoautotrophicum 9:606 Methanobenzoxazecines synthesis of 6:474 Methanodibenzazocine ()-argemonine from 6:471 5,6-Methanoleukotriene synthesis of 14:489,490 5,6-Methanoleukotriene A4 1:629 Methanolysis 6:276,390-395;19:42,442 acid-catalyzed 14:563,564 alkoxyacrylate from 14:563,564 Methionine 9:606 from 5-methyltetrahydrofolate 11:210 Methionme sulfoxide 9:581 Methionine sulfoximine as glutamine synthetase inhibitor 7:6 Methiony 1-enkephalin 2:21 negative ion LSI mass spectrumm 2:22 positive ion LSI mass spectrum 2:21 Methmycins 13:158 Methoprene 10:152;13:667 Methoxatm 1:163 synthesis of 1:170-172 Methoxbipyrrole aldehyde synthesis of 8:273 a-Methoxy alkyl plumbane 16:350 (Methoxycrotyl) boronic ester from (a-chlorocrotyl) boronic ester 11:424 6-Methoxy dihydrochelerythrine (angolme) 14:773-775 11-Methoxy ferruginol methyl ether totaxodione 14:678-681 transformation of 14:678-681 Methoxy pyrazines 5:247-249 l-(2-Methoxy)naphthylsulfinyl chloride 10:684,685 8-Methoxy-1,2,3,4-tetrahydro-isoquinolines 10:121, 122 6-Methoxy-1 -indanone 6:195 6-Methoxy-1-tetralone 12:235 dihydrospiniferin-l derivative from 6:72 11 -Methoxy-19(/?)-hydroxygelselegine 15:483 from Gelsemium elegans 15:484 A^a-Methoxy-19(Z)-anhydrovobasinediol 15:466,467 12-Methoxy-19a,20a-11,12- dimethoxykopsinaline 9:189 12-Methoxy-19a,20a-epoxyakuammicine 1:36 (5)-2-(6-Methoxy-2-naphthyl) propanoic acid anti inflammatory activity of 14:473 synthesis of 14:473 ^rflrAw-4-Methoxy-2-oxazolidinone chiral synthon of 2-amino alcohol from 12:425 from cycloadduct 12:425 4-Methoxy-2-oxazolidinone acid catalyzed 12:426-428 4-alkyl-2-oxazolidinones from 12:428 4,5-disubstituted-2-oxazolidinones from 12:427,428 via-iminium cations 12:426-428 N-deacylated 12:427,428

1100

substitution of 12:426-428 with cuprate reagents 12:428 4-Methoxy-2-oxazolidinone from Diels-Alder adducts 12:435,436 4-substituted-2-oxazolidinones 12:435,436 with organocuprates 12:435,436 4-Methoxy-2-oxazolidione 12:426-428 from 2-oxazolidione 12:437,438 4-substituted-2-oxazolidinones 12:43 7,43 8 10-Methoxy-3,4,5-6-tetradehydrocorynantheol 1:124 4-Methoxy-3-(triisopropylsilyl) pyridine 12:351 2-Methoxy-3-isobutyl pyrazine 13:320 2-Methoxy-3-isobutylpyrazines 5:221,225,247-249,266 2-Methoxy-3-isopropyl pyrazine 13:320 2-Methoxy-3-isopropyl-1,4-benzoquinone from resorcinol dimethyl ether 14:692,693 taxodionefrom 14:692-695 2-Methoxy-3-isopropyl-pyrazines 5:225,247-249,266 2-Methoxy-3-methylpyrazines 5:225 2-Methoxy-3-5gc-butylpyrazines 5:225,247-249,266 (i?)-(-)/(5)-(+)-3'-Methoxy-4'-0-methyljoubertiamine from chiral enone acetal 14:501,502 synthesis of 14:501,502 via Claisen Eschenmoser rearrangement 14:501,502 (4/?,5/?)-4-Methoxy-5-phenylseleno-2-oxazolidinones from 3-[ 1 S)-2-exo-alkoxy-1 -apocamphanecarbonyl]2-oxazolones 12:421,422 5-Methoxy-7-hydroxyphthalide 9:400 8-Methoxy-8,10-dihydrogentianine from Strychnos dinklagei 6:529 spectral data of 6:528,529 6-Methoxy-8-hydroxyflavone 5:640 ()-a-Methoxy-a-trifluoromethylphenylacetylimide 12:483 (/?)-(+)-a-Methoxy-a-(trifluoromethyl) phenyl acetyl chloride [(+)-MTPACl] MTPA esters from 14:557,558 (/?)-(+)-a-Methoxy-a-(trifluoromethyl) phenyl acetyl esters from piperidine derivatives 14:557,558 sythesis of 14:557,558 5-Methoxy-melicopicine 13:364 2-Methoxy-A^,A'-diethylbenzamide lithiation of 5:827,828 11-Methoxy-A^-methyl dihydropericyclivine 13:386 5-methoxynormelicopicine 13:364 12-Methoxy-iV4-methylvoachalotme 5:128 12-Methoxy-A'4-methylvoachalotine ethyl ester 5:128 12-Methoxy-nor-C-fluorocurarine 1:36 11 -Methoxy-0-acetylisoretuline 9:189 11 -Methoxy-rankindine (humantenirine) 9:196,197 11 -Methoxyakuammicine 1:35 4'-Methoxyavarone 15:301 4'-0-Methoxybavachalcone synthesis of 4:378,379 3-Methoxybenzaldehyde 9:343 p-Methoxybenzyl (pyrichalasin) 15:355 Methoxybrominations diastereoselective 12:419-421 of 3-[(IS)-2-exo-alkoxy-1 -apocamphanecarbonyl]-2-

oxazolones 12:420,421 of 3 [(IS)-ketopinyl]-2-oxazolone 12:420,421 9-Methoxycamptothecin 5:128 l-Methoxycanthin-6-one 7:389,390,394 Methoxycarbonyl as activating group 6:540 1-Methoxycarbonyl pyridinium chloride reaction with alkynyl Grignard reagents 6:448 l-(Methoxycarbonyl)-2-methoxypyrroline ()-elacokanine from 12:292 cyclohexen-1-one 12:25 aldol reaction of 12:25 with TBS ether of glycoaldehyde 12:15 (-)-iV-Methoxycarbonyl-11,12-methylenedioxykopsinaline 9:189 (-)-A^-Methoxycarbonyl-12-methoxykopsinaline 9:189 '^0-NMR of 9:113 A^-Methoxycarbonyl-ethenyl carboxaldimines 4:460 Methoxycarbonylation 6:547 5-(3'-Methoxycarbonylbutyroyl)aminomethyl/row^-quinolizidine N-oxide from Sophora tomentosa 15:522 3-Methoxycarbonylpyrrol -2(5H)-one 13:113 from pyroglutamic acid 13:112 12-Methoxycompactinervine 1:36 7-Methoxycoumarin (hemiarin) 9:113,114;18:976 5-Methoxycurcumin 17:364 7-Methoxydehydronoraporphine 16:516 10-Methoxydeplancheine 9:174 5-Methoxydesoxypodophyllotoxin 18:576 11 -Methoxydiaboline 9:189,190 Methoxydidenone by anodic oxidation of phenols 8:169,170 6-Methoxyepicamphor exo-2-allyl derivative from 4:657,658 Methoxyethoxy group protection with 6:298,299 3-[(LS)-2-exo-Methoxyethoxy-1 -apocamphanecarbonyl]-2-oxazolone X-Ray crystal analysis of 12:423 4*-Methoxyflavanone 9:112 2'-Methoxyflavone '^C-NMR spectrum of 5:14 ' H - N M R spectrum of 5:13,14 3-Methoxyflavone 5:625,626,628,630,634-636,640 4'-Methoxyflavone 5:653 11-Methoxygelsemamide from Gelsemium elegans 15:472,473 11 -Methoxyhenningsamine 9:189,10 iVa-Methoxyindole 15:497 11-Methoxyisoretuline 1:38,39 11-Methoxykoumine 15:501 Methoxylation anodic 1:247 Methoxylimatine 1:40 11-Methoxylimatine 1:40 10-Methoxymacrocarpamine 13:393 10-Methoxymacrocarpamine A^-4-oxide 13:393 6-Methoxymellein ^omSporormia fungi 15:384 5-Methoxymellein 9:288,289

1101

Methoxymercuration-demercuration 1:510 Methoxymethyl group protection with 6:282,283 7-Methoxymitosene Wender synthesis of 13:445,446 7-Methoxynogarene 14:78 A^a-Methoxyoxindoles 15:497 2-(4-Methoxyphenoxy) propanoic acid 15:36 2,4-^w (4-Methoxyphenyl)\,3,2XA,^^dithiadiphosphetane-2,4-dithione 12:301 6-Methoxypipecolate 13:474,475 5'-Methoxypodorhizol 18:559,566 ^om Hernandia cordigera 18:561 8-Methoxyprotoberberingphenolbetaines synthesis of 1:190-192 11 -Methoxyretuhne 1:38,39 30-Methoxyscillatoxin D 18:294 synthesis of 18:294-309 Methoxyselenylations of 3 [IS)-2-exo-alkoxy-1 -apocamphanecarbonyl-2oxazolone diastereoselective 12:421,422 Methoxysiloxyfuran 13:452 3-Methoxytabemaelegantine 5:129 16-Methoxytabersonine synthesis of 1:68-70 (21)-11 -Methoxytabersonine conversion to vindoline analogues 4:35 11 -Methoxytabersonine 9:193 5-Methoxytetralone 15:245 4-Methoxytoluene Birch reduction of 12:22-24 11-Methoxytubotaiwme 1:40 8-Methoxyumbelliferone apigravinfrom 4:378,381 10-Methoxyvellosimine 13:386 10-Methoxyvillalstonine 13:392 10-Methoxyvillastonine-//-4 oxide 13:392 12-Methoxyvoaphynine 5:124 3P-Methoxy-2,3-dihydrowithaferin A 20:224 5a-Methoxy-4,5-dihydrojaborosalctone B 20:223 A^-Methoxy-norcepharadione-A 20:480 U-Methoxyacronycine 20:792 [2.2.1]-Methoxycarbonyl-7-azabicyclo-A'-heptane 19:78 //a-Methoxyyohimbine 15:497 Methuenine 5:123 Methuenine-A^-oxide 5:126 3-Methybutylaminodihydroisocoumarins 15:388 7,6a-Methylhydrocortisone 9:424 Methyl bixin 20:602 (PZ)-Methyl bixin 20:602 Methyl Grignard reagent 19:208 Methyl (2jE0-2,4,5-tetradecatrienoate 10:153 Methyl (2,4)-2,4-nonadienoate synthesis of 10:166 Methyl (2Z,4Z)-2,4-decadienoate 10:152 Methyl (methyl 4-deoxy-P-I-flfr^/o-hexopyranoside) uronate uronate 14:172 from methyl (methyl-4-deoxy-p-I-arabinohexopyranoside) uronate 14:172

Methyl (methyl 4-deoxy-p-Z,-^/2reo-hex-4-enopyranoside)-uronate methyl (methyl 4-deoxy-P-Z,-arabinohexopyranoside) uronate from 14:172 Methyl (/?)-a-hydroxyphenylpropionate (37?,45)-statine from 12:480 Methyl (5)-3-hydrox-2-methyl propionate from isobutyric acid 12:155 Methyl (triphenylphosphoranylidene) acetate 12:488 A^-Methyl l-deoxynojirimycin derivatives 7:42 synthesis of 7:42 Methyl 2,3,4-tri-0-benzyl-a-Z)-glucopyranoside 13:200 Methyl 2,3,4-tri-(9-benzyl-P-D-glucopyranoside 8:365, thermal glycosidation of 8:366 Methyl 2,3,6-tri-0-acetyl-4-5-(2,3,4,6-tetra-0-acetyl-pD-galactopyranosyl)-4-thio-a-D-galactopyranoside synthesis of 8:335 Methyl 2,3,6-tri-<9-benzoy l-4-deoxy-a-D-;[;y/ohexopyranoside 14:168 Methyl 2,3,6-tri-0-benzoyl-4-deoxy-D-jc>;/ohexopyranoside synthesis of 14:158,159 Methyl 2,3,6-tri-0-benzoyl-4-0-trifluoromethylsulfonyl-a-Z)-galactopyranoside 8:330-334 Methyl 2,3,6-tri-O-benzoy 1-a-D-galactopyranoside 14:168 Methyl 2,3,6-tri-(9-benzyol-4-0-(trifluromethanesulfony l)-p-)- galactopyranoside 14:164,165 synthesis of 14:164,165 Methyl 2,3-anhydro-4,6-0-benzylidene-a-Dmannopyranoside 12:314 Methyl 2,3-di-0-acetyl-4,6-0-benzylidene-a-Dgalactopyranoside 14:171 Methyl 2,3-di-0-acetyl-4-0-benzoyl-6-deoxy-a-Z)galactopyranoside 14:171 Methyl 2,3-di-0-acetyl-6-0-benzyol-4-deoxy-a-Z)jcy/o-pyranoside 14:171 Methyl 2,3-di-0-benzyl-4-deoxy-a-D-A:>'/ohexopyranoside synthesis of 14:153 Methyl 2,3-di-0-benzyl-4-deoxy-P-I-threo-hex-4enopyranoside derivative 14:173 Methyl 2,3-dimethoxy-7-oxo-7H-benzocycloheptene6,8-dicarbozylate 9:225 Methyl 2,3 -O-isopropylidene-a-D-mannopyranoside 14:152 Methyl 2,6-di-0-methyl-3,4-0-thiocarbonyl-P-Dgalactopyranoside from D-galactose 14:158 Methyl 2-arylpropanoates synthesis of 6:323 Methyl 2-azido-4,6-0-benzylidene-2-deoxy-aD-altropyranoside 12:327 Methyl 2-azido-4,6-0-benzy lidene-3 -deoxy-a-Daltropyranoside 6,7-dihydroxyindolizidine from 12:348 6,7,8-trihydroxyindolizidine from 12:348 Methyl 2-chlorocyclopropylidene acetate 8:419 Methyl 3,3-dimethylacrylate 8:410

1102

Methyl 3,4,6-tri-2-amino-2-deoxy-glucopyranoside 14:189 Methyl 3,4-anhydro-a-D-galactopyranoside 13:237 Methyl 3,4-dideoxy-a-D-ery//2ro-hex-3 -enopyranoside from methyl a-Z)-glucopyranoside 10:419 Methyl 3,4-0-(dibuty lstanyl)-a-I-arabinofiiranoside 6:363 Methyl 3,5-dimethyl benzalmalonate 9:225 Methyl 3,5-dimethylbenzoate 9:224 Methyl 3,6-di-O-pivaloy 1-a-D-mamiopyranoside photo-induced reduction of 14:166 Methyl 3-acetamido-2,4,6-tri-0-acetyl-3-deoxy-a-Dmannopyranoside 12:315 Methyl 3-acetamido-2-0-acetyl-3-deoxy-4,6-Di-0mesyl-a-D-glucopyranoside (-)-l,8 fi?/-ep/-swainsonine from 12:326,327 Methyl 3-acetamido-2-0-acetyl-4,6-0-benzylidene-3deoxy- a,Z)-glucopyranoside (-)-8-ep/-swainsonine from 12:326 Methyl 3-amino-3-deoxy-a-Z)-mannopyranoside hydrochloride 12:314 Methyl 3-deoxy-4,6-0-benzylidene-)-/vJcohexopyranoside synthesis of 14:167 Methyl 3-deoxy-a-D-arabmo-hexopyranoside 14:180 (/?)-Methyl 3-hydroxybutyrate 4:462,463,465,475 dianion of 4:562 Methyl 3-hydroxypentanoate as chiral building block 1:693,708 pheromones synthesized from 1:708 Methyl 3-0-carbamoyl-2-deoxy-(3-D-rhamnoside 5:598 Methyl 3-tert-butoxy-carbonyl-2-oxo-oxazolidine4-carboxylates with cesium carbonate 12:430 A^-boc-2-aminoacrylate from 12:430 Methyl 3P-hydroxyfriedelan-29-oate 7:168 Methyl 4,4'-dithiocellotrioside acetolysis of 8:344,346 Methyl 4,6-(9-benzylidene 2,3,6,2',3'-penta-0benzyl-p-maltoside 14:160 Methyl 4,6-(9-benzylidene-2,3-di-0-tosyl-a-Dglucopyranoside selective reduction of 14:145 Methyl 4,6-0-benzylidene-2,3-O-thiocarbonyl-a-Dglucopyranoside 14:158 Methyl 4,6-(9-benzylidene-2-deoxy-a-D-erv//7rohexopyranoside-3 -ulose Wittig olefmation 10:421 Methyl 4,6-0-benzylidene-2-0-tosyl-P-Dglucopyranoside 14:156 Methyl 4,6-(9-benzylidene-3-0-benzyl-2-deoxya-Z)-ribohexopyranoside from Z)-glucose 6:282,283 5(-)-3-Methyl-butyrolactone 16:344 Methyl 4-deoxy-2,3-di-0-methyl-a-Z)-jc>'/ohexopyranoside 14:157 Methyl 4-deoxy-2,6-di-0-methyl-P-)-xv/ohexopyranoside 14:158 Methyl 4-deoxy-p-Z-arabino-hexopyranoside 14:172 Methyl 4-deoxy-D-(vxo-hexopyranuronate 14:143

Methyl 4-O-triflylgalactoside 8:330-335,343 Methyl 4-5-p-Z)-galactopyranosyl-4-thio-a-Dgalactopyranoside 8:335 Methyl 5'- hydroxyepijasmonate 6:557 Methyl 5-acetamido-4,7,8,9, tetra-(9-acetyl-3,5didQoxy-2-Mo-D-glycero-a-D-galacto-2-nonulopyranosonate 8:340,341 Methyl 5-0-benzyl-4-deoxy-D-/>^o-hexonate 14:182 Methyl 6-O-benzoy 1-2,3-O-isopropylidene-a-Dmannopyranoside 14:158 Methyl 6-O-benzoy 1-2,3 -O-isopropylidene-a-Dtalopyranoside 12:316 Methyl 6-thio-a-D-glucopyranoside 8:337,338 Methyl 6-thiogentiobioside 8:337,338 Methyl a,I-rhamnopyranoside 6:287,288 Methyl a-(phenylsulfonyl) acetate 10:12 Methyl a-2-thiosophoroside synthesis of 8:328 5-Methyl a-ketocarbothioates synthesis of 6:335 Methyl a-I-mycaminoside synthesis of 4:148 Methyl a-peracetyl hikoseminide synthesis of 11:449-451 Methyl acarviosin 13:280,240-244 Methyl acetoacetate hydrogenation of 13:72,73 a-Methyl aldehyde 12:48-53 from levoglucosan 12:45 Methyl anacardate 9:337 Methyl anagolensate 9:94 Methyl aplysinopsin antidepressant activity 5:410 A'-Methyl ascorbigen 4:725 exo-Methylation 4:655,658,659 of camphor 4:658,659 of camphor derivative 4:658,659 Methyl p-cellobioside 7:51,52,56,64-66 Methyl p-D-gentosammide 14:50 Methyl p-D-glucopyranoside 15:431 Methyl p-gentiobioside kinetic parameters of 7:52 Methyl p-lactoside kinetic parameters of 7:52,54 Methyl benzalmalonates 9:224,227 (5)-2-Methylbutanol synthesis of 13:77 1-Methyl camphene fromfenehone 4:649 (-)-4-Methyl camphor 4:650-652 C(3)-methylation of 4:657,658 optical purity of 4:652 3-endo-MQthy\ camphor bromination of 4:656-658 by C(3)-methylation of camphor 4:657,658 3-ex:o-Methyl camphor by C(3)-methylation of camphor 4:657,658 Methyl carbenoid asymmetric cyclopropanation with 14:488

1103

Methyl cw-(45',55)-5-methyl-3-/er^butoxycarbonyl2-ojco-oxazolidme-4-carboxylates iV-boc-Z,-///o-threonine methyl ester from 12:430 Methyl cis-Z,4-dimethoxycimiamate 9:219,220,223, 226,228 Methyl c-ferulate 9:219,220,226,227 ()-Methyl dihydroepijasmonate synthesis of 6:558,559 Methyl dihydroepijasmonate 6:557 .S-Methyl dithiocarbonate from di-O-isopropyliden glucofijranose 14:157 Methyl dithiocarbonates from 1,2,5,6-di-0-isopropylidene-Z)-hexofuranoses 14:160 N-Methyl ekeberginine 2:118,119 '^C-NMR of 2:120 (-)-A^-Methyl ephedrine resolution with 4:326 Methyl epijasmonate 6:558-559,8:152-155 plant growth inhibitor 8:140 ()-Methyl epijasmonate 6:558,559 synthesis of 6:558,559 Methyl ester pentalenolactone E 13:29,30 pentalenolactone P 13:30-32 Methyl ether ferruginol 14:668,670,676 Methyl eugenol 5:473 Methyl fiiranosides 1:404,405 Methyl y-oxosenecioate in ()-ireinianin synthesis 6:8 Methyl glycookadaate 5:385,388 Methyl glyoxal synthase 11:208 i?-(+)-3-Methyl hexadecane-dioate 8:224,225 (-)-2-Methyl isobomeol acid catalysed rearrangement of 4:650,651 e^Methyl isocopolate from ()-manool 6:56,57 in ()-isoagatholactone synthesis 6:56,57 Methyl jasmonate 6:557;7:484,8:140 partial synthesis of 7:485 pheromone activity of 8:153 synthesis of 8:152-155 (+)-0-Methyljoubertiamine 10:408 0-Methyl jubertimine 4:3-5,6-10 from Sceletium species 4:3,4 retrosynthesis of 4:4,5 synthesis of 4:8-10 A^-Methyljulifloridine 9:70,77 Methyl ketones Claisen condensation of 11:130 from ester 11:130 synthesis of 11:130 Methyl Z,-arabino pyranose from Z,-arabino pyranose 7:155 from L-arabinopyranosyl 3p-acetyl oleanotate 7:155 Methyl malonate alkylation of 13:79 Methyl malonic acid 13:69 Methyl methylthiomethyl sulfoxide preparation of 6:309-325 Methyl methylthiomethylsulfone 6:309,325-328,332 synthesis of 6:326

Methyl nuapapuanoate 9:18,19,23 stereochemical revision of 9:19 Methyl okadaate 5:385,388 (/?)-(+)-Methyl/7-tolyl sulfoxide 10:679-685 Methyl peracetyl a-hikosaminide synthesis of 1:413-416 Methyl perillate 6:545 (+)-Methyl phaseate 16:245 ()-Methyl phaseate 6:559,560 synthesis of 6:559,560 Methyl phenacyl-1,1 -dimethylprop-2-enylmalonate 5:759 Methyl phosphonates 13:271-281,287,290 by phosphoramidite method 13:272 by phosphotriester method 13:272 diastereoselective synthesis of 13:279,280 a-Methyl piperidine 14:572,573 6-a-Methyl prednisolone 9:428,429 Methyl pyrazines 5:222,234-236,267 mass spectrometry of 5:267 Methyl reserpate 9:174 A^-Methyl secodine 5:188,190 synthesis of 5:188,190 1,2-Methyl shift ().A^^^^^-capnellene from 6:48 in ()-africanol 6:37 2,3-exo-Methyl shifts in camphor derivatives 4:633,634,639,643 in rearrangement of camphor 4:626,627 2,3-endo-Methy\ shifts 4:638,639 (-)-Methyl shikimate synthesis of 16:674 A^b-Methyl strictamine 9:195 ' H - N M R spectrum of 5:152 mass spectrum of 5:152 NOE difference measurements 5:152 UV spectrum of 5:152 24-Methyl thomasterols A 15:48 Methyl/rfl[5-(45,5^)-5-Methyl-3-/er/-butoxycarbonyl2-oxo-oxazolidine-4-carboxylates A'-boc-I-threonine methyl ester from 12:430 Methyl ^aAM-3,4-dimethoxycmnamate 9:223 Methyl /rfl5-4-methoxy-2-oxo-3 -butenoate 14:179 (+)-Methyl /r^w^-chrysanthemate synthesis of 16:242 Methyl transferases 9:592,598,601,603-605 i'-adenosylmethionine dependent 11:208 Methyl tri-O-benzyl-6-bromo-a-D- glucopyranoside from methyl-a-Z)-glucopyranoside 12:331 3'-Methyl tyrosine 10:106 Methyl vinyl ketone 14:559 a-keto acetal with 14:510 Methy l-()-3 -acetoxyacry late Diels Alder reaction of 11:306,307 withisoprene 11:306,307 A^a-Methyl-1,2-dehydrostrictamine 9:183 (/?)-2-Methyl-l,3-butane diol sulfiir analogue of 12:160,161 2-Methyl-1,3-cyclohexadione reaction with ethyl vinyl ketone 6:19 Robinson annulation of 6:19 trimethyl decalone from 6:19

1104

2-Methyl-1,3-cyclopentanedione 13:27 2-Methyl-l,6-dioxaspiro [4.5] decane from (5)-malic acid 14:526,527 from Paravespula vulgaris 14:526 isomers of 14:526-531 synthesis of 14:526-531 1 -Methyl-1 -phenyl cyclohexane 8:7 1 -Methyl-1 -phenyl-2-(methy Iseleno) methyl cyclopentane cyclization of 8:7,8 synthesis of 8:7,8 (15/?)-15-Methyl-12-er/7/-PGF2P 7:484 (15/?)-15-MethyM2-e/7/-prostaglandin F2P 7:484 iVi-Methyl-16-e/7/-affmine 5:77,124 ()-10-O-Methy 1-18,19-dihydrohunterbumine from ()-18,19-dihydrohimterbumine 14:706-708 synthesis of 14:706-708 3-(5-Methyl-2 fiiryl) propionaldehyde (5Z,8E)-2-heptyl-5-methylpyrrolizidmefrom 6:445,446 A^a-Methyl-2,16-dihydroakuammicine 1:35 2-Methyl-2-(4-methylpent-3-enyl)-2H-chromen-6-ol 10:248 Methyl-2-acetamido-4,6-0-benzylidene-2-deoxy-a-Z)glucopyranoside 0-alkylation of 6:386 with 5',/?-2-chloropropionic acid 6:386 Methyl-2-deoxy-P-erythro-pentopyranoside 6:362 3-Methyl-2-hydroxoindolizidines 12:284 (5)-A^-Methyl-2-hydroxysuccinimide 8:140 6-Methyl-2-lithio-2-phenyl-6-heptane 8:13 Methyl-2-methoxy-6-(hexa-2,4-diynyl) benzoate 9:317 7-Methyl-2-methylseleno-2-phenyl-6-octene synthesis of 8:9,10 2-Methyl-2-nitrosopropanol 9:573 3-Methyl-2-norbomanone 8:146,147 3 -Methy 1-2-oxo-indolizidine from ethyl 2-[l-ethoxycarbonyl methyl) piperidinyl) propanoate 12:284 6-Methyl-2-phenyl-6-heptene cyclization of 8:10 6-Methyl-2-phenyl-6-lithio-2-heptane 8:13 24-Methyl-25,26-dihydroxy-steroids absolute configuration of 15:84-86 24-Methyl-26-hydroxy and 24-methyl-26-oic-steroidal side chains absolute configuration of 15:81-84 A^b-Methyl-2P-16P-dihydroakuammicine N^methochloride 1:35 Methyl-3,4-dimethoxybenzahnalonate 9:225,226 5-Methyl-3-(2-methylbutyl)-2-(-3-methylpent-1 -enyl)pyrazines 5:226,230,242-244,262-264 5-Methyl-3-(2-methylbutyl)-2-(Z-3-methylbut-1 -enyl)pyrazines 5:226,230,242-244,262-264 A^-Methyl-3-(3-chloro-4,5-dihydroxyphenyl)-3hydroxyalanine 15:347 1 -Methyl-3-acyl-5-hydroxymethyl-2,4-dione 13:548 2-Methyl-3-buten-2-yl acetate decarboxylation of 11:130 2-Methyl-3-buten-2-yl-ester 11:129

2-Methy 1-3 -buten-2-ol in coumarin synthesis 4:377 C-prenylation by 4:375-482 (35,45)-4-Methyl-3-heptanol 1:681,682 (35',45)-4-Methyl-3-heptanol from (/?,i?)-diisopropylethanediol propylboronate 11:415 from (S)-pinane diol propyl boronate 11:412,413 from Scolytns multistriatus 11:142 synthesis of 11:412,413,415 (3/?,45)-4-Methyl-3-heptanol from (5,<S)-diisopropylethan diol methyl boronate 11:415,416 from Leptogenys diminuata 11:415,416 synthesis of 11:415,416 2-Methy 1-3-hydroxy-piperidine 9:70 1-Methy 1-3-indolylacetic acid 12:381 with 1-methy lindole-3-glyoxylylchloride 12:381 5-Methyl-3-isopentyl-2-(-3-methylbuten-1 -enyl)pyrazines 5:226,230,242,244,262 5-Methyl-3-isopentyl-2-(Z-3-methylbuten-1 -enyl)pyrazines 5:226,230,242-244,262 5 -Methyl-3 -isopenty l-2-(Z-3 -methy Ipent-1 -eny 1)pyrazines 5:226,230,242-244,262 5-Methyl-3-n-propyl-2-(-1 -butenyl)-pyrazines 5:226, 242-244,262,264 5-Methyl-3-n-propyl-2-(Z-1 -butenyl)-pyrazines 5:226, 242-244,262 2-Methyl-4-isopropyltetronic acid 10:260,261 3-Methyl-4-oxoadipate 8:298,299 4-Methyl-5 (1-hydroxyethyl) nicotinic acid 6:527 5-(-)-Methyl-5,6-dehydrocamphor 16:144 7-0-[4-Methyl-5-( 1 -hydroxyethyl) nicotinoyl] strychnovoline from Strychnos dinklagei 6:522,527 spectral data of 6:526,527 (/?)-4-Methyl-5-hexenoic acid from (/?)-citronellol 11:260 24-Methyl-5a-cholest-22(E)-ene-3p,6a,8,15p, 16P,28-hexaol 15:79 10p-Methyl-5//-oxazolo [2,3-A] isoquinoline derivatives ^H-l,5-methano-2,5-benzoxazonine derivatives from 6:474 3-Methyl-6-(3-methyl-l-azulenyl)-l(6H)azulenone 14:335 2-Methyl-6-alkyl-1 -piperideine 6:424-426 in Solenopsis xylonio 6:422 2-Methyl-6-vinyl-pyrazines 5:222,239 4-Methyl-7-isopropyl-l-azulenecarboxylic acid 14:328 iV-Methyl-a-aminobutyric acid 9:496 Methy 1-a-D-arabinopyranoside 15:431 Methyl-a-D-glucopyranoside 15:431 Methyl-a-D-pyranoside 14:180 Methyl-a-D-ribopyranoside 15:431 Methyl-a-ethylacrylate preparation of 14:850 Methyl-P-C-glycosides 10:345,346 Methyl-p-D-xylopyranoside 15:431 3-Methyl-cw,cw-muconate 8:299 cycloisomerisation of 8:305

1105

3-Methyl-c/5,cw-muconate (3-methyl- muconic acid) 8:299 3-Methyl-cw,cw-muconic acid 8:298,299,308,302 3-Methyl-cw,/r<25-muconic acid 8:308 6-O-Methyl-D-glucose 15:435 3-0-Methyl-Z)-glucose 7:268,275,277 4-(9-Methyl-Z)-glucuronic acid 7:181 Methyl-Z)-glycero-pentopyranoside 6:361 3-0-Methyl-Z)-xylopyrasone derivatives 6:374,375 3-O-Methyl-D-xylose 7:275 Methyl-DOPA from (3,4-dimethoxyphenyl) methyl methyl ketone 6:334 5'-Methyl-DOPA (dihydroxy-phenylalanine) 10:106 3-O-Methyl-glucose 7:272 Methyl-histamine 15:328 10-Methyl-hydronaphthalen-1 -ol-monosulfonate esters 14:356 Wagner-Meerwein rearrangement 14:135 0-Methyl-Z-arabinose 7:297 Methyl-L-sibirosaminide synthesis from Z,-a//o-threonin 4:135 A^-Methyl-7V-nitro-A^-nitroso-guanidine 5:599 ()-A^a-Methyl-iVp-acetylphlegmarine 18:341 Methyl-0-/7-tolylsulfonyl-a-D-glucopyranoside 8:337,338 /?-Methyl-/7-tolyl sulfoxide 6:263 as chiral precursor 6:3 01,3 02 a-Methyl-phenylacetic acid alkylationof 10:412 by lithium isopropylamides 10:412 (Methyl-i?) [methyl-^H,, ^H] methionine 11:207,209, 210 ip-Methyl-RS-533 12:145-148 synthesis of 12:147 (Methyl-5)-[methyl-^Hi, ^H] methionme 11:207,209, 210 (Methyl-5)-[methyl-^Hi, ^H] reticuline 11:204 lp-Methyl-SM-7338 12:145-148 synthesis of 12:147 3-Methyl-valerolactone 8:45,52 (+)-4/?-Methyl-valerolactone 8:56 /?-(+)-3-Methyladipic acid 15:229 11,15-Z)w-nor-Methylallopumiliotoxin 12:267,298 Methylamine dehydrogenase 9:582 X-ray crystal analysis of 9:582 Methylarctigenin 5:525 JV-Methylarcyriaflavin A aglycone of AT2433-Bi and B2 12:378 from cyclohexene imides 12:378 synthesis of 12:377-379 A^-Methylarcyriarubin A acid catalyzed rearrangement of 12:383 arcyriarubin A from 12:375,376 arcyrin/arcyrinin model compounds from 12:383 A^-methylarcyriaverdin C from 12:375,376 A^-methyldihydroarcyriarubin A from 12:375,376, 383 A^-Methylarcyriarubin B arcyriarubin B from 12:375,376

A^-Methylarcyriaverdin C from A^-methyl arcyriarubin A 12:376 ()-(3-Methylaspartic acid 14:102 P-Methylaspartic acid 14:105 A^a-Methylaspidospermatidine 1:40 11-0 -Methylatalphillidine 13:356,357 from Atalantia ceylanica 13:348,349 AT-Methylated ant alkaloids by reductive iV-mehylation 6:435,443 synthesis of 6:435,443 a-Methylation 11:43,44 of 2-ethyl-3-vinylcyclopentanone 8:192,193 Methylation 19:134 chemoselective 19:92, deoxygenative 19:519 Hakamori method 2:336 of 3-oxovincadifformine in tetrahydrofiiran (THF) 13:63 with sodium hexamethyl disilazide (NaHMDS) 13:63 with trimethyl orthoformate 1:448,449 iV-Methylation 19:321 ;6:478,491,492 of indolines 4:79 of 1,4-dideoxy-1,4-imino-Z-allitol 7:41 -43 0-Methylation 6:76,77 ofcoumarins 5:516-520, oflignans 5:525-532 in ()-sinularene synthesis 6:76,77 C-Methylation in Artemisia austriaca 7:207 P-Methylation 8:192,193 p-Methylbenzene sulfinates menthyl esters of 14:736 quinolizidine from 14:736 /?-(+)-a-Methylbenzylamine 4:438 as chu-al auxiliary 4:438 (-)-a-Methylbenzylamines 13:191 (/?)-a-Methylbenzylammonium salt 12:27,28 25-Methylbrassinolide 19:477 6-(3-Methylbut-2-enyl) narigenin synthesis of 4:378,381 3-Methylbutylamino derivatives 15:382 Methylbutylamino-3,4-dihydroisocoumarin 15:381 (5)-2-Methylbutyric anhydride 11:369;13:558 Methylbuxene 2:207 A^-Methylcaaverine 3:426 11-O-Methylcaesalpin 5:22,23 l3-epi-l l-(9-Methylcaesalpin 5:22,23 1 |3-Methylcarbapenem 13:84 1 p-Methylcarbapenems by C4-alkylations 12:159-177 by methylation of thienamycin 12:148-150 by reduction of exomethylene group 12:150-154 from amino acid 12:155-159 key intermediates 12:145-177 synthesis of 12:145-177 2-Methylcardols 9:315,318,324,325,332,333,335-227, 341-343 Methylcastasterone synthesis of 19:477 (3/?,75)-de-0-Methylcentrolobin 17:366

1106

3-Methylcholanthrene 5:448,452 (24i?)-24-Methylcholest-5,7,22-trien-3 P-ol (ergosterol) 9:447 24-Methylcholesta-5,22-dien-3 P-ol 9:471 24-Methylcholesta-5,24-diene-3P-ol 20:234 (+)-A^-Methylconiine 13:479 A^^*^6a-Methylcortexolone 9:425,428 (a-Methylcrotyl) boronic ester from (S, S)-1,2-dicyclohexy 1-1,2-ethanediol dichloromethy 1 boronate 11:423,424 preparation of 11:423,424 Methylcyanodithioformate 6:433,434 2-Methylcyclobutanone synthesis of 6:314 1-Methylcycloheptatriene 13:32 1-Methylcyclohexanol 8:365,366 Methylcyclopentanoid monoterpenes biogenesis of 20:43-48 stereoselective synthesis of 20:41-76 synthesis of 20:48-76 (+)-0-Methyldehydroancistrocladine 20:431 7-Methyldecalin 9:113 cw-9-Methyldecalin 9:272,280 /ra5-9-Methyldecalin 9:272,280 A^-Methyldecarine(8-0-demethylchelery-thrine) from 7-O-demethyl oxychelerythrine 14:783,784 synthesis of 14:783,784 A'-Methyldehydrobutyrin 9:496 A'^-Methyldeoxynojirimycin 10:540 P-Methyldigoxin 13:663 ;664 A^-Methyldihydroarcyriarubin A from A^-methylarcyrinrubin A 12:376 Methyldilactone 8:312 Methyldolichosterone isolation of 19:261 5-(9-Methylembelin 7:83 a-Methylenation 8:21,29;10:13,17,25;13:33 Methylenation 8:26,29,30 with Lombardo reagent 11:40,41 Methylene 2,3'-biplumbagin 2:213,215-217 biosynthesis of 2:229,230 24-Methylene cycloartenyl linolcate 9:461 Methylene cyclohexane Piers annulation of 6:21,22 7,8-Methylene dioxyanthracene 11:120 2-Methylene glutarimides isonitramine from 14:747 nitramine from 14:747 24,28-Methylene-24-propylchoesterol 9:36-38 from Pseudaxinyssa species 9:38 Methylene-3,3'-biplumbagin 5:754,755 1,1 '-Methylene-bis (3,7-diisopropylazulene) oxidation of 14:340,341 1,1'-Methylene-bis (3-methylazulene) 14:335,336 3,3'-Methylene-bis (guaiazulene) 14:328 oxidation of 14:343-345 Methylene-bis-(dichlorophosphane) 9:527 y-Methylene-y-butenolide (protoanemonin) 10:149 a-Methylene-y-butyrolactone 8:198 synthesis of 8:195,196 a-Methylene-y-lactone (-)-3-ep/-zaluzanin C 14:366 Methyleneazulenones 14:332

(+)-2-Methyleneborane 4:650-652 acid catalysed rearrangement of 4:650,651 optical purity of 4:652 (22/?,23/?)-22,23-Methylenecholesterol 9:36,37 from Z>y5/flfea species 9:37 from Siphonoborgia species 9:37 from Xestospongia species 9:37 X-ray analysis of 9:37 24-Methylene cycloartenol from Salvia nemorosa 20:702 (23/?,24/?)-23,24-Methylenecholesterol 9:36,40,41,43 from Colletotrichum nieaeensis 9:37 from Petrosiaficiformis 9:37 (28-^^C)-24-Methylenecholesterol 9:42,43 (24-^'*C)-24-Methylenecholesterol 9:44 24-Methylenecycloartan-3-one 9:288,289 24-Methylenecycloartan-3 p-ol 9:288,289 Methylenecyclohexane annulation of in ()-amijitrienol synthesis 6:53 in isoamijiol synthesis 6:54 24-Methylenecholesterol 20:234,20:238 a-Methy lenecyclopentanone moiety 15:176 3,4-Metiiylenedioxycinnamic acid 5:479,480 (Z)-Methyleneiminium ion 11:203 a-Methyleneindolenines 9:190-194 (-)-Methylenolactocin antitutmor antibiotic 16:699 synthesis of 16:699 Methylenomycin antibiotics 3:44 Methylenomycins 14:589,610 O-iV-Methylephedrine 13:118,119 0-Methylepoxyshikoccin 15:163 ^^C-nmrof 15:165 from Rabdosia shikokiana var. occidentalis 15:174 ^H-nmrof 15:164 5'-0-Methylerbstatin 15:448 6-O-Methylerythromycin A 165,179 synthesis of 13:165 ^-Methylfmdersine 7:191,192 O-Methylflavinanthme synthesis of 3:426 (+)-3'-0-Methylfukugetin 5:758 O-Methylfumarofme 1:205-201,211 3-O-Methylgalactose 15:431 (+)^'.O.Methylglabridin 4:391,392 synthesiof 4:391,392 (5)-(+)-2-Methylglutarate 15:228 1-0-Methylglyfoline 13:363 6-0-Methylglyfoline 13:376 Methylgrandiflorenate 17-nor-ketone 19:395 (+)-0-Methylhamatme 20:432 2-Methylheptadecane pheromoneof 19:125 (/?)-2-Methylhexanal 19:54 0-Methylhoslundm 2:133 6a-Methylhydrocortisone 9:427,428 12-Methylidene-10Z,13Z-nonadecadienoic acid 9:570 Methylidenenorbomene 8:150 3-Methylidolizidine-1,2-diols from 2-cyano-6-oxazolo-piperidine 12:351 1,1', 1 "-Methylidynetri(3-methylazulene) 14:335

1107

1 -Methylimidazole as catalyst 4:270 2-Methylindolo (2,3-a) quinolizidine synthesis of 14:720-722 1-Methylindolo [2,3-a] quinolizine 1:147 synthesis of 1:207-209 Methyline iminium ylide 1:249 0-Methylipalbidine synthesis of 1:284,285 A^-Methylisoindoline 8:402,403 (Z)-Methyljasmonate 19:158,19:161 3'-0-Methylkanamycin 14:145 17-0-Methylkribine 9:179 (+)-5-0-Methyllicoricidine synthesis of 4:388,389 TBDMSCI protection in 4:384,389 0-Methylmacusine B 13:387 Methylmalonyl CoA 11:194,195 hypothetical incorporation of 11:195 with macrolide antibiotic 11:195 (/?)-Methylmalonyl CoA 11:195 (5)-Methylmalonyl CoA 11:195 (2/?)-Methylmalonyl CoA from succinyl CoA 11:195-198 (25)-Methylmalonyl CoA from propionyl CoA 11:195,196 Methylmalonyl CoA mutase coenzyme B 12-dependent 11:195-197 (2/?)-methylmalonyl CoA by 11:195-197 5-Methylmellein 15:383 from Euphorbia fidjiana 15:385 from Fusicoccum amygdali 15:385 from Hypoxylon and Numularia spp. 15:385 ^om Phomopsis oblonga 15:385 from Valsa ceratosperma 15:385 5-Methylmellein 9:288,289 A^-Methylmorpholine A^-oxide (NMO) 8:23;14:270 3-Methylmuconate 8:298-300 synthesis of 8:300 2-cw,4-rrarrt5-3-Methylmuconic acid 8:302 (45)-3-Methylmuconolactone 8:302 bromolactonisation of 8:301 (5)-(+)-4-Methylmuconolactone 8:302 4-Methylmuconolactone 8:298,299 (+)-3-Methylmuconolactone 8:300 from 2-nitro-4-methyl-phenol 8:300 3-Methylmuconolactone 8:306 absolute configuration of 8:301 cw-10-Methylnaphthalenol monotosylates 14:363 /r<2fw-10-Methylnaphthalenol monotosylates 14:363 2-Methylnaphthazarin 2:213,215,216 2-Methylnaphthazirin 5:754,755 7-co-0-Methylnogarol 14:47,78,79 antitumor activity of 14:48 (+)-7-co-0-Methylnogarol total synthesis of 14:72-76 ()-7-co-0-Methylnogarol 14:83-90 synthesis of 14:83-90 0-Methyhiormacusine B 4:386 4'-0-Methylosajin from 5,7-dihydroxyisoflavome 4:382,385 Methylotrophic bacteria 1:170

()-0-Methylpallidinine from Chamaecyparis pisifera 1:702 synthesis of 12:470,471 4-Methy Ipheny 1 thiochloroformate 13:10 O-Methylpisiferic acid 1:702-704 synthesis of 1:702-704 2-Methylpropane-l,3-diol 13:84 5-(2-Methylpropyl) pyrrolidinone 13:131,132 13-Methylprotoberberine alkaloids synthesis of 1:219-221 (-)-7V-Methylpseudoconhydrine 13:479 2-Methylpyridinium salts reaction with alkynyl Grignard reagents 6:429 4-Methylpyrocatechol 8:299,309 4-Methylquinol reaction of 16:618 Methylrhodomelol 4:712,714,725 synthesis of 4:712,714 6-Methylsalicylic acid biosynthesis of 11:198,199 by Penicillium patulum 11:198,199 Methylseleno acetal reaction with n-butyllitium 8:6 reaction with 14-dibromopentane 8:6 2-Methylseleno-2-phenyl-6-heptene 8:12,13 from 1-methylseleno-1-phenyl-ethyllithium 8:7 from 5 -bromo-1 -pentene 8:7 synthesis of 8:7 transformation of 8:7,8 2-Methylseleno-2-phenyl-6-methyl-6-heptene 8:7 A^-Methy Isempervirine 1:159 synthesis of 1:139 A^-Methylserotonine 15:328 0-Methylshikoccin 15:163-165,174 *^C-nmrof 15:165 from Rabdosia shikokiana var. occidentalis 15:174 *H-nmrof 15:164 30-Methylspergulagenate 7:144,145 (Methylsulfinyl) (methylthio) methane 11:351 13-Methyltetrahydro protoberberine ()-ambinine from 14:790,791 ()-ll-epiambininefrom 14:790,791 synthesis of 14:790,791 1 -p-Methylthienamycin antibiotic potency of 4:432 by azetidione synthesis 4:437, synthesis of 4:460,462,465,469,470 3-5'-[(Methylthio)carbonyl]-3-thiohexofuranose derivative 14:168 (Methylthio) methyl group as carboxy protecting group 1:272,273 3-Methylthio-2-oxopropanals acetal derivatives of 6:335,336 acetal of 6:335,336 synthesis of 6:335,336 3-Methylthio-2-propenyl/7-tolyl sulfone 6:309,340343 Methy Ithioadenosine 17:15 Methylthiolation 6:329 2-Methyltryptophan from tryptophan 11:209 S (+)-iV-Methyltryptophan methyl ester of 5:752

1108

16p-Methyltubifolidme (curan) 1:38,39 13a-MethyItylohirsutine 12:301 13a-Methyltyohirsutidine 12:301 4-Methylumbelliferone 7:53;18:985 6-Methyliiracil 4:226 Methylvinyl ketone in solenpsin A synthesis 6:427,428 A'^i-Methylvoaphylline 5:126 O-Methylvulgarolide 18:20 4'-0-Methylwaranglone from 5,7-dihydroxyisoflavone 4:382,385 2-0-Methylxylose 7:297,299 Methymycin synthesis of 11:151 Methynolide 11:151,152 synthesis of 11:158-163 Metridium illicifolia 18:665 Metridium loesner 18:757 Metridium senile 18:813 Mevalonate 13:553 Mevalonate 5-diphosphate isopentenyl diphosphate from 11:219,220 Mevalonate 5-diphosphate decarboxylase monoterpene from 11:219,220 sesquiterpene from 11:219,220 Mevalonic acid 7:324,325,327,329-331,340-343, 346-349,351,352,357,358,:360,361,363;ll:200 from acetyl CoA 7:322 from glucose 7:345 phosphorylation of 7:322 prenyl diphosphates from 7:322 (/?)-Mevalonolactone 1:271 Mevalonolactone 13:621 Mevinic acids synthetic studies 13:553-625 (+)-Mevinolin biological activity of 11:335,336 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor of 11:335,336 total synthesis of 11:335-377 Mevinolin biogenesis of 4:620 synthesis of 13:553,561 Meyers oxazoline coupling 20:419 Mezerein 20:22 MgBr2-catalyzed cyclocondensation 11:451 MgO procedure 6:411 Micaculin from Richardella dulcifica 15:36 Michael (1,4-addition) reaction 147-199 Michael acceptors 16:650;18:315,329,334,339,369 a,P-unsaturated orthoesters 3:146 Michael addition 5:181,182;6:5-7,7,74,75,8:224,277; 9:343,347;10:61,164,183,412;11:96,97,123;14:5,37, 39,42,118,274;15:272;16:30,155,424,582,700; 18:10,63,81,333,343,355,374,378,369 2-amino alcohol by 12:411,413 asymmetric 14:510 base catalyzed 14:521 carbocycles 8:409-428 diastereoselective 11:286

enantiospecific 16:221,262,613 in the synthesis of 8:409-428 intermolecular 14:524 intramolecular 3:83;10:51;11:312;12:17;14:521, 523,524,736;16:695 natural products 8:410-412 ofalcohol 16:104 ofalkoxides 12:411,413 ofdiene 16:548,595 ofenolates 10:407 of levoglucosenone 14:271,272 of methyl group 10:414,415 ofMT-sulfone 6:337,347 of nitroalkane dianion 1:311,312, of trimethy Isily 1 ketene acetal 10:353 of a-ethylidene-y-lactone 10:405,406 of a-formyl-a-phenyl acetic acid 10:408 of a-keto acetal 14:510 stereoselective 1:489,490 Stork modification of 10:185 tandem 4:556,557 to nitro olefins 10:407;12:411,413 to P-methylated enone 10:414,415 with methyl vinyl ketone 14:510 Michael cyclization 16:437 intramolecular 14:552 Michael reaction 6:70,71;9:435,437,516;11:31,38,39, 41,42;13:29,30,180,398,404-406,417,418,437,440, 448,458,609,618;16:494 aliphatic acceptors 4:705,706 alkenoylcyanide acceptors 4:709-711 asymmetric 14:551-567 chiral building block from 14:551-567 cyclic ene-dione acceptors 4:709 cyclic enone acceptors 4:707-709 intramolecular 14:551-567 reaction mechanism of 14:551-567 with quinone methides 4:712 withvitamicC 4:705-715 Michael type addition 18:65,269,302,303,305,307,309 of nucleophilic glycosyl radical 11:464 (3-amino ketone 8:286 Michael-Aldol reaction 3:132-143 Michael-Arbuzov transformation 13:273 Michael-induced cyclization 14:755,756 Michael-Michael construction 12:203 Michael-type acceptors 12:99 Michael-type addition 8:286 Michaelis-Arbuzov reaction 4:68 Michaelis-Menten model 7:29 Michellamine A 20:408,442,443-446 Michellamine B 20:443,446,451 from Ancistrocladus korupensis 20:442 Michellamine C 20:445,446 Microcystin-LR 20:896,905,907,909,910 M/co/1/a species 9:321 Miconidin 9:321,329 Microbes for chiral synthesis 1:677-708 Microbial degradation 9:411,413 ofp-sitosterol 9:411 Microbial hydroxylation 9:416

1109

Microbial oxidation ofarenes 18:430-432 Microbial reductases 17:491 Microbial reduction of keto acids 4:493 by Baker's yeast 6:13 of Kloeckera magna 6:13 Microbial secondary metabolites screening of oncogene function inhibitor from 15:439-463 Microbial transformation 9:416;13:298 oflimonene 16:208 Microbiological reduction 13:556 of racemic dione 13:556 Microcionin-2 17:15 Micrococcus flavus 12:400 Micrococcus leuteus 12:400;13:283;15:389 Micrococcus varians 8:102 Microcystins 9:496,498,499;18:269 Microcystis 9:496 Microdilution method 20:712 Microsomal oxidation 19:188 Microstegiol from Salvia candidissima 20:680 Micromonospora halophytica subsp. exilisia 10:652 Microozonolysis 6:455 Microphyllinin acid 9:317,328 Microsomal oxidase 6:374 Microsomes 5:448,452 Microsporum canis 12:400 Microsporum guinckeanum 5:294 Microsporum gypseum 12:400 Midecanolide 11:160 Midecanolide Ai 11:163,170 Midland's pinyl borane 11:424 Miglyol 7:113 Miharamycins 11:434,19:129 Milbemycin a and p series of 12:4-9 Milbemycin Pi synthesis of 12:22 Milbemycin ai-aio 12:4-9 Milbemycin PrPa 12:4-9 Milbemycin Ps homochiral synthesis of 1:451-454 synthetic routes to 1:448-462 Milbemycin P3 synthesis of 12:26 Milbemycin D synthesis of 1:469 Milbemycin D-K 12:6 Milbemycin E from Streptomyces sp. 16:659 (-)-Milbemycin I 16:661 Milbemycins 14:519 structure of 1:435-495 synthetic approaches to 1:435-495 Mildiomycin 4:241, activity of 4:245 structure of 4:246 Milimorin 5:678 Millingtonia hortensis 5:14

Milius banacea exoaporphines of 20:483 MiMiharamycins 1:398 synthesis of 1:404-410 Minabeolide-3 isolation of 19:470 from Minabea species 19:470 Mimulaxanthin 6:136,137,143,144 Mimulus species mimulaxanthin in 6:137 Miniatoside A and B from Patiriaminiata 15:61 Minimal inhibitory concentration 9:413 Minimization method BDNR 17:500 Minimum inhibitory concentration (MIC) of phenylpropanoids 5:512 Minovine 19:92 synthesis of 14:635,636 Minoyobates bombetes 19:81 Misakmolide 5:396 Misakinolide A 5:355,358,396,397 Mislow-Evans sulfoxide rearrangement 8:216 Mithramycin 3:173 Mitomycin 1:340;4:573;5:439,440; 16:573 Danishefsky synthesis of 13:433 from D-glucosamine 13:434 from isomitocins 13:445-467 Kishi synthesis of 13:436-442 synthesis of 13:433-471 Mitomycin A 13:434,435,445-447,460,467 from Streptomyces caespitosus 13:433 synthesis of 13:439-442 X-ray crystal analysis 13:434 Mitomycins 13:439 from Streptomyces caespitosus 13:433 synthesis of 13:439-442 X-ray crystal analysis 13:434 Mitomycin C 13:435,460,467 from Streptomyces caespitosus 13:433 synthesis of 13:440 X-ray crystal analysis 13:434 Mitomycin M 13:433 Mitomycin rearrangement 13:446,460 Mitosane 13:434,436,437,443,444 Mitosene 13:434,436,437 synthesis of 1:340 Mitotic activity of the cells 2:380 Mitotic index (MI) 2:373,376,380,385 Mitoxanthrone 1:514 Mitraphylline 14:751 Mitsonubu activation 3:328 Mitsonubu alkylation 3:313 Mitsunobu condensation 18:88 Mitsunobu conditions 16:461 Mitsunobu coupling of 3,4-dimethoxyphenethyl alcohol 12:448 of l-methyloxazolidien-2,4-dione 12:453 Mitsunobu displacement reaction 12:281 Mitsunobu inversion 1:695,697,698;4:449,459;6:553, 554;13:499,502;18:7,237,246,259,281,470,893,903

1110

Mitsimobu procedure 1:456;14:182 ring closure by 11:10 Mitsunobu reaction 1:205;4:86,456,457,478,515,519; 6:294,295;10:603;11:404;12:305,312,319,468; 13:201,443,485;14:15,275;16:79,350;18:174,217, 235,471 with phthalimide 11:236 Mixed function oxidases 7:8 Mixed inhibitors 7:40 Michael reaction 3:125-155 MMP2-CONFLEX 11:3 method 11:157,162,168 Mmyrcene 3:107 MNDO calculation 13:164,165 Modhephene 1:632,637;3:6,8,11,16,24,61;13:37-39; 14:490 e/7/-Modhephene 3:6,11,62 Modifications of p-lactam antibiotics 12:135-140 Modified Eschenmoser method 3:482 Modified Eschweiler-Clarke conditions 6:476 Modified Schollkopf s procedure 15:443 Moenjodaramine 2:175,176,205 ^C-NMR spectrum of 2:176 structure of 2:175,2:176 Moflfatt oxidation 12:325,335;14:814,815 MogrosideV 15:22 (+)-Mokko lactone 14:368 Molander's conditions 14:490 Molar decadic absorption coefficient 2:156 Molar ellipticity 15:424 Molar rotation 2:159 Molarellipticity 2:160 Molecular complexity C 3:29 Molecular dynamics (MD) 10:269 Molecular dynamics simulation ofmicrocystins 20:907-910 ofnodularins 20:907-910 Molecular interactions of oligo (pyrrolecarboxamido) amidine antibiotics 5:575-581 Molecular mechanics 10:17,22,36 Molecular mechanics calculations 3:351;5:579;9:3,281283;11:31,33 of [5.5.5.7] fenestrenes 3:118,119 Molecular mechanics simulation 3:339-351,363 Molecular modeling (MOMO) 10:269;15:213,344 Molecular rearrangements ofperezone 5:792-794 of sesquiterpenes 5:794-800 ofgrandiflurenicacid 19:389-410 Molecular recognition 18:819 byDNA 19:345 Molluscicide 7:425-427 Mollusks 17:3 Moloney sarcoma virus 5:565 Moltilin 13:156,158 Molybdate complexes from di-and trisaccharides 15:436,437 Molybdenum (VI) oxidiperoxo compled for asymmetric epoxidation 4:344,345 with (5) piperidine lactamide ligands 4:344,345 MOM group removal 1:452,453 Momordica grosvenorii 15:22

MonacolinK 13:553 Monatin [4-hydroxy-4-(indol-3-ylmethyl) glutamic acid 15:35 Molt-4 p-glucocerrbrosidase 19:352 Monascus ruber 19:168 Monellin 15:36 Monensin 3:58;10:424 MonensmA 11:196,197 Monilia spp. 2:323 Moniliformin 6:219,220 Moniliformin 9:203,204,214,215 Moniliniafructigena 5:278 (Mono)-piperidine-p-carbolines 14:758,759 Mono-6-0-/7-tolylsulfonylcyclomaltoheptaose 8:340 Mono-6-5'-a-D-glucopyranosyl-6-thiocyclomaltoheptaose 8:340 Mono-6-5'-p-D-glucopyranosyl-6-thiocyclomaltoheptaose 8:340 Mono-a-oxidation 12:83 a-Mono-alkoxylatedpiperazinediones cyclization of 12:84 synthesis 12:83 9-Mono-c/5-tetradehydrocarotenoids 6:5 Mono-substituted azulenes oxidation of 14:335,336 Monoacetylenic-7,8-didehydroastaxanthin stereomutation sutdies of 6:153 C37-Monoacetylenic apo-carotenoids 6:149 C37-Monoacetylenic nor-carotenoids 6:149 2'-or 3'-Monoacylated ribonucleoside 2',3-acyl migration in 14:285 Monoalkylation 6:341 ofMT-sulfone 6:330,331,339, Monoalkylmalonic acid condensation of 13:74 Monoallenic carotenoids 6:135,136 Monoamino oxidase 5:411 Monobenzylation 11:253,254 Monobromination of A^,A^-dialkyl glycine anhydrides 12:83 C(3 )-Monobromination of 8,9,10-trinoreamphor 4:656,657 C4o-Monocacetylenic carotenoids 6:149 Monochlorinated sulfoxide a-alkoxysulfoxide from 6:310 chemcial reactions of 6:310 epoxysulfoxide from 6:310 from A^-chlorosuccinimide 6:310 from sulfoxides 6:310 Monoclonal anti-I biosynthesis of 10:484 I-antigenic determinant of 10:480,481 inhibition of 10:482 Monocrotalic acid synthesis of 1:262 Monocrotaline 8:223 macrocyclic dilactone from 8:222 Monocyclic P-lactams from Nocardia uniformis 12:118 synthesis of 12:120,121

nil
Monocyclic ketones to bicyclic enones 10:311-313 Monocyclic sesquiterpenes 5:803-805 Monodesmosides 15:188 Monodeuterated tripeptides monodeuterated penan from 11:212,213 Monodora tenuifolia 2-dimethylallylindole from 2:446 Monofluoroestradiol derivatives 5:453 Monogagaine 5:125 Monoglycosides 7:268,272,273 Monogynol A from Salvia montbretii 20:704 Monohba quadridens 5:225,231,253 Monohexosylceramide 18:799,814 from Sporothrix sohenckii 18:807 from Fusicoccum amygdali 18:807 from Fusarium lini 18:807 from Fusarium solani 18:807 from Aspergillus oryzae 18:807 f[om Aspergillus fumigatus 18:807 from Aspergillus versicolor 18:807 Monolignols 5:463 trans ()-Monolignols 5:472 Monomethoxytritylation 4:286 Monomethoxytrityloxyethylamino as protecting group 4:289 Monom irium foricola pyrrolidine venom alkaloids in 6:436 Monomethoxychrommene 2:125 (+)-Monomorine synthesis of 16:488,490 Monomorine 10:186 ^^C-NMRof 14:575 ' H - N M R of 14:575 as 3-butyl-5-niethyloctahydroindolizidine 6:445,447 asymmetric synthesis of 6:449,450 from 1,2-oxazine 6:449 from 2,6-lutidine 6:445,447 from Monomorium pharaonis (pharah ants) 14:575 from pyrrolidine synthesis 14:575 MS of 14:575 synthesis of 6:445,447-449;14:575,476 Monomorine I 4:606;14:575,576 synthesis of 1:290,291,293,389-391 3-er/7/-Monomorine I 1:391 (+)-Monomorine I from (5)-alanine 11:241,242 from Monomorium pharaonis 11:231 from (5)-pyroglutamic acid 11:241,242 synthesis of 11:231-244 ()-Monomorine I absolute configuration of 6:449,450 from diethyl-I-tartarate 6:449,450 synthesis of 6:449,450 (-)-Monomorine I synthesis of 6:449,450 Monomorium carbonarium pyrrolidine venom alkaloids in 6:436 Monomorium cyaneum pyrrolidine venom alkaloids in 6:436 Monomorium ebeninum pyrrolidine venom alkaloids in 6:436 Monomorium latinode 16:441 pyrrolidine venom alkaloids in 6:436 Monomorium minimum pyrrolidine venom alkaloids in 6:436 Monomorium minutum pyrrolidine venom alkaloids in 6:436 Monomorium near emersoni pyrrolidine venom alkaloids in 6:436 Monomorium near metoecus pyrrolidine venom alkaloids in 6:436 Monomorium pharaonis L. 1:389;6:336,445,454; 14:575 indolizidine alkaloids in 6:445 pyrrolidine venom alkaloids in 6:436 (+)-monomorine I from 11:231 Monomorium species 6:443 2,5-dialkylpyrrolines in 6:434,443 /ra5-2,5-dialkylpyrrolidines in 6:434 pyrrolidine venom alkaloids in 6:436 Monomorium subopacum 6:436 Monomorium viridum 6:3436 Monooxygenase 17:491 2'-or 3'-Monophosphorylated ribonucleosides phosphoryl migration in 14:286 Monosaccharides 7:18,29,31,62;13:207-212 as chiral synthons 4:625 C(3)-monosubstituion reactions 4:653 stereoselectivity of 4:653 synthesis of 4:625 Monosaccharide-molybdate complexes 15:437 Monosaccharides with CpP bond 6:352-356 Monosaccharides with C2-P bond 6:357-359 Monosaccharides with C3-P bond 6:357,360 Monosaccharides with C4-P bond 6:360-365 Monosaccharides with C5-P bond 6:365-375 Monosaccharides with Ce-P bond 6:375-377 Monosaccharides with C7-P bond 6:377 Monosodium glutamate 7:457 Monoterpene 5:343;6:110;7:95,98,106-109,112,114118,120,124,126,427;8:220;9:529 alcohols 17:79 synthesis 17:603 chiral 16:123,124 chiral pool 16:123 Monoterpene alkaloids 7:443,444;9:163-199 from Strychnos dinklagei 6:522-530 from Valeriana officinalis 6:524 Monoterpenoids 4:625;16:123,124 Monotropein 7:440 Monoterpene synthetase 7:123 Monovalent peptide 18:914-918 Montanine 20:325,353 Montanoa tomentosa 389 Montbretyl-12-methyl ether from Salvia candidissima 20:661 Montanone 7:235 (9/?)-(+)-Mophinandienone 16:505 Moraceae 2:249;17:456 Moracenin Aand B from Morus alba Linne 4:618 relation to albanins F and G 4:619 Moraceous plants 17:451

1112

Moradial from Salviapomifera 20:705 Moraprenyl(2,3,4,6-tetra-0-acetyl-p-Dglucopyranosyl) phosphate 8:107 Moraprenyl (P-D-glucopyranosyl) phosphate 8:108 Moraprenyl diphosphate 2-acetamido-2-deoxy-a-Dglucose 8:91 Moraprenyl diphosphate a-D-galactose 8:89 Moraprenyl diphosphate monosaccharides 8:90,91 Moraprenyl monophosphate sugars synthesis of 8:86 Moraprenyl phosphate 8:105,106 Moraprenyl trichloroacetimidate 8:107 P'-Moraprenyl, P^-(a-)-glucopyranosyl)uronic acid diphosphate 8:108 Morelloflavone 5:758 Moronic acid from Salvia pomifera 20:705 Mori synthesis of azitidinone derivative 13:5 00 Mori-Matsui synthesis totaxodione 14:667-670 Morin 5:678 structure of 5:677,683 Morinda lucida I'All Moritoside 15:294 Morphinan 18:76 Morphinandienone synthesis of 3:425 Morphine 12:456,457; 18:43-109 biosynthesis of 18:51-55 from Papaver somniferum 13:631 history of 18:45-55 semi synthesis 17:633,636 synthesis of 18:56-98 Morphine alkaloids 20:292 Mortierella ramannianus 19:578 Morphine synthesis 18:56-98 historical perspective of 18:43-107 Morpholidate method 14:295 Morpholine 6:456 Morroniside 7:442 from Lonicera morrowii A. Gray 16:307 Mortania palmeri 5:678 Mortonia greggi 18:751 Mortonins A,B,C and D 18:751 Mortonol from Mortonia greggi 18:751 Morusalba 17:47,451,465 cell cultures 17:471 polyprenols from 8:36 Morus alba Linne moracenin A and B from 4:618,619 Moschus moschiferus musconefrom 8:219 Mosher ester 11:361;12:478 absolute configuration of 13:77 Mosher's (+)-MIPA ester 1:370,371 Mosher's method 15:76;17:264,271,276 Mossambine 1:35 MT-sulfone acidity of 6:329 alkylation of 6:334

dialkylation of 6:332 from DMSO 6:329,330 Michael addition of 6:337-339 monoalkylation of 6:330,331,339 organic synthesis with 6:329,330 properties of 6:329 synthesis of 6:329,330 MTPA esters 12:431,432,434 Muconate pathways 8:295-313 stereochemical study 8:296 cw,cw-Muconicacid 8:295 syn addition of 8:296 Muconic acid pathways 8:295-313 cyclisation of 8:298 Muconolactone 8:295,296 (45)-Muconolactone 8:308,312 Muconolactone isomerase 8:298 Mucormiehi 13:303 Mucor rhizopus 9:203 Mucorrouxii 5:276 Mucor spp 2:323 Mucorales 9:203 Mueller Li-bronze reduction of(+)-carvone 10:408 Mugil cephalus 18:486 Mugil umbelata 18:665 Mukaiyama ADD reagent 10:23,24 Mukaiyama aldol process 19:203 Mukaiyama aldol reaction 18:292 Mukaiyama condensation 10:187 intramolecular 10:181,182;10:218 Mukaiyama conditions 12:244 Mukaiyama's protocol 11:289,296,297 Mukaiyama-Michael aldol condensation 16:664 Mukulol 10:25-29 synthesis of 8:178 Mulberrofiirans 17:459 Mulberry tree 17:519 Mulberry, Diels-Alder type adducts 17:451 Mulheim isolation of 19:552 Multicaulin 20:673 Multi-step homologation 13:698 Multidrug-resistant human cancer cell staurosporine activity against 12:390 (-)-Multiflorine AT-oxide from Lupinus hirsutus 15:524 Multiple antigen 18:920 Multiple hydrogen bonding 17:564 Multiple quantum spectra 9:143,144 (+)-Multistriatin 19:127 from levoglucosenone 14:267 synthesis of 14:267 (-)-5-Multistriatin from levoglucosenone 14:273,274 from Scolytus multistriatis (elm-bark-beetle) 14:274 synthesis of 14:273,274 Munchnones 1:339,340 Muqubilin 9:15,16,18-23 Muramic acid 2-azido-2-deoxy derivatives of 6:388,388

1113

intramolecular reactions of 6:389,380 synthesis of 6:385-388 Muramic acid 6-lactam l,4,5-tri-(9-acetyl derivative of 6:389 Muramine synthesis of 6:491,492 Muramyl peptides 6:385,404 Murashige-Skoog medium 7:91,97 (+)-Muricatacin 16:695 Muricatacin 17:252,277-279;18:195,213-218 (+)-Muricatacin 18:198 Murisolin 17:267 MurNAc 6:409,410 ^H,^^C-NMR of analogs 6:413-416 structure modification in 6:405-407 MurNAc 5-lactones A^-acetylmuramoylamide derivatives of 6:393 aminolysis of 6:393 a-benzyl glycosidesd of 6:390,395 NMR spectra of 6:390,391 reactions of 6:390-395 stability of 6:395 [p-MurNAc-(l 6)-Glc Nac] disaccharide synthesis of 6:403 Murraquinone B synthesis of 1:172,174 Murraya 1:172 Murrayaquinone-B 1:163,164 Musca domestica 18:698,19:124 Muscarin from 2-deoxy-Z)-erythro pentose 10:394 from I-erythro pentose 10:394 MuscarosideC 15:200 Musci (mosses) 2:277 (/?)-Muscone asymmetric synthesis of 14:490 synthesis of 1:632,633 via asymmetric cyclopropanation 14:490 (-)-Muscone by three carbon ring expansion 10:330,331 Muscone 8:225,239,245;19:171 from Moschus moschiferus 8:219 [5,5]-Oxy-Cope rearrangement 8:247 synthesis of 8:224,242,243,247 Mushroom amino acid 3:254 synthesis of 3:254 Mushroom monophenol (O-monooxygenase) 5:448 Mushroom tyrosinase 5:455 Mushrooms 1:680;17:153 Mutagenic activity of estrogen 5:447 offiimonisins 13:532 Mutagenicity 7:9 Mutamicins 5:615 Mutamycin 13:435 Mutamycin (mitomycin C ) 13:435 Mutarotase 7:71 Mutatis mutandis 15:262 Muurolane 15:247 Muzigodial 14:414;17:235 MVA 7:110 MVA-5-diphosphate 7:322,323

MVA-5-phosphate 7:322,323 MVAP 7:98 MVAPP 7:98 MycalamideA 5:366;10:413 MycalamideB 10:413 Mycale adhaerens 15:386,19:558,613 Mycalesip. 5:366;9:19,22,24 Mycaminose 5:614 5-O-Mycaminosyl protylonolide 5:611,612,615,616 Mycaminosylmcaose 5:614 Mycarose 5:614 I-Mycarose nucleosides 4:256 Mycelia sterilia 9:203 Mycinamicin 5:613 Mycinolide from allylic boronic ester 11:423,424 synthesis of 11:423,424 Mycinolide V 10:153 Mycobacteria 18:393 Mycobactericum tuberculosis H37R 4:244 Mycobacteriosis 2:434 Mycobacterium avium 13:183 Mycobacterium aviumintracellulare 2:424 Mycobacterium intracellulare 2:428 Mycobacterium leprae 9:322 Mycobacterium phlei 12:103 Mycobacterium smegmatis 12:400 Mycobacterium sp (all ) phytoene from 7:327 Mycobacterium tuberculosis 12:398;18:351 Mycobacterium vaccae 9:411 Mycoplasma sp. 12:48 Mycorhodin 2:139-152 Mycosamine 6:262 glycosidation by 6:276,277 in amphotericin B 6:261 Mycosphaerella pinode 5:278 Mycotoxicoses 9:5 Mycotoxins 9:202-208,216;13:519;17:475 Mydriatics 17:395 5'-(+)-Mymontanone 15:232 M>;o-inositol 7:181;18:391;19:352-353 MyO'\nos\io\ 1-phosphate by myo-inositol-1 -phosphate synthase 11:216,217 from glucose-6-phosphate 11:216,217 Afyo-inositol triflates 18:439 Afyo-inositol-1-phosphate synthase from beef testes 11:216 from Lilium longifolium 11:216 wyo-mositol 1-phosphate by 11:216,217 Myodesmanones 15:231 Myodesmonoid 15:232 Myomontanoid p-ketols 15:232 Myomontanones 15:231 Myoporone synthesis of 15:228 /?-(+)-Myoporone 15:229 Myoporum bontioides 15:229 Myoporum deserti 15:228,229 Myoporum laetum (-)-ngaione from 15:236 Myoporum montanum 15:229

1114

Myoporum species 15:227 Myrcenes 5:343,696;7:100,101;11:17,18;17:604 Myriapora truncata ll'.ll Myricagale 17:371 eudesm-1 l-en-4-ols from 14:450 (-)-selin-ll-en-4a-olfrom 14:450 Myricanagi 17:371 Myrica rubra 17:371 Afynca species 17:375 Myricaceae 17:371 Myricanon 17:372 Myricetin 5:657 Myricetin-3'-methyl ether 5:657 Myricetin-3-5'-dimethyl ether-3-glycosides 5:658 Myriogloia sciurus marine sterols from 9:83,84 Myriosterol 9:83,84,87 Myristic acid 5:753 Myrmecia gulosa 5:223,233,254 Myrmecocystus testaceus 15:383 Myrmica 6:454 Myrmica afracticornis 5:250 Myrmica americana 5:250 Myrmica brevispinosa 5:250 Myrmica emergana 5:250 Myrmica lobicomis 5:233,235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica rubra 5:235,250,254 2,5-dimethyl-3-methyl-pyrazines of 5:222 2,5-dimethyl pyrazines of 5:222 methyl pyrazines of 5:222 Myrmica ruginodis 5:235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica rugulosa 5:235,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica sabuleti 5:235,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica scabrinodis 5:235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 2,5-dimethyl-3-methyl-pyrazines of 5:222 2,5-dimethyl pyrazines of 5:222 Myrmica schencki 5:235,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica sp. 5:233,235,236,250,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica sulcinodis 5:235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmicinae 6:421,422,454,455 Myrrhis odor ata 15:29 Myrsinaceae 5:819;9:321,328,400;17:240 Myrsine africana 9:400 Myrtaceae 19:778 (+)-Myrtine synthesis of 16:461 (+)-Myrtine synthesis of 16:476-477 Mysorenone-A 5:759 Mysorenone-B 5:759 Mysorenone-C 5:759 Mytilitol 18:434 Mytiloxanthione from Halocynthia roretzi 6:152 Mytiloxantin 10:153

Mytilus edulis 6:142,143,156;17:21 Myxococcus xanthus 10:78,79 Myxoderma platiacanthum 15:58,75,81 3b,5,6b, 15a-tetrahydroxy-5a-stigmastan-29-oic acid from 15:81 Myxodermoside A 15:74 Myxomycota 9:202

A^, A^-Dimethyl propylene urea 16:731 A ^ -Glycoprotiens of lactosamine 10:479 A^,A^'-/7-methoxybenzyl glycine anhydride oxidation of 12:76 with sodio-2-thiopyridine 12:76 1 -A^-(-/?-bromobenzoyl)mitomycin A,C X-ray crystal structure of 13:434 A^-(p-MPS)-indole 2-indolylacetaldehyde from 11:315,316 N-a-desmethylalstophylline 13:395,397,406,407 iV-Acetyl neuraminidases from influenza virus 16:112 A^-Acetylneuraminic acid 16:77,96,101,105,108,110, 111,113 crystal structure of 16:107 iV-Acetyl-P-D-glucosaminidase 16:77,81 A/^-acetyl-D-mannosamine 18:469 iV-acety 1-muramy 1-I-alany 1-D-isoglutamine 18:923 iV-acetyl-muramyl-I-alanyl-D-isoglutaminyl-A^ palmitoyl-L-lysyl-iS-rerr-butyl-thio-cysteamine 18:923 A^-Acetyldesalanyl actinobolin 16:9 A^-acetylgalactosamine 18:786,792 A^-acetylglucosamine 18:786,789 A^-acetylmuramyl-dipeptide 18:928 N-Acetylneuraminic acid 11:429,464 (7V-Acryloyl) boman-10,2-sultam cycloaddition of 11:307,308 iV-Acylation with Cbz-L-alanine 16:22 ^-Acyliminium ion cyclization 11:290 intramolecular 11:284,285 A^-Alkenylbenzotriazoles photolysis of 13:445,446 iV-Alkylation reductive 16:99,104 with D-glyceraldehyde 16:99,104 with Z-glyceraldehyde 16:99 A^-(3-desmethylalstophylline 13:388 A^-BOC-tyrosine photooxygenation of 16:609 (+)-Ar-Ethoxycarbonylnorglaucine 16:514 AT-Formyldehydronoraporphine 16:515 A^-Glycolylneuraminic acid 16:82 A^-Glycosidation oxetanocin-A synthesis by 10:595-607 with 1-0-acyl-oxetanose 10:597-604 with oxetanosyl derivative 10:595-607 with oxetanosyl halide 10:604-607 A^-Heterosugar inhibitors 10:524-552 AT-Linked glycans 10:499

1115

iV-methylnoracridin-9-one (1 -hydroxyacridm-9-one) 13:348 iV-methyl tetramic acid 13:545 A^-methyl valine 13:533,535 A'-methyl-isoleucine 13:533 A^-methyl-leucine 13:533 iV-methylatalphylline 13:350,358 from Atalanatia monophylla 13:350 iV-methylatalphyllinine 13:370,371 from Atalintia ceylanica 13:348,349 A^-methylation ofisoxazole 16:233 7V-Methyldeoxynojirimycin 10:527,528,540 (+)-iV-methyllaurotetanine 16:512 A^-Methylmitomycin A 13:440 A^-methylmitomycin C (porfiromycin) 13:433 A^-methylmorpholine-A^-oxide ascooxidant 16:323 A^-monosubstituted formamides dehydration of 12:113 isocyanides from 12:113 A'-A'^-dimethyl-4-desmethylenebicylomycin synthesis of 12:68-70 iV-phenyldehydronoraporphine 16:516 ()-^-pi varoy Itetrahydroisoquinoline 16:512 A'-sulfonation of 3-indolyacetic acid 11:291 N.M.R spectroscopy 7:29 ()-A^a-benzyl-20-desethylaspidospermidine synthesis of 18:323 A^a-methyl sarpagine methosalt 13:386,387,405 A^a-methyl vellosimine 13:386 NaamidineA 17:17 Naamine A 17:17 Nabilone synthesis of 19:197 NADP oxidoreductase 18:55 Nadsoniafulvescens 5:290 Naftifme 2:423 Nagata hydrocyanation 11:87 Nagata's reagent 16:13 Nakafiiran-9 by Wittig olefmation 6:70 from Chromodoris maridaditus 6:70 from Hypselodoris godefroyana 6:70 synthesis of 6:69,70 Nakanishi's induced CD method 5:700 Nakanishi's method 15:190,193,194 Naked sugar 12:338;14:179 NANA (A^-acetyl neuraminic acid) 13:207-210 Nanamycin A synthesis of 4:591-593,609 Nanaomycin D synthesis of 4:591-593 ()-Nanaomycin-A biomimetic 11:127-130 from4,10-dihydro-3H-naphtho [2,3-c] pyran-10one (yellow pigment) 11:127 synthesis of 11:127-130 Nanaomycins 11:127 Naphthacene 11:113

Naphthacene glutarate 8,13-benzo [1 ]-naphthacene quinone from 11:123 Claisen condensation of 11:123 with acetoacetate dianion 11:123 6,11 -Naphthacene quinones from anthraquinone glutarates 11:122,123 from unprotected quinone 11:123 pentacene quinone from 11:123 synthesis of 11:122,123 Naphthacenequinone 11:123 //a-Naphthalene-1,3,8-trisulfonate 2:51 Naphthalene-diene derivatives 41,45,47,48 Naphthalene-isoquinoline alkaloids 13:646 Naphthaleneacetic acid as auxin 7:90,94 1,8-Naphthalenediol 11:131 from p-hydroxyglutarate 11:119 Naphthalenediol 11:127 from p-hydroxyglutarate and acetoacetate 11:127 2-Naphthalenethiol conjugated addition of 14:509 to enones 14:509 Naphthoquinones 20:276,20:283 Naphtho [2.3-c] pyran-5,10-quinone antibiotics synthesis of 14:271 Naphthocyanidine 10:106 antitumor activity of 10:104 X-ray crystallographic analysis of 10:104 Naphthofiirans 7:184 Naphthols 20:276,20:283 P-Naphthol 4:400 1 -(3,3-dimethylallyl)-2-hydroxy-napthalene from 4:396, a-Naphthol 4:400 Naphthopyran antibiotics by p,P,5,5'-tetraoxoalkane dioates 11:127-131 synthesis of 11:127-131 Naphthopyrans 4:398,400 from Tebebuia chrysantha 4:400 from Glaium species 4:400 from Tecona grandis 4:400 Naphthoquinones 4:388,389;7:435 biosynthesis of 2:226 molluscicidal activity of 7:427 with isovaleraldehyde 4:396,398 synthesis of 3:450,451 Naphthoquinones 7-methyljuglone 7:423 Naphthoxirene 7:407,408,423 Naphthyl bomeol 13:76 Naphthyl C-glycoside reaction of naphtyl-O-glycoside with boron trifluoride etherate 10:379 (/?)-(+)-l-(r-Naphthyl) ethanol 13:573 P-Naphthylamine 8:378,388 (/?)-l-Naphthylethylisocyanate 13:324 Napthylisoquinoline alkaloid, 7,1'-linked asymmetric synthesis of 20:438-441 Napthylisoquinoline alkaloids total synthesis of 20:407-451 Napthylisoquinoline alkaloids, 5,1'-linked asymmetric synthesis of 20:420-438

1116

Napthylisoquinoline alkaloids, 5,8'-linked asymmetric synthesis of 20:442-451 Naphthyridinomycin 10:108-115 antitumor activity of 10:107 biosynthesis of 10:104-106 synthesis of 10:107 Naphthyyridine alkaloids 4:524 Naphtooxirene derivatives antifungal activity of 7:407 cytotoxicity of 7:407 glucosides of 7:407,408 Napoleogenin B 7:141 X-ray analysis of 7:139 NAPRALERT 19:751 Naproxen 6:309 Naproxene antiinflammatory drug 14:505 synthesis of 14:505 Napthalenones 5:754 NapthomycinA 9:434 Napthoquinones 5:3,9,10 Narburgia stuhlmanni antifeedant from 1:701,702 Narciclasine 20:325,353,356 Narcissus alkaloids 20:233 Narcissus pallidulus mesembrenone from 20:234 Narcissuspseudonarcissus 20:353,359,391 lycorine from 20:233 a-Narcotine TV-oxide benzoxazocine derivative ring expansion of 6:468 thermally-induced rearrangement of 6:468 Nardoa gomophia 15:46 Nardoa novaecale donia halityklosides A,B,D from 7:298 Nardoa tubercolata 15:71 (-)-Nardol from Nardostachys jatamansi 14:374,375 ()-5-e/7/-Nardol synthesis of 14:374,375 Nardostachys jatamansi guaiane alcohol from 14:375 (-)-nardol from 14:374 Nargenicins 17:288 biosynthesis 17:286 chemistry of 17:286 macrolides 17:283 synthesis 17:291 Naringenin 7:207,228 Naringinase 7:272 Narwedine 20:359 Nash-Davies media 7:97 Nasutitermes exitiosus 5:702 Natsucitrines I,II from Citrus natsudaidai 13:370 Natural abundance o f % 9:110 of^^S 9:110 of^^Se 9:110 of ^^^Te 9:110 Natural inhibitors of phosphatases 20:889

Natural products 17:117,747-789 ^^0-NMR spectrum of 17:566 by cationic intermediates 12:443-496 by oxidative phenolic coupling 20:263-315 by radical intermediates 12:443-496 chirality of 7:3-28 dereplication of 19:747-789 plant derived 19:747-789 stereoselective synthesis of 12:443-496 synthesis of 19:117 Natural regulation of gene expression 13:257-261 by antisense RNA 13:257-261 Naucletine synthesis of 3:405 Nauphoeta cinere 9:488,489 Navanax inerm is 10:152; 17:2 8 NavenoneB 10:152 Navonones 17:28 Nazarov cyclizations 3:11 ;13:34,35 BF3-OEt2 mediated 10:412 in ()-A^'^^ capnellene synthesis 6:43 of(+)-limonene 10:412 with BF3-Et20 8:242 Nazarov reaction 14:592,611 Nazarov's reagent 14:734 Nazlinin 14:758 biosynthesis of 14:760 from Nitraria schoberi 14:759 serotonergic activity of 14:759 Nb-methyl suaveoline 13:402,403,411 Nb-methy l-A^b-21 -secotalpinine 13:3:391 NCI assay 18:878 NDGA synthesis of 17:316 Ndifloretin-6,7-disulphate 5:648,655 FAMBS fragmentation of 5:647, Nebramine 14:145 Necic acids 19:464 synthesis of 1:260-269 Necrodol synthesis of 16:153 a-Necrodol synthesis of 16:153 P-Necrodol 16:153 synthesis of 8:279 /7/-a-Necrodol 16:153 Nectandra salicifolia 20:522 Nectriafuckeliana 15:383 Nectria gibberella 9:203 Nectria haematococca 18:709 Nectriapyrone 15:351 Nef reaction 10:464;14:39,;19:120,141,146,152,153, 173 reductive 14:633,634 Negamycin synthesis of 1:370-377 Negative cotton effect 4:707 Negative ion chemical ionisation (NIC!) 9:468,473,475 Neighboring group participation acetamide assisted displacement 1:204,205 for hydroxyl inversion 1:427,428 Neisosperma glomerata 1:124

1117

Neisseria 12:63 Neisseria meningitides diheptosesin 4:196,206 Neisseria perflava 7:69 Nejkpetin 5:654 Nematocidal activity against Bursaphelenchus lignicolus 12:396 Nematode endoparasites 12:7 Nematodes against active against 1:435 Nematospiroides dubius 12:3 Nemorensic acid synthesis of 1:263 Nemorosine from Salvia nemorosa 20:669 Neo-sarpagine 13:386 Neoartanin 7:224 Neocapillene 7:222 Neocarzinostatin 10:150,154,171,175,190 5-Neocedranol ^^C-NMR spectrum of 5:792 Neodihydrothebaine fromthebaine 6:479 synthesis of 6:478,479 Neohesperidin dihydrochalcone 15:5,30 Neohesperidyl saccharide 15:20 (+)-Neohobartine structure elucidation of 11:294,295 Neointermedeol from Amitermes excellens 14:451,452 from Artemisia schmidtiana 14:450 from Bothriochloa bladhi 14:4510 from Bothriochloa glabra 14:450 from Bothriochloa insulpta 14:450 from Bothriochloa intermedia 14:450 from P-eudesmol 14:453,454 from Geigeria burkei 14:450 from Subulitermes bailey 14:451,452 from Subulitermes oculatissimus 14:451 from Subulitermes parvellus spA-B 14:451 synthesis of 14:450-465 total synthesis of 14:453,454 Neolaulimalide cytoxicity of 19:569 Neolaurallene 5:361 Neolaurencenynes 19:454 Neolemnane 10:182 Neolignans 5:5,459-462,464,495,797;8:159-161; 16:561-564;17:311;20:631 from Chosemia arbutifolia 20:640 from Eucommia ulmoides 20:647 from Salix sachalinensis 20:627,629 synthesis of 5:797 Neolignan rhamnoside 5:476,477 Neomenthol 17:605 Neoneptalactone 16:289 2-Neopentyloxy-l -apocamphanecarboxylic acid 12:422,423 Neopinone 18:55 synthesis of 10:180 Neoplastic transformation 5:448 of subclone A-31-1-13 of BALB/c3T3 cells 5:452

Neoproaporphine intermediates dibenz [d,f] azonine derivative from 6:480 Neorabdosin (novetabdosin) 15:112,137 *^C-nmrof 15:154 from Rabdosia eriocalyx 15:171 from Rabdosia nervosa 15:173 ^H-nmrof 15:145 Neorautanenia pseudopachyrrhiza 1:417 Neosachaftoside 7:207,227 NeosamineC 11:217,218 Neosidomycin 14:143 Neosiphonia superstes 19:596,19:607 Neosmilaster georgianus 15:58 Neosolaniol 6:242 Neosolaniol derivative 6:230,232 Neospirene intermediates dibenz [d,f] azonine derivative from 6:478 Neothyone gibbosa neothyoside A from 15:92 Neothyonidioside 7:279 from Neothyonidium magnum 1'21^ Neothyonidium magnum neothyonidioside from 7:278 Neothyoside A from Neothyone gibbosa 15:92 Neoxanthin 6:133,136,141,146;7:98,320,321 as ant repellant 6:142 stereoisomer of 6:139 Neoxanthin derivatives 6:135,136 Neoxygambirtannine 1:125,126 Nepeta cataria 4:604;6:522 Nepetalactam 6:522 (+)-Nepetalactone 7:7 Nepetalactone 4:604,605;7:441,442 synthesis of 4:557,558 Nepetin-7-sulphate 5:655 Nepodin 9:400 Neptunia antiqua 1:4 Neptunia contraria 7:4 Neral 13:333 Nereistoxin 18:697 Nerifol 9:293,296 Nerine bowdenii 20:352 Nerinejonquilia 20:391 Nerinepapyraceus 20:391 Nerine poeticus 20:391 Nerine tazetta 20:391 Neriucoumarin acid 9:293,294 Nerium oleander cyctotoxic agents from 9:293-315 Neriumol 9:293,295 Neriumoside 9:293,294 Nerolicacid 20:5 Nerolidol 9:531 Nerolidyl pyrophosphate 6:247,248 Nerve growth factor effect of K-252a on 12:394 effect of staurosporine on 12:3 94 Nervosanin 15:120 ^^C-nmrof 15:134 from Rabdosia nervosa 15:173 *H-nmrof 15:127

1118

Nervosin 15:141 '^C-nmrof 15:158 from Rabdosia nervosa 15:173 H-nmrof 15:150 (l/?)/(15)-[l-^H] Neryl diphosphate 11:219,220 Neryldiphosphate (+)-bomyl diphosphate from 11:219,220 Netol 7:100,101,104,107,108,125 degradation of 7:105 Netropsin analogues of 5:558 binding of DNA 5:575 structure of 5:549,550 synthesis of 5:554-556 Netropsin analogues synthesis of 5:558,561-563,566 Netropsinin 5:552 Netschnikowia reukaufii 5:282 Netzahualcoyene 18:777 Netzahualcoyondiol 18:777 Netzahualcoyonol 18:777 Netzhualcoyone S:1A1,1^9\1\ 147-149;18:764,765,777, 778 from Orthosphenia mexicana I'AAl Neuraminic acid 11:466;16:105 Neuraminidase 16:75,93,105,106,107 from viruses 16:108 inhibitor of 16:95,111 of bacteria 16:112 Neuropeptides from marine invertebrates 9:493-495 Neurospora crassa 5:277-279,8:297 Neurosporene 7:30-354;20:588 cyclization 7:330-329 from 7,8,11,12-tetrahydro-v|/,vt/-carotene 7:330-329 lycopenefrom 7:330-329 (9Z,7'Z,9'Z)-Neurosporene 7:335 from (9Z,Z,9')-carotene 7:332 (7Z,9Z,7'Z,9'Z)-lycoptne from 7:332 Neurotoxin alkaloids 1:385 Neurotoxins 17:3 (-)-Ngaione from Myoporum laetum 15:236 Ngouniensine 1:55 biogenesis of 6:503 Nic-1,10,11,17 20:182 Nic-1-lactone 20:242 Nic-2 lactone 20:215,224 NicalbinA 20:180,242 NicalbinB 20:181,242 Nicandra physalolides 20:248 Nicandra steroids 20:180,182 Nicandrenone 20:181 Nicandria physaloides 20:238 Nicasterol 9:36,37,43 biosynthesis of 9:43 from Calyx nicaeensis 9:37 Nicholas reactions 3:83,84 Nichora's method 12:175 Nickel boride desulfiirization with 3:472 Niclosamide 7:428

Nicotiana glutinosa 7:101,110 sclareolfrom 7:121 Nicotiana setchelli 1:662 Nicotiana tobaccum 20:135 Nicotiana tabacum 1:671 Nicotinasp.l:\24,\26 nicotine synthase from 11:204,206 Nicotinamide coenzyme 17:481 (5)-Nicotine biosynthesis of 11:204,206 by nicotine synthase 11:204,206 from nicotinic acid 11:204,206 Nicotine synthase from Nicotina sp. 11:204,206 Nicotinic acetylcholine receptor 18:695 Nicotinic acid (5)-antabme from 11:204,206 by nicotine synthase 11:204,206 (5)-nicotine from 11:204,206 Nicotmic toxins 18:697-699 Niddanolide 11:162-164 Nigeran 5:299,310 antitumor activity of 5:317 Nigericin 3:58 Nigroporus durus 13:305 Nimbidin 9:296 Nimbocinone 9:297,298 Nimocinolide 9:297-299 Nimolicinoic acid 9:297,298 Nine-carbon sugars by ascent of sugar series 4:179 osmylation 4:180-182 synthesis of 4:179 Wittig olefmation of 4:180 Nine-membered rings by Claisen rearrangement 3:77 by intramolecular Diels-Alder/ozonolysis 3:79,80 by ring expansions 3:76 from 1,3-diolmonotosylates 3:73,74 synthesis of 3:73,111;6:472-482 by ring contraction 6:474-482 of ring destruction 6:475,482 by ring interconversion 6:472-482 Ninhydrin 10:258 Nipoglycosides A, B, C, D 15:55 Niranthin synthesis of 17:318 Nirurine 5:49-51 Nishimura's catalyst 6:80,81 Nishizawa complex 16:665 Nitensidines A-C 20:488 Nitidme 4:544;13:656;14:770 antileukemic activity of 14:769 from pseudoberberine 14:775,776 synthesis of 4:544;14:775-777 Nitrabirine 14:742,743 Nitramidine (dehydronitrarine) 14:759 biosynthesis of 14:760 (+)-Nitramine from Nitraria sibirica 14:541 via Sharpless asymmetric epoxidation 14:544 (-)-Nitramine from Z,-prolinol 14:544

1119

Nitramine 14:731,762 biomimetic synthesis of 14:748-750 biosynthesis of 14:748 '^C-NMRof 14:742 diastereoslectivity in 14:743-747 enantioselectivity synthesis of 14:743-747 from L-prolinol 14:743-747 from Nitraria sibirica 14:743 'H-NMRof 14:742 Nitraraine biosynthesis of 14:765 cardiovascular activity 14:764 from (5)-glyceraldehyde 14:765 synthesis of 14:765 Nitraramine biomimetic synthesis of 14:755,756 biosynthesis of 14:754,755 biosynthesis retroanalysis of 14:754,755 from Nitraria schoberi 14:750 via Diels-Alder reaction 14:751 -754 stereochemistry of 14:752 synthesis of 14:751-754 X-ray analysis of 14:750 Nitraria alkaloids synthesis of 14:731-768 Nitraria indole alkaloids 14:758-765 Nitraria komarovii isokomarovine from 14:762 komaroine from 14:762 komarovicine from 14:762 komarovidine from 14:762 komarovine from 14:762 komarovinine from 14:762 nitramarine from 14:762 tetrahydro-komarovinine from 14:762 tetrahydronitramarine from 14:762 tetramethylene tetrahydro-b-carboline from 14:758 Nitraria schoberi 1:125 isonitrarine from 14:759 nazlinin from 14:758 nitramidine from 14:759 nitraramine from 14:750 nitrarine from 14:759 schoberine from 14:757 schoberidine from 14:759 spiroalkaloids from 14:742 Nitraria sibirica isonitramine from 14:541 nitramine from 14:541 (-)-sibirine from 14:541 spiroalkaloids from 14:542 Nitraria species 14:742-765 Nitraria spiro alkaloids 14:742-765 Nitraria tripipendinQ alkaloids 14:757,758 Nitrarme 14:731 biological activity of 14:759 biomimetic synthesis of 14:761,762 biosynthesis of 14:760 retroanalysis of 14:761,762 Nitrene insertion 1:8,9,167 Nitrile ionization 1:328

Nitrile oxide cyclization intramolecular 12:20-22 isonitramine by 14:745 Nitro p-C-glycoside from Seebach silyl nitronate nitroaldol 10:394 stereoselective cyclization of 10:394 ()-l-Nitro-1-pentadecene 19:118 (5)-5-Nitro-2-pentanol 19:155 Nitro C-glycoside from Seebach silyl nitronate nitroaldol 10:394 stereoselective cyclization of 10:394 synthesis of 10:394 2-Nitro-4-methyl-phenol 8:300 Nitro-olefins alkoxides 12:411,413 2-amino alcohols from 12:411,413 Michael additions of Nitroaldol condensation 19:159 Nitroaldol (Henry) condensation 1:408,409,417418 KF catalysed 1:417,418 Nitroaldol reaction 1:427,428 2-Nitrobenzenesulfonyl chloride conversion of alcohols to chloride 1:443,444 0-Nitrobenzyl as protecting group 4:302 4-Nitrobenzyl bromide quatemization by 6:513,514 Nitroblue tetrazolium reduction 20:515 Nitrocyclitol 7:157 Nitrocyclitol diglycoside 7:157,158 2-Nitrocyclopentadecanone 19:172 a-Nitrocycloalkanones Michael addition of 8:244 11-Nitrodaunomycinones 14:23 (Z)-l-Nitrodec-4-ene 19:124 Nitrogen inversion 1:369 ofquinolizidines 1:387 Nitrogen sugar inhibitors 7:41-48 Nitrogen ylide 1:249 (o-Nitroesters 19:133 Nitroindole condensation 11:437,438 Nitroketone cyclization of 6:447,448 C-Nitromethyl nucleosides 4:252 22-Nitromethylene nucleosides 4:251,252 Nitronate addition 1:505 Nitrone 1,3-dipolar cycloaddition of 1:230,254,277; dibenz [c,g] azonine derivative from 6:474,475 from cis (trans) canadine N-oxide 6:474,475 photolysis of 6:474,475 synthesis of 1:230 Nitrone cyclization procedure 14:737 Nitrone cycloaddition 1:282,283,37-375;12:290,291 asymmetric 1:374,375 intramolecular 14:744 nitramine synthesis by 14:744 Nitrone-based synthesis 6:442

1120

Nitrone-olefin 1,3-dipolar cycloaddition of 11:283 intramolecular 11:283 10-Nitronoracronycine 20:796 9-Nitronoracronycine 20:796 /7-Nitrophenyl 1,4-dithiomaltotrioside 8:344,351 X-ray data of 8:351 o-Nitrophenyl 1-thio-p-D-galactopyranoside 8:315 /7-Nitrophenyl 1-thiogalactopyranoside derivative 8:341,342 o-Nitrophenyl 4-0-triflylgalactoside 8:343 o-Nitrophenyl 4-thiomaltoside 8:350 /7-Nitrophenyl 4-thiomaltoside 8:350 o-Nitrophenyl 4-thioxylobioside 8:351 o-Nitrophenyl a-maltoside 8:350 o-Nitrophenyl a-maltotrioside 8:350 o-Nitrophenyl P-D-galactopyranoside 8:315 p-Nitrophenyl glycosides 7:56 o-Nitrophenyl 5-a-D-glucopyranosyl-(l 4)-5-4-thioa-D-glucopyranoside (O-nitrophenyl 4,4-dithiomaltotrioside) 8:341,342 Nitrophenyl thiogalactoside P-galactoside inhibition with 7:48 p-Nitrophenyl-A'^-acetyl-p-D-glucosaminide (NAG) 7:415,417 /7-Nitrophenylethyl 4:285 5-/?-Nitrophenyltetrazole as activating agent 4:304 3-Nitropropanoic acid biological activity of 19:117 from Viola odorata 19:117 3-Nitropropanoic acid 15:351 Nitrosine 7:232 [4+2] Nitroso cycloaddition 1:378 Nitroso Diels-Alder reaction 1:378,380,381,383 intramolecular 1:385-392 Nitrosobenzene 9:573 iV-Nitrosopyrrolidine alkylationof 6:439,441 Nitzschia palea 18:698 NMMNO method 19:277 NMR 13:334-337 isotopic analysis by 13:334-337 NMR 9:93-161 structure elucidation by 9:127-161 ofchalcogens 9:109-126 NMR data of Aspidosperma alkaloid analogues 4:60-67,69,70 NMR spectra of brassinosteroid metabolites 18:534-546 of disaccharide lactone 6:395 ofdisaccharidemethylester 6:395 ofMurNAcS-lactones 6:390,391 of oligosaccharides 17:128 of steroid epimers 17:131 "No name" lactones 10:17-25 NO^ reaction with alkenes 2:6 reactions with hydrocarbons 2:4,5 Nocamycin 14:97 from Nicardiopsis syringae 14:98 Nocardia aerocolonigenes 5:55

Nocardia aeroligenes 1:3 Nocardia interforma 10:587 Nocardia mediterranei 9:431,433,435,440,441 rifamycin S from 12:37 rifamycin W from 12:39 Nocardia species 9:433,434 Nocardia uniformis monocyclic p-lactams from 12:118 Nocardicine A synthesis of 12:118,119 3-Nocardinic acid synthesis of 12:118 Nocardioides 17:285 Nocardiopsis dassonvillei TAN-999from 12:366,367 Nocardiopsis sp. 5:55 Nocardiopsis sp. K-252 1:4 Nocardiopsis sp. K-252a K-252afrom 12:366,368 Nocardiopsis sp. K-290 K-252bfrom 12:366,368 K-252cfrom 12:366,368 K-252dfrom 12:366,368 Nocardiopsis syringae nocamycin from 14:97,98 Noctiluca milliaris 5:353 Noctuidae 18:772 Nodifloretin-7-sulphate 5:655 Nodosin from Rabdosia longituba 15:173 from Rabdosia nervosa 15:173 Nodososide 7:296-297,300;15:76 from Pentaceraster alveolatus 7:298 from Protorester nodosus 7:295 6-e/7/-Nodososide 7:300 from Pentaceraster alveolatus 7:298 Nodularia species nodularin from 9:496 Nodularia spumigena 20:894,896 Nodularins 9:498,18:269 from Nodularia species 9:496 dihydronodularin from 9:496 biological activities of 20:896,897 biosynthesis of 20:899 chemical structure of 20:894-897 structure-activity relationship 20:897-899 synthetic approaches for 20:899-902 inhibition of protein phosphatases by 20:903 three dimensional structure of 20:903-907 molecular dynamics simulation of 20:907-910 Nodusmicin biogenesis of 4:620 Nodusmicin activity 2i%dmsi Staphylococcus aureus 17:290 NOE difference experiments 6:140,163;11:303,304; 19:398 ofenukokurin 2:226 of marchantin A trimethyl ether 2:104,105 oligosaccharides 17:129 NOE effects 19:398 NOESY spectrum 2:63,64,272;10:268,269 of sacculaplagin triacetate 2:83

1121

Noformycin 5:554 Nogalamycin 4:345,358;14:47,48 absolute configuration 4:355 synthesis of 4:330,355-357 synthesis of DEFfi-agment 4:359 Nogalamycin congeners antitumor activity of 14:76 synthesis of 14:76-83 Nogalamycines synthesis of 4:330 Nogalamycinone construction of DEF rings 4:358 synthesis from arabinose 4:355,356 7-i/w-Nogalarol 14:86 Nogarene 14:47 (+)-Nogarene total synthesis of 14:65-68 Nojigiku alcohol synthesis of 16:147 (+)-Nojigiku alcohol 4:676 Nojirimycin 6:351;42,50;11:267 enzymatic aldol condensation 10:535,536 from Bacilus 10:524 from Bacilus amylocique faciens 10:524 from Bacilus polymyxa 10:524 from Bacilus subtilis 10:524 from Streptomyces ficellus 10:524 from Streptomyces lavendulae 10:524 from Streptomyces nojiriencis 10:524 from Streptomyces roseochromogenes 10:524 glucoamylase inhibitors of 10:525 a-glucosidase inhibitors of 10:526 P-glucosidase inhibitors of 10:526 glucosidases inhibiton with 7:41 invertase inhibitors of 10:526 synthesis of 10:529-538 takadiastase inhibitors of 10:525 trehalase inhibitors of 10:526 Nojirimycin analogues 7:70 sialidases inhibition by 7:42 Nojirimycin C-glycoside disaccharide by Wittig reaction 10:390,391 with tetra-O-benzyl-D-glucose 10:390,391 Nojirimycin hiptitol derivatives 7:42 a-glucosidase inhibition with 7:43 Nomamyrmex esembecki 5:250 Nomenclature ofcarotenoids 7:318 Nominal mass 2:26 (5,8Z)-3-9(l-Non-8-enyl)-5-(^-l-prop-l-enyl] pyrrolizidine 6:446 in Celaner antarcticus 6:445, Non-acetylenic a-ketols optical purity of 6:153 Non-Adrenaline 15:328 Non-classical p-lactams 12:112 Non-competitive inhibitors 7:40,58 3-deoxy-3-fluoro sucrose as 7:69 Non-covalent peptide 18:918-920 Non-isoprenoid phenolic lipids from 9:313-381 Non-metastatic cells 16:76

Non-nucleosides 20:533 Non-peptide antagonists 18:863 Non-phenolic oxidative coupling 20:304-307 Non-terpenoid-type alkaloids 5-hydroxytetrahydroxyharmane 5:111 5-hydroxytryptamine 5:111 tetrahydroharmane 5:111 Non-trichothecene secondary metabolites of Fusarium 13:519-551 (-)-Nonacetic acid from 2,3-unsaturated C-glycoftiranosyl 10:341,423 synthesis of 10:341,423 Nonactic acid intermediate synthesis of 1:600,601 Nonactic acids 3:58;18:229-268 synthesis of 3:228 Nonactin 10:424 Nonactin-potassium thiocyanate complex 18:229 y-Nonanolide 13:311,312 Nonaols 15:74 Nonaribonucleotide 4:302 (Z)-3-Nonen-l-yl-anion synthon 19:122 Nonitol synthesis of 11:464 Nonmeningeal crytococcosis 2:423 Nonofiiranose synthesis of 11:458 Nonulosonic acid preparation of 11:466 4-t-Nonylphenol 9:371 sulphurisation of 9:372 (+)-Nooktatone from (+)-valencene 13:300 (+)-Nootkatone 16:239 (-)-Nootkatone 16:267 Nopalea coccinellifera 20:734 (l/?)-(+)-Nopinone 19:190,207 (5)-(-)-Nopinone 19:207 (+)-Nopinone 16:235,239 24-Nor thomasterol A 15:48 ()-3-e/?/-18-Nor-18,19-dihydroantu-hine by alkaline decarboalkoxylative cyclization 14:708 from tetrahydropyridine 14:708 28-Nor-22,23-diepibrassinolide 16:344 24-Nor-25-hydroxy-vitamin D3 9:515 Nor-6,7-secoangustilobine 9:178 23-Nor-6-oxodemethyl pristimerol 7:147,148 23-Nor-6-oxopristimerol 7:147,148,150 Nor-C-fluorocurarine 1:36 synthesis of 1:40,46-48 Noracronycine 20:793 Noracronycines (6-hydroxypyrano[2,3,-c] acridin-7ones) 13:348,357,359 (+)-Norallosedamine 13:475,476 Norambrenolide from Salvia yosgadensis 20:692 (+)-Noraporphines 16:509 Z)-Noraspidospermane skeleton 19:114 Norbelladine 20:325,347,359 Norbixin 20:726 5-Norbome-2-one 13:557

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Norbomene ()-sinularene from 6:16 Jl rrfl5-5-Norbomene-2,3-dicarboxylic acid 8:153,154 (+)-(i?)-5-Norbomene-2-carboxylic acid 8:148,149 (L/?)-5-Norbomene-2-one synthesis of 8:148,149 (+)-A'b-Norbuxupapine structure of 2:189,190 Norcapillene 7:222 Norcaradine 13:32 Norcardia argentisis 17:283 Norcardia species 10:153 Norcarene derivative photoinduced preparation of 1:567 Norcaronols in poitediol synthesis 6:36 Norcepharadione-A 20:481 Norcepharadione-B 20:481 synthesis of 3:439,440 Norcitronellol 19:83 Norcoclaurine 13:662 S-Norcoclaurine 18:53 Norcoradiene cycloheptatriene-type electrocycHc rearrangement In dihydrospiniferin 1-synthesis 6:72,73 5,15-Norcorrinoids 9:598 Norcrassin 8:29,30 17(+)-Norcyclomicrobuxeine strcuture of 2:195,196 NordidemninB 10:257,271 synthesis of 10:294-298 Norditerpene 9:16,17,21 3,5Z-Norditerpene diene 9:24,25 Norditerpenes 17:11 Nordoa gomophia 7:298 hahtylosides A,B,D,E,H,I from 7:290 marthasteroside Ai from 7:290 thomasteroside A from 7:290 Norepinephrine 9:579 a-subtype 8:395 P-subtype 8:395 synthesis of 8:395-406 Noreugenin 6,8-diprenylnoreugenin from 4:382,384 prenyl bromide with 4:382,384 6-prenyl noreugenin from 4:382,384 8-prenyl noreugenin from 4:382,384 Norficisterol 9:579 Norfluorocurarine 5:123;9:190-192 ()-Norglaucine 16:508 Norhalichondrins A 5:378,380,382,383 Norhalichondrins B 5:378,381,382 Norhalichondrins C 5:378,381,382 Norharman 5:353 Norhebesterol 9:40,41,43 Norhyoscyamine 17:398 7-Norisocrassin 8:29,30 Norisoflavone 17:19 Norlabdane diterpenoids from Salvia yosgadensis 20:692 Normacusine B 5:124;9:171;13:386,400,401,429 Normelicopicine 13:352,363-365,368,378 Normelionine F 1:127

(+)-Normetazocine synthesis of 16:478 (+)-Normorphinandienones 16:505 Nomicotine synthesis of 16:427 Nomomanone 20:74 Noroleanane saponins 7:139 from Clemisia petrici 7:138 Noroxymorphone 18:47,48 (+)-Norpatchoulenol 4:674 Norpinguisone 2:227,228 Norpinguisanolide 20:469 Norplicacetin 4:244 Norpluviine 20:351,20:352,20:356 Norpontevedrine synthesis of 3:439,440 Norreticuline 11:205 (-)-Norreticuline 18:86 Norrish type 1 photo-cleavage upon UV irradiation 19:35 Norrish cleavage of alkylphenacyl sulfides 8:207 Norrish reaction 20:74 Norrish II reaction of gibberellm aldehyde ester 8:128-131 Norrish II process 7:147 Norrish type II photocyclization 14:659-664 Norrish type II photofragmentation 14:659-664 in carbohydrate 14:659-664 Norrish type II reaction 4:419,420;14:645-665 Norrisolide 17:12,13 (+)-Norruspoline 13:476 Norsalanodione 19:135 ()-Norsolanadione 19:135 Norsecurine 10:155 Norsecurinine 10:153;14:657 Norsesterpene 9:16-18,25 Norsesterpene cyclic peroxides 9:15,16,18,22 Norsesterterpene diene 9:24,25 3E,5ZNorterpene biosynthesis of 9:15-33 marine 9:15-33 Norterpene cyclic peroxides 9:15-33 19-Nortestosterone 5:449,450 Northern blotting analysis 15:449 Nortrachelogenin 5:522 0-glucosylation of 5:531-533 0-methylation of 5:531-533 Nortrachelogenin methyl ether 0-glucosylation of 5:531-533 0-methylation of 5:531-533 Nortrachelogenin-di-P-D-glucoside 5:522 Nortracheloside 5:522,532 0-glucosylation of 5:531-533 0-methylation of 5:531-533 A^-Nortropacocame synthesis of 1:383-385 Nortropine 1:378 Z)-Norvaline 19:18 (5)-Norvaline 13:512 Nostoc linckia 19:587 Nostocsp. 9:496-499

1123
Nostoc sphaericum indolo [2,3 a] carbazoles from 12:366,370 Notholaena qffinis 5:678-680 Notholaena aschenborniana 5:676,681 Notholaena californica 5:677-679 Nothomyrmecia macrops 5:233 Notodoris citrina 17:17 Notodor is gar diner i 17:18 Notoncus ectatommoides 5:224,230,254 Noyori BINAL-H reagents 10:22-24,37 Noyori procedure 11:96 Noyori Ru-BINAP catalyst 13:503 Nozaki reaction intramolecular 12:13 Nozaki's reagent 14:637 Nozaki-Oshima methylenation 6:185 Nozaki-Oshima reagent deuterated 6:189 Nuclear Overhauser effect 2:57-77 Nuclear Overhauser experiments 5:3 of artemisinin 5:26 ofeupatoreone 5:29 of 10-hydroxy-11 -methoxydracaenone 5:18 oflareantin 5:10 ofprionitin 5:31 Nuclease 13:271,288,289 Nucleobase 19:511 Nucleophile 16:399 Schollkopftype 16:403 Nucleophilic addition intramolecular 16:439 Nucleophilic addition 16:439;19:527 2-amino alcohol by 12:411,413 of 2-lithio-3,3-diethoxy-1 -propen with N bulc 12:36 ofketonucleosides 19:527 of organolithium reagents 12:411,413 of a-alkoxydimethyl hydrazones 12:411,413 to a-amino aldehydes 12:411,414 to carbonyl compounds 12:36 by allyltm derivatives 11:442,443 by carbanion reagents 11:439-443 by vinyl carbanions 11:440,441 ofchirala-ketoacetals 4:330-332 of nonylmagnesium bromide 19:493 Nucleophilic agents 19:121 Nucleophilic conjugate addition to 2-(r-hydroxyethyl) propenoates 4:479 Nucleophilic epoxidation 19:167 Nucleophilic displacement 19:68,191 intramolecular 16:426 of allylic acetate 16:426 Nucleophilic substitution 14:438-445 Lewis acid-mediated 14:484 ofacetals 14:484 Nucleoside antibiotics synthesis of 1:397-431 Nucleoside phosphoramidites synthesis of 4:272,273,291 Nucleosides 8:373,10:568 hexopyranose 4:221-265 Nucleoside analogues 20:532 Nucleotide 9:605 Nudibranchs 17:105 Numida meleagrus hemoglobin components of 5:836 Nuphar indolizidine synthesis of 1:292 ()-Nupharolutine synthesis of 13:488,489 Nutrient media 2:366,367 Nymania-1 20:492 Nypafruticans 7:176 Nysson spinosus 5:225,231,251,253

(/?)-(0)-benzylglycidol 13:624 0-Methylancistrocladine 20:408,426,427,432,436 0-Methyl derivative of kidamycin "glycone" 11:137 O-methyltetradehydrotriphyophyllme, 7,1 -Linked 20:417 O-methyl psychotrins 13:656 12-0-tetradecanoylphorbol-13-acetate 20:513 0-methylfurodysinin 17:9 '^0-NMR spectroscopy 17:557 of 1 -adamantyl phosphoryl derivatives 9:116-118 of aryl derivatives 17:557 ofchromones 9:113-116 ofcumarins 9:113-116 offlavones 9:113-116 of 7-methoxychromanone 9:113 of psoralen 9:114,115 OA-antibiotics incarbapenem 4:434 Oat carcinoma of lung 1:276 Obesine 20:370 Oblongolide 15:473 Obtusifoliyl linoleate 9:461 Obtusifuluol from cycloeucalenol 9:39 Occelasterol 9:41 (+)-Occidol 16:214 Ochnaceae 7:408 Ochratoxin A and D 15:388 Ochratoxins 15:387,388 from Aspergillus ochraceus 15:382 Ochrobirine synthesis of 1:199,200 (-)-Ochropposinine from piperidine 14:565 synthesis of 14:565 Ochrosia elliptica epchrosine from 6:521 Ochtodenes 5:343 P-Ocimene 7:95 Ocimum basilicum 5:473,474,7:108,109 Octa-0-acetyl 1-thio mannosyl disaccharide 8:319,321 Octa-O-acetyl-1 -thio-a,a-trehalose 8:318,321 Octa-O-acetyl-a-D-mannopyranosyl 1 -thio-a-Dmannopyranoside 8:321 Octa-0-acetyl-P-p-/nao-trehalose derivative

1124

from 2,3,4,6-tetra-O-acetyl-p-D-mannopyranosyl chloride 8:319-321 synthesis of 8:319-321 Octa-O-acetylated 2-thiosophorose 8:327 (9,12Z)-Octadecadienoate 9:566 (9,12Z)-Octadecadienoic acid (linoleic acid) 9:560 Octadecane-l,2,3,4-tetrol 5:704 Z-r/Z)o-Octadecane-1,2,3,4-tetrol 5:705,707 I-xv/o-Octadecane-l,2,3,4-tetrol 5:705,707 Octadecanoids 1:528 Octadecyne-6 CI (NO) mass spectrum 2:14 (3)-3,7-Octadien-l-ol stereospecific preparation of 2:466,467 3,7-Octadien-l-ol stereoselective synthesis of 12:467,468 Z-Octadocene-6 CI (NO) spectrum 2:7 (l/?,25,37?,4aS',7/?,85',8aS',9a/?)-Octahydro-l,2,7,8tetrahydroxy-3-[(1R)-1 -hydroxy ethyl]-6hydroxymethyl-pyrrolo-[2,l-b] benzoxazole 10:506 Octahydro-1 H-[ 1 ]-benzopyrano-[4,3,2,-e,f|isoquinolines 18:81 Octahydro-lH-benzofuro-[3,2,-e]-isoquinolines 18:81 Octahydro-5-oxoindolizine-1,28-triol 12:328 Octahydro-benzazecine synthesis of 6:483 Octahydrobenzofliran 12:10,11 from cyclohexanone 12:22-24 (+)-Octahydrodeacetyldebromolaurencin 10:233 ^ra5-Octahydroflavopereirine synthesis of 1:143 Octahydroflavopereirmes synthesis of 1:133,134 Octahydroindolizine 12:275 Octahydroindolizine (1-azabicyclo [4.3.0] nonane) 11:229 (15,2/?,8/?,8a/?)-Octahydroindolizine- 1,28-triol from Astagalus emoryanus 12:313 from Metarhizium anisopliae 12:313 from Oxytropis sericea 12:313 from Rhizoctonia leguminicola 12:313 from Swainsona canescens 12:313 synthesis of 12:313-325 Octahydroindolizine-1,2-diols 12:303-306 Octahydroindolizine-l-ol 12:278 Octahydroindolizine-2-ols synthesis of 12:283,284 Octahydroindolizme-7-ols 12:285-289 Octahydroindolizine-8a-ols 12:300-303 (-)-l,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a] quinolizine 12:383 Octahydroisoquinoline diastereoslective synthesis of 12:457 from6-hydroxy-4a-aryl-^a5-decahydroisoquinoline 12:457 Octaketides 9:267 trans-Octalin (-)-polygodial from 6:13,14 Octalin coupling reagent 13:586

c/5-Octalone dimethylsulfoxonium methylide addition to 6:550,551 ()-Octalone 6:552-554 [3.3.0] Octan-2-one derivative 10:412 Octanedioic acid derivative tetraoxoalkane dioates from 11:117 (/?)-y-Octanolide 13:310 5-Octanolide 13:312 Octant rule 2:167;9:255,743,18:623,628 m 5a-cholestan-3-ene 2:168 in citronellal 2:168 for conjugated ketones 2:168 for cyclopropyl ketones 2:168 for a-halogeno ketones 2:168 for oxido ketones 2:168 Octapeptides 9:487-489 Octatrienal pentaenefrom 6:292,293 6- Octen-1-al RH(I) catalyzed 14:506,507 stereoselective cyclization of 14:506,507 2-Octen-l-ol 13:304 l-Octen-3-ol 13:304,326 Octose derivatives synthesis of 11:462-464 Octosyl acids 1:398 synthesis of 1:422-431 Octotea pretiosa 19:117 5-(+)-Octoteine 16:506 Octulosonic acid preparation of 11:466 Octyl-P-Z)-glucopyranoside 18:832 Octyl-P-D-glucopyranoside micelles 18:838 ODN analogues 19:539 Odakaic acid 5:384,385,388 Odonicm 15:171,176 from Rabdosia eriocalyx 15:173 from Rabdosia longituba 15:173 from Rabdosia nervosa 15:173 Odonticin 5: 66,204 *H-NMR spectrum of 5:205 Odonticmin 5:66 ^^C-NMR spectrum of 5:209 ' H - N M R spectrum of 5:209 Odontin 5:204,66 Odontinin 5:208,66 Odontomachus brunneus 5:223-225,237,254 Odontomachus clarus 5:224,228,254 Odontomachus hastatus 5:224,228,254 Odontomachus sp. 5:221,232,225,228,237,238 Odontomachus troglodytes 5:223-225,237,238,254 Oestrogenic activity 20:659 Officigenin 7:140 from Guaiacum officinale 7:139, Offord method electrophoretic mobility 9:541 6a-14a-OH-withanone 20:205,20:220 Ohno's cyclization method 4:466,467 Ohno's lactone synthesis of 8:148,149

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Ohtsuk-Tahara synthesis oftaxodione 14:677,678 Oils of Artemisia species 9:529-536 Oishi's macrocyclic lactam contraction 12:187 Okadaic acid 17:19;19:128;20:896,897,907,908 Okenone 7:339,361 9(1 l)-en-12a-01 bivittosides A, B and D 15:91 Old world cutaneous leishmaniansis 2:314 cause of 2:312 Oleacapensis 5:514 Oleaeuropa 3:254 Olea europaea L 5:505,515,521,523,524,531,7:427,477 Oleaceae 7:427 01ean-12-en-3P,lla-diol 5:747 Olean-12-ene sapogenol anodic oxidation of 7:161,163 Oleanane 9:267 Oleanane triterpenes 7:131 -174 Oleanderol 9:293,294 Oleanderolic acid 9:293-295 Oleandomycin 5:613 Oleanen-28,30-dioic acids 7:145 9'-01eanoglycotoxin-A moUuscicidal activity of 7:428 Oleanolic acid 2:129,7:134,154,189,429,430,432,434; 9:51,55,57,293;20:6 from Eremophila caerulea 15:281 antiviral activity of 17:135 against carrageenan edema 17:138 3-epi-Oleanolic acid 15:281 from re/wc/7^/7a platycalyx 15:281 from Terminalia data 7:134 from Salvia divaricata 20:702 from Salvia glutinosa 20:707 from Salvia montbretii 20:704 from Salvia nemorosa 20:702 Oleanolic glycosides 17:126-127 Olefin reduction of 12:151,152 with high stereoselectivity 12:151,152 cw-Olefin benzylation of 14:569 from propargyl alcohol 14:569 trans-OXtfm -allylic alcohol from 14:570 benzylation of 14:570 Olefin conjugation withDBU 1:442 Olefin cyclization biomimetic 1:655-673 using mercury (II) triflate/amine complex 1:655673 Olefin isomerization of allyl acetates 4:49 with Pd (MeCN)2 CI2 4:49 Olefin metathesis 3:18 Olefin stain 12:207 Olefin-arene photocyclization 3:28 Olefin-ketocarbene cyclization reaction in ()-isocycloeudesmol synthesis 6:41

Olefinic dioxolane acetal cyclization of 14:471 from(2i?,3/?)-2,3-butanediol 14:471 Olefins 1:451,453,4:503,504,7:390,9:315,13:313 conversion to chlorohydrins 1:451 isomerization 1:453 with Rh (PPh3)3 CI 1:453 Oleic acid biosynthesis of 11:192,193 in Cladosporium eladosporioides 11:194 in Penicillium brefeldianum 11:192 Olentes 17:200 Oleoresin 10:3,26 1 -Oleoyl-2-acetyl-rac-glycerol induced platelet aggregation 12:397 l-Oleoyl-2-acetylglycerol 12:390 Oleum chenopodii 20:12 Oleuropein 7:442,472 partial synthesis of 7:471 Olide from Salvia potentillifolia 20:660 from Salvia yosgadensis 20 : 660 Oligazulenes 14:314 Oligo (iV-methylpyrrolecarboxamide) antibiotics isolation and structure of 5:549-554 molecular interactions of 5:575-581 synthesis of 5:575-581 01igo-2'-5'-adenylates synthesis of 14:286 Oligocerus hemorrhages 17:14 Oligodeoxyribonucleotides 4:269-307 automated synthesis 4:280-276 deprotection 4:282,283 hydrogen phosphonate method for synthesis 4:274-276 phosphite method for synthesis 4:271-274 phosphotriester method for synthesis 4:268-271, 301-303 purification 4:282,283 synthesis of 4:268,307 synthesis on polymer supports 4:274-276 uses of 4:267,268 Oligoheptoses 4:195,196,198 by trichloroacetimidate method 4:203-208 synthesis of 4:203-208 Oligomer 8:377 Oligomeric DNA 8:373,374,376 Oligomerization 12:189 base-catalyzed 14:271,272,274 of levoglucosenone 14:271,272,274 ofPBG 9:595 Oligonucleotides 4:264-266 purification of 4:282,283 synthesis of 4:264-316 Oligopeptides biomimetic studies of 10:639-669 synthesis of 10:639-669 Oligophylidene from Acronychia oligophylebeia 13:348,350 Oligoribonucleotide synthesis by phosphite method 4:303 by H-phosphonate method 4:304,305

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by phosphortriester method 4:301 -303 protecting group for 2'-hydroxy 4:296 Oligosaccharides 4:203-208,11,18,29,31-36,39,42,45, 62,69,72,270,278,287-289,291,315-338,216-218,235, 143;6:397,398,406 ^^C-NMR of 4:207,219 ^H-NMRof 10:461 biosynthesis of 10:468 chemical synthesis of 14:283-312 FAB-MS of 10:461 from diheptoses 4:204-206 from glycosidases 10:468,470,471 from glycosyl transferase 10:468-470 ofZ-glycero-Z)-manno-heptoses 4:207 synthesis of 10:457-493 synthesis of 4:2-7-212;8:315-338 Oligosaccharyltransferase 10:501 Oligosporic actinomycete 14:98 Oligostatins C 10:515,516,236 Oligostatins 10:517 amylase inhibitor of 10:516 antibacterial activity of 10:516 from Streptomyces myxogenes 10:515 mammalian a-amylase inhibitors 10:516 microbial a-amylase 10:516 synthesis of 10:516 Oligostatins D 10:516 from Streptomyces myxogenes 10:515 Oligostatins E 10:516 from Streptomyces myxogenes 10:515 Oligotide degradation 3'-exonuclease in 13:288 Olivacine 5:125 Olivacine-type alkaloids olivacme 5:88,89 Olivacinic acids 4:435,457 as epithienamycin A,B,E and F 4:434 as epithienamycin C and D 4:434 ()-01iveroline 16:511-512 Olivetol (l,3-dimydorxy-5-pentylbenzene) 9:344; 19:186 for 3,5-dimethoxybenzoic acid 9:344 5'-(^H3)-01ivetol 19:191 Olivetol dimethyl ether 19:188 (-)-Olivil 5:525 (-)-01ivil-4"-p-Z)-glucoside 5:525 (-)-Olivil-di-P-D-glucoside 5:525 Olivin 3:173,175 synthesis of 3:191-197 Olivomcin 3:173,175,245 Oltremare process 9:331 Operophtera brumata 4:566 Omphalea diandra 11:431 Onchidal 17:27 Onchidella benneyi 17:27 Onchocerciasis (river blindness) treatment of 1:435 Oncogene function inhibitor from microbial secondary metabolites 15:439-463 screening of 15:463 Oncogenesis 19:351

Oncogenic viruses 15:439 Oncomelania 7:425 Oncosperma tigillaria 7:176 One-carbon homologation of allylic alcohols 3:238 Onekotanogenin 7:278-280 OnnamideA 5:364,365 HETCOSY of 5:367 a,Y-Onoceradienedione synthesis of 1:658,659 Onocerane triterpenoids synthesis of 1:658-660 Ononis natrix 6,8-dihydroxy-3-undecyl-3,4-dihydroisocoumarin from 15:386 Onychine anticandidal activity of 2:443,443 Onychopetalum amazonicum 2:442 Oochromonas malhamensis 2:293 Oomycetes 9:202,203 Operon protein synthesis 8:315 Ophiarachna incrassata 7:308,309 Ophiarthrum elegans 7:308,309;15:96 Ophidianoside B,C 7:290,293 Ophidianoside F 7:293,399 from Linckia laevigata 7:290 Ophidiaster ophidianus 7:290; 18:460 Ophiobolane 3:93,94 Ophiobolane sesquiterpenes 1:563 Ophiobolin 16:138 (+)-Ophiobolm C synthesis of 16:141 Ophiobolin F 1:563,569 Ophiocarpine synthesis of 1:190,191 (-)-e/7/-Ophiocarpine 1:190,191 Ophiocoma dentata 7:308,309;15:96 Ophiocomina nigra 15:100 Ophioderma longicaudum 7:309,96 longicaudoside A and B from 7:94,308 Ophiodiaster ophidianus 15:46 Ophiolepis superba 15:84,96 Ophiomastix annulosa 15:99 Ophiorachna incrassata 15:96 OphiorineA 1:125,126 OphiorineB 1:125,126 Ophiorrhizajaponica 1:125 Ophiosparte gigas 15:99 Ophiura sarsi cholest-5-ene-3a,4p,21 -triol-3,21 -disulphate from 15:98 Ophiuroidea 15:43,94-100,265,307-309 Opisthiolopis heterophylla 9:320 Opisthobranchia 17:3 Opium alkaloid 18:45 (+)-Oplopanone 15:247 Oplopanone 15:250 Oppenauer oxidation 13:451,20:749 Oppolzer-Battig synthesis of()-A^^'^^capnellene 6:45,46 Oppolzer's aldehyde ()-vmcamine from 14:726

1127

Oppolzer's chiral acryloyl sultam 19:314 Oppolzer's chiral auxiliary from (+)-camphorsulfonyl chloride 11:307,308 preparation of 11:307,308 with ()-3-chloroacryloyl chloride 11:307,308 Oppolzer's acryloyl sultams 10:138 Oppositol from Laurencia subopposita 6:9,10 synthesis of 6:9,10 Opsins 10:150 Optical activity detection 9:462 Optical purity of acetylenic a-ketols 6:153 of non-acetylenic a-ketols 6:153 Optical resolution 6:544,552 of ()-3-oxycyclopentane carboxlic acid 6:559 Optical rotatory dispersion 2:153 Optically active sulfoxides synthesis of 4:489-491 Opulus iridoids 7:41 Orcinol reagent 19:755 Orconecttes limosus 19:628,668 Oreaster reticulatus 7:304-306,15:61 asterosaponin Pi from 7:297,300 Oregonin 17:360 Organic synthesis by 1,3-dithiane 6:301-303 withFAMSO 6:311-323 with MT-sulfone 6:330-340 Organoboranes 8:472,473,478 Organocopper reagents addition to a,P-unsaturated acetals and ketals 1:626,627 Organocuprate reagent conjugated addition of 14:509 toenones 14:509 Organogenesis of cell cultures 7:94-96 Organolithium reagents 2-amino alcohol by 12:411,413 to a-alkoxydimethyIhydrazones 12:411,413 nucleophilic addition of 12:411,413 Organometallic addition to A ' ^ O-protected D-a//o-threoninal 4:142 Organometallic reactions in prenylation methods 4:396,398 Organometallic reagents nucleophilic additions of 4:328-333 Organometallic tropone derivatives addition of Gringard reagent 1:573 addition of organolithium reagents 1:573 Organopalladium reactions 16:367 Organoselenium technology 13:5 Organosilicon compounds 13:473-518 Oricia renteri 2:121 Oridonin from Rabdosia eryocalyx var. laxiflora 15:171 from Rabdosia japonica 15:172 from Rabdosia longituba 15:173 from Rabdosia macrophylla 15:173 from Rabdosia rosthornii 15:174

from Rabdosia rubescens 15:174 from Rabdosia ternifolio 15:175 Oriola xanthornus hemoglobm components of 5:837 Ormosanine 14:738,739 biosynthesis of 14:738,739 froml-lysine 14:738,739 I-Omithine nitro derivative condensation of 11:437 Ornithine decarboxylase 20:513 by staurosporine 12:393 mduction of 12:393 in human bladder carcinoma T24 cells 12:393 Ornithopus sativus 18:514,520,523,529-533 castasterone from 18:503 24-epicastasterone from 18:503 Orotidine monophosphate decarboxylase 7:387 Orsellinic acid 9:328,341,346-348,366,367;11:536 biosynthesis of 11:199 by Penicillium madriti 11:198 Orr/jo-alkoxyacetophenones 14:648 Or^/?o-alkoxyphenyl ketones 14:647-650 Or/Zio-alkoxyphenylglyoxalate esters 14:648 Or//;o-benzyloxyacetophenone by Norrish type II photoelimination 14:655,656 from or^/zo-benzyloxyvalerophenone 14:655,656 Or//2o-benzy loxybenzophenone 14:64 8 Or^/?o-benzy loxyvalerophenone 14:647 or^/?o-benzyloxyacetophenone from 14:655,656 Ortho-ester Claisen rearrangement 3:34 ofdivinylcarbinols 3:41 0/"//io-methoxyacetophenone 14:647,648 Or^Ao-methoxybenzophenone 14:647,648 photocyclization of 14:647 photoreduction of 14:647 Orthoester Claisen rearrangement 1:446,447,598 Ortholactone formation 457 Orthometallation 14:684,686 Orthoquinodimethanes synthesis of 3:434 Orthoscuticella ventricosa 17:90,95,101 Orthosphenia 18:754 Orthosphenia mexicana 7:756,758 netzahualcoyon from 7:147 orthosphenic acid from 7:147 triterpenes of 7:147 Orthosphenic acid 7:148,167 from Orthosphenia mexicaca 7:\41 X-ray analysis of 7:147 Orthosphenin 18:755 Orygyia pseudotsugata 20:124 Oryzasativa 1:529,522,20:247 Oscillatoria nigroviridis 18:294 Oscillatoxin D synthesis of 18:269-309 Oscillariolide isolation of 19:567 NOESY data of 19:567 relative stereochemistry 19:567 Oscillatoria species 19:567 Oscillatoria nigroviridis 19:586 Oscillaxanthin 20:592 Oscillol 20:592

1128

Osladin 15:27 Osmium (III) chloride 12:162 Osmium tetraoxide 4:169,178 liydroxylation with 4:508,509 in cw-bishydroxylation 4:160,163 selectivity of 4:160-162,172,180 Osmylation 1:413,141,441;4:160,162,175-185;6:182; 13:400,401;16:323,324,326,329,332;19:226-275 a//-stereoselective 4:161,162,167,170,171,178 in synthesis of eight-carbon sugars 4:163-172 in synthesis of eleven-carbon sugars 4:188 in synthesis of nine-carbon sugars 4:180-182 in synthesis of seven-carbon sugars 4:175-179 in synthesis often-carbon sugars 4:192-185 Kishi's rules 1:413,414 of allylic ethers 1:413,414 ofchiralallylic alcohols 4:160 of bis-allylically substituted cyclopentenes 19:355 5y-stereoselective 19:355 Osteomalacia 9:509 Osthol 20:497 from Limonia acidissima 20:497 Ostryajaponica 17:369 O^^ry^ species 17:369 Otivarin 18:193 Otonecine synthesis of 1:242 Otonecine synthesis of 8:211 Ouchterlony plate technique 7:115 Oudemansiella mucida 3:257 Oudemansin A synthesis of 3:257-259 Oudemansin B synthesis of 3:257-259 Ouregidione 20:481 Ourouparia gambir 1:25 Ourouparine 1:125,126,137,138 synthesis of 1:137,138 Ovaliflavanone 8-prenylfavanone in 4:378 Ovaliflavanone B 4:378 allylationof 4:21 and 6,8-diprenylflavanone in 4:378 Overhauser effect 11:293,15:204-206 in saponins 15:204-206 Overman synthesis of(+)-elaeokanine B 13:487,488 of(+)-streptazoline 13:514,515 Oviposition attractant pheromone 3:157-157 Ovoverdin 6:161 Oxa concept 9:515 cis-5 -Oxa-1 -indanones d5-selective formation of 6:558 20-Oxa-la,25-dihydroxy-vitamin D3 9:518 22-Oxa-1 a,25-dihydroxy-vitamin D3 9:518,519 20-Oxa-1 a-hydroxy-vitamin D3 9:518 22-Oxa-1 a-hydroxy-vitamin D3 9:518,519 25-Oxa-25-phospha-vitamin D3 total synthesis 9:509-528 25-Oxa-25-phospa-vitamin D3 9:520,521 synthesis of 9:521 1-Oxabenz [a] anthracene 11:136,137

Oxabicycles synthesis of 10:214 (-)-(15',45)-7-Oxabicyclo [2.2.1] hept-5-en-2-one 12:340 7-Oxabicyclo [2.2.1] hept-5-en-2-yl-derivatives 11:462 7-Oxabicyclo [2.2.1 ] heptan-2-ones 14:180 Oxabicyclo [3.2.1] octane 12:28,29 Oxabicyclo [4.3.1] decane synthesis of 10:214 7-Oxabicyclo [4.30] nonane 12:28 (+)-(17?,4/?)-7-Oxabicyclo[2.2.1] hept-5-en-2-one 12:340 Oxacillin 9:413 A^'^-Oxahydrindene 12:18,19 Oxahydrindene subunit of avermectins Barrett's approaches for 12:9-11 Crimmins synthesis of 12:11,12 Danishefsky synthesis of 12:12,13 Fraser-Reid synthesis of 12:13,14 Hanessian synthesis of 12:14,15 Hirama synthesis of 12:15,16 Ireland approach for 12:15,16 Julia synthesis of 12:19,20 Jung synthesis of 12:19,20 Kozikowski approach 12:20-22 Ley synthesis of 12:25,26 Smith synthesis of 12:25,26 vang synthesis of 12:26,27 White synthesis of 12:27,28 Williams approach for 12:28-30 9-Oxaisotwist-8-en-2-one synthesis of 8:166-168 7-Oxalactone regioselective preparation of 19:252 Oxalic acid in mangrove plants 7:180 Oxalyl chloride 9:526 Oxamicetin 4:234,241 7-Oxanorbomenyl derivatives homologation with 11:462-464 Oxaphosphetane 6:545 Oxaspiropentane 10:616,617 Oxaspiropentane rearrangement 10:616-618 1,2,3-Oxathiazolidin-2-ones 14:518,519 Oxatricyclo [4.4.2.0* ^] structure 6:538,539 Oxatropane solenopsin A from 6:433,434 Oxaunomycin synthesis of 14:493,495 [l,2]-0xaza ring formation by Meisenheimer rearrangement 6:472 1,2-Oxazine monomorine I from 6:449 Oxazine 8:291 Oxazolidene-2,4-dione 13:483 Oxazolidin-2-ones 12:446 Oxazolidines cycloreversion of 1:337 2-Oxazolidinone 3-acetyl-2-oxazolone from 12:411,415 acyclic amino alcohol from 12:428-430 acyclic A^-boc amino alcohols from 12:428-430

1129

from 1,35-tris (2-hydroxyethyl) cyanuric acid 12:411,415 A^-protection of 12:428-430 2-oxazolone from 12:411,415 ring opening of 12:428-430 with di-^er/-butyl dicarbonate [B0C)20] 12:428-430 debenzylation of 14:569 from A^-benzoy Icarbamate 14:569 pyrrolidine derivative from 14:569 Oxazolidinone auxiliaries 18:161 2-Oxazolidinone ring 4-methoxy group on 12:428-430 substitution of 12:428-430 2-Oxazolidone derivatives synthesis of 12:166 A-2-Oxazoline from D-threonine 4:140,141 with fiirfiirylithium 4:140,141 Oxazoline 10:474-477 as chiral auxiliary 4:327,332,333 of 2-acetamido-2-deoxy-Z)-glucose 6:399 m the synthesis of Li substances 10:473 in the synthesis lacto-A^-biose 10:473 Oxazoline derivative 6:399 Oxazoline method 6:393 Oxazoline rings synthesis of 4:86 Oxazolo [4,3-a] decahydroisoquinolines 12:464 2-Oxazolone from 2-oxazolidione 12:411,415 preparation of 12:411,415 A^-acetyl derivative 12:411,415 Oxepan-4-ones 10:219 Oxepane synthesis of 10:202,205-207,209-212,214,215, 224-226 cw-Oxepane 10:211,212 6w-0xepane 10:205 ^ra5-0xepane synthesis of 10:211,212 Oxepanols synthesis of 10:230 3-Oxepanols synthesis of 10:231 Oxepanone 10:205,209 3-Oxepanones 10:209,210 Oxepins synthesis of 10:236 Oxetanocin synthesis of 10:585-627 OxetanosinA 19:511 Oxetanocin A antiviral activity of 10:619,620 by N-glycosidation 10:595-607 from acyclic nucleoside derivative 10:588,592 from Bacillus megaterium 10:585 from fiiranosyl nucleoside 10:592-595 total synthesis of 10:587-608 transformation of 10:586,587 with 1-0-acyl-oxetanose 10:597-604

with oxetanosyl derivative 10:595-607 with oxetanosyl halide 10:604-607 Oxetanocin G 10:586,587 antivu-al activity of 10:619,620 Oxetanocin H 10:586,587 Oxetanocin X 586,587 Oxetanosyl halide synthesis of 10:604-607 Oxidation aerial 16:66 byninhydrin 16:83 by Sharpless procedure 8:23 enantioselective 13:54 enzymatic 13:58 in vitro 6:138 in vivo 6:138 Lemieux-Johnson, 4:592,593 nitrotoketo 1:417,418 of(-)-bomeol 16:124 of (+)-5-methoxylaudanosine 16:506 of(+)-camphor 16:149,153 of(+)-laudanosine 16:506 of l,r-methylene bis (3,7-diisopropylazulene) 14:340,341 ofl,3dimethylazulene 14:336,337 of 1,5-diisopropylazulene 14:337,338 of 1-isopropylazulene 14:336 of2-ethyl-5-pentylpyrrolidine 6:444 of2-fiirycarbinol 19:473 of 3,3'-methylene bis (guaiazulene) 14:343-345 of 3,3'-methylene bis (guaiazulene) 14:344 of4,6,8-trimethylazulene 14:341,342 of alcohol 16:40,350 ofalcohols to ketones 4:331 ofaldehyde 16:294;19:210 ofalkene 16:459 of allylic alcohol 16:296 of amides 1:10 of aromatic compounds 6:509 of azulenic hydrocarbons 14:313-354 of benzylic alcohol 19:225 ofbromonaphthol 16:48 of cholesterol 17:207 of conjugated dienes 16:420 of dimethyl 2-amino-1,3-azulenedicarboxylate 14:339 ofdi-substitutedazulenes 14:336,337 ofellipticine 6:509 of enol acetate 19:207 of enol ether 16:85 ofenolate 16:474 ofFAMSO 6:326 of formaldehyde dimethyldithioacetal 6:326 offriedelin 7:160,161 ofgenipin 16:313 of guaiazulene 14:313-354 ofhemiacetal 1:453,454 ofhydrazide 16:473 oflactol 19:473 of oleanane triterpenoids 7:159-161 of olefin 10:111 of olefins to ketones 4:333

1130

ofphenolate 19:233 ofphenylsulfide 16:296 of phosphite linkage 4:280 of phosphonate linkage 4:280 of phosphonium ylides 4:558,559 ofsecondaryhydroxyl group 19:489 of sulfide to sulfone 1:454,456 of taraxerone 7:160,161 of tertiary allylic alcohol 19:262 of tetrahydroisoquinolinols 16:519 of tetra-substituted azulenes 14:343-345 of tri-substituted azulenes 14:339-342 of unactivated carbons 2:90-103 of a, p-unsaturated aldehyde functionality 214 of a,p-unsaturated ketones 4:100 Pd (II) catalysed 4:100 photochemical 1:159 regioselective 19:262 Swem 1:453,454 using Kelly procedure 10:111 with AC2O-ACOH 8:160,162 with Attenburrow-Mn04 8:119 with benzeneselenic anhydride 4:40,41,52 with eerie ammonium nitrate 4:331,332;6:472 with eerie sulphate 1:159 with Collin's reagent 1:360,363,367 withDDQ 8:169;19:473 with HjOj-aq. NaOH, 8:163 withHgO/l2 1:454,456 with iodine 1:126,138 with Jones reagent 19:136 with KMn04-NaOtBu 1:417 withwCPBA 2:90-103 with manganic acetate 4:72 withwCPBA 19:71 withMnOz 8:198;16:294 with N(n-Prop)4 RUO4 8:150-152 with o-chloranil 1:131,132,135,137 with osmium tetraoxide 10:111 withOs04 8:23;16:292 with oxone (KHSO5) 1:454,456 with palladium 1:131,133 withPb(0Ac)4 8:165 withPCC 19:62,19:473,19:541 withPDC 19:145,19:265 with Ph I (OCOCF3)2 4:73 withPPC 1:440 with pyridinium chlorochromate (PCC) 8:22,23, 163;11:401 with pyridinium chlorochromate 1:208;6:117 with pyridinium dichromate 4:331 withRu04 1:404,405;8:150-152 with Ru04-NaI04, 8:162 with SeOi/t-BuOOH 8:2,3 with silver carbonate 1:453,454 with silver oxide 11:86 with sodium chlorite 16:83 with sodium metaperiodate 4:50;19:354 with sodium periodate 16:293 with Swem oxidant 6:119,120 with tetrapropylammonium metaperiodate 1:379,380 with thallium acetate 4:72

with thallium nitrate 4:338;8:166,167,169 Oxidation potentials of alky 1-substituted azulenes 14:347 ofguaiazulene 14:326 Oxidation state of carbon 6:327 of sulfur 6:307,309,311 Oxidation-Wittig homologation 13:612,613 stereospecific 9:255,256 Oxidative conversion 19:484 Oxidative coupling reaction olefin 8:160 of phenol 8:160 Oxidative Nef conditions 19:73 Oxidative cyclization ofdavanones 9:533 Oxidative phenolic couplmg in biosynthesis of 20:291-293 natural products by 20:263-315 Oxidative decarboxylation 1:536 of a-keto acids 1:536 Oxidative degradation of fatty acids 13:303-306 ofilimaquinone 9:31 Oxidative demethylation 5:769 Oxidative elimination ofarylselenide 3:260 Oxidative hydroboration 12:318,322,344,14:460,461 Oxidative olefmation 4:448 Oxidative rearrangement 16:650 Oxidative transformations 7:159-168 Oxidative-degradation system 7:105 Oxidative-hydralase system 7:105 A^-Oxide of allopumiliotoxin 267 A from Dendr abates speciosus 12:294 A^-Oxides of pumiliotoxin 12:323 from Dendrobates speciosus 12:294 Oxidising action of NO in CI (NO) mass spectra 2:3 Oxidizing agents 19:120 Oxidizing enzymes in Strychnos dinklagei 6:520 Oxido ketones CD of 2:169 octant rule for 2:168 12,135-Oxido-9Z, 11 -octadecadienoic acid 9:577 3,19/?-Oxido-coronaridine 5:127 Oxido-reductase 17:480,481 6/?-3,6-Oxido-voacangine-A'4-oxide 5:127 22,25-Oxidoholothurinogenin 7:268 Oxidopyraziniums 1:341,342 Oxidopyridinium ions 1,3-dipolarcycloadditionsof 1:340 Oxidopyrylium-alkene cycladdition 12:269 C-Oxidoreductase 7:105 Oxime sulfonate solenopsin B from 6:433,43 Oxindole alkaloids 15:485-487 Oxindole-type alkaloids conopharyngine oxindole 5:107 75-isovoacristine 5:107 Oxindoles 9:196,197

1131

Oxirane opening influence of a-OH 1:560,561 reaction with lithiated nucleophile 1:157 regiospecifity of 1:560,561 with dilithioacetate 1:558,560,561 Oxirans 2-amino alcohol by 12:411,413 ring opening of 12:411,413 with nitrogen nucleophiles 12:465 Oxo reaction 3:223,4:255 Oxo-(^-2-decenoic acid synthesis of 19:123 queen substance 19:123 cis-3 -0x0-1 -hydroxyindolizidines 12:279 /ram-3-0x0-1-hydroxy indolizidines 12:279 2-Oxo-4-phenyl-3-butenoate 20:849,20:851-853 6-0x0-16-e/?/-silicine 5:126 6-Oxo-12-methylroyleanone-18-oic acid from Salvia divaricata 20:661 7-0x0-13-e/?/-pimara-8,15-diene-18-oic acid from Salvia heldrichiana 20:690 8-Oxo-2'-deoxyguanosine (8-oxo-dG) 8:376,378,388, 392 /-4-Oxo-2,33-dihydrosolamin synthesis of 18:197-199 1 -Oxo-7a-hydroxysitosterol from Salvia glutinosa 20:707 1 -Oxo-abieta-8,11,13-triene-18-oic acid from Salvia tomentosa 20:667 11-Oxo-a-amyrin 20:707 11-Oxo-P-amyrin 20:707 4-Oxo-2,33-dihydrosolamin 18:199 3 -Oxo-20'-deoxy leurosidine from 20'-deoxyleurosidine 14:812 25-Oxo-25-phosphacolecalciferol 9:522 9-Oxo-3-fluorenelacetate from diethyl phthalate 11:124 6w-(2-Oxo-3-oxazolidinyl) phosphinic chloride 12:46, 47 19-0x0-3 P,20S'-dihydroxydammar-24-ene 18:650 3-Oxo-4,5-oxidosteroids photoisomerization of 12:236 6-Oxo-4,8-dimethylnonanoic acid 15:228 3-Oxo-4-methyladipic acid 8:306 2-Oxo-carboxylates (/?)-2-hydroxycarboxylates to 20:840-842 reduction of 20:840-842 2-Oxo-D-gluconate 20:857 2-Oxo-I-gulonate 20:858 1 -Oxoaethlopinone from Salvia candidissima 20:680 2-Oxoaldonates 20:857 2-Oxo-7,7-dimethylbicyclo [2.2.1] heptane-1carboxylic acid (ketopinic acid) 12:416,417 1-Oxo-a-longipinene (vulgarone B) 9:534 6-Oxo-B/C-^ra5-morphinan 12:465 3-Oxo-cholesta-4,23-dien-22-ol 9:84,85,87 3-Oxo-conoduramine 5:129 3-Oxo-conopharyngine 5:128 3 -Oxo-coronaridine 5:124 5-Oxo-coronaridine 5:127 6-Oxo-coronaridme 5:127

3-Oxo-coronaridine hydroxyindolenine 5:127 1-Oxo-costicacid by Collins oxdation 6:16 synthesis of 6:16 5-Oxo-cylindrocarpidine 5:128 13-Oxo-dodeca-5Z,8Z,10-trienoic acid 9:534 3-Oxo-erythrinans by [2+3] cycloaddition 3:469 by non-oxidative coupling 3:468,469 19-Oxo-gelsevirine from Gelsemium elegans 15:481 1-Oxo-gibberellin synthesis of 8:121,122 3-Oxo-heyneanine 5:127 6-Oxo-isophorone 6:144,145 23-Oxo-isopristimerin 5:744,745,748 3-Oxo-isovoacangine 5:125 6-Oxo-methuenine 5:126 (+)-3-Oxo-minovincine 5:125 4-Oxo-mytiloxanthin 6:152 from Asterias rubens 6:151 3 '-Oxo-iVa-demethy 1-A^a formy lleurosine from 14:818, 819 3'-Oxo-A^a-demethyl-A^a-formylleurosine from 3'-oxoleurosine 14:818,819 13-Oxo-octadecadienoates 9:563 3-Oxo-oxepanes 10:209 24-Oxo-reissantiadiol 5:744,748,750 3-Oxo-reissantiadiol 5:744,748,750 6-Oxo-silicine 5:126 3 -Oxo-tabersonine 5:127 19-0x0-voacangine 5:128 3-Oxo-voacangine 5:128 3-Oxoadipic acid 8:295-297 13-Oxoambliofiiran synthesis of 1:671 P-Oxoamides N-alkyl-4-hydroxy-2-pyrrolidinones from 14:650, 651 photochemistry of 14:650,651 3 '-Oxoanhydro vinblastine from anhydrovinblastine 14:812-814 from anhydrovinblastine N-oxide 14:812-814 Oxoaporphme alkaloids in candidiasis 2:434 Oxoaporphines of Milius banacea 20:483 ofXylopia acthiopica 20:483 synthesis of 3:441 Oxoavicine synthesis of 3:446,447 Oxobutryric acid 9:548 4A^-(3-Oxobutyl) cytisine from Echinosophora koreensis 15:525 cw-Oxocan-3-one 10:235 Oxocan-4-ones from titanium tetrachloride mediated cyclization 10:219 Oxocane synthesis of 10:213,214,219,220,232,236 c/5-Oxocane (p^ewflfo-gloeosporone) synthesis of 10:217,218

1132

3-Oxobicyclo [4.3.0.] nonan-2-one-type skeleton 20:68 l-Oxoferruginol from Salvia acetobulosa 20:673 from Salvia multicaulis 20:673 from Salvia napifolia 20:670 3-Oxoferruginol from Salvia acetobulosa 20:673 from Salvia multicaulis 20:673 7-Oxoferruginol-18-al 20:669 3-Oxocanones 10:235 by [3,3]-sigmatropy 10:235 synthesis of 10:235 6-Oxoferruginol from Salvia napifolia 20:670 Oxocarbenium ion 16:94,95,108 formation of 16:94 Oxocene oxidation of 10:204 synthesis of 10:203,204,211,218,224,225 unsaturated 10:231 Oxocenones synthesis from 5-lactones 10:217 ()-8-Oxocephalotaxine 18:319 Oxocompostelline synthesis of 3:428 3 -Oxoconopharyngine 9:174 3-Oxocoronaridine 9:171 Oxocularine synthesis of 3:428 3-Oxocyclopentane carboxylic acid 6:558,559 Oxodienoic acids 9:563 17-OxoeUipticine 6:508-510,512 biosynthesis of 6:521 by regiospecific oxidation 6:508 from ellipticine 6:508 from A^-p-oxy-17-oxoelUpticine 6:515 17-hydroxyelHpticine from 6:515 reduction of 6:509,515 spectral data of 6:509 synthesis of 6:509,510,511 Oxofemiginol from Salvia acetobulosa 20:673 from Salvia multicaulis 20:673 ()-Oxogambirtannine 13:489,490 21-Oxogelsemine 15:478 from Gelsemium sempervirens 15:479 19-Oxogelsenicine 15:481,482 from Gelsemium elegans 15:482 21-Oxogelsevirine 15:478,479 from Gelsemium rankinii 15:479 4-Oxogeranyl acetate 9:530 Oxoglaucine 2:436,441;20:483 p-Oxoglutarate derivative ()-semivioxanthin from 11:130,131 (-)-(5)-1 -Oxoindolizidine configuration of 12:279 ()-1 -Oxoindolizidine hydrogenation of 279 synthesis of 12:279 with (+)-3-bromocamphor-8-sulfonic acid 12:280 with (3)-3-bromocamphor-8-sulfonic acid 12:280

7-Oxoindolizidine 7-ethyl-7-hydroxyindoHzidine 7-hydroxy-7-phenylindolizidine from 12:286 reduction of 12:286,287 synthesis of 12:286,287 (5)-1-Oxoindolizidine 12:314()-2-Oxoindolizine reduction of 12:283,284 synthesis of 12:283,284 6-Oxoisophorone 20:573 Oxoisophorone 20:607 14-Oxoisopimaric acid from Salvia candidissima 20:689 from Salvia wiedemanni 20:688 23-Oxoisopristimedrin III 7:147-149 3'-Oxoleurosidine from leurosidine 14:813 3'-Oxoleurosine fromleurosine 14:813 2r-Oxoleurosine fromleurosine 14:813,814 5-Oxomilbemycin D conversion to milbemycin D 12:20 3-Oxominovine 19:92 11-Oxomogroside V 15:24 13-Oxomyricanol 17:371 Oxonane 10:209 Oxonantenine 2:436 Oxone (KHSO5) oxidation of sulfide to sulfone 1:454,456 4-Oxonerol 9:530 Oxonitidine synthesis of 3:446-447 3-Oxopachysiphine 9:190 3-Oxopentanoic acid 12:172 (4-Oxopentyl) Z)-glycoside photolysis of 10:420 Oxoperexinone conversion to dehydrooxoperexinone 5:773 synthesis of 5:772,773 Oxophoebine 20:483 3-(l-Oxopropyl) pyrrol-2 (5/f)-one 13:111-113 3-(2'-Oxopropyl-)-19-gp/-heyneanine 5:128 3-(2-Oxopropyl-)-coronaridine 5:126 21 -Oxopseudotabersonine 19:108 7-Oxoquinocarcinol methyl ester 19:296 7-Oxoroylcanone 20:712 6-Oxoroyleanone-18-oic acid from Salvia divaricata 20:661 3-Oxosalvipisone from Salvia candidissima 20:680 1-Oxosalvipisone 20:688 from Salvia candidissima 20:680 3-Oxosilphenene 3:6,62 5-Oxosilphiperfol-6-ene 3:6,63 (-)-5-Oxosilphiperfol-6-ene 13:11-13 20-Oxosteroid 19:467 3-Oxotabersonine 9:190;19:103 7-Oxotetradehydronoraporphine 16:504 l-Oxotrienylpyrrol-2(5i/)-ones 13:121-124 3'-0x0 vinblastine from vinblastine 14:813

1133

3-Oxovincadifformine 9:190; 19:93-94,99,102-103 formation of 19:102 from Amsonia elliptica 19:93 synthesis of 19:92 A^-b-Oxy-17-oxoellipticine 6:513 from A^-b-oxyellipticine 6:515 from Strychnos dinklagei 6:515 17-oxoellipticine from 6:515 reduction of 6:515 spectral data of 6:515,519 17-Oxy-20-desethyl-A^^^*^-didehydroebumamonine from desethylebumamonine enamine 14:729 Oxy-Cope rearrangement 3:96;6:28,29,36,538-540; 7:216;8:179,234,246,249;10:61,416;ll:43,45-49, 627;18:17 anion assisted 16:459 anionic 4:591;16:127;19:6 in the synthesis of macrocycles 8:245 of tertiary alkoxide 16:127 suprafacial 16:12 Oxyallyl zwitterion 14:587 Oxyaminations 2-amino alcohol by 12:411,413 ofalkenes 12:411,413 OxyayaninA 5:679 Oxybisberberine 1:191 Oxychelerythrine fromberberine 14:773-775 reduction of 14:773-775 synthesis of 14:773-775 through enamide-aldehyde cyclization 14:774,775 to chelerythrine 14:774,775 Oxychelirubine chelirubine from 14:777,778 macarpine from 14:781-783 13-Oxycoptisine from protopine alkaloids 6:492 in fiirodysinin synthesis 6:28,29 in fiirodysin synthesis 6:28,29 in poitediol synthesis 6:36 Oxycyclopropanes synthesis of 8:34,35 Oxydifficidin 5:606,607 A^-b-Oxyellipticine 6:507,519 N'b-oxy-17-oxoellipticine from 6:516 spectral data of 6:516 Oxygen-containing heterocycles by cyclization of mixed acetals 10:220,221 from Lewis acid catalyzed reaction 10:220,221 6-Oxygenated4a-aryldecahydroisoquinolines stereospecific synthesis of 12:457,458 A^-7-Oxygenated brassinosteroids synthesis of 18:515-520 Oxygenated cembranes 8:15 Oxygenated homophthalates polysubsituted anthracenes from 11:120 Oxygenated pyrazines 5:246,247,251 Oxygenated trichodiene 13:524 P-Oxygenated-t-amino acids stereoselective synthesis of 12:476-489 Oxymercuration 10:67,324,185 Oxymercuration cyclization 1:423,425

Oxymercuration-demercuration procedure 14:538,539 Oxynitidine nitidinefrom 14:775,776 Oxysanguilutine sanguilutine from 14:777,778 Oxystiols 5:405-410 cytotoxic activity of 5:406 Oxyterihanine from protoberberine 14:776,777 synthesis of 14:775-777 Oxytocin reduction durmg FAB MS 2:30 Oxytropis sericea (-)-swainsonine from 12:313 Oxyberberine magallanesine from 6:470 Ozone-triphenylphosphine adduct 4:554 oxidation of ylides with 4:558,559 Ozonization 1:264,265 of olefin 1:439 of()-dihydroiimonene 6:541 Ozonization reaction with thuj one 14:416,417 Ozonolysis 4:523;5:590;6:137,298,299;8:139;9:338, 359,525,527;11:337,338,369;12:81;14:101;16:495,64 9,712;20:409 cardanol methylether by 9:338 ofalkene 16:462 ofdiacetate 5:599 ofdiacetylirumamycin 5:599 of enol ether 16:495 ofenyne 16:384 ofergosterol 16:336 of olefins 10:565 of seleno ether 16:7 ofstigmasterol 16:324,336 ofstreptolydigin 14:101 reductive 4:523 Ozonolytic cleavage 13:604,258 of(+)-A^-carene 16:258 Ozonolytic degradation 6:137 of 19'-hexanoylfiicoxanthin 6:137 ofperidinin 6:137 Ozoroa mucronata 5:824,830;9:316,327

P -Moraprenyl, P -(a-Z)-galactopyranosyl) diphosphate 8:108 P388 mouse leukaemia staurosperme activity against 12:390 Pachiclavularia violacea 17:610 Pachodynerus erynnis 5:223 ()-Pachydictyol-A by reductive transposition 6:11 from Pachydictyon aociaceum 6:11 from a-santonin 6:13 synthesis of 6:11,13 Pachydictyon coriaceum ()-pachydictyol A from 6:11,70 sanadaol (p-crenutal) from 6:70 Pachygrapsus crassiples 628

1134

Pachyman 5:288,317 antitumor activity of 5:317 Pachysiphine 5:127,9:190 Pachystazone from Salvia napifolia 20:670 Pachystima 18:741 Pacifagorgiol from Pacifigorgia adamsii 9:254 X-ray crystal analysis of 9:254 Pacifigorgia adamsii 18:614,615 pacifigorgiol from 9:254 Pacifigorgiol 6:11 ;18:624,625 Clardy synthesis of 6:10 from Pacifigorgia admsii 6:10;18:624 synthesis of 6:10,11 Pacifigoria adamsii 6:10 Packed column GC in gas chromatography 9:453-456 Padmatin 7:228 Paecilomyces varioti 2:341; 12:103 Pafficacid 7:5 Pagicerine 5:128;9:181 Pagisulfme 5:126;9:172 Paitantin synthesis of 4:588-590 Palauolide 10:152 Piers synthesis 6:22 synthesis of Palavolide 6:22,23 Palladium (II) acetate 10:344 Palladium (0) for macrocyclization 3:82,83 Palladium (0) catalyzed cyclization of allylic acetates 8:228 Palladium (O)-catalyzed condensation 12:300 Palladium acetate coupling with 1:19 Palladium black as catalyst 14:763 Palladium catalysed acetalization 1:584 Palladium catalysed coupling 3:258 with [PdCl2(PPh3)-Cu I) 1:532 Palladium catalyzed rearrangement 14:625 Palladium dehydrogenation 1:129,130 Palladium mediated coupling regiospecificity of 10:341 stereochemistry of 10:342 stereospecificity of 10:341 Palladium mediated oxidation 12:241 Palladium-induced indolizidine ring formation 12:299 Palladium-promoted reaction of vinylie bromide 16:3 67 (+)-Pallescensin A from marine sponge 10:409 synthesis of 10:409 (+)-Pallescensin A 18:17 Pallescensin-1 from (/?)-(-)-cyclocitral 6:31 palleseensin F from 6:31,32 palleseensin G from 6:31,32 synthesis of 6:31 Pallescensin-A from Disidea pallescens 6:20,23

from trimethyl decalone 6:20 Gariboldi synthesis of 6:20 synthesis of 6:20,23 Pallescensin-C 6:69 Pallescensin-D 6:69 Pallescensin-E from Disidea pallescens 6:31 from palleseensin-1 6:31,32 synthesis of 6:31,32 Pallescensin-G from Disidea pallescens 6:31 from palleseensin-1 6:31,32 synthesis of 6:31,32 Palliferidin 5:722-724 Palliferinin 5:723 Pallinin 5:722-724 Palmatine 1:214 Palmitate esters 9:469 ofspinasterol 9:470 Palmitic acid 9:315 Pahnitoleic acid 9:341 A^-Palmitoyl-S-[2,3-bis (palmitoyloxy) propyl]-L-CysSer 18:926 Palustrin from Equisetum palnstre 16:453 Palustrol 20:17 Palythoa toxica 5:390 Palythoa tuberculosa 5:390,391,393 Palytoxin 3:209;5:390-394,403 Panal from Eupatorium trapezoideum 15:247 Panarine 13:387 Panax ginseng 10:153 Panaxacol 10:153 Pancratium maritimum A'iO-dimethyhiorbelladine from 20:359 Pancreatic acinar cells 18:857 Pancreatic acini from rat and mouse 12:394 Pandalus sp. 19:672 Pandaros acanthifolium 5:384 Pandicine 5:129;13:393 Pandine 5:127 Pandine-type alkaloids 5:127 pandine 5:105 Pandoline dehydrosecodme 14:832 from indoloazepine 14:831,832 from dehydrosecodine 14:832 from indoloazepine 14:831 synthesis of 14:831-833 20-e/7/-Pandoline 5:124 synthesis of 14:831-833 (+)-Pandoline 9:190 Panicein-A 15:295 Panicein-Bi 15:296 Panicem-B2 15:295 Panicein-Bj 15:296 Panicein-Ci 15:296 Paniculatine 18:4 Paniculides 7:118 (/?)-Panolactone 13:326

1135

Pantalenolactone ^-methyl ester synthesis of 1:698,700 /^-Pantolactone 16:475 /?-(-)-Pantolactone synthesis of 3:252,253 (/?)-Pantolactone 8:140,141,145-147,150 Pantolactone homologue [(35,45)-dihydro-4-ethyl3-hydroxy-4- methy 1-2(3 H)-fliranone] absolute stereochemistry of from Marshallia tenuifolia 10:442,443 synthesis of 10:442,443 Papakusterol (glaucasterol") 9:36,37,41 from Pseudothesis species 9:37 from Sarcophyton glaucum 9:37 Papavarine 2,7-benzoxazacycloudeeine derivative from 6:495 Papaver somniferum 17:633;18:45,54;20:292 Papaveraldine synthesis of 8:265,266 (+)-Papilamine 2:181,182 *^C-NMR shifts 2:182 structure of 2:182,182 Papilamine 2:205 (+)-Papilicine '^C-NMR shifts 2:205 structure of 2:182,183 (+)-Papilinine 2:205 structure of 2:178 Papilioxuthus 18:682 Paprika oleoresin 20:721 Papulacandin from gluconolactone 10:387 Papyraceabromine-A 18:692 Paracaudina ransonetii caudinoside A from 7:278 Paracentrone 6:136;10:153 Paracentrotus lividus 15:104 Paracoccidioides brasiliensis 5:307,323,326 Paracoccidioides sp. 5:307,325,328 (5)-(-)-Paraconic acid 1:687 Paracresol oxygenation of 16:580 (+)-Paradisiol from (-)-7-e/7/-cyperone 14:453 from grape fiaiit oil 14:449 synthesis of 14:456-465 total synthesis of 14:453 5-g/7/-Paradisiol (+)-dihydrocarvone 14:454 synthesis of 14:456-465 total synthesis of 14:454 Paraensidimmerins A and C X-ray structure of 2:122 Paramuricea camaleon 6:72 Parancistrocerusfulvipes 5:223-225 Parancistrocerus perennis 5:224 Parancistrocerus rufovestis 5:224 Parancistrocerus sp. A 5:224 Parancistrocerus sp. B 5:224 Pararespula vulgaris 19:130 Parasorbic acid 13:539

Parastichopus californicus holotoxins A, Ai, B and Bi from 15:87 Parathymosin a 8:433,434 Parathyona sp. parathyonoside R from 7:277 parathyonoside T from 7:277 Parathyonoside R from Parathyona sp. 7:277 Parathyonoside! 7:277 Paravespula vulgaris 2-methyl-l,6-Dioxaspiro [4.5] decane from 14:526 Parikh oxidation 12:305 Parikh-Doering oxidation 14:60 ParishinA-C 7:235,237 Parmelia sulcata 5:313 Parsons approach for hexahydrobenzoftiran component 12:24 ofavermectins 12:24 Partial synthesis of acetylenic carotenoids 6:157-160 ofanguidine 6:225,226 of carotenoid sulfates 6:150 ofgibberellins 6:186-194 Parus gambeli hemoglobin components of 5:836 Parvifoline conversion to isoparvifolinone 5:800,801 Parvifoline A 15:118 ''C-nmrof 15:132 from Rabdosia parvifolia 15:173 'H-nmrof 15:125 Parvifoline B 15:116 ^^C-nmrof 15:130 from Rabdosia parvifolia 15:173 ^H-nmrof 15:123 Parvifolinoic acid from Rabdosia parvifolia 15:174 Parvifoliside 15:140 '^C-nmrof 15:157 from Rabdosia parvifolia 15:173 *H-nmrof 15:148 Paspalum scrobiculatum 15:352-356 Passeer domesticus hemoglobin components of 5:836 Passerini reaction 12:131,138 Pasteurella multocida 4:196 riheptosesin 4:196 Patchino (P-patchouline oxide) 11:56,57 Patchomik mehtod 12:120 a-Patchoulene 4:677 P-Patchoulene 4:677 (-)-(3-Patchoulene oxide 12:201,202 Patchouli alcohol 4:677;16:151 (-)-Patchouli alcohol synthesis of 16:245 Patchoulin alcohol 11:55 p-Patchouline oxide (patchino) 11:56,57 (-)-Patchoulol 8:423 ()-Patchoulol synthesis of 8:423-425

1136

Patellamide A revised structure 4:93-99 synthesis of 4:97-99 Patellamide B revised structure 4:93-99 synthesis of 4:97-99 Patellamide C 5:419,420 cytotoxic activity of 5:419 revised structure 4:93-99 synthesis of 4:97-99 Patellamides A-D 5:419,420;10:242,243 Patellamides synthesis of 4:93-99 Patellamides B 5:419,420 cytotoxic activity of 5:419 Patellazoles A-C 10:243 Patemo-Buchi photocycloaddition 10:440 Pathenolide 7:117,120 Pathogenic fungi Alternaria kikuchiana 5:598 Botrytis cinerea 5:598 Piricularia oryzae 5:598 Pathogenic toxins 6:538 Patinopectin yessoensis 17:20 Patinopecten yessoensis 19:5 79 Patina miniata 15:55 miniatoside A and B from 15:61 patirioside A from 15:48 Patiriapectinifera 7:297,302;15:61 Patirioside A 15:48 Patrinoside 7:441 Pattende's synthesis ofverticillene 12:180,181 Patuletin 3-glucoside 7:227 Paulsen method 6:357 Pauly's reagent 17:396 Pauson-Khand cyclization 3:83,84 Pavine alkaloids 6:471 Payne rearrangement 4:173,179,186,344;11:10,36,38; 12:209 PBG (Porphobilinogen) 9:591-593,596,607 oligomerization of 9:595 PBG deaminase 9:592-597,604 PBP-2 4:433 PCC Oxidation 6:545 Pd-(0)-catalyzed carbonylation 10:29 Pd-catalyzed cross couplmg reactions 10:161 -163 PDC oxidation 16:23 PDE-1 1:163,164,178-180 synthesis of 3:306-319 PDE-IDimer 3:331 synthesis of 3:331 PDE-II 1:163,164,178,180 Pectachol 7:224 PectenolA,B 6:147 Pectenotoxin-1 and-2 17:19,20 2-Pectenotoxin cytoxic activity of 19:580 Pectenotoxin-3 17:20 Pectenotoxin-4 19:579 Pectinioside E 15:47,48 Pectinioside G 15:57 Pectinophora gossypiella 20:25,20:28

Pectinosides A-F 7:290,293,304 Pectolinarigenm 7:227 fiom Salvia limbata 20:712 Pedaliaceae 1A01,41'7A23 Pedamide enantioselective synthesis 1:623 (+)-Pedamine synthesis of 14:499 Pederin 5:336;14:499 (-)-Peduncularine absolute configuration of 11:284 from (5)-malic acid 11:284,285 synthesis of 11:284,285 Peduncularine 9:178 (-)-Peduncularine {Aristotelia alkaloid) synthesis of 13:491,492 Peduncularistine (18,19-dehydroaristotelin-15 -one) 9:171 (+)-aristoserratine from 11:296 Peganum harmala 2:369 Perhydrophenanthrene group 6:54-58 PEL (Pseudomonasfluorescens lipase) 13:54,55 Pelagococcus subviridis 6:135 Pelandjauic acid 9:316 Pelargonidin-3-rutinoside-5-glucoside 5:658 Pelargonidin-4,5-diglucosides 5:658 Pelargonium fragrans 7:112 Pelargonium graveloens 7:100,101 Pelargonium sp. 7:95,96,100,112 Pelenolide 7:230 Pellegata oxidation 19:226 Pellia endiviifolia 2:278,279 Pelliasp. 2:90 Pellinasp. 5:419 Pellitorine 10:152 from A nacyckus pyrethrum 10:162 Pehnatozoa 7:265,266 a-Peltatin 5:481,483 P-Peltatin 5:481,483,493 ()-p-Peltatin A methyl ether 18:586,589,592,596 Peltigera aphtosa 5:313 Penaeus vannamei 19:628 Penam carboxylic acid synthesis of 12:127-129 Penam derivatives 12:127 Penam product by isopenicillin-A^-synthase 11:212,213 formation of 11:213 from a-aminobutyrate 11:212,213 stereochemical course of 11:213 Penaressp. 18:460 Penaresidines from Penares sp. 18:460 DS-Penaustrosides A and B from Pentacta australis 15:91 Pendolmycin 15:456,462 tumour promoter activity of 15:462 Penduletin 7:227 Penems 4:448,476 absolute stereochemistry of 4:435 by azetidinone synthesis 4:437 synthesis 8:262

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Phenethylisoquinoline derivative 6:487 Penicillin 6:385;9:413 Penicillin derivatives synthesis of 12:129-131 Penicillinates stereoselective reduction 4:437 Penicillins 4:432,433,435,442;17:614-617 biosynthesis of 11:211 -213 cephalosporin C from 11:211-213 chemical shifts of 4:442 from5-(I-a-aminoadipoly)-I-cycteinyl-)-valine (LLD-ACV) 11:211-213 semi synthesis of 17:614-617 Penicillium alladadense 5:300 Penicillium atrovenetum 19:117 Penicillium brefeldianum 11:192 Penicillium brevicompactum 5:299;13:553;17:475; 19:168 Penicillium calaviforme 5:300 Penicillium caseiculum 13:305 Penicillium charlesii 5:296,299 Penicillium chrysogenum 5:299,300,15:351,17:616 Penicillium citrinum 5:300,13:553,19:168 Penicillium digitatum 12:103 Penicillium erythromellis 5:300 Penicillium expansum 5:299,7:13,14 Penicillium frequentans 4:588 Penicillium grisofulvium 9:341 Penicillium islandicum 5:299,300 Penicillium javanicum 5:299 Penicillium luteum 5:299 Penicillium madriti 11:198 Penicillium notatum 7:71; 17:615 glucose oxidase from 7:71 Penicillium ochrochloron 5:300 Penicillium palitans 4:588-590 Penicillium patulum 5:300,11:198 Penicillium raistrickii 5:300 Penicillium roqueforti 13:305 Penicillium rugulosum 10:646 Penicillium scleriotorum 5:299 Penicillium sp. 5:299,301,325,326;17:475 Penicillium turbatum antibiotic A 26771B by 11:194 Penicillium varians 5:300 Penicillium zacinthae 5:300 Penicillus dumetosus 18:688 Pennogenin 2:445 Pentafiibalol 20:273 Penstemide 7:441 activity against P-388 lymphocytic leukemia 16:295 from Penstemon deutus Dongl. ex. Lindl. 16:295 synthesis of 16:295 Penstemonoside 7:486 ()-Penta-A^, 0-acetyl-validamine 13:196 Penta-A^, 0-acety 1 valiolamine 13:199 Penta-A', 0-acety Ivalienamine 13:198 Penta-A^-0-acetyl-^/-validamine stereoselective synthesis of 10:521 synthesis of 10:518-521 Penta-0-acetyl-Z)-gulopyranose synthesis of 14:659-664

Penta-O-acetyl-D-iodopyranose synthesis of 14:659-664 Penta-O-acetylgalactoftiranose 14:232 Pentaacetyl pyranoses 14:663 1,2,4,7,8-Pentaacetyl-D-gluco-octopyranose derivatives 11:468 Pentacenediquinone 11:122 5,7,12,14-Pentacenediquinone 11:124 Pentacenequinone 11:121-123 from naphthacenequmone 11:123 pentacenediquinone 11:122 synthesis of 11:121,122 Pentaceraster alveolatus 7:290,304-306;15:46,61 6-e/7/-nodosides from 7:34 nodososide from 7:298 Pentacta australis DS-penaustrosides A and B from 15:91 Pentacyclic triterpenoid esters 9:460 3-[(Z)-Pentadec-8-enyl] phenol 9:323 Pentadecadeoxy nucleotide 13:261 1 -Z-8-Pentadecadiene CI (NO) mass spectrum 2:8 6-(Pentadecenyl) salcyclic acid ^^C-NMR spectrum of 5:825 form alkyllithium 5:826 ^H-NMR spectrum of 5:825 synthesis with metallic salts 5:826 6-(10'-Z-Pentadecenyl) salicyclic acid '^C-NMR spectrum of 5:825 ^H-NMR spectrum of 5:825 3-Pentadecyl phenol 2:280281 6-Pentadecyl salicylic acid 2:280281 3-Pentadecylphenol 9:323,343 Pentadecylresorcinol 9:314 (2,4)-2,4-Pentadienamide 10:155 Pentadienols asymmetric hydroxylation of 9:572 Pentadin 15:36 Pentaene from octatrienal 6:292,293 Pentaglycoside 7:276,286,287,289,290 Pentahydroxy-agarofiiran 18:744 2a,3 P, 12p,205,25-Pentahydroxydammar-23-ene 18:650 3p,16(3,2ip,23,28-Pentahydroxyolean-12-ene 18:650 A'^-3 P,6P,8,15a, 16p-Pentahydroxysteroids 15:64 Pentalenene synthesis of 13:6-8 e/7/-Pentalenene 3:6,61 Pentalenene synthesis of 3:8,9,12,19,25,44 Pentalenic acid 3:6,61 e/7/-Pentalenic acid 3:6,61 Pentalenolactone 13:6,26 biosynthesis of 13:30 Pentalenolactone E methyl ester 13:29,30 Pentalenolactone antibiotic 18:7-10 Pentalenolactone P methyl ester 13:30-32 3,5,6,7,8- Pentamethoxyflavone 5:652 3,5,6,7,8-Pentamethoxyflavone 7:413

1138

Pentamethyl ether 17:459 Pentane as marker 9:564 in lipid autoxidation 9:564 (2/?,4/?)-2,4-Pentanediol acetalfrom 14:507,508 (2/?,4/?)-2,4-Pentanediol acetals diastereoselective allylation 1:605 (2/?,4i?)-2,4-Pentanediol ketals diastereoselective reductive cleavage 1:591,594 Pentaporafasciata 18:715 Pentasaccharides by glycosylation 10:475,476 synthesis of 10:475,476 Pentaspadonmotleyic 9:316 Pentaspadon officinalis 9:316 Pentenal from (5)-(-)-citronellol 11:343,344 methyl-substituted 11:343,344 Pentenolides 10:11,12 Pentenylation 12:466 Pentodialdofiiranose Wittig olefmation of 4:190 6-Pentyl-Y-pyrone 13:297 PEP (phosphoenolpyruvate) 11:182 Pepstatin synthesis of 12:476 Pepstatin (Z,-valyl-I-valyl-(35,45)-statinyl-Z.-alanyl(35,45-statine) 12:432,433 Peptic enzyme inhibitors 12:411 a,Y-^ra/w-Peptidation 6:410-412 Peptide from bacteria 9:537-557 semi-synthesis of 17:646 siderophores 9:537-557 tandem mass spectrometry of 9:537-557 Peptide antagonists 18:863-865 Peptide cross linkages 2:19-42 Peptide derivatives 12:155 Peptidoglycan 6:385-420 biosynthesis of 6:404 relation of sugar-peptide structures to 6:385-420 Peptidoglycan-related compounds 6:404-420 structural confirmation of 6:406 Peptidomimetic chemistry 12:477 Peptidophospogalactomannan 5:301 Peptidorhamnomannans 5:324 Peptidyl transferase 7:387 Peptolide 10:280 Peracid oxidation ofguaiazulene 14:320-324 Peraksine (vomifoline) 13:389 Pereziae sp. 5:805 Perezinone allylic oxidation 5:772 derivatives of 5:771,772 structure of 5:771,772 a-Perezol 5:765,767,781,782 synthesis of 5:799 P-Perezol 5:781,782 Y-Perezol 5:781,782,786

Perezone 5:763-813 chemistry of 5:763-813 Diels-Alder reactions of 5:768 intramolecular cycloaddition 5:782 structural modifications of 5:798 synthesis of 5:769,770 transformation to pipitzol 5:792-800 (-)-Perezone 8:39 Perforanes 10:182 Peridinin 10:153 Perforene from chamigrene precursor 6:30 from Laurencia perforata 6:30 structure confirmation of 6:30,31 Perforenone 6:29,30,32,33 epiguadalupol from 6:30 from cyclophptenone enolate 6:29,30 from Laurencia perforata 6:29 guadalupol from 6:30 Majetich synthesis of 6:32,33 synthesis of 6:29,30,32,33 Perhydroazulene 1:547 Perhydroazulene synthesis l:541-556;3:44 Perhydrogenation of (3^,3/?')-zeaxanthin 6:149 (+)-Perhydrohistrionicotoxin 19:14,19:17 (-)-Perhydrohistrionicotoxin 16:443 synthesis of 16:480 Perhydroindane esters preparation of 6:179,180 Perhydroisoindol-1-one 15:355 Perhydronaphthalene derivative 6:179,180 Perhydrophenanthrene skeleton synthesis of 1:661 Periandra dulcis 15:26 periandrins from 7:142 Periandra mediterranea 15:26 Periandradulcins 15:191 Periandric acids I-IV 7:142 PeriandrinI 15:22 Periandrins 7:142 Periandrins I-IV 15:26 [2a+2a+27t]-Pericyclic reaction 16:621 [27t+2a+27i]-Pericyclic reaction 16:628 Pericyclic reactions ofarynes 3:418 Pericyclivine 5:124;9:171 Peridinin 6:133,134,136,137,141,142,145,20:581,583 stereoisomer of 6:139 synthesis of 6:144 Peridinin derivatives 6:135,136 Peridininol 6:136,142,143 (S)-Perilla alcohol 324 oxymercuration of 11:324 Perilla alcohol 19:214 Perillafrutescens 15:5 (/?)-(+)-Perillaldehyde 19:205;16:230 (+)-Perillaldehyde 19:206 5-(-)-Perillaldehyde 16:230 Perillaldehyde 20:6

1139

(-)-Perillaldehyde 14:361;16:245 perillic acid from 6:545 (-)-sirenin from 6:545,546 Perillartine 15:14 Perillene chiral acetals from 14:506 Perillic acid from (-)-perillaldehyde 6:545 Perindrins I-IV from Periandra dulcis 7 A 42 Per/interaction 1:386 Periodate 2:346 oxidation of glucoamylase 2:346 perrottetianal 2:278,280 Periodate-nitromethane procedure for purine synthesis 4:240 trans-anti-?Qnp\ana.r fashion 11:3 01,3 02 Periplaneta americana 6:538;8:182,221 ;9:488-490 Periplaneta bunnea 8:182 Periplanetajaponica 8:182 ()-Periplanone synthesis of 8:182 Periplanone-A 6:538,539 (-)-Periplanone-B synthesis of 16:218 (-)-Periplanone-B from ()-dihydrolimonene 6:541,542 synthesis of 6:538-542 Periplanone-B synthesis of 8:179-182,226,227 Still's synthesis of 8:247-249 Periscogenin 7:228 Periselectivity 1:569,570 Peritassa 18:754 PerrottetinE 2:285 Peritassin A and B 18:755 Perivine 5:112,114 Periwinkle 4:29 Perkin condensation intramolecular 12:381 Permethyl cyclopentanone synthesis of 8:4,5 Permethyl cyclohexanone synthesis of 8:4,5 Permethyl-p-cyclodextrin 13:328,329 Permethylated (we5o)-pentitols 4:182 Permethylated L-arabinitol 4:18,182 Permethylation 5:199 Peronosporales 9:203 Peroxidase 14:820,821 5a,8a-Peroxycholesterol cytotoxic activity of 5:406 PerrotetinE 20:280 Perrottetins E-G 2:283,284,285 Persea major 9:402 Persoona elliptica 9:320,355 Persoonal 9:320 Persoonal dimethylether synthesis of 9:355 Perulactone 20:194,223,224,241 Perun conformation 13:156,157 Pervicosides A, B and C 15:92

Pestalotan 5:308 Pestalotan polyol 5:319-321 antitumor activity of 5:391,320 Pestalotia sp. 5:307,308 antitumor activity of 5:319 Pestalotin enantioselective synthesis of 1:637,638 Pesticidal activity 18:196 of staurosperine 12:397 Pesticides 9:383,391 Petasinecine 1:237 enantioselective synthesis of 1:637,638 Petchia ceylanica 5:135,140,147,149,173 Petchicine 9:190,192 Peterson olefmation 3:202;8:247,248;11:10,11;19:374 in P-dictyopterol synthesis 6:189,19 (-)-Petiodial from Udoteapetiolata 16:310 Petrosiaficiformis 9:42 26-dehydro-25-epiaplysterol from 9:40 dihydrocalysterol from 9:37 (23R,24R)-23,24-methylenecholesterol from 9:37 Petrosia hebes dihydrocalysterol from 9:37 hobesterol from 9:37 petrosterol from 9:37 Petrosterol 9:36,37,40-43 biosynthesis of 9:41-43 from Cribrocalina vasulum 9:37 from Helicondria species 9:37 from Petrosiaficiformis 9:37 f[om Petrosia hebes 9:31 synthesis 9:37 Peturin chloride 20:738 Peziza vesiculosa 5:271 Pezizales 9:203 Pfqffia baniculata pfaffic acid from 7:135 pfaffosides A-F from 7:135 Pfaffic acid from Pfiaffiapaniculata 7:135 X-ray analysis of 7:135 Pfaffosides A-F from Pfaffiapaniculata 7:135 PGM 6:385 antimetastatic properties of 6:386 Phaeocystis spQCiQs 6:135 Phaeolus vulgaris L. 19:247 Phaeophyceae 6:134 Phqffia rhodozyma 7:361 (3i?,3'^)-astoxanthinfrom 7:321 Phalacrocorax niger hemoglobin components of 5:837 Phallusia manillata 10:249 Phanerochaete chrysosporium 13:309 Pharaoh ants 6:445 Pharbitis purpurea 19:247 Pharmacognosy 13:629-669 Pharmacological activity ofquinocarins 10:115-117 Pharmacophore incarbapenem 4:434 Pharmacophore models 12:264

1140

Pharoah ant trail pheromone synthesis of 1:276,277 Phase distribution techniques 7:488 Phase transfer catalysed oxidation 7:161,163 Phase-transfer conditions 6:326,327,330,332;19:277, 279 Phase-transfer reaction 19:231 catalyzed by 19:100 Phaseicacid 6:559-562 Phaseolinone 6:555,556 synthesis of 6:556 X-ray crystallography of 6:555 Phaseollidin 20:496,497 PhaseoUin synthesis of 4:391,392 Phaseolus vulgaris 19:268 23-0-P-Z)-glucopyranosyl-2-epi-25-methyldolichosteron from 18:495,522 cell suspension of 2:369 isozymes from 9:563 Phasianus colchius hemoglobin components of 5:836 Pheidole pallida (minors) 5:254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Pheidolepallidula 5:235,236 (-)-a-Phellandren-8-ol 11:307,308 P-Phellandrene 7:100,101 Phellibiline 3:256 Phelline comosa 3:484 Phellinespp. 3:456 Phellinus genus 19:351 Phellinus tremulae 19:171 Phenanthrene annulated 8-hydroxyindolizidine 12:300 Phenanthrenes 20:280 Phenanthridines from anils 4:542 Phenanthroindolizidine alkaloids from Tylophora hirsuta 12:300 (i?)-a-Phenethylamine 10:31 (5)-a-Phenethylamine 10:31 Phenidone 9:579 Phenol oxidase systems in plants 16:584 Phenol/formaldehyde resins 9:330 Phenolic a-diazoketone bromochammigrene from 6:60,61 spiroannulation of 6:60,61 Phenolic cinnamic acid derivatives 9:219,220 Phenolic components of Morus alba 17:455 Phenolic coupling reactions 16:504 Phenolic lipids 17:645 biosynthesis of 9:341,342 non-isoprenoid 9:313-362 synthesis of 9:343-369 utilisation of 9:369-372 Phenolic triterpenes biogenesis of 7:150-152 from Kokoona zeylanica 7:147-149 Phenolics in adventitious root cultures m hairy root cultures 17:444 '^0-NMR 17:586

Phenols 17:586 anodic oxidation of 8:159-172 chemoselective protection of 19:304 chromanesfrom 4:394 oxidation with TI (03)3 (TTN) 8:166,169 photosenstized oxygenation of 16:582 Phenoxychromones from Artemisia capillar is 7:220 Phenoxyl groups 16:611 quenchers of 16:611 Phensulfmylation 19:470 Phenyl 4,6-di-0-benzyl-2,3-dideoxy-Z)-grv//iro-hex-2enopyranoside a-C-glycopyranoside from 10:354 P-C-glycopyranoside from 10:354 Phenyl 4-deoxy-p-D-xv/o-hexopyranoside 14:148 Phenylalanine 7:111 Phenyl P-D-galactopyranoside 8:315 Phenyl cyclohexyl selenoxide 9:120,121 Phenyl cyclohexyl sulphones "S(NMR) of 9:118,119 Phenyl cyclohexyl telluride '^^TeNMR of 9:123,124 P-Phenyl glucoside 16:589 coupling of 16:595 Phenyl glucosides 17:437 a-Phenyl selenide in P-dictyopterol precursor synthesis 6:16 v/c-Phenyl thiobenzoate metal reduction of 6:541-542 Phenyl thiogalactoside 7:48 4-Phenyl-l,2,4-triazoline 3,5-dione (PTAD) 11:388393 l-Phenyl-2-nitroethane 19:118 1 -Phenyl-2-buten-1 -one reaction with silyl enol ether 3:129 2-Phenyl-2-methylseleno-6-bromo heptane 8:6 3-Phenyl-3,4-dihydroisocoumarins 15:387 Phenyl-p-D-glucopyranoside derivatives kinetic parameters of 7:55,56 a-Phenyl-y-lactone derivative alkylationof 10:410,411 stereoselective 10:410,411 /ra5-5-Phenyl-seleno-4-methoxy derivatives as 2-amino alcohol synthon 12:418,419 Phenylacetaldehyde 6:312 synthesis of 6:312 Phenylacetic acid derivatives synthesis of 6:320-322 Phenylalanine hyoscyamine from 11:204,206 scopolamine from 11:204,206 synthesis of 11:417,418 I-[U-C^^] Phenylalanine 15:347 Z-Phenylalanine 5:467,470,474;19:323 Phenylalanine ammonia-lyase 5:467,469 Phenylalanine lyase 7:111 (25',35)-Phenylalanine-3-dfrom (5)-pinanediol phenyl boronate 11:417,418 (5)-a-Phenylamine 19:18 as a chiral auxiliary 19:18

1141

Phenylation of aldehyde 19:497 chemoselective 19:497 24-/?-Phenylbrassmolide 19:477 23-Phenylbrassinosteroid 19:277-278 y-Phenylbutyrophenone 14:648 3 -Pheny Icyclohexanone sulfenylation of 12:25 10-Phenylcytochalasins 15:353 4a-Phenyldecahydroisquinolme 12:458 3-Phenyldihydroisocoumarms 15:387 Phenyldizene 9:581 0-Phenylene phosphorochloridate 8:74 0-Phenylenedimethanol 11:130,131 ketalof 11:130,131 2-Phenylethanol 7:104,105,111,112,125 (/?)-Phenylethylisocyanate 13:324,325 (5)-l-Phenylethylamine 13:485 (5)-(-)-2-Phenylethylamine 8:300 X-ray crystallography of 8:300 (5)-2-Phenylethylamine 8:301 (5)-l-Phenylethylamines 14:555,556 Phenylglycinol 19:311 (/?)-Phenylglycinol 19:38 (R)-1 -Phenylethylamines piperidine derivative from 14:555,556 pyrrolidine derivative from 14:555 pyrrolidone derivative from 14:560,561 N-(R)-1 -Phenylethylcarbamates 18:427 (5)-1 -Phenylethylglutarimide 13:477 9-Phenylfluoren-2-yl amine 12:338 (-)-Phenylglycinol condensation of 14:744 with glutaric dialdehyde 14:744 6-Phenylhydrazine 12:377,378 into A^-methylarcyriaflavin A 12:337,338 Phenylhydrazine autoxidation of 9:581 1,2-Z?/5-Phenylhydrazone Fischer indolization of 12:377 Phenyllactate synthesis of 12:223,225 8-Phenylmenthol 13:76 (-)-8-Phenylmenthyl 19:14 8-Phenylmenthyl ester 13:74,76 (-)-Phenylmenthyl ester of methylmalonic acid asymmetric alkylation of 10:411 8-Phenylmenthylglyoxalates 18:190 Phenylobacterium immobile K2 triheptoses in 4:196 9-Phenylphenalenones 17:372 Phenylpolysiloxane 9:457 Phenylpropanoid wood 20:613 Phenylpropanoids 5:419,420,426,427;15:29 biological activity of 5:505 Phenylpropargylic ethers chromenesfrom 4:368,369 Phenylselenyl alkanes 9:119 '''Se-NMR of 9:119 Phenylselenyl bromide in quinolizidine formation 14:737

Phenylselenyl cyclohexane ^^Se-NMR of 9:119-120 Phenylselenylation 1:242,248 ()-bis(Phenylsulfonyl)ethylene 19:6 l-(Phenylsulfonyl)mdole 6:509,510 regiospecific lithiation of Phenylthio ester zirconium enolate of 13:506 2-Phenylthio glucals by direct lithiation 10:346 Phenylthiohydantoin (PTH) derivative 2:33 phorbol 2:261 3-(Phenylthiomethyl) camphor 4:763,764 4,5-trans and 4,5-c/s-5-Phenylthiooxazolidin-2-ones 12:481 5-Phenylthiooxazolidin-2-ones 12:481 A'-PhenyItrifluoromethanesulphonimide 20:5 81 Pheromone of California red scale 16:138 Pheromonal function 6:458 Pheromonal specificity 7:6 Pheromones 1:276,389,682-684,695;7:193;19:122 fire ant 1:682,683 from Pharoah ants 1:389 from pharaoh ants 4:606 macrocyclic 8:219 of cigaratte beetle 1:695 of Vespa orientalis 1:684 oriental hornet 1:684 synthesis 1:681-684 synthesis of 4:566,569-571 synthesis of 9:351 Pheromone activity 7:6 Phidolopora pacifica 17:92 Philanthus triangulum 5:223,224,231,251,253 Phillygenin 5:489-491,522 Phillygenin 4-0-glucoside 5:476,490 Philodendron scandens 9:317,321 Phlomis betonicoides 1:666;15:20 Phlomisoside I 15:20 Phlomisoside II 15:20 Phloroacetophenone 9:341 Phloroglucinol 4:391;9:328,329,341;13:355-359 Phenylselenyl chloride cyclofunctionalization with 6:426-428 Phocomelia 7:10,21 Phoenix dactylifera 18:507 Phoenix paludosa 7:189 Pholacantha synonyma 10:320 Phomabetae 4:601 Phoma destructiva 6:555 Phoma exigna var. indoxi dabilis 6:555 Phomenone 6:554-556 synthesis of 6:556 ()-Phomenone synthesis of 6:555 Phomolactone 15:350,351 Phomopsis 9:203 Phomopsis citri 15:341 Phomopsis convolvulus 15:341-345 Phomopsis helianthi 15:341,345,346 Phomopsis juniperovora 15:346

1142

Phomopsis leptostromiformis 15:341,347 Phomopsis longicolla 15:341 Phomopsis oblonga 15:383,388-392 5-methylmellein from 15:385 Phomopsis paspalli 15:352 Phomopsis phaseoli 15:341 Phomopsis viticola 15:341 Phomosin 15:346 Photoxygenation 6:123 Phoracantha synonyma 6:542;8:222 macrocycles from 8:221 ()-Phoracantholide isolation of 19:154 Phoracantholide I 8:222 (-)-Phoracantholide I synthesis of 10:320-323 Phoracantholide J 8:222 Phoracantholide K 8:222 Phoracantholide M 8:222 Phoracantholide O from Phoracantha synonyma 8:222 Phoracantholides 8:222,242 Phoracantholides I,J,K,M,0 8:222 Phorbassp. 19:601 Phorbol 1:546,547,20:19 synthesis of 12:245-272 total synthesis of 12:265-272 Phorbol ester (tumor promotor) from croton oil 12:392 Phorbol ester-induced activation by staurosporine 12:389 inhibition of 12:389 Phorbol esters 10:4 Phorbol mimic intramolecular 12:264 from fulvene 12:264 stereoselective 12:264 synthesis of 12:264 Phorbol myristate acetate 12:245 Phorboxazole A antifiingal activity of 19:600 constituent of 19:600 Phosgene isocyanides from 12:113 Phosphaheterocyclics 9:509-528 Bis-Phosphaneoxide 9:527 Phosphatase 14:304 Phosphate derivatives antileukemic activity of 4:231 antivirus activity of 4:231 of2,4-pyrimidinedione 4:231 Phosphate protecting groups 4:285 Phosphatidyl-/n>'o-inositol-4,5-bisphosphate 18:392 Phosphatidylcholine 9:565 Phosphatidylcholine vesicles 18:848,856 Phosphatidy linositol 15:441 Phosphatidylinositol-3,4,5-trisphosphate 18:410,427 Phosphatidylinositol 3-kinase 18:394 Phosphatidylinositol turnover 15:452 Phosphatidylinositols synthesis of 18:445-450 5-Phosphino-aldopyranoses 6:366-375

Phosphino-aldoses 6:360-365 5-Phosphino-aldoses 6:365,366 6-Phosphino-aldoses 6:375,376 Phosphinothricin 6:352 4-Phosphinyl aldoses 6:360-365 Phosphinyl-I-fricosamine analogs 6:369 7-Phosphinyl-aldoctanose 6:377 4-Phosphinyl-aldofuranoses 6:360-365 5-Phosphiny 1-aldopyranoses 6:366-375 1-Phosphinyl-aldoses 6:353-356 2-Phosphinyl-aldoses 6:357,358 3-Phosphinyl-aldoses 6:359,360 5-Phosphiny 1-aldoses 6:365,366 6-Phosphinyl-aldoses 6:375,376 1-Phosphinyl-ketoses 6:353-356 Phosphite method for oligonucleotide synthesis 4:271-274,4:280 in oligoribonucleotide synthesis 4:303 mechanism 4:272 oxidation reaction 4:280 Phosphitylating agents 4:272,273;13:276 Phosphitylation 8:388,389 6-Phosphinyl-aldoseptanose from 6-deoxy-6 [(ethoxy), alkyphosphinyl]-/)glucopyranose 6:377 2',5' -Phosphodiester antiviral activity of 14:283 cyclic 14:283 synthesis of 14:283 Phosphodiester method for oligonucleotide synthesis 4:267 Phosphodiesterase 5:512;12:399;13:288 Phosphodiesterase inhibitors 1:178-180 Phosphoenol pyruvate (PEP) 11:182 Phosphoenol pyruvate synthetase 11:182,208,209 (Z)-[3-^H] Phosphoenolpyruvate 11:183,184 Phosphofructokinase 7:387 Phosphogalactomannan 5:299 Phosphoglyceric acid 11:208 Phospholipase A2 12:397 Phospholipase C 15:448 Phospholipid bilayer 18:848 Phospholipids 12:233;17:644 Phosphomannans 5:280 O-Phosphomannans 5:284,285 Phosphomonoester formation phospate protecting groups for 4:285 3 -Phosphomonoesterase staurosporine effect on 12:399 Phosphonate condensation 19:83 Phosphoniosilylation ofenones 3:79,80 Phosphonium mercaptides 4:554 Phosphonium ylides 4:553-578 acylation with thioesters 4:554 acylation with trimethylsily esters 4:564 oxidation 4:558,553 Phosphopolyprenols biosynthesis of 8:100-103 glycosyl esters of 8:63 Phosphoramidate linkage stability of 4:293

1143

Phosphoramidates 13:273,274 Phosphoramidite 8:373 synthesis of 8:388-390 Phosphoramidite in coupling reactions 4:306 Phosphoramidite cycle 13:268 Phosphoramidite method 13:270 methylphosphonates by 13:270 Phosphoramidites 13:265,267,268,269,270;18:398 Phosphoribosyl pyrophosphate aminotransferase 7:387 Phosphoric acid diesters of 8:63 Phosphorodichloridate 8:83 Phosphorodithioates 13:268,269,270,271,274 from thiophosphoramidites 13:272,273 Phosphoroimidazolidate 8:90 Phosphorothioates 13:263,268,269 diastereoselective synthesis of 13:276 Phosphorus analogs ofD-arabinitol 6:355 ofZ)-arabinofuranose 6:352,355 ofD-fiirctofuranose 6:352,355,357,358 ofZ)-fructose 6:355 ofD-glucopyranose 6:352,355,370,373,376 ofD-gycitol 6:355 ofZ)-mannofuranose 6:355 ofD-ribofuranoses 6:352,355,359,363,364 Phosphorus oxychloride 8:72,73 with diisopropylamine 12:113 5'-Phosphoryl oligonucleotides synthesis of 4:286,288,294,294 Phosphorylases 7:35 3'-Phosphorylated adenosine derivative 14:288 2'-Phosphorylateddu-ibonucleotides by calf intestinal alkaline phosphatase 14:308,309 dephosphorylation of 14:308,309 Phosphorylated oligodeoxyribonucleotides 4:284-289 5-protecting groups in 4:84 synthesis of 4:284-289 2-Phosphorylatedoligoribonucleotides synthesis of 14:688-696 2-Phosphorylated RNAs [A(2'-p)pA(2'-p)pU] 14:308,309 synthesis of 14:308,309 Phosphorylation 8:97,100;9:391;12:384;18:395, 397-402 dihydrogen phosphate 8:105 methylphosphonates by 13:272 of alcohols 8:80 ofcitronellol 8:76 of-geraniol 8:76 of mevalonic acid 7:322 ofprenols 8:75,80 with tetra--butylammonium Phosphotriester method 13:271,272 methylphosphonates by 13:272 Phosphotriester method 4:268-271,301-303 for oligodeoxyribonucleotides synthesis 4:268-271, 301-303 in oligoribonucleotide synthesis 4:301-303 reaction mechanism 4:270 using polymer support 4:271

Phosphotriesters 13:263,271 synthesis of 13:272 2-Phospinyl-ketoses 6:357,358 Photo-Fries rearrangement 499 Photo-induced annulation of A^-alkylated pyrrolidinones 12:293 Photo-induced deoxygenation process 14:166 Photo-induced electron-transfer 14:166 Photo-induced reduction ofesters 14:166,167 Photo-initiated radical allylation 12:487 Photoaddition 3:102,103 Photoautotrophic cell lines 7:9 A'-phthalylaspartic acid 7:10 Photochemical hydrolysis 6:331,333 Photochemical [2+2] cycloaddition 1:548 Photochemical acyl migration 1:51 Photochemical annulation in (+)-A^^'^^-capnellene synthesis ofp-diketone 6:48 Photochemical decarboxylation of allylic carboxyls 3:487 Photochemical olefin isomerization 1:413,414 Photochemical oxidation 1:159 Photochemical reaction 6:330,331 Photochemical rearrangement l:547;14:356-360 Photochemical synthesis 20:302,303 Photochemical transformation protoberberine 1:218,219 spirobenzylisoquinoline 1:218,219 Photochemical valence isomerization 1:189 Photocyclization 3:14-17,19,20,309,414;14:651 non-oxidative 3:403-406 ofenamides 3:401-403 reductive 3:402,407,407-410,414 Photocyclization 1:45,52,63,141;6:32; of oxopropy 1 ester 8:131 of phenacyl ester 8:133 Photocycloaddition 11:20; 16:651 Photocycloaddition [2+2]-Photocycloaddition 3:97;6:39;8:251 ;10:405,406; 16:264 diastereoselective 14:502 of cyclic enones 14:502 with chiral a,(3-unsaturated acetals 14:502 [67c+27t]Photocycloadditions intramolecular 1:568,569 ofalkenyltropones 1:568,569 Photodeoxygenation 3:199 Photodiode array detection 9:462 Photoisomerization 3-oxo-4,5-oxido steroids 12:236 Photolactone 8:134 Photolithography 13:646 Photolysis of ()-laudanosine methiodide 6:475,476 of (-)-orientalinone 16:512 of(4-oxopentyl)D-glycoside 10:420 of carbohydrate derivatives 14:649,650 ofenamine 16:469 ofiV-alkenylbenzotriazoles 13:445,446

1144

ofnitrone 6:474,477 of phthalimide derivatives 14:649,650 of/raAw-canadineiV-oxide 6:474 ofp-ketoester 14:652 Photooxidation 6:472,491,492;16:604 Photooxygenation 1:190,214;4:419-421,424; 14:597,601 ofcoptisine 1:191 ofpalmatine 1:191 ofprotoberberine 1:203 Photopyridone frompyridone 10:618,619 Photorearrangement 16:512 Photoreduction intramolecular 1:257 Photosensitized oxidation 6:138,142 Photosolvolysis of2,5-benzoxazonine 6:475,476 ring destruction by 6:475,476 Photosolvolytic reactions 6:472,475,477,484 Phototoxic 17:378 Phragmalin derivative 9:105 Phthoramycin 5:607-609 Phthalicacid 17:441 Phthalide annelation 4:322,341 Phthalideisoquinoline alkaloids 1:187,189 JV-Phthalyl-I-glutamic acid 5-thalidomide from 7:10 A^-Phthalylglutamic acid thalidomide from 7:9 Phycorny ces blakeslearus 18:806 Phycomyces sp. 5:276,294 Phycomyces blakesleeanus (15^-phytoenefrom 7:327 Phyllanthocin 8:281 synthesis of 8:281 (+)-Phyllanthocindiol synthesis of 16:255 Phyllanthus niruri 5:49;17:317,343,421,441,443 Phyllantoside 14:519 Phyllatocin 19:128 Phyllidia bourguini 17:16 Phyllidia species 2-isocyanopupukeanene from 6:80 Phyllidia varicosa 6:79,17:15 2-isocyanopupukeanene from 6:79 Phyllidiidae 17:15 Phyllodulcin 15:5 from Hydrangea macrophylla 13:660;15:30 from Melaleuca leucadendron 15:387 Phyllostachysin A 15:163-165,167 '^C-nmrof 15:165 from Rabdosia phyllostachys 15:174 'H-nmrof 15:164 Phyllostachysin B 15:118 ^^C-nmrof 15:132 from Rabdosia phyllostachys 15:174 ^H-nmrof 15:125 Phyllostine synthesis by retro-Diels-Alder reaction 4:610,611 PhysagulinC 20:180,242

Physagulins E from Physalis angulaten 20:194 Physagulins G from Physalis angulaten 20:194 PhysalinA 20:182 from Physalis angulaten 20:182 PhysalinB 20:183-189,234 from Physalis alkekengi 20:182 Physalin C from Physalis alkekengi 20:182 from Physalis minima 20:234 Physalin D 20:182,238 from Physalis minima 20:234 Physalin E 20:182 Physalin F 20:182 from Physalis minima 20:234 Physalin G 20:182 Physalin H 20:182 Physalin! 20:182 Physalin J 20:182 Physalin K 20:182 Physalin L 20:189 Physalin N 20:189 Physalin O 20:189 Physalindicanol A 20:238 Physalindicanol B 20:238 Physalin 20:247 Physalis acnes 20:32 Physalis alkekengi 20:182,189,191,247 physalmAfrom 20:182 physalin B from 20:182 physalin C from 20:182 physalin L from 20:189 physagulins E from 20:194 physagulins G from 20:194 Physalis angulata 20:180,182,194,247 Physalis berghei 20:522,524 Physalis cordeana 20:470 Physalis cubeba 20:619 Physalis lancifolia 20:182 Physalis minima 20:234,238,247 A'*,6-hydroxyphysalin from 20:189 Physalis mirabilis 20:859 Physalis peruviana 20:247 Physalis pubescens 20:180,189,191,247 physapubescin from 20:189 physapubenolide from 20:189 pubescenin from 20:191 Physalis vulgaris 20:845,849,851,853,854,857 Physalis yoelii 20:521 Physalis alkekengii zeaxanthin from 7:360 Physalolactone 20:246 PhysalolactoneB-3-0-p-())-glucopyranoside from Physalis peruviana 20:191 Physangulide 20:246 Physapubenolide 20:180,191,242 from Physalis pubescens 20:189 Physapubescin 20:180,189,191,224,224,242 from Physalis pubescens 20:189 Physarium sp. 5:275 Physarium polycephalum 5:275,276

1145

Physical properties oflipo-gastrin 18:844-848 oflipo-CCK 18:844-848 Physiological properties ofgalanthamine 4:13 ofpretazetting 4:13 (-)-Physostigmine for Alzheimer disease 14:637 from (-)-eserethole 14:637,638 synthesis of 14:636-638 (-)-Physostigmine 19:144-145 Physotigmine 13:70,631 Phytesterol 9:454 Phytoalexin 4:391,392;7:119,184;9:221;13:637 antimicrobial properties of 16:564 production of 16:573 Phytoecdysteroids 20:114 Phytochrome 7:92 Phytoene 7:330-335,360;20:588,590 desaturation reactions of 7:327-329 from geranylgeranyl diphosphate 7:321,322,325 from prephtoene diphosphate 7:325-327 geometrical isomers of 7:329 phytofluene from 7:327329 (AU-^-Phytone 7:325-325,327,329 from Mycobacterium sp. 7:327 (15-Z)-Phytoene 7:325-326,329,335 from Phycornyces blakesteeanus 7:327 (15Z,9'Z)-phytofluenefrom 7:332 Phytofluene 7:330-335;20:588,590 ^-carotene from 7:327-329 from phytoene 7:327-329 (15Z,9Z)-Phytofluene 7:335 (9Z,9'Z)-^-carotene from 7:332 from(15Z)-phytoene 7:332 Phytohormones 8:115-135,227 Phytolacca acinosa triterpenoids of 7:144,145 Phytolacca americana 13:655 Phytolacca dodecandra lAllA^^A'^^A'^^ Phytolaccagenin A 7:144,145 Phytolaccanol 7:144,145 Phytophthora parasitica 5:607 Phytophthora sp. 5:276;7:183;9:203 Phytophthora infestans 5:276 Phytosphingolipids synthesis of 18:457-490 biological activities of 18:459,460 D-r/6o-Ci8-Phytosphingosine 18:471,478,485 D-xv/o-Ci6-Phytosphingosine 18:479 D-r/6o-Phytosphingosines 18:465 Phytosphingosines 5:709;18:786,806 Phytosterol esters 9:458 Phytosterolemia (lipid storage disease) 9:478 Phytosterols 18:520 Phytotoxic activity 15:345 Phytotoxicity 15:479 Phytotoxins 6:554-556;15:342;17:475 PI turnover inhibitors 15: 452 biological activity of 15:461,462 echiguanine 15:458-461 inostamycin 15:453-456

pendolmycin 15:456 piericidins 15:457,458 psi-tectorigenin 15:452,453 Pi-Pd complex 10:59 Pica pica hemoglobin components of 5:836 Piceaabies 18:498 Picea sitchenesi 19:247 Piceatannol from Euphorbia lagascae 9:391 protein-tyrosine kinases (PTK) inhibition by 9:390,391 Picha strasssburgensis 5:287 Pichiabovis 5:287 Pichiafarinosa 5:283 Pichiaohmeri 5:283 Pichia pastor is 5:283 Pichia sp. 5:281,297 Pichia terricola reduction with 1:706 Pichia totetana 5:283 Pichia vanriji 5:283 Picicularia oryzae 5:287,598 Piclavine A antibacterial activiy of 16:453 antifimgal activity of 16:453 from Clavelapicta 16:453 Picraline 5:125;9:183,184 Picrasane 11:71,73,96,105 PicrasidineF 1:126 (+)-Picrasin B synthesis of 11:76,77 (+)-A^'^Picrasin B synthesis of 11:76,77 PicrasinB 5:38-41;7:396 Picrasinoside A-G 7:384,385 Picrasma ailantholides 7:369,385 Picrasma quassioides 1:126 Picrolemmapseudocoffea 7:369,381 Picromycin 5:615,616 Picronolide 5:615 '^C-NMR spectrum of 5:39,40 ' H - N M R spectrum of 5:41,41 Picropodophyllone 18:600 Picrotoxinin 17:608 Pictet-Spengler condensation 1:72;14:633 Pictet-Spengler cyclization 8:265,266,288,289;19:301 Pictet-Spengler reaction 1:139,140;4:13,16,17,23, 10:87;13:408-410;14:633,759,761,763 (+)-eJo-6-bromocamphor from 4:644 Pictyogenes chalcografus 19:128 Pictet-Spengler type reaction oftryptamines 19:91 Piericidin Bi A^-oxide 15:457 Piericidins 15:457,458 Pieris rapae 18:771 Pierreodendrom kerstingii 7:369,379,398 Piers annulation of methylene cyclophexane 6:21,22 Piers synthesis ofpalauolide 6:22

1146

Pig liver esterase asymmetric hydrolysis with 1:685 Pig liver esterase (PLE) 13:56 Pigment-Dispersing Hormone (PDH) 19:656 Pig pancreatic lipase asymmetric hydrolysis 1:685,686 Pikramycin 11:161 Pikronolide synthesis of 11:158-163 (a S, p/?)-Pilocarpine synthesis of 16:697-698 Ent-PimaranQ 9:267,283-288 Pimarane skeleton 19:395 Pimarane-type diterpenoids 20:688-690 Pimaricin relative configuration of 6:261 Pimpenella anisum 5:473 Pimpinellin 205,225 Pinaceae 7:119,120 Pinacol titanium induced coupling 8:18 Pinacol (1-bromoallyl) boronate (a-alkoxyallyl) boronic ester from 11:424 Pinacol coupling 18:443 Pinacol rearrangement 11:52-54;14:360-362;15:500; 18:174;19:397 of hydronaphthalene-l,10-diol monosulfonate esters 14:356 of 9p-hydroxy-11 -oxoderivative 19:399 Pinacol-pinacolone rearrangement ofdiol 16:127 Pinacol-type derivatives 8:4 (-)-d5-Pinane 17:605 (7?)-Pinane diol 11:410 (5)-Pinanediol from (+)-a-pinene 11:410 synthesis of 11:410 (5)-Pinanediol (dichloromethyl) boronate 11:411 (5)-Pinanediol [(7/?)-l-chloroalkyl] boronate 11:411 (/?)-Pinanediol [(//?)-1-chloroethyl] boronate 11:414 (5)-Pinanediol l(/5)-l-chloroalkyl] boronates 11:410, 411 synthesis of 11:411 (5)-Pinanediol [(benzyloxy) methyl] boronate L-ribosefrom 11:420,4421 serine from 11:420 (5)-Pinanediol boronic esters 11:410,411 Pinanediol esters insect pheromones from 11:412-414 (/?)-Pinanediol methyl boronate eldanolide from 11:414 (iS)-Pinanediol phenylboronate (25,35)-phenylalanine-3-d from 11:417,418 (5)-Pinanediol propylboronate (35,45)-4-methyl-3-heptanol from 11:412,413 Pine tall oil 14:642 Pine 20:16 a-Pinene 7:95,99-101,105-107;8:474,475,478 as chiral auxiliary 8:475 hydroboration of 8:475 (3-Pinene 9:350;13:336;20:594

(+)-a-Pinene 4:644;8:477;13:72;16:147,234,242; 20:594 (-)-a-Pinene 8:477;11:280 (-)-P-Pinene 16:234,235,239,245,248 Ritter reaction of 11:281,282 with 3-indolyl acetonitrile 11:281,282 Pinguisenol 2:283,287 (-)-Pinidine from Pinus sp, 14:572 synthesis of 16:482 ()-Pinitol 18:431 Pinitol 7:181 Pinna m uricata 19:616 Pinnaicacid 19:616 Pinnatazane 5:216,9:81 Pinnatifidone 5:216,217;9:81-83,87 ()-Pinnatol-D from Laurenciapinnata 6:26 synthesis of 6:26 Pinnatoxin 19:616 Pinner reaction 5:557,558,561,566,574 Pinocarvon 20:13 Pinocembrin 7:228;9:399,400 Pinoresinol 5:464,465,557,558,561,566,574 ep/-Pinoresinol 5:489-492 (+)-^p/-Pinoresinol 5:522,526,530 0-glucosylation of 5:525 0-methylation of 5:525 (+)-Pinoresinol 20:619 (+)-Pinoresinol-di-0-p-D-glucoside 20:646 (+)-Pinoresinol 5:523,526,526,538 (+)-g/7/-Pinoresinol dimethyl ether 5:526 (+)-Pinoresinol dimethyl ether 5:526,536 (+)-Pinoresinol monomethyl ether 5:526 (+)-Pinoresinol monomethyl ether P-D-glucoside 5:526 (+)-Pinoresinol-4'-P-D-glucoside 5:523 (+)-e/7/-Pinoresinol-4'-P-D-glucoside 5:526 (+)-Pinoresinol-di-p-D-glucoside 5:523 Pinostrobin 7:228 Pinus koraensis 5:701,702 Pinus radiata 7:99,101,105,106,108,109 Pinus sp. 7:106 Pinus silverstris 17:604,19:247 Pinus thunbergii 19:247,18:498 Piophocarpus tetragonolobus 19:247 Pipecolic acid 13:475 Piper clusii 20:619 Piper guineense 17:317 Piper methysticum kawain from 13:660 Piper nigrum 10:152 Piper officinarium 10:151 Piper sumatranum 17:348 Piperaceae 18:558 Piperadinoisoquinolines 12:447 2,5-Piperazine dione 10:84,90,125 Piperazinedione from <i,/-homoserine 12:81,82 sulfenylated 12:81,82 Piperazines 10:638,640 from diketopiperazines 10:638

1147 Piperazinomycin 10:630,631,652 synthesis of 10:638-640 X-ray crystal structure of 10:638 Pipericide 10:152 A'-Piperideine 14:739,753,759 A^-Piperideine 14:739 1,4-additionof 14:754,755 A^-Piperideine 14:753,754 Piperideine from cyclopentanone 6:424,429 CIS reduction of 6:428 trans reduction of 6:428 synthesis of 6:422-434 Piroxicam 20:514 Pisiferal from Salvia acetobulosa 20:673 from Salvia multicaulis 20:673 Piperidine 9:70-73;14:739 Piperidine alkaloids 6:422-434;13:474-483 from Nitraha species 14:742-765 synthesis of 16:453-502 Piperidine derivatives H - N M R spectra of 14:557,578 (/?)-(+)-a-methoxy-a-(trifluoromethyl) phenyl acetyl ester from 14:557,578 (-)-ajmalicine from 14:563,564 (-)-tetrahydroalstonine from 14:563,564 (+)-yohimbine from 14:566,567 absolute configuration of 14:557,558 diastereoselective synthesis of 12:471-476 from (7?)-l-phenyl ethyl amine 14:555,556 from (iS)-l-phenyl ethyl amine 14:555,556 optical purity of 14:557,558 Swem oxidation of 14:572 synthesis of 12:471-476;14:553-559 Piperidine venom alkaloids distribution of 6:423 in ants 6:422-434 Piperidines 10:671,672 glycosidase inhibitors of 10:524 Piperidinium salt 14:753,754 A^-piperdeine from 14:753,754 reduction of 14:753,754 4-(4-Piperidly) indoloquinolizidine 14:761 fromnitrarine 14:761 via schoberidine 14:761 l-(2-Piperidyl)-propan-2-ol 12:284 (+)-c/5-Piperitol 5:701,702 ()-Piperitone 16:264 (-)-Piperitone (-)-zonarene from 6:15 Piperitone 9:530 Piperonal 4:13,14 Piperonyl butoxide 5:402 Pipitzol synthesis of 1:568 P-Pipitzol CD curves of 5:781 chemistry of 5:782-785 isolation/structure of 5:778-782 stereochemistry of 5:781 synthesis of 5:782,799,800

a-Pipitzol CD curves of 5:782,799 chemistry of 5:782-785 ^^C-NMR spectrum 5:786-785 isolation/structure of 5:778-782 stereochemistry of 5:781 Pipitzol 5:792-794 transformation from perezone 5:792-794 P-Pipitzol derivatives chemistry of 5:783-785 Piptocalyx moorie Oliv. 4:709 P-Piptzone from (9-methyl-b-pipitzol 5:783 Piricularia oryzae 2:434 Pirkle reagent 9:241 Piroxicam 20:215 Pisaster brevispinus pisasteroside A from 15:61 Pisaster giganteus 15:66 Pisaster ochraceus pisasteroside A from 15:61 Pisasteroside A from Pisaster brevispinus 15:61 from Pisaster ochraceus 15:61 Pisatin 12:399 byK-252a 12:399 inhibition of 12:399 in pea epicotyls 12:399 Piscicidal activity of frullanolide 2:289 of liverwort terpenes 2:289 of plagiochiline A 2:289 ofpolygodial 2:289 ofsacculatal 2:289 Pisidium guajava eudesm-ll-en-4-ols from 14:450 (-)-selin-ll-en-4a-ol 14:450 Pisiferal from Salvia acetobulosa 20:673 from Salvia multicaulis 20:673 Pisittacula cyanocephela hemoglobin components of 5:837 Pistachia \era 9:316,327,339 Pisum sativum 17:402,18:708,710,19:247 Pitasalbine synthesis of 4:615 Pithomyces 9:203 Pityol formation from sulcatol 1:692 synthesis of 1:691,692 Pityophthorus pityographus 1:692 Pityrosporium species 13:309 Pivalate ester 1:312,313 Pivaloyl chloride 12:322 in aldolate trapping 4:17,18 Pivaloyl group 6:292,293 protection with 6:264,268,276,282,283 Pivaloylation 13:32 Placentoside A 7:302 icom Sphaerdiscus placenta 7:298 Plactranthus caninus 7:119 Plagiochila acanthophylla 2:81,280

1148
Plagiochila hattoriana 2:280 Plagiochilayokogurensis 2:280 Plagiochiline A 2:279,280,288 Plagiochiline B 2:279,280 Plagiochiline C 2:287 Plagiochiline I 2:279,280 Plagiochins 20:291 Plagiolactone 16:216 Plakortin 5:354,355;9:18 Plakortis angulospiculatus 18: 719 Plakortis halichondroides 18:719 Plakortis lita 5:353,354;18:718,719 Planaxis sulcatus 17:22,28 Planaxool 17:22,23 Plane of polarization rotation of 2:159 Planotortaix excess an 7:193 Planotortaix leafroller 7:193 Plant growth regulation 1:545 Plant growth regulatory activity of liverwort terpenes 2:289 ofpolygodial 2:289 Plant growth stimulants 9:383,384 Plant polysaccharides 19:692 Plant tissue culture applications of 7:120-126 degradation processes in 7:103-107 techniques of 7:89-96 terpenoids synthesis by 7:87-129 Plasma desorption (PD) MS 2:50;9:487 Plasma ions 2:3 Plasmid 9:592,593 Plasmodium lAlA Plasmodium genus 19:587 Plasmodium falciparum 20:516,517,519-522 Plasmodium malariae 20:516,517 Plasmodium ovale 20:516 Plasmodium vivax 20:516 Plasmodium berghei 7:391,394,395 Plasmodium falciparum 7:391,392-394,424;13:656 antimalarial activity of 7:424 Platelet aggregation by staurosperine 12:397 collagen induced 12:397 inhibition of 12:397 Platelet aggregation inhibitor 1:4 Platelet-activating factor by inhibiting phospholipase A2 12:397 Platelet-activating factor 17:326 Platelet-derived growth factor 15:441 Platenonolide 11:163 Plausibe mechanism 19:392 Platyconin 5:640 Platynecine 1:237,238;3:54;13:484,485 synthesis of 1:246 Platyphyllone 17:361 (PLE) (Pig liver esterase) 13:56 Pleiocarpa mutica 1:124 Pleiocarpa talbotii 13:397,424 Pleiocarpamine 5:125,126;9:179;13:397,405 16-e/?/-Pleiocarpamine 5:126,128 Pleiocarpamine-type alkaloids pleiocarpamine 5:82,83 16-ep/-pleiocarpamine 5:83 Pleisopermium alatum 13:351,20:497 Pleraplysilla spinifera spiniferin 1 from 6:72 ()-Pleuromutilin by double Michael additon 8:418 synthesis of 8:418 Pleuromutilin 3:88,89 Pleurotellol 3:7,65 Pleurotus ostreatus 5:288 Plexaura homomalla 9:570 Plicacetin activity of 4:244 synthesis of 4:244 Plinthogali 17:200 Plocamium cartilagineaum 18:714 Plocamium coccineum 17:9 Pluchea arguta 5:202,204;9:65 Pluchea species sesquiterpenes from 9:65-68 Pluchecin 5:203,204;9:66 Pluchecinin 5:205;9:66 4-e/7/-Pluchecinol 9:66 Pluchidinol 9:66-69 Pluchidione 9:66,67,69 Plumaran-type akaloids 5:71,89,165-174 Plumbagic acid biosynthesis of 2:228 Plumbagin 2:212,214,215,222 Plumbagin 4:612,613 synthesis of 4:612,613 Plumbago scandens 2:225 Plumbago zeylanica 2:215,226 quinonesof 2:212-231 Plumbaseylanone biosynthesis of 2:229,230 conversion to methylene-3,3'-biplumbagin 2:218, 219 conversion to plumbagin 2:218,219 mass spectral fragmentation of 2:221 structure of 2:218-221 Plumericin 7:441 synthesis of 16:299-301 Plumieride 7:439 Pluradomycins incarbapenem 4:432 PLUTO plots 9:281 Pluviatilol 5:703 Pluviine 20:352 Pneumocystis carina 2:421 (+)-Podocardic acid synthesis of 14:639-642 Podocarpane 9:297 (+)-Podocarpic acid 10:407 Podocarpic acid taxodione from 14:667-670 Z)-Podocarpic acid in (+)-confertifolin synthesis 4:405-408 in (+)-isodrimenin synthesis 4:405 synthesis of 4:405-407

1149
Podocarpus dacrydioides (-)-selin-ll-en-4a-ol from 14:449,450 Podochaenium eminens 7:416 Podophyllotoxin 5:461,462,475,477,478-483,485,488, 489,493,494;11:5;18:554,555,561 synthesis of 3:435;18:597-601 Podophyllotoxone 5:480,481,483;18:599 Podophyllum emodi 17:341 podorhizol from 18:556 Podophyllum hexandrum 5:474,477,480,482,483,485497,488,493,494 Podophyllumpeltatum 5:480,483-485,493;17:341; 18:557 podorhizol from 18:556,557 podophyllotoxin derivatives of 7:416 Podophyllum sp. 5:461,477,481,483,485,489,493 Podorhizol 5:484;18:554,565 from Podophyllum emodi 18:556 from Podophyllum peltatum 18:557 acid catalysed cyclization 5:485 ep/-Podorhizol 5:486 (+)-Podorhizon 18:588 Poecillastra species 19:580 Pogonomyrmex barbatus 5:250 Pogonopus speciosus 9:401 Pogonopus tubulosus 9:401 Pogostemon purpurascens 5:681 Pogostemon sp. (-)-patchoulol from 8:423 (-)-seychellen from 8:423 Poison gland alkaloids 6:422-465 Poitediol by Claisen reaction 6:36 by intramolecular aldol-cyclization 6:36 by oxy-Cope rearrangement 6:36 from bicyclo [6.3.0] undecanone 6:36 from Laurencia poitei 6:35 from norearonols 6:36 Gadwood synthesis of 6:35-37 relation to dactylol 6:35 synthesis of 6:35-37 Polar get theory 7:30,50,51 Polarized light circularly 2:154 elliptically 2:154 linearly 2:154 Polyene cyclization acid catalyzed 8:188 Polonovski reaction 1:105-110,112;14:715-746,811, 815,816,857,858,869-872 modified 4:31 Polonovski-Potier-Husson reaction 1:79,80 Polonvski-Potier reaction 1:49 Polpunonic acid 7:146,150 Poly-3-hydroxybutanoate (PHB) 1:690 Poly-A^-acetyllactosamine by regioselective P-glycosylation 10:477 synthesis of 10:477 Polyacrylamide gel electrophoresis for oligonucleotide purification 4:283 Polyacrylamide 7:92 Polyamme biosynthesis 1:408 Polyandrocarpa species 10:248 Polyaromatic alkaloids 17:23 Polyazulenes 14:314 Polybrominated biphenylethers 17:10 Polycarbocyclic marine triterpenoids total synthesis of 6:3-105 Polycarpol 9:399,400 Polycavernosa tsudai 19:570 Polycavemoside A stereochemistry of 19:571 toxicity of 19:572 Polycavemosides 19:570 Polycis-carotenoids 7:330-335 Polycis-prenols 8:66 Polyclonal antibodies 15:368 Polycondensation 7:458 Polycycles synthesis of 8:278 Polycyclic aromatic compounds 7:8-10 polyfimctionalized 11:113 synthesis of 11:119-127 via aromatic P,p,5,5'-tetraoxo-alkanedioates 11:119-127 Polycyclic arenes 11:113 functionalization of 11:113 Polycyclic terpenoids 6:3-105 biomimetic synthesis of 6:23 Polydimethylacrylamide resin 18:921 Polyenal macrolides biological activity of 6:261 incandidoses 6:261 in tumor therapy 6:261 Polyene acetal tetracyclization of 14:471 Polyene synthesis 20:571 Polyene cyclization biomimetic 14:740 initiators 1:656 steroids from 14:740 Polyester sesquiterpenes 18:743 Polyether antibiotic synthesis of 10:340 Polyether antibiotic 11:194 methylmalonyl CoA with 11:195 Polyether toxin 17:20 Polyethers 5:377-398 Polyfibrospongia species 19:577 Polygalafruticosa 7:415 Polygala polygama 17:341 Polygalaceae 7:415 1,4-p-Polyglucuronide 14:254 Polyglycosyl ceramides 10:459 Polygodial 1:467,468;2:278,279,286,289;6:108;7:103, 110,121-123;17:235,244 chiral synthesis 1:701,702 piscicidal activity of 2:289 from thuj one-derived synthons 14:413-421 Ju-Fang synthesis of 6:14 synthesis of 14:413-421 Yu-Lin-Wu synthesis of 6:14 ()-Polygodial by Ley's procedure 6:13

1150

Ju-Fang synthesis of 6:14 synthesis of 6:13,14,19,125 Yu-Lin-Wu synthesis of 6:14 Polygonaceae 7:427;17:237,421,439 Polygonum hydropirer 7:100,101,103,110,121;17:237 sesquiterpene from 1:701,702 Polygonum nodosum I'All Polygonum senegalense I'All Polyhydroxy sterols 5:410 Polyhydroxyindolizidines 12:275 Polyhydroxysteroids 15:72-76 Polyketide 7:266 Polyketide antibiotics 5:589,601,613 biosynthesis of 5:598 Polyketide biosynthesis 5:613 Polyketide methodology ()-semivioxanthin synthesis by 11:130,131 Polyketide sulfates of Comantheriaperplexa 7:266 of Comatualpectinata 7:266 Polyketides 13:664 aromatic natural products 11:113-149 biosynthesis of 11:191-207 synthesis of 18:155-192 Polylactosaminoglycans 10:461,486 Polymastia sp. 18:716 Polymer semi-synthesis of 17:646 Polymer support synthesis 4:274,277-283 protecting groups 4:276 protocol for oligonucleotide synthesis 4:288 Polymer supports for macrocyclization 3:82,83 Polymixin B protein kinase inhibitor of 12:387 Polyneuridine 5:74,75,124;9:171 Polyols 9:267 Poly orchis penicillans 9:493,494 Polyoxin C synthesis of 1:399-400 Polyoxins 1:404 antifungal action of 1:399 chitin synthetase mhibition 1:399 Polyphenols 7:409;17:421,427-429 antifiingal activity of 7:408 Polyphenylalanine synthesis 7:386 Polyphosphoric acid cyclization 1:58 Polyphosphoric acid trimethyl silyl ester (PPSE) 12:377 Polypodium glycyrrhiza 15:28 Polypodium vulgare 15:28 Polypodogenin 15:28 Polypodosides A and B 15:27 Polyponus circinatus 5:288,308 Polyporus betulinus 5:288 Polyporusfomentarius 5:289 Polyporus giganteus 5:288 Polyporus igniarius 5:289 Polyporus tumulosus 5:288,290 Polyprenols (dolichols) as antiinflammatory agents 8:64

N.M.R spectroscopy 8:97 synthesis of 8:68-114 Polyprenyl diphosphate sugars 8:63,64,68-106 deacetylation of 8:88 from phosphorobenzimidazolidate 8:90 from phosphoroimidazolidates 8:89,107,108 synthesis of 8:68-70,86-92 Polyprenyl monophosphate sugars from glycosylcation 8:82 from glycosyl-oxyanion 8:83 from phosphoroamidates 8:80,81,107 synthesis of 8:68,69,82-86 synthesis with prenyl cation 8:69 synthesis with prenyl halides 8:69 synthesis with tosylates 8:69 Polyprenyl phosphates from prenyl trichloroacetimidates 8:70,71 synthesis of 8:68-72 Polypropionates 17:25,26;18:155 Polyquinane 13:39 Polyquinane terpenes synthesis of 3:117-124 PolyrhaphinA 17:12 Prazosm 8:395 Polysaccharides 5:275-340;7:31-33,72;8:315;9:296,297 antigenicity of 19:689-745 as antitumor agent 5:315 as cell-surface antigens 5:322 from microorganisms 19:689-745 from plants 19:689-745 offimgi 5:309 of lichens 5:309-339 structure of 19:689-745 synthesis of 201-259 Polyscias 7:435 Polysialoglycoprotein of rambow trout eggs 11:429 Polysiloxanes 13:327 synthesis of 13:327 Polysiphonia lanosa 4:712 Polysubstituted 7-oxabicyclo [2.2.1] heptan-2-ones 14:179 Polysubstituted anthracenes 11:120 Polysubstituted dihydropyrans from enolate Claisen rearrangement 10:340 synthesis of 10:340 Polytomella coeca 2:294 Polyurethane 7:92 1,3-P-Polyuronide 14:254 Pomeranz-Fritsch isoquinoline synthesis 129 Pomeranz-Fritsch reaction 16:510 Pomiferin GA from Salvia pomifera 20:665 Pomiferin A from Salvia pomifera 20:665 Ponaras reagent 13:16 Ponera pennsylvanica 5:224,230,254 Ponerinae 6:421 Ponicidin from Rabdosia rosthornii 15:174 from Rabdosia rubescens 15:174 from Rabdosia ternifolia 15:175

1151

Pondorf-Meerwein-Verley method 17:605 Pontevedrine synthesis of 3:439,440 Pontia triene 7:221 Populus maximowiczii 20:627 Poracantholide I,J absolute configuration of 6:544 synthesis of 6:542-544 Porania pulvillus 7:298 poranoside A from 7:299,301 PoranosideA 7:299 from Porania pulvillus 7:301 P oraster superbus 7:299 Porcine pancreatic lipase 16:664 Porcine spleen byK-252a 12:390 protein kinase in 12:390 Porellaperrottetian 2:280 Porella sp 2:90 Porella cordeana 20:469 Porfiromycin 13:433 synthesis of 13:440 Porfiromycin (TV-methyl-mitomycin C ) from Streptoverticillium ordum 13:433 synthesis of 13:440 Poriacocos 5:288 Poriferasterol 9:399;16:323,332 Pominsal 17:155 Pominsol 17:155 Porphobilinogen (PBG) 9:591-593 isolation of 19:173 Porson 17:371 Porthetria dispar 19:481 Porteresia coarctata 7:189 Portulaceae 7:427,435 "Post-malonate" exchange process 11:193 Potassium graphite (CgK) 11:366,367 Potassium kojate O-alkylation of 12:261 Potassium tri (seco-butyl) borohydride 1:261 Potato disc bioassay 9:399,401,402 Potato discs crovm gall tumors on 9:399 Potier's synthesis of vinblastine 14:869-873 (PPL) (pig pancreatic lipase) 13:54,55 PPSE for cyclization 1:15 PQQ (Pyrroloquinoline quinone) synthesis of 1:170-172 Prasinophyceae 6:134,147 Pravastatin 13:598;15:450 Preakuammicine 1:31-35 Precapnelladiene synthesis of 3:89-91 e/7/-Precapnelladiene synthesis of 89-91 Precapnelladiene by enone-alkene photocycloaddition 6:33,34 from Capnella imbricta 6:33 from triquinane 6:33,34 synthesis of .6:33,34

()-Precapnelladiene by Baeyer-Villiger oxidation 6:34,35 by endo-D'\Q\s Alder reaction 6:3,34 by Sharpless oxidation 6:34 by Wittig olefination 6:33,34 synthesis of 6:33,34 ()-e/7/-Precapnelladiene by intramolecular photocycloaddition 6:34,35 synthesis of 6:34,35 Precipitation technique 13:647 Preclathridine A 17:18 Preclavulone A 8:140 Precocenel 2:126,2:127 Precocene I and II synthesis of 4:395,397,398 Precondylocarpine 1:31-33,40 Precorrin-N 9:597 Precorrins 1-8 9:597,598,600-604,607 Precyclospongiaquinone-I 15:298 Prednisolone 9:411,419-421 (20/?)-5a-Pregn-9(l l)-ene-3(3,6a,20-triol (asterogenol) 7:288,291 17(20) Z/-Pregnenes ene reaction of 10:59 Pregnenolone 5:711;10:68;16:322 from chloesterol catabolism 5:709 Prelog-Djerassi lactone 3:227,225-257;10:423 synthesis of 3:227,255-257;16:711 Prelog-Djerassi lactonic acid synthesis of 14:267 Prenyl bibenzyls 2:283,285,286 distribution in Radula sp. 2:286 Prenyl bromide 4:382-387,389,398 C-alkylation of phenolates with 4:382-386 with Diels-alder adduct 4:388,389 with 3,4-dihydroumbelliferone 4:398 with 5,7-dihydroxyisoflavone 4:382,385 with 2,6-dimethoxy-4-hydroxyacetophenone 4:386, 387 with noreugenin 4:382-384 with umbelliferone 4:385,386 7-O-Prenyl coumorin from umbelliferome 4:385,386 Prenyl diphosphates from mevalonic acid 7:322 Prenyl monoesters of 8:33 Prenyl transferase 7:96,108,323,324,348 Prenyl transferase reactions 7:321 Prenylated benzophenones 4:375,379 in Visima decipiens 4:378 Prenylated biphenyl synthesis of 4:389 para-Prenylated phenol 4:375,376 Prenylated phenolic compounds synthesis of 4:367-402 Prenylated xanthones 7:410,411,423 Prenylation methods 4:367-402 by alkali metals 4:386-400 bychromanes 4:394-396 by Friedel-Crafts alkylations 4:391,394 by organometallic reactions 4:396,398 by silver oxide method 4:386

1152

by trimethylsilyl intermediates 4:394 in basic media 4:386-391 of 2,6-dihydroxy-4-methoxy-acetophenone 4:386, 387 of 1,3-dimethoxybenzene 4:89 Prenylcitpressine from Citrus grandis 13:350 6-Prenylflavanone jfrom 7-hydroxyflavanone 4:378,380 8-Prenylflavanone 4:378,380 from 7-hydroxyflavanone 4:378,380 Prenylhydroquinone 5:440;10:248 2-Prenyljuglone synthesis of 4:388,389 8-Prenylnoreugenin from noreugenin 4:382,384 4-Prenyloxycoumarin 4:375,376 7-Prenyloxyflavanone from 7-hydroxyflavanone 4:378,380 Prenylquinone 10:248 iV-Preotected a-amino aldehydes 4:122-114,117,118, 125-127,130 inl-alaninal 4:127 synthesis by oxidative methods 4:113,114 synthesis by reductive methods 4:114 asymmetric synthesis 4:117,118 Preparation of(+)-6-e;/7/-a-cyperone 10:408 of(a)-terpineol 11:307,308 of2,2-Di-C-methyl-3-deoxy-4-ulose 10:414,415 of 2,3-unsaturated allyl glycoside 10:420 of 2-indolyl acetaldehyde 11:315,316 of a building block 11:307,308 of acyclic a,a-dialkylated ester 10:411 ofaristotelin-19-ol 11:312 ofaristotelin-19-one 11:312 of4-acetoxy-(3-lactam 12:160-162 of3-acetyl-2-oxazolone 12:411,415 of 2-axazolone 12:411,415 of chiral auxiliaries 12:416-418 ofchiral building blocks 13:73-84 of C-methylated hexopyranose 10:414,415 of diastereomeric aminonitrile 10:126,127 of hexopyranose derivatives 10:426-428 of indoIo-[2,3-a] quinolizidine 14:704-706 of indoloquinolizidine enamines 14:727 of indoloquinolizidine A^b-metho salt 14:718,719 of indoloquinolizidine A'b-oxides 14:711-714 of lo w-valent-titanium reagent 11:3 64 of monofluorinated chiral building blocks 13:81 of nonulosonic acid 11:466 ofoctulosonicacid 11:466 of Oppolzer's chiral auxiliary 11:307,308 of sulfoxides 14:517-519 oftetrahydropyrazinone 10:138-140 of titanium trichloride 11:364 of (3-hydroxybutanoic acid ester 10:410 titanium (O) 11:366,367 with zinc/copper couple 11:364 Prephenic acid 11:188 formation of 11:188

Prephytoene diphosphate phytoenefrom 7:325-327 Prepimmaterpene 6:9,10 from Laurencia pinnata 6:9 from Laurencia subopposita 6:9 synthesis of 6:9,10 Preseychellogenin 15:91 Presilphiperfolan-9-ol 9:535 Presqualene diphosphate squalenefrom 7:325 Pretaxoids 20:107 Pretazettme 15:135 from Amaryllidaceae 4:3,4 from haemanthidine 4:17 physiological properties of 4:13 retrosynthesis of 4:3,4 synthesis of 4:17,20 Preurogen (hyroxymethylbilane) 9:591,592,596 Previtamin Z)-form 9:515 Prevost reaction 5:189;14:853,858 (-)-Prezizaene synthesis of 10:410 Prezizaene synthesis of 15:248 (-)-Prezizanol synthesis of 10:410;15:248 Prianicin-A 9:15 Prianos species muqubilinfrom 9:15 Primary hydroxyl protection as pivalate ester 1:312,313 Primin 9:338 Primula denticulata 5:211 Primula obconica I'All Primula viscosa 20:740 Primulaceae 7:427 Prhnulagenin A 9:400 cw-Principle 4:584,585 in Diels-Alder reactions 4:584,585 Prins cyclization 18:174 Prins reaction 13:41,42;18:882,891 Prionitin APT spectrum of 5:31 '^C-NMR spectrum of 5:31,32 COSY spectrum of 5:31,32 CSCM ID spectrum of 5:31,32 H - N M R spectrum of 5:31,32 INEPT spectrum of 5:31,32 NOE spectrum of 5:31,32 Pristimerin 7:147-152;18:757,760,765,776,778 Proansamycins A,B 9:439,440,443 Proanthocyanidin dibenz [b,d] oxocin L-[U-C^^] Proline 15:347 Proanthocyanidins 15:33,34 Proaporphine dienones correlation between specific rotation and absolute configuration 2:259 Proaporphines 2:251-259 absolute configuration of 2:253 stereochemistry of 2:253 Procambarus bouvieri 19:665 Procambarus clarkii 19:627

1153

Prochiral carbonyl groups asymmetric addition to 4:332,333 Prochiral ketones chiral alchohols from 1:689 reduction with yeast 1:689 Prochiral naphthalene rings asymmetric additions to 4:332 Prochiral sulfides asymmetric oxidation 14:517,518 Prochloron 10:243 Procumbide 7:477 Prodigiosin synthesis of 8:272,273 Projulinme 5:211 Proliferation of lymphoblastoid cells 12:389 ofT and B normal 12:389 Proline photooxidation of 16:603-608 /-Proline piperidine derivative from 14:555,556 pyrrolidine derivative from 14:555 Proline endopeptidase 2:35 Prolines as chiral auxiliaries 4:327 /-Prolinol as chiral auxiliary 14:743-747 Prolycopene 7:330-335 Propacin 5:5,8,497 Propane-1,3-diols asymmetric synthesis of 13:53-105 enantioselective 13:53-55 enzymatic 13:55 transesterification of 13:53-55 1,3-Propanediol 8:373,376;14:653 1,3-Propanedithiol 11:357 Propanedithiol 6:301,302 protection with 6:301,302 (5)-Propargyl alcohol 13:585 Propargyl alcohol cw-olefinfrom 14:569 pyrrolidine derivative from 14:569,570 Propargylic alcohols synthesis of 14:473 Propargylic titanium reagent fromalkyne 12:24 with methacrolein 12:24 Yamamoto condensation of 12:24 [3.3.3]-Propellane 13:3-39 Propellane sesquiterpenes 13:37-39 [m,n,l]Propellanes asymmetric synthesis of 14:490 via asymmetric cyclopropanation 14:490 (/?)-(Z)-Propenyl/7-tolyl sulfoxide 10:671,672 Propenylphenol 5:459,472,473 Prophylactic activity 13:666 [2-%2,2-*^C] Propionate incorporation of 11:196,197 incorporation into erythromycin A 11:196,197 incorporation into erythromycin B 11:196,197 incorporation into lasalocid A 11:196,197 incorporation into monensin A 11:196,197

Propionibacterium shemanii 9:598,600-604;ll:182 Propionic acid derivatives 12:163,165,169 PropionylCoA 11:195 carboxylation of (25)-methylmalonyl CoA from 11:195 (5)-Propanolol synthesis of 6:346,347 Propyl l-thio-(3-D-galactopyranosides 8:315 2--Propyl-4-tert-butyl-cyclohexanone 14:645 Propylidene-a-D-r/Zjo-hexafuranose 14:155 24-Propylidenecholesterol biosynthesis of 9:37 Prorhinotermes simplex 19:118 Prorocentrolide stereochemistry of 19:617 Prorocentrum lima 5:384,17:20,19:617 ()-Prosafrinine 13:482 Prosapogenols 7:268 Prosobranchia 17:3,19 Prosoflorine 9:72,73,77 ()-Prosophylline 13:481 Prosopidione 9:68,69 ()-Prosopinine 18:347 Prosopinoline 9:71,77 Prosopis juliflora 5:211 ;9:68-73 alkaloids from 9:70-73,290 terpenoid diketone from 9:68,69 Prostacyclin (prostaglandin I2) 12:399;16:388 preparation of 16:386 Prostaglandm E 20:534 (-)-Prostaglandin El 19:163 Prostaglandin lactones 19:549 Prostaglandins A2 19:571 Prostaglandins (PGs) 19:162 Prostaglandins E2 19:571 Prostaglandin l:686,687;5:377,815-833;7:483;9:290, 559,571 ;13:659;17:642;19:550 anticancer clavulones 16:366 asymmetric synthesis of 4:607 synthesis of 16:364-394 A-Prostaglandin 16:366 (+)-(! 55)-Prostaglandin A2 synthesis of 10:418 Prostaglandin analogue 7:479-483 Prostaglandin derivative 2:51 Prostaglandin E2 12:399 by staurosperine 12:399 production of 12:399 Prostaglandin F2a 10:419 Prostaglandm F2a 8:140 Prostaglandin I2 (prostacyclic) byK-252a 12:399 by staurosperine 12:399 production of 12:399 Prostaglandin synthetase 5:816,819 Prostaglandin synthetase inhibitors 5:815-833 Prostoglandin F2 synthesis of 3:227 Prostoglandin PGA2 synthesis of 3:247 Proteacea 9:319,328 Protease 6:551:16:737

1154

A'^-O-Protected a-amino aldehyde in cyclocondensation 4:130 3',5'-Protected adenosine derivative 2'-phosphorylation of 14:286 iV-Protected alaninals 4:121,122 and//zreo selectivity 4:122 A^-O-Protected D-a//o-threoninal 4:143 organometallic addition to 4:142 Protected ribonucleotides for oligoribonucleotide synthesis 4:300 Protecting groups acid labile 4:299 anilido 4:286 base labile 4:299 benzyl 4:299 2'-0-t-butyldimethylsilyl (TBDMS) 4:299 1 -[(2-chloro-4-methyl) phenyl]-4-methoxypiperidin-4-yl (CTMP) 4:299 5-chloro-8-quinolyl 4:286 2-cyano-l,l-dimethylethyl 4:285 2-cyanoethyl group 4:285 dimethoxytrityloxyethyl sulfonyl ethyl 4:285 for 2'-hydroxyl 4:296 for 5'-hydroxyl 297 for intemucleotidic phosphate group 4:268 for phosphomonoester formation 4:285 in polymer support synthesis 4:276 /7-methoxybenzyl (MBn)) 4:300 3-methoxy-1,5-dicarbomethoxypentanyl (MDMP) 4:300 methoxytetrahydropyranyl 4:297 (1-methyl-1-methoxy) ethyl (MME) 4:300 monomethoxytrityloxyethylamino 4:289 o-nitrobenzyl (NB) 4:300,301 /7-nitrophenylethyl 4:285 e/-pseudoguaianolide intermediate 4:675 2-(2-pyridyl) ethyl 4:286 tetrahydrofuranyl 4:297 tetrahydropyranyl 4:297 trihaloalkyl 4:285 3,4,5-trimethoxybenzoyl 4:299 Protection with cyclocarbonate group 6:284,285 with lauryl chloride 6:429 with MEM 6:558,559 with methoxyethoxy group 6:298,299 with methoxymethyl group 6:282,283 with 0-isopropylidene 6:269,270 with pivaloyl ester 6:264,268 with propanedithiol 6:300,301 with ?er^butyldimethyl silyl ether 6:264,268 with tetrahydropyranyl ether 6:264,268 Protection of alcohol with tert-Bu MezSiOCHzCOCl, 1:440,442,443 Protection of inositols 18:403-421 Protection/deoxygenation procedures regioselective 14:744 Protein cross-links 2:30-41 Protein kinase 5:384 Protein kinase A (PKA) 12:384 Protein kinase C 12:233,253,364 from Dictyostelium discoideum 12:384

from mammalian cells 12:384 used for anticancer drug design 12:384 Protein kinase C inhibitor 4 Protein kinase G (PKG) 12:384 Protein-tyrosine kinases (PTK) inhibition by piceatannol 9:390,391 Proteolytic enzymes 16:93 Proteus 12:63 Proteus mirabilis 12:400;20:712,837,840,842,853, 855,858 Proteus vulgaris 9:308;12:103,400;20:831,837,839, 840,859,879 Prothymosin 8:433-435 Protoanemonin 10:186 Protoanemonin (y-methylene-y-butenolide) 10:149 Protoberberine 5:42 Protoberberine alkaloids from spirobenzylisoquinolines 1:217,218 photochemical formation 1:217,218 ring D inversion 217,218 synthesis of 1:217-221 Protoberberinephenolbetaines synthesis of 1:190-192 Protoberberines 14:769-803 synthesis of 3:444-446 Protocatechuic acid 8:295,296 Protodesilylation 12:322 Protodestannation 1:490 Proton-proton NOB 2:70 exo-Protonation 4:654,655,657,658 Protonolysis of 19:59 Protopine alkaloids 1:187,189 by Hofinann elimination 6:488,489 dihydrocoptisine conversion to 6:491 from tetrahydroberberine derivatives 6:488,489 from tetrahydroprotoberberine precursors 6:491 Protopine alkaloids A^-oxide derivatives dibenzo oxazacycloundecine derivatives from 6:494 Protopine A^-oxide corydalisol from 6:494 hypcorine from 6:494 Protoreaster nodosus 7:290,304-306;15:46,60 5a-cholestan-3p,6a,8,15a,16(3,25-hexol from 15:77 nodosocide from 7:295 Protoreasteroside 7:290,293 Protorifamycin I 9:440 Protosappanine B 20:276 Protostephanine biosynthesis of 6:480 from 1-benzyltetrahydroisoquinoline system 6:480 in Streptomyces japonica 6:480 synthesis of 6:478 Prototype antibiotics 2:426,427 Protozoa 2:293-319 glycocomplexes of 5:612 Protylonolide 5:611-615 Proxiphomin synthesis of 13:123,125 Prunus cerasus 20:721 PSbioassay 18:878

1155

(+)-PS-5 key intermediate to 14:497,498 synthesis of 14:497,498 Psalliota bispora 13:310,304 Psalliota campestris 5:289 Psathyrotes ramosissima 7:421 Pschorr reaction 20:301;16:504 Pschorr-type diazo-couplings 20:301,302 Psendomonas aureginosa 20:712 Pseudaminyssa species 9:38 Pseudoaspidosperma alkaloids 19:90,103 Pseudoaspidospermanes 19:105 Pseudobersana mossambicensis 20:478 bioactive steroids from 20:476 Pseudo-cellobiose 13:213,215,219 Pseudo-disaccharides 13:195218,219,221,223-225, 236,238,240,241,244,246,247 synthesis of 13:212-216 Pseudo-gloeosporone synthesis of 10:220 Pseudo-isomaltose 13:213,215,219 Pseudo-laminarabiose 13:213 Pseudo-maltose 13:212,213,215,219 Pseudo-NANA synthesis of 13:210 Pseudo-oligosaccharide inhibitors 10:503 Pseudo-oligosaccharides 13:235-246 synthesis of 13:235-246 Pseudo-sugars (carba-sugars) 13:187-255 Pseudo-tetrasaccharides 13:238 Pseudo-trehalose 13:213,215 Pseudo-trisaccharides 13:237,238 synthesis of 13:212-217 Pseudoakuammicine 1:32 (-)-Pseudoakuammigine 9:183 (+)-20/?-Pseudoaspidospermidine 5:123 (-)-205'-Pseudoaspidospermidine 5:125 Pseudobactin (pyoverdins) 9:537-539,541,547,551,553 X-ray crystal analysis of 9:539 Pseudoberberine reduction of 14:775,776 ()-Pseudocarpamic acid 13:482 Pseudodilution 3:82,83 Pseudodistoma kanoko 10:249 Pseudodistomins A,B 10:249 Pseudodoynerus quadrisectus 5:224,232 (+)-Pseudoephedrine synthesis of 12:479,480 <i-Pseudoephedrine 18:602 Pseudoerythromycin A 13:159 Pseudoginsenoside 15:191 Pseudoguaiane 7:209 e^Pseudoguaianolide intermediate 4:675 Pseudoguaianolide sesquiterpenes 1:545,546 Pseudoheliotridane 1:242,257 synthesis of 1:258 Pseudohypericin retroviral activity of 7:421 Pseudoindoxyl-type alkaloids conopharyngine pseudoindoxyl 5:102 19/?-hydroxyibogamine-pseudoindoxyl 5:102 ibogaine pseudoindoxyl 5:102

ibogamine pseudoindoxyl 5:102 voacangine pseudomdoxy 1 5:102 voacristine pseudoindoxyl 5:102 Pseudolaric acid B as fertility-regulating agent 13:653 Pseudomonas aerginosa 1:370,377;3:302;5:434; 9:308,537,540,553,555;12:63,103,401;14:144,236; 19:601 Pseudomonas aureofanines 9:527 Pseudomonas cepacia 4:432 Pseudomonas chloroaphis 9:537 Pseudomonas cichoriae 9:537 Pseudomonas coriacea 12:294 Pseudomonas denitrificans 9:600,603,604,606 Pseudomonasfluorescens 3:263;9:537,553; 10:78 Pseudomonas fluorescens lipase 1:685;13:54,55 Pseudomonas genus 19:791 Pseudomonas lipase PSL 13:55 Pseudomonas maltophilia 4:432 Pseudomonas morganii 5:434 Pseudomonas perolens 13:320 Pseudomonasputida 4:647;8:296,298,303,305,309; 9:537;13:58,299;18:430 Pseudomonas sorghi 9:220 Pseudomonas species 5:434;9:37;18:429,430 papakusterol (glaucasterol) from 9:37 for enantioselective hydrolysis 12:337 Pseudomonas striiformis 9:220 Pseudomonas syringae 4:590;9:537 Pseudomonas taetrolens 13:320 Pseudomonic acid by Claisen rearrangement 10:339 synthesis of 10:339,425 Pseudomonic acid C synthesis of 3:263-267 Pseudomyrmecine species 6:421,422 Pseudonigeran 5:276,280,288 Pseudophrynamines 18:726 Pseudophrynaminol 18:725 Pseudophryne coriacea 725 Pseudophryne genus 19:52 Pseudophryne guentheri 726 Pseudophryne Occidentalis 18:726 Pseudoplexaura crucis 8:20 Pseudoplexauraflagellosa 8:20 Pseudoplexaura porosa (Plexaura crassa) crassin acetate from 8:20 Pseudoplexaura wagenaari crassin acetate from 8:20 Pseudopterins 15:259 Pseudopterogorgia americana (-)-P-gorgonene from 6:18,27 Pseudopterogorgia elisabethae 15:259 pseudopterosins A-D 6:74 3-e/?/-Pseudopterosin 15:259 Pseudopterosin A 16:214,262 Pseudopterosin E 16:262 (-)-Pseudopterosin-A Broka's synthesis of 6:74,75 by Chan-Brownbridge procedure 6:74,75 by Friedel-Crafts alkylation 6:74,75 by glycosidation 6:74,75

1156
by Michael addition 6:74,75 by selenation-oxidation 6:74,75 from (5)-(-)-Limonene 6:74,75 Pseudopterosins A-D 6:75 from Pseudopterogorgia elisabethae 6:74 Pseudostichoposide A from Pseudostichopus trachus 15:94 Pseudostichopus trachus pseudostichoposide A from 15:94 Pseudosuberites hyalinus 18:696 Pseudotabersonine 5:124 Pseudotropine synthesis of 1:383-385 Pseudovincadifformine 19:103,19:105 Pseudovincadifformine-type alkaloids 5:103-105 14,15-anhydrocapuronidine 5:103-105 14,15-anhydro-1,2-dihydrocapuronidine (+)capuronidine 5:104 (+)-20/?-1,2-dehydropseudoaspidospermidine 5:104 (+)-205-hydroxy-1,2-dehydropseudoaspidosper midine 5:104 (+)-20R-18,19-dihroxypseudovincadifformine 5:104 (+)-19-hydroxy-20-e/7/-pandoline 5:105 20-e/7/-pandoline 5:105 (+)-20/?-pseudoaspidospermidine 5:104 (-)-205'-pseudoaspidospermidine 5:104 (+)-20/?-pseudovincadifformine 5:105 (+)-205'-pseudovincadifformine 5:105 Pseudovincamines 1:114 Pseudovobparicine 5:125 (-)-Pseudoyohimban 10:155 PseurataA 15:116 *^C-nmrof 15:130 from Rabdosia pseudo-irrorata 15:174 'H-nmrof 15:123 PseurataB 15:118 ^^C-nmrof 15:132 from Rabdosia pseudo-irrorata 15:174 ^H-nmrof 15:125 PseurataC 15:116 ^^C-nmrof 15:130 from Rabdosia pseudo-irrorata 15:174 'H-nmrof 15:123 PseurataD 15:118 ^^C-nmrof 15:132 from Rabdosia pseudo-irrorata 15:174 'H-nmrof 15:125 PseurataE 15:120 ^^C-nmrof 15:134 from Rabdosia pseudo-irrorata 15:174 ^H-nmrof 15:127 PseurataF 15:118 '^C-nmrof 15:132 from Rabdosia pseudo-irrorata 15:174 'H-nmrof 15:125 Psi-tectorigenin 15:452,453,456 Psiadia 7:411 Psiadia trinervia 7:411-413 Psilostachyins 7:215,237 Psittacula krameri hemoglobin components of 5:837 PSL {Pseudomonas lipase) 13:55 Psolus fabricii 15:89 Psolusfabricii 7:278,279 PsolusosideA 7:278,279 from Psolus fabricii 7:278 Psolusoside B 7:278,279;15:89 PsoluthurinA 7:278,279 Psoralen 9:402;18:978,20:499 ^^0-NMR of 9:111,112 Psoriasis 9:514,517 Psorospermin from Psorospermum febrifugum 13:368 (+)-Psorospermin synthesis of 4:371,372 Psorospermum febrifugum 7:417-420,424 psoprspennin from 13:368 Psychotropic activity 7:7 Psyllium 13:660 Pteridium aquilinum 6:194 Pterocarpans 20:496 Pterocarpans 4:377,378,383,385,386;20:730,774,775 synthesis of 16:564-565 Pterocarpus santalinus 1^:11 A Pterogyne nitenes 20:489 guanidine alkaloids from 20:488 Pterogynidine 20:488 Pterogynine 20:489 Pterostilbene 20:730,20:774 Pterogorgia citrina 17:99 ()-Pteropodine 13:490,491 Ptilocaulin synthesis of 6:4 Ptilostemonal 8:39,40 Ptilostemonol synthesis of 8:46,47 Ptilostemonol acetate 8:40,41 synthesis of 8:47 Ptychodiscus brevis 6:135 Pubescenin from Physalis pubescens 20:191 Pubescenol 20:180,20:181,20:194 Puccinia 9:203,220,222 Puccinia antirrhini 9:220 Puccinia arachidis 9:220 Puccinia coronata 9:220,226 Puccinia coronata f sip. avenae 9:220-223,228 Puccinia coronata fsp.festucae 9:221 Puccinia graminis 9:220,226 Puccinia graminisfsp. tritici 9:220,221,228 Puccinia helianthi 9:220 Pulchea indica 7:185 Pulcherrimins A 20:475 Pulcherrimins D 20:475 (+)-Pulegone 8:224 (5)-Pulegone 13:598 5-(-)-Pulegone 16:192 Pulegone ketone chiral auxiliaries from 1:579 preparation of 1:579 (/?)-(+)-Pulegone 9:535;10:410;13:11,13; 16:192,225; 18:319

1157

Pullulan 5:288,289,307,314 PuUulanases 10:498 Pulmericin antifungal activity of 16:299 antileukemic activity of 16:299 cytotoxic activity 16:299 Pulmiliotoxins 16:426 Pulmonary colonization 19:370 Pulmonata 17:3 Pulse experiment 9:598,599 Pumiliotoxin 12:294;19:53,463 enantioselective synthesis of 4:584,585;19:53 Pumiliotoxin A synthesis of 19:52-59 Pumiliotoxin B synthesis of 19:54 (-)-Pumiliotoxin C 6,19:8-10,12-13 hydrochloride salt of 19:4 racemic synthesis of 19:4 total synthesis of 19:4 X-ray crystallographic analysis of 19:4 Pumilitoxin251D 19:52,19:486 synthesis of 12:296 Pumiliotoxin A synthesis of 1:287 synthesis of analogues 1:294 Pumiliotoxin A (6-alkylidene-8-hydroxy-8methylindolizidines) 11:244 Pumiliotoxin A-C 9:321,323 Pumiliotoxin B absolute configuration of 12:294 activity of 12:294 diastereomer of 12:294 (155,165)-erythro diastereomer of 12:294 ^om Dendrobates pumilio 12:294 synthesis of 12:296 (+)-Pumiliotoxin C synthesis of 16:459-460 (-)-Pumiliotoxin C 18:319 Pumiliotoxin C (decahydroquinolines) 11:244 Pummerer intermediate 3:461;4:646 Pummerer reaction 1:63-65;4:139,464;10:678,682; 11:326,327;14:539-546,747;19:14 Pummerer rearrangement 4:36-39,496,505,506,510; 6:317-319,321,328,335;12:160,161,324;14:539; 16:230,671 Punaglandin synthesis of 1:687 Punctatin synthesis of 14:646,647 Pungency 17:379 Punglandis 5:377,385 ()-Pupukeanone from Diels-Alder adduct 6:83,84 from 4,6-dimethyl-l,3-cyclohexadiene 6:83,84 synthesis of 6:83,84 (+)-9-Pupukeanone by Birch reduction 6:83,84 by intramolecular Diels-Alder reaction 6:83,84 fromp-cresyl methyl ether 6:83,84 Schiehser-White synthesis of 6:83,84 Purification of oligonucleotides 4:282,283

Purines 220 9:73 Pyocheline 9:539,540 Puromycin reaction 7:386 Purpurea glycoside A 15:362 Purpurea glycoside B 15:362 6-ep/-Purpurosamine B synthetic approaches to 4:120-127 Purpurosamine B synthetic approaches to 4:120-127 6-gp/-Purpurosamine B derivative synthesis of 4:125 Purpurosamine C from levoglucosenone 14:268 synthesis of 14:268 Purpurosamine C by [4+2] cycloaddition 4:115 synthesis of 4:115-118 total synthesis fo 4:123 Pusescenol 20:242 Pustulan 5:311,322 Puupehenone 15:299 from Meteronema species 6:23 from Hyrtios eubanuma 6:23 synthesis of 6:23,24 Pycnogonids 17:105 Pycnonotus cafer hemoglobin components of 5:837 Pycnonotus jocosus 5:837 hemoglobin components of 5:837 Pycnopodia heliantoides 15:46 pycnopodiosides A,B and C from 15:61 Pycnopodiosides A, B and C from Pycnopodia heliantoides 15:61 Pygmol from Artemisia pygmaea 7:218 Pyicularia oryzae 12:401 Pyoverdins (pseudobactin) 9:538,539,541-547,549-555 biogenesis of 9:552,553 Pyrano [2,3-b] pyridin-2-one 13:545 Pyrano [2,3-c] acridin-7-one-(acronycine) derivatives 13:348 Pyrano [3,2-b] acridin-6-one(isoacronycine) derivatives 13:348 Pyranoacridone 13:347,358,370,-374 Pyranoannulated diquinane derivatives 10:426-428 Pyranocoumarin 20:497,499 Pyranofoline 13:348,349,370,372 Pyranoid glycal palladium-mediated reactions of 10:342 stereoselective arylation of 10:345 Pyranonaphthoquinones 4:591 Pyranose derivative of 17:638 semi-synthesis of 17:638-640 Pyranoside enol esters from 10:373 stereoselective C-glycosylations 10:373 4-O-Pyranosyl sugars 15:436 6-O-Pyranosyl sugars 15:436 Pyranoxanthones 7:411 Pyrazinamide 2:424

1158

Pyrazines 13:318-321 synthesis of 5:254-258 Pyrazoflirin synthesis of 10:355 Pyrazofurm A by Wittig reaction 10:392 from ribofuranose 10:392 PyrazofiirinB 10:392 by Wittig reaction 10:392 from ribofuranose 10:392 Pyrazoiopyridines 1:167 Pyrenophora avenae 19:154 (-)-Pyrenophorin antifungal antiobiotic 19:154-155 produced by 19:154 synthesis of 19:154 Pyrenophorin synthesis of 4:518-520 Pyrethrin analogues 14:397-405 insecticidal activity of 14:398 synthesis of 14:397-405 Pyricularia oryzae 1:404;4:598;15:385 Pyriculariasp 16:302 Pyridine monoterpene alkaloids 6:527-530 Pyridine nucleotides 20:868 Pyridine substrates 18:369 Pyridine-2,5-dicarboxylic acid bicyclic keto-acid from 12:283 Pyridine-2-carboxamide-netropsin 5:570 Pyridinium acetate lactonization with 11:84,85 Pyridinium chlorochromate 7:478;11:93,94;12:492 oxidation with 4:117,118;6:116,118 Pyridinium dichromate 11:350 Pyridinium methylides cycloaddition with 1:334,335 Pyridinium salts reduction with dithionite 1:91 Pyridinone 13:545 2-Pyridne carboxaldehyde from 2-bromopyridine 6:312 Pyrido [4,3b] carbazole alkaloids 6:513,514 in Loganiaceae from 6:507 Pyridone photopyridone from 10:618,619 Pyridones selective synthesis of 18:315-386 Pyridoxal phosphate 10:148 Pyridoxine 2:424 2-(2-Pyridyl) ethyl as protecting group 4:286 2-Pyridylcarbinol hydrogenation of 12:283 Pyrilium oxide isomerization of 1:189 Pyrilium salt 7:459 Pyrimethamine 20:526 Pyrimidine nucleoside 4:223,224 Pyrimidine phosphorylase mhibition of 4:230 Pyrimidine-2-amino-2-deoxynucleosides synthesis of 4:239

Pyrocatechol 8:305 from phenol 8:295 from benzene 8:295 Pyrogallol 20:273 Pyroglutamic acid 3-acylpyrrol-2(5//)-ones from 13:112 3-methoxycarbonylpyrrol-2(5//)-one from 13:112 (5)-Pyroglutamic acid 19:32 chiralpool 19:32 ofkuwanonG 17:455 Pyrolysis 14:268;17:455 levoglucosenone from 14:268 of isoquinoline A^-oxide 6:468 ofA^-acyllactams 6:430,431 of A^-lauryl-6-methyl-2-piperidone 6:430,431 of acid-treated cellulose 14:268 of protopine A^-oxide 6:494 of microgranular cellulose 14:268 a-Pyrone 5:590;15:474 y-Pyrone 5:591 a-Pyrone convolvupyrone 15:342 Pyrrhoxanthinol synthesis of 6:143,145 Pyrrocorphins 9:604,605 Pyrroglutaic acid (25,5/?)-cw-5-butyl-2-heptyl pyrrolidine from 6:438-440 Pyrrole synthesis of 8:269 Pyrrole alkaloids 17:88 Pyrrole-amidine antibiotics 5:561 Pyrrolidine 5:3 (2/?,55)-cM-Pyrrolidine from I-glutamic acid 6:438 synthesis of 6:438 (3R,5S)-trans-PyrroMme from I-glutamic acid 6:439-440 synthesis of 6:439,440 Pyrrolidine (2/?,3/?) 12:281 Pyrrolidine alkaloids 12:472;13:474-483 asymmetric synthesis of 6:442,443 synthesis of 6:442,443,445 Pyrrolidine derivatives absolute configuration of 14:556,570 alkaline hydrolysis of 14:569,570 from alkyne compound 14:570 from a-allokanic acid 14:556,557 from allyl alcohol 14:571 *H-NMR spectra of 14:556 from (/?)-l-phenyl ethyl amine 14:555 from (5)-1 -phenyl ethyl amine 14:555 from propargyl alcohol 14:569,570 fromZ,-serine 14:568 from I-tartaric acid 14:568 pyrrolizidine alkaloids from 14:568-571 synthesis of 14:553-559,568-571 via asymmetric intramolecular Michael reaction 14:553-559,568-571 via Sharpless asymmetric epoxidation 14:568-571 Wittig reaction of 14:556,557

1159

Pyrrolidine derivatives diastereoselective synthesis of 12:471 synthesis of 12:471-476 ()-Pyrrolidine oxime 19:84 Pyrrolidine ring construction in pyrrolidine venom alkaloid synthesis 6:437-439 Pyrrolidine venom alkaloids by pyrrolidine ring construction 6:437-439 distribution of 6:436 in ants 6:434-444 relative configuration of 6:435 synthesis of 6:436,443,444 Pyrrolidines glycosidase inhibitors of 10:524 p-Pyrrolidino-I-rhodino-pyranoside 14:132 2-Pyrrolidones absolute configuration of 14:560,561 a-allokainic acid from 14:560,561 from (/?)-l-phenyl ethyl amine 14:560,561 from (5)-1-phenyl ethyl amine 14:560,561 synthesis of 14:560,561 via asymmetric intramolecular Michael reaction 14:560,561 Wittig reaction of 14:560,561 Pyrroline alkaloids synthesis of 6:436,443,444 [2+3]Pyrroline annulation 3:55 intermolecular 3:57 Pyrroline intermediate 5'>'-addition to 6:447,448 1 -Pyrroline-1 -oxide cycloaddition with pentene 12:290 3-(A'-Pyrroliniumyl) propanal with benzyl-3-oxohexanoate 12:293 Pyrrolizidine synthesis of 10:564 Pyrrolizidine alkaloids 13,14,23,483-489,568-571 synthesis of 1:267-275,325,326 from pyrrolidines 14:568-571 total synthesis of 3:49-55 Pyrrolo[l,2-a] indoles 13:437 Pyrrolo-2(5//)-ones 13:110,112,113,117,118,120130,133,136,139,140,144,150 Pyrroloindole 1:178,180 Pyrroloquinoline alkaloids 7:444 Pyrroloquinoline quinone 9:581 1-Pyrrolylaceticacid 19:18 Pyrromethene 9:592,593 Pyrromycin 4:317 8-Pyrromycinone 11:120 Pyrromycinone 4:330 synthesis of 4:330 Pyruvate 20:855-859 Pyruvate kinase 11:208 Pyruvate orthophosphate dikinase from Propionibacterium shermanii 11:182 Pythium acanthicum 5:276 Pythiumsp. 5:276 Pythium ultimum 7:183,190 Pytophthora cinnamomi S'216

Quadrature detection 9:97 (-)-Quadrone 16:127 (+)-Quadrone 4:674 Quadrupole mass spectrometers 9:487 Quantamycin synthesis of 1:429,430 Quasi-dimeric-type alkaloid ceridimine 5:111 Quasi-molecular ions 2:4,43,47 Quassi excelsia 7:124 Quassia amara quassinfrom 7:392 Quassia amora 7:124 Quassimarin synthesis of 11:79,80,95-105 Quassin 11:71,105 15 (3-acyloxyquassin from 11:79,80 synthesis of 11:73-76 (+)-Quassin synthesis of 11:76,77 Quassin 7:124,392,396 f^om Quassia amara 7:392 Quassinoids '^C-NMR spectrum of 5:38-40 ^H-NMR spectrum of 5:39-41 antileukaemic activity of 7:382-387 antimalarial activity of 7:391-394 antitumor 11:71-111 APT spectrum of 5:39 CSCM ID spectrum of 5:39 DEPT spectrum of 5:39 from Brucea antidysenterica 7:374-376 from Brucea javanica 7:377-379 metabolism of 7:388 SFORD spectrum of 5:38 SINEPT spectrum of 5:39 synthesis of 11:71-111 toxicity of 7:388,389 Quaternary carbon 8:3-14,14:631-644 asymmetric 10:405-412,426-428 asymmetric induction of 10:412 chiral construction of 14:631-644 synthesis of 8:3-14 through addition elimination process 4:4-27; 14:631-644 Quatemization 6:513,514 by 4-nitrobenzyl bromide 6:513,514 Quebrachamine synthesis of 14:632-636;19:143 Quebrachidine 5:127,9:183,13:405 Quebrachidine-type alkaloids 14-ethoxy-15,18-oxido-quebrachidine (hyderabadine) 5:78 quebrachidine 5:78 tetraphyllicine 5:79 tetraphyllicine monomethoxybenzoate 5:79 tetraphyllicine trimethoxybenzoate 5:79 Quebrachitol 10:521,522 D-and I-Quebrachitol 18:396 I-Quebrachitol 13:190,201,219;18:439 valiolamine from 13:199

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Queen substance synthesis of 4:554,555 Quercetagetin 7:227 Quercetin-3-methyl ether &om Salvia limbata 20:712 Quercetin 5:652,7:206,227,15:460;20:782 Quiesone 9:219,220 Quillaic acid 7:155,156 Quinaldic acid 20:118 by Streptomyces azurens 11:209,210 from I-tryptophan 11:209,210 Quinghaosu 7:238 (-)-Quinic acid 13:201,422 Quinic acid enoate triol from 12:15 derivatives of 17:144 Quinine 3:385,7:424,13:656 Quinizirine attachment of sugars 4:350 Quinocarcin absolute configuration of 10:126 antitumor activity of 10:117 chemical modification of 19:290 inhibitor of DNA 19:290 structure of 19:289 structure-activity relationship of 19:289 synthesis of 1:341,342;10:120-141 (-)-Quinocarcin absolute stereochemistry of 19:311 antimicrobial activity of 19:289 antitumor activity of 19:289 isolation of 19:289 retro-synthetic plan of 19:311 total synthesis of 19:311-316 Quinocarcinamide retrosynthetic analysis of 19:304-305 structure of 19:289 Quinocarcinol 19:289,291 pharmacological activity of 19:290 ()-Quinocarcinol 19:293-294 retrosynthetic analysis of 19:293-294 Quinocarcins pharmacological activity of 10:115-117 transformation of 10:119-120 o-Quinodimethanes generation of 4:582,583 Quinoline alkaloids 13:662 Quinoline quinone methide 2:128 Quinoline-5-carboxylic acid isokomarovine from 14:763 komarovidine from 14:763 Quinoline-6-carboxaldehyde 14:763 komarovidine from 14:763 Quinoline-8-carboxaldehyde 14:763 Quinolines 10:185;20:517,518 Quinolizidine alkaloids 13:483-489,732-742 biosynthesis of 14:738,739 synthesis of l:365-367;14:732-738 Quinolizidines nitrogen inversion in 1:369 ^ra5 to cw epimerization 1:369

Quinolone alkaloids dimeric 2:121 Quinone 5:429-441,754,821,822 o-Quinone 5:434 Quinone methide 5:464-466,487,492,744,745,747 o-Quinone methides 4:582,583 Quinone-Diels-Alder adducts 16:548 Quinone-methide triterpenes 5:745 Quinone-styrene reaction 16:547,551-552,559,560,564, 565 Lewis-acid promoted 16:565 Quinonemethide 5-isopropylidene-3,8-dimethyl-1 azulenone 14:320 Quinonemethide compounds 2:408 Quinones molluscicidal activity of 7:427 Quinonoid 7:408 Quinoproteins 9:581 Quinovicacid 7:218,60 derivatives of 17:123 glycosides of 17:124-125 antiviral activity of 17:134 from Artemisia vulgaris I'.l 18 D-Quinovose 7:268,270,273,275,277,278,190 Quinovose 7:270,272,275,286-289,292,293,302 Quinuclidine derivative 1:112

Rabbit muscle aldolase (RAMA) 11:467 Rabbit pancreas by staurosporine 12:390 study of protein kinase in 12:390 Rabbit veins study of protein kinase in 12:390 Rabdocoetsm B from Rabdosia coetsa 15:171 Rabdocoetsin C 15:171 from Rabdosia coetsa 15:171 Rabdocoetsin D 15:138 ^^C-nmrof 15:155 from Rabdosia coetsa 15:171 *H-nmrof 15:146 Rabdoepigibberellolide from Rabdosia shikokiana 15:112 Rabdoforrestin A 15:120 ^^C-nmrof 15:134 from Rabdosia forresti 15:171 ^H-nmrof 15:127 Rabdohakusin 15:162,63 ^^C-nmrof 15:165 from Rabdosia umbrosa var. hakusanensin 15:175 ^H-nmrof 15:164 Rabdoinflexin A 15:140,149,157,172 ^^C-nmrof 15:157 from Rabdosia inflexa 15:172 'H-nmrof 15:149 Rabdoinflexin B 15:118 ^^C-nmrof 15:132 from Rabdosia inflexa 15:172 'H-nmrof 15:125

1161 Rabdokaurin A 15:138 '^C-nmrof 15:155 from Rabdosia longituba 15:173 'H-nmrof 15:146 Rabdokaurin B 15:143 ^^C-nmrof 15:161 from Rabdosia longituba 15:173 'H-mnrof 15:152 RabdokuminA 15:118 ^^C-mnrof 15:132 from Rabdosia kunmingensis 15:172 'H-nmrof 15:125 RabdokumninB 15:116 '^C-nmrof 15:130 from Rabdosia kunmingensis 15:172 ^H-mm-of 15:123 RabdokunminC 15:118 '^C-mm-of 15:132 from Rabdosia kunm ingensis 15:172 ^H-nmrof 15:125 RabdokunminD 15:118 ^^C-nmrof 15:132 from Rabdosia kunmingensis 15:172 'H-mm-of 15:125 RabdokunminE 15:120 ^^C-nmrof 15:134 from Rabdosia kunmingensis 15:172 ^H-mnrof 15:127 Rabdolasional 15:143,153,162 ^'C-nmrof 15:161 from Rabdosia lasiocarpa 15:172 ^H-nmrof 15:153 Rabdolatifolin 15:162,163 ^^C-mnrof 15:165 from Rabdosia umbrosa 15:175 from Rabdosia umbrosa var. latifolia 15:175 *H-nmrof 15:164 RabdolonginA 15:139 from Rabdosia langituba 15:173 'H-mm-of 15:148 RabdolonginB 15:112 RabdoloxinA 15:119 ^^C-nmrof 15:132 from Rabdosia loxothyrsa 15:173 'H-nmrof 15:126 RabdoloxinB 15:119 *'C-mnrof 15:133 from Rabdosia flexicaulis 15:171 from Rabdosia kunmingensis 15:172 from Rabdosia loxothyrsa 15:173 from Rabdosia parvifolia 15:173 *H-mnrof 15:126 Rabdophyllin G (rabdosin C) 15:112,144,162,176 from Rabdosia gaponica var. glaucocalyx 15:171 from Rabdosia henryi 15:172 from Rabdosia japonica 15:172 from Rabdosia longituba 15:173 from R. macrophylla 15:173 ^H-mnrof 15:153 Rabdophyllin H 15:140 ^^C-nmrof 15:157 ^om Rabdosia macrophylla 15:173 *H-nmrof 15:148 RabdoserrinA 15:140,149 *^C-nmrof 15:157 from Rabdosia inflexa 15:172 from Rabdosia serra 15:174 'H-nmrof 15:172 RabdoserrinB 15:172 RabdoserrinD 15:119,174 Rabdosia amethystoides 15:167 Rabdosia diterpenoids classification of 15:112 Rabdosia eriocalyx 15:176 Rabdosia gerardiana 15:167 Rabdosia glutinosa 15:167 Rabdosia japonica 15:111 Rabdosia laxiflora 15:176 Rabdosia lophanthoides 15:167 Rabdosia macrophylla 15:167 Rabdosia occidentalis 15:176 Rabdosia parvifolia 15:167 Rabdosia shikokiana 15:162,176 rabdoepigibberellolide from 15:112 Rabdosia species diterpenoids from 15:111-185 Rabdosia stracheyl 15:167 Rabdosia trichocarpa 15:13 5,176 Rabdosichuanin A 15:142 *^C-nmrof 15:159 from Rabdosia setschwanensis 15:174 *H-nmrof 15:151 Rabdosichuanin B 15:141 '^C-nmrof 15:158 from Rabdosia setschwanensis 15:174 'H-nmrof 15:150 Rabdosichuanin C 15:142 '^C-nmrof 15:159 from Rabdosia setschwanensis 15:174 'H-nmrof 15:151 Rabdosichuanin D 15:140 ^C-nmrof 15:157 from Rabdosia setschwanensis 15:174 ^H-nmrof 15:148 Rabdosidel 15:140 *'C-nmrof 15:157 from Rabdosia eriocalyx 15:171 ^H-nmrof 15:148 Rabdoside2 15:140 *^C-nmrof 15:157 from Rabdosia eriocalyx 15:171 'H-nmrof 15:149 Rabdosin A from Rabdosia japonica 15:172 Rabdosin B 15:112,162 Rabdosin C 15:112 Rabdosinate 15:144 ^C-nmrof 15:161

1162
from Rabdosia gaponica var. glaucocalyx 15:171 from Rabdosia japonica 15:172 'H-nmrof 15:153 Rabdosinatol (glaucocalyxin C) 15:112,116 '^C-nmrof 15:130 from Rabdosia japonica 15:172 ^om Rabdosia japonica \ar. glaucocalyx 15:172 'H-nmrof 15:123 RabdoteminA 15:139 'C-mm-of 15:156 from Rabdosia ternifolia 15:175 *H-nmrof 15:147 RabdoteminB 15:140 *^C-nmrof 15:157 ^om Rabdosia ternifolia 15:175 'H-nmrof 15:148 RabdoteminC 15:139 ^^C-nmrof 15:156 from Rabdosia ternifolia 15:175 'H-nmrof 15:147 Rabdoumbrosanin 15:162,163 '^C-nmrof 15:165 from Rabdosia umbroba 15:175 'H-nmrof 15:164 Rabyuennane A 15:119,133 from Rabdosia yuennanensis 15:175 ^H-nmrof 15:126 Rabyuemiane B 15:119 from Rabdosia yuennanensis 15:175 *H-nmrof 15:126 Rabyuennane C 15:120 ^^C-nmrof 15:134 from Rabdosia yuennanensis 15:175 'H-nmrof 15:127 Racemic alcohol 11:348 by lithium aluminum hydride reduction of methyl ester 11:348 preparation of 11:348 Racemic compactin synthesis of 13:562,563 Raddeanamine 1:201,202 synthesis of 1:201,202 Raddeanidine synthesis of 1:203,204 Raddeanone synthesis of 1:203 Radical chemistry 16:30 "Radical clock" 9:568 Radical coupling reactions 11:464,465 Radical cyclization 1:256-258,292 ofhaloolefms 3:13 of phenylselenyl derivative 3:462 of tertiary alcohol 16:235 stereoselective 19:54 thermal 16:41 tin mediated 1:483,490 with R3 SnH 3:38 Radical induced deoxygenations of carbohydrates 14:157-162 Radical mechanism 14:166 Radical Michael addition 12:281 Radical olefin cyclization 3:327 Radical polymerization 6:541,542 Radical reduction 2-deoxy-1 -hydroxysugars from 11:141 of dithiocarbonates 3:475 Radical spirocyclization 16:28,33,35,41,51,53,63 thermal 16:55 Radical-alkene cyclization 3:327,328 Radicinin 9:417,418 Radioimmunoassay 2:368,92,114,115;15:361,500; 19:628 of(+)-carvone 7:114,115 of(-)-carvone 7:114,115 Radula complanata 2:283 Radula kojana 2:283 Radulaperrottetii 2:283 Raeedeanine synthesis of 1:203,205,206 Rahydroshikoccin 15:167 Rainbow trout eggs polysialoglycoprotein of 11:429 RAMA (rabbit muscle aldolase) 11:467 RAMA-catalyzed reaction 14:176 Ramalina usnea 5:310,313 Ramberg-Backlund olefmation 18:205,206 Ramberg-Backlund reaction 8:208 Ramulosin from Pestalotia ramulosa 16:3 Random Bi-Bi process 11:201 Raney nickel 6:150,151 desulfiirization 11:357 catalytic hydrogenation with 6:425 Raney nickel desulfiirization 1:66;14:736,828 Rankinidine 9:196,472 Ranunculaceae 7:427 Rao synthesis ofisozonarol 6:17 ofzonarol 6:17 Rapanea laetevirens 9:321 Rapanone 7:183 Raphanation 4:227 Raphanus sativus 19:247 homoteasterone from 18:507 Raphidophyceae I,II 6:134 Ras fiinction inhibitors compactin 15:450,451 oxanosine 15:449 Ras oncogene 15:441 Rat brain protein kinase C 12:389 Ratibida columnifera 19:771 Rattle box 1:514 Raucubaine 9:183,184 Raucubainine 9:183 Rauflorine 9:183 Raumacline 13:390,391 Rauniticine 9:171 Rauwolfia alkaloids 14:553,19:748 Rauwolfia heterophylla 1:125 Rauwolfia nitida 1:125,126 Rauwolfia sellowii 1:125 Rauwolfia serpentina 660;19:748 1:125,126,283,390;2:369;13:629,

1163 deserpidine from 8:283 reserpine from 8:283 Rauwolfia suaveolens 13:390,411 Rauwolfia tetraphylla 1:126 Rauwolfia verticil Iata 13:391 Rauwolfia vomitoria 1:125,427 Rauwolscine 8:395,400,429 Ravidomycin 10:343 C-glycoside analogues of 10:374 Reaction mechanism of asymmetric intramolecular Michael reaction 14:561,562 Rearranged abietane diterpenes 20:680-688 Rearranged lanostanes 5:750 Rearranged quinone-methide 5:744,745 [3,3]-Rearrangement 10:236 1,2-Rearrangement 10:412 of P,Y-epoxy alcohols 10:412 Rearrangement 3:467,342,480,355-387;10:233-236 in C-glucoside synthesis 3:225-228 intramolecular 3:226-228 of substituted hydronaphthalene 14:355-387 of [4.3.1 ]-bicyclodecanes 14:355 anionic 3:467 of sulfonyl group 6:342 of 1-benzyl tetrahydroisoquinoline system 6:480 reductive 3:227 Rearrangement of camphor 2,6-hydride shifts in 4:626,627 2,3-exo-mQthy\ shifts in 4:626,627,633,634 1,2-Rearrangement reaction from pyranosides 10:592,593 pinacoltype 10:592,593 Rebaudioside A 15:16 Rebaudioside B 15:17 Rebaudioside C 15:16 Rebeccamycin 5:55,56 aglyconeof 1:15,19 antitumor activity 1:394 biosynthesis of 12:374 from Saccharothrix aerocolonigenes 12:366,368, 374 synthesis of 1:21 synthesis of aglycone 1:15,19 Receptivity 9:110 of "O 9:110 of'^S 9:110 of^'Se 9:110 of'^^Te 9:110 a2 Receptor 8:395-397,399 Recifeiolide synthesis of 4:573 total synthesis of 8:176 Recinoleic acid 13:308-310,312,313,315 Recombinant DNA 7:122 Recombinant DNA methods 2:352-360 Recombinant DNA techniques 7:29,609 Recombinant DNA technology 2:322 Recombination energy ofNO^ 2:3

Red-Al 19:482 reduction with 6:289,290 Red-Pigment Concentration Hormone (RPCH) 19:656 Reducing agents 19:120 3a-Reductase 19:636 3P-Reductase 19:636 Reduction 1:10,131,315,316,386,592-595,698-701,2830,33,155-159,165,166;3:253,237,339-345,358,590, 660,718;6:115,116,119,124,126,129,229,285,286,288, 289,292,295,296,298,299,428,426,509,511-515; 8:6,7,19,23,34,162,163,165,181,322,323,388,8184,87,91-93,98-100,103-106,288;ll:364-366;12:151, 152,281,283,283,287,290,297,300,301,411,414; 13:54,58,72,499-502,19,45;16:155,294,295, 301,307,348 2-amino alcohol by 12:411,414 acetal/ketal cleavage 1:591-595 asymmetric 4:339-345 baker's yeast 19:129 by Ueno method 10:322,323 catalytic 19:475 chelation controlled 3:253 chemoselective 16:307;19:299,19:329 diastereoselective 1:591-595;14:499-502;19:334 during FAB mass spectra 2:28-30,33,35 enantioselective 13:54 enzymatic 13:58 H-H-C-Relayed '^C-^H correlation spectrum 2:101 intramolecular 12:283;16:420 1-selectride 11:365,366 of()-2-oxoindolizine 12:284 of(-)-camphorquinone 4:660 of 17-oxoellipticine 6:509,511 of 1-piperideines 6:426 of2-enals 20:831-839 of2-enoates 20:824 of 2-methylseleno-2-phenyl-6-heptene 8:7 of 2-0X0 carboxylates 20:840-842 of3-ketofrichothecene 6:229 of7-oxoindolizidine 12:286,287 of8-azido-l-/?-menthene 11:288 of allyl alcohol 20:831-839 of allylic alcohol 16:348 of amide 19:145 ofazide 16:19 of carbonyl group 19:226,229 ofC-C double bond 20:824 of conjugated double bond 16:155 ofC-Sebond 8:7 ofcuparenones 8:6 of cyclic P-keto esters 1:697-701 of cyclopropane carbonitrile 12:287 ofenamines 1:386 of exocyclic double bond 19:53 of ejco-methylene-y-lactone carbonyl 1:315,316 offamesal 8:19 offiimarates 20:831-839 ofhalide 11:364 ofimines 6:426,428 ofindolizomycin 12:301 ofisoxazolidine 12:290 of keto group 16:348

1164

of keto lactone 16:301 of ketones 1:131 of kingiside-aglycone-O-silyl ether 16:307 of lactone to lactol 1:315,316 of A^-P-oxy-17-oxoellipticine 6:511 of primary mesylate 16:19 of symmetrical diketones 19:129 ofTiCl3(DME) 8:19 of titanium trichloride 11:3 64 of a,p-acetylenic ketones 13:72 of a-amino ketones 12:411,414 of a-halo ketones 19:193 regioselective 6:288,289;16:135 selective 19:119,228 stereoselective 11:91;12:151,152;19:259, 473-474, 476 stereospecific 11:98 //;reo-selective of 12:300 under Luche conditions 12:297;19:357 with (5)-Alpine-hydride 19:158 with Baker's yeast 12:281 withBH3-Me2S 12:281 withBuzAlH 8:163 with Bu3SnCl-NaBH4 1:512 with Clostridium formicoaceticum 20:831-839 with Clostridium thermoaceticum 20:861 withDIBAH 6:426 withDIBAL 6:285,286;8:165;16:295 with diisobutyl aluminium hydride 1:315,326;4:589, 590;6:115,116;11:105,106 with EtsSiH/BFs 10:388 with hydrazine 1:131 with K-selectride 12:151,152 withLAH 19:475 withLiAia, 8:23,162,163,181 with lithium aluminum hydride 11:364 with lithium triethylborohydride 11:83,84 with I-Selectride 6:2989,299;19:147 withNaBHaCN, 8:162 with NaBH4 16:348 withNaBH4/Mo03 4:237 withNaBH4/NiCl2 4:237 withNaCNBH3 1:386 withNiCl3-NaBH4 3:165,253 withPhsP 12:281 withRaneyNi 16:294 with REDAL 6:288,289 with Selectride 8:181 with sodium borohydride 19:296 with sodium cyanoborohydride 11:87 with sodium dithionite 16:45 with sodium hydrotelluride 11:81,82,92,93 withTiCU 1:591-595 with trialkyl aluminium 6:426 with tributyl tin hydride 4:718 with tri-A^-butyltin hydride 8:34 with yeast 1:697-701 with zinc/copper couple 11:364 Reductive elimination 19:6 Reduction of substrate 17:495 Reductive acetylation 4:232,324

Reductive alkylation of a(phenylthio) methyl enone 10:409 Reductive amination 1:253,289,290,301 ;11:302,350, 429,437,438,445,446,450 with acetone/cyanoborohydride 11:301,302 of 1,4-diketones 6:437,438 of ketones 6:429 triketones 6:445,446 2,6,9-undecatrione 6:450 Reductive aminocyclization ofalkane-2,6-diones 6:433,434 Reductive cleavage withLAH 1:439 Reductive cyclization 1:106,279,281 indolizidine from 11:241,242 ofketones 11:241,242 Reductive decyanation of 2,6-dialy-2-cyanopiperidines 6:431,432 Reductive demercuration 14:185 Reductive desulfurization 12:81,167,307-309,319 Reductive elimination ofacyloxysulfones 4:522 of allylic radicals 4:525 with low valent titanium 4:521-535 with zinc copper couple 4:119 Reductive hydrolysis 19:155 Reductive methylation 4:55;6:553,554 Reductive A^-methylation m ant alkaloids synthesis 6:435,443 Reductive opening with Et3AlCl-CH2Cl2/Et3SiH 1:519 Reductive oxygenation withNaBH4-DMF-02 10:532 Reductive ozonolysis 4:523 Reductive rearrangement 3:253 of 3,4,6-tri-O-acetyl-D-glucal 3:253 Reductive transposition in ()-pachydictyol-A synthesis 6:11 Reflectance fluorometry 9:453 Reflexin 4:712 Reformatsky reaction 1:312,313,520,41 ;8:232;14:478, 727;20:569 ofethylbromodifluoroacetate 16:727 of chiral 2-bromopropionic acid derivative 12:166 P-selectivity of 12:167 with 4-acetoxy P-lactam 12:166 vinylogous 3:38,39 Refractive index detection 9:462 Regio-pyranocoumarins 18:993 Regioselective ketalization 11:315,316 oxymercuration 11:324 ring expansion 11:280,281 Regioselective acylation 12:346,404 Regioselective alkylation 6:546,547 Regioselective aza-annulation 18:319,327 Regioselective P-glycosylation 10:477 Regioselective dehydration 13:561 Regioselective Diels-Alder reaction 14:48 Regioselective glycosidation 6:262 Regioselective hydroboration 13:130 Regioselective Michael addition 18:319

1165

Regioselective nucleophilic substitution 18:406 Regioselective phosphorylation 18:399 Regioselective reduction 6:289,290 Regioselective tosylation 12:218 Regioselectivity 4:372,373,391118,142 in Diels-Alder reactions 4:584-586 of C-aryl glycoside 11:142 of 2-substituted 1,2,3,4-tetrahydronaphthaiene acetate 11:118 of Claisen rearrangement 4:368,369 ofFriedel-Craftsalkylations 4:391 ofhydroboration 4:116 Regiospecific cleavage ofoxiranering 11:267,268 Regiospecific enolization 12:84 Regiospecific lithiation of l-(phenylsulfonyl) indole 6:509,510 Regiospecific oxidation ofellipticine 6:508 17-oxoellipticine from 6:508 Regiospecific sulphonation of camphor 4:633 Regiospecificity of Friedel-Crafls allylations 4:391 Reguiaroside B 15:51,52 Regularosides A,B 7:290,293,299 Reichstein substance-S 21-acetate of 9:417 17,21-diacetateof 9:416,417 3-enol-17,21-triacetate of 9:416,417 17-monoacetateof 9:416,417 Reimer-Tiemann reaction ^^C-Relaxation measurements 2:67,68 ^H-Relaxation measurements 2:67,68 of phenol 8:33,34 Reissantia indica 5:743,744,749 Reissantiatrol oxide 5:744,748 Reissantiol oxide 5:744,748,750 Relative configuration 5:704,39-59,261 ofbisabolones 8:39-59 of(+)-castanospermine 12:332 of2-hydroxyindolizidines 12:284 of(-)-slaframine 12:309,310 of (-)-swainsonine 12:313 of antibiotics 6:261 oflienomycin 6:261 ofpimaricin 6:261 of pyrrolidine venom alkaloids 6:435 of tetramycines A,B 6:261 oftetrols 5:705 Relative stereochemistry 9:18-23 oftaxanes 12:191 Relayed COSY 9:151,152 Relectional symmetry 7:3 Remote flinctionalisation 7:166-168 of camphor 4:625-697 Remote oxidation 4:645,646 of (+)-bomyl acetate 4:645,646 of(+)-camphor 4:645,646 of (+)-isobomyl acetate 4:645,646 Renal dipeptidase insensitivity with 13:84

Renghol 9:319 Rengyo antibacterial effect of 16:576 as antinflammatory agent 16:576 Rengyol synthesis of 16:587-588 Rengyolone 16:616 Rengyoside synthesis of 16:584-587 Rengyoside A synthesis of 16:587-588 Rengyoside B reduction of 16:587 synthesis of 16:584-587 Rengyoside C synthesis of 16:588-592 Reniera s^QCXQS 10:79 Renieramycin A synthesis of 10:97-100 Renieramycm analogues 10:100 Renieramycin B 10:79,97 Renieramycin C 10:79,97 Renieramycin D 10:79,97 Renieramycin E 10:79 Renieramycin F 10:79 ReniforminA 15:112 ReniforminB 15:119,126,133,172 ReniforminC 15:137,145,154,172 Renilla koellikeri 9:493,494 Repellant activity 20:248 Replacement of sulfur by oxygen 1:560 by [2,3]-sigmatropic rearrangement of sulfoxide 1:560 Reserpine 1:159 conversion to 3,4,5,6-tetradehydroreserpine 1:159 oxidation of 1:159 photochemical oxidation of 1:159 reaction with eerie sulfate 1:159 Replic plating technique 7:115 Reproduction of chirality 4:345 Resacetophenone 4:388,389 Rescinnamidine 9:174 Rescinnamine 9:174,19:748 Reserpiline 5:128 Reserpine 2:369,399,400,415,283,174,410, 13:631,267;18:64 from levoglucosenone 14:267 synthesis of 14:267 synthetic approaches to 3:339,400,415 Resolution 1:319,324-327 diastereomeric 1:585-588 kmetic 1:589 through chu-al ketones 1:585-588 ofketones 4:342,325 of racemic anthracyclinones 4:319 with Ender's reagent 4:327 with (-)-N-methylephedrin 4:326 with (+)-threitol 4:324,325 Resonance frequency 9:110 of ^^O 9:110 o f " S 9:110

1166

of^^Se 9:110 of ^^^Te 9:110 Resorcinol 9:341 Resorcinol dimethyl ether 14:692,693 p-Resorcylic acid 13:539 Respiration in birds 5:858,859 Restriction enzymes 13:636 Resveratpole 20:782 R-Reticuline 18:53,54 Reticulatacin 17:270;18:205 hemi-synthesis of 18:219,220 Reticulatamol 18:212 Reticulatamone 18:195,212 Reticuline 11:205 (i?)-Reticuline 20:291,20:292 (5)-Reticuline 8:53,14:771 Reticulose 20:531 Retigeranic acid 3:5,6,8,67 synthesis of 3:10 retroaldolization 3:74,75,100,101 retronecine 3:54 (-)-Retigeranic acid A 13:23-25 from Loberia retigera 13:22 X-ray crystal structure of 13:22 (-)-Retigeranic acid A 16:227 Retigeranic acid B 13:23-25 (llZ)-Retinal 10:150 Retinal 10:153 trans-Reims^. 527 13-c/s-Retinioic acid 4:526,531-534 synthesis of 4:531-534 Retinoicacid 10:154,20:514 rr^Aw-Retinoic acid 4:527 Retinoic acid analogues synthesis of 4:534,536 13-cw-Retinol synthesis of 4:513-534 Retinyl phosphate synthesis of 8:78 Retro-Michael elimination 12:490 Retro[2+2]cycloadition 19:221 Retro Diels-Alder cleavage 5:634;9:295,300 Retro Diels-Alder fragmentation to secodine 4:40,41 Retro Diels-Alder reaction synthesis of actinidine 4:614,615 synthesis of a-caryopterone 4:612-614 synthesis of crotepoxide 4:162 synthesis of epiepoformine 4:612,613 synthesis of epiepoxydon 4:610 synthesis of epoformine 4:612 synthesis of epoxydon 4:610 synthesis of ligularone 4:615 synthesis of petasalbine 4:615 synthesis of phyllostine 4:610 Retro Michael reaction 14:748 Retro-aldol reaction 7:286,288,291 ;10:168,303,329; 18:284,285 Retro-aldolisation 14:180 Retro aldol process 19:194 Retro-ene reaction 11:46,47,16:246

Retro-Mannich reaction 1:157,158;6:497;10:682,99, 333;11:55,56;13:181,397,423,460;18:18 of 0-quinol acetate 16:521 Retro-Prins reaction of 16:248 Retro-Wittig reaction 18:78,176 Retro-Aldol degradation 12:216 Retro-Aldol fragmentation 12:212 Retroaldolization 4:4,7,56 Retrochinensin synthesis of 17:335 Retrograde aldol reaction 6:78 Retrograde Michael reaction 6:173,187,199,200 Retronecic acid synthesis of 1:264-266 Retronecine 8:222,223,13:484,485,14:568,19:489 coupling reagent 1:268,269 chiral synthesis of 19:489 synthesis of 1:228,231,232,234-239,241,246,249, 325,326 unnatural monoesters of 1:268 Retroprotoberberines biogenesis of 1:218,219 Retrosynthesis 4:20 of 5,1 OP-ethanophenanthridine nucleus 4:4,5 ofgalanthamine 4:4,5 oflycoramine 4:4,5 ofmesembrine 4:4,5 of 0-methyljoubertiamine 4:4,5 ofpretazetting 4:4,5 Retrosynthetic analysis ofaristolasicone 11:306,315,316 of (+)-aristoserratine 11:296 of amphotericin B 6:261-263 Retulinal 1:36 Retuline 1:38,39 Reverse Michael addition 3:473,25 Reverse transcriptase 4:267 Reversed-phase HPLC 5:651-659 Reversible inhibitors glycosidase mhibitors as 7:40 Reversion of asymmetric induction 4:123 Reymosin 7:232 Rh (Il)-catalyzed carbenoid insertion 13:501,502 a-Rhammosidation reaction 8:359 Rhamnazin 7:228 Rhamnocitrin 7:228 Rhamnomannans 5:303,305,309,325 Rhamnopyranosides 5:657 I-Rhamnopyranosyl 15:7 P-I-Rhamnopyranosyl glycosides 7:70 9-(a-I-Rhanmopyranosyl purines synthesis of 4:233 Z,-Rhamnose 1:261,387,144,181 synthesis of 1:510 furaneolfrom 13:318 Rhamnosidase 7:70 a-I-Rhamnosidase 7:70 from Aspergillus niger 1:1{) Rhamnosidation 8:359 ofcholestanol 8:366 of cholesterol 8:366

1167

a-Rhamnosides 8:359,366 P-Rhamnosides 8:366 Rhamnosyl chloride 8:359-362,368,369 (2,3,4-Tri-O-benzyl-a-L-rhamnosyl chloride) thermal glycosidation with 8:359-362,368,369 (-)-(/ra5-4'-Rhamnosyloxy-3'-methoxycinnamoyl) lupinine from Lupinus luteus 15:521 (-)-(^m5-4'-a-Z-Rhamnosyloxy-ciimamoyl)epilupinine from Lupinus hirsutus 15:521 (-)-(rra5-4'-Rhamnosyloxy-cimiamoyl) lupinine 15:521 (-)-(c-4'-a-I-Rhamnosyloxy-cinnamoyl) epi- lupinine from Lupinus hirsutus 15:521 Rhatannins 17:439 Rhazigine 5:144 biogenesis of 5:144 Rhazimanine 9:170,172 Rhazimine 5:180,181 Rhazine (-akuammidine) 13:403 Rhazizine 5:178-180 Rhazya stricta 5:135,140-144,150,152,153,165,167, 169,176,178 Rheum palmatum 17:421,439 Rheumatic inflammations 5:745 Rhinotermitidae 19:118 Rhipocephalus phoenix 18:689 Rhizocotonia solani 7:190 Rhizoctonia 9:203 Rhizoctonia leguminicola 7:11 ;19:468 (-H15',2/?,8aS)-indolizidine-l,2-diol from 12:303 slaframine from 12:306 (-)-swainsonine from 12:313 Rhizoctonia solani 13:233,234 Rhizophora apiculata 7:180-182,189,194,195 Rhizophora mangle 7:175 Rhizophora mucronata 7:176,180,188,189,192,194,195 Rhizophora sp. 7:176 Rhizophora stylosa 7:179-181,193 Rhizophoraceae 7:175,184,189,191-193 Rhizophorine 7:192 Rhizopus arrhizus 17:629 Rhizopus delemar 2:322,341 Rhizopus nigricans 17:629 Rhizopus niveus 2:322,341 glucoamylase from 7:49 Rhizopus sp. 2:322,323,276 glucoamylase from 2:341 Rho plus values 17:553 Rhodium catalytic hydrogenation with 6:424 Rhodium (1) decarbonylation by 1:177-179 Rhodium catalyst in carbene insertion reaction 4:436 Rhodium catalyzed isomerization 4:22,23 Rhodoccus rhodocrous 8:299,302,303,312 muconolactone methyl isomerase from 8:307 Rhododendron chrysanthum 20:17 Rhododendronferrugineum 20:17 Rhododendron hirsutum 20:17 Rhododendron luteum 20:17

Rhododendron molle rhomitoxin from 13:660 Rhododendron ponticum 20:17 Rhododendron simsii 20:17 Rhodomelaceae 9:81 Rhodomelol 4:712,725 p-Rhodomycinone enantioselective synthesis of 4:347,348 (-)-Y-Rhodomycinone enantioselective synthesis of 14:14-17 Rhodomycinones synthesis from amino acids 4:345-349 synthesis from hydroxy acids 4:345-349 Rhodophida bifida 20:356 Rhodophyceae 6:134 Rhodophyllis membranacera 5:410 Rhodopin 18:823;20:591,592 Rhodosamine 4:317 Rhodotorula glutinis 5:292,309 Rhodotorula lactosa IF01424 13:233 Rhodotorula minuta 5:292,299 Rhodotorula peneaus 5:292 Rhodotorula rubra torularhodin from 7:340 Rhodotorula sp. 5:291,292 Rhodotoxin 20:17 Rhodoxanthin 20:118 Rhoeadine biogenesis of 1:218,219 Rhoeadine alkaloids 1:187,189 from indenobenzazepines 1:212-214 from spirobenzylisoquinolines 1:212-214 synthesis of 1:212-217 Rhoeagenine synthesis of 1:213,213 Rhomitoxin 13:660 RHPLC 9:333 Rhus species 9:337 Rhus succendanea 9:319 Rhus toxicodendron 9:318,328,339 Rhus toxicodendron diversilobum 9:318 Rhus toxicodendron radicans 9:318 Rhus vernicifera 9:318,328,329,331,339 Rhynchoidomonas 2:298 Rhynchophylline ent-allo A-\l-demethoxy 5:127 Rhynchophylline-type alkaoids ent-allo'A-17-demethoxyrhynchophy Uine (eatharinensine) 5:83,84 Rhytidoponera aciculata 5:224,229,254 Rhytidoponera chalybaea 5:224,225,229,246,254 Rhytidoponera metallica 5:224,226,229,243-247,251, 252,254,255,262,266,15:384 Rhytidoponera sp. 5:230,247 Rhytidoponera victoriae 5:223,224,229,251,254 Ribes nigrum 20:721 Ribi cell fractionator 19:694 Ribitol synthesis of 4:510 Riboflavm 20:730,773 D-Ribo-hexitol C2-P bond analog of 6:357,358

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D-Ribo-hexofiiranose 2-azido-Z)-arabino-hexofuranoses from 6:369 from D-allofliranose 6:369 D-Ribofiiranoses phosphorus analogs of 6:352,355,359,363-366,368 synthesis of 6:363,364 P- Ribofiiranosyl heterocycles 10:369,370 Ribofiiranosylethynes 10:359 D-Ribonolactone 6:292 (4iS)-hy(iroxymethyl butanolide from 6:292 /^-Ribonolactone 19:357 L-Ribonolactone 19:359 Ribonuclease Ti gene synthesis 4:271 Ribonucleotide resin preparation of 4:301 Ribooligonucleotides synthesis of 4:268 Ribosomal protein S6 kinase 12:390 Ribostamycin biosynthesis of 11:216-218 by Streptomyces ribosidificus 11:216 from glucose 11:216-218 D-Riboypyranoses synthesis of 6:366,367 D-Riburanitrose 19:118 Riccardiajackii endesm-ll-en-4-olsfrom 14:450 (-)-selin-l l-en-4a-ol from 14:450 RiccardinA 2:282,283 RiccardinB 2:282,283 RiccardinC 2:282,283 Riccardins 2:109,282,283 distribution in Hepaticae 2:283 structure of 2:109 Rice blast disease 1:404,529 Rice lamina inclination assay 19:248 Richardella dulcifica miraculin from 15:36 Ricinoleic acid 9:387 Riddellinne 7:23 Ridentin 7:231,232 Rieke'szinc 13:146 Rifampicin 9:431-435,439-443,37,38;12:39-47,37,38; 20:714 Rifampin 2:424 synthesis of 12:39-45 total synthesis of 12:46,47 RifamycinS 1:521-528,10:150,153 RifamycinW 10:153 Rifamycins 9:431-435,439-443 Rigidin 10:247 Ring (C)-homoberberin analogue spiro-isoquinoline derivative from 6:496 Stevens rearrangement of 6:496 Ring B-homoberberine analogue 6:496 dibenz [c,g] azacycloundecine derivative from 6:496 reaction with dimsyl sodium 6:496 Ring cleavage 16:139 of(+)-9,10-dibromocamphor 16:139

Ring cleavage reactions of camphor 4:667-673 of camphor derivatives 4:667-673 Ring closure by Mitsunobu procedure 11:10 Ring construction 3:226,310;6:482,474,475 by diazotization 3:225,226 in benzazocine derivative synthesis 6:468-471 in benzoxazocine derivative synthesis 6:468-477 intramolecular 11:42,43 nine-membered rings from 6:474,475 of fiiranosyl nucleoside 10:592-595 of lactone triflate 10:605 oxetanocin A synthesis by 10:592-595 thermal 3:310 to eight-membered rings 3:67,77 to nme-membered rings 3:76 to oxetane-2-carboxylate 10:605 Ring destruction 6:468-471,475-497 by CNBR-induced reaction 6:476,477,484,486 by chloroformate ester-induced reaction 6:477 by photosolvolysis 6:475,476 in benzazocine derivative synthesis 6:468-471 in benzoxazocine derivative synthesis 6:468-471 nine-membered rings formation by 6:468-471 of tetrahydroisoquinoline systems 6:477 Ring enlargement by migration 10:232,233 by rearrangements 10:232,233 Ring expansion 6:468,472,477,478;11:6,7,28-31,109 regioselective 11:6,7 2,4-benzoxazocine derivatives from 6:469 in aporphme alkaloids 6:469 in ()-spiniferin-l synthesis 6:73,74 oferythrinan-3-one 6:477,478 of a-narcotineA^-oxide 6:468 Ring interconversion 6:468-475,478,482-497 in benzoxazocine derivative synthesis 6:468-471 in benzoxazocine derivative synthesis 6:468-471 nine-membered rings from 6:468-471 Rmg opening 12:411,413 2-amino alcohol by 12:411,413 ofoxu-ans 12:411,413 with nitrogen nucleophiles 12:411,413 Ring transformation 10:303-336 Ring transposition procedure 6:374,375 Ring-phosphino-)-xylopyranoses synthesis of 6:374,375 Ristocetin 10:657-659 Ritter reaction Hg(II)-mediated 11:281,282 Ritterazines 18:881-884 synthesis of 18:900-902 Ritterella sigilloides 5:253 Ritterella tokioka 18:881,882 Rivulalactone 20:473 RNA antisense 13:257-294 synthesis of 13:284-285 Sp6 RNA polymerase enzymatic ribonucleotide synthesis 4:306

1169

T7RNA polymerase enzymatic ribonucleotide synthesis 4:306 /w-RNA polymerase 7:387 RNA polymerase I 13:258,259 RNase II 13:289,290 RNaselll 13:260 Robinson annelation 1:81,446,478,17-21,29;6:30, 18,57,58,55,56,148,182;11:78,93-96,108,678,679,33 bicyclic enone from 14:678,679 of()-carbomenthone 6:547,548 of 2-carboethoxycyclohexanone 14:678,679 of ethyl vinyl ketone 14:678,679 ofcycloheptenoneenolate 6:29,30 ofethyl vinyl ketone 6:19 of 2-methyl-1,3-cyclohexadione 6:19 trimethyl decalone by 6:19,20 Robinson annulation reaction 13: chiral sesquiterpenes from 14:406-425 Robinson-Schopf condensation 1:294,295 Robustic acid by C-prenylation 4:382,384 from desoxybenzoin 4:382,384 Rocaglamide antileukaemic activity of 16:565 synthesis of 16:565 Rocaltrol 9:513 Roche acid 1:471 Rodobyrum giganteum 2:277 Roemeria species 2:253 (-)-Roemerialinone 2:257,512 ROESY spectrum of oligosaccharides 17:129 Rohituka-3 20:492,493 Rollinia mucosa rolliniastatin from 18:208 Rollinia sylvatica 9:399 Rolliniastatin I 17:262,272 /-Rolliniastatin-1 synthesis of 18:210,211 Rolliniastatin-2 from Rollinia mucosa 18:208 synthesis of 18:208,209 Rollinicin 17:277 Rollinone 17:278 Romalea microptera 9:488,489 Rosa damascena 14:425 a-damascenone from 14:425 P-damascenone from 14:425 y-damascenone from 14:425 a-damascone from 14:425 P-damascone from 14:425 y-damascone from 14:425 5-damascone from 14:425 Rosa damascena cw. trigintipentalla 7:125 Rosa damascena 7:104,107,109-112,125 Rosasp. 7:102,105,107,108,125 Rosaceae 17:421 Rosamine 5:160 Rosane diterpenoids of Vellozia Candida 20:474 Rosaramicin 5:613

Rosaranolide 11:160 synthesis of 11:164 Roscoe 9:321 Rose bengal 1:190 Rosefiiran 19:174 Rose oil components synthesis of 14:425-431 Rose oil ketones (damascones) 14:425 Roseaceae 7:97,119,120 Rosenmund reduction 8:153,154 Rosenolactone synthesis of 19:402 ROSEY 6:140 Rosibiline 9:183 Rosicine 5:170,171 biogenesis of 5:171 Roskamp condition 14:653 Rosmarinecine 1:29,7:15 (-)-Rosmarinecine isolation of 19:149 Rosmarinic acid from Coleus sp. 7:96 Rosmarinus officinalis 7:94,95,108-110,119 RosthorinA 15:139 ^^C-nmrof 15:156 from Rabdosia coesta 15:171 from Rabdosia japonica 15:172 from Rabdosia rosthornii 15:174 ^H-nmrof 15:147 RosthominA 15:123 '^C-nmrof 15:130 from Rabdosia rosthornii 15:174 'H-nmrof 15:116 RosthominB 15:119 '^C-nmrof 15:133 from Rabdosia rosthornii 15:174 ^H-nmrof 15:126 Rotation locular counter current chromatography 7:429 Rotational correlation time 2:61,62 Rotational strength 2:145 Rotational symmetry 7:4 Rotenone 7:193 RothinA,B 7:232 Rothrockene 7:208,209 from Artemisia tridentata sp. nothrockii 7:208 Rous sarcoma 5:592 Roxithromycin 13:169,183 Royleanone 14:684,692 Royleanone from Rabdosia lophanthoides var. gerardiana 15:173 /?-Pulegone 20:272 (/?,5)-2-(4-Chlorophenoxy)-propanots 20:863 Rubescensin C from Rabdosia rubescens 15:174 Rubescensin D 15:163,164,167 '^C-nmrof 15:165 from Rabdosia rubescens 15:174 'H-nmrof 15:164 Rubia cordifolia 10:640,19:776 Rubiaceae 7:417,423,427,9:401,10:640,19:175

1170

RubiflavinA 11:136 Rubixanthin 20:727 Rubottom epoxidation 11:75 Rubottom oxidation 12:215 Rubradirins 9:438,19:118 Rubusfructicosus 20:721 Rubus ideans 20:721 Rubus suavissimus 15:16,18 desglucosylstevioside from 15:14 rubusoside from 15:14 Rubusoside from Rubus suavissimus 15:18 Rufescine 1:167 Rugosanin 15:142,151,159,174 *^C-nmrof 15:159 from Rabdosia rugosa 15:174 'H-nmrof 15:151 endo-K\x\Q 4:568,587 in Diels-Alder reactions 4:586,587 Rupe rearrangement 13:34,35 Rupestomic acid 7:237 RupicolinA,B 7:235 RupinA,B 7:235 ()-Ruspolinone 13:477 /?w55w/a species 17:153 Russulares 17:200 Ruta chalepensis 7:427 Rutaceae 7:427;9:402;13:347,348,355 Ruthenium (III) chloride 12:162 Ruthenium tetraoxide 1:27,28 Ruthenium-catalyzed oxidation 12:175 Rutin 7:228 3-Rutinoside 5-glucoside 5:658 Rydon bromination 6:287,288 Rylander oxidation 12:198 Rzedowskia tolantonguensis 18:756,764

"S 9:109-126 natural abundance of 9:110 respectivity of 9:110 resonance frequency of 9:110 spin quantum number of 9:110 (+)-cw /trans -Sabinene biosynthesis of 11:221,222 from geranyl diphosphate 11:221,222 stereochemistry of 11:222 (-)-Sabinene 16:267 Sabinene 7:98-101;9:530;20:16 Saccharide synthesis of 19:465 Saccharomyces bailii 8:238 Saccharomyces carlsbergensis 19:601 Saccharomyces bailii 1:689 Saccharomyces cerevisiae 1:689,694;2:353,390;3:302, 5:418;10:526;12:103;13:302,307,312;17:241; 18:721, 722,727;20:470 dimethyl allyldiphosphate isomerase from 11:201 Saccharomyces dobzhanskii 5:287 Saccharomyces drosophila 5:287 Saccharomyces lactis 5:287 Saccharomyces lodderi 5:283 Saccharomyces microellipsodes 5:283

Saccharomyces phaseolosporus 5:287 Saccharomyces pretoriensis 5:283 Saccharomyces rosei 5:283 Saccharomyces sake 12:401 Saccharomyces sociasi 5:287 Saccharomyces sp. 5:279 Saccharomyces vager 5:283 Saccharomyces wieckerhamii 5:287 Saccharothrix aerocolonigenes bromorebeccamycin from 12:366,368 11-dechlorobeccamycin from 12:366,368 rebeccamycin from 12:366,368 Saccharothrix mutabilis 19:290 Saccharothrix mutabilis subsp. chichijimaensis 10:117 Saccharum officinarum 15:3 Sacculaplagin 2:81-90 absolute configuration of 2:89 derivative of 2:89 ^H-NMRof 2:82 structure of 2:81-90 sacculaplagin triacetate 2:83-88 ' ^ C , ' H - C 0 S Y spectrum of 2:86 COSY spectrum of 2:83 2D-INADEQUATE spectrum of 2:88 long range '^C,^H-COSY spectrum of 2:87 NOESY spectrum of 2:84,88 Sacculatal 2:278,279,289 piscicidal activity of 2:289 Sacculatane diterpenoids 2:90278,279 Saegusa oxidation reaction 16:430 Saegusa ring expansion 6:37,38 in tricarboxylic epoxide 6:37 SafracinA 10:78,79 SafracinB 10:78,79 Saframycin antibacterial activity of 10:78 antitumor activity of 10:78 synthesis of 10:83-100 transformation of 10:101 -103 Saframycin A 10:77-87,101,103 synthesis of 10:84-87,92-96 Saframycin B 10:77-79,82,86,88-93,101 Saframycin C 10:77-82,86,97 synthesis of 10:101-103 Saframycin D 10:77-79,82,86 synthesis of 10:101-103 Saframycin E 10:77-79 Saframycin F 10:78,79,82 Saframycin G 10:78,79,82,103 Saframycin H 10:78,79 Saframycin Mxl 10:78,79,101,102 Saframycin Mx2 10:78,79 Saframycin R 10:78,79 Saframycin S 10:78,79,101 Saframycin Y3 10:78,79 Safronitrile p-damascenone from 14:430,431 Sage (Salvia officinalis) 11:220 Sakurai reaction 10:182 Sakuranetin 7:207,228

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Salacia 18:741 Salacia macrosperma salaspermic acid from 7:150 Salaspermic acid 7:146,147,167 from Salcia macrosperma 7:150 Salcolene axide 9:534 Salcomine 5:823,824 Salcomine-oxygen 14:780 Salicyclic acids 9:327 Salicyloyl ester of jaeschkeannadiol 5:722,723 Salinomycin 11:152 (+)-Salivene 16:265 Salix pet-susu 20:627 Salix sachalinensis 20:613,627,628,631,641,645 Salmonella 12:63 Salmonella anatum O-antigenfrom 6:262 Salmonella enteritidis 12:401 Salmonella monteyideo 8:102 Salmonella newington 8:101 ;14:233 O-antigenic polysaccharide from 14:233 Salmonella paratyphi 9:308 Salmonella schottmuelleri 9:308 Salmonella thompson 8:102 Salmonella typhi 9:308,12:401 Salmonella typhimurium 5:440;9:214,606;12:401; 20:512 Salmonella typhosa 12:401 Salsolane 9:534 Salutaridine 18:54,58,71,73,20:292 Salutaridinol 18:54,55 Salvia acetobulosa hormonone from 20:673 l-oxofemiginol from 20:673 3-oxoferruginol from 20:673 18-oxoferruginolfrom 20:673 pisiferal from 20:673 sempervirol from 20:673 Salvia candidissima 11 -hydroxy-12-methylabieta-8,11,13-triene 1 Ip-hydroxymanoyl oxide from 20:691 14-oxoisopimaric acid from 20:688 1-oxoethiopinone from 20:680 1-oxosalvipisone from 20:680 3-oxosalvipisone from 20:680 7-acetyhorminone from 20:660 7P-hydroxysandracopimaric acid from 20:688 8,13-di-e/?/-manoyl oxide from 20:691 candidissiol from 20:680 cryptanolfrom 20:660 crysoeriol from 20:712 diosmetinfrom 20:712 ferruginol from 20:660 horminone from 20:660 isopimaric acid from 20:688 manoyl oxide from 20:691 microstegiol from 20:680 montbretyl-12-methyl ether 20:661 salvipisone from 20:680 Salvia divaricata 6-horminone-18-oic acid from 20:661

6-0X0-12-methylroyleanone-18-oic acid from 20:661 P-sitosterol from 20:702 oleanolic acids from 20:702 oxoroyleanone-18-oic acid from 20:661 salvinine from 20:660 ursolic acid from 20:702 Salviaforskahlei 20:672,20:710 Salvia glutinosa 3-acetoxy-olean-9,ll-diene from 20:707 a-amyrin acetate from 20:707 ll-cholest-5-ene-3p,7a-diol-l-one from 20:707 erithrodiol 28-acetate from 20:707 3P-hydroxy-ll-oxo-oleana-12-ene from 20:707 3P-hydroxy-ll-oxo-ursa-12-ene from 20:707 7a-hydroxysitosterol from 20:707 lupeolfrom 20:707 l-oxo-7a-hydroxysitosterol from 20:707 oxo-a-amyrin from 20:707 11-oxo-p-amyrin from 20:707 oleanolic acid from 20:707 stigmasterol from 20:707 sitosterol from 20:707 ursolic acid from 20:707 Salvia heldreichiana 7-0X0-13-e/7/-pimara-8,15-diene-18-oic acid from 20:690 7P-hydroxy sandracopimaric acid from 20:690 di (4,4'-hexyloxy-carbonylphenyl) ether from 20:709 heldrichinic acid from 20:670 isopimaric acid from 20:690 salvigenin from 20:711 Salvia hierosolymitana forskalinone from 20:672 Salvia leucophylla 20:4 Salvia limabata abieta-8,11,13-triene from 20:673 a-amyrin from 20:702 dehydrosalvilimbinol from 20:683 eupatilinfrom 20:712 ferruginol from 20:673 12-hydroxysapriparaquinone from 20:683 3,12-hydroxysapriparaquinone from 20:683 2-hydroxysaprorthoquinone from 20:683 limbinol from 20:683 luteolinfrom 20:712 manoolfrom 20:691 pectolinarigenin from 20:712 quercetin-3-methyl ether from 20:712 salvilimbinol from 20:683 stigmasterol from 20:702 vergatic acid from 20:702 Salvia montbretii 20:666,678,712,704 a-amyrin from 20:704 apigeninfrom 20:712 7,7'-bistaxodione from 20:678 cirsitiolfrom 20:712 3P-0-/ra5-/7-coumroylmonogynol A from 20:704 3p-0-/rflrt5-cw-coumaroylmonogynol A from 20:704

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11,11 '-didehydroxy-7,7'-dihydroxytaxodione from 20:678 demethyleryptojaponol from 20:666 femiginol from 20:666 ferruginyl 12-methyl ether from 20:666 hypargenin F from 20:666 6-hydroxy-salvinolone from 20:666 7-hydroxy-axodione from 20:666 14-hydroxyferruginol from 20:666 luteolinfrom 20:712 lupeol from 20:704 monogynol A from 20:704 oleanolic acid from 20:704 salvinolone from 20:666 salvinolonyl-12-methyl ether from 20:666 P-sitosterol from 20:704 taxodionefrom 20:666 ursoUc acid from 20:704 Salvia multicaulis 7P-hydroxy-3,11 -dioxo-pimara-8( 14), 15-diene from 20:690 horminone from 20:673 12-methyl-5-dehydrohorminone 20:676 12-methyl-5-dehydroacetythorminone 20:676 1-oxoferruginol from 20:673 3-oxoferruginol from 20:673 18-oxoferruginolfrom 20:673 pisiferalfrom 20:673 sempervirol from 20:673 salvipimarone from 20:690 Salvia napifolia 20:670 acetyl-horminone from 20:670 cryptanolfrom 20:670 cryptojaponol from 20:670 ll,12-dioxoabieta-8,13-diene from 20:670 7,20-epoxyroyleanone from 20:670 femiginol from 20:670 horminone from 20:670 1-oxoferruginol from 20:670 6-oxoferruginol from 20:670 pachystazone from 20:670 sugiolfrom 20:670 6,12,14-trihydroxyabieta-6,8,11,13-tetraene from 20:670 Salvia nemorosa apigeninfrom 20:712 a-amyrinfrom 20:702 2a,14-dihydroxydehydroabietic acid from 20:669 eupatilinfrom 20:712 luteolinfrom 20:712 24-methylenecycloartenol from 20:702 nemorosine from 20:669 oleanolic acid from 20:702 salvipisone from 20:683 salvinemoral from 20:702 P-sitosterol from 20:702 stigmast-7-en-3-one from 20:702 stigmast-4-ene-3-one from 20:702 stigmast-7-en-3-ol from 20:702 ursolic acid from 20:702 Salvia miltiorrhiza Cell suspension cultures of 2:402

Salvia officinalis 7:119;11:220 Salvia pomifera a-amyrinfrom 20:702 erithrodiol from 20:705 ferruginyl 12-methyl ether from 20:663 23-hydroxygermanicone from 20:705 18-Hydroxyabieta-8,l l,13-triene-7-one from 20:663 lupeol from 20:702 moradiolfrom 20:705 moronic acid from 20:705 pomiferin A-G from 20:663 P-sitosterol from 20:702 taraxasterol from 20:702 Salvia potentillifolia 20:660 Salviaprionitis 5:31,33,36 Salvia sclarea 7:101,103,110,123;20:660,669,633,691, 712 sclareolfrom 7:121 Salvia species biological investigations of 20:659 chemical investigations of 20:659 Salvia splendens 5:646 Salvia tchihatcheffii 3-acetylerythrodiol from 20:707 28-acetylerythrodiol from 20:707 3-acetyloleanolicaldehyde from 20:707 3P-acetylolean-12-en-28-al from 20:707 salvitchitatine from 20:676 tchitatine from 20:676 Salvia tomentosa femiginol from 20:667 horminone from 20:667 1 -oxo-abieta-8,11,13-triene-18-oic acid from 20:9 Salvia triloba salvigenin from 20:711 Salvia wiedemanni 7P-hydroxysandracopimaric acid from 20:688 isopimaric acid from 20:688 14-oxoisopimaric acid from 20:688 salvigenin from 20:711 Salvia yosgadensis ambrenolide from 20:692 apigenin-7-methyl ether from 20:712 apigenin-4-methyl ether from 20:712 apigenin-7,4-dimethyl ether from 20:712 apigenin-6,4-dimethyl ether from 20:712 apigeninfrom 20:712 6a, 14-dihydroxymanoy 1 oxide-15,17-diene16,19-olidefrom 20:697 6a, 16-dihydroxymanoyl oxide-14,17-diene16,19-olidsfrom 20:697 6a-hydroxyambrenolide from 20:692 6a -hydroxynorambrenolide from 20:692 6a-hydroxy-8a-acetoxy-13,14,15,16tetranorlabdane-12-oic acid 20:692 kaempferol-3-methyl ether from 20:712 luteolinfrom 20:712 norlabdane diterpenoids from 20:692 norambrenolide from 20:692 yosgadensonol from 20:696

1173

13-ep/-yosgadensonol from 20:696 yosgandensolide A and B from 696 Salvigenin from Salvia triloba 20:711 from Salvia heldrichiana 20:711 from. Salvia wiedemannii 20:711 Salvilimbinol from Salvia limbata 20:683 Salvinemorol from Salvia nemorosa 20:702 Salvinine from Salvia divaricata 20:660 Salvinolone APT spectrum of 5:34 *^C-NMR spectrum of 5:33,34 CSCM ID spectrum of 5:34 ^H-NMR spectrum of 5:33,34 INEPT spectrum of 5:34,35 Salvinolone from Salvia montbretii 20:666 Salvinolonyl-12-methyl ether from Salvia montbretii 20:666 Salvipimarone 20:714 from Salvia multicaulis 20:690 Salvipisone from Salvia candidissima 20:680 from Salvia nemorosa 20:683 Salvitchitatine from Salvia tchihatcheffii 20:676 Salvitin 7:206-228 SAM (5-adenosylmethionine) 9:597,601,603,604 Samarium iodide mediated cyclization 8:232 Sambucinic acid 6:213,214,252;9:211 Sambucinol 6:213,214,246 biosynthesis of 6:249,250 Sambucinol 9:207,210-215,216 Sambucoin 6:213,214,237,247,249;9:211 Sambucoinol from sambucoin 6:247 Sandalwood 20:730,774 ()-Sanadaol by intramolecular Michael addition 6:70,71 from bicyclo [2.2.2] octane derivative 6:70,71 synthesis of 6:70-72 Sanadaol (P-crenutal) 6:71 from Dictyota crenulata 6:70 from Pachydictyon coriaceum 6:70 Sandmeyer reaction 16:39 Sanguilutine protoberberines 14:777,778 synthesis of 14:777,778,780,781 Sanguinarine biosynthesis of 14:770,771 from coptisine 14:793-795 synthesis of 14:793-795 through cationic cyclization 14:793-795 Sanguinarine 5:42-46 APT spectrum of 5:45 *^C-NMR spectrum of 5:45 CSCM ID spectrum of 5:46 ^H-NMR spectrum of 5:42

INEPT spectrum of 5:45 SINEPT spectrum of 5:46 Sanguirubine 14:770 Sanguisorba officinalis 17:421,423 polyphenols 17:423 Sanguiwarine 13:662 Y-Sanshool 10:152 P-Santalene asymmetric Diels-Alder reaction 4:607,608 (+)-a-Santalene 4:674;16:136 (+)-p-Santalene 4:675 (+)-ep/-P-Santalene 4:675 (-)-p-Santalene 8:145-148;16:136 synthesis of 8:145 P-Santalol from Santalum album 8:145 (-)-i;-P-Santalol 8:145-147 synthesis of 8:145 (-)-Z-P-Santalol synthesis of 8:145 (+)-a-Santalol 4:674;16:128 (+)-P-Santalol 4:674;16:128;8:145-148 synthesis of 8:145 Santalum album P-santalol from 8:145 Santamarin 7:232 Santin 7:228 (-)-a-Santionin 6:11,12,548;20:760 guaianolide from 6:548 ()-pachyictyol-A from 6:11,12 Santolina chamaecyparissus 7:100,101 P-Santonin 2:163 Santonin from Artemisia maritima 13:660 (-)-a-Santonin eudesmane alcohol from 14:464 photochemical rearrangement of 14:357-360 (l)-a-Santonin synthesis of 14:406-413 6-ep/-a-Santonin (-)-dictyolene from 6:27 i[/-Santonm 7:212,213 a-Santonin 7:212,232 Sapindaceae 7:427 Sapintoxin 7:188,189 Sapium indicum 7:188 4a-sapinine from 7:187 Sapogenin 1:305;9:51,61,73;18:649,650 Sapogenol 7:139,156,157,270,286 Saponification 6:146,162,445,447,19:322 4a-Saponine from Sapium indicum 7:187 Saponins 1:305 ;9:50-64,402;7:155,156,190,426432,434,435;18:649,650 from Caralluma tuberculata 9:62-64 from Guaiacum officinale 9:50-59 from Symphytum officinale 9:60-62 from Zygophyllum propinquum 9:59-62 molluscicidal activity of 7:427,428 ofquillaicacid 7:155,156 structure elucidation of 15:187-224

1174
Saprolegnia parasitica 9:577,578 Saprophyton glaucum papkusterol (glaucasterol) from 9:37 Saprorthoquinone 5:36 Sarasinoside Ai 192 Sarcina lutea 12:401 Sarcinaxanthin 7:355-357,20:597 M5076-Sarcoma 19:289 Sarcomelicepe agyrophylla 20:807 Sarcomelicepe simplieifolia 20:807 Sarcomelicope dogniensis 20:806 Sarcomelicope glance 20:806 Sarcocapnos enneaphylla 3:428 SarcophytolA 10:4,5 Sarcophytol B antileukemic activity 8:18 carbonyl coupling 8:18,19 synthesis of 8:18,19 Sarcophytol B Sarcophyton glaucum 8:18 Sarcosine decarboxylation of 1:335,336 Sarett oxidation 14:635 Sarett reagent 4:434;6:27,28 Sargassum tortile 20:25-27,29,34-36 Sargramostim 13:661 Saringosterol(24-hydroperoxy-24-vinyl-cholesterol) 10:249 Sarisan 7:415 Sarkommycin synthesis of 3:44 Sarkomycin as antitumor agent 8:150 synthesis of 8:150 Sarotherodon nilotica 7:184 Sarpagine 13:384-386,403,427,429 Sarpagine-type indole alkaloids 15:466-471 Sarracenin 3:239 synthesis of 3:44,243 Sarracenin 7:442 Sativene 17:608 (-)-Sativene 4:675 ()-cw -Sativenediol 16:265 Saucy-Marbet rearrangement 10:417 Saururus cernuus 17:319 Saussurea lactone 7:216,237 Savinin as cytotoxic agent 13:653 Saxicola insignis hemoglobin components of 5:837 Saxidomus gigantius 5:3 Saxifragifolins A and B from Androsce saxifragiifolia 15:200 Saxitoxin 5:403;17:3;18:697,698 synthesis of 1:342 Scaberoside Bs 15:211 Scaevola racemigera strychnovoline from 6:522 Scalaradial 6:111 from Dictyoceratidae 6:58 12-ep/-Scalaradial 6:111 from Dictyoceratidae 6:58 Scalarane 6:111,123 Scalarane ring system 6:58 ()-Scalarane-type sesterterpenes synthesis of 6:122-129 Scalarene-type sesterterpenes stereoselective synthesis of 6:107-132 12-ep/-Scalarin 17:10 Scapaniapyrone A 9:95 Sceletium alkaloid At synthesis of 1:333 Sceletium alkaloids synthesis of 4:4,5,8-12 Scenario reaction 8:246 Schaefferia cuneifolia 18:761 Schelhammera spp. 3:455,483 e/7/-Schelhammericine 3:483,484 e/7/-Schelhammeridme synthesis of 3:486,456 Schelhammmera pedunculata 3:484,486 Schelhammmericine 3:501,484 Schiehser-White synthesis ()-9-pupukeanone 6:83,84 Schiffbase 14:175,16:397,401 Schiff s base mechanisms 20:833 Schiff formation 19:42 Schill's synthesis ofvinblastine 14:861,862 Schistocerca 9:498 Schistochila appendiculata 2:280281 Schistosoma haematobium 7:425 Schistosomajaponicum 7:425 Schistosoma mansoni 7:425,428 Schistosomiasis (Bilharzia) 7:405,408,425,426,435 Schistosomicidal activity 1:545 Schizaeaceae 6:194,210 Schizandra sp. 5:462 SchizandrinB 5:461,462 (-)-Schizandrin 20:412 Schizophyllan 5:321 Schizophyllum commune cellulasefrom 8:352 Schizophyllum commune fruiting body formation of 1:680,681 Schizophyllum commune 5:288,316;18:460,813,814 Schizosaccharomyces octosoporus 5:280,286,293 Schizosaccharomycespombe 5:280,286;12:398;18:721 Schizothrix calcicola 18:294,20:586 Schlerochiton ilicifolius 15:335 Schlosser-Wittig reaction 16:482 Schmidt reaction intramolecular 16:472 Schmidt rearrangement 13:95;16:472 Schoberidme 1:125,126 Schoberidine (dihydronitrarine) 14:759 biosynthesis of 14:760 Schoberine biosynthesis of 14:758 from Nitraria schoberi 14:757 X-ray analysis of 14:757 Schoellkopf reagent chiral induction with 10:653,655 Scholaricine 1:32,36;5:176-178

1175

Schollkopf system 4:125 Schollkopf s isocyanides a-metalated 10:88 Schotten-Baumann acylation with 2,2,3-trimethylethanolamine 10:131 Schotten-Baumann reaction 11:448 Schreiber's procedure 6:542 Schwanniomyces alluvius 5:283 Schwanniomyces castelli 5:283 Schweinfurthia papilionaceae alkaloids from 9:75,76,78 Schweinine 9:75,76,78 Scidopitys verticillata 20:107 Scintillation proximity assay 13:646 ScitoneminA 5:429 Sclareol 7:100,101,103,110,122-123 from Nicotiana glutinosa 7:121 from Salvia sclarea 7:121 ;20:691 Scleroglucan 5:279,314 antitumor activity of 5:317 Sclerosporal 6:546 synthesis of 6:549-551 Sclerosporene 6:546 Sclerosporin absolute configuration of 6:549-551 from Sderotiniafructicola 6:546 structure elucidation of 6:546-549 synthesis of 6:546-551 ()-Sclerosporin from (-)-carvone 6:549-551 Sclerotinia 4:246 Sclerotinia cinera 12:401 Sderotiniafructicola 6:546,547 sclerosporin from 6:546 Sclerotinia sclerotiorum 15:385;18:269 Sclerotinin A and B 15:385 Sclerotium cerevisiae 5:279-282,285,323 Sclerotium fermenti 5:280 Sclerotium fragilis 5:280,282 Sclerotium glucani 5:277 Sclerotium glucanicum 5:314 Sclerotium libertiana S'211 Sclerotium rolfsii 5:314 Sclerotium rouxii 5:282 (5) Coclaurin 20:292 Scolytus multistriatis (elm-bark beetle) multistriatin from 14:274 Scolytus multistriatus 19:127 (35,45)-4-methyl-3-heptanol from 11:412 Scolytus multistriatus 15:348 Scolytus scolytus 15:348,349 Scopariosides A-D 15:68 Scoparone 5:515,516 Scopine synthesis of 16:442 Scopodrimol 7:224 Scopofamol 7:204,205,224 Scopolamine 5:515,520,521;13:662 (s)-tropic aicd moiety of antichlolinergic agent 17:395 from Hyoseyamus niger 13:631 from phenylalanine 11:204,206

Scopoletin 5:515,520;7:117,120,204,205,224 analgesic activity of 5:521 hypertensive activity of 5:521 Scopolia genus 17:395 Scopoliajaponica Maxim. atropine from 5:505 Scopolin 5:515,516;7:204,205,224 Scorbethane 4:725 Scorpiurus muricatus 19:117 Scoulerine aromatization of 11:204,205 by ^-tetrahydroprotoberberine oxidase 11:204 to dehydroscoulerine 11:204,205 Scoulerine synthase 13:662 Scripus maritimus 9:391 Scrophularia canina 7:476 Scrophulariaceae 16:295 Sculponeatin A 15:141 *X-nmrof 15:158 from Rabdosia sculponeata 15:174 ^H-nmrof 15:150 Sculponeatin B 15:142 ^X-nmrof 15:159 from Rabdosia sculponeata 15:174 *H-nmrof 15:151 Sculponeatin C 15:141 *X-nmrof 15:158 from Rabdosia sculponeata 15:174 ^H-nmrof 15:150 Sculponeatin D 15:144 *X-nmrof 15:161 from Rabdosia sculponeata 15:174 'H-nmrof 15:153 Scutellaria tenax 5:678 5cv//o-inositol from a-glucosidases 7:37,38 5cv//o-nitrocyclitols 7:157 Scyphyphora hydrophyllaceae 7:176 Scytonemasp. 5:429 SDS micelles 18:832 SDS-electrophoresis 7:284 ^^Se-NMR of phenylselenyl alkanes 9:119 of phenylselenyl cyclohexane 9:119,120 of 1,2,3-selenadazoles 9:121-123 ^^Se 9:109-122 natural abundance of 9:110 respectivity of 9:110 resonance frequency of 9:110 spin quantum number of 9:110 Secale cereale 18:500,502,512,19:247 6,7-Seco-19,20-epoxyangustilobine 9:178 6,7-Seco-6-cyanostemmadenine 9:178 Seco-acid lactonization of 12:52,53 via-2-pyridine thiol ester 12:52,53 Seco-ajmalicine 14:563,564 Seco-analogues 15:229 Seco-iridoids 13:67 Seco-polyol 12:48,49 Seco-Pseudoaspidospermane skeleton 19:104

1176

Seco-taxane synthesis of 12:181,182,203 Seco-yohimbine yohimbine from 14:566,567 9,10-Secoabieta-8,11,13- trien-18,10-olide 13:70 6,7-Secoangustilobine A,B 9:178 2,3-Secoaromadendrane sesquiterpenoids 2:280 Secodehydroabietane 10:407 Secodehydroabietane from pine tall oil 14:642 synthesis of 14:642 Secodeoxybouvardin 10:640-642 D-Secodesethylcleavamine vinblastine analogues from 4:33 D-Secodesethylvincadifformine synthesis of 4:33 Secodine-type alkaloid 5:110 decarbomethoxy-15,20,16,17-tetrahydrosecodine 5:110 Secodines 4:39-41 Secodolastane 9:79 Secoemetine derivatives synthesis of 6:485 1,2-Secoemetine derivatives amoebicidal activity of 6:485 synthesis of 6:485 Secoiridoids 16:289 Secoiridoids (isoprenoids) 7:185,442,443 gentiopicroside type 7:443 oleuropem type 7:443 secologanin type 7:443 Secoisolariciresinol 20:108 (+)-Secoisolariciresinol di-p-coumarate 20:620 Secologanin 1:31,32;7:442,477,478;13:662;15:487; 20:47 from Lonicera morrowii A. Gray 16:307 tryptamine condensation with 6:520 Secomanoalide 18:717 "Second generation" synthesis ofphorbol 12:269 Secondary allylic ethers [2,3]-Wittig rearrangeent of 3:249 Secondary hydroxyl protection as rer/-butyldimethylsilyl ether 1:312,313 Secondary isotope effects 9:572 Secondary metabolism 7:93,98,110,112,114,119,120 Secondary metabolites 15:226,227;18:677-728 biosynthesis of 20:291-293 evolution of 18:677-728 production of 2:369-415 sector rules 2:165 Secosterol 9:510 Securiflustra securifrons 18:691 Securmega alkaloids 5:49 Securinega species 10:153 Securinine alkaloids synthesis of 14:657-659 via Norrish type II reaction 14:657-659 SecurinolA 14:657 SecurinolB 14:657 ()-Sedacryptine 13:481 (-)-Sedamine 10:677;13:475,477

()-Sedridine 16:457 Selagin 7:228 Selection byautoxicity 7:116,117 of metabolically-active cells 7:114-117 Z-Selective Wittig olefmation of 4:125 Selective acylation 12:346;13:586;14:163 Selective aldehyde reduction 13:579 Selective antitumor activity 15:355 Selective benzoylation 13:557;14:244 Selective cleavage ofbisdesmosides 7:155 of ester type glycoside linkage 7:154,155 of glucuronide linkage 7:156-158 of sugar aglycone linkage 7:154-158 Selective cytotoxicity 13:648 Selective deoxygenation of maltose 14:160 Selective deoxygenations of primary alcohol 16:348 Selective deprotection 12:345 P-Selective glucosylation 15:28 Selective heteronuclear J-resolved spectroscopy 2:147 Selective hydrogenation in ()-9-isocyanopupukeanane synthesis of 6:83 with iridium black 6:83,85 Selective hydrolysis 12:343;13:571 Selective J-resolved spectra 2:115 2D Selective ketalization 6:33 Selective mesylation 12:326,335 Selective monotosylation 13:620 Selective 0-methylation 12:485 Selective reaction acylation 6:282,283 esterification 6:276 formation of cM-5-oxo-l-indanones 6:558 hydrolysis 6:285,286 Selective redox reaction chu-al synthesis by 20:817-881 Selective reduction of methyl 4,6-(9-benzylidene-2,3-di-0tosyl-a-D-glucopyranoside 14:145 Selective silylation 12:330 K-selectride 12:475 oftriol 4:184 Selective skeletal rearrangement 14:377 Selective synthesis of5-lactams 18:315-386 ofpyridones 18:315-386 a-Selective thermal glycosidation ofcyclooligosaccharide 8:367 ofcyclo-I-rhamnohexaose 8:367 a-Selective thermal rhanmosylation 15:28 Selective thiocarbonylation of sucrose derivative 14:162 with thiocarbonyl diimidazole 14:162 5y-Selectivity to (2/?)-methyl aldehyde 12:58

1177 //zreo-Selectivity in cyclocondensation 4:130,145 in A^-protected alaninals 4:122 erythro-SQlQCtiwity 4:143 endo-SQlectivity (f/Z,-addition) 6:549,550;8:411, 415-417 K-Selectride 14:179 anhydride reduction with 3:489 in stereoselective reduction 4:437,459 I-Selectride 16:454;19:72,419,478,494,629 reduction with 4:470,516;6:38,39;14:378,379; 18:235 1,2,3-Selenadiazoles '^Se-NMR of 9:121-123 Selenation-oxidation in (-)-pseudopterosin-A synthesis 6:74,75 Selenium dioxide for allylic oxidation 1:549,550 Selenium dioxide oxidation 1:74 Selenium glycoside 10:382,383 Seleno-lactonization 13:622,623 a-Selenoalkyllithiums 8:5,11 as key intermediates 8:3 a-Selenobenzyllithiums 8:3,5,11 Selenocyclization 11:98,99,101,102 Selenoetherification 10:207;11:109 Selenoxide-based elimination 1:248 Selenylation 1:452;6:70 Self-inhibitors bioassay of 9:230,231 biological activity of 9:222,237 fungal spore 9:219-248 germination 9:219-248 (-)-Selin-ll-en-4a-ol biological activity of 14:450,451 from Euginia uniflora 14:450,451 from Humulus lupulus 14:450 from Myhca gale 14:451 from Pisidium guajava 14:450 from Podocarpus dacrydiodes 14:449,450 from Riccardiajackii 14:450 synthesis of 14:456-465 (-)-a-Selinene from tosylhydrazone 14:411 synthesis of 14:406-413 (+)-p-Selinene 16:214 (+)-a-Selinene 16:220 ()-a-Selinene from cycloeudesmol 6:40 Selinum vaginatium 5:728 Selligueafeei 15:33 SelligueainA 15:33 Semecarpus heterophylla 9:319 Semecarpus vernicifera 9:319 Semenochromene-A 15:295 Semibullavene '^C-NMR spectrum of 5:776 Semiochemicals chu-al synthesis of 6:537-566 synthesis of 8:219-256 ()-Semivioxanthin(9,10-dihydroxy-7-methoxynaphtho-[2,3,c] pyran-1 (IH)-one) antibiotic activity of 11:130 antifiingal activity of 11:130 by polyketide methodology 11:130,131 from P-oxoglutarate derivative 11:130,131 synthesis of 11:130,131 Sempervirine 15:466,467 synthesis of 1:136,140,141,145,146,157 Sempervirol from Salvia acetobulosa 20:673 from Salvia multicaulis 20:673 Senecio amplexicaulus endesm-ll-en-14-olsfrom 14:450 (+)-intermedeol from 14:450 Senecio oxyodontus senoxydene from 13:13 Senecio toxicosis 7:23 6a-Senecioloxychaparin 7:380,381,396 6a-Senecioyloxychaparrinone 7:380-383,396 Senecivemic acid 1:264 Senercinine synthesis of 1:203 Sennosides A,B,C and D 11:127 Senoxydene 13:14-20 from Senecio oxyodonius 13:13 Senoxydene 3:6,8,62,118 synthesis of 3:10 Sephadex G-200 chromatography 2:392,395,399 Sepositoside A 15:59,60;7:295 from Echinaster sepositus 7:294 ()-Septicme 16:454 synthesis of 16:454 Septicine synthesis of 1:277,284,287,293,360,361 Sepulchre's method 19:367 Seqarine 1:35 Sequencerules 5:774 Sequential Homer-Emmons condensation 13:608 Sequestration 17:93,104 Seratia marcescens 12:103 "Serendipitous" deconjugation 12:28 Sergeolide 7:381,382 "Serial" Michael additions 14:756 I-Serinal 4:122,127,130 and Danisefsky's- diene addition 4:130 in cyclocondensation 4:122 Serine synthesis of 11:420 L-Serine pyrrolidine from 14:568 I-Serine 4:130 Z-alanine analogue of 4:127 Serotonin secretion inhibition by K-252a 12:390 Serpenticine 1:125 Serpentine 1:125;5:125 Serpentinine 1:126,147 Serratenone 11:309 fromhobartinl9-ol 11:305 Serratia marcescens 12:401 Serratia marcescens 9:308

1178
Serratia sp. 4A34;12:\03 (-)-Serratoline 1,2-rearrangement of 11:321,322 Serricomin synthesis of 1:695 Serricomin absolute configuration of 14:275 from cigarette beetle {Lasioderma serricorne) 14:275 from levoglucosenone 14:267,275 synthesis of 14:267,275 Serrulatane from Eremophila drummondii 15:259 Serrulatane 15:259 em-Serrulatane 15:259 Serrulatanes 15:257-260 Serum lipid extracts cholesteryl esters from 9:453 Sesamin 5:461,462,703 ;7:219 Sesamin-type lignanes 219 Sesamum angolense 7:407,417,423 Sesbania drummondii 1:305,514 Sesbania punicea 1:305 Sesbania sesban 7:427,432,433 Sesbania vesicaria 1:305 Sesbanimide A synthesis of 1:306-320,514,521 Sesbanimide B synthesis of 1:306-320 Sesbanimide B2 1:515 Seselin 20:497 Sesquicamphenes 16:136 Sesquicamphors 16:136 Sesquicarene 17:609 Sesquilignans from Abies sachalinensis 20:613,621 from Chosema arbutiflia 20:644 from Eucommia utomoidis 20:644 from Salix sachalenensis 20:627 |3-Sesquiphellandrene 8:46,51,55 synthesis of 8:45 from /?-(+)-citronellal 8:45 Sesquiterpene 5:3,368,721-741;6:110,125,133;7:95, 98,100,102,117,120,122,124,185-187,205,427;9:6468,531,534,535;13:3-52;15:227-251;17:8,27,28,153154,196-197,607;18:743-752;20:468 form Stylotrichium rotundifoluim 8:58 from Ammania baccifera 9:65 from Cadabafarinosa 9:64,65 torn Curcuma longa 8:52 from Ferula communis 8:59 from Fusarium sporotrichiodes 9:210,212 from Lychnophora sellowii 8:48-50 from Pluchea arguta (Conyza odentophylla) 9:65-68 from Zingiber officinale 8:52 in Artemisia sp. 7:209-218 molluscicidal activity of 7:427 synthesis of 8:39-59,165-172;13:3-52 triquinanes 13:3-52 Sesquiterpene alkaloids 18:753 Sesquiterpene hydrocarbon 5:728,729 Sesquiterpene isocyanides in Halichondride 6:79 in nudibranchs 6:79,80 Sesquiterpene ketone eremophilone 15:226 Sesquiterpene lactone 7:426;8:195-201 m Artemisia sp. 7:202,209-218,230,231 molluscicidal activity of 7:427 Sesquiterpene quinones antimicrobial activity of 5:429 cytotoxic activity of 5:429 synthesis of 5:768-771 Sesquiterpene synthetase (cyclase) 7:109,110,123 Sesquiterpenoid intermediate 4:767 Sesquiterpenoids 8:39,9:81,249-256,20:659,660 Sessibugula translucens 17:88,94,98 Sesterpenes 6:110,123 ;20:696 Setomimycine 20:277 Seven membered cyclic ethers 10:209,224-26,234 by rhodium carbenoid mediated cyclization of hydroxy a-diazo-P-keto esters 10:209 Seven-carbon sugars synthesis by osmylation 4:175-179 Seven-membered cyclic-a-adduct 12:117 Seven-membered oxepane 10:202 Seven-membered rings from five-membered rmgs 10:309-311 Sex pheromone synthesis of 6:537-546 Seychellene synthesis of 8:423-425 Seychellogenin 7:270 Seyfert's reagent 12:259 SFORD spectrum 2:93 SFORD techniques 18:972 ShahaminC 17:12 Shanzhiside methyl ester 7:471 Shapiro reaction 13:509,578 Shapiro reaction, modified 1:460,461 Shapiro synthesis 11:84 Sharpless asymmetric dihydroxylation 16:332;18:197; 20:592 Sharpless asymmetric epoxidation 1:265,266,487,488, 507,508,510,532,538;4:496;10:534,598,599;12:11,18; 13:621;14:568-571,828;16:296,342;16:492;18:217; 19:431,435,443,478;20:450 diastereofacial-selective manner 19:492 dihydroxylation of 19:246 of2-ethyl-2-propen-l-ol 14:828 of2-heptenol 19:61 of allylic alcohol 10:534 of allylic alcohol 12:11 of allylic alcohol 19:45 ofgeraniol 19:139 osmium-catalyzed 19:246 pyrrolidines from 14:568-571 regioselective manner 19:492 Sharpless epoxidation 4:173,174,179,186,187,203,339345,506,514,516;6:268,269,287,289;10:39,40,66; 11:7,8,59,60,83,93,94,267,268;14:746;18:197,204, 205,244 (+)-nitramine by 14:746 enantioselective 4:343,344:6:287

1179

of 1-cyclohexenyl alcohol 14:746 of allylic alcohols 4:312,516 kinetic resolution by 4:342 Sharpless method in thienaycin synthesis 4:483 Sharpless hydroxylation 12:218 Sharpless kinetic resolution 10:236 of ()-iV-benzy loxy carbonyl-3 -hydroxy-4pentenylamine 12:281 Sharpless oxidation 4:602;10:289;12:353;16:296,342; 19:463 of p-hydroxyl olefin 16:296 with diethyl Z,-(+)-tartrate 16:342 in ()-precapnelladiene synthesis 6:34 Sharpless reaction 13:203,204;19:375 Sharpless vicinal hydroxyamination 12:219 SHELXTL program series 9:8 Shermilamine A,B 10:245 Shermilamine B 17:23 [1,5]-Shift of cw-alkyl vinylcyclopropanes 3:34 1,2-H Shifts 1:331,332 Shigella sip. 12:63 Shigella flexnert 0-antigenic polysaccharide from 14:233 Shigella dysenteriae 9:308 Shigella sonnei 9:308;12:401 Shikimate 3-phosphate with phosphoenolpyruvate 11:185,186 Shikimate pathway 17:471-472 Shikimicacid 10:45;11:182-191 antibiotics 11:182-191 synthesis of 4:561,552;13:188 Shikoccidin 15:119 from Rabdosia shikokiana var. occidentalis 15:174 from Rabdosia umbrosa 15:175 from Rabdosia umbrosa var. latifolia 15:175 Shikoccin 15:162-164 '^C-nmrof 15:165 frora Rabdosia shikokiana \da. occidentalis 15:174 from Rabdosia umbrosa 15:175 from Rabdosia umbrosa var. hakusanensis 15:175 from Rabdosia umbrosa var. latifolia 15:175 Shikokianal acetate from Rabdosia nervosa 15:173 Shikonin 7:96,112,116 from Lithospermum erythrorhizon 7:88 Shimming 9:112 Shine-Dalgamo sequence 13:262 Shinjulactone C formation from ailanthone 5:800 Shizandra chinensis B 18:589 Shodoptera littorolides 20:245 Shogaol 9:321 Shonachalin A-D 7:231,232,237 from cyano derivative 10:355 from free sugars 10:393,394 from 2,3-0-isopropylidene ribofiiranose 10:393 from ribofiiranosyl anisyl telluride 10:385 from (3-ribosyl trimethoxybenzene 10:382

synthesis of 10:355,381,382,385,393,394 Wittig reaction of 10:393,394 (-)-Shyobunone 16:264 Sialic acid 2:309 Sialidase 16:76,86,87,93,112 crystal structure of 16:93 from Streptococcus sp. 16:86,87 Sialidases 7:42,70 nojirimycin analogues inhibition with 7:42 Sialylaldolase catalyzed condensation 11:466 Sialyltransferase 10:500,501 Sialyltransferase activity 16:81 Siamenoside I 15:24 Siamine 1:163,164 synthesis of 1:174,175 SiastatinA 10:551 from Streptomyces verticillus var. quintum 10:550 Siastatin B absolute configuration of 16:77;10:550 antimetastatic activity of 16:81 from Streptomyces culture 16:76 methyl ester 16:97 iV-acetyl-P-D-glucosaminidase 10:550 neuraminidase inhibitor of 10:550 relative configuration of 10:550;16:77 stereoselective synthesis of 16:75-122 synthesis of 10:551,552 P-glucuronidase 10:550 Sibiricine 1:203 Sibiricol synthesis of 4:375,376 (-)-Sibirine asymmetric synthesis of 14:539-544 froml-prolmol 14:542 from Nitraria sibirica 14:541 Sibirine synthesis of 14:744 Sibirinine fromnitramine 14:743 synthesis of 14:743 3-ep/-Sibirosaine synthesis of 4:135,138,139 Sibirosamine synthesis of 4:135,138,139 Sida acuta 5:751 Sida carpinifolia 5:752 Sida cordifolia 5:75 Sida rhombifolia 5:751 Sidasp. 5:751 Sideritissp. 5:658 Siderophores from bacteria 9:537-557 peptide 9:537-557 Siderphores from flourescent Peseudomonads 19:791-833 Sidnyaxanthin 6:151 Sieversin 7:236 [ 1,2]-Sigmatropic (Stevens) rearrangement 6:315 2,3-Sigmatropic rearrangement [l,3]-Sigmatropic rearrangement 16:254,617

1180

[l,5]-Sigmatropic rearrangement 4:333;11:27,3:289 [2,3]-Sigmatropic rearrangement 1:401,560;3:354; 6:316;8:209;11:15,16,24,30,326,327,45,46,48,49,188; 12:93,95,467;13:418,519,589,72;14:533,534;16:255, 173,621,622-623,627;19:259 for C-S to C-0 conversion 1:560 ofallylicsulfoniumylide 16:255 of sulfoxides 1:560 of allylic sulfoxides 11:326,327 of 6-alkenyl-4-oxapyran-2-ones 10:460 of allylic (alkyl) ketene acetal 10:417 of allylic azides 10:418 of allylic thiocyanates 10:418 of allylic trichloroacetimidates 10:421 of allylic sulfoxides 11:326,327 suprafacial 16:627 [3,3]-Sigmatropic rearrangement 1:53,228,401 ;3:228; 4:522;6:222,224,225;8:245,251;10:333,416-420; 11:15,16,45,46,48,49,188;12:95,193,249;13:418,519, 589;14:625;19:6 Sigmatropic rearrangement 12:246-250;13:420,564; 16:340 Sigmatropic migration phenylselenium 19:208 Sigmatropic 1,3-H-migration 18:166 [2,3]-Sigmatropic elimination 12:11 ofPhSeOH 12:11 [l,5]-SigmatropicH shift 10:70 [l,7]-Sigmatropic shift 2:128 [ 1,5]-Sigmatropic shift of hydrogen 12:182 [3,3]-Sigmatropy 10:235 Sigmosceptrella laevis sigmosceptrellin-A fi"om 9:16 Sigmosceptrellins A-C 9:20,22,24-29 absolute stereochemistry of 9:16 from Sigmosceptrella laevis 9:16 X-ray analysis of 9:16,20 Sih's compactin synthesis 13:593 Silicine 5:126 20-e!p/-Silicine 5:126 Silicon ethers in glycosidation 6:262 Silicon-contaming nucleophiles 14:472 Siloxane bridged oligonucleotides 13:271 Siloxy methyl 8:179,180 [l,3]-Siloxy-Cope rmg expansion 8:246 P-Siloxyacetals with organometallic reagent 14:483 Siloxydiene 4:334 asymmetric Diels-Alder reaction with 4:34 Silphinene total synthesis 8:165,166 Silphinene 13:9-11,20 from Silphium perfoliatum 13:8 Silphinene 3:62,118 synthesis of 3:8,9,16,25 Silphinium perfoliatum silphinene from 8:165 Silphiperfol-5-en-3-ol 9:515,516 13 (+)-Silphiperfol-6-ene from Silphium perfoliatum 13:11

Silphiperfol-6-ene 3:6,8,14,15,62 synthesis of 3:14,15 9-ep/-Silphiperfol-6-ene 3:62 Silphium perfoliatum silphinene from 13:8 (-)-silphiperfol-6-ene from 13:8,11 7aH-Silphiperfol-5-ene 3:6,63 synthesis of 3:15 7pH-Silphiperfol-5-ene 3:6,63 synthesis of 3:15 Silver (II) oxide oxidative demethylation with 5:769 Silver cyanide allyl isocyanide from 12:113 Silver oxide oxidation with 11:86 Silver oxide method in prenylation methods 4:386 Silver staining 17:396 Silver sulphamate 9:433 Silver triflate in C-glucosidation 3:216 Silver trifluoroethane sulphonate method 4:323,324 Silylated phosphonium ylides reaction with acid silyl esters 4:546 synthesis of 4:563 Silybum marianum 5:496 silymarinfrom 13:660 Silydianin as antihepatotoxic agent 8:166 synthesis of 8:166-168 Silyl enol ether reaction with l-phenyl-2-buten-l-one 3:129 reaction with unsaturated ketones 3:129 Silyl enolate Claisen rearrangement 1:563 ;2:685 Silyl group removal with n-Bu4 NF 1:452,453 Silyl ketene acetals Claisen rearrangement of 10:422,423 0-Silyl ketene acetals in Claisen-rearrangemment 3:243 Silyl Pummerer rearrangement 4:550 Silyl-Wittig reaction 14:461,463,464 Silylacetylenic reagents 14:473 Silylation 6:16,19,20,25,26,30-33,39-41;ll:338,369; 19:518 Silylenol ethers 4:475-477 a'-Silyloxy ()-enone 19:59 co-Silyloxy propargylsilanes by exocyclic ring closure 10:227 synthesis of 10:227 Silyloxydienes in cyclocondensation 4:113 Silymarin 5:496;13:660 Silyvinylalane 12:295 Simabaamara 7:369,381 Simabacedron 7:392 Simaba cuspidata 7:369,381 Simaba multiflora 7:369,380,396 Simalikalactone-D 7:391,392,395,396,398;11:72,79 Simarolide 7:392,396;11:71

1181

Simarouba glauca glaucarubin from 13:660 Simaroubaceae species 11:71 Simaroubaceous plants 7:369-404 Simiarenol 20:17 from Artemisia anomala 7:218 from Artemisia argyi 7:218 Simmons-Smith cyclopropanation 6:72;11:29,30; 16:703 Simmons-Smith reaction 6:5,234,235;8:34;14:490 annulationby 6:5 diastereoselective 14:487-489 ofchiral vinyl ether alcohols 14:487,488 of a,P-unsaturated acetals 14:489-491 Simmons-Smith reagent 14:490 chelation controlled delivery 1:637 cyclopropanation with 1:631,63 2 Simplexin 20:234 Simvastatin 15:450 Sinapaldehyde 5:471 Sinapicacid 5:469,470 (Z)-Sinapyl alcohol 5:472 Sinapyl alcohol 5:767,771,774,775 Sindbis virus 17:135 Sinefungin synthesis of 1:408-410,11:437,438 isolation of 19:177 Singlet oxygen addition to isoquinolines 3:439,440 asdienophile 4:612 (-)-Sinularene from Sinularia mayi 6:75 synthesis of 6:75,76 ()-5 -e/7/-Sinularene synthesis of 6:76,77 Sinularin 8:15 ll-e/7/-Sinulariolide 17:22 12-gp/-Sinulariolide 17:22 ll-e/7/-Sinuriolide 17:28 Siol acetate 724,728 Siphonaria atra 17:25 Siphonaria baconi 17:25,28 Siphonaria diemenesis 17:24 Siphonaria laciniosa 17:25 Siphonaria maura 17:25,26 Siphonaria normalis 17:25,27 Siphonaria species 17:23,26,28 Siphonaria zelandica 17:25 SiphonarinA 17:25,27 SiphonarinB 17:25 Siphonoborgia species 9:37 (22/?,23/?)-22,23-methylene cholesterol from 9:317 Siphonodictyal-A 15:297 Siphonodictyal-B 15:293,298 Siphonodictyal-C 15:298 Siphonodicytal-D 15:300 Siphonodicytal-E 15:294 Siphonodictyoic acid 15:293 Siphonodictyol-G 15:293 Siphonodictyol-H 15:298 Siraitia grosvenorii 15:5,22 Siraitia siamensis 15:24

Sirenin 17:609 (-)-Sirenin from (-)-perillaldehyde 6:545,546 synthesis of 6:544-546 Su-icic acid methyl ester from diacetyl dimethyl bartogenate 7:132,133 from Terminalia siricia 7:132 Siroheme 9:583,586 Site-selective Baeyer-villager oxidation 13:608 Sitophilus granarius 18:698 Sitophilus oryzae 9:299 Sitosterol 5:753,7:124,9:454 (24R)-24-ethyl cholest-5-en-3b-ol) 9:447 from Salvia glutinosa 20:707 P-Sitosterol 2:129,9:288,289,399,412,413,20,707 androstenedione from 9:411 microbial degradation of 9:411 from Salvia divaricata 20:702 from Salvia montbretti 20:704 from Salvia nemorosa 20:702 from Salviapomifera 20:702 Sitosterol 3-glucoside from Artemisia rupestris 7:218 from Artemisia valentina 7:218 Sitosterol palmitate 9:472,473 Sitosterone 9:288,289 P-Sitosteryl linoleate 9:461 Sitosteryl stearate 9:454 ^/YM ketalization 11:361 Slum latifolium 5:724,728,20:6 Sium latijugum 5:728 Six-membered ring 8:175 Six-membered cyclic ethers by rhodium carbenoid mediated cyclization of hydroxy a-diazo-P-keto esters 10:209 Skeletal rearrangements 7:159-168 Skimmianine 3:385,386 Skimmin 3:224 Skin cancer 5:747 SKKMoth juvenile hormone from 1:704-706 Skytanthine 7:444 (5)-lactate dehydrogenase 20:872 Slaframine synthesis of 1:289 (-)-Slaframine 18:386 activity of 12:306 biosynthesis of 12:307 enantioselective synthesis of 12:309,310 relative configuration of 12:309,310 synthesis of 12:307-312;16:484 ()-1 -e/7/-Slaframine synthesis of 12:309 ()-6-e/7/-Slaframine synthesis of 12:311,312 Slaframine 14:568 Slave-keeping ants 6:454 Sleeping sickness 2:293,302 Smenochromene-B 15:295 Smenochromene-C 15:295 Smenochromene-D 15:295 Smenodiol 15:293,297

1182

Smenoquinone antimicrobial activity of 5:434,425 Smenorthoquinone 5:431,432;15:291,292 antimicrobial activity of 5:434,435 Smenospondiol 5:431-433,435-437,439;15:292,293 Smenospongia aurea 5:437 8-epichromazonaral from 15:291 Smenospongia sp. 5:429,43-0,432-434,439 Smenospongiarine 5:431-433,435,436 Smenospongidine 5:431-433,435,436 Smenospongine antimicrobial activity of 5:434,435 cytotoxic activity of 5:435 Smenospongorine 5:431,432,433,436 Smilagenin 7:138 ^om Echinophora lamellosa 7:136 Smith degradation 1:436,439;5:197 Smith indole synthesis 1:155 Smith reaction 7:270 Smith synthesis of avermectin oxahydrindene subunit 12:25,26 Smith's degradation Smodingium argutum 9:318 Smooth muscle Na^/H^ antiporter system 12:390 SNAr reaction 20:410 SN'-process 11:323 intramolecular 11:323 SN^-products 11:319,320 SN^ reaction 11:207;14:747;16:296 oftriflate 16:296 SN^ type cyclocarbamation 12:479 SN^-alkylation 13:585 SN^-displacement 13:589;14:156 SN^-nucleophiles 16:415 SN^-type condensation 14:147 SN^-type reaction 14:269 Snail enzyme 7:268 "5-NMR of phenyl cyclohexyl sulphones 9:188,119 SNIF-NMR 13:334,336 ()-Snularene by Claisen rearrangement 6:78,79 by intramolecular [4+2] cycloaddition 6:85 by intramolecular type-I Mg-ene reaction 6:76,77 bymesylation 6:76,77 by O-methylation 6:76,77 by Wittig condensation 6:85 by Wittig olefmation 6:79 from bicyclo [3.1.0] hexan-2-one 6:79 from bicyclo [3.2.1] octanone 6:78,79 from Collins-Wege intermediate 6:78,79 from exo (ef/o)-methylbicyclo [2.2.1]-hept-5-ene2-carboxylic acids 6:76 fromnorbomene 6:16,11 synthesis of 6:76-79,85,86 Sodium amalgam desulfonylation with 11:349 Sodium artesunate 13:657 Sodium bistrimethylsilylamide cyclization by 6:540 Sodium borohydride 8:468-470 Sodium cyanoborohydride reduction with 11:87

Sodium hexamethyl disilazide (NaHMDS) methylation with 13:63 Sodium hydrotelluride reduction with 11:81,82,92,93 Sodium methanethiolate 6:340 Sodium naphthalene 11:371 Sodium naphthalenide 6:541,542 Sodium phenylselenide reaction with ()-canadine 6:489,490 Sodoponin from Rabdosia eriocalyx 15:171 from Rabdosia setschwanensis 15:174 from Rabdosia ternifolia 15:175 Sodoptera littorais 18:772 Soft acids/bases 3:409 Soft ionization method 2:50;9:467 Solamin asymmetric synthesis of 18:202-206 hemi-synthesis of 18:219-220 Solanaceae 7:427,19:470,20:135,139 Solanaceae alkaloids steroidal type 11:229 Solanaceous plants 17:395 Solanapyrone A bioietric synthesis 4:620 synthesis of 4:598,599 solanapyrone B 4:598 Solanapyrone A 17:475 Solanesol 8:66,78 Solanidane 7:17-22,24 Solanidane A^-oxide 7:23 22/?,255'-Solanidines 7:20 Solanidine 7:18,19,21 22/?-Solanidine 7:18,22 225',25/?-Solanidine 7:19-21 225,255-Solanidine 7:22,23 a-Solanine 7:18-20,22,23 5o/flM/w alkaloids 7:17,19,21,22,24 Solanum dulcamara 20:135 Solanum eleagnifolium 7:19 iSo/aM/w glycoalkaloids 7:17 Solanum indicum 20:135 Solanum mammosum 1:421 Solanum melongena 20:135 Solanum ridellii 7:23 Solanum sp. 7:21,22 Solanum tuberosum 7:20,22;20:135 Solanum umbelliferum steroidal alkaloids from 20:489 Solanum xanthocarpum 20:135 Solasodine 7:19,21;15:28;20:489,490 Solasodine-3-O-P-D-glucopyranoside 20:489 Solasodine glycoside from Solanum elegnifolium 7:19 Solaster borealis solasteroside from 15:55 Solasteroside A from Solaster borealis 15:55 Solenopis aurea piperidine venom alkaloids in 6:423 Solenopsin A antibiotic activity of 16:453

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hemolytic activity of 16:453 insecticidal activity of 16:453 Solenopsin A from methylvinyl ketone 6:426,427 from oxatropane 6:433,434 synthesis of 6:426,433,434,448 Solenopsin B absolute configuration of 6:430 enantioselective synthesis of 6:429,430,433,434 from oxime sulfonate 6:433,434 ()-(5,5)-Solenopsin-A asymmetric synthesis of 6:431,432 Solenopsins synthesis of 6:422-434 Solenopsis (fire ants) 6:422 SolenopsisA 1:389,390 Solenopsis carolinensis piperidine venom alkaloids in 6:423 Solenopsis conjurata indolizidine alkaloids in 6:450 piperidine venom akkaloids in 6:423 Solenopsis eduardi piperidine venom alkaloids in 6:423 Solenopsis fugax piperidine venom alkaloids in 6:436 Solenopsis geminata piperidine venom alkaloids in 6:423 Solenopsis invicta pheromone synthesis 1:682 Solenopsis invicta 3:273 ;5:228 piperidine venom alkaloids in 6:423 Solenopsis littoralis 6:423 piperidine venom alkaloids in 6:423 Solenopsis molesta 6:436 pyrrolidine venom alkaloids m 6:436 Solenopsis pergandei piperidine venom alkaloids in 6:423 Solenopsis punctaticeps pyrrolidine venom alkaloids in 6:423 Solenopsis richteri ^'Allt piperidme venom alkaloids in 6:423 Solenopsis saevissima piperidine venom alkaloids in 6:423 Solenopsis sp. arthropod alkaloids from 11:231 Solenopsis species 6:450,454 alkyl-1-piperideine m 6:422 Solenopsis texanas 6:436 pyrrolidine venom alkaloids in 6:436 Solenopsis xyloni 6:422,423 2-methyl-6-alkyl-l-piperideine in 6:422 piperidine venom alkaloids in 6:422,423 Solid-phase method in MDP analogs synthesis 6:405 Solidago altissima \9'2^1 Solidago saponins 15:191 Solidago species kolavenic acid from 6:28 Solmonella anatum 8:101,103 Solvolysis 6:320,19:236 Somatostatin gene synthesis 4:271 Somatotropin 13:661

Sonneratia alba 7:176,194,195 Sonneratia apetala 7:188 Sonneratia caseolaris 7:176 Sonneratia griftithie 7:195 Sonneratia ovata 7:176 Sonneratia sp. 7:176 Sonneratiaceae 7:175 Sophora chrysophylla 15:522 Sophoraflavescens 9:148 Sophora griffithii 9:149 Sophora tomentosa (-)-epilamprolobine from 15:522 (+)-epilamprolobine A^-oxide from 15:522 5-(3 '-methoxycarbonylbutyroyl) aminomethyl/rafAM-quinolizidine A^-oxide from 15:522 Sophorosyl (P-D-glucopyranosyI-(2-> 1 )-p-Dglucopyranosyl) sugar unit 15:20 Sorbicacid 10:152 Sorbic acid (2,4^-2,4-hexadienoic acid 10:149 D-Sorbitol 1:307 Sorbus aucuparia 10:152 Sorelline formation of 11:310,311 fromhobartin-19-ol 11:305 from (+)-20-hydroxyhobartine 11:323 indole-protected 11:310,311,328-330 synthesis of 11:326-328 Sorelline 9:178 Sorghum bicolor 9:322,344 Sorocea bonplandii 17:458 Sotolon 13:318,319 Soulamea soulameoides 7:396 Soulamea tomentosa 7:369,381 Soulameanone 7:395,396 Soularubinone 7:381,382,392 Sowden method in Z-glycero-Z)-mannoheptose synthesis 4:197,203 Soya bean flour enzymatic hydrolysis of 9:412,413 Soyasapogenol B 15:187 Soyasaponin A3 ^om Glycine max 15:196 Soyasaponin! 15:187 22,24-di-O-methyl soya-sapogenol B from 7:157,158 Sparteine biosynthesis of 14:738,739 froml-lysine 14:738,739 (-)-Sparteine 15:520 Spasmolytics 17:395 Spatane diterpenoids biological activities of 6:39 ^om Dictyotaceae 6:38 synthesis of 6:39,40 tricyclo [5.3.0.0^'^] decane m 6:38,39 (+)-Spathulenol from Eremophila cuneifolia 15:248 from Eremophila paisley 15:248 from Eremophila racemosa 15:248 from Eremophila arummondi 15:248 from Eucalyptus spathulata 15:248 from Salvia sclarea 20:660

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(-)-Spathulenol 16:245 Spathulenol 9:531 Spatol biological activities of 6:39 ()-Spatol by aldol cyclization 6:40,41 synthesis of 6:40,41 Specific rotations of proaporphine dienones 2:259 (-)-Specionin antifeedant activity of 10:425 synthesis of 10:425,426 Spectaline 9:70-72 (-)-Spectaline 20:486 (-)-Spectalinine 20:486 Spectinomycin biosynthesis of 11:216 by TDP-glucose oxidoreductase 11:216 from glucose 11:216 from Streptomyces sp. 11:216 Spectral data of acetylenic carotenoids 6:148,150,155,156 ofapparicine 6:505 ofbrafouedine 6:503-506 of 19'-butanoylfiicoxanthin 6:138 of3,14-dihydroellipticine 6:518 ofdinklageine 6:524,526 ofellipticine 6:519 ofepchrosine 6:505 ofgentianine 6:528,529 ofgyroxanthin 6:162 of 16 (5)-hydroxy-16,17-dihydroapparicine 6:505 of 10-hydroxyellipticine 6:518 of 18-hydroxyellipticine 6:515,519 ofisobrafouedine 6:503-506 of 8-methoxy-8,10-dihydrogentianine 6:528,529 of 7-0-[4-methyl-5 hydroxyethyl nicotinoyl] strychnovoline 6:526 of 17-oxoellipticine 6:509,519 ofA^-b-oxyellipticine 6:519 of A^-b-oxy-17-oxoellipticine 6:515,519 ofstrellidimine 6:516,518 of strychnovoline 6:524,526 of 3,14,4,21 -tetrahydroellipticine 6:518 Spegatrine 13:387 Spergulagenic acid A 7:144,145 Spermatophyta 18:740 Spermidine 9:74 Spermidine alkaloid 9:73 synthesis of 16:423 Spermine alkaloids 9:75;13:650 Sphacriales 9:203 Sphaerantnus indicus 9:145 Sphaerechinus granulans 15:104 Sphaereophorus globosus 5:310 Sphaerodiscus placenta 7:3 04-3 06 22-dehydrohalitylosides D,E from 7:298 halitylosides A,B,E from 7:298 placentoside A from 7:298 Sphaerophorin cetraria 9:317 Spheciospongia vagabunda (245,255)-24-26-cyclocholesterol from 9:37 Sphenostylins A 7:413,414

Sphenostylins D 7:413,414 Sphingadienine 1:681 Sphingofiingins 18:460,469 Sphingolipids 13:533 Sphingosine 12:412;13:531;18:786 D-(+)-erythro-SphingosmQ 18:461 Sphinxolide 10:153;17:17 antitumor activity of 17:17 Spiciformin 7:211,231 Spider mite hatching inhibitor 1:702 Spilanthes alba 10:152 Spin quantum number 9:110 of^^O 9:110 o f " S 9:110 of^^Se 9:110 of^^^Te 9:110 Spin trapping experiments 9:573 Spinaceamin 15:328 Spinacetin 7:228 Spinasterol palmitate ester of 9:470 Spiniferin-1 from Pleraplysilla spinifera 6:72 ()-Spiniferin-l by intramolecular cyclopropanation 6:73,74 by ring expansion rearrangement 6:73,74 synthesis of 6\13>JA Spinning band distillation 11:359 Spinning-band column distillation 11:288 Spinus tristis hemoglobin components of 5:836 Spiramycin 5:613,614 Spiranolide 11:160 Spirastrella spinispirulifera 19:581 Spirilloxanthin 20:591 Spiro [4.5] decane 10:315 Spiro [4.5] decane synthesis of 14:544-546 Spu-o [4.5] decane group 6:59-65 Spiro [4.5] decane system construction of 6:59 Spiro [5.4] mdolenine system 11:329 Spiropentanopyrrolizine oxime synthesis of 19:84,19:146 Spiro [5.5] undecane group 6:59-65 construction of 6:59 Spiro [5.5] undecanone derivative 6:61 Spiro compound 16:46 Spiro systems construction 6:60-65 by intermolecular cyclization 6:59 Spiro-dehydration reaction 12:64 Spiro-diastereomers 8:382-384,386 Spiro-diterpenes 15:260-263 Spiro-indolenine derivatives 11:392-395 Spiro-isoquinolme derivative of ring C-homoberberine analogue 6:496 Spiro-rearrangement 12:99 Spiroacetal subunits White synthesis of 12:27,28 Spiroalkaloids diastereomeric 14:743-756

1185
from Nitraria schoberi 14:742 from Nitraria sibirica 14:742 Spiroamielation 4:7,12;14:546 in bromochamigrene synthesis 6:60,61 of cyclohexanone aldehyde 6:61 of phenolic a-diazoketone 6:60,61 Spirobenzylisoquinoline alkaloids 1:187-189 formation from 8,14-cycloberbines 1:198-202 from8-methoxyprotoberberinephenolbetaines 1:202-204 synthesis of 1:197-206 Spirobenzylisoquinolines biogenesis of 1:218,219 Spirobncarbocyclic chamigranes from Laurencia species 6:60 synthesis 6:59,60 Spirobenzoquinone ftiran unit in stypolidione 6:55 synthesis of 6:55 Spirocyclic systems 6:59-65,85 Spirocyclization 10:170;14:649,755;16:28 enantioselective 14:750 Spirodysin intermediate 4:676 Spkoepoxynucleosides synthesis of 4:252,257 Spiroethers synthesis of 18:269-309 Spongian diterpenes 9:4 Spiroketal enol ethers 7:220 Spiroketal reduction withDIBAH 18:276,277 with Silane-Lewis acid 18:277,278 Spiroketals 9:530;13:60 diaxial configuration 1:476 stereoselective synthesis of 14:519-521 Spiroketone 8:288 from ketolactam 8:287 Spirolaurenone from homogeranonitrile bromohydrin 6:64 relation to glanduliferol 6:63 synthesis of 6:64,65 Spu-osolanes 7:17-22,24 Spirostane glycosides 17:136 Spirovetivane as sesquiterpene 6:59 Spirovetivane-type sesquiterpenes enantioselective synthesis of 14:546 Spizella arborea hemoglobin components of 5:837 Spizella passerina hemoglobin components of 5:837 Splicing reaction 13:261 ;13:290 Spodoptera frugiperda (army worm) 14:451 Spodoptera eridania 7:396 Spodoptera littoralis 18:772,20:245 Spongia hispida 15:312 Spongia mycqfijiensis 19:568 Spongia nitens 17:10 Spongia officialis 17:10 Spongia officinalis isoagatholactone 6:56,107,108 Spongia sp. 5:371;6:107,111 Spongia-13 (16),14-dien-19-oic acid 6:107,109 Spongia-13 (16),14-diene 6:107,109 ()-Spongia-13 (16),14-diene 6:1112 synthesis of 6:116,118 Spongiadiol 6:107,109 e/7/-Spongiadiol 6:107,110 Spongian diterpenoids synthesis of 1:662 Spongian-type diterpenes stereoselective synthesis of 6:107-132 Spongiaquinone 15:298,318-321 Spongiaquinone potassium salt 15:298 Spongiatriol 6:107,109 e/7/-Spongiatriol 6:107,109 Spongiidae 6:107,19:568 Spongionella species 17:12 Songistatinl 19:580 Spongouridin 5:403 Sporobolomyces odorus 13:309,312 Sporobolomyces reseus 5:291 Sporobolomyces sp. 5:291 ;13:315 Sporogen-AO 1 6:551-556 ()-Sporogen-AO 1 synthesis of 6:553,554 Sporogen-AO 1:697,698 synthesis of 1:697,698 Sporogenic substances 6:538-546 Sporogensis 6:546 Sporomia fimgi 6-methoxymellein from 15:384 Sporothrix curviconia 5:304 Sporothrix inflata 5:304 Sporothrix schenckii 5:302-305,322,325 monohexosylceramides 18:807 Sporothrix schenckii var. luriei 5:304 Sporothrix sp. 5:302,304,325,328 Sporotrichum dimorphosporum 8:349 xylanaseA 8:349 xylanaseB 8:349 Sporotrichum thermophile 2:323 Sporulation 6:552 classification of fiingi by 6:546 ^-Pulegone 20:74 Sprekeliaformosissima 20:356 Sputtering of ions (SIMS) by bombardment with fast ions 5:632 Squalene 7:131;9:39 from presqualene diphosphate 7:325 Squalene biosynthesis 7:322 Squalene cyclization 1:655 Squalene oxide cyclase 14:740 Squamone 9:398 SRE oncogene 15:443 (+)-Srilankine synthesis of 16:525-527 Stachybotrys 9:203 7r-Stacking model 4:609 Standinger reaction 1:352,353 Stannoxane 1:274 Stanols 9:469,470 Stansioside 7:462,463 Stapfinine 5:125,172,173;9:172

1186

Staphylococcus aureus 3:302;5:368,370;505,511 ;7:282, 304,309;9:308,500;8:102;10:117;12:401;13:162,164,1 73,181,183;17:285;18:777,778;19:556,601,712; 20:30,32 Staphylococcus citerus 9:308 Staphylococcus epidermidis 9:308;12:401;13:164,173; 20:712 amylopectin in 7:32 amy lose in 7:32 enzymatic conversion to glucose 2:321 enzymatic hydrolysis of 10:496-503 Statine 10:260,261,263,266,267,272 diastereoselective synthesis of 12:479-481 from (/?)-a-hydroxy-P-phenylpropionate 12:479 from methyl (/?)-a-hydroxyphenyl propionate 12:480 synthesis of 12:477,480 ()-Statine mutual transformation of 12:430,431 with epistatine 12:430,431 (35,45)-Statine 12:476 (35,4/?)-Statine synthesis of 13:513 (-)-Statine(35,45)-4-amino-3-hydroxy-6methylheptanic acid biological activity of 12:432 from(4S,5S)-allyl-4-methoxy-2-oxazolidinone 12:432,433 synthesis of 12:432,433 Staurosponine ("AM-2282") from Streptomyces staurosporeus 12:365 Staurosporine 1:3,4;5:55-61 aglyconof 12:379-381 aglyconeof 1:10,22 antibacterial activity of 12:384 biosynthesis of \l'312>,'ilA dynamic NMR study of 12:367 from Streptomyces diastatochromogenes 12:366 from Streptomyces sp. C-71799 12:366 from Streptomyces sp. PK-286C 12:366 from Streptomyces staurosporeus 12:367 synthesis of 1:5,22 X-Ray crystal structure of 12:367 Staurosporine ("M-193") 12:365 from Streptomyces sp. M-193 12:165 Staurosporme (NB-2025) from Streptomyces actuosus 12:411 Staurosporine aglycone 5:55 ' H - N M R spectrum of 5:58 Staurosporinone (K-252c) 12:379-381 synthesis of 12:379-381 Stearic acid biosynthesis of in Penicillium brefeldianum 11:192 Stearic acid 13:308 Steffimycin 4:350 Steganacin 5:461,462 Steganotaenia araliaceae 17:346 Stelospongia conulata 15:312

Stemmadenine conversion to condylocarpine derivatives 1:49 oxidative cyclization of 1:49 synthesis 1:41,43-55 Stemmadenine derivative 6:520 Stemphylium radicinum 19:154 Stenodynerusfloridans 5:223,253 Stenodynerusfulvipes 5:223,224,232,253 Stephania erecta 20:522 Stephaniajaponica protostephanine in 6:480 Stephania pierrei 20:522 {+)Stephania venosa 2:253 Stepharine. hydrogenation of 2:254,225 Steracaulon ramulosum 5:310,311 Sterculiaceae 7:177 Stereo-controlled syn aldol reaction 13:546 Stereocaulonjaponicum 5:310 Stereochemical inversion 6:178 Stereochemical revision of methyl nuapapuanoate 9:19 Stereochemistry of3-carboxymuconate 8:296-298 of acetylenic carotenoids 6:152-138 ofalleniccarotenoids 6:135-138 ofbicyclomycin 12:64 of C45 carotenoids 7:355-360 of C50 carotenoids 7:355-360 of carotenoid biosynthesis 7:317-367 of cw,cw-3-carboxymuconic acid 8:297 of cyclization 7:338-354 ofcycloaddition 4:122,123 of lithio dianion-imine condensation 4:446,447 ofspiroethers 18:303-305 of^raw^BC-ring fusion 12:205 Stereochemistry ofcycloaddition in Diels-Alder reaction 4:122,123 Stereocontrol methods 1:578 Stereodifferentiating reactions 16:399 using chiral auxiliaries 4:327-345 Stereogenicity 7:5 Stereoisomeric mixtures 6:152 Stereoisomers 17:483 offucoxanthin 6:139 ofneoxanthin 6:139 ofperidinin 6:139 Stereomutation mixture iodme catalyzed 6:139-141 Stereomutation studies of acetylenic carotenoids 6:154 ofdiacetylenicalloxanthin 6:153 of monoacetylenic- 7,8-didehydroastaxanthin 6:153 of tetradehydroastaxanthin 6:153 Stereoselective arylation C-glycosidation 10:345 Stereoselective a-hydroxylation 9:518 Stereoselective addition 19:33 in D-glycero-D-galactoheptose synthesis 4:198,199 Stereoselective aldol condensation 6:264,268 Stereoselective construction ofwithanolideD-type side chain 19:470 Stereoselective C-glycosylations 10:373

1187

Stereoselective epoxidation 4:505;6:553,554;11:165, 166,172;14:366 of tetracyclic intermediates 14:148-150 Stereoselective glycosidation 8:359 Stereoselective hydrogenation 10:551,552 Stereoselective intramolecular reductive alkylation 10:541 Stereoselective ketone reduction 13:600 Stereoselective Michael addiction 13:619 Stereoselective pinacol-type rearrangement 15:509 Stereoselective reduction 10:537;11:91,99,100,103; 11:104,170-172;12:337;14:72,378,529 by 1,3-asymmetric induction double bond hydrogenation 14:147 ofazetidinone 4:437 ofbrasilenone 6:7,8 of chiral P-keto sulfoxide 14:529 ofpenicillinates 4:437 of P-ketoester 6:429,430 with diisopropylamine borane 4:437 with Dipodascus sp. 12:337 with K-Selectride 4:437 withNaBH4CeCl3 3:483-485 with tetrabutylammonium borohydride 3:483-485 Stereoselective ring opening 12:346 Stereoselective synthesis cw cyclopentane 8:9 of ()-dolasta-l (15),8-dien- 14p-ol 6:54 of()-eremophilone 15:243 of(-)-swainsonine 12:330 of(+)-castanospermine 12:353,354 of3,7-octadien-l-ol- 12:467,468 of acetogenins 18:193-227 of bicarbocyclic fused systems 6:5-38 ofcarbonolides 11:163-172 of cw-2,6-dialkylpiperidines 6:431,432 of doxorubicin 14:3-46 of forsythide aglycone dimethyl ester 16:294 ofleuconolides 11:163-172 of maridonolides 11:163 -172 of methyl cyclopentanoid monoterpenes 20:41-46 of natural products 12:445-498 of oligonucleotides 13:275-281 ofspu-oketals 14:519-521 oftetraponerine-8 6:452 of//zreo-2-amino alcohols 12:489-493 of /ra5-2,6-dialkylpiperidines 6:431,432 of vitamin D 10:43-75 of p-oxygenated y-amino acids 12:476- 489 /rafw cyclopentane 8:9 Stereoselective Wittig reaction 12:312 P-Stereoselectivity 10:466 Stereoselectivity of oxazolo [4,3-a] isoquinolmes 12:452 of (Z)-conjugate esters 4:177,178 of C(3)-monosubstitution reactions 4:653 of ()-nonenopyranuronate 4:180,181 ofosmylation 4:161,162,167,168,170-172,175,178, 183,188 of Wittig reaction 4:175 ewfi^o-Stereoselectivity 4:657,659

Stereospecific iminium ion-vinylsilane cyclization 12:298 reduction 11:98 Stereospecific cationic cyclization 12:456 Stereospecific deuteration 20:839 Stereospecific hydroxylation withOs04 1:404,405 Stereospecific intramolecular-Diels-Alder cycloaddition in 7,20-diisocyanoadociane synthesis 6:86,87 Stereospecific oxidation/reduction 17:484 Stereospecific preparation of(3)-3,7-octadien-l-ol 12:466,467 of 6-oxygenated 4a-aryldecahydroisoquinolines 12:457,458 Stereospecific reduction ofketonucleosides 4:234 Stereospecific synthesis fi-om chiral pool 18:197-202 Stereospecificity of glycosylation reactions 14:201 -259 Sterepolide asymmetric synthesis of 8:280 Steric effects ^^ONMR spectrum of 17:624 Steric preference in acetylenic carotenoids 6:154 Steric symphoric effect 4:543 Stem-Volmer iodide-quenching constant 18:847 Stem-Volmer quenching constant 18:832,844 Steroid hormones 13:634 Steroid intermediate 4:674,675 Steroid saponins 7:426;15:27-29 moUuscicidal activity of 7:427 Steroid-alkaloid glycoside 5:110 Steroid-pyrazine 18:875-905 via a-amino ketones 18:885-887 Steroidal alkaloids 2:175-207 from Veratrum califorincum 7:16 fi-om Solarium umbelliferum 20:489 Steroidal amines 7:16-24 teratogenic metabolites of 7:21-24 toxic 7:16-24 Steroidal estrogens 5:448 Steroidal glycosides 7:286,303 substrates 17:483 Steroidal ketones 5:698-701 Steroidal lactones 14:439,20:135-148 cardiac active steroids 14:439 fi-om Digitalis purpurea 14:43 9 Steroidal type solanaceae alkaloids 11:229 Steroids 5:46 C-27 synthesis of 8:188-195 semi-synthesis of 17:622-631 Sterols 5:403,405;17:78-79,153,207,474 Sterulic acid 9:38,44,45 biosynthesis of 9:45 Steryl esters catalytic deuteriation of 9:476 chromatographic analysis of 9:457-486 extraction of 9:449,450 HPLC analysis of 9:460-464

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LC/MS of 9:476-478 mass spectrometric analysis of 9:447-486 Steryl ferulates 9:473,474 Steryl palmitates of5a/5P-cholestanol 9:454 of cholesterol 9:454 Steryl xylosides 7:282 Stetter thiazolium salt method 6:437-438 Stevens [l,2]-sigmatropic rearrangement 6:315 Stevens and Bisacchi synthesis oftaxodione 14:684-686 Stevens condensation 3:463 Stevens rearrangement 6:497;16:470-471 of ring C-homoberberine analogue 6:496 Stevia phlebophylla 15:16 Stevia purpurea 1-bisasolones from 8:44-46 Stevia rebaudiana 15:4,5 Steviol 13-0-p-Z)-glucoside 15:18 Steviolmonoside 15:18 Stevioside 15:16 Stichlorogenol 7:272 Stichloroside Ai 7:272,274 Stichloroside A2 7:272,274 Stichloroside Bi 7:272,274 Stichloroside B2 7:272,274 Stichloroside Ci 7:272-274 Stichloroside d 1:212-21 A Stichlorosides Ai, Bi, Ci and A2, B2, C2 from Stichopus chloronotus 15:87 Stichopodiadae 7:272-274,282 Stichoposide A 7:272-274,282 Stichoposide B 7:272-274 Stichoposide D from Stichopus variegatus 7:273 Stichopus chloronotus stichlorosides Aj, Bi, Ci and A2, B2, C2 15:87 Stichopus chloronotus 7:272 Stichopus japonicus 7:277 holotoxinsA, Ai, BandBi, 15:87 Stichopus sp. 7:282 Stichopus variegatus 7:272,282 stichoposide D from 7:273 Stictanin 9:186 Sticticine 9:190,192 Stigmasteryl linoleate 9:461 Stigmastanyl ferulate 9:454 Stigmasterol 2:129;9:284,295;7:124;18:515;16:323 from Salvia glutinosa 20:707 from Salvia limbata 20:702 Stigmast-4-ene-3 -one from Salvia nemorosa 20:702 Stigmast-7-ene-3 -ol from Salvia nemorosa 20:702 Stigmast-7-ene-3 -one from Salvia nemorosa 20:702 Stigmasterol [(245)-24-ethyl-cholest-5,22-dien-3 (3-ol] 9:447,454,455 Stigmasteryl-p-D-glucopyranoside 7:190 Stigosine 1:260 ()-Stilbene 20:302

//flf/u-Stilbene 11:423,424 pallescensin-E from 6:31 Stilbene 9:391 Stilbene dimer 9:258-263 fromGnetumla 9:258 Stilbene estrogens 5:453 Stilbenes 5:467 Still olefmation 10:157;12:46,47 Still procedure 13:88 Still rearrangement 13:22 Still synthesis of()-A^^^^^-capnellene 6:47 ofasperdiol 10:18 Still's product 6:542 Stille-type Pd (0) catalysis 16:435 Stillingia lineata 7:417 Stimasteme 9:288,289 Stipitatic acid synthesis of 1:340,341 Stirling reaction 10:672,673,675,678 ()-Stoechospermol by Baeyer-Villiger oxidation 6:39 by [2+2] photocycloaddition reaction 6:39 by Wittig olefmation 6:39 enantioselective synthesis of 6:39,40 synthesis of 6:39 Stomphia coccinea 15:66 Stongylocentrotus purpuratus 9:575 Stork modification of Michael addition 10:185 Stork's vinyl radical cyclization 12:15 Stork-Boeckmann enone 12:262 Stowell's iodide 8:146,147 Strecker reaction 6:312 intramolecular 19:36 Strecker-type reaction 10:463 Strellidimine biogenesis of 6:516,519 from Strychnos dinklagei 6:516 spectral data of 6:516,518 synthesis of 6:516,517,519,520 Strempeliopme 9:186 Streotpmyces lysosuperficus 1:417 Streptal 14:102 Streptavidin 18:919 (+)-Streptazolin Overman synthesis of 13:514,515 Streptococcal carbohydrates 19:696 Streptococcus bovis 19:696 Streptococcus faecalis 12:401,19:696 Streptococcusfaecium 4:432,12:103,401 Streptococcus mutans 7:69;18:673,20:32,34,36 Streptococcus pneumoniae capsular polysaccharide 14:233 Streptococcus pyogenes 5:601,9:308,10:117,13:162, 173,181,183,19:492 Streptococcus sanguis 7:69 dextransucrase from 7:41 Streptococcus sp. 5:325;16:108 Streptolic acetate 14:104 Streptolic acid 14:102,104

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(+)-Streptolic acid synthesis of 14:112-114 Streptolydigin 14:97,98,100,101 Streptolydigin phosphonate tetramic acid synthesis of 14:117,118,132-134 Streptomyces actuosus staurosporin ("NB-2025") from 12:365 Streptomyces aizunensis aizumycin from 12:63 Streptomyces amakusaensis 19:178 Streptomyces ambofaciens 5:613,614 Streptomyces antibioticus 11:214,215 chlorothricin producer 11:214,215 Streptomyces aureus 5:429,434 Streptomyces avermitilis 1:435 avermectins from 12:3 Streptomyces azureus thiostrepton from 11:209 Streptomyces bikiniensis 18:700 Streptomyces cacoi\ar. asoensis 1:399 Streptomyces caespitosus 9:431 ;13:434 albomitomycin A from 13:433 isomitomycin A from 13:433 mitomycins A-C from 13:433 Streptomyces cattleya thienamycin from 11:210;12:145 Streptomyces cellulosae 12:103,54 Streptomyces chrysomallus 8:102 Streptomyces cinnamonensis 11:197 Streptomyces coelicolor 5:617,618 Streptomyces collinus ansatrienin (mycotrienin) from 11:189 enoyl CoA reductase from 11:190-191 Streptomyces diastatochromogenes staurosporine from 12:366 Streptomyces distallicus 5:551 Streptomyces erythreus 13:166 Streptomyces flaveolus tirandamycin A from 14:98 tirandamycin B from 14:97,98 Streptomyces flavogriseus 10:103 Streptomyces flavopersicus 11:216 Streptomycesfradiae 5:591 urdamycin from 11:134 Streptomyces gougerotti 4:242 Streptomyces griseochromogenes 18:269 Streptomyces griseochroogenes 4:242 Streptomyces griseoflavus 12:63 ;19:165,167 Streptomyces griseolavendus 15:445 Streptomyces griseolus 1:408 Streptomyces griseoplanus 10:104 Streptomyces griseus 1:514;7:388;18:700;19:587 Streptomyces griseoflaus 19:165,177 Streptomyces grisline indolizomycin from 12:300 Streptomyces hygroscopicus subsp limoneus 13:223 Streptomyces incarnatus 19:177 Streptomyces lavendulae 10:77-80 Streptomyces lusitanus 10:103 Streptomyces lydicus 14:105 streptolydigin from 14:97,98,100

Streptomyces matensis 11:113 vineomycin A i from 11:113 Streptomyces matensis subsp. vineus 5:594 Streptomyces mediocidicum telocidines from 11:278 Streptomyces melanovinaceus 10:115,19:289,340 Streptomyces miharaensis 1:404 Streptomyces mobaraensis 15:457 Streptomyces morookaensis 4:242 Streptomyces noboritoensis 5:590 Streptomyces nodosus 4:513 amphotericin B from 6:261 Streptomyces nodosus var. asukaensis asukamycin from 11:189 Streptomyces nogalater nogalamycin from 14:47 Streptomyces novoguineensis 1:404 Streptomyces OM-4842 5:597 Streptomyces oxamicetus 4:234 Streptomyces pactum 15:457 Streptomyces phaeochromogenes 18:10 Streptomyces phaeochromogenes 5:553 Streptomyces plicatus 4:243,244 Streptomyces ramulosus (-)-acetomycin from 10:443 Streptomyces rhishiriensis ansatrienin (mycotrienin) from 11:189 Streptomyces rimoss tetrangomycin from 11:135 tetrangulol from 11:135 Streptomyces rosa var. OS-3966 11:127 Streptomyces sandaenis 13:434 Streptomyces sapporonensis bicyclomycin from 12:63 Streptomyces sp. 5:35,55,377,607,615-618 Streptomyces sp. C-71799 staurosporin from 12:366,367 Streptomyces sp. M-193 12:365 Streptomyces sp. N-126 12:366,368 Streptomyces sp. PK-286C staurosporine from 12:366 Streptomyces sp. RK-286 RK-286 C from 12:366 Streptomyces species 9:433-435;ll:189;18:229 validamycin A from 13:189 Streptomyces spectabilicus 20:796 Streptomyces spiroverticillatus tautomycin from 18:269 Streptomyces staurosporeus 1:3 ;5:5 5; staurosporine ("AM-2228") from 12:365 BMY-41950from 12:366,368 Streptomyces subflavus subsp. irumaensis 5:597 Streptomyces tanashiensis 5:618 Streptomyces teryimanensis indolizomycin from 12:300 Streptomyces tirandis 3:270; tirandalydigin from 14:97,98 tirandamycin A from 14:98 Streptomyces venezuelae 5:552 Streptomyces verticillatus 9:433-434 Streptomyces violaceoniger 4:255

1190
Streptomyces violaceoruber granaticin producer 11:214,215 Streptomyces viridosporus 15:441 Streptomyces zelensis 1:180 ;3:310 Streptomycin 2:424,9:413,14:144,20:714 Streptonigrin 3:385 synthesis of 3:387 A-fldf^Streptonigrin 20:465 Streptopelia chinensis suratensis hemoglobin components of 5:837 Streptopelia orientalis hemoglobin components of 5:837 Streptoverticilium rimofaciens B98891 4:245 Streptoverticillium ardum porfiromycin from 13:433 Streptoverticillium mobaraense BE-13793 C from 12:366,370 Streptoverticillium olivoreticuli subsp. neoenacticus 10:638 Streptoverticillium verticillus 19:351 Strictalamine 5:155,154 Strictaminolamine 5:157,158 Strictanine 5:167 Stricticine 5:176 Strictine 5:153 Strictosidine 1:89-91;2:376 biosynthesis of indole alkaloids 1:90,91 Strictosidine 15:486 dehydrogeissoschizine from 15:487,488 Strictosidine lactam 2:375 Strictosidine synthase 13:662 Striga asiatica 5:823;9:364 Stromelsin/w-RNA 12:398 Stronglyophora hartmani 15:312 Strongylin-A 15:300 Strongylocentrotus droebachiensis 7:285;15:104 Strongylocentrotus intrmedius sulfated sterols from 7:285 Strongylocentrotus purpuratus 15:104 Strongylostatin 7:1,2,285 Structure activity relationship inacronycine 20:791-798 ofmicrocystins 20:897-899 ofnodularins 20:897-899 Structural elucidation of saponins 15:187-224 Structural studies ofxenocoumacins 15:392-408 Structure confirmation of peptidoglycan-related compounds 6:406 ofperforene 6:30,31 Structure determination of allenic carotenoids 6:135-138 Structure elucidation ofabscisicacid 6:559 ofsclerosporin 6:546-556 Structure modification inMurNAc 6:405 Structure-activity profile oftaxol 12:220,221 Strurnus vulgaris hemoglobm components 5:836

Stryhcynan-type alkaloids biosynthesis of 1:31,32 Strychnan-type alkaloids 5:71,85,174-180 Strychnane alkaloids 6:520 Strychnine 7:444;9:186-188 Strychnine 1:74,75 Strychnochromine 9:183 Strychnofluorine 1:38 Strychnopivotine 1:38,39 Strychnos species 6:503 Strychnos z)k?Xo\ds 16:435 from 2-pyrrolidones 14:560,561 nomenclature of 1:33 numbering of 1:33 synthesis of 14:560,561 Strychnos dinklagei 6:503-536 alkaloids of 6:503-506 brafouedme from 6:503-506 cantleyine from 6:503-506 dinklageine from 6:522 ellipticine from 6:506 gentianine from 6:529 10-hydroxyellipticine from 6:509 18-hydroxyellipticine from 6:513 isobrafouedine from 6:503-506 8-methoxy-8,10-dihydrogentianine from 6:529 7-0-[4-methyl-5-( 1 -hydroxyethyl) nicotinoyl] strychnovoline from 6:522,527 monoterpene alkaloids from 6:522-527 oxidizing enzymes in 6:520 A'-b-oxy-n-oxoelipticine from 6:513,515 strellidimine from 6:516 venoterpine from 6:527 Strychnos gossweileri 1:125 Strychnos longicaudata 1:124 Strychnos melinoniana 1:124,125 Strychnos ngouniensis 1:124 Strychnos nux-vomica cantleyine from 6:503 Strychnos usambarensis 1:124,126 Strychnos vacacoua bakankoside from 6:503 Strychnovoline from loganin 6:523,524 from Scaevola racemigera 6:522 from Strychnos dinklagei 6:522 spectral data of 6:524,526 synthesis of 6:523,524 Strychnoxanthine 1:125 Strychnozairine 1:38,39;9:186 Stubenrauch's technique 4:414 Sturmus pagodarun 5:837 hemoglobin components of 5:836 Stylocheilus longicauda 17:4,104,19:549 (,^-Stylopine biosynthesis of 14:771 from (5)-reticuline 14:771 Stypodiol from Stypopodium zonale 6:54 Stypodiol methyl ether 14-deoxy-stypodiol from 6:55 reaction with Jones reagent 6:55

1191

Stypoldione 5:439;6:55;17:8 from Stypopodium zonale 6:54 Stypopodium zonale 5:439;6:54 stypodiol from 6:54 stypoldione from 6:54 Styracaster caroli carolisterol A-C 15:75,76 Styrene-quinone reactions 16:551-552 Styrenes cycloaddition reactions of 16:561 polymerization of 16:551 Styryl azide thermolysis 3:314,315 Styrylpyrones 9:393-395,403 Suaveoline 13:383,390,391,402,403 synthesis of 13:408,411-418 Subclone of BALB/c 3T3 embryo derived mouse fibroblasts 5:448 (+)-Subcosine I synthesis of 16:477 Subcosinel 1:367,370 Subcosinell 1:367,368 Suberenol from Pleisopermium datum 20:497 Subergorgia suberosa 13:26 Subergorgic acid 13:26-29 Subergorgic acid 3:6,60 Suberosin 20:497 from Pleisopermium alatum 20:497 Substantial kinetic isotope effect 11:212 3-Substituted 2'-hydroxyflavonoids 5:631 2-Substituted 2,4,5-trimethyl-l ,3-dioxolanes "with mixed hydride reagent" (LiAIIVAlCla) 14:480 /r/-Substituted azulenes 14:339-351 Substituted benzo[c] phenanthridines in cancer chemotherapy 4:544 3-0-Substituted glycals from(l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidin-5-yl) mercuric acetate 10:343 2-Substituted glycals a-anomers from 10:348 5-Substituted indolizidines 11:245 A^-Substituted oxazolidin-2,4-diones 12:464 2-Substituted oxepanes 10:215,216 Substituted phenols biogenesis-like transformation of 16:571-638 2-Substituted quinolines 3:391-393,395 4-Substituted quinolines 3:396 5,6-Substituted tetralin a-adrenergic activity of 8:396 6,7-Substituted tetralin P-adrenergic activity of 8:396 A^-Substituted valiolamine derivatives 7:47 4-Substituted-2-oxazolidinones from ketopinic acid 12:416,417 from 4-methoxy-2-oxazolidinones 12:435-438 optical resolution of 12:437,438 preparation of 12:437,438

(i?)-4-Substituted-2-oxazolidinones from (i?)-A^-Boc-2-aminoalcohol 12:435,436 use as chiral auxiliaries 12:435,436 Substrate binding domain 17:487,494 forHLADH 17:500,502-503 surrogates 17:498 Subulitermes bailey eudesm-11 -en-4-ols from 14:451 neointermedeol from 14:451,452 Subulitermes oculatissimus neointermedeol from 14:451 Subulitermes parvellus neointermedeol from 14:451 Succinic acid dehydrogenase 7:387 Succinyl CoA (2/?)-methylmalonyl CoA from 11:195-197 Suchilactone 18:590 Sucrase 7:38,57,69,181 ;10:504,505 castanospermine inhibition with 7:12 Sucrase isomaltase 10:498 Sucrononic acid 15:6 Sucrose (P-D-friictofiiranosyl)-l -thio-a-Dglucopyranoside 2:414;8:325 1-thio analog of 8:322 FD spectrum of 2:52 synthesis of 8:322 Sugar aglycone linkage 7:154,157,158 cleavage by diazomethane 7:155,156 Sugar analogs 6:351-384 Sugar components 11:213-219 Sugar derivatives 20:116 Sugar enones 10:337 Sugar impersonator swainsonine as 7:14 Sugar-epoxide reductive cleavage of 14:168 Sugar-peptide structures reactions of 6:385-420 relation to peptidoglycan 6:385-420 synthesis of 6:379-414 Sugar-shape alkaloids 12:276 Sugars as chiral building blocks 4:349-359 iL-Sugars advantages of 4:504 Sugiol from Salvia napifolia 20:670 Suicide inhibitors 9:593 Suicide substrates (irreversible inhibitors) 7:36-40 Sukurai reaction 12:175 Sulcatol conversion to pityol 1:692 synthesis of 1:691,692 Sulfated sterols from Strongylocentrotus intermedius 7:285 a-Sulfenylacetamide cyclization to erythrinans 3:461 rrfl5-Sulfenylation intramolecular 12:73,76 Sulfide contraction reaction 6:438,439 Sulfidopeptide lipoxins 9:576

1192

Sulfinates 4:490 Sulfinyl carbanion 1:451 a-Sulfinylesters in Aldol type condensations 4:491-494 syntliesis of 490,491 Sulfite reductase 9:603 Sulfonation 16:127 of endo-3-bromocamphor 16:127 Sulfone anion addition to epoxide 1:471 Sulfone coupling reaction 4:526,528 Sulfones 17:91 Sulfonium ion-induced cyclocarbamation 12:487 Sulfonyl group 6:342 1,3-rearrangement of 6:342 O-Sulfonylation 12:338 Sulforhodamin B 20:524,537 Sulfoxides optically active 489-491 preparation of 14:517-519 monochlorinated sulfoxide from 6:310 synthesis of 4:489-491 Sulfur 6:307-349 properties of 6:307,309 Sulfur accumulation in liverworts 2:275 Sulfur analogue by Pummerer rearrangement 12:160,161 from (/?)-2-methyl-l,3-butanediol 12:160,161 Sulfur-assisted C-C bond formation 6:308 Sulfur stablized carbanions 3:81,82 Sulfur-containing compounds 17:81 Sulpheno-cycloamination 1:228 Sulphonation 4:628,633,634 of camphor 4:628 of (+)-ertfi?o-3-bromocamphor 4:628 regiospecific 4:633,634 Sulphonium ylids 13:144 sigmatropic rearrangement of 13:144 Sulphurisation 9:371,372 of4-t-nonylphenol 9:372 Sultam 1:24,25 SUMT 9:603,604,606 Supercritical fluid chromatography (SFC) 9:464,466 Super-hydride reduction with 3:279 Superstolide A absolute configuration of 19:597 NOESYdataof 19:597 relative stereochemistry of 19:597 Supinine 1:339 Supinidine 1:229,233,234,237,248-250,259,339 Supinidine 3:51,54 1,3-Suprafacial migration 8:297 SuranginB 4:390,391 icom Mammea longifolia 4:391 Surface ionization techniques 2:46-53 Surface-immunoglobulins 18:915,916 (-)-Suspenol enantiospecific synthesis of 16:595-601 stereo structure of 16:592,595

Suspensaside antihypertensive activity of 5:513 Suspension cultures 7:92,93 Suspensolide synthesis of 8:234-236 oxy-Cope rearrangement of 8:234 from Anastrepha suspensa 8:222 ,-Suspensolide via Mitsunobu cyclization 8:236 Z,-Suspensolide 8:236 Suzuki coupling of organoboronic acids 16:435 Suzuki reaction 20:300 Suzuki-type coupling 20:445 Swainsona canescens (-)-swainsonine from 12:313 Swainsona species 7:11 ;10:558 8a-ep/-Swainsonine synthesis of 1:280 8-e/7/-Swainsonine synthesis of 1:280 Swainsonine 7:32,44,112 absolute configuration of 7:14;10:558 as sugar impersonator 7:14 asymmetric epoxidation of 10:561 enantioselective synthesis of 10:561 enantiospecific synthesis of 10:564 from Astragalus lentiginosis 7:11 from Astragalus lentiginosus 10:558 from Metarhizium anisopliae 10:558 from Rhizoctonia leguminicola 10:558 from Swainsona species 10:558 Homer-Emmons olefination of 10:561 immunomodulation by 7:16 isolation of 19:487 lysosomal inhibitor of 10:559 mannosidase I inhibitors 10:527 mannosidase II inhibitors 10:527 relative configuration of 10:558 synthesis of 1:280,281,289,290;10:541;19:487 a-mannosidase inhibition by 7:11 a-mannosidases 10:559 (-)-Swainsonine absolute configuration of 12:313 biosynthesis of 12:313,314 enantiospecific synthesis of 12:313,314 from (-)-(lS',2/?,8aS)-mdolizidine-l,2-diol 12:303 from Astragalus emoryanus 12:313 from Astragalus lentiginosus 12:313 from Astragalus oxyphysus 12:278 from Metarhizium anisopliae 12:313 from Oxytropis sericea 12:313 from Rhizoctonia leguminicola 12:313 from Swainsona canescens 12:313 relative configuration of 12:313 stereoselective synthesis of 12:330 synthesis of 12:313-325 (-)-8-ep/-Swainsonine benzylidene-3-deoxy-a-D-glucopyranoside 12:326, 327 divergent synthesis of 12:330

1193 from methyl 3-acetamido-2-0-acetyl-4,6-0from (/?)-glutamic acid 12:325 synthesis of 12:328 (-)-l-ep/-Swainsonine 12:322,325 from (S)-glutamic acid 12:325 (-)-8a-e/7/-Swainsonine divergent synthesis of 12:330 from 2,3-O-isopropylidene-L-erythrose 12:330, 331 synthesis of 12:328,329 ep/-Swainsonine 7:44 (-)-Swainsonine N-oxide 12:276 Swainsonine stereomers 12:325 Swartzia madagascariensis 7:417,427,429,431,432 Swartzia simplex 7:427,429 Sweet marjoram {Marjoram hortensis) cyclase from 11:222 Sweeteners 2:357 Swenton's bicyclic intermediate 14:13 Swem method 19:452 Swem oxidant 6:119,120 oxidation with 6:119,120 with oxalyl chloride 8:25 Swem oxidation 1:451,4:19,200,210,418,425; 5:822,20,21,254-257,447,449,386,497,705-708,821824,826;6:11,13,21,25,57,58,62,66,67,74,75,129,192, 193;8:3-59,64,65,68,69,81,82,115-135,139--157,159172,175-201,205-217,219-256,261,274,277-282,283292,315-350,359-370,373-392,395-406,409-428,433463,466,467,478,25,50;9:37,224,225,228,241-243, 248,343-369,434;10:3-42,51,52,59,65,69,70,77145,155,156,159,166,167,168,171,180,188,241302,307-311,315-317,320-323,330,331,350,351, 386,414,418,419,421,423-428,436,437,439-448,457493,507-511,514-516,585-627,629-669,682685,15,16,20,24,34,38,47,289,290,532,534,551,552,5 61,589,590,597;11:3-69,71-111,117,119-144,151172,229-275,277-377,379-425,429-480,85,86,105, 106,156,233,236,249,267,268,365-367,421;12:933,35-62,65-95,113-135,145-177,181-225,233274,275-363,375-383,411-444,445-498,15,88,321, 324,331,336,343,465,468,469;13:3-52,84,108120,165,187-255,264-281,288,289,328,353-367,383471,473-518,22,125,132,138,139,142,416,420,422, 487,488;18:91,176-178,198,201,210,260,282,283,297, 475,623,633,641;19:22,33,42,45,62,207,238,296,304, 307,341,373,426,452,473,497-498;20:50,75, 592 in synthesis of (-)-warburganal 4:418,425 of ()-10-O-methyl-18,19-dihydrohunter-bumine 14:706-708 of()-ll-epiambinine 14:790,791 of()-ll-epicorynoline 14:785-787 of ()-l 1-epiisocorynoline 14:785-787 of ()-16-hydroxy dihydrocleavamine 14:850-853 of ()-18,19-dihydroantirhine 14:406-408 of ()-18,19-dihydrohunterbumine 14:406-408 of ()-3-gp/-18,19-dihydroantirhine 14:707,708 of()-3-epicorynantheidol 14:790,791 of()-5-ep/-nardol 14:374,375 of ()-alloaromadendrane-4b, 1 Oa-diol 14:379-3 84 of()-alloaromadendrane-4a,10a-diol 14:379-384 of()-alloyohimbane 14:710,711 of()-ambinine 14:788-791 of()-bulnesol 14:365 of()-chelamine 14:793-795 of()-chelidonine 14:793-795 of()-confertin 14:362 of()-corynanthediol 14:709,710 of()-corynoline 14:785-787 of ()-ebumamonine 14:72 8 of ()-epialloyohimbane 14:710,711 of()-homochelidonine 14:796 of()-isocorynoline 14:785-787 of ()-tirandamycin A 14:120-123,129-132,134-138 of()-tirandamycinB 14:123-126 of()-vincamine 14:726 of()-a-bulnesene 14:364,365 of(-)-(10/?)-hydroxydihydroquinine 14:564,565 of (-)-7-deoxydaunomycinone 14:493,494 of(-)-ajmalicine 14:563,564 of(-)-//o-yohimbane 14:267,277,278 of(-)-ambrox 14:420-425 of(-)-chokol 14:490 of(-)-eburunamenine 14:636 of(-)-eldanolide 14:272,273 of(-)-ep/-ambrox 14:420-425 of(-)-eserethole 14:636-638 of(-)-esermethole 14:639 of (-)-Ireland alcohol 14:119,120 of(-)-lardolure 14:487 of (-)-A^-acetylamphetamine 14:496,497 of(-)-ochropposinine 14:565 of(-)-physostigmme 14:636-638 of(-)-polygodial 14:413-421 of (-)-selin-l l-en-4a-ol 14:456-465 of(-)-talaromycmB 14:538,539 of (-)-tirandamycin A 14:114-117 of (-)-/rflr5-cognac lactone 14:272-273 of (-)-rrfl5-whisky lactone 14:272,273 of(-)-warburganal 14:413-421 of(-)-a-selinene 14:406-413 of(-)-5-multistriatin 14:273,274 of(+)-africanol 14:487,488 of(+)-arborescin 14:365,366 of(+)-carissone 14:406-413 of(+)-dihydropinidine 14:572,573 of(+)-ebumamine 14:636 of(+)-isoambrox 14:420-425 of(+)-multistriatin 14:267 of(+)-pedamine 14:499 of(+)-PS-5 14:497,498 of(+)-streptolicacid 14:112-114 of (+)-tirandamycic acid 14:110-112,127-129 of(+)-yohimbine 14:566,567 of(+)-zaluzanin 14:366,367 of (+)-a-eudesmol 14:406-413

1194

of(+)-P-eudesmol 14:490 of ()-olefmic alcohol 19:452 of(l)-a-santonin 14:406-413 of(/?)-(-)/(5)-(+)-3'-methoxy-4'-0-methyl joubertiamine 14:501,502 of (5)-2-(6-methoxy-2-naphthyl) propanoic acid 14:473 of (5)-5-hydroxy-2-penten-4-olide 14:273,274 of(5)-/ra5-g-butenyl 14:473 of (5)-Y-acetylenic-Y-aminobutyric acid (GABA) 14:473 of 1,2,4,6-tetra-0-acetyl-2,3-didehydro-3-deoxy-aD-threo-hexopyranose 14:173 of 1,2,4,6-tetra-0-acetyl-3-deoxy-a-Z)-/y:cohexopyranose 14:173 of 1,2-dehydroaspidospermidine 14:635,636 of 1,3-diols 16:11 of 10-hydroxy corynanthediol 14:709,710 of 13 -methy Itetrahydroprotoberberine 14:790 of 16-carbomethoxyvelbanamine 14:831,832 of 16'-demethoxycarbonyM6'-e/7/-deoxy vinblastine 14:850-852 of 2-methyl-l,6-dioxaspiro [4.5] decane 14:526-531 of 2'-phosphorylated ribonucleotides 14:304-312 of2-pyrrolidones 14:560,561 of 3,4-anhydro-a-D-altropyranoside 14:170 of 3-arylisoquinoline alkaloids 14:796-799 of 3-deoxy-1,2:5,6-di-0-isopropylidene-Z)-x;;/ohexofuranose 14:172 of 3-deoxy-1,2:5,6-di-0-isopropylidene-a-D-ribohexofliranose 14:168-171 of 3-deoxy-D-r/6o-hexofuranoside 14:164 of 3-deoxy-Z)-/"/6o-hexose derivative 14:163 of3-deoxy-hexoses 14:143-200 of 3'-deoxykanamycin A 14:145 of 4-deoxy-AZ,-xy/o-hexopyranose 14:178 of 4-deoxy-Z)-/>':co-hexose 14:158 of 4-deoxy-Z)-r//?o-hexopyranoside 14:164 of 4-deoxy-hexoses 14:143 -200 of 5,6-methanoleukotriene 14:489,490 of 5-carba-levoglucosenone 14:279 of 5-e/7/-paradisiol 14:454,456-465 of 7,8-demethylene sanguinarine 14:783,784 ofadriamycin 14:474,475 ofaflatoxinMz 14:651-657 of alcohol 16:313,480 of alkaloids 14:632-639 of allylic alcohol 16:261 of ambergris fragrances 14:420-425 ofaminocyclitol 14:147 ofamiteol 14:456-465 ofanthracyclines 14:271 ofapovincamine 14:635,636 ofaspidospermidine 14:632-636 of benzyl 4,6-O-benzy lidene-3 -deoxy-^-D-ribohexopyranoside 14:153,154 of branched RNAs 14:284-303 ofbulgecinine 14:193

of calabarbean alkaloids 14:636-638 of carbohydrate derivatives 14:659-664 ofcardenolide 14:440-444 ofcatharinine 14:847 ofchelamidine 14:796 ofchelerythrine 14:773-775,796 ofchelirubine 14:777,778 ofchiralalkoxy-allenes 14:480 of chiral sesquiterpenes 14:406-425 of chiral steroid analogues 14:431 -444 of chiral vinyl ether alcohol 14:486 of c-a,a'-disubstituted pyrrolidines and piperidine 14:571-574 ofcleavamine 14:810 ofcorydaline 14:790 of damascones 14:425-431 of D-and I-lividosamine 14:186-193 ofdaunomycin 14:474,475 ofdaunomycinone 14:5-8,24-42 ofdesepoxymethylenomycin 14:602 ofdihydrobenzofiiranol 14:651 ofdihydrochelerythrine 14:773-775,796 ofdihydronitraraine 14:765 ofdihydrosanguinarine 14:793-795 ofditerpenoids 14:639-642 of flf/-carbomethoxydihydrocleavamine 14:831 -833 ofofZ-coronaridine 14:847,850-853 ofdl-dihydrocatharanthine 14:850-853 ofebumamonine 14:632-636 of emetine 14:565 ofepilupinine 14:704-709 ofepivincadine 14:635,636 of eudesm-11 -en-4-ols 14:449-467 offagaronine 14:775-777 of guaiani alcohol 14:374 of homoallylic alcohol 19:238 of hydroazulene sesquiterpenes 14:355-387 ofibophyllidine 14:847 of iboxyphylline 14:847 of indole alkaloids 14:632-636,703-730 of insect juvenile hormone analogues 14:391 -397 ofintermedeol 14:452,453,456-465 ofisoebumamine 14:635,636 of isokomarovine 14:763 ofisolevoglucosenone 14:279 of isonitramine 14:543,743-747 ofisoretronecanol 14:737 ofisovelbanamine 14:865-869 ofisovincadifformine 14:850-853 ofkomarovicine 14:763 ofkomarovidine 14:763 ofkomarovine 14:763 ofkomarovinine 14:763 oflamberticacid 14:640-642 ofleurosine 14:811 of lupine alkaloids 14:731 -768 oflupinine 14:737,738 ofmacarpine 14:781-783

1195 of methyl 2,3,6-tri-0-benzoyl-4-deoxy-Z)-r^/ohexopyranoside 14:158,159 of methyl 2,3-di-0-benzyl-4-deoxy-a-Z)-jcy/ohexopyranoside 14:153 of methyl 3-deoxy-4,6-0-benzylidene-Z)-/y;:ohexopyranoside 14:167 of methy 1-2,3,6-tri-0-benzoyl-4-0-(trifluoromethane sulfonyl)-(3-D-galactopyranoside 4:164 ofminovine 14:635,636 ofmodhephane 14:490 of monomorine I 14:575 of A^-acetyl-D-lividosamine 14:188,191 of naphtho [2.3.c] pyran-5,10-quinone antibiotics 14:271 ofnaproxene 14:505 ofneointermedeol 14:453,454,456-465 ofnitidine 14:775-777 ofnitramine 14:743-747 ofnitrarine 14:765 ofnitraramine 14:751-754 of Nitraria alkaloids 14:731 -768 of iV-methyl decarine 14:783,784 of oligoribonucleotides 14:283-312 ofoxaunomycin 14:493-495 ofoxychelerythrine 14:773-775 ofoxyterihanine 14:775-777 ofpandoline 14:831-833 ofparadisiol 14:453,456-465 of penta-O-acetyl-D-glucopyranose 14:659-664 of penta-O-acetyl-D-isopyranose 14:659-664 ofpiperidine 14:553-559 of piperidine derivative 14:572 of podocarpic acid 14:639-642 of polysaccharides 14:201-259 of Prelog-Djerassi lactoic acid 14:267 of primary alcohol function 19:42 of propargylic alcohols 14:473 ofpunctatin 14:646,647 of purpurosamine C 14:268 of pyrethrin analogues 14:3 91 -3 97 ofpyrrolidine 14:553-559,568-571 of quebrachamine 14:632-636 of quinolizidine alkaloids 14:731 -768 ofreserpine 14:267 of rose oil components 14:425-431 ofsanguilutine 14:777,778,780,781 ofsanguinarine 14:793-795 ofsecodehydroabietane 14:642 of securinine alkaloids 14:657-659 ofserricomin 14:267,275 ofsibirine 14:744 ofsibirinine 14:742,743 ofspiro [4.5] decane 14:544-546 of stereoisomers of eudesm-11 -en-4-ols 14:456-465 of streptolydigin phosphonate tetramic acid 14:117,118,132-134 oftaxodione 14:667-702 oftetrahydroalstonine 14:563,564 oftetrahydrocorysamine 14:790 of tetramic acid 14:110 oftetrodotoxin 14:267,276,277 ofthalictricavine 14:790 ofvelbanamine 14:810,865-869 of vinblastine 14:805-884 ofvincadifformine 14:635,636 ofvincadine 14:635,636 ofvincamine 14:635,636 ofvincaminorine 14:635,636 ofvitaminEandK 14:478,479 of a-cyanobenzylalkyl ether 14:473 of a-linked 3'-deoxy cyclitol 14:147 of P-adrenergic blocking agents 14:473 ofp-cyperone 14:406-413 ofp-damascenone 14:430-432 ofp-elemol 14:406-413 ofy-citromycinone 14:8-10 of\|/-tabersonine 14:847 Swem reaction 4:425,6:125,9:526,11:90 Sweroside-gentiopicroside series 6:529 Swem-Wittig protocol 19:22 Swertiajaponica 17:421 Swinfolide 5:356,357396,397,15:589 Swinholide A synthesis of 18:186-190 stereostructure of 19:589 X-ray analysis of 19:589 Sydnone 1:343 Sylvaticin 9:399 Sylvestroside I 7:443 a-Symmetric ketones asymmetrization of 11:241,242 Sympathomimetic amines 12:411 Symphytoside A 9:61,62 Symphytum officinale 9:60-62 saponins from 9:60-62 Syn elimination ofselenoxide 16:335 oftrifluroacetate 16:357 5>'-enoate 8:140 5y-epoxidation 16:442 iSyw-isomerization metal ion-assisted 11:220,221 tertiary allylic isomer from 11:220,221 Synechocystis trididemni 10:251 Synergistic combinations 2:431 5>^ hydrostannation 19:62 Synthase 9:435 Synthesis of(+)HON 13:512-513 of()-l-ep/-slaframine 12:309 of ()-1 -oxoindolizidine 12:279,280 of()-2-oxoindolizine 12:283,284 of()-5-epipumiliotoxin 18:340 of()-6-demethylstatine 13:514 of()-6-g/7/-slaframine 12:311,312 of ()-apovincamine 18:331 of()-cathenamine 13:490,491 of ()-CM-l-hydroxy indolizidine 12:279

1196 of()-dihydroanatoxin-A 13:494 of ()-elacokanine C 12:289-293 of ()-elaeokanine A 12:289 of ()-elaeokanine A,C 13:487 of()-epilupmine 13:483,484 of ()-eremophilone 15:243 of()-gabaculine 13:509,510 of()-indolyzomycin 12:301-330 of()-isoretronecanol 13:483,484 of()-mesembrine 13:492,493 of()-A'a-benzyl-20-desethylaspidospermidine 18:323 of()-nanaomycin-A 11:127-130 of()-nupharolutine 13:488,489 of ()-0-methylpallidinine 12:470,471 of()-pleuromutilin 8:418 of ()-semi vioxanthin 11:130,131 of()-seychellene 8:412,423-425 of()-slaframine 12:307-312 of()-statine 12:432,433 of()-tashiromine 18:353 of ()-tetrahydroalstonine 13:490,491 of()-tetrangomycin 11:135-139 of ()-a-allokainic acid 13:508,516 of()-5-coniceine 13:486,487 of (-)-(l/?,8aS)-1 -hydroxyindolizidine 12:281 of(-)-(15,2/?,8aS)-mdolizidine-l,2-diol 12:303,305 of(-)-l,8a-e/7/-slaframine 12:312 of (-)-1 -e/?/-castanospermine 12:333-335,344 of(-)-15,2/?,8a^)-indolizidine-l,2-dioI 12:303,304 of (-)-8,8a-di-e/7/-swainsonine 12:329-332 of (-)-8a-e/7/-swainsonme 12:328,329 of (-)-8-e/7/-castanospermine 12:344 of(-)-8-ep/-swainsonine 12:328 of(-)-alstonerine 13:383 of(-)-anatoxm-A 13:493,494 of (-)-aristeromycin 8:148,149 of(-)--P-santalene 8:145,146 of(-)--P-santalol 8:145,146 of(-)-hobartine 11:280-283 of(-)-muscone 10:330,331 of(-)-patchoulol 8:423-425 of (-)-peduncularine 11:284,285; 13:491,492 of (-)-periplanone B 8:227 of (-)-phoracantholide I 10:320-323 of(-)-specionin 10:425,426 of(-)-Z-P-santalol 8:145,146 of(-)-P-santalene 8:145,146 of(-)-p-turmerone 8:51-54 of(+)-(155)-prostaglandmA2 10:418 of(+)-(15,8a5)-l-hydroxyindolizidine 12:281 of (+)-(6/?,75,85,8a/?)- trihydroxyindolizidine 12:347 of (+)-(65,7/?,8/?,8a/?)- trihydroxyindolizidine 12:347,348 of (+)-1,8 a-di-ep/'-castanospermine 12:335,336 of (+)-6,7-di-ep/-castanospermine 12:342-344 of(+)-6-deoxycastanospermine 12:337,338 of (+)-6-ep/-castanospermine 12:342-344 of(+)-acetomycin 10:443-448 of (+)-allopumiiiotoxins 267A 12:297 of (+)-anopumiliotoxins 339B 12:298-300 of (+)-and (-)-indolizidine alkaloids 11:246-267 of(+)-aristofruticosine 11:323-325 of(+)-aristoserratine 11:296 of(+)-aristoteline 11:280-283 of(+)-asteltoxin 10:439-442 of(+)-biotin 13:514-516 of(+)-castanospermine 11:267-271 of(+)-castanospermine 12:321,332-342,353,354 of(+)-compactin 11:335-377 of(+)-compactin 13:555-615 of(+)-hastanencine 12:472 of(+)-heliotridine 12:472-474 of (+)-isoeremolactone 8:423,425-428 of(+)-makomakine 11:280-283 of(+)-mevinolin 11:335-377 of(+)-mevinolin 13:561 of (+)-monomorine I 11:231 -244 of(+)-picrasinB 11:76,77 of(+)-pseudoephedrine 12:479,480 of(+)-quassin 11:76,77 of(+)-streptazoline 13:514,515 of(+)-thienamycin 13:498-504 of(+)-A^'^picrasinB 11:76,77 of (+)-a-homonoj irimycin 11:431,432 of(+)-a-santalol 8:145,146 of (l^l)-aldosyl aldoside 8:317-327 of (l->2) aldosyl ketoside thiodissacharide 8:324 of (1-^2) linked thiodisaccharides 8:327,328 of (l->4) linked thiodisaccharides 8:331-338 of (2/?,3/?)-3-hydroxyglutamic acid 12:477 of (25,3/?)-3-amino-2-hydroxy-4-phenylbutyric acid (AHPBA) 12:433,434 of (25,3/?)-P-hydroxy-I-glutamic acid 12:431,432 of (3i?)-y-amino-P- hydroxybutyric acid 12:434 of (3i?,45)-4-methyl-3 -heptanol 11:415,416 of(35',3/?)-3-amino-2-hydroxy-5-methylhexanoic acid(AHMHA) 12:433,434 of(35',47?)-statine 12:480 of(35,4/?)-statine 13:513 of(35,45)-4-methyl-3-heptanol 11:412,413,415 of(d:/)-bulnesol 10:310,311 of(fi^,0-trichodiene 10:307-309 of(fi?/)-acorenone 10:315-317 of(^/)-a-cuparenone 8:3,4 of()-3-bromoacrylates 8:150,151 of {E)-trans-1 -hydroxy-10-vinyl-2-cyclodecene 8:196 of (,)-diallylic ether 8:176 of {E,Z)-2,6-cyclodecadiene 8:177 of(,Z)-2,6-cyclodecadiene 8:177 of(i?)-(-)-homolaudanosin 13:494 of (/?)-(+)-tetrahydro-palmatine 10:682,683 of(/?)/(5)-homoproline 13:513,514 of(S)-pinanediol 11:410 of {Z)-trans-1 -hydroxy-10-vinyl-2-cyclodecene 8:196

1197 of (a-chloroalkyl) boronic ester 11:410 of (a-haloalkyl) boronic ester 11:425 of 1,2-disaccharide 8:362,366 of l,3,5-trihydroxyacridin-9-one 13:357,358 of l,3-dihydroxyacridin-9-one 13:355 of l,5>diepoxy l,5-immo-D-g/ycero-D-<2//o-heptitol 11:461,462 of l,5-dihydroxy-2,3-dimethoxy- lO-methylacridin9-one 13:354,355 of 11-hydroxynoracronycine 13:356-358 of 15-tritiatedGA3 8:128,129 of 19,10-thio-3-e/7z-gibberellin Aj 8:125,126 of 19,10-thiogibberellms 8:125 of 19,20-dehydrotalcarpine 13:411,427,428 of 1-aldo-C-glycosides 10:350,351 of 1-aryl bicyclo [3,10] hexane derivatives 8:12 of l-aryl-2-methyl cyclohexane 8:9 of l-aryl-2-methyl cyclopentane 8:9 of 1-deoxynojirimycin 12:332 of 1 -methyl-1 -pheny l-2-(methy lseleno)methyl cyclopentane 8:7,8 of 1-0-acetyl oxetanose 10:597-604 of 1-thio analog of sucrose (p-D-fixictofiiranosyl 1thio-a-D-glucopyranoside) 8:324 of 1-thiosucrose 8:326 of 1 -thio-a,a-trehalose 8:318 of 1 a,24^-dihydroxyvitamin D3 11:384,385 of la,245-dihydroxyvitamin D3 11:384,385 of 1 a,25-dihydroxy-(24/?)-fluorocholecalciferol 10:69 of la,25-dihydroxycholecalciferol 26,23(S)-lactone 10:59 of la,25-dihydroxyvitamin D2 11:393-395 of 1 a,25-dihydroxyvitamin D3 11:3 84,3 85 of la,255,26-trihydroxychoIecalciferol 10:69 of 1 a,3p-diacetoxy-23,24-dinorchola-5,7-dien-22-al 11:398-402 of la,3p-diacetoxy-23,24-dinorchola-5,7-dien-22ol 11:398-402 of la,3p-diacetoxychola-5,7-dien-24-al 11:398402 of la,3P-diacetoxychola-5,7-dien-24-oI 11:398402 of la-hydroxy vitamin D3 10:59 of la-hydroxyvitaminD2 11:381-383 of la-hydroxyvitamin D2 (IS-hydroxycalciol) 11:380,381 of 1 p-hydroxyvitamin D2 11:402-404 of 1 P-hydroxyvitamin D3 11:402-404 of 1 P-methy Icarbapenem 13:84 of 1 P-methylcarbapenems 12:145-177 of 2-(a-hydroxyalkyl) piperidines 12:453-456 of 2-(a-hydroxyalkyl) pyrrolidines 12:473 of 2,3,4,5-substituted tetrahydroflirans 11:433 of 2,3,4,6-tetra-O-acetyl-1 -5-acetyl-1 -thio-a-Dglucopyranose 8:316,318 of 2,3-unsaturated 1-thioglycosides 8:346 of2,6,7-trideox-2,6-imino-D-glycero-D-mannoheptitol 11:467 of2,6,7-trideoxy-2,6-imino-Z)-glycero-Z)-glucoheptitol 11:467 of 22,23 -dihydro-1 a,25-dihydroxy vitamin D2 11:395-398 of 24,24-dihomo-la,25-dihydroxy vitamin D3 11:385-387 of 24-epiteasterone 18:515 of24-epityphasterol 18:515 of 25,26-hydroxy vitamin D2 10:65,69 of 25-hydroxy vitamin D2 10:69 of25-hydroxyvitaminD3 11:388-393 of2-allylphenol 8:169 of 2-amino alcohols 12:411-444 of 2-deoxy-24-epibrassinolide 18:515 of 2-deoxy-2-desmethylene bicylomycin 12:87 of 2-deoxy-3,24-diepibrassinolide 18:515 of2-flurorostradiol 5:447,449 of 2-hydroxy-6-methylbenzoic acid 9:347,350 of 2-hydroxyindolizidines 12:283,284 of2-isocephems 12:126,127 of2-iso-oxacephems 12:128,129 of 2-lithio-2-phenyl-6-heptene 8:7,8 of 2-methylseleno-2-phenyl 6-heptene 8:7 of3,13-diacetyl-GA3 8:122,123 of 3,13-diacetyl-GA3 phenacyl ester 8:133 of3,4-dihydroisoquinoline 8:230 of 3,5-disubstituted indolizidine alkaloids 11:245259 of 30-methyloscillatoxin D 18:294-309 of 3-amino-5-hydroxybenzoic acid 9:434 of 3-cyanocephem derivative 12:135 of3-dehydro-24-epiteasterone 18:512,513 of3-dehydroteasterone 18:512,513 of 3-deoxy-la,25-dihydroxy vitamin D3 10:70 of 3 -deoxyrosaranolide 11:164 of3-hydroxy-2-hydroxymethyl-6-substituted piperidines 12:474 of 3-nocardinic acid 12:118 of3-thioxylobiose 8:329 of 4 5-P-D-gaIactopyranosyl 4-thio-D-galactose 8:339 of 4a-arylisoquinoIine ring system 12:457,458 of 4-acetoxy-P-lactam 12:160-162 of 4-aryl-1,2,3,4-tetrahydroisoquinoline derivative 12:451 of 4-aryltetralin-type lignan 18:586-588 of 4-5-D-xylopyranosyl 4-thio-D-xylose 8:338,339 of 4-iS'-a-Z)-gIucopyranosyI 4-thio-Z)-glucose 8:331,332 of 4-^-P-Z)-galactopyranosyl 4-thio-D-glucose 8:335 of 4-5-p-Z)-glucopyranosyl 4-thio-D-glucose 8:336,337 of 5,8-disubstituted indolizidine alkaloids 11:260267 of 5-amino-7-methoxy-2,2-dimethyl chroman 13:358,359 of 5-demethylene-6-deoxy-bicyclomycin 12:75,76 of 5a-carbahexopyronoses 13:190-207 of6()-alkylidene-8-hydroxy-8-methylindolizidines 12:294,295

1198 of6(Z)-alkylidene-8-hydroxy-8-methylindolizidines 12:295,296 of6,78-trihydroxyindolizidine 12:348 of6,7-dihydroxyindolizidine 12:348 of6-acetamido-6-deoxy-castanosperimme 12:345,346 of 6-deoxy-24-ep/-castasterone 18:512,513 of 6-hydroxy-4a-aryl-cw-decahydro- isoquinoline 12:458,459 of 6-hydroxyindolizidines 12:285,286 of6-0-methylerythromycin A 166 of 6-5'-P-D-galactopyranosyl 6-thio-Z)-glucose 8:339 of 6-5-P-Z)-glucopyranosyl 6-thio-)-glucose 8:339 of 7-hydroxy-3-oxomdolizidine 12:287,288 of 7-hydroxy-7-methyl-5-oxomdolizidine 12:289 of 7-hydroxyindolizidines 12:286-289 of7-methyl-2-methylseleno-2-phenyl-6-octene 8:9,10 of7-oxoindolizidine 12:286,287 of7-thiogibberellmA3 8:123-127 of 8-(3,5-dimethoxyphenyl) octan-1 -ol 9:339 of8,14-cedranoxide 8:163-165 of 8-fluoroerythromycin A 166 of8-hydroxyindolizidines 12:293 of 9-hydroxyanthracene 11:119 of a( 1 ->4)-linked 4,4'-dithiotrisaccharides 8:344,345 of A-62232 8:400 of A-65265 8:399,400 of A-65638 8:400 ofabscisicacid 10:167 ofacarbose 10:511,515 ofacoragermacrone 8:178 of acridin-9-one derivatives 13:353-361 of ACRL toxin 18:178-185 of acyclic amino acids 13:512-516 of acyclic bastadins 10:629-631,634,635 ofadiposin-1 10:514,515 ofadiposin-2 10:514,515 ofagelasphin-9b 18:467-469 ofAI-77-B 15:412-418 of aklavinone 11:121,122 of alkaloids 8:283-292 of a//o-aristoteline 11:318-322 ofallopumiliotoxins 12:297-300 of alstonerine 13:383,408,411,416,-423 of aluminum borohydride 8:467 ofambrucitin 10:386 of amino acids 11:417;13:507-516 of amino sugars 13:190-207 of amino-5a-carba-deoxyhexopyranoses 13:203-207 of aminoacylheptoglycosides 11:433-435 ofamylostatin 10:507-509 ofamylostatinXG 10:507,510,511 of anacardic acids 5:826 of Aniba neolignans 8:159-161 of anisomelic acid 10:13-17 of antisense oligonucleotides 13:264-281 ofarcyriacyaninA 12:382,383 ofarcyriaflavin-A 12:376-379 ofarcyriaflavin-B 12:379 ofarcyriarubin-A 12:375,376 ofarcyriarubin-B 12:375,376 of arcyrin/arcyrinin model compounds 12:383 of aristolasicone 11:315-317 of aristotelia alkaloids 11:277-334 of aromatic selenoacetals 8:5 ofasatone 8:168 ofaspochalasin C 13:131,132,134 ofaspochalasinB 13:142,143 ofatisirene 10:180 ofavermectins 12:9-33 ofaziridinomitosenes 13:444 ofazocine 8:207 ofbastadin-6 10:636-638 of benz[a] anthracene antibiotics 11:134-144 ofbenzalmalonates 9:224,225 ofbenzyllithuim 8:5 of beryllium borohydride 8:467 of bicyclo [2.2.2] octanes 8:412-417,419,422,423 of bicyclo [3.2.2] piperazinedione 12:71 of bicyclo [5.2.2] piperazinedione 12:84,85 of bicyclohumulenone 8:161 -166 ofbicyclomycin 12:65-95 ofbilobol 9:354 ofbinaphthaleneterol 8:221-223 of bioactive natural products 13:473-518 ofbisabolones 8:39-59 of6w-indolymaleimides 12:375-383 of blood group I active oligosaccharides 10:457493 of blood group i active oligosaccharides 10:457493 ofboromycin 10:414 of branched amino sugar 10:421 of branched pentasaccharide 10:476,477 of branched tetraacetate 10:476,477 of branched trisaccharide 10:474-476 ofbrasilenol 9:249 ofbrassinosteroids 18:507-520 ofbruceantin 11:71-73,79-95 ofbutenolides 11:453 of Ci8-desmethylcytochalasin D 8:212-217 ofcalamanenenes 15:251 ofcalichemicin 12:283 ofcarbacepham 8:262 ofcarba-disaccharides 13:219-221 ofcarbapenam 8:262 ofcarba-sugars 13:187-255 ofcarbocycles 8:410-422 of carbocyclic oxetanocins 10:608-619 of carbohydrates 11:420-422 ofcarbonolide 11:158-172 of carbonolide A 11:165,166 of carcinogenic adducts 8:373-392 ofcardolmonoene 9:354 . of carotenoids 20:561 ofcarpanone 8:168 ofcarpetimycins 12:135 ofcasbene 8:16,17 ofcastelanolide 11:74-76

1199 ofcembranes 10:3-42 ofcembranoid 8:18-32 ofcembranolide 8:16,17 ofcembrene 8:15,16 of cembrenediterpenes 8:15,32 ofcephalostatins 18:900-902 of cepham derivatives 12:131-133 of C-glycopyranosyl-a-amino acid 11:470-472 ofC-glycosides 11:139-144 of chiral allyl boronates 11:393,394 of chiral P-lactams 12:121 of cholesta-5,7-diene-1 a,3 p,25-triol 11:390-393 ofchroman 13:359,360 ofcivetone 8:224 ofcodeinone 10:180 of conjugated dienes 8:275 of convergent lactone synthon 13:604 ofcostunolide 8:175-181 ofcoumarinolignanpropacin 5:497 ofcrassin 8:19-32 of crassin acetate 10:6,7 ofC-sucrose 11:469,470 ofcuanzin 8:283-292 ofcubitene 8:221,230 ofcuparene 8:6 ofcuparene analogue 8:6 of cyanocycline A 10:108-115 ofcyanohydrin 8:225,226 ofcyclaradine 8:148,149 of cyclic amino acids 13:507-512 ofcyclodextrins 8:367 ofcyclo-I-rhamnohexaose 8:359-370 ofcyclooctenone 8:35 ofcyclooligosacharides 8:359-370 of cyclopropane derivatives 8:11,12 of cyclosarkomycin 8:150 of cycloundecenones 8:214 ofcytochalasin B 10:166;13:116,117 ofcytochalasin C 13:148,199 ofcytochalasin D 13:134-139 ofcytochalasin G 13:130,131 ofcytochalasin H 13:125-129 ofcytochalasins 8:213 of d, /-chaparrinone 11:105,106 of Z)-<af//o-a-amino acid 11:460,461 of dendrobatid alkaloids 11:244-267 ofdeoxybouvardin 10:640-642 of deoxybouvardin methyl ether 10:640-642 ofdesmethoxycuanzine 8:285-292 of des-iV-methylnoracronycine 13:355,356 ofdesoxyasperdiol 10:29,30 ofD-g/vcero-D-talo-L-fa/o-undecosepentaacetonide 11:455-458 ofdiacetoxybinaphthyl 8:222,223 of dibenzylbutryrolactone lignans 5:486 ofdiborane 8:466-468 ofdidemnin-A 10:275,276,281 ofdidemnin-B 10:276,281 ofdidemnin-C 10:276,281 ofdihydroacarbose 10:508 ofdihydromevinolin 13:575,608,609 ofdihydronapthalene 8:402 ofdihydropyrrole 10:112,113 ofdihydrothiopyrone 8:207 of diisopropyl (bromomethyl) boronate 11:425 ofdiquinanes 13:3-52 ofdisaccharides 11:469 of diterpenes (tumor-promoting) 12:233-274 off/Z-camptothecin 12:283 ofDNA 8:373-392 ofdolaisoleucine 12:477,483-486 ofdracaenones 5:20,21 of D-a-aminouronic acid 11:459,460 ofebumamonine 8:264 ofelaeocanine 12:454 ofeldanolide 11:414 ofenone 8:279 of e^4-oxo-2,33-dihydrosolamin 18:197 ofent-brefeldin A 8:148,149 ofe^brefeldin A 8:148,149 of e/-rolliniastatin-1 18:210,211 ofe/-rolliniastatin-2 18:208,209 ofenyne 8:280 of enzymes 8:315 ofep/'-corrossoline 18:200 ofepigloeosporone 9:241,242 of epimeric 2,3-epoxy brassinosteroids 18:512 ofepipodophyllotoxin 18:597-601 of epoxyallylic ether 10:589,590 ofepoxysesquiphellanhdrene 8:57,58 ofequisetin 13:545-547 oferemophilone 10:436,437 oferythromycm A 12:48-54 oferythronolideA ll:152,:153,157;12:46-54 of erythronolide A seco acid 11:154-156 of ethyl 2-methoxy-6-methylbenzoate 9:345,346 ofexo-brevicomin 11:413,414 offlexibilene 8:16,17 offreelingyne 10:167 offruticosonine 11:286 offutoenone 8:159 offutoquinol 8:169 ofgangliosides 18:486-488 ofgermacrone 8:178 of gibberellic acid 8:119 ofgibberellins 8:115-135 of gibberellms GA4 8:115,119 of gibberellins GA55 8:119,121 ofgibberellins GA57 8:121-123 of gibberellins GAfio 8:119,121-123 ofgibberellins GA7 8:115,119 ofginkgolicacid 9:355 ofglaucarubinone 11:79,80,105 ofgloeosporone 9:228,241 of glutamic acid 11:419 of glycerol 11:392,393 of glycosyl ester 8:66 ofglyfoline 13:361-367,375-380 ofguggultetrols 5:707 ofguianin 8:159 ofhaageanolide 8:175-181 of helminthosporal 8:162,163 ofhemandin 18:579-584

1200 of heteroatom mediated 8:205-217 of hexalin alcohol 13:601 of hexepi-maricin 18:207-216 of higher carbon sugars 11:429~480 of hobartine derivatives 11:3 09,310 ofhobartine-19-ol 11:309 of homothienamycin 8:262 ofhumulene 8:156 of hydroxy amino acid 12:431 -43 8 of hydroxylated indolizidines 12:275-263 of I-active oligosaccharide containing lactose 10:477-479 of I-active oligosaccharide containing lactose 10:477-479 of li-active oligosaccharide containing mannose 10:477-479 of indolizidine alkaloids 11:229-275 ofindolo[2,3-a]carbazoles 12:375-383 ofingenol 12:233-345 of inositol phosphates 18:391-451 ofionophoreX-14547A 10:425 ofipsenol 10:188 ofisocyanides 12:113 ofisodeoxybouvardin 10:644,645 of isodeoxybouvardin methyl ether 10:644,645 of isodihydrofutoquinol 8:169,170 ofisodityrosine 10:630 of isoindolone 8:212 ofisoingenol 12:234-245 ofisolobophytolide 10:10-13 of isolobophytolide 8:205-217 ofisomaltoside 11:469-471 ofisomitomycin A 13:35-37 ofisopeduncularine 11:284,285 of isoquinoline quinone antibiotics 10:77-145 ofisosilybin 5:486 ofjatrophone 10:155,156 of K-252C (staurosporinone) 12:379-381 of keto phosphonate 13:560 of kidamycin "aglycone" 11:135-139 ofklaineanone 11:74-76 oflacto-A^-biosel 10:467,468 of lactone synthon 13:615-628 of lactosamine 10:461 -467 of L-allo-a-amino acid 11:460,461 of large rmg compounds 8:19-32 oflasalocidA 10:424 ofleukotrieneBs 10:159 ofleukotrieneB4 10:168 oflignans 18:551-606 oflignarenones A,B 10:167,171 oflitiiiumborohydride 8:467 oflongipinene 8:33,36,37 ofl-ribose 11:390,391 ofZ-xv/o-guggultetrol 5:705-708 of I-xy/o-octadecane-1,2,3,4-tetrol 5:707 of I-a-aminouronic acid 11:459,460 of macrocarbocyclic 8:16-18 of macrocycle A 10:280,281 of macrocyclic cytochalasans 13:108-120 of macrocyclic semiochemicals 8:219-256 ofmacrolide 8:176;10:423 of macrolide antibiotics 12:35-62 ofmacroline 13:383,411,423,424 of macroline-related alkaloids 13:383-432 ofmaesanin 5:821-824 ofmelicopicine 13:353,354 of methoxybipyrrole aldehyde 8:273 of methyl (2,4^-2,4-nonadienoate 10:166 of methyl epijasmonate 8:152-157 of methyl jasmonate 8:152-157 of methyl-a-peracetylhikosammide 11:449-451 ofmethynolide 11:158-163 ofmethyomycin 11:151 of mevinic acid 13:553-625 ofmevinoline 13:605 of mitomycin A 13:439-442 ofmitomycin B 13:439,441 of mitomycin C 13:440 of mitomycins 13:433-471 of monocyclic p-lactams 12:120,121 of monosaccharides 13:207-212 ofmorphine 18:56-98 ofmukulol 8:178 ofmuscone 8:242,243 ofmycinolide 11:393,394 ofmyoporone 15:228 ofA^,A^-dimethyl-4-desmethylenebicyclomycin 12:68-70 ofA^-acetyllactosamine 10:461-467 of A^-alkyl analogues 8:211 of naphthopyran antibiotics 11:127-133 of natural products 8:175-201,409-428 of A^-benzoyl-iso-serinate 12:223,225 of A^-benzoylpyrrolinone 8:212 ofneolignans 8:159-172 ofneopinone 10:180 ofnitrosterene 8:230,232 of A^-methylcyriaflavin A 12:377-379 of nocardicine A 12:118,119 of nonactic acid 10:423,424 of nonactic acid 18:229-268 ofnonactm 18:260-265 ofnonitol 11:464 ofnonofuranose 11:458 ofnordidemnin-B 10:294-298 of norepinephrine 8:395-406 of octahydroindolizidine-8-ols 12:293 of octahydroindolizine-2-ols 12:283,284 of octahydroindolizine-6-ols 12:285,286 of octahydroindolizine-7-ols 12:286-289 of octa-0-acetyl 1-thio-mannosyl disaccharide 8:320 of octose derivatives 11:462-464 of Ohno's lactone 8:148,149 ofoligomericDNA 8:373 of oligopeptides 10:629-669 of oligosaccharides 8:316 ofoligostatins 10:516 ofO-methylancistrocladine 8:228,229 ofoscillatoxinD 18:269-309

1201 ofotonecine 8:211 ofoxetanocinA 10:587-608 ofoxetanocins 10:585-627 of oxetanosyl chloride 10:604-607 ofoxycyclopropane 8:34,35 of pantolactone homologue 10:442,443 ofpapaveraldine 8:263 of penam carboxylic acid 12:127-129 ofpenems 8:262 of penicillin derivatives 12:129-131 of penicillins 12:115,116 ofpentacenequinone 11:121,122 of pentacyclic diterpenoids 8:418 ofpentalenene 13:6-8 ofpepstatin 12:476 of periplanone B 8:156,179-182,226,227 of permethyl cyclohexanone 8:4,5 of permethyl cyclopentanone 8:4,5 of persoonol dimethylether 9:355 ofpetrosterol 9:37 of phenolic lipids 9:343-369 of phenylalanine 11:417,418 ofphenyllactate 12:223 ofpheromones 9:351 ofphorbol 12:245-272 of phosphatidylinositols 18:445-450 ofphosphoramidite 8:388,389 of phosphorylated polprenols 8:64,65 ofphosphotriesters 13:272,273 ofphyllanthocin 8:280 ofphytosphingolipids 18:457-490 ofpicrotoxinin 8:279 ofpikronolide 11:158-163 ofpiperazinomycin 10:638-640 ofpodophyllotoxin 18:597-601 of polene synthons 20:571,573 ofpolycycles 8:278 of polycyclic aromatic compounds 11:119-127 ofpoly-A^-acetyllactosamme 10:323 of polyprenyl diphosphates 8:65,68,69,81 of polyprenyl monophosphates 8:65,68,69,82 ofpolysiloxanes 13:328 ofporfiromycin 13:440 ofprezizanol 15:248 of protein 8:315 ofproxiphomin 13:122,123 ofpseudo-disaccharides 13:212-216 of pseudomonic acid 10:425 ofpseudo-NANA 13:210 ofpseudo-oligosaccharides 13:235-246 ofpseudo-trisaccharides 13:212-216 ofptilostemonol 8:45,47 of ptilostemonol acetate 8:47 ofpumiliotoxin 12:294,296 ofpumiliotoxin251D 12:294,295 of putative epoxyenone intermediate of estradiol metabolism 5:449 ofpyrazines 5:254 of pyrrole formation 8:269 ofquassimarin 11:79,80 ofquassin 11:73-76 ofquassmoids 11:1-111 of quaternary carbons 8:3-14 ofquinocarcin 10:125-141 ofquinocarcinol 10:120-124 ofR (-)-muscone 8:224,225 of/?-(+)-/7-carvomenthene 8:49 of racemic compactin 13:562,563 ofrecifeiolide 8:176 ofrenieramycin A 10:97-100 ofrifamycinS 12:37,38 ofrifamycinW 12:39-47 ofritterazineK 18:900-902 ofRNA 13:284,285 ofrosaranolide 11:164 ofsaframycinA 10:84-87,92-96 ofsaframycinB 10:88-93 ofsaframycins 10:83-100 ofsarcophytolB 8:18,19 ofsecasterone 18:512 ofseco-taxane 12:179,180,201 of serine 11:420 ofshikimicacid 13:188 ofsildydianin 8:166,167 ofsilphinene 8:165,166 ofsilybin 5:486 ofsinefungin 11:437,438 of sodium trimethoxyborohydride 8:467 ofsorelline 11:326,327 ofspiroethers 18:269-309 ofsterepolide 8:280 of steroid 8:167-174 ofsuaveoline 13:383,408,411-417 ofsupensolide 8:222,234,236 ofswinholideA 18:178-185 oftalcarpine 13:383,411,424-426 oftautomycin 18:269-309 oftaxane 12:181-216 oftaxanes 11:3-69 oftaxol 12:217-221 oftaxusin 11:55-59 oftaxusin 12:200,221 ofterpenes 8:33-37 of terpenoid alkaloids 8:418 of tetracyclic diterpenoids 8:418 oftetramethoxyturriane 8:228,229 of tetraoxoalkanedioates 11:117 oftetrols 5:708 of thiodisaccharides 8:316-330,339,342,343,346 ofthiolactone 8:205-207 of thiooligosaccharides 8:316,317-330 ofthiotrisaccharides 8:340 of///reo-(45',55)-4-benzylamino-5-hydroxy-2methyl-6-phenylhex-1 -ene 12:478,479 of thromboxane B2 10:419 of thymosin ai 8:437-446 of thymosin an 8:447 of thymosin P4 8:447-453 of thymosins 8:437-454 of thymosins Bg 8:456,457 of tjipanazole D 12:382

1202

of tjipanazole E 12:382 of ^a/w-7-formyloxy-8a-methylindolizidine 12:288 of/raAM-hydrindane 10:51 oftricarbonyls 8:261-274 of triquinane terpenes 10:426-428 oftriquinanes 13:3-52 oftunicamycins 11:446-449 ofuranium(iv)borohdride 8:467 of urdamycinone B 11:134,135,142-144 of uridine diphosphate-galactose 10:468 ofvalidamine 13:190 ofvaUdamycin A-H 13:228-232 ofvalienamine 10:507 ofvaHenamine 13:199 of valine 11:418,419 ofvaliolamine 13:201 of vancomycin 10:661-669 ofverrucarol 10:426-428 ofverticillene 12:182,183 ofvillalstonine 13:405 of vinblastine 14:805-884 ofvincristine 14:805-884 ofvinylsilanes 8:242,243 of vitamin D 11:379-408 of vitamin D aldehyde 10:52 ofxylosides 8:362 ofZ,Z-l,4-dienicmacrolides 8:242 ofzearalenone 13:536-543 ofzeralenone 8:176,177 ofzygosporin E 13:146,147 of Z-p-y-unsaturated macrolide 8:222,232 of Z-y-unsaturated carboxylic acids 8:239 of A^'^-unsaturated brassinosteroids 18:515-520 of A^-7-oxygenated brassinosteroid 18:515-520 of A^^^^^-capnellene 13:34,13:35 of A-benzyl-1,2,3,4-tetrahydro-isoquinolone alkaloids 10:683-685 ofadicarbonyls 8:261-274 ofa-l,4-disccharide 8:369 of a-aminoacid 12:435-438 ofa-copaene 8:33-36 ofa-cyclodextrins 8:367,368 of a-D-fiructofuranosyl-1 -thio-P-D-glucopyranoside 8:325,327 of a-enamino derivative 8:262 ofa-halomethylcycloheptane 8:35-37 ofa-hydroxy-P-aminoacid 12:493 ofa-longipinene 8:33,36,37 of a-mono-alkoxylated piperzinediones 12:84 of P (l->4) linked 4,4'-dithiotrisaccarides 8:347,349 ofp,P-trehalose 8:317,318 ofp-copaene 8:33-36 ofp-galactosidase 8:315,316 of P-hydroxy ester 11:395 of P-hydroxy macrolides 8:231,232 ofp-longipinene 8:33,36,37 of P-necrodol 8:279 of p-sesquiphellandrene 8:45,46,51,55 ofp-turmerone 8:51,52

ofy-allenyl-GABA 13:514 of y-aminobutyric acid (GABA) 13:514 of y-dehydro-a-amino acid 11:471,472 reaction with lead tetraacetate 5:21 reaction with tristrifluoroacetate (TTFA) 21 via phenolic oxidative couplmg 5:21 Synthetase 7:123 Synthetic acronycine 20:789 Synthetic approaches to vinblastine 14:805-884 to vincristine 14:805-884 to purpurosamine B 4:120 to 6-ep/-purpurosaine B 4:120 ofmicrocystins 20:899-902 ofnodularins 20:899-902 Synthetic consonance 3:4 Synthetic dissonance 3:4 Synthetic methods of biaryls 20:294-307 ofdiarylethers 20:307 Syringaresinol-P-syringaresinol ether 4,4'-di-0-P-Dglucopyranoside 20:700 (+)-Syringaresinol-di-0-P-Z)-glucoside 20:646 Syringylglycerol-p-sinapyl alcohol ether di-p-hydroxybenzoate 20:636 Syringylglycerol-p-syringaresinol ether glycoside 20:700 Synthetic peptide 18:920-926 Synthetic reagents dithioacetal S-oxides as 6:307-349 dithioacetal 5,5'-dioxides as 6:307-349 Synthetic studies of humantenine-type oxindole alkaloids 15:493-500 of koumine-type alkaloids 15:500-503 of sarpagine-type alkaloids 15:487-493 Synthetic substrate analogues in enzyme-carbohydrate interactions 7:29-86 Syringaldehyde 18:569 Syringaresinol 5:475,476 (+)-Syringaresinol 5:524,526,530 O-glucosylation of 5:525 0-methylation of 5:525 (+)-Syringaresinol dimethyl ether 5:526 (+)-Syringaresinol-p->-glucoside 5:524 (+)-Syringaresinol-di-p-Z)-glucoside 5:524 Syringin 5:471 System resonance 3:46

Tabersonine from Amsonia tabernaemontana 19:90 synthesis of 19:103 T and B-cell epitope chimeras 18:929,930 T-2 toxin from Fusarium sporotrichioides 13:522 Trypanosoma dionis a 18:801-804 Trypanosoma verpertillionis 18:801,804 T4 polynucleotide kinase 13:289 T7 RNA polymerase 13:284 Tabarin 7:232 Tabebuia avellondeae 5:16;15:385 Taber's intramolecular Diels-Alder method 6:549,550

1203 Tabemaelegantine-A 5:128 Tabemaelegantine-B 5:128,129 Tabemaelegantine-C 5:128 Tabemaelegantine-D 5:128 Tabemaelegantinine-A 5:129 Tabemaelegantinine-B 5:129 Tabernaemontana ciliata 5:83 Tabernaemontana divaricata 9:166-168 Tabernaemontana eglandulosa 5:109 Tabernaemontana orientalis 5:70 Tabernaemontana pachysiphon 5:110 Tabernaemontana rigida 5:107 Tabernaemontana sp. 5:69-70,83,84,86,89,93 indole alkaloids 5:69-134 Tabernaemontana species 9:164,165 Tabemaemontaninol 5:125 Tabemaemontine 5:112,125 Tabemamine 5:129 Tabemanthine 5:124 Tabemulosine 5:126 H/-Tabersonine 14:833 synthesis of 14:847 (-)-Tabersonine conversion to vindoline analogues 4:35 enantioselective synthesis 4:41,42 hydroxylation of 4:35 Tabersonine 5:124;9:190 biosynthesis of 4:616 Tabidi 17:200 Tabotoxin synthesis of 4:582 Tacamin-type alkaloids 5:71 Tacamine 1:114;9:179,180 16-ep/-Tacamine 5:127 16/?-Tacamine 5:127 Tacamine-type alkaloids 16,17-anhydrotacamine 5:109,110 16/?-decarbomethoxytacamine 5:109 195-hydroxytacamine 5:110 17-hydroxytacamonine 5:109 tacamine (16/?) 5:110 16-e/7/-tacamine (165) 5:110 tacamonine 5:109 Tacamonine 5:109,126;9:180,181 Tachykinin 9:318 Tachytes guatemalensis 5:223,253 Tacraline 5:125 Taiwania cryptomeroides 17:333 Taka-amylase (ei/o-glucanase) maltotetraoses from 7:34,35 Takano's reaction ofenoate 12:26,27 with cyclopentadiene 12:26,27 Takano's synthesis ofvinblastine 14:865-867 of vincristine 14:865-867 Talarommycin A synthesis of 3:262,264 Talaromyces stipitatus talaromycin A and B from 14:531 Talaromycin 19:128

Talaromycin A synthesis of 1:700,701 ;14:531-539 via Evans asymmetric induction procedure 14:531 via asymmetric reductions of p-keto esters 14:533, 534 via [2,3] sigmatropic rearrangement 14:533,534 Talaromycin A and B asymmetric synthesis of 14:531-539 (-)-Talaromycin B synthesis of 14:538,539 Talaromycin B 3:262 synthesis of 3:262 Talcarpine 13:383-385,388,391,397-399,411,423-426 synthesis of 13:383,411,424-426 fromajmaline 13:424-426 Talcarpine 5:83,125 ep/-Talcarpine 5:83,127 Talekin derivatives 7:233 Talinum tenuissimum 7:427,435 Z-Talitol advantages of 4:505 Z)-Talopyranose C4-P bond analogs of 6:360 Zz-Talopyranoside C4-P bond analogs of 6:360 Talpmine 13:388,389,391,397-399 (-)-Tamariscol 18:625 from Frullania tamarisci 18:614-624 Tamariscol 9:255 from Frullania tamarisci 9:254 oxidation of 9:254,255 Tamao oxidation 19:536 TamaulipmA 7:231 from Artemisia hispanica 7:211 Tambjamines 17:89,94,105 A , B , C & D 17:89 E & F 17:94 Tamoxifen 20:515 Tammariscol 2:278,279 Tamus communis 17:130,132 TAN-1030A from Streptomyces sp. C-71799 12:366,367 NOB experiment of 12:367 TAN-999 &om Nocardiopsis dassonvillei 12:366,367 TANSY {Tanacetum vulgare) 11:221 Tanacetrum vulgare 7:94,95,98,101,102,108,109, 112,120 Tanacetum parthenium 7:119,120 Tanacetum vulgare 11:221 (+)-Tanakamine 9:178 (+)-Tanakine 9:178 Tanaparthin derivatives 7:236,237 Tandem Grignard reaction 19:11 Tandem mass spectrometry (FABMS/MS) ofpeptides-protein 9:468,487-507 Tandem Michael addition 4:556,557 with Cu (I)-tributylphosphine 4:556,557 Tandem Michael-aldol reaction 3:138-143 Tandem process (two-stage couplmg process) mechanistic consideration of 12:55-58

1204

Tangeretin (5,6,7,8,4'-pentamethoxyflavone) 7:413 TANGO sequence 9:97,98 Tangulic acid 7:133 from Barringtonia acutangula 7:132 Tannins 7:194,426,427;20:16 molluscicidal activity 7:427 Taondiol from Taonia atomaria 6:54 ()-Taondiol 6:56 synthesis of 6:56 Taondiol methyl ether biomimetic synthesis of 6:56 from all-rra5-geranylgeraniol 6:56 Taonia atomaria taondiol from 6:54 Tar cancer 7:8 A^-Tararic acid /?,5-4-hydrocyclopentenones from 6:315 Tararomycin stipitatus 3:262 Taraxasterol 9:267 from Salvia pomifera 20:702 Taraxerane derivatives 7:144,145 Taraxerol 7:189 Taraxerone oxidation of 7:161,162 Taraxeryl cw-/?-hydroxycinnamate 7:189 Targionia hypophylla I'.llZ Tarichatorosa 18:724 TaridinA-C 7:231 (/?,/?)-Tartaric acid (3/?,4/?)-3,4-Z?/5-(benzyloxy) succinic anhydride from 12:295 1,2-dihydroxy-hexahy dro-3 (2H)-indolizidines 12:295 L-Tartaric acid pyrrolidine from 14:568 Tartaric acid in mangrove plants 7:180 (/?,/?)-Tartaric acid salt of(5)-a-terpinylamine 11:289 recrystallization of 11:289 Tashiromine from Maackia tashiroi 15:523 ()-Tashiromine 18:353 synthesis of 18:353 Tasmanin 9:196 Taste principles hot and bitter 2:278-280 liverwort 2:278-280 Taurin 7:183,184,186,232;17:90 Taurookadaic acid 5:385,388 Tautoeric fors of ascorbic acid 4:724,725 Tautomeric rearrangement 19:406 Tautomerism in tetramic acids 14:100 Tautomycin synthesis of 18:269-309 from Streptomyces spiroverticillatus 18:269 Taxaceae 7:416;11:3 Taxagifme 11:5;20:81 Taxamairins A and B 20:118

Taxane biological activity of 11:4-6 relative stereochemistry of 12:191,195 synthesis of 11:3-69;12:181-216 Taxane diterpenes 12:179-231 chemical studies of 12:179-231 synthesis of 3:100-110 Taxane derivatives 20:80,107 Taxchinine A and B 20:101 TaxineAandB 20:80 Taxinine 11:4;12:179,208-210 Taxiresinol 20:107 ^om T.paccata 20:108 Taxodione 19:405,20:712 Banerjee and Carrasco synthesis of 14:695-699 biological activity of 14:667 Bumell synthesis of 14:685,687-689 Engler synthesis of 14:692-695 from abietatriene-7-one 14:685,687-689 from abietic acid 14:672-74,676,677,689-692 from p-cyclocitrol 14:673-676 from dimethoxy benzene 14:670-74,681,682 fromferrugmol 689,690 from isopropylcatechol 14:684-686 from 2-methoxy-3-isopropyl-l ,4-benzoquinone 14:692-695 from podocarpic acid 14:667-670 from Salvia montbretti 20:666 from Taxodium distichum 14:667 Haslinger and Michael synthesis of 14:692-695 Johnson synthesis of 14:681-684 Matsumoto synthesis of 14:670-676 Mori-Matsui synthesis of 14:667-670 Stevens and Bisacchi synthesis of 14:684-686 synthesis of 14:667-702 Watt synthesis of 14:681-684 Taxodione synthesis of 3:436 Taxodium distichum 14:667 taxodione from 14:667 Taxol absolute configuration of 11:3 antitumor activity of 12:180 biological activity of 12:179,180 from Taxus brevifolia 11:5;12:180;13:654 partial synthesis of 12:208,210 structure-activity profile of 12:220,221 synthesis 13:654 Taxol C and D 20:81 Tethys fimbria 19:552 nudibranch 19:551 Taxopneustespileolus 7:283-285 Taxotere biological activity of 12:179,180 X-Ray crystallography in analysis of 12:225 Taxus baccata 11:61,20,79,80,112,116,118 10-deacetylbaccatin III from 11:61 abscessic acid from 10:118 betuloside from 20:111

1205

escholtzxanthine 20:118 isotaxiresinol from 20:108 secoisolariciresinol from 20:108 taxiresinol from 20:108 taxicatin from 20:116 Taxus brevifolia taxolfrom 11:5,12:180 diterpenes of 7:416 Taxus brevifolia 20:140 Taxus canadensis canadensiene from 20:107 Taxus chinensis 20:107 Taxus cuspidata 20:80 Taxusfloridata 20:81 Taxus mariei a-conidendrine from 20:108 kojic acid from 20:118 Taxus media 20:81 Taxus species chemical constituents of 20:79-123 Taxus wallichiana wallifoliol from 20:107 Taxusin synthesis 11:55-59;12:200,201;16:151 (-)-Taylorione 16:259 Tazettine 20:325,353,370,385 Tazetting 4:17 TBDMSCi protection 4:388,389 in (+)-5-0-methyllicoricidin synthesis 4:388,389 O-TBDPS lactaldehyde 18:164 TCDD (2,3,7,8-tetrachlorodibenzo-/7-dioxin) receptor 1:5 Tchitatine from Salvia tchihatcheffii 20:676 TDP glucose oxidoreductase 11:214-216 TDP-4-oxo-6-deoxy-Z)-glucose by 11:214,215 TDP-4-oxo-6-deoxy-)-glucose 11:214,215 by TDP glucose oxidoreductase 11:214,215 from TDP-D-glucose 11:214,215 (6S)-TDP-Z)- [4-^Hi, 6-^H] glucose 11:214 (6/?)-TDP-Z)-[4-^Hi, 6-^H] glucose 11:214 TDP-D-glucose 11:214,215 by TDP glucose oxidoreductase 11:214,215 TDP-4-oxo-6-deoxy-Z)-glucose from 11:214,:215 Te'^^ 9:109-126 natural abundance of 9:110 receptivity of 9:110 resonance frequency of 9:110 spin quantum number of 9:110 Te^^^NMR 9:123,124 of phenyl cyclohexyl telluride 9:123,124 Teasteron 18:500,512,520 Teasteron 3-myristale 18:495,500 from Lilium longiflorum 18:495 Teasterone from cyclosterol 16:324,334 Tebbe olefmation 3:270 Tebbe rearrangemet in ()-A^^^^^-capnellene synthesis 6:46,47 Tebbe's reagent 14:119;16:226 Tebebuia chrysantha naphthopyrans from 4:388

Techniques of plant tissue culture 7:89-96 Teclea natalensis 13:348,350 Tecleanthine from Teclea natalensis 13:348,350 Tecomoside 7:440,455 Tecona grandis naphthopyrons from 4:388 Tedania ignis 19:558 Tedanolides 19:558-566 Teferidine 5:722,723 Teferin 5:722,723 Teleocidin 10:4 TeleocidinA 2:286 Teleogryllus commodus 5:815,830,831 Telesto riisei punaglandin from 1:687 Telocidines from Streptomyces mediocidicum 11:278 Telomer 8:224 Telomerizations 12:416 Temisin 7:237 Template selectivity 1:608 Ten-carbon sugars by epoxide route 4:182-187 byosmylation 4:182-187 Teniposide 5:461,462,13:654,20:458 Tenuiorin 20:471,472 Tenuispinoside A, B, C 15:51,52 Tenulin 20:10 Teratogenic metabolites of steroidal amines 7:21-24 Teratogenicity 7:19-22,24 l-(Terbutylstannyl)-D-glycal 10:344 5'-Terminal guanylic acid cyclization of 14:283 v/a 2'-5'phosphodiester 14:283 Terminalia alata (Terminalia tomentosa) arjunolic acid from 7:134 maslinic acid from 7:134 maslinic lactone from 7:134 oleanolic acid from 7:134 terminolic acid from 7:134 Terminalia arjuna arjunosides I-IV from 7:133 terminic acid from 7:133 terminoic acid from 7:133 Terminalia siricia siricic acid methyl ester from 7:132 Terminalia tomentosa {Terminalia alata) 7:134 Terminalis sp. triterpenes of 7:133-135 Terminic acid 7:134 from Terminalia arjuna 7:133 Terminoic acid 7:134 from Terminalia arjuna 7:133 Terminolic acid 7:135 from Terminalia alata 7:134 Termite soldiers defensive secretion of 14:451 Termitinae 8:220 Ternary complexes 9:563,567,569-571,575

1206

Temifolin 15:140 from Rabdosia ternifolia 15:175 *H-nmrof 15:148 Terpenes 5:403;7:208-219;8:219;17:4,15,613,642 as antihealants 14:451 as glues 14:451 as irritants 14:451 as repellents 14:451 by plant tissue culture 7:87-129 in Artemisia sp. 7-208-219 synthesis of 7:87-129;8:33-37 Terpeneacid 5:756 Terpene metabolism 7:108-110 Terpenoid biosynthesis 7:322,330 Terpenoid diketone from Prosopisjuliflora 9:68,69 Terpenoid intermediates 4:676,677 (5)-a-Terpineol 11:288,289 (a)-Terpineol preparation of 11:307,308 (5)-a-Terpinyl amine alkylationof 11:283 from (-)-a-pinene 11:288 from (5)-a-terpineol 11:289 synthesis of 11:288 with indole-protected tryptophyl bromide 11:283 withHN3/BF3 11:288 (5)-a-Terpinyl tryptamine from a-terpinyl carbenium ion 11:278,279 synthesis of 11:289 Terramycin synthesis of 4:609 (+)-Terrecyclic acid A 4:674 Terrin 10:152 Terron phoenicoptera hemoglobin components of 5:837 Terpineol-4 20:16 2'-0-rier^butyldimethylsilyl-3'-ketoadenosine 19:514 TerZ-butoxycarbonylation 12:488 A^-^er^butyloxycarbonyl groups thermolytic removal 3:356 2,3,4,5-Tetra-0-acetyl-D-flraZ)/>2o-hex-2-ulosonate 20:859 2,3,4,6-Tetra-O-acetyl-a-D- glucopyranosyl bromide condensation of 12:382 tjipanazole D with 12:382 Tertiary metabolites 18:680,681 Tessaria dodoneifolia 15:31 2,3,13,15-Tetra-deoxy-evoninol 18:744 Tetra-A^-propylammonium perruthenate 12:312 Tetra-A^-butylammonium fluoride deprotection with 6:119-121 2,3,4,6-Tetra-(9-acetyl-1 -5-acetyl-1 -thio-a-Dglucopyranose synthesis of 8:316,318 2,3,4,6-Tetra-O-acetyl-1 -thio-a-D-glucopyranoside 8:319 2,3,4,6-Tetra-O-acetyl-1 -thio-a-D-mannopyranoside 8:320,321 Tetra-0-acetyl-1 -thio-^-D-galactopyranose 8:317,339

2,3,4,6-Tetra-O-acetyl-1 -thio-(3-Z)-glucopyranose 8:323,326 1,2,4,6-Tetra-0-acetyl-2,3-didehydro-3-deoxy-aD-threo- hexopyranose 14:173 synthesis of 14:173 1,3,4,6-Tetra- aacetyl-2-O-trifluoro methylsulfonyl-(3D-mannopyranose 8:327 1,2,4,6-Tetra-0-acetyl-3 -deoxy-a-D-Zyjco-hexopyranose synthesis of 14:173 1,2,3,4-Tetra-0-acetyl-6-deoxy-6-iodo-P-Dglucopyranose 8:339 2,3,4,6-Tetra-0-acetyl-a-Z)-glucopyranosyl 2,3,4,6tetra-0-acetyl-1 -thio-a-D-mannopyranoside 8:320, 321 2,3,4,6-Tetra-O-acetyl-a-D-glucopyranosyl bromide (acetobromoglucose) 8:317,332,338,363,364 Tetra-(9-acetyl-a-Z)-glucosyl bromide 14:227 3,21,22,28-Tetra-O-acetyljegosapogenol 7:141 1,3,4,6-Tetra-O-benzyl-1 -thio-p-D-fructopyranose 8:322 2,3,4,6-Tetra-O-benzyl-a-D-galacto-pyranosyl bromide 14:150 2,3,4,6-Tetra-(9-benzyl-a-D-glucopyranosylchloride 8:360,361 thermal glycosidation with 8:360,361 1,3,4,6-Tetra-O-benzy 1-D-fructofuranose synthesis of 8:323-326 Tetra-0-benzyl-D-glucose by Wittig reaction 10:390 Tetra-0-benzyl-Z)-mannose 10:391 for synthesis of 10 DO C-glycosyl derivative 10:390 Z)-l,2,5,6-Tetra-0-benzyl-/w>'o-inositol 18:425 3,7,11,15-Tetamethylhexadeca-2,6,10,14-tetraene-1,9diol 20:25 2,3,4,6-Tetra-O-methylglucose 15:431 Tetra-substituted azulenes oxidation of 14:343-345 Tetraacetyltubastrine 5:360 Tetrabenzyl-w^o-inositol 18:444 Tetrabutyl ammonium fluoride 11:369 Tetracarbocyclic bridged systems 6:86-87 Tetracarbocyclic sesterterpenes 6:58 Tetracarbocyclic fused systems 6:58 1,1,6,6-Tetrachloro-3,4-diphenylhexane 9:86,88 Tetracyclic diterpenes 6:107;8:220 Tetracyclic intermediates 14:736-738 stereoselective epoxidations 14:736-738 Tetracyclic naphthacene derivative from 1,8-dimethoxynaphthalene glutarate 11:120 Tetracycline antibiotics 20:520 (+)-(5)-Tetradecan-13-olide isolation of 19:158 Tetradecano-14-lactone isolation of 19:157 12-0-Tetradecanoyl-phorbol-13-acetate (TPA) 2:286 12-0-Tetradecanoylphorhol-13-acetate (TPA) (phorbol- 12-myristate-13-acetate) 12:390 (2)-5-Tetradecenyl acetate 7:193 (2)-8-Tetradecenyl acetate 7:193

1207

Tetradecyl acetate 7:193 3,4,5,6-Tetradehydro-18,19-dihyclrocorynan-thenol 1:124 3,4,5,6-Tetradehydro-P-yohimbine 1:125,126 7,8,7',8'-Tetradehydroastaxanthin 6:153 from Asterias rubem 6:152,161 Tetradehydroastaxanthin 6:153 stereomutation studies of 6:15 (35,35')-7,8,7',8'-Tetradehydroastaxanthin 6:159 synthesis of 6:157 Tetradehydroastaxanthin diacetate 6:154 Tetradehydroglaucine 3:428 3,4,5,6-Tetradehydrositsirikine 1:124 2,3,13,15-Tetradeoxy-isoeuoniminol 18:745 Tetradeuteropyrocatechol 8:296 Tetraglycoside 7:268,269,273,275,281,286 Tetraheptoses in Aeromonas hydrophila chemotype II 4:196 in Vibrio ordalii 4:197 Tetrahydro-l,2-oxazines 1:359 Tetrahydro-l,2-oxazoles (isoxazolidines) 1:359 reduction of 1:359 D' 1,4,5,6-Tetra-0-benzyl-/w>;o-inositol 18:444 Tetrahydro-2-oxazinones acyclic amino alcohol from 12:382-384 Tetrahydro-2H-pyran fromlactol 11:140,141 l,2(3)-Tetrahydro-3,3'-biplumbagin 2:213,215,216 ' H - N M R spectrum of 2:226,227 UV spectrum of 2:226 structure of 2:226 1,2(3)-Tetrahydro-3,3'-biplumbagin 5:754,755 Tetrahydrobisanhydrobacterioruberin 20:599,601 (5)-Tetrahydro-5-oxo-2-furancarboxylicacid 13:311,325 Tetrahydro-anabasine nitramine from 14:739 via retro Michael reaction 14:748 Tetrahydro-eremophilone 15:240 Tetrahydro-oxepine 10:588,589 7,8,11,12-Tetrahydro-vi/,\|/-carotene from \|/-carotene 7:327-329 neurosporene from 7:327-329 Tetrahydroalstonerine 13:420,421,423 ()-Tetrahydroaistonine synthesis of 13:490,491 (-)-Tetrahydroalstonine from piperidine 14:563,564 synthesis of 14:563,564 Tetrahydroalstonine 5:127;9:171 Tetrahydroanthracenes (vismiones) 7:418-420 antiproliferative activity 7:419 Tetrahydroaplysulphurin 17:15 Tetrahydroaplysulphurin-1 9:7,8 Tetrahydrobenz [a] anthracene fromtriketone 11:134,135 5,6,7,8-Tetrahydrobenze [b] indolizidine from allohobartine 11:318,319 Tetrahydrobenzofiirofiiranol preparation of 14:654

Tetrahydroberberine derivatives protopine alkaloids from 6:488,489 Tetrahydrocannabinol 7:7 psychotropic activity of 7:7 A^-Tetrahydrocannabinol (A^-THC) 19:185 Tetrahydrocephalostatin Fuchs synthesis of 18:892-895 Tetrahydrocorysamine 1:221 synthesis of 1:221 Tetrahydrocorysamine corydalic acid methyl ester from 14:796 corynoline from 14:796 synthesis of 14:790 3,14,4,21 -Tetrahydroellipticine 5:125 Tetrahydroeucarvone 8:34 Tetrahydroeucarvone trimethylsilyl enol ether synthesis of 8:34-36 Tetrahydrofrirans 17:325 Tetrahydrofiirofiirans 17:344 Tetrahydrohalichondramide 17:17 Tetrahydroharmane 5:124 1,2,3,4-Tetrahydroindolo [2,3-a] quinolizine synthesis of 1:148 (+)-Tetrahydroionone 2:163 Tetrahydroisoquinoline systems ring destruction of 6:477 5,6,7,8-Tetrahydroisoquinolme 18:58,59 3,14,4,21 -Tetrahydroisoquinoline precursors cyclodimerization of 6:495 macrocyclic derivatives from 6:495 Tetrahydroisoquinolines CD of 2:172 helicity rule for 2:172 1,2,3,4-Tetrahydroisoquinolines 12:446 S'-Tetrahydroisoquinoline 16:506 Tetrahydrokomarovonine 14:762 from Nitraria komarovii 14:762 Tetrahydronaphthalene 11:115 Tetrahydronaphthopyrone derivatives of 17:361 Tetrahydronitramarine from Nitraria komarovii 14:762 3,14,4,19-Tetrahydroolivacine 5:125 (/?)-(+)-Tetrahydropalmatine synthesis of 10:682,683 (+)-15,20,15',20-Tetrahydropresecamine 5:124 S-Tetrahydroprotoberberine-oxidaseCSTOX) 11:204,205 Tetrahydroprotoberberine precursor protopine alkaloids from 6:491 Tetrahydropyran from Claisen ester enolate rearrangement 10:339 Tetrahydropyrans enantioselective synthesis of 1:637 Tetrahydropyranyl ether protection with 6:264,268 Tetrahydropyranylation 14:694,695 Tetrahydropyrazinone preparation of 10:138-140 Tetrahydropyridine alkaline hydrolysis of 14:708

1208

()-3-e/7/-18,19-dihydroantirhine from 14:708 ()-3 -epi-18-nor-18,19-dihydroantirhine from 14:708 Tetrahydropyridinium salts in coccinelline synthesis 6:447 Tetrahydroschelhammeridine 3:484 Tetrahydrosecodine from Rhazya stricta 19:90 16,17,15,20-Tetrahydrosecodine 19:91 1,2,3,4-Tetrahydrosempervirine 1:139 Tetrahydrosquamone 9:398,399 (+)-Tetrahydrostepharine 2:255 Tetrahydroxanthyletin synthesis of 4:396,398 (22R,23R,24S)-2a,3a,22,23-Tetrahydroxy-24methyl-B-homo-6a-oxa-5a-cholestan-6-one 18:495 5,6,7,4'-Tetrahydroxy-3,3',5-5-trimethoxyflavone 5:757 3 P,6a, 12a,20-Tetrahydroxy-5a-cholest-9( 11 )-en23-one 15:51 3 p, 5,6p, 15 a-Tetrahydroxy-5 a-stigmastan-29-oic acid from Myxoderma platiacanthum 15:81 (15',65',7/?,8a/?)-TetrahydroxyindoUzidine 12:332 Tetrahydroxylated alkaloids 12:349 3p,16p,23,28-Tetrahydroxyolean-12-ene 18:650 Tetrahymena pyriformis 2:294 Tetrahymena thermmphila 2:306 Tetrahymena thermophilas 4:268 1 (2,3,4,6-tetra-0-benzoyl-P-glucopyranosyl)-2pyriidine 4:224 1,1,3,3,-Tetraisopropyl disiloxane-l,3-diyl (TIPS) desilylation of 14:287 Tetrakis (triphenyl phosphine) palladium (0) 10:342 Tetralms 10:185 P-Tetralone 9:439 Tetralones 8:401 reduction of 8:402 (245) 3 p,5,6p, 15a-Tetramethoxy-5a-chole-st-8(9)-en24-ol 15:76 5,6,7,8-Tetramethoxyflavone 5:652;7:413 3,5,6,7-Tetramethoxyflavone 5:652,654;7:413 1,1,3,3-Tetramethyl guanidine (TMG) 14:272;19:525 Tetramethyl urea 6:395,396,400 Tetramethylene tetrahydro-P-carboline (l,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizidine) 14:758,759 biosynthesis of 14:759 from Nitraria komarovii 14:758 Tetramethylene tetrahydro-P-carboline A^-oxide 14:758,759 biosynthesis of 14:759 from Nitraria komarovii 14:758 Tetramethylethylenediamine TMEDA 5:823 2,2,6,6-Tetramethylpiperidme 12:261 A',A',A'^',A/^-Tetramethylsuccinamide 3,5,8,10-tetraoxododecanedioate from 11:115 Tetramic acid antibiotics 14:97-141 biological activity of 14:107-110 synthesis of 14:97-141

Tetramorium caespitum 5:235,254 2,5-dimethyl-3-ethyl-pyrazines from 5:223 2,5-dimethyl pyrazines of 5:222 methyl pyrazines from 5:222 Tetramorium impurum 5:235,254 2,5-dimethyl-3-ethyl-pyrazines from 5:223 2,5-dimethyl pyrazines of 5:222 methyl pyrazmes from 5:222 Tetramycines A,B 6:261 relative configuration of 6:261 Tetranactin synthesis of 16:658 (+)-Tetrangomy cin 11:136-139 from Streptomyces rimoss 11:135 synthesis of 11:135-139 Tetrangulol 11:135-139 from Streptomyces rimoss 11:135 synthesis of 11:135-139 Tetranortriterpenoids 2:269;9:94,95,101,297,299 Tetranychus urticae 1:702 Tetraol 12:237 Tetraol derivative 6:291,292 P,P,5,5'-Tetraoxoalkanedioates aromatization of 11:114-119 formation of 11:114-119 naphthopyran antibiotics by 11:127-131 Tetraoxoalkanedioates BF3 mediated 11:117 from glutaric acid derivative 11:118 from heptanedioic acid derivatives 11:117 from octanedioic acid derivative 11:117 synthesis of 11:117 3,5,8,10-Tetraoxododecanedioate from A^.A^.A^'A/^-tetramethyl succinamide 11:115 Tetraphyllicine 5:126 Tetraphyllicine dimethoxybenzoate 5:128 Tetraphyllicine monomethoxybenzoate 5:128 Tetraphyllicine trimethoxybenzoate 5:128 Tetraplaura tetraptera 7:434 Tetraponera alkaloids 6:451-454 Tetraponera species 6:451 Tetraponerine 1-8 6:451,452 Tetraponerine-7 6:452 Tetraponerine-8 stereoselective synthesis of 6:452 synthesis of 6:451 X-ray analysis of 6:451 Tetrapyrrole synthesis enzymes of 9:592-597 Tetrasaccharide globoside towards . coli 14:150 Tetrasaccharides 6:406;7:320,337 as transition state analogues 7:337 Tetrastachyne B6 5:124 Tetrasubstituted enamino esters 18:358 2,3,4,5-Tetrasubstituted tetrahydrofiirans synthesis of 11:433 C4oTetraterpenes 7:317 Tetraterpenoids 17:611 Tetrazole-catalyzed reaction 14:288 Tetrazolium blue reagent 19:755

1209 Tetrazomine 10:117,19:289-290 antibacterial activity of 10:117 antitumor activity of 10:117;19:290 antimicrobial activity of 19:290 cytotoxicity of 19:290 isolation of 19:290 structure of 19:289 )-Tetritol phosphorus analogs of 6:357 Tetrocarcins A 19:118 Tetrocarcins B 19:118 Tetrodotoxin 5:403;7:306;18:697 from levoglucosenone 14:267,276,277 synthesis of 14:267,276,277 Tetrol 5:704-709 hbo'TQtrol 5:705,706,708 L-jcv/o-Tetrol 5:707,708 synthesis of 5:707,708 Tetrol esters 5:708,709 Tetronic acid 6:111;10:261,262,266,272 Teucriumfruticans 7:119 Teucriumlactone 20:74,20:76 TG-1 anti-fungal activity of 2:445,446 TG-11 anti-fiingal activity of 2:446 Thadiantha grosvenorii 15:22 ()-Thalicsimidine 16:506 Thalictricavine synthesis of 1:220,221 ;14:771 5-Thalidomide from A^-phthalyl-Z-glutamic acid 7:10 Thalidomide from iV-phthalyglutamic acid 7:9 synthesis of 7:9 (/?)-Thalidomide (hypnotic) 14:517 (5)-Thalidomide (teratogenic) 14:517 ()-Thaliporphine 16:509 Thaliporphine synthesis of 3:426,428 Thallium nitrate 4:338 oxidation with 4:338 Thalicsimidine 20:301 Thallium (III) compounds 20:305,306 Thallium nitrate (TTN) oxidation 10:631-635,637,638, 640,641,644-647,653,654,661,662,666,667 Thallium triacetate 4:72-72 oxidation of 17-hydroxyaspidospermidines 4:74 oxidation of 3-oxo-tabersonine 4:72 oxidation with 4:70-76 Thapsia villosa 18:685 Thaumatin 15:5,36 ThaumatinsI 15:5 Thaumatins II 15:5 Thaumatococcus daniellii 15:5 THC metabolites detection of 19:188 in human urine 19:188 Thea sinensis 19:247 Theaflavin 20:782 Thebame 18:49,55,57 neodihydrothebaine from 6:479

P-Thebainone 18:65 Thelenota ananas I'.lll thelothurin A from 7:273 theothurin B from 7:273 Thelenotoside A 7:273,274 Thelenotoside B 7:273,274,282 Thelothurin A from Thelenota ananas 7:273 Thelothurin B from Thelenota ananas 7:273 Theonella sp. 5:355,364 Theonella swinfoei 5:356,396,20:894,896,589 7-A^-Theophylline derivatives 4:225 ofgalactopyranose 4:225 ofglucopyranose 4:225 of glucose 4:225 ofmannopyranose 4:225 Therioaphis maculata germacrene-A from 8:221 Thermal glycosidation (metal free) of allyl glucoside 8:365,366 ofallylrhamnoside 8:365,366 of(+)-baiyunol 8:362 ofcholestanol 8:365,366 of cholesterol 8:361,362,365,366 ofdecanol 8:362,365 ofdihydrolanosterol 8:362,365,366 ofgeraniol 8:362,365 of glucoside 8:362,365,366 of glucosyl chloride 8:361,362 of mannosyl chloride 8:361,362 of methanol 8:365 of 1-methylcyclohexanol 8:365,366 of methyl glucoside 8:365 of rhamnosyl chlorides 8:361,362 of xylosy 1 chlorides 8:361 Thermal [4+2] addition 8:412 Thermal fragmentation of [2'-(phenylselenyl) ethyl] glycoside 10:420 Thermal mannosidation 8:359,369,370 Thermal rhamnosidation 8:359,369,370 Thermally-induced rearrangement 6:468 ofp-hydrastineA^-oxide 6:468 of a-narcotine A^-oxide derivative 6:468 Thermodynamic control 1:260 Thermolysis 3:314,315 of 1,5-benzoxazocineA^-oxide 6:472 of 2-benzazocine A^-oxide derivative 6:472 of camphor-10-sulphonyl bromide 4:626,627 of()-laudanosineA^-oxide 6:472 ofstyrylazides 3:314,315 Thermolytic cyclization alkenyl azides 6:429 ofazides 6:429 Thermophilic bacteria 11:190 Thermopsis chinensis 15:523 (+)-5,6-dehydrolupanine from 15:523 Thermopsis lupinoides 15:523 (+)-lupanine A^-oxide from 15:523 Thermospray Ionization Mass Spectrometery (TSP-MS) 19:750 Thevisidol 7:467

1210

Thexyl borane hydroboration with 11:83 reduction with 4:116,117 Thiaarachidonic acids 9:569,570 Thiazole amino acids Hantzsch synthesis 4:85,86 synthesis of 4:83-86 via thiazoUdine 4:85 Thiazole nucleoside by Wittig condensation of 10:392 from ribofuranose 10:392 ThiazoUdine chiral auxiliaries from 14:735 mto tin(II) enolates 14:735 transformation of 14:735 3-Thiazoline derivatives 12:129 Thiazolo [4,3-a] isoquinoline 12:447 2-Thiazolyl methylenetriphenyl phosphorate (2-TMP) 11:443,444 2-Thiazolylcarbonitrile iV-oxide (2-TNO) 11:443,444 Thief ants /ra5-2,5-dialkyulpyrrolidines in 6:434 2,5-dialkylpyrrolines in 6:443 (5Z,8)-3-heptyl-5-methyl pyrrolizidine in 6:445 Thiele acetylation 10:120,121 Thienamycin absolute stereochemistry of 4:433,435,440,464 antibacterial activity of 4:431,432;12:145 antibiotic activity of 12:122 biosynthesis of 4:434;11:210,211 by Sharpless method 4:438 carbapenem antibiotic 11:210 chemical shifts of 4:442 from 3-hydroxybutyric acid 4:438 from glutamic acid 11:210,211 from methionine 11:210,211 from Streptomyces cattleya 12:145 inmiipenem derivative of 4:431,432 Kuhn-Roth oxidation of 11:210,211 PBP-2 affinity for 4:433 structure elucidation of 12:145 structure of 4:433 p-lactamase inhibition by 12:145 P-lactamase stability of 4:431 (+)-Thienamycin synthesis of 13:498-504 or-Thienamycine 4:434 4H-Thieno [2,3-D] azonine derivative synthesis of 6:476 Thieno analogues of protopine alkaloids 6:491 synthesis of 6:491,492 X-ray analysis of 6:491 Thienopyridines 1:167 (2)-5-(2-Thienyl)-2-penten-4-ynal 10:153 (2-Thienyl)-acetic acid synthesis of 6:322 from 2-thiphene carbaldehyde 6:322 Thin layer chromatography 2:368;9:164 for culture development 2:368 of indole alkaloids 9:164

Thio sugars 6:351-384 19,10-Thio-3-ep/-gibberellin Ai synthesis of 8:125,126 l-Thio-a,a-dimannosyl analog of a,a-trehalose 8:321 1 -Thio-a,a-disaccharide 8:319,320 l-Thio-a,a-trehalose 8:318-322,347,348 l-Thio-a,P-disaccharide 8:318,319 1 -Thio-a-D-glucopyranose 8:318,340 Thio-analogues ofgalactosides 7:48 l-Thio-P,P-trehalose 8:317,347 1-Thio-p-D-galactopyranose tetraacetate 8:317 1 -Thio-p-Z)-galactopyranoside 8:315 1-Thio-P-D-glucopyranose 8:332,333,340 1 -Thio-p-galactopyranosides mhibition constants of 7:48 Thiocarbonylimidazole 19:54 Thio-Claisen rearrangement l:53;14:865-867 isovelbanamine from 14:865-867 velbanamine from 14:865-867 5-Thio-D-glucose 6:351 5-Thio-D-mannopyranose 6:351 2-Thio-hexopyranose-4-ulose nucleosides synthesis of 4:252 5-Thio-I-rhamnose 6:351 Thio-oligonucleotide 13:283 Thio-oligosaccharides reaction with enzymes 8:315 synthesis of 8:316-346 4'-Thio-toyokamycin 6:351 Thioacetal hydrolysis of 14:660,661 with cadmium carbonate 14:660 with mercury (II) chloride 14:660 Thioaldehyde cycloaddition 8:207-217 Thioaldehyde Diels-Alder reaction 8:207,210,213 6-Thioallolactitol 8:353 6-Thioallolactose 8:338,339 Thioallolactose 8:339,342,353 a-Thiocarbocation 1:240 Thiocarbonate 1:442,443 pyrolytic elimination of 1:442,443 4-Thiocello-oligosaccharides 8:348,349 4-Thiocellobiose 8:332,333,351,352 Thiocyanates 8:316 4-Thiodisaccharide 8:330,332 1 -Thiodisaccharides 8:317-326 synthesis of 8:317-326 1,2-trans 1 -Thiodisaccharides 8:317,318 Thiodisaccharides (l->4) linkage 8:329 Thiodisaccharides synthesis of 8:317-340 Thiodisaccharides ( 1 ^ 2 ) linkage 8:327 Thiodisaccharides (l->3) linkage 8:329 Thiodisaccharides (l->6) linkage 8:338 Thiodisaccharides (6-6) linkage 8:340 Thioesters acylation of phosphonium ylides 4:554 6-Thiogentiobiose 8:337,338 7-Thiogibberellin synthesis of 8:123,124

1211

19,10-Thiogibberellins synthesis of 8:124,125 3-Thioglucofuranose-(3^ 1 )-P-xylosyl-3thioglucofuranose thiodisaccharides 8:329 1-Thioglycerol in FAB mass spectrometry 2:20 1-Thioglycoses 8:316,323,326,328,329,332 1-Thioglycosides 8:315-317 Thioglycosides synthesis of 1:429,430 Thioglycosidic Unkage 16:114 4-Thioglycosyl maltotriosides 8:343,344 1-Thioisosucrose (a-D-fructo-furanosyl l-thio-(3-Z)glucopyranoside) 8:324 synthesis of 8:326 ThioketaUzation 14:680,681 2-Thiolacetate 8:322 Thiolacetates 8:317 Thiolactone synthesis of 8:206,207 y-Thiolactone 8:125,126 4-Thiolactose 8:334,335 Thiolbenzoates 8:316 Thiolester with triethy 1 phosphite 12:147 Thiolester enolates 4-acetoxy-P-lactam with 12:167-170 C4-alkylation with 12:167-170 Thiolesters 8:316 4-Thiomaltose 8:331,332 4-Thiomaltoside synthesis of 8:330,331 4-Thiomaltotriose 8:343,344 4'-Thiomaltotrioside derivative synthesis of 8:343,345 Thiomercury derivatives 8:316 a-Thiomethylpyrrole 9:593 Thionolactones by macrolactonization 10:208 desulphurization of 10:208 synthesis of 10:208 Thiophene 7:202,203,222 Thiophene C-glycosides fromglycals 10:349 2-Thiophenecarbaldehyde (2-thienyl)-acetic acid from 6:322 Thiophenol 6:542;14:750 elimination of 6:540 Thiophenolate complex non-chelating 14:750 Thiophenyl-glycosides 10:381 allylation of 3:222 Thiophosphoramidites phosphorodithioates from 13:269,270 Thiophene derivatives 7:222 2-Thiosophorose synthesis of 8:326,327 Thiostrepton biosynthesis of 11:209,210 from quinaldic acid 11:209,210 from Streptomyces azureus 11:209

1-Thiosucrose synthesis of 8:323,325,326,348 Thiosugars 8:315 Thiotrisaccharides 8:340,341 3 -Thioxovincadifformine 19:103 2-Thioxylobiose synthesis of 8:328 3-Thioxylobiose 8:329 4-Thioxylobiose 8:336 4-Thioxylobioside 8:349 4-Thioxylooligosaccharides 8:348,349 1-Thioxylose 8:336 Thitsiol 9:319,340,336,360 Thladiantha grosvenorii 15:5 Thomasic acid synthesis of 17:338 Thorecta choanoides 15:312 Thorecta sp. 5:410 Thorectandra excavatus 18:717 Thorectolide monoacetate 18:717 Thomasterol A 7:286,288,290 retro-aldol reaction of 7:291 Thomasteroside A 7:286-290,293,299;15:45,52 from A canthaster planci 7:288 from Asterias annurensis versicolor I'.l^l from Linckia laevigata 7:290 from Luidia maculata 7:289 from Nordoa gomophia 7:290 from Thromidia catalai 15:46 24/?-and (245)-Thoronasterol A 15:48 Thorpe-Ziegler reaction 10:328 Three component reaction 4:572,573 Three-carbon annulations 6:42,49,50,52,74,75 m ()-A^^^^^ capnellene synthesis 6:42 in capnellenol synthesis 6:48,50 in dolasta-1 (15), 7,9-trien-14-ol synthesis 6:52 Three-carbon ring expansion (-)-muscone by 10:330,331 Three-dimensional structure of microcystins 20:903 -907 ofnodularins 20:903-907 (+)-Threitol ketalisation with 4:325,326 resolution of ketones with 4:325,326 synthesis of 4:324,325 Z)-Threitol 6:355 phosphorus analogs of 6:355 I-Threitol derivative 11:238,239,246-249 Z-Threitol tetraacetate synthesis of 4:505 Threo ethyl P-hydroxy-P-(2-piperidyl) propanooates from ethyl P-hydroxy-P-(2-pyridyl) propanooates 12:279 Threo'2-dimmo alcohols interconversion of 12:430,431 stereoselective synthesis of 12:489-493 to erythro-2-dimmo alcohol 12:430,431 r/zreo-a-methyl-P-bomyl carboxylic ester from (a-bromoalkyl) boronic ester 11:425

1212

TT^reo-p-hydroxyglutamic acid mutual transformation of 12:430,431 with eryZ/zro derivative 12:430,431 L-Threo-P-methylaspartic acid 14:102 TTzr^o-configurational product 12:415,416 Threo-erythro interconversion 12:430,431 of 2-amino alcohol 12:430,431 TTzreo-selective reduction 12:300 D-Threonin 4:134-136 in lincosamine synthesis 4:140,141 A'^-oxazoline from 4:140,141 L-a//o-Threonin 4:134 in methyl-L-sibirosaminide synthesis 4:135 D-a//o-Threonin 4:134-136 in D-glycero-D-mannoheptose synthesis 4:205 D-Threoninal 4:135,136 D-a//o-Threoninal 4:135,137,143-145 A',A^-diprotected 4:145 in heterodienophile 4:143 I-Threonine 4:134,149;16:4,7-9 D-Threose 3:185 synthesis of 3:185 Thromboxane synthesis from glucose 3:226,227 Thromboxane 5:513 Thromboxane B2 synthesis of 10:419 Thromboxane synthetase inhibitory activity 2:288 Thromboxanes semi-synthesis of 17:642 Thromidia catalai 7:299;15:46 thomasteroside A from 15:45 Thromidioside 7:299,302 Thrush 2:422 tomatine 2:46 DCI spectrum of 2:46 Thuja occidentalis 2:402,20:16 Thuja orientalis 20:16 Thuja plicata thujonefrom 14:389,390 Thuja plicata 5:476 Thuja plicata D.Don 16:269 Thuja plicata Don 17:338 a-Thujaketonic acid fromthujone 14:392,393 c/5-P-Thujaketonic acid 14:392,393 /raAM-(3-Thujaketonic methyl ester 14:393,395 (3-Thujaplicin 1:572 synthesis of 1:572 Thujia orientalis 8:3 essential oil from 8:3 Thujone 14:390-447;20:16 from cedar leaf oil 14:389 from Thuja plicata 14:389 insect juvemile hormone analogues from 14:391-397 a,P-Thujone 9:530 Thymine polyoxin C 1:404,405 Thymocytes 9:390 Thymol 13:299,300 Thymoquinones 5:774

ai-ttii -Thymosin 8:433 Thymosin tti 8:1,433,434 by recombinant DNA cloning 8:437 by solid-phase 8:437-439 by solution 8:439-446 synthesis of 8:437-446 Thymosin a n 8:433,434 synthesis of 8:447 1 8:435 Thymosin p 1 Thymosin P12 8:435 Thymosin P4 by recombinant DNA cloning 8:448 by solid phase 8:448,449 by solution method 8:449-453 synthesis of 8:447-453 Thymosin ^4"'" 8:435 Thymosin P4^^" 8:435 Thymosin P9 by solid phase method 8:453-455 by solution method 8:453-455 synthesis of 8:453-458 a-Thymosins 8:433 Thymosins synthesis of 8:433,437-458 p-Thymosins 8:433,436 y-Thymosins 8:433 Thymus peptides 8:433 Thyrsiferol 5:361-363 biogenesis of 5:363 Thyrsiferyl-23-acetate 5:361-363 Tigliane 12:246 Tigliane ring system construction of 12:245-265 Tiglicacid 5:778 HETCOR spectrum of 5:778 a-Tigloyloxy chaparrinone 11:4 6 6a-Tigloyloxy chaparrin 7:381,382 (-)-13 a-Tigloyloxymultiflorine from Lupinus hirsutus 15:524 Tilapia mossambica 5:370 Tilapia nilotica 7:183,185,187 Tilletiopsis sp. 5:291 Tin (II) enolate of achiral thiazolidin-2-thione derivative 12:166 with tin triflate 12:164 Tin a-alkoxyanions Z-trisubstituted olefins from 3:281 Tin acetylide palladium mediated acylation 1:475 Tin enolate from ketone 12:170 with 4-acetoxy-P-lactam 12:170 with high p-selectivity 12:170 Tin hydride reduction 12:271 Tin(II) enolates thiazolidines from 14:735 Tingenol 18:778 Tingenone 5:744,746,747,750;7:145,146,149;18:757, 760,776 Tiphia sp. 5:225,253

1213

Tirandalydigin 14:97,104 from Streptomyces tirandis 14:98 (+)-Tirandamycic acid 16:661 synthesis of 14:110-112,127-129 Tirandamycic acid from pyranosidic glycal 10:423 synthesis of 14:103 Tirandamycin 3:268 (-)-Tirandamycin A 16:661 total synthesis of 14:114-117,129-132 ()-Tirandamycin A 14:120-123,129-132,134-138 total synthesis of 14:120-123,129-132, 14:134-138 Tirandamycin A 14:97,100,101,103,115 from Streptomyces tirandis 14:98 total synthesis of 14:115 ()-Tirandamycin B total synthesis of 14:123-126 Tirandamycin B from Streptomyces flaveolns 14:97,98 Tirucalla-7,24-dien 16P-ol (limocinol) 9:301 Thiicalla-8,24-diene-16-one 9:302 Tirucallanes (euphanes) 9:297,300,302,307 D^-Tirucallol 9:301 Tissue culture 7:146,371,376,389 of Maytenus buchanii 7:146 of Tripterygium wilfordii 7:146 Titanium reductive elimination with 4:421-535 Titanium (IV) catalyzed cyclization 12:241 Titanium (O) by titanium trichloride 11:366,367 preparation of 11:366,367 with potassium graphite 11:366,367 Titanium reagent application of 11:371 discovery of 11:366,367 Titanium tetrachloride 11:358 Titanium tetrachloride catalyzed reaction 8:141-43, 146,151 ofacrylate 8:142 Titanium tetrachloride method 4:252 for 6-deoxynucleoside synthesis 4:232 Titanium tetraisopropoxide 4:505 in stereoselective epoxidation 4:505 Titanium trichloride titanium (O) from 11:366,367 with potassium graphite 11:366,367 Titanium-induced carbonyl coupling reactions 8:15,25,31 Titanium-induced coupling 11:345,368 Titanium-induced intramolecular pmacol coupling 8:18 Titanium reagents in dicarbonyl coupling 3:80,81 Titanocene dichloride 10:30 Tjipanalzole Ai 12:371 from Tolypothrix tjipanasensis 12:366 Tjipanazole A2 from Tolypothrix tjipanasensis 12:366,371

Tjipanazole B from Tolypothrix tjipanasensis 12:366,371 Tjipanazole Ci from Tolypothrix tjipanasensis 12:366,371 Tjipanazole C2 from Tolypothrix tjipanasensis 12:366,371 Tjipanazole C3 from Tolypothrix tjipanasensis 12:366,371 Tjipanazole C4 from Tolypothrix tjipanasensis 12:366,371 Tjipanazole D condensation of 12:382 from Tolypothrix tjipanasensis 12:366,371 synthesis of 12:282 tjipanazole E from 12:382 with 2,3,4-/e/A'a-0-acetyl-a-D-glucopyranosylbromide 12:382 Tjipanazole E from Tjipanazole D 12:382 from Tolypothrix tjipanasensis 12:366,371 synthesis of 12:382 Tjipanazole Fi from Tolypothrix tjipanasensis 12:366,371 Tjipanazole F2 from Tolypothrix tjipanasensis 12:366,371 Tjipanazole Gi from Tolypothrix tjipanasensis 12:366,371 Tjipanazole G2 from Tolypothrix tjipanasensis 12:366,371 Tjipanazole I from Tolypothrix tjipanasensis 12:366,371 Tjipanazole J from Tolypothrix tjipanasensis 12:366,371 TMAO-urea complex 18:678 2-TMP (2-thiazolyl methylene triphenyl phosphorate) 11:443,444 TMSenol ether 4:8,10,36,38 formmation from ketone 4:8,10 TMStriflate 1:514 TMSOF (2-(trimethylsiloxy) fiiran) 11:451,453 TMSOTF 1:308 TMSOTf 4:91,92 deblocking of BOC 91,92 2-TNO (2-thiazolylcarbonitrile A^-oxide) 11:443,444 Tobacco budworm 12:397 Tobacco norsesquiterpenes 3:58 Tobramycin 14:145 a-Tocopherol 9:313,579,580 synthesis of chroman ring 1:644,645 synthesis of side chain 1:644,646 synthesis of 4:494-501 T0CSY2D 6:140 TOCSY-ID 6:140 TodolactolA 20:619 TodolactolB 20:614,616,617,619 TodolactolC 20:616,619 TodolactolD 20:618,619 Todomatsu 20:613 (7?)-Tolbinap-ruthenium (II) complex 12:153 (5)-Tolbinap-ruthenium (II) complex 12:153

1214

Tollens oxidation withAgNOs 8:25 (p-Toluenesulfonyl) methyl isocyanide(TOSMIC) 3:321,322 double addition of 3:321,322 Tolypothrix tjipanasensis tjipanazole Ai from 12:366,371 tjipanazole A2 from 12:366,371 tjipanazole B from 12:366,371 tjipanazole Ci from 12:366,371 tjipanazole C2 from 12:366,371 tjipanazole C3 from 12:366,371 tjipanazole C4 from 12:366,371 tjipanazole D from 12:366,371 tjipanazole E from 12:366,371 tjipanazole Fi from 12:366,371 tjipanazole F2 from 12:366,371 tjipanazole Gi from 12:366,371 tjipanazole G2 from 12:366,371 tjipanazole I from 12:366,371 tjipanazole J from 12:366,371 TOMAC 6:326,330 Tomatidine 7:19,21 Tomatine 7:18,19,21 Topoisomerase I 16:27 Topoisomerase I and II 12:370,394,396,20:500 Topoisomerase II 5:581,16:27,20:246 Topotecan 13:655,20:458 Torpedo califronica 18:721 Torrentin 7:233 Torularhodin 7:339 from Rhodotorula rubra 7:340 Torulopsis colliculosa 5:283,292 Torulopsis gropengiesseri 5:293 Torulopsis lactis-condensi 5:293 Torulopsis magnoliae 5:293 Torulopsis sp. 5:292 Tosicacid 19:208 Tosylation 6:287,288,11:359,19:518 of nucleosides 19:516 2'-0-Tosyl-5'-0-trityladenosine 19:519 co-Tosyloxy-a-phenylthiocrylontriles 6:540 Total Ion Chromatogram (TIC) 19:766 Total synthesis of 25-oxa-25-phospha-vitamin D3 9:509-528 ofdestomicacid 4:130 of erythromycin A 12:53,54 oferythronolide A 12:46-53 of galantinic acid 4:127 ofkoumidine 15:493 ofA^a-Methyl-D'^-isokoumidine 15:493 ofphorbol 12:265-272 of purpurosamine C 4:123 ofrifamycinW 12:46,47 of vitamin D3 9:510 Totarol 2:403 Totarol derivative 9:297 Totipotency of cell cultures 7:94-96 Totoacetate 7:464

Toumefortiolide derivatives 7:233 frova. Artemisia tournefortiana 7:212 Toxicity offiimonisine 13:532 Toxicity of asterosaponins 7:303 ofholothurins 7:279-282 ofquassinoids 7:388,389 Toxigenic moulds 9:201-203 T-2Toxm 9:28,210 Toxin 5:403,404,411;9:9-11,209-211 ofechinoderms 7:265-316 T-2 Toxin analogues 6:242 Toxisterol-B 2:162 Toxocara canis 17:379 Toxoplasma gondii 13:183 Toxotrypana curvicauda 5:239,252 2-methyl 6-vinyl-pyrazines of 5:222 Toyocamycin 15:459 TPA-induced secretion from pancreas islets 12:397 of insulin 12:397 TPA-responsive element 15:441 TPSTe as condensing agent 4:269 (+)-Trachelanthamidin isolation of 19:145 synthesis of 19:145 /ra5-Nerolidol 20:588 Trachelanthamidine synthesis of 1:246,228,232-237,240,246,248-250, 259,260,325,326,339 ()-Trachelanthamidine 13:483 Trachelanthamine synthesis of 1:267 Trachelanthic acid 1:260,261,270 Trachelanthimidine synthesis of 3:51 Trachelogenin 5:522,531,533 Tracheloside O-methylation of 5:532,533 0-glucosylation of 5:532,533 Trachelospermum asiaticum Nakai var intermedium 5:505,515,521,526,545 Traditional medicine 17:113 Tragopogon saponins 15:191 Tranquilizing activity 20:79 Trans aldehydo lactol 8:22,23 (E)-Trans-1 -hydroxy-10-vinyl-2-cyclodecene synthesis of 8:196,197 (Z)-Trans-1 -hydroxy-10-vinyl-2-cyclodecene synthesis of 8:196,197 Trans-anti-trans-anti stereochemistry 8:188 (+)-7>a5-chrysanthemic acid 16:221,257,258 (+)-7>a5-cognac lactone 16:693 7>aA25-Hydroxylation of olefmic double bond 16:16 (+)-7>a5-isopiperitenol 17:605 (+)-7rfl5-sesquifenchene 16:236 (+yTrans-'whiskQy lactone synthesis of 16:695

1215

Transacetalation 8:287,288;! 1:82,83,109 acid-catalyzed 14:654 intramolecular 14:654;11:109 Transannular [2,3]-Wittig rearrangement synthesis of costunolide 8:195-201 synthesis of haageanolide 8:195-201 Transannular [4+2] cycoaddition 5:796,797 Transannular acylation ofsulfurstablizedcarbanions 3:81,82 medium ring formation by 3:81,82 Transannular cyclization 13:440 Transannular deprotonation 10:222 Transannular Diels-Alder reaction 8:187-195 Transannular ketal cyclization 11:59 Transannular reaction 8:175,19:66,418 Transannular SN^ cyclization 15:500 Transcription initiation 5:580 Transesterification 1:267,8:288,292 enantioselective 1:685;13:53,54 enzymatic 13:55 of tricyclic lactones 12:30 of propane-1,3-diols 13:53-55 Transferase 7:58;17:480 Transferrins 9:537,555 Transformation biomimetic 11:292-295 hobartine-aristoteline 11:292-295 of bile alcohols 17:217 ofoxetanocinA 10:586,587 ofquinocarcin 10:119,120 of saframycins 10:101-103 Transglycosylation 7:54,55,61 Transilin 7:228 Transition probabilities 2:57,58 Transition state analogue oflysozyme 7:49 tetrasaccharides as 7:49 Transition state analogue inhibitors 7:40,41,48-50 Transition state models 4:144 Transketalization 1:415,417,45 7 Translactonization 8:21,29 intramolecular 13:159 Transmethylation 2:53 in FAB spectra 2:53 Transmethylation inhibition of 1:408 1,3-Transposition of allylic system 4:165 Transylidation 4:560,563,564 Tr-B 20:492,493 Trechonolide A 20:181 a,a-Trehalase 7:32,69;10:498 Trehalase 7:50,58,60,69 Trehalases 8:318-322 a,a-Trehalose 10:499 a,a'-Trehalose 14:148 a,a-Trehalose 8:347,348;13:216,223 Trehalose derivative 6:40,401 Tremaster novaecaledoniae 15:45,72,75,96 Tremasterol A, B and C 15:72 Trematode (fluke) 12:7

Tremella mesenterica 5:288,289,307 Tremellasp. 5:288 Trestatins A 10:517 Trestatins B a-amylases inhibitor of 10:517 amylo-a-1,4-a-1,6-glucosidase 10:517 from Streptomyces dimorphogenes 10:517 11,12,13-Tri-or-3,4-cuauthemone 9:66,69 Tri-or-sesquiterpene 9:66 3,4,6-Tri-O-acetyl-1,2-0-cyanoarylidene-a-Dgalactose 14:224 3,4,6-Tri-O-acetyl-1,2-0-cyanoethylidene-a-Dmannose 14:229 2',4',5-Tri-(9-acetyl-1,3,3'-tris(A^-benzyloxycarbonyl) geramine 14:146 2,3,4-Tri-O-acetyl-1 -thio-p-Z)-xylopyranose 8:328,329,336 3,4,6-Tri-0-acetyl-2-0-benzyl-glycosyl bromide 14:258 2,4,6-Tri-0-acetyl-3-(9-trityl-P-D-galactopyranoside 14:225 7-Tri-0-acetyl-6-deoxy-{3-Z,- galactopyra-nosyl) (2,3,4theophylline synthesis of 4:232 3,4,6-Tri-(9-acetyl-P-D-glucopyranosyl chloride 8:360362 Tri-O-acetyl-D-glucal 6:221,222;10:338;14:193 3,4,6-Tri-0-acetyl-Z)-glucal 8:343,344 3,4,6-Tri-0-benzoyl-2-phthalmiido-2-deoxy-a-Z)glycosyl bromide 14:242 1,2,3-Tri-0-benzoyl-4-(9-triflyl-Z-arabinose 8:336 l,2,3-Tri-0-benzoyl-4-5'-(2,3,4-tri-0-acetyl-P-Dxylopyranosyl)-4-thio-P-Z)-xylopyranose 8:336 1,3,5-Tri-0-benzoyl-/w;;o-inositol 18:422 2,3,4-Tri-O-benzyl-a-L-rhamnosy 1 chloride thermal glycosidation with 8:360,364 2,3,6-Tri-(9-butyroyl-m>'o-inositol 1,4-5-trisphosphate 18:409 2,3,4,Tri-0-methylgalactose 15:431 Triabunnme 9:195;11:299,300 (15)-( 1,3,6/2)-1,2,3-Triacetoxy-4-acetoxy-methyl-6azidocyclohex-4-ene 10:507 Triacontanal 7:189 2'-/3'-Trialkyl silyl ribonucleosides silyl migration in 14:285 Trialkylaluminium compounds addition to a,P-alkynyl acetals 1:624,625 addition to a,P-unsaturated acetals 1:624,625 diastereoselective addition of 1:624,625 Trialkylalumnium 6:428 Trianion of indole-3 -acetic acid 1:13 Tribenzo[a,c,e] cycloheptatrien-5-one from diethyl 2,2'-Bi-1 -benzoate 11:125 synthesis of 11:125 Tribenzotropone 11:125 Z)-2,3,6-Tribenzyl-/w};o-inositol 18:397 Tribolium castaneum 9:299 ip,4p,10p-Tribromo-3-chloro-7(14)-ene-a-chamigrene 9:81

1216

1,4,10-Tribromo-3-chloro-7( 14)ene-a-chamigrene 5:217 Tributyltin radical addition to olefin 1:490 (Z)-Tributylvinylstannanes cross coupling reactions with 10:162 Tricarbocyclic bridged systems 6:74-86 Tricarbocyclic epoxide by Saegusa ring expansion 6:37,38 ()-dactylol from 6:37 synthesis of 6:37,38 Tricarbocyclic fused systems stereoselective synthesis of 6:38-58 Tricarbonyl (diene) iron complex 12:280 Tricellaria ternata 17:92 Trichilia emetica 20:492,493 Trichilin-4 20:492 Trichilme-A 20:493 Trichloroacetamidate from D-glucose 6:276,277 3-Trichloroacetamido-3-C-vinyl-derivative 10:421 Trichloroacetimidate method condensation of 4:207-209 in oligoheptose synthesis 205,206 Trichloroacethnidate method 6:402 a-Trichloroacetimidates 14:212,213 P-Trichloroacetimidates 14:212,213 Trichloroethyl carbamate 1:71 Trichocolea tomentella 2:21 S Trichocoleopsis sacculata T21%XI^ Trichocoleopsis sp 2:90 Trichoderma harzianium 4-thiocellobiose from 8:352 Trichoderma lignorum xylanases from 8:352 Trichoderma reesei cellobiohydrolases from 8:348,351 cellobiohydrolase A from 8:351 cellobiohydrolase B from 8:351 Trichoderma sp. 5:368;7:406 Trichoderma viride 4-thiocellobiose from 8:352 Trichodermin 6:233 (f//)-Trichodiene 10:307-309 synthesis of 10:307-309 Trichodiene 6:247-250;9:212-214;13:524 Trichodiene-derived compounds 6:213,214 Trichodienoids 13:524,525 Trichodiol 6:247,248;13:524 Trichodonm 15:112,162 Trichoguattine from Guatteria trichostermon 16:515 Trichokaurin from Rabdosia longituba 15:173 Tricholomoidei 17:198 Trichommonasfoetus 2:293 staurosporine against 12:397 Trichomonas gallinae 2:294 Trichomoniasis 12:397 Trichomycetes 9:202 Trichonine 10:152

Trichophylline 9:190-192 X-ray crystal analysis of 9:192 Trichophyton granulosum 5:294 Trichophyton interdigitale 5:294,298,598;12:401 Trichophyton mentagrophytes 2:446;12:401;20:28, 30,31 Trichophyton rubrum 5:294,236,12:401 Trichophyton schonleinii 5:294 Trichophyton sp. 5:294,328 Trichophyton tonsurans 12:401 Trichoplusia ni 5:832 Trichorabdal A 15:142 ^^C-nmrof 15:158 from Rabdosia trichocarpa 15:175 from Rabdosia weisiensis 15:175 *H-nmrof 15:150 Trichorabdal B 15:142 '^C-nmrof 15:160 from Rabdosia trichocarpa 15:175 'H-nmrof 15:151 Trichorabdal C 15:143 ^^C-nmrof 15:160 from Rabdosia trichocarpa 15:175 'H-nmrof 15:151 Trichorabdal D 15:144 "C-nmrof 15:161 from Rabdosia trichocarpa 15:175 *H-nmrof 15:153 Trichorabdal E 15:144 from Rabdosia trichocarpa 15:175 ^H-nmrof 15:152 Trichorabdal F 15:143 from Rabdosia trichocarpa 15:175 ^H-nmrof 15:152 Trichorabdal G-acetate 15:143 from Rabdosia trichocarpa 15:175 'H-nmrof 15:152 Trichorabdal H 15:112,143,162 ^C-nmrof 15:160 from Rabdosia trichocarpa 15:175 'H-nmrof 15:152 Trichorabdonin 15:144 ^C-nmrof 15:161 from Rabdosia trichocarpa 15:175 ^H-nmrof 15:153 Trichosanthes kirilowii 13:655,660 a-Trichosanthin 13:655 Trichosanthin 13:660 Trichosporon aculeatum 5:283,292 Trichosporon cutaneum 5:292,294 Trichosporonfermentans 5:292 Trichosporon inkin 5:294 Trichosporon sericeum 5:294 Trichosporon s^. 5:292 Trichosporon undulatum 5:294 Trichothecene mycotoxins 13:517 Trichothecenes 9:203,205,207-213;10:307;13:524 biosynthesis of 6:249-259 synthesis 9:213-247 Trichothecium roseum 10:307 Trichothecolone 6:237,239 Tricin 7:228

1217
Tricophyto mentagrophytes 9:297 Tricycic diterpenes 6:108 Tricyclic aromatic glutarates pentacyclic derivatives 11:121,122 trans Tricyclic compounds 8:397 CIS Tricyclic compounds 8:397 Tricyclic gephyrotoxins (perhydrobenzoindolizidines) 11:244 Tricyclic ketal 17:27 Tricyclic lactone 17:608 Tricyclic natural products by intramolecular cycloalkylation 6:74 synthesis of 6:74-86 Tricyclic resin acid 15:16 Tricyclo [3.2.1.0^''] octane 8:419 Tricyclo [5,3.1.0*'^] undec-9-ene-8,ll-diones 8:163 Tricyclo [5.2.2.0^'^] undecane 8:426,427 Tricyclo [5.3.0.0^^] decane group 6:40 spatane diterpenoids in 6:38,39 Tricyclo [6.3.0.0"^^] undecane group 6:42-50 Tricyclo [6.3.0.^''] undecane 13:3,4,37 Tricyclo [6.3.0.^'*] undecane 13:3,13:4,13:37 Tricyclo [7.1.0.0*^] decane group 6:40-42 Tricyclo [8.1.0.0^^ undecane group 6:50.51 Tricyclo [9.3.0.0] tetradecane 12:246 Tricyclo [9.3.0.0^^] tetradecane group 6:52-54 Tridecyl phenol 2:280,281 36-Tridecyl salicyclic acid 2:280,281 Tridedemnum sp. didemnine A from 12:477 didemnine B from 12:477 Tridensone 18:640-643 from Bazzania tridens 18:639 1,2,4-Trideoxy-l-nitro-2-phosphinyl-I-pentitol 6:357 2,6,7-Trideoxy-2,6-imino-Z)-glyceroD-manno-heptitol synthesis of 11:467 2,6,7-Trideoxy-2,6-imino-D-glycero-Z)-gluco-heptitol 11:467 synthesis of 11:467 2,3,4-Trideoxy-Z)Z-glycero-hexopyranose 7:35,36 ewfi^o-dextranase reaction with 7:35,36 13-Trideoxy-evoninol 18:745 2,3, 3,4,13-Trideoxy-evoninol 18:745 2,3,13-Trideoxy-isoeuoniminol 18:746 Trideoxynucleosides synthesis of 4:525 Tridesmosides 15:188 Trideuteriolactone 8:303,304 Trideuteriopyrocatechol 8:303 Trididemnum cyanophorum 4:102;5:427,428;10:244, 250,251,252,262,294 Trididemnum palmae 10:252 Trididemnum solidum 10:245,250,252,253 Trididemnum solidum 4:102 Trididemnum species 10:245 Trididemum sp. (cf olidum) 5:422 Tridiemnum genus 17:23 3-Triethylsilyloxy-1,4-pentadiene to 2-methy lene-1,3 -dithiane 12:242 l,4,6-Trien-3-one 11:379,380,388 l,5,7-Trien-3P-ols 11:379,380 (,,)-Triene synthesis of 8:188-190 (Z,i5;,^-Triene synthesis of 8:188-190 Trienomycin from Streptomyces sp. 11:189 3-Trienoylpyrrol-2(5/f)-ones 13:140 Trienylpyrrol-2(5//)-one 13:122,123,133,134 Triethyl silane reduction of hemiketal 3:218 Triethylammmonium formate Pd2 catalysed reduction 3:184 Triethylsilyl silyl ethers 11:339 bis (Triethylsilylacetylene) 10:249 Triethylsilylation 11:363,364 Trifluoroacetoxy-selenylation \1-A12> 3 -Trifluoroacety 1-allohobartine from allohobartine 11:318,319 A^-Trifluoroacetyl-Z-acosamine synthesis of 4:150,151 A^-Trifluoroacetyl-I-daunosamine synthesis of 4:150,151 Trifluoromethanesulfonates 8:316 ()-a-Trifluoromethyl-a-methoxyphenylaceticacid 12:478 Trifluoroperazine protein kinase inhibitor of 12:387 4-O-Triflylgalactoside derivative synthesis of 8:330,331 5-exo-Trigaryl radical-alkene cyclization 3:327,328 14-endo-Trigcyclization 13:589 Triglycosides 7:270,273,275,286,287 Trihaloalkyl protectmg group removal of 4:286 Triheptoses 4:196 in Aeromonas salmonicida 4:196 in Enterohacteriaceae 4:196 in Pasteurella multocida 4:197 in Phenylobacterium immobile K2 4:196 M4[5],16a,17-Trihydroxy atisan-3-one 9:268,269, 274,275 M4[51,16p,17-Trihydroxy atisan-3-one 9:268,269, 276 /-6a,16a,17-Trihydroxy atisan-3-one 9:268,269, 276,278,280,281 Ent-1^, 16a, 17-Trihydroxy atisan-3-one 9:268,269,276 6,12,14-Trihydroxyabieta-6,18,l 1,13-tetraene 20:670 5,3',5'-Trihydroxy-3,6,7,4'-tetramethoxyflavone 5:757 (15)-2,3,4-Trihydroxy-5-(hydroxymethyl)-l-cyclo-hexy -lamine [5a-carba-a-D-glucopyranosylamine] 13:195 2a,3P,6P-Trihydroxy-5a-pregnane-20-one 18:532,532 5,8,4'-Trihydroxy-6,7,3'-trimethoxyflavone 5:628,655 5,3',4'-Trihydroxy-6,7,8-trimethoxyflavone 5:655 5,8,4'-Trihydroxy-6,7-dimethoxyflavone 5:628,629 5,3',4'-Trihydroxy-6,7-dimethoxyflavone 5:655 5,6,4,-Trihydroxy-7,3-dimethoxyflavone 5:655 la,255',26-Trihydroxy-cholecalciferol synthesis of 10:69 1,3,5-Trihydroxyacridin-9-one 13:352 synthesis of 13:357,358 Trihydroxyicosadienoic acid 9:577

1218

(+)-(65,7S',8/?,8a/?)-Trihydroxyindolizidine synthesis of 12:347 6,7,8-Trihydroxyindolizidine from methyl 2-azido-4,6-0-benzyUdene-2-deoxya-D-altropyranoside 12:348 synthesis of 12:348 (+)-(65',75,8/?,8a/?)-Trihydroxyindolizidine enantiospecific synthesis of 12:347,348 5,6,7-Trihydroxylated coumarin 5:516,517,520 4,5,6-Trihydroxynorleucine 14:192 1,24,25-Trihydroxyvitamin D2 9:513 la,24-/?,25-Trihydroxyvitamin D3 9:521 6,7,8-Trihyroxylated coumarin 5:516,517,520 2,4,6-Triisopropylbenzenesulfonyl chloride as condensing agent 4:269 2,4,6-Triisopropylbenzenesulfonyl-4-nitro-imidazole TPSNI as condensing agent 4:269 2,4,6-Triisopropylbenzenesulfonyl-tetrazole Trijugin A 2:267,268;9:94,95 TrijuginB 2:267,268 Triketones reductive amination of 6:445,446 Trillium glycosides antifungal activity of 2:443 Trillium grandiflorum 2:443 Trillium tschonoskii 2:443 Trilobatin 15:31 Trimethylsilyl triflate 12:168 Trimer ofplumbagin 5:754 ofplumbazeylanone 5:754,756 Trimethoxy benzohydroheptalone synthesis of 3:289,290 2,4,6-Trimethoxyacetophenone 9:288,289 3,4,5-Trimethoxycinnamate 18:580 5,6,7-Trimethoxyflavone 5:640,652,654;7:413 3,5,7-Trimethoxyflavone 5:652-654;7:413 5,7,8-Trimethoxyflavones 5:640 2,4,5-Trimethoxystyrene 9:402 Trimethyl decalone by Robinson annulation 6:19,20 from ethyl vinyl ketone 6:19 from 2-methyl-1,2-cyclohexadione 6:19 in euryfuran synthesis 6:20 in pallescensin-A synthesis 6:20 synthesis of 6:19,20 Trimethyl orthoacetate corynan-17-oic acid methyl esters from 14:725 0,(9,0-Trimethyl korupensamine A and B 20:450 Trimethyl orthoformate methylation with 1:448,449 Trimethyl silyl enolate ozonolysis of 14:572,573 piperidine derivative from 14:572,573 l',3,3'-Trimethyl-l,2'-biazulene 14:336 2-(3,7,11 -Trimethyl-2,6,10-dodecatrienyl)hydroquinone 15:294 6-(3,7,11 -Trimethyl-2,6,10-dodecatrienyl)-2methoxy-p- hydroquinone 15:294 1,1,2-Trimethyl-2-phenyl cyclopentane 8:6,7,10,13

2,2,5-Trimethyl-5-hexenal 6:45,46 ()-A^^^^^-capnellene from 6:45,46 4,6,8-Trimethylazulene oxidation of 14:341,342 [3,3-(Trimethylendioxy) propyl] magnesium bromide 11:284,285 Trimethylpyrrocorphin 9:604 2-(Trimethylsiloxy) fiiran (TMSOF) 11:451,453 2-TrimethyIsiloxyfliran 3:167 3-exo-Trimethylsilyl camphor 4:663,664 A^-Trimethylsilyl cinnamylidene imine 4:455,457 Trimethylsilyl cyanide 1:156 in glycosylcyanide synthesis, 3:210-212 Trimethylsilyl derivative 4:223 in nucleosides synthesis 4:223 Trimethylsilyl esters acylation of phosphonium ylides 4:564 Trimethylsilyl intermediates in prenylation methods 4:394 A^-Trimethylsilyl iodohydrin 1:277 Trimethylsilylmethylation 1:249 Trimethylsilyl triflate (TMSOT) 12:419,420 bis-(Trimethylsilyl) hydrogen phosphate 8:69 2,3-^w-[(Trimethylsilyl)oxy butadiene 1,2-^w-phenylhydrazonefrom 12:377 with maleimide 12:377 A'^-Trimethy Isily 1-3 -(trimethy Isily) propynal-dimine 4:457 Trimethylsilyl-3-butyn-l-ol 12:473 2-Trimethylsilyl-1,3-dithiane 12:156 2-(Trimethylsilyl)oxy] butadiene 12:377 Trimethylsilylation 1:272,273 3-ec?o-Trimethylsilylcamphor 4:663,664 Trimethylsilyldiazomethane esterification of 4:91,92 Trimethy Isily lisocyanate 3:309 A^-acylationof indoline 3:309 Trimethylsilyloxy butadiene with methylene glutarimide 14:751,752 4-(Trunethylsilyloxy)-p-lactam from enolsilyl ether 12:160,161 2-Trimethylsilyloxybutadienes in Diels-Alder reactions 4:581 2-Trimethylsilylthiazole (2-TST) 11:443,444 Trimethylsilyvinylalanate reagent 12:295 Trimusculus reticulatus 11:21 Trimyristin 5:753;9:455 8,9,10-Trinor camphor C(3)-monobromination of 4:656,657 Triol 4:166 selective silylation of 4:184 Triose-phosphate isomerase 7:30 2,4,8-Trioxabicyclo [3.3.0] octane cw-fused 10:412 Trioxilin 9:576 Tripartol 7:204,205,224 Tripdiolide 2:404,405 production of 2:407,409,411 Tripeptide 9:494 Triphenylmethyl phosphonium permanganate 3:182 Triphenylphosphme 11:342

1219

Tripheny Iphosphonium methylide 11:351,352 deprotonation of 11:351,352 with sec butyllithium 11:351,352 A'^-(Triphenylphosphoranylidene)-p- alanine methyl ester 12:301 Triphenyltin hydride in reductive of selenides 6:427,428 Triphosgene isocyanides from 12:113 Triphyophylline 20:418,420,438 Triple dioxygenation 9:651 Tripneustes gratilla 7:283,284 Tripterygium wilfordii 2:403,404,414,416;7:146 tissue culture of 7:146 triterpenes of 7:146 Triptolide 2:404 Triquinane angular 13:3-25 diterpenes 13:3-52 linear 13:34-56 sesquiterpenes 13:3-52 sesterterpenes 13:3-52 synthesis of 13:3-52 Triquinane 6:33,34 precapnelladiene from 6:33,34 synthesis of 6:33,34, Triquinane derivatives 7:216 Triquinane terpenes Claisen rearrangement by 10:426-428 synthesis of 10:426-428 Triquinanes angular 3:5-7 linear 3:5 synthesis of 3:5-48 Tris (4,5-dichlorophthalimido) trityl bromide (CPTrBr) 14:288 Trisaccharide 7:31,181 Trishomononactate 18:253 Trisporic acid 7:341,342 from Blakeslea trispora 7:340 2',4',5'-Trisubstituted flavones 5:630 (i)-Trisubstituted olefin 1:406,407 synthesis of 1:406,407 Trisubstituted olefins synthesis of 4:565 Triterpene 5:3,38-41;7:124,131-174;17:80 derivatives 17:118 from p-amyrin 7:131-145 ofBarringtonia sp. 7:132,133 of Guaiacum officinal 7:139 of Terminalia sp. 7:133-135 CaoTriterpene 7:317 Triterpene glycosides 7:267,281 Triterpene saponins molluscicidal activity of 7:426,427 Triterpenes 6:110;15:281,282;18:757-769 Triterpenoid intermediate 4:676 Triterpenoids 5:743-745,750;7:l 89-191;9:293-295,297, 300,302,307,308;20:702 Triterpene qumone methides biogenesis of 7:150-152

from Cassine balae 7:145,150 from Kokoona zeylanica 7:148-152 Trithiane 10:244 1,4,4'-Trithiocello-oligosaccharides 8:348,349 1,4,4Trithiocellotrioside 8:348,349 15-TritiatedGA3 synthesis of 8:128,129 Triticum 9:321 Triticum aestivum 18:503,512,520,19:247 3-dehydroteasteron from 18:500 Triticum vulgare 9:321 Triton 11:347 Triton B 6:320-322;12:244 6-(9-Trityl protection 6:370 Trityl-cyanoethylidene condensation 14:219-226 polysaccharides by 14:228 Tritylation 6:282,284,292,293 Tritylperchlorate as catalyst 4:236 Triumbellatin 20:283 Trixikingolide 13:39,41-46 Tropacocaine synthesis of 1:383-385 Tropane synthesis of 1:380-382 Tropane alkaloids biosynthesis of 17:395 *^C-incorporation 17:416 distribution of 17:401,406 synthesis of 1:378-385;16:442 Tropical ulcers 5:745 Tropine 1:378;7:191 Tropinone 1:378 Tropolones 1:340 synthesis of 1:340 Tropone 1:549,554-573;10:178;13:624 1,8-addition of lithio tert butyl acetate 1:554 addition to enolates 1:554,555 as diene in [47i + 2n\ cycloadditions 1:566,571 cw-hydroazulene from 12:251 diazoketone insertion 1:555 for perhydroazulene synthesis of 1:549-556 iron tricarbonyl complexes 1:572 organometallic derivatives of 1:572,573 photochemical electrocyclic closure 1:549 vinyl sulfide cycloaddition 1:567 Tropone alkaloids 11:204 Trost cyclization of allylic acetate 16:423 TrunculinA 5:354,355 Trunculins A-B 9:18 from Latrunculia brevis 9:20 X-ray analysis of 9:20 Trypamosoma 18:791,793 Trypanosimatids 18:793 Trypanosoma burcei 18:448,449 polysaccharides of 2:310 Trypanosoma conorhini 2:311 Trypanosoma cruzi 18:796-802 glycosphingolipids 18:796-802 glycocomplexes of 2:302-309

1220
Trypanosoma mega 18:804 glycocomplexes of 2:310,311 polysaccharides of 2:310,311 Trypanosoma spp. glycocomplexes of 2:301-310 polysaccharides of 2:301-310 Trypanosomatides higher 2:301,314 lower 2:295-301 polysaccharides of 2:295-301 Trypsin 9:500 Tryptamine 9:167,168,177,178;13:662;15:487;19:100 secologanin ondensation with 6:520 Trypterigium sp. 18:753 Trypterigium wilfordii 18:771 Tryptic digest 9:499,503,504 Tryptic peptide 9:499,503 Tryptofordm 18:772 from Trypterigium wilfordii 18:771 Tryptophan 1:31;11:200 by 4-(y,y-dimethylallyl) tryptophan synthase 11:200 isoprenylation of 11:200 quinaldic acid from 11:209,210 stereochemical course of 11:200 Tsilanimbine 1:38,39 2-TST (2-trimethylsily 1 thiazole) 11:443,444 (-)-Tsukushinamine-A 15:520 TTN (thallium nitrate oxidation) 10:631-635,637,638, 640,641,644-647,653,654,661,662,666,667 Tu-bei-Mu {Bolbostemma paniculatum) tubeimoside I from 7:143,144 Tubastraea aurea 5:359 Tubastrea micrantha 5:360 Tubastrine 5:359-361 Tubatosides 15:191 Tube dilution test 20:712 Tubeunoside I from Bolbostemma paniculatum 7:143,144 Tuberculosis rifampicin for 12:37 Tuberine isolation of 178 Tulipa gesneriana 19:247 Tuberostan from (+)-isomedicarpin 4:382,383 Tubifolidine synthesis of 1:41,42,45,46,51,52,67 20-e/7/-Tubifolidine synthesis of 1:67 Tubifoline synthesis of 1:41,45,46,51,52 Tubocurarine from Chondodendrum tomentosum 13:631 of-Tubocurarine 18:698 Tubotaiwinal 1:40 Tubotaiwine 1:33,40 synthesis of 1:41,49,50 (+)-Tubotaiwine 5:125 Tubotaiwine biogenesis of 6:503 Tubotaiwine 9:190,191

Tubotaiwine-A^4-oxide 5:125 Tubulanus punctatus 18:725 Tubulm 11:5 ()-Tubulosine 18:330 Tubulosine 9:401;13:92 X-ray crystal analysis of 9:401 Tulipinolide 7:231 Tumor necrosis factor staurosporine effect on 12:396 Tumor necrosis factor 5:385,387 Tumor promoters 2:286,287 Tumor therapy polyene macrolides in 6:261 Tumor-promoting diterpenes 12:233-274 synthesis of 12:233-274 Tumour-inhibiting activity 17:341 ;20:408 Tumour-promoter activity ofpendolmycin 15:462 Tunaxanthin 7:320 Tunicaminyl uracil asymmetric induction of 10:572 Tunicamycins 1:398,417-42;l 1:430,446-449 dolichyl-pp-Glc NAc inhibitor of 10:569 from Streptomyces lysosuperificus 10:568 total synthesis of 10:570-572 synthesis of 1:417-421;11:446-449 Tunicates 19:549 Tunichlorin 10:245,246 TunichromeA 10:241,242 Turbo connutus mixed glucosidase from 7:270 Turdoides somerville hemoglobin components of 5:837 (-)-P-Turmerone synthesis of 8:52,55,56 (-)-ar-Turmerone 8:39 P-Turmerone 8:51,55,56 from Curcuma longa 8:52 Tumefocidine synthesis of 1:228,246 Tumeforcidine 3:54 Turus migratorius hemoglobin components of 5:836 Tussilagin synthesis of 1:230,231 Tutufa lissostoma 18:724 Twelve-carbon sugars synthesis of 4:190 Twisted Ti-electron system 17:41 Two-spotted spidermite 12:397 Two-stage coupling process (tandem process) 12:35-62 Tylohirsutidine 12:301 Tylohu-sutine 12:301 Tylonolide 10:170;11:152,158-163,164 synthesis of 11:158-163 Tylophora hirsuta phenanthroindolizidine alkaloids from 12:300 Tylophora specks 1:360 Tylophorine synthesis of l:360-362;4:604,605

1221

Tylosin 5:609,612,10:153,170 Typha latifolia 19:247 Typhasterol 16:324;18:500,512,520 synthesis of 19:258 Tyramine 6:525,529 (-)-Tyrosine photooxygenation of 16:595 Tyrosine mechanisms of 16:608 oxygenation of 16:595 Tyrosine-specific kinase inhibitor of 19:178 L-Tyrosine 5:467 Tyrosine ammonia-lyase (TAL) 5:467,468 Tyrosine kinase 12:394 Tyrosine kinase activity 15:441 Tyrosine kinase inhibitors biological activity of 15:447-449 Tyrosol photosensitized oxygenation of 16:582

Uang synthesis avermectin oxahydrindene subunit 12:26,27 (7-hydroxystaurospermines) 12:26,27 Ucapugilator 19:628 Uchotensimine 1:201,202 synthesis of 1:201,202 UCN-Ol-UCN-02 12:386 antitumor activity of 12:395 from Streptomyces sp. N-126 12:366,368 protein kinase inhibitor of 12:386 Udoteaflabellum 16:312 Udoteatrial 16:312-316 antimicrobial activity of 16:312,315-316 f![om Udoteaflabellum 16:312 synthesis of 16:312-316 UDP glucose coniferyl alcohol glucosyltransferase 5:471 UDP-GlcNAc distribution of metabolism 1:417 Ueno method reduction by 10:322,323 Ugi reaction 12:114-138 Ulapualides A antifungal activity of 19:609 Ulapualide A and B 17:16 Ulbelliferae 7:115,119,120,415 Ulbelliferone 7:224 Uleine synthesis of 1:56-58 Ulicyclamide 5:419,420;10:242 cytotoxic activity of 5:419 Ulicyclamide group 4:83,84 Ulithiacyclamide 5:419;10:242 cytotoxic activity 4:101,102;5:419 synthesis 4:89,90,99,100 UUmann biaryl synthesis 20:294-301 Ullmann diarylether synthesis 20:307-310 UUmann macrocyclization 20:308 Ulmann reaction 10:629-631,641,644,646-653,655, 661,667;13:353,354,364;20:294,296,297

intramolecular 10:640 Ulmus thomasii 17:338 Ultracentrifugation 20:497 Ultraviolet spectrophotometry (UV) offlavonoids 5:621,622 offlavonols 5:622 of 3 -methoxyflavones 5:622 2'-substituted flavonoids 5:622 of2*,4',5'-trisubstitutedflavonol-3-methyl ether 5:630 Ulvalactuca 7:338 (65,6'iS)-8,8-carotene from 7:338 (+)-Umbelactone synthesis of 16:694 Umbelliferae 18:8 Umbelliferone in6-(3,3-dimethylallyl)-7-hydroxycoumarin synthesis 4:385,386,20:497 in osthenol synthesis 4:385,386 in 7-O-prenylcoumarin synthesis 4:385,386 in xanthone synthesis 385,386 with prenyl bromide 4:385,386 from Pleisopermium alatum 20:497 Umbellifolide 7:215,237 from Artemisia umbelliformis 7:215 Umbellifrone (7-hydroxycoumarin) 9:114 Umbelliprenin epoxide cyclization of 1:661 Umbilicaria angulata 5:311 Umbilicaria caroliniana 5:311 Umbilicaria polyphylla 5:311 Umbrosianin 15:119 ''C-nmrof 15:133 from Rabdosia umbrosa 15:175 'H-nmrof 15:126 Umbrosin A from Rabdosia umbrosa 15:175 from Rabdosia umbrosa var. hakusanensis 15:175 Umpolung 10:160,167 Umpolung-Michael-Addition 8:46 Uncaria genus 17:122 Uncaria guaianensis 17:116,124 Uncaria tomentosa 116,118,124 Uncatalyzed thermal cycloaddition reaction 12:425 Uncompetitive inhibitors 7:40 (Z)-Undec-8-ene-2,5-done 19:161 (Z)-5-Undecen-2-one 19:123 iV-Undecane as alarm pheromone 6:453,454 Undecatrione reductive amination of 6:450 Undecyl catechol 2:280 63-Undecyl phenol 2:280,281 6-Undecyl salicylic acid 2:280,281 Undecylenic acid 8:224 Undecylprodigiosin 8:272 Unedoside 7:440 Unprotected quinone naphthacenequinone from 11:123 2,3-Unsaturated 1-thioglycosides synthesis of 8:343 (11)-Unsaturated 5a-8a peroxystrerols 5:406

1222

2,3-Unsaturated a-C-glycopyranosylarenes 10:345 a,P-Unsaturated acetal cyclic enones with 14:502 from dialkyl tartrates 14:489-491 photocycloaddition of 14:502 Simmons-Smith reaction of 14:489-491 Unsaturated acetals cyclopropanation of 14:490 from (-)-(25,35)-1,4-dibenzyloxy-2,3-butanediol 14:490 2,3-Unsaturated allyl glycoside preparation of 10:420 A^'^-Unsaturated brassinosteroids synthesis of 18:515-520 a,p-Unsaturated butyrolactones 11:453 Unsaturated C-18 fatty acids 1:528-533 2,3-Unsaturated C-glycofuranosyl by Claisen reaction 10:341 fromglycal 10:341 Unsaturated C-glycopyranoside from pyranoid glycals 10:345 synthesis of 10:345 2,3-Unsaturated C-glycoside 10:346,349,350 from Claisen rearrangement 10:338 from lithioglycal 10:312 from peracetylated glycals 10:350 regioselectivity of 10:350 stereoselectivity of 10:350 synthesis of 10:350 Unsaturated C-glycoside alkylation with dibenzylidene acetal bis (diphenylphosphino) ethane 10:343 alkylation with trifluoroacetate ester 10:343 by palladium (0)- 10:354,355 P-dicarbonyl C-glycoside 10:348 from glycosyl fluoride 10:368 from peracetylated glycols 10:343 1,2-Unsaturated C-glycoside 10:349 2,3-Unsaturated C-nucleoside 10:341,342 by reaction of ftiranose-glycals 10:341 synthesis of 10:341 with pyrimidine-mercury/palladium acetate 10:341 a, P-Unsaturated carbonyl compounds oxidation of 4:46 (^-a,p-Unsaturated ester 13:89 5,6-Unsaturated hexopyranosyltheophylline synthesis of 4:237 a, P-Unsaturated imide 12:162 asymmetric aldol reaction of 12:162 4-unsubstituted P-lactam from 12:162 a, P -Unsaturated ketone 4:129 in Luche-type reduction 4:130 reduction of 4:382,383 a,P-Unsaturated ketone ' H - N M R spectrum of 12:46 NOE experiments of 12:46 stereochemistry of 12:46 a,P-Unsaturated ketones 14:438,753 with 2-methyl-6-vinylpyridine 14:438

a,P-Unsaturated ketones reaction with silyl enol ethers 3:126,127,129 a,P-Unsaturated ketones synthesis of 6:339,340 Unsaturated ketonucleosides synthesis of 4:248,253 tumor inhibition by 4:253 A-8,9-Unsaturated lactol in endoperoxide rearrangement 4:420,421 Z-P,Y-Unsaturated macrolide synthesis of 8:232 a,P-Unsaturatedmethoxymethylester fragmentation-recombination of 10:412 a,p-Unsaturated nitroolefms 14:636-638 2,3-Unsaturated nucleosides 1,3-intramolecular shift of 4:223 2-Unsaturated nucleosides 4:225 Unsaturated nucleosides 4:235-237 synthesis of 4:235-237 Unsaturated 0-glycosides 10:354,355 a,P-Unsaturated orthoesters Michael acceptors 3:146-149 A'^-Unsaturated oxepene 10:221 A'^-Unsaturated oxocenes 10:223 2,3-Unsaturated pentose fromD-xylal 10:425 Unsubstituted 2-oxazolidone derivative low P-selectivity of 12:166 with 4-acetoxy p-lactam 12:164,166 4-Unsubstituted P-lactam 4-acetoxy p-lactam from 12:162 by asymmetric aldol reaction 12:162 by asymmetric hydrogenation 12:162 of P-keto amide 12:162 of a,P-unsaturated imide 12:162 oxidation of 12:162 withperacids 12:162 Unsymmetrical chiral biaryls 20:410 Unsymmetrical onoceranoid triterpene synthesis of 1:543 Unsymmetrical pyrazines 18:887-892 ()-Upial from Dysideafragilis 6:65 synthesis of 6:65,66 (-)-Upial by haloform reaction 6:66,67 by intramolecular aldol cyclization 6:66,67 from (-)-carvone 6:66,67 synthesis of 6:66,67 14-e/7/-Upial by Knoevenagel condensation 6:67,68 byvinylation 6:67,68 by Wittig reaction 6:68 synthesis of 6:67,68 Uranium (IV) hexafluoroacetylacetonate 8:466,467 UrapualideA 5:396,397 UrapualideB 5:396 Urdamycin A antifimgal activity of 11:134

1223

antitumor activity of 11:134 from Streptomyces fradie 11:134 Urdamycin B urdamycinone B from 11:134 Urdamycin E 5:596;11:134 Urdamycin G 11:134 (+)-Urdamycinone B fromZ-rhamnal 11:142-144 from urdamycin B 11:134 synthesis of 11:134,135,142-144 Urdamycins 5:596;11:134 Uredinales 9:203 Urediniomycetes 9:202,203 Uredospores bioassay of 9:220-222 Urethane cyclization of 14:566,567 Uridine diphosphate A^-acetylglucosamine 1:399 Uridine diphosphate-galactose (UDP-gal) synthesis of 10:468 Urogen III synthesis 9:592-597,604 Urogens I-IV 9:591,592,596,598,600,602-605,607 Uromyces phaseoli 9:220 Uronate 14:180 Uronicacid 7:156 Uronolactones 14:192 Uroporphyrmogens 9:607 Ursolic acid 2:129,7:189;9:293,295,402 from Eremophila caerulea 15:281 Urushiols (catechols) 9:318,325,328,329,331,334,338, 352-354,356,358-360,:364 from anacardic acid 9:341 ()-Ushinsunine 16:511 Usnea rubescens 5:310 Usneasxi. 5:311,313 Usnic acid 9:387 Ustilaginales 9:203 Ustilago s^QziQS 9:203 Ustillaginomycetes 9:202,203 Utilin 9:96 X-ray crystal structure of 9:95 UV spectroscopy of indole alkaloids 9:164,173 Uvaol 9:293,20:6,17 Uvaria accuminata 17:251 uvaricinfrom 18:193 Uvaria narum isodencetyl uvaricin from 18:221 Uvaricin 17:271 from Uvaria acuminata 18:193 Vachanic acid (illicic acid) 7:212,236 Vadrikine 9:193 Vaginatin 5:724,725,728 Valence isomerization photochemical 1:189 (+)-Valencene (+)-nooktatone from 13:300 Valepotriates from Valeriana officinalis 13:660 -Valeraldehyde 19:484

Valerian 13:660 Valeriana officinalis monoterpene alkaloids from 6:524 Y-Valerolactone 18:198 Validamine from Streptomyces hygroscipieus subsp. limoneus 10:518 porcine intestinal disaccharidases 10:518 yeast a-glucosidase inhibitor of 10:518 Validamine 13:189,195,225 synthesis of 13:190 Validamycin as a-glucosidase inhibitors 7:47 Validamycin A from Streptomyces species 13:189 synthesis of 13:228-231 Validamycin B 13:195,223,224 synthesis of 13:231,232 Validamycin G 13:195,223,224 Validamycins A-H 13:223,235 synthesis of 13:228-232 Validone 13:195 Validoxylamin A 7:46;13:195,223-228 Validoxylamines B,G 13:224-228 Valienamine 13:189,195,198 a-glucosidase inhibitors of 7:46;10:518 by [2,3]-sigmatropic shift 10:523 from Streptomyces hygroscopicus subsp. limoneus 10:518 from L-quebrachitol 13:199 porcine intestinal disaccharidases 10:518 stereoselective synthesis of 10:521,522 synthesis of 10:507;13:199 valiolamme from 13:201 yeast a-glucosidase inhibitor of 10:518 (3SARy [4-^Hi, 4-^Hi]Valine 11:211 Valine synthesis of 11:418,419 L-[U-C^^] Valine 15:347 5-Valinol 10:406 /-Valinol 10:406 (5)-Valinol 20:436 Valinomycin 10:256 Valiolamine 13:189,195 from valienamine 13:201 porcine mtestinal disaccharides 10:518 synthesis of 13:201 yeast a-glucosidase inhibitor of 10:518 Valoneanic acid 20:272 Vallapin 7:185,187 Vallartanone A 17:26 Vallartanone B 17:26 ()-Vallesamidine 18:318 19,20-Z-Vallesamine 5:137,138 ^^C-NMR spectrum of 5:137,138 H - N M R spectrum of 5:137,138 COSY-45 spectrum of 5:138 IR spectrum of 5:137 mass spectrum of 5:137 UV spectrum of 5:137 Vallesamine 5:87,88,123,135;6:504;9:171-173

1224

Vallesiachotaman-type alkaloids 5:71,84 isovallesiachotamine 5:85 vallesiachotamine 5:85 Vallesiachotamine 1:89,90;2:375 synthetic derivatives 1:91 -94 Vallesiachotamine 5:127 Vallesiachotamine lactones 1:95-98 Valsa ceratosperma 5-methylmellein from 15:385 Valtrate 7:441 Vanadium (V) compounds 20:305 Vancomycenic acid 20:283 Vancomycins 20:283,20:296 VandeWalle approach in p-dictyopterol synthesis 6:16 in dictyopterone synthesis 6:16 Van Deemter curve 9:458 Van der Waals effects 17:556,558 Vancomycin 10:629,630,657-660 synthesis of 10:661-669 Vandewalle (iridoids) 8:139 Vandrikidine 9:193 o-Vanillin allylationof 4:21 Vanillin 7:88,457;8:309;9:457;13:337,338,362,363 VaramineA,B 10:243,244 Vasicine 5:751,752 from vicinal tricarbonyl 8:274 Vasicinol 5:752 Vasicinone 5:752 Vaucheriaxanthin 6:135,136 Veatchine synthesis of 3:435 Vedejs reagent 11:80,81 Velbanamine 14:810,862,863 from 1-glutamic acid 14:866-867 synthesis of 14:810,865-869 \ia thio-Claisen rearrangement 14:865 Velbanamine 5:124 14,20/?Vellosimine 13:386,403 Vellozia Candida rosane diterpenoids of 20:474 Velocitermes velox 14:451,452 (+)-intermedeol from 14:451,452 Velutin 7:228 Venom gland alkaloids 6:422-465 Venoterpine 6:527 Venustatriol 5:361-363 biogenesis of 5:363 Vepridimerine A biosynthesis of 2:122-124 structure of 2:121 synthetic approaches to 2:125-128 total synthesis of 2:127,128 Vepridimerine B biosynthesis of 2:122,123 structure of 2:121 synthetic approaches to 2:125-128 total synthesis of 2:127,128 Vepridimerine C biosynthesis of 2:123,124 structure of 2:122

synthetic approaches to 2:125-128 total synthesis of 2:127,128 Vepridimerine E 2:128 Vepridimerines 2:121-128 Veprislousii 2:121 Veprisimmerines AC and E biosynthesis of 2:123 Veprisine dimerization of 2:121,122 thermolysis of 2:127,128 Veratraldehyde (3,4-dimethoxyphenyl) methyl ketone from 6:334 Veratrate ofepoxyjaeschkeanodiol 5:725,726 of lancerotol 5:725,726 rem/z-M/w alkaloids 7:16,20-22 Veratrum califormicum steroidal alkaloids from 7:16 Verbenaceae 7:408,417,423,427 Verbenalin 7:349,476,490 (+)-Verbenone 15:227;16:242 from Eremophila dempsteri 15:227 Verbesina rupestris 16:131 Vergatic acid from Salvia limbata 20:702 Verlotorm 7:231 Vermeerin 20:10 Vermeersiekate 20:10 Vemolepin synthesis of 4:584,585 Vernonia galpinii 5:728 Verongia species 10:632 Verongia spengelii 5:410 Verrucarinolactone synthesis of 3:252-259 Verrucarol 6:225,227,237,241 2,13-deoxygenationof 6:234 Claisen rearrangement by 10:426-428 synthesis of 10:426-428 (+)-Verrucosidin 10:439 Verrucosin A-B 17:15 Versicoside A (forbeside A) 7:288,293;15:47 Versicosides A-C 7:293 from Arterias amurensis versicolor 7:2S1 Verticelline 11:25-28 synthesis of 11:26-28 Verticillane 18:607 Verticillene synthesis of 12:182,183 Verticillol 11:28,12:181 from Seidopitys verticillata 20:107 (-)-Vertinolide synthesis of 16:700 Vesicant activity 1:365 Vespa orientalis 4:494,19:133 Vespidae 6:421 Vetiver oil sesquiterpene 15:273 (-)-a-Vetivone 16:267 Vibrio cholerae 4:195 Vibrio ordalii tetraheptoses in 4:195 Vibumium dilatatum 4:712

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Viburtinal 7:458,459 from Viburnum tinus 16:302 from Viburnum opulus 16:302 Vicenin 7:228 Vicinal oxyamination reaction 11:61 1,2,3-Vicinal tricarbonyl unit synthesis of 8:261-274 Viciafabah. 19:247 Vicinal tricarbonyls 8:261-274 Vigna radiata 23-(9-P-Z)-glucopyranosyl brassinolide from 18:522 Villamine 13:396,397 Villastonine 13:383,392,397,404,429 synthesis of 13:405 X-ray analysis of 13:399 Villastonine A^-4 oxide 13:392 Vilsmeier reaction 6:322 Vilsmeier formylation 1:507,508;18:233 Vinamidine 2:389,390,398 Vinblastine 2:370,372,287,389,390;4:29;8:283;12:179; 13:633;14:805-884;19:748;20:458 3'-oxovinblastine from 14:813 anticancer activity of 14:805 Atta-ur-Rahman's synthesis of 14:850-859 biosynthesis of 4:31 Buchi's synthesis of 14:868,869 deacetylvindoline from 14:862,863 first synthesis of 4:32 from anhydrovinblastine 14:820,821,871 from catharanthine 14:854-858 from Catharanthus roseus 8:283;14:805 from leurosine 14:860 Gorman's synthesis of 14:862-864 Kuehne's synthesis of 14:831-849 Kutney's synthesis of 14:806-821 Magnus's synthesis of 14:821-830 Potier's synthesis of 14:869-873 Schill's synthesis of 14:861,862 synthesis of 5:185-187 synthetic approaches to 14:805-884 Takano's synthesis of 14:865-867 velbanamine from 14:862,863 Vinca major elegantissima 1:124 Vinca minor 2:370 (-)-ebumamonine from 8:283 (+)-vineamine from 8:283 Vincadiffme 5:125 Vincadifformine 2:370;19:101-102,115 derivatives of 19:115 enantioselective synthesis of 4:40,41 from Vinca difformis 19:90 preparation of 19:101 synthesis of 14:635,636 total synthesis of 19:93 transformation of 19:89 ^'-Vincadifformine 14:833,19:92 from Panadaca caducifolia 19:90 (-)-Vincadifformine conversion to vindoline analogues 4:35 (+)-Vincadifformine 5:124

(-)-Vincadifformine 5:126 20/?-pseudovincadifformine 5:123 205'-pseudovincadifformine 5:125 Vincadifformine-type alkaloids (-)-vincadifformine 5:92 (+)-3-oxo-minovincine 5:92 (+)-demethylaspidospermine 5:92 (+)-minovincine 5:92 (+)-vincadifformine 5:90,92 10-hydroxy-l 1-methoxytabersonine 5:93 12-demethoxycylindrocarpidine 5:92 12-hydroxyvincadifformine 5:92 14,15-dihydroxyvincadifformine 5:92 5-oxo-cyclindrocarpidine 5:93 apodine 5:92 apodinine 5:93 cylindrocarpidine 5:93 desoxoapodine 5:92 haxuntine 5:93 hazuntinine 5:93 homocylindrocarpidine 5:93 lochnericine 5:92 mehranine 5:90,92 O-demethylpalosine 5:92 tabersonine 5:92 Vincadine synthesis of 14:635,636 Vincaleukoblastine 13:634 Vincamajine 9:183 Vincamine 2:370;8:283,292,13:660;19:89 from Vinca minor 8:283;13:660 synthesis of 1:117,118;5:187,189,190;14:635,636 ()-Vincamine from Oppolzer's aldehyde 14:726 synthesis of 14:726 16-^/7/-Vincamine 2:370 (+)-Vincamine 5:127 (+)-16-ep/-Vincamine 5:127 (+)-21 -ep/-Vincamine 5:127 (-)-Vincamine 5:127 (-)-16-ep/-Vincamine 5:127 (-)-21 -e/7/-Vincamine 5:127 Vincamine-ebumamine type alkaloids 10:411 Vincamine-related alkaloids synthesis of 8:266 Vincamine-type alkaloids 5:107,108 Vincaminoreine synthesis of 14:635,636 Vmcaminorine synthesis of 14:635,636 Vincamone 19:90 Vincanicine 1:36;9:193 Vincanidine 1:36;5:126 Vmcarpine 1:124 Vincomycins B2 5:594,595 Vincosan-type akaloids 5:71 (-)-vincamine 5:108 (+)-14,15-dehydro-16-ep/-vincamine 5:108 (+)-16-e/7/-vincamine 5:108 (+)-apovincamine 5:107,108 (+)-vincamine 5:108 14,15-dehydro-12-methoxyvincamine 5:108

1226

vincamine 5:108 Vincovaline enantioselective synthesis of 14:840-846 Vincristine 2:390,398;9:387;11:5,12:396;13:633; 20:458 anticancer activity of 14:805 Atta-ur-Rahman's first synthesis of 14:850-859 biosynthesis of 4:31 Buchi's synthesis of 14:868,869 first synthesis of 4:32 from catharanthine 14:854-858 from Catharanthus roseus 8:283;14:805 Gorman's synthesis of 14:862-864 Kuehne's synthesis of 14:831-849 Kutney's synthesis of 14:805-821 Magnus's synthesis of 14:821-830 A^-demethyl deacetylvmdoline from 14:862,863 Potier's synthesis of 14:869-873 Schill's synthesis of 14:861,862 synthetic approaches to 14:805-884 synthesis of 5:187-189 Takano's synthesis of 14:865-867 velbanamine from 14:862,863 19-ep/-Vindoline 2:375 Vindoline 2:370,371,373,375,390,392,398,399,400, 401,402;5:185;14:806-884 conversion to 16'-decarbomethoxy-20'-deoxy vinblastine 4:30,31 coupling with 16-hydroxydihydrocleavamine 4:30,31 coupling with catharanthine 4:32 enantiosynthesis of 4:38,39 in biosynthesis of vinblastine 4:31 synthesis of 4:55 Vindoline analogues synthesis of 4:29-81 Vindoline-A'-methylamide from 15,205'-dihydrocatharanthine N-oxide 14:870,871 Vindolinine 2:377;9:183,186 Vindorosine synthesis of 4:34,55 VmeomycinAl 5:594,595 from Streptomyces matensis subsp. vineus 5:593 Vineomycin Ai antibacterial 11:113 antitumour 11:113 from Streptomyces matensis 11:113 Vineomycin B2 synthesis of 10:370 Vineomycin B2 methyl ester 11:140 Vinervine 1:35 Vinervinine 1:35 8-Viniferin antifungal agent 16:565 synthesis of 16:565 Vinlogous phenylseleno etherification 12:11,12,25 Vinorine 13:400,402 Vinoxine total synthesis of 1:62

Vinrosidine synthesis of 14:857,859 Vinyl acetate reaction with methyl lithium 1:562,563 Vinyl azides preparation of 1:165 Vmyl carbanions nucleophilic addition with 11:440,441 Vinyl cuprate addition 3:189,190,195,196 Vinyl ether 14:487,488 from(35,55)-2,6-dimethyl-3,5-heptanediol 14:487,488 from (2i?,4^)-2,4-pentanediol 14:487,488 Vinyl iodide 12:48-53 from D-glucose 12:37,38 from l,2,5,6-Di-0-isopropylideneZ)-glucose 12:41 fromD-ribose 12:50 Vinyl palladation of 4-cyclopentene-1,3 -diols 16:371 Vinyl radical cyclization 12:24 Vinyl stannane synthesis of 1:490 from tributyltin/acetylene 1:490 Vinyl sulfoxides cyclization of 10:673-676 Vinyl sulfoximines 10:679 cyclization of 10:679 Vinyl tricarbonyl hydrate 8:267-272 Vinylaziridine cleavage of 3:50 Vinyl carbene 3:27 Vinylacetyl chloride condensation of 14:453,454 with 9-chloro-l-/7-menthene 14:453,454 Vinylallenes 4:522 sigmatropic rearrangement 4:522 Vinylation in 7,20-diisocyanoadociane synthesis 6:86,87 in 14-e/7/-upial synthesis 6:67,68 of olefins 16:416 Vinylaziridination 3:55 [2+3] 3:55 [4+1] 3:55 Vinylcyclobutane rearrangement of 3:465,466 Vinylcyclopropane isomerization 3:15 Vinylcyclopropane-cyclopentene rearrangement 3:38,44,47 Vinylcyclopropanes from 1,4-dienes 3:34-36 pyrolysis of 3:34 via ally lie SN^ process 3:47 Vinylcyclopropylcarbene 14:627 Vinylic anions inversion of 4:497 Vinylic ethers hydroboration 4:116 Vinylic sulfoxides for synthesis of esterone 4:501,502 for synthesis of vitamin E 4:494-501

1227

Vinylketene acetals asymmetric Diels-Alder reaction of 14:503,504 Vinylnitrene cyclization 1:178-180 Vinylogous amide susbtrates 18:376,386 Vinylogous carbamate substrates 18:344,377 Vinylogous urea substrates 18:363 Vinyloxetane 10:588,589 Vinyloxiranes synthesis of dihydrofurans 3:55-58 Vinyloxyborane-imine reaction 4:465,466 carbapenem precursors by 4:469 stereochemistry of 4:467,468 Vinylpicoline 14:437,438 bis-annelating agent 14:437,438 Violaxanthin 20:575,727 Viologen oxidoreductase 20:840,858 Vinylpyridine 14:438 Vinylsilane AICI3 catalyzed Friedel-Crafts acylation 8:242 synthesis of 8:242 Vinylsilane-medicated bicyclization 13:615 Violanin 5:646 Violoxanthin 7:98 Viral adhesion 16:113 Vh-al sialidase 16:112 Virginiamycin 5:606 Vu-idifloric acid enantioselective synthesis of 1:260,261 Viridiflorine synthesis of 1:267 Virola elongata 17:319 Virola sebifera 18:726 Virustatic pharmaceuticals 17:421 Viscidulinl 5:678 Viscidulin A-C 7:236 Visconolides 20:180 Vismia decipiens 4:378 Vismiaphenone A 378,379 Vismiaphenone B 4:378,379 Vismione D antimalarial activity of 7:424 antiproliferative activity of 7:419 Vismione F 7:419 Vismiones 7:418,419 Vitamin A 7:114,9:412,413;20:569,570,605,720, 748,750 by diene synthesis 6:308 synthetic approaches to 4:526-531 Vitamin B-12 intermediates 4:674-677 Vitamin B12 synthesis 16:150 Vitamin B12 evolutionary aspects of 9:591-609 mechanistic aspects of 9:591-609 Vitamins C 20:34 Vitamin D stereoselective synthesis of 10:43-75 Vitamin D 9:509-511,515 synthesis of 4:522;11:379-408 semi-synthesis of 17:621 Vitamin D aldehyde synthesis of 10:52

Vitamin D metabolites stereoselective synthesis of 14:471 Vitamin D receptors 9:512 Vitamin D2 10:43,63,64;11:381 Vitamin D2 (ergocalciferol) 9:510,513,521,522,524 Vitamin D3 11:380 degradation of 4:523 fluorinated analogs of 9:517 metabolism of 9:514,521 total synthesis of 9:510 X-ray crystal analysis of 9:510 Vitamins E 4:494-501,9:580,20:34 Vitamins E and K synthesis of 14:478,479 Vitamin L2 6:351 Vitamins 2:366,367 semi-synthesis of 17:620,640 (+)-Vitemal 16:257 (-)-Vitrenal 16:260 Vitisvinifera 20:721,723,724,731 Vittatine 20:352,20:356 Viverra civetta 8:219 Vilsmeier's reagent 9:422-424 V0-(acac)2-TBHP 10:39,40 epoxidation with 10:39,40 of allylic alcohols 10:39,40 Voabasine 5:112 Voabasine-type alkaloids 10-hydroxy-16-e/7/-affmine 5:77 16-ep/-affmine 5:75,77 16-e/7/-vobasinic acid 5:77 3-(2-aminoethylthio) desoxovobasine (pagisulfme) 5:78 accedme 5:77 affinine 5:75,77 anhydrovobasindiol 5:77 dregamine 5:75,77 dregaminol 5:77 dregaminol-methylether 5:78 A^i -demethy 1-16-rp/-accedine 5:77 A^i-methyl-16-ep/-affinine 5:77 pagicerine 5:78 pagisulfine 5:75 perivine 5:75,77 tabemaemontanine 5:75,77 tabemaemontaninol 5:75,77 vincadiffme 5:78 voacarpine 5:75,77 vobasinol 5:75,77 Voacamidine 5:129 Voacamine 5:113,125 Voacamine-A'^Voxide 5:129 19-e/7/-Voacangarine 9:174 Voacangine 5:99,127,174 Voacangine hydroxyindolenine 5:100,128 16-e/7/-Voacarpine 15:466,467 from Gelsemium elegans 15:469 Voacarpine 5:127 Voachalotine 5:75,127,179 Voacorine 5:123 19-ep/-Voacorine 5:129

1228

Voacristine 5:127 hydroxindolenine 5:101 19-e/7/-Voacristine 5:128,130 Voacristine hydroxyindolenine 5:128 Voacristine pseudoindoxy 1 5:128 Voaphylline 5:124,172 Voaphylline hydroxyindolenine 5:126 Voaphylline-14,15-diol-19-hydroxy 5:126 Voaphylline-14/?,155'-diol 5:124 Voaphylline-type alkaloids 5:90 Voaphylloine 9:171 Vobasine 9:181,182,503 16-ep/-Vobasinic acid 5:127 Vobasinol 5:111,123,171 Vobparicine 5:123 Vobparicine-A'4-oxide 5:123 Vobtusine 5:124 Volume of activation in Diels-Alder reaction 4:112 Volvariella volvacea 5:287,288,290,316,320 Vomifoline (peraksine) 13:389 Vomitoxin (desoxynivalenol) 9:204-207,215,216 Von Braim degradation 18:51 VPC coinjection experiments 14:684 Vulgarin 7:233 Vulgarol 7:209 from Artemisia vulgaris 7:208 (-)-Vulgarolide 18:19,20 Vulgarone B (1-oxo-a-longipinene) 9:534 Vulgaxanthine I,II 20:725 Vulvovaginitis 2:422

"W" arrangement 14:742 Wachendorfia 17:372 Wacker oxidation 10:308,309,316;13:494;14:560,561, 584;16:481;18:633,273,283;19:29 in ()-brasilenol synthesis 6:7 Wacker process 11:238,241,246,16:85 Wadsworth-Emmons chain extension 13:596 Wadsworth-Emmons condensation 1:52,60,13:573 Wadsworth-Emmons reaction 1:176,177;7:480;11:89; 12:328;16:349;18:897 intramolecular 11:108 Wadsworth-Emmons-Homer reduction 20:450 Wadsworth-Homer-Emmons reaction 1:401,402 Wagner- Meerwein rearrangement 4:38,39,626628,633,634,637,643;6:181,149,52;12:245,37,356,363 -368,131,147,236,248 of end-6-silyloxy-isobomeol 16:147 of (+)-isoepicmpherenol 16:131 1,2-Wagner-Meerweinshift 18:882 Waixenicin-A 5:370 Wallenberg's procedure 6:298,299 warburganal 6:108 WALTZ sequence 15:205 Warbugia stuhlmannii 17:234 Warbugia ugandensis 17:234 (-)-Warburganal antifeedant properties 14:413-421 by Swem oxidation 4:418,425 from (+)-confertifolin 4:418 from 1-abietic acid 4:416

frommanool 4:418,420,424,425 from Warburgia stuhlmanii 4:403 from Warburgia ugandensis 4:403 synthesis of 4:403,416-418,424;14:413-421 Warburganol 2:288 Warburgia stuhlmanii 4:403,427 Warburgia ugandensis 4:403,427 Warren procedure 3:257 Wartski imine Diels-Alder reaction 16:458 Wasmannia auropunctata 5:224,229 Water-soluble materials 17:481 Watt synthesis oftaxodione 14:678-681 Wax esters 9:452,455,463,470 Webiol angelate of 5:725,727 Wedelia asperrima 20:8 Wedelia glauca 20:8 Wedelia scaberrima I'All Wedeloside 20:8 Weiler's reaction 11:115 WeisiensinA 15:112,120 '^C-nmrof 15:134 from Rabdosia calcicolus 15:171 from Rabdosia nervosa 15:173 from Rabdosia weisiensis 15:175 H-nmrof 15:127 Weiss - Cook condensation 3:23,24 Weiss reaction 18:286 Welch procedure demethoxycarbonylation by 10:308,309 Welch synthesis ofisozonarol 6:17 ofzonarol 6:17 Wender synthesis of7-methoxymitosene 13:445,446 Wender's [4+4] cycloaddition strategy 12:189 Wenkert's enamine 1:113 synthesis of 14:727 Wenkert-type enamine 8:284,285 Wessley-Moser rearrangement 2:133,665 Western blotting analysis 15:449 Wharton reaction 10:47 Wharton rearrangement 10:36,37 (-ytrans-Whisky lactone from levoglucosenone 14:272,273 synthesis of 14:272,273 (+)-rra5-Whisky lactone 19:152 Whisky lactones 13:328 synthesis of 3:169 Whistler method 6:367 White synthesis of avermectin Bia aglycone 12:15,27,28 Wieland-Gumlich aldehyde 9:183 Wieland-Gumlich diol 1:38,39 Wieland-Miescher ketone endesmanes from 6:18,19 endesmanolides from 6:18 synthesis of 6:18,19 (+)-Wieland-Miescher ketone 10:409 Wieland-Miescher ketone 11:16-18,50,51,53;17:608,29 absolute configuration of 17:53

1229

Wierenga intramolecular alkylative closure 3:325,326 Wihtacinstin 20:246 Wihtangulatin A 20:246 Wiesnerella denudata 2:280 Wilcoxontest 2:434 Wildman procedure 4:19,22 Wilfordin 18:772 from Maytenus rigida 18:771 Wilkinson catalyst 6:10,11;9:459,474;10:39;11:354, 363;12:8,35,37,38,40,50,267,311;13:564;18:207; 19:500 for decarbonylation 16:340,345,350 Wilkinson complex decarbonylation with 11:363 Willgerodt reaction 14:681,682 Williams approach for avermectin oxahydrindene subunit 12:28-30 Williams enantioselective synthesis of(-)-zonarene 6:15 Williamson ether synthesis 6:386 Wilson synthesis 10:48 Winstein spirocyclization 3:325 Winterfeldt synthesis of K252c (staurosporinone) 12:381 Wiothanicandrin 20:242 Wistariasaponin Bi 15:206 Wistarin from Ircinia wistarii 6:8 Withaferin A 20:138,180,194,204,214,215,220,234,245 Withaferoxolide 20:221,223 Withania coagulans 20:238 Withania somnifera 20:13 8,180,181,234,238,241,246, 247 Withanicandrin 20:182,223,224 Withanolide 19:463,470 antitumor activity of 19:470 biological activities of 19:470 insect antifeedant properties of 19:470 novel structure of 19:470 Withanolide D 20:180 Withanolide E 20:204,214,220,221,245,246 Withanolide G 20:139 Withanolide glycosides 20:191 Withanolide M 20:180,242 Withanolide Q 20:180,20:241 Withanolide R 20:180.241 Withanolide S 20:245 Withanolide Y 20:180 Withanone 20:220 Withaperuvin F 20:181 Withaphysalins 20:241 Withaphysalins A from Physalis minima 20:189 Withaphysalins B from Physalis minima 20:189 Withaphysalins C from Physalis minima 20:189 Witharingia cocculoides epidihydrophysalm from 20:189 epidihydrophysalin C from 20:247 Withasomniferol 20:181

Withasomnine synthesis of 1:343 Witkop photocyclization 1:52 Wittig condensation 3:462;12:281;13:620;14:112; 19:59;20:582 of olefin 5:708 in ()-sinularene synthesis 6:85 Wittig coupling 10:9,15,13:617 in 7,20-diisocyanoadociane synthesis 6:86,87 Wittig homologation 3:268,269;11:100,101;18:196,216 Wittig methylenation 6:185,165;19:42;18:177 Wittig olefination 1:460,461,473,487,488;4:252,123, 163,164,169,176,279,280,285,286;8:413;10:429; 12:327,330;13:604;14:129,132,460,461;16:377,378,38 8,484,18:8;19:22;137 for fiised lactone nucleoside synthesis 4:254 in ()-precapnelladiene synthesis 6:39 in ()-stoechospermol synthesis 6:39 in nakafiiran-9 synthesis 6:70 in nine-carbon sugars synthesis 4:180 of amino aldehyde 16:490 of D-galacto-hexodialdopyranose 4:163,4:164 of Z)-lyxo-pentodialdofiiranoside 4:176 of heptodialdopyranose derivative 4:180,181 of hexodialdopyranoside derivative 4:169 of pentodialdofiiranose 4:190 of r-butyl 2-C-methy 1-2,3,4,7-tetradeoxyhept-6ulopyranoside 10:414 with A^-pentylidene triphenylphosphorane 5:822 Z-selective 4:125 Wittig reaction 1:221,399,400,447,448,531,533,535, 538;3:258,288,488,4:126,150,175,202,553-578; 5:828;6:16-19,21,61,68,125,157,158,225,226,269, 279,281,285,286,301,302,425,558,559;8:46,146,147,1 61-164,223,224;9:351,352,354,356,358,360,362; 10:48,55,68,166,308,309,389-392,510;11:367; 12:319,321,350,488;13:32,35,37,125,141,175,200,208 ,482,508,594;16:4,39,60,85,248,352,702;18:178,233,2 34,255,256,288,297,618;19:10,20,43,72,267,367,373, 396495;20:563,566,567,571,572,578,584,586592,594,599,601,602,606,759 C-glycosides by 3:218-220 hydroxyl directed 1:406,407 intramolecular 4:573,575 iodide 14:556,557 of aldehyde 8:163,164,223,224,19:495 ofglutarimide 14:560 of ketone 8:162 of pyrrolidme derivative 14:556,557 stereoselective 12:12 stereoselectivity 4:175 unstabilized 1:406,407 with Corey reagent 19:452 with ethyl (triphenylphosphoranylidene) acetate 14:553,554 with formyulmethylene triphenylphosphorane 1:535,536,538 with glutaric dialdehyde 14:560 with heptylidene triphenylphosphorane 5:828 with hexylidenetriphenylphosphorane 19:495 with methyl triphenyl phosphonium with sugars 3:218-220

1230

Wittig reagent 4:126;158;11:78;6:71,72;10:63,16:64; 19:57 conformational models 3:248,252 in lactone synthesis 3:252,255 in synthesis of higher-carbon sugars 4:158 ofsecondaryallylic ethers 3:249 of tertiary allylic ethers 3:251 of zirconium enolates 3:241 of a-allyloxy anions 3:248-250 stereochemical induction 3:248-252 [2,3]Wittig ring contraction 10:34-42 by chiral amide bases 10:31-33 [2,3]-Wittig sigmatropic rearrangement 10:61,62 Wittig ylide 6:181,183 Wittig-Homer condensation 11:159,298 Wittig-Homer cyclization intramolecular 12:292 Wittig-Homer homologation 18:333 Wittig-Homer olefmation 11:431 -43 5 Wittig-Homer reaction 4:602,603;7:484;10:673; 12:324,462;18:247,623;19:256 Wittig-Homer reagent 19:84 Wittig-methylenation ofl-mannose 10:413 Wolff rearrangement 19:18 ofdiazoketone 10:593-595 oxetane ring formation 10:592,593 Wolff ring contraction 6:178,179 Wolff-Kishner cyclization 1:58 Wolff-Kishner reaction Huang-Minion modification of 14:684 Wolff-Kishner reduction 2:235;4:416;6:6,17,509;8:164, 165;13:6,11,12,21-23,403;14:277,278,359,417,419, 452,453,728;15:231;19:135;18:35 Woodchuck hepatitis virus 20:535 Woodward reaction 19:363 Woodward reagent K 6:238,247,405 Woodward-Hofmann mle 2:128,3:401 Wortmannin 6:219,220 Wurmbea species synthesis of 6:158 Xanthophils 6:158 Wurtz coupling 9:344

X-ray analysis 5:474,478,488,494,508,509,750,754,755 carbonyl]-2- oxazolone 12:423 of()-isoconcinndiol 6:26 of(+)-aristoserratine 11:296 of(+)-aristoteline 11:278 of (+)-retigeranic acid A 13:22 of (22R23,R)-22,23-methyenecholesterol from 9:36,37 of 1,1,6,6-tetrachloro-3,4-diphenyl hexane 9:86,88 of 11 -bromoebenzoate 7:389 of l-A^-(-p-bromobenzoyl) mitomycin A 13:434 of 2,5-benzooxazonine derivatives 6:180,181 of 2,7-benzooxazacycloundecine 6:199 of 3-[( 15)-2-exo-methoxy ethoxy-1 -apocamphane of 5-deoxygoniopypyrone 9:394

of 7-/7-bromoanilino-7-demethoxy mitomycin B 13:434 of amphotericins 6:261 ofaureol 9:31 of cyclofriedo-oleanone 7:152 ofdidemnin-B 10:266-268 ofdiphosphaneadamantane 9:528 of erythromycin A 13:156 ofglocosporone 9:228 ofgonioflifurone 9:394 ofgoniopypyrone 9:394 of isomitomycin A 13:468 oflaurenene 13:19,20 of maytensifolic acid 7:152 of methylamine dehydrogenase 9:582 of mitomycin A,C 13:334 of mitomycins 13:334 of mitomycin C 13:334 of A^-acetyl muramic acid 6:387 of napoleogenin S 7:139 of netzahualcoyon 7:147 oforthosphenicacid 7:147 ofpacifigorgiol 9:254 of pfaffic acid 7:135 ofphaseolinone 6:555 ofplumbazeylanone 5:754,755 ofpseudobactin 9:539 ofreissantioloxide 5:750 of retigeranic acid B 13:25 of sigmosceptrellins-A-C 9:16 oftetraponerine-8 6:451 of thieno analogue 6:195 oftrichophylline 9:191 oftmnculins-A-S 9:20 oftubulosine 9:401 ofvillalstonine 13:399 of vitamin D3 9:510 X-Ray crystal stmcture ofascidiacyclamide 4:93 ofazadirachtin 9:94,103,105 ofcadlinolideA 9:7-9,272,283 ofcaudicifolin 9:288 ofchromodorolide A 9:4,5 of ent-13 [5]-hydroxyatis-16-ene-3,14-dione 9:272,273 ofpiperazinomycin 10:638 ofstaurosporine 12:367 ofutilin 9:3 ofzoanthaminone 9:10,11 X-ray crystal studies 15:213 brominated, nargenicine 17:296 of novel natural products 9:3-13 ofoxazoline 17:303 oftaxotere 12:225 ofurdamycinA 11:134 X-ray diffraction 6:196 Xanthate 1:452,453 formation 1:452,453 rearrangement to dithiocarbonate 1:452,453 Xanthoceras sorbifolia triterpenoids of 7:139,141 Xanthocidin 14:602,603,610

1231

Xantholignans 5:495,496 Xanthomonas campestris 5:314;12:401 Xanthomonas oryzae carboxylate against 12:398 Xanthones 5:495,595,705,706,759;7:410,411;17:436; 20:285 Claisen rearrangement of 4:368,370-372 from umbelliferone 4:385,386 derivative of 5:759 Xanthonoids 5:758 Xanthonolignans 5:5 Xanthoperyl methyl ether 14:673,674,676 Xanthophyceae 6:134 Xanthophylls 7:318,360 C4o-Xanthophylls 20:607 Xanthorrhizol 5:802,804 synthesis of 5:802 Xanthotoxin 9:402;10:153 from Limonia acidissima 20:497 Xanthoxyletin 2:118;9:288,289;20:497 Xenobiotic metabolites 7:103 Xanthurenic acid 19:649 Xenobiotics and cooxidation 9:582,583 Xenochemicals 18:680;18:680,681 Xenocoumacins 15:381-472 biological activities of 15:408-412 from Xenorhabdus nematophilus 15:389 introduction of 15:381,382 isolation of 15:388-392 structural studies of 15:392-408 Xenopus laevis 8:435 P-thymosin from 8:435 thymosin P4xen 8:435 Xenopus oocyte 15:451 Xenorhabdus nematophilus xenocoumacins from 15:389 Xenorhabdus s^^. 15:381 Xeromphis spinosa 1:427 XestinAB 18:718,719 Xestoquinol total synthesis of 17:62 CD and absolute stereochemistry of 17:66 Xestoquinone total synthesis of 17:62 CD and absolute stereochemistry of 17:66 Xestospongia exigua 15:312;17:33 Xestospongia sapra 15:312;17:33 Xestospongia sp. 5:350,353;18:718 (22/?,23/?)-22,23-methylenecholesterol from 9:37 XHCORRD 9:268,285 XindongninA 15:116 '^C-nmrof 15:130 from Rabdosia dawoensis 15:171 from Rabdosia rubescens 15:174 ^H-nmrof 15:123 XindongninB 15:119 ^^C-nmrof 15:133 from Rabdosia rubes cens 15:174 'H-nmrof 15:126 Xiphidium 17:372 XylanaseA 8:349,351 XylanaseB 8:349,351

Xylanases 8:336,349,351,352 Xylitol pentaacetate synthesis of 4:509 D-Xylo-hexofiiranose 6:365,367,372 Cs-P bond analogs of 6:365,367,372 Xylobiose 8:352 Xylocarpin 7:190,191 Xylocarpus grantum 7:190,191,195 Xylocarpus moluccensis 7:176,191,195 xylomollin from 7:185 Xylocarpus sp. 7:176 Xyloccensins A,B,D,F 7:191 D-Xylofiiranose C3-P bond analog of 6:359 C5-P bond analogs of 6:365-367,375 Xylomannans 5:290,294 Xylomollin 7:185 fjcom Xylocarpus moluccensis 7:185 Xylopinine 1:217,218 synthesis of 1:217,218 Xylopia aethiopica 20:484 oxoaporphines of 20:483 Xylopinine 3:435 synthesis of 3:433 D-Xylopyranosyl 15:7 D-Xylopyranoses synthesis of 6:366,367 3-0-P-Xylopyranosides 15:64 4-S-Z)-Xylopyranosyl -4-thio-Z)-xylose 8:336 D-Xylose 6:263,278 1,2-0-isopropylidene derivative from 6:269,270 L-Xylose 6:263,278 1,2-0-isopropylidene derivative from 6:269,270 D-Xylose 7:144,268,270,275,277,278,299 Xylose 7:71,72,181,270,272,273,275,292,293,299 Xylosidase 7:270 P-Xylosidase 7:58,70;8:352 from Bacillus pumilus 1'210 P-Z)-Xyloside permease 8:352 Xylosides synthesis of 8:362 Xylosyl chlorides 8:359-362 P-Xylosyl-( 1 ->3)-thioglucofiiranose thiodisaccharide 8:329

Yadanzioside A-G,I-L,N,0 7:378-379,392 Yadanziosides M,P 7:376 Yadanziosides-G,N 7:275,376 YADH 17:482 Yahazunol 15:297 Yakuchinone A and B 17:362 Yamada's synthesis 12:203 Yamaguchi method 11:154,157,158 Yamaguchi reagent 11:157 Yamamoto condensation ofpropargylic titanium reagent 12:2 regioselective 12:24 stereoselective 12:24 Yamayomogenin 7:236 Yarrowia lipolytica (Candida lipolytica) 13:308,312, 313

1232

Yashabushidiol A 17:359 Yashabushiketodiol 17:359 (-)-Yatein 18:557,566 Yatein 5:484-488 cw-Yatein 5:486 /ram:-Yatein 5:487 Ydiginicacid 14:101 Yeast alcohol dehydrogenase 17:482 Yeast reduction 1:482;13:560 Yeasts for asymmetric reduction 1:689 "Yellow pigment" 11:127-129 Yenhusomidine synthesis of 1:204,205 Yenhusomine 1:204,205 Yersinia 4:195 Yessotoxin 17:20 Ylides acylation of 4:554-556 Yohambinine 9:171 (-)-Yohimban 18:384 Yohimbane 2:173,357,377;5:74,127;11:302,303; 14:751,765 synthesis of 3:406,407 (-)-a//o-Yohimbane from levoglucosenone 14:267,277,278 synthesis of 14:267,277,278 Yohimbanoid alkaloids 10:688 Yohimbine 2:375,377;8:395 from Corynanthe yohimbe 8:283 lead tetraacetate oxidation 1:158 oxidation of ring C 1:158 synthesis of 3:407-410 (+)-Yohimbine enantioselective synthesis of 14:566,567 from piperdine derivative 14:566,567 Yohimbine precursor synthesis of 3:435 Yohimbine-type alkaloids 5:73,74 Yohimbines 3:399,403 Yomogi alcohol 9:530 Yomogiartemin 7:236 Yomogin 7:233 Yu-Lin-Wu synthesis of()-polygodial 6:14 (-)-polygodial 6:14 Yuanhuacine 13:660 Yunganosides 15:297

(Z)-zinc (II) enolate 12:166 Z-Diene 16:4 Z-Enediones 16:648 Z-Enolate 16:661 Zaitev reaction 1:318,517,518 (-)-3-e/>/-Zaluzanin 14:365 (+)-Zaluzanin C synthesis of 14:366,367 (+)-Zaluzanin D 14:366 Zamthaxylum americanum 9:402 Zanthoxylum ailanthoides 10:152 ZeamaysL. 19:247

Zearalenols 13:536-543 Zearalenone 6:213,214;9:203,204,206 synthesis of 13:536-543 Zearalenone glycoside 13:539 Zearalenone-4-sulfate 13:539 Zeatin 4:227 (3/?,3/?')-Zeaxanthin 6:136,149 Zeaxanthin 7:320,330,336,343,349,351,358,363 '^C-NMR of 7:342,345,346 'H-NMR of 7:347,348 absolute configuration of 7:360 C-3 hydroxylation of 7:359-361 from Physalis alkekengi 7:360 Zeaxanthin (p,P-carotene-3,3'-diol) allenic carotenoids from 6:139 m biosynthesis 6:139 Zeaxanthin 20:573 Zelus leucogrammus 2:299,301 Zemple'n conditions 6:409 Zemple'n O-deacetylation 6:412 Zemple'n reaction 6:411 Zemplen de-0-acetylation 12:348 Zincke'ssalt 19:38 Zeralenone 8:176,177 from o)-iodoalkyl-2-phenylthiomethyl-4,6dimethoxybenzoate synthesis of 8:176,177 Zevxis siquizorensis 18:724 Zeylandiol 5:744,746;7:147,148 Zeylanol 5:744,745;7:147,148 Zeylanone 2:212-215;5:754,755 Zeylanonol 5:744-747;7:147,148 Zeylasterone 5:744-747;7:147-150 Zeylasterone-2,3-dimethyl ehter 18:765 Zimmerman-Traxler transition state 4:445 Zinc (II) iodide 12:164 Zinc borohydride reduction with 1:261 ;4:348 Zinc bound alkoxide 17:481 Zinc clathridine 17:18 Zinc mediated coupling 1:264;265 Zinc-copper couple in deoxygenation 4:424 in reductive elimination 4:165 Zinc-dust 12:166 in deoxygenation 4:424 Zincophorin synthesis of 3:276,277 Zinc (II) chloride 1,4-dehydro-P-lactam from 12:172,173 with 4-acetoxy-p-lactam 12:172,173 Zingerone 9:321 Zingiber officinale 9:321 ;17:365 sesquiterpene from 8:52 Zingiber officinarum 17:378 Zingiber species 17:365 Zingiberaceae 9:321 ;17:358,362,364,377,379 (-)-Zingiberene from i?-(+)-citronellal 8:45 synthesis of 8:45 Zinnolide 4:598 Zinziber cassumar 17:365

1233
Zinziber officinale 17:365 Zirconium (IV) enolate 12:168 Zirconium derivatives 9:453 as fluorescence-inducing reagent 9:453 Zirconium enolate of phenylthio ester 13:506 Zirconium enolates 3:249 [2,3]-Wittig rearrangement of 3:249 Zizaane sesquiterpenoids 16:125 g/-Zizaenes 15:251 Zizaenes 15:273 Zizane 15:227 (+)-Zizanoic acid 4:674 (-)-2-gp/-Zizanoic acid 4:674 (+)-Zizanoic acid 8:425 Ziziphin 18:671 Ziziphus jujuba 15:36,18:671 Ziziphus mauritiana 20:507 Zoapatline isolation of 19:389 Zoanthaminone biogensisof 9:10 X-ray crystal structure of 9:10,11 Zoanthid 9:10 Zoapatanol total synthesis of 10:210 Zoapatline isolation of 19:389 (-)-Zonarene by transannular ene cyclisation 6:15 from Dictyopteris zonaroides 6:15 from (-)-piperitone 6:15 synthesis of 6:15,16 Williams enantioselective synthesis of 6:15 Zonaricacid 15:297 Zonarii 17:198 Zonarol 6:18;15:296,320 from Dictyopteris undulata 6:17 Rau synthesis of 6:17 synthesis of 6:17,18 Welch synthesis of 6:17 Zonarol 9:40 Zonarone 15:296 Zonotrichia leucophyrys hemoglobin components of 5:837 Zoobotryon verticillatum 17:85 Zoogloea ramigera 1:689,690 Zooxanthellae 9:47 Zuurbergenin 7:236 Zwitterion 6:336 Zwitterionic anthocyanins 5:664 Zwitterionic aza-Claisen rearrangement 16:466 Zygomycetes 9:202,203;18:814 glycosphingolipids from 18:806 Zygomycotina 9:202 Zygophyldsides A,B 9:59,60 Zygophyllum propinquum saponins from 9:59-62 Zygosporin E synthesis of 13:146,147 Zygosporium masonii 15:356

1234

CUMULATIVE ORGANIC SYNTHESIS INDEX

VOLUMES 1-20
Abnormal Beckmann rearrangement 16:133 Abramov reaction 6:353 Acetalization 1:584 trans-Acetalization 4:325,326,331,338,339,495 Acetylation of 5y alcohol 19:480 p-Acetylation procedure for acetomycin synthesis 10:447 stereoselective 10:447 2-Acetylbutyrolactone 8:284,285 Acetylenation of acetals diastereoselective 1:611,612 Acetylenic oxy-Cope rearrangement 8:250 Acid-catalysed rearrangement 6:115 of (+)-endo-3-bromocamphore 16:147 of spiro cyclic lactone 16:225 Acylation ofhexaenal 6:264,267 selective 6:283,284 with A', A^-diisopropyIcarbamoy 1 chloride 10:15 intramolecular 16:18 with Cbz-L-alanine 16:18 with ethy Ichloroformate 16:19 Acyliminium ion cyclization 1:244;12:305,320,335 A^-Acyliminium ion-polyene cyclization 12:464 A^-Acyliminium ion-vinylsilane cyclization 12:453 1-Acylindoles photoisomerisation 1:51 Acylnitrosocycloaddition 19:355 Acylnitroso Diels-Alder reaction 1:386,4:606 syn Addition 8:296-298,304 Addition reaction of chiral vinyllithium compounds 12:35-62 to a-methyl-substituted aldehyde 12:35-62 1,4-Addition reaction 14:696,697 Addition to allylic A-systems Felkin-Anh model 3:248 Addition-elimination mechanism for 5-enolpyruvylshikimate 3-phosphate synthase 11:185,187 SE'Additions 10:17-25 Aflatoxin M2 Norrish type II reaction 14:651-657 ()-Africanol Claisen rearrangement 6:51 Alcohol dehydrogenase 17:479 Alcohol inversion 1:456,457,459 Alcohol protection as MEM ether 1:558 Aldoheptofuranoses asymmetric quaternization 10:428-432 Johnson-Claisen rearrangement 10:432-436 Aldol condensation 13:448,468 (3-elimination 12:13 acid-catalyzed 16:216,220 asymmetric induction in 4:328,329 base-catalyzed 16:220 chelation controlled 10:286 crossed 11:296,297 diastereoselective 4:328,329;12:15,16 intermolecular 10:182,183,318-320;11:113,115 internal 1:363-365 intramolecular 10:303,306,318,329,330;16:141,216, 216,221,228,259,260 of silyl enol ether and acetone 11:296,297 offiiranone 12:13 stannic chloride catalysed 4:328,329 TiCU catalysed 1:537,538 Aldol coupling reactions 11:435-439 Aldol cyclization 2-amino alchohol by 12:411,414 asymmetric 4:327 chiral acetals in 4:329 chiral synthons for 4:491 of a-sulfinylesters 4:491-494 of aldehyde 12:174,411,414 of ascorbic acid 4:699-705 ofenolate 160 stereoselective 12:154 with enolsilyl ether 12:174 with isonitrile 12:411,414 with A^-acylimine 12:160 Aldol stereoselectivity 12:72 Aldol type addition 16:656 Aldol type condensation of aldehydes 8:426,427 with 2-trimethylsiloxy-3-methylfuran 8:426,427 Aldol cyclization 6:49,50 in (+)-spatol synthesis 6:40,41 Aldol reaction intramolecular McMurry approach 13:602 Aldol-type reaction stereocontrolled 12:36 stereoselective 12:166 Aldolization 6:7,9,10,17 Alkanol 7:231 asymmetric hydration of alkene 13:451 asymmetric hydroboration of alkene 13:451,452 oxyamination of alkene 12:411,413 photochemical additions to alkene 1:642 A^-'^Alkene 12:22 o-Alkenyl dehydroglycosides 3:245 6-Alkenyl-4-oxapyran-2-ones 10:340 by enolate Claisen rearrangement of 10:340 Claisen rearrangement of 3:245 hydroboration of cw-Alkenes 8:471,472 thermolytic cyclization of 6:429 5-Alkylation 8:214 intramolecular 13:145 0-Alkylation a-Z)-glucopyranoside 6:385 glucopyranoside 6:388 A^-substituted amides 10:215 of potassium kojate 12:261 of>v-haloalcohol 8:195 Alkylation

1235 asymmetric 11:367 base (LDA) mediated 10:408,409 diastereoselective 14:491-499 enantioselective 10:412 in basic media 4:389-391 intramolecular 16:125;19:486 of (5)-a-terpinylamine 11:283 of l,5-acetyl-l-thiohex-2-enopyranosides 10:342 of l-benzyl-2,6-dicyanopiperidine 6:433 of 1-phenyl-1-methyl 6,7 seleno-1-ethyllithium 8:6,7 of2-acetoxy-5,6-dihydro-2H-pyrans 10:342 ofacetals 1:613-616 ofbenzyllithium 8:6 ofcarbanion 8:176 ofcarvone 10:408,409 of chiral acetals 12:489-493 ofcyanohydrin 8:16 of cyanohydrin ethers 8:177-179,183 ofdianion 11:284,285 of dimethyl malonate 8:185,186 of dioxolane enolates 1:644 ofFAMSO 6:313 of fluoromalonate 13:82 ofmethylmalonate 13:79 ofMT-sulfone 6:334 of A^-nitrosopyrrolidine 6:439,441 of silver cyanides 12:113 of sulfur stabilized carbanion 8:16 of trans-2,5-bis (methoxymethoxymethyl) pyrrolidine 10:412 of w-haloalkylphenylthioacetate 8:176 of a-methyl-phenylacetic acid 10:412 of a-phenyl-y-lactone 10:410,411 ofp-ketoester 8:181,191 palladium-mediated 16:422 regioselective 10:342 stereoselective 10:342,410,411;11:284,285 synthesis of 3:166,167 TiCU catalysed 1:615 via sequential dianion generation 16:371 with l-TMS-2-pentyne 11:284,285 with 2,5-dibromo-2-methyl pentane 8:6,7 with 3-butynyl p-toluene sulphonate 14:559 with allylic halide 8:178 with benzyloxymethyl chloride 6:561 with di-/-butyl dicarbonate 14:559 with House procedure 10:308,309 with indole-protected tryptophyl bromide 11:283 with organometallic reagents 1:613-616 y-Alkylation in (+)-sinularene synthesis 6:76,77 Alkynyl Grignard reagents reaction with 1-methoxycarbonyl pyridinium chloride 6:448 reaction with 2-methylpyridinium salts 6:429 Allene epoxide rearrangement of 8:36 Ally! acetates isomerization of 4:49 allylation 4:21 Allyl ether isomerization to vinyl ether 1:453 Allyl glycidyl ether cyclization of 10:588,589 oxetane ring formation by 10:588,589 a-Allyl glycosides by anti SN^ displacement 10:348 from D-glucal triacetate 10:419 Allyl isocyanide from allyl iodide 12:113 from silver cyanide 12:113 Allyl mangenese reagent 4:34,344 7C-Allyl palladium complex 4:500;10:214,215 711-Allyl Pd alkylation intramolecular 10:10-13 Allyl sulfones addition to enones 3:23 Allyl sulfoxide anions addition to enones 3:21,22 synthesis of 3:435 Allylamines 2-amino alcohol by 12:411,414 cyclocarbamations 12:411,414 Allylation diastereoselective 1:604-610 of2-acetylcyclohexanone 10:412 ofFAMSO 6:315,316 with allyl acetate 10:412 Allylation reaction 12:484,14:474 0-Allylation-Claisen rearrangement 12:269 Allylboration 8:477,478 Allylboronate stereoselective addition to glyceraldehyde 1:311,312 TT-Allylcation complex 3:82,83 Allylcerium 8:24 Allylchromium species coupling with carbonyls 3:81 medium ring compounds from 3:81 a-Allylglucosides synthesis of 3:214,215 Allylic polyprenols synthesis of 8:66,67,72 Allylic acetoxylation 16:420 Allylic alcohol allylic aldehyde from 12:46,47 amides from 14:722,723 asymmetric cyclopropanation of 14:490,491 biomimetic cyclization of 14:717-720 by Claisen rearrangement 14:722,723 epoxidation of 10:39,40 2,3-epoxy alcohol from 14:570 from (/?,/?)-2,3-butanediol 14:490 from acetylenic ketone 11:424 fromD-glucose 10:428-438 from dimethyl-tartrate 11:267,268 Johnson-Claisen rearrangement of 10:428-438 mesylationof 4:172,173 one-carbon homologation 3:238 oxidation of 12:46,47,16:594 preparation of 11:424 Sharpless epoxidation of 14:570

1236
withMn02 12:46,47 with VO (acac)2-TBHP 10:39,40 Z-Allylic alcohols cw-hydroxylation of 4:203 Ally lie p-hydroxy sulfoxides stereoseleetive hydroxylation 4:503,504 Z-Allylic (3-ketosulfoxides synthesis of 4:509,510 Allylic bromination 6:207 Allylic C-0 bond cleavage with dissolving lithium/amine reduction 1:557,558 Allylic carbocation asymmetric epoxidation of 4:172-174 Allylic carboxyl group phytochemical removal 3:487 Allylic displacement reactions palladium catalyzed 16:397 Allylic ethers hydroboration of 4:116 Allylic glycolate esters Ireland-Claisen rearrangement of 10:437 Allylic hydroxylation with Se02/tert-butylhydroperoxide 1:535 Allylic hydroxylation 6:200,201 Allylic oxidation 3:448;6:126,159,162;8:197,198; 11:11,40,41;12:311;16:420,669 ofperezinone 5:722 with Collins reagent 11:83,84 with manganese dioxide 11:356,357 withSe02 1:549,550 Allylic radicals reductive elimination 4:525 Allylic rearrangement 4:556,6:159,14:191,16:305, 617,669 Allylic sulfoxide rearrangement 1:560,564 Allylmetal additions 8:16 a-Allyloxy anions [2,3]-Wittig rearrangement of 3:248-250 Allylsilane 14:482 Allylstannane 1:247,256,312,313,10:17-25 Allyltin derivatives nucleophilic addition by 11:442,443 Allysilane 1:314 (Allyloxy) methyllithium rearrangement of 8:200 Aluminium hydride selective reduction with 3:474 Amadori rearrangement 18:680 Amalgam procedure 14:746 Amide cyclisation 4:546 Amidoalkylation intramolecular 10:108 Amidoalkylation reagents (A^-acyliminium ions) 13:473-518 Amidocarbonylation 16:408 Amidocyclization 1:382 Amination intramolecular 6:429;16:438 Amines formation from ketones 6:429 photosensitized oxidation of 16:604 reductive amination of 6:429 (Z,-a-Aminoadipoly)-L-cysteinyl-D-valine 5(LLD ACV) cephalosporin C from 11:211-213 penicillins from 11:211-213 I-a-Aminouronic acid synthesis of 11:459,460 L-a//o-a-Amino acid synthesis of 11:460,461 Amino acid 16:395-414,604 as chiral synthons 4:625 by a-halo boronic ester 11:417-420 photooxidation of 16:604 synthesis of 11:417-420,13:507-516,16:395-414 a-Aminoacid 12:115,435-438 as chiral building blocks 1:678-684 by hetero Diels-Alder adducts 12:435,436 conversion to amino sugars 4:111-156 synthesis of 12:435-438 (3-Amino acids by hetero-Diels Alder reaction 12:158,159 cyclization by UG1 -reaction 12:116 cyclization of 12:115,116 p-lactamsfrom 12:115 synthesis of 12:155,158,159 a-Amino acids/esters conversion to azomethine ylides 1:331-338 decarboxylation of 1:331-336,337 imines from 1:331 Amino acylase for synthesis of a-amino acids 1:678-680 2-Amino alcohols by aldol reaction 12:411,414 by cyclocarbamation 12:411,413 by electrophilic addition 12:411,414 by Michael reaction 12:411,413 by nucleophilic addition 12:411,413,414 by oxyaminations 12:411,414 by reduction 12:411,414 by ring-opening of oxirane 12:411,413 from 2-oxazolone 12:411-444 synthesis of 12:411-444 a-Amino aldehydes in [4+2] cycloaddition 4:111 in Diels-Alder reaction 4:120 metalloorganic addition to 4:124 A^,A^-diprotected 4:124 A^-monoprotected 125 preparation of 4:113,114 iV,0-protected 4:130 a-Amino aldehydes 2-amino alcohol by 12:411,414 nucleophilic addition 12:411,414 Amino carbonylation intramolecular 14:568 palladium (2^) catalyzed 14:568 a-Amino ketones 2-amino alcohol by 12:411,414 reduction of 12:411,414 a-Amino ketones steroid-pyrazine dimers via 18:885-887

1237 Amino sugars synthesis from glycine 4:115-118 synthesis of 13:190-207 3-Amino-3-deoxynucleosides synthesis of 4:240 3-Amino-3-deoxy sugars synthesis of 4:150 6-Amino-6-deoxysugars from a-amino acids 4:111,127 6-Amino-6-deoxyuloses synthesis of 4:124 5-Amino-7-methoxy-2,2-dimethylchroman synthesis of 13:358,359 Aminoalcohol benzyl-protected 11:298,299 with aldehyde 11:298,299 5'-Aminoalkyl oligonucleotides synthesis of 4:294,295 Aminodeoxyhexosyl-purines synthesis of 4:238-248 Aminodeoxyhexosyl-pyrimidines synthesis of 4:238-248 Aminohexose derivatives synthesis of 1:25-27 Aminolysis intramolecular 12:279 of disaccharide lactone 6:407 ofMurNAc6-lactones 6:393 a-Aminonitriles formation of 14:716-718 via Polonovski reaction 14:716-718 2-Aminonucleosides frision reactions for 4:238 synthesis of 4:238,239 4-Aminooctanal diethyl acetal condensation of 6:445,447 with diethyl-3-oxo-glutarate 6:445,447 withethanal 6:445,447 5-Aminooligonucleotides synthesis of 4:294-292 Aminyl radical heterocyclization of chloramines 1:292 Ammonolysis with ammoniacal methanol 16:97,98 Anion mediated alkylation of difunctional acyclic terpenoids 8:229 [3,3]Anionic oxy-Claisen 12:93 Anionic oxy-Cope rearrangement eight-membered rings by 3:77,78 Anionic pinacol rearrangement 14:360 Annelation ofresorcinol 19:227 of substituted phenol 19:227 regiospecific 19:227 Annelation reaction 14:694,695 Annulation by Simmons-Smith reaction 6:5 intramolecular 10:407 of 1 methyl-2-tetralone 14:670,671 of a-diazo-P-keto ester 10:407 of cyclohexane ring system 6:5,6,29,30 of cyclopentane ring system 6:6-8,30,31 ofenolate 10:414,415 ofmethylenecyclohexane 6:21,22,53,54 of piperidone derivative 14:734 Piers annulation 6:21,22 Rh (Il)-mediated 10:407 Robinson annulation 6:17-21,29,30 with 3-methylsilyl-3-butene-2-one 10:414,415 [2+3] Annulation of aldehydes 3:5-58 triquinane synthesis by 3:47,48 annulation methods 3:7 for five-membered rings 3:7 [4+1] Annulation triquinane synthesis by 3:40-45 [4+4]-Annulation Danheiser version 3:78 for 8-membered ring synthesis 3:78-79 intermolecular 3:78 Nickel catalysed intramolecular 3:78 Anodic methoxylation 13:485,494 Anodic oxidation 7:161,163;8:159-172;13:474,475,479 of a-A^-acetyl-8-A^-tosy-L-lysine methyl ester 12:309,310 Anomeric deprotection of disaccharide dipeptides 6:413-416 Arenecarbene 3:324,325 Arene-metal 7i-complexes 20:310-312 Arene-olefm metaphotocycloaddition 3:14 Arenes microbial oxidation of 18:430-432 Arndt-Eistert reaction 13:79,93 Amdt-Eistert homologation 1:237;13:116 Aromatic compounds oxidation of 6:509 Aromatic phosphoramidates 14:286 Aromatization 7:360-363;ll:114-119 Aryl p-C-glycosides by condensation with tribenzyloxy benzene 10:377 by Lewis acid assisted condensation of aryl ether 10:375 Aryl C-glycosides from ribofuranosyl chloride 10:362,363 N-(Arylidene) benzyl amines 1:343 2-azaallyl anions from 1:343 isomerization of 1:343 Aryl methyl ketone chiral acetal of 14:473 asymmetric cyanation of 14:473 Aryl-C-glycosides by condensation 11:13 9-142 via polyketides 11:139-142 synthesis of 11:139-142 Arynes generation of 3:418-421,422-454 nucleophilic additions of 3:418,421-437 Asinger condensation 12:127,129 Asymmetric alkylation 11:367 catalytic epoxidation 11:431,432 catalytic osmylation 11:431,432 cycloaddition 11:358

1238

dihydroxylation of 11:423,424 of trans-stilhQne 11:423,424 Asymmetric cyclization 10:611,631-633 Asymmetric [3+2] dipolar cycloaddition 13:500 Asymmetric 1,3-dipolar cycloaddition 1:371-375 Asymmetric additions to prochiral carbonyl groups 4:332 to prochiral naphthalene rings 4:332 Asymmetric aldol condensation 12:162;13:63 Asymmetric alkylation of methylmalonic acid 10:411 of (-)-pheny Imenthy 1 ester 10:411 Asymmetric allylboration 8:477,478 Asymmetric aza-annulation reaction 18:378,379 Asymmetric bromolactonization with acetals from tartaric amides 4:338,339 with N-bromoacetamide 4:338,339 with chiral acetals 4:338,339 with unsaturated (5)-proline amides 4:336,337 Asymmetric carbocyclization in (-)-2/?,65',85',95)-2,8-dibromo-9- hydroxy-achamigrene synthesis 6:62,63 Asymmetric cyclization biomimetic 14:506,507 of chiral acetal 14:506,507 Asymmetric cyclopropanation with methyl carbenoid 14:488 Asymmetric Diels-Alder reaction 8:139-157 chiral auxiliaries 4:607 prostaglandin synthesis 4:607 P-santalene synthesis 4:607 tetramycin synthesis 4:607 using chiral boron reagent 4:609 Asymmetric Diels-Alder technology 13:602 Asymmetric dihyroxylation ll:60;19:269-270,274, 278,284 Asymmetric dimethylation 10:412-415 Asymmetric epoxidation of ()-N-benzyloxycarbonyl-3-hydroxy-4ofallylicalcohol 10:561 ofallylicalkohols 12:323 of allylic alcohols 4:172-174 pentenylamine 12:281 of swainsonine 10:561 Asymmetric esterification 9:25 Asymmetric hydration 13:71 ofalkenes 13:71 Asymmetric hydroboration 8:473,474,478;13:71,72 Asymmetric hydrogenation 12:162;16:411 Asymmetric hydrogenation BINAP-Ru-catalyzed 4:439 of P-keto esters 4:439 Asymmetric hydrolysis by esterases 1:684,685 by lipases 1:684,685 of N-acetyl a-amino acids 1:678,679 Asymmetric hydrosilylation intramolecular 13:72 Asymmetric hydroxylation ofpentadienols 9:572 Asymmetric induction 10:412;12:153,156;14:471, 507,508,524,553

1,2-Asymmetric induction 11:231 -23 8 1,3-Asymmetric induction 14:529,552 1,4-Asymmetric induction 12:156 1,5-Asymmetric induction 14:499 1,6-Asymmetric induction 14:530 1,4-Asymmetric induction Cram's cyclic model of 4:203,495 in (-)-piperitone 6:15 in aza-annulation reaction 18:373-386 in dienolate addition 3:47 in diyl trapping 3:20 in Ireland-Claisen rearrangement 3:237 reversion using sulfoxides 4:511 self-immolative 3:237 with chiral auxiliaries 4:499-517 Asymmetric ketoester cyclization 4:328-330 Asymmetric metallation of chiral arylaldehyde acetal chromium tricarbonyl complexes 14:511 Asymmetric Michael addition in estrone synthesis 4:501,502 Asymmetric osmylation 19:269 Asymmetric oxidation of prochiral sulfides 14:517,518 of sulfide 4:489 sulfoxides from 14:517,518 with chiral sulfamyloxaziridines 4:489 with chiral titanium complexes 4:489 Asymmetric quaternization by Claisen rearrangement 10:426-428 by consecutive alkylation 10:405,406 of aldohexofuranose derivatives 10:428-432 of a-carbon of y-lactones 10:405 Asymmetric reduction with Baker's yeast 1:689 Asymmetric reduction by Baker's yeast 10:410 of acetoacetic acid ethyl ether 10:410 of acetylenic ketone 11:424 of acyclic (3-hydroxy ketones 14:183,184 of p-keto esters 14:533,534 withlpcjBH 8:476 Asymmetric reductions 4:339-345,448 Asymmetric synthesis by diastereofacial selection 13:62-70 by enantiofacial selection 13:70-73 by enantiotopic discrimination 13:60-62 of(-)-ajmalicine 14:563,564 of(-)-sibirine 14:539-544 of (+)-(5',5)-solenopsin A 6:431,432 of (+)-castanospermine 12:346 of (+)-elaeokanine A 12:351,352 of(+)-elaeokanineC 12:351,352 of(/?)-muscone 14:490 of (/?/5)-l,6-dioxaspiro [4.5] decane 14:523,524 of (i^5)-l,7-dioxaspiro [5.5]-undecane 14:521-526 of [m, n, 1] propellanes 14:490 of 2-dQOxy-D-arabmo-hQxosQ 14:176,177 of 3-deoxy-D-r/6o-hexose 14:176 of 4-acetoxy-3-[ 1 '-(tert-butyldimethyl-silyloxy) ethyl]-azetidinone 4:448

1239
of 4-deoxy-D-/>'A:o-hexopyranose 14:176 of 5,1-linked naphthylisoquinoline alkaloids 20:420-438 of 5,8-linked naphthylisoquinoline alkaloids 20:442-451 of 7,1-linked naphthylisoquinoline alkaloids 20:438-441 of anthracycline antibiotic 14:492,493 ofazetidinone 4:448 ofbuphanisine 4:14,15 of chiral alkaloids 10:671-689 of chiral building blocks 14:551-581 of chiral isoquinolines 10:671 of chiral piperidines 10:671 ofcrinine 4:14,15 ofdesoxydaunomycinone 14:23 of indolizidine alkaloids 6:442,443 of monomorine I 6:449,450 of pyrrolidine alkaloids 6:442,443 of pyrrolizidine alkaloids 6:442,443 of/?,5'-4-hydroxycyclopentenones 6:315 ofsolamin 18:202-206 of talaromycin A and B 14:531-539 propane-1,3-diols by 13:53-105 via chiral organoboranes 8:465-478 with chiral sulfur reagents 10:671-689 Asymmetric transformation crystallization-induced 13:77 of malonic acid derivative 13:88 Asymmetric catalysts hydrogenation 17:323 synthesis of 17:479 Asymmetrization of a-symmetric ketones 11:241,242 Atta-ur-Rahman synthesis of ()-16-hydroxydihydrocleavamine 14:850 of ()-16-methoxycarbony Idihydrocleavamine 14:850 of ()-coronaridine 14:850 of ()-dihy drocatharanthine 14:850 of ()isovincadifformine 14:850 of()-a-dihydrocleavamines 14:850 of()-p-dihydrocleavamines 14:850 ofanhydrovinblastine 14:857 of vinblastine 14:850-859 of vincristine 14:850-859 Automated synthesis of oligonucleotides 13:257-294 ofoligodeoxyribonucleotides 4:280 reaction cycle 4:281 Automatic DNA synthesizer 4:304 Autooxidation of 1-methylazulene 14:335,336 of benzylic positions 16:571 ofguaiazulene 14:316-319 of phenyIhydrazine 9:581 Axial 2-lithiotetrahydropyrans 10:380 by reduction with lithium di-/er/-butylbiphenylide 10:380 from 2-(phenylthio)-tetrahydropyrans 10:380 Axial C-glycopyranosides 10:365,366,382 Axillarin 7:26 Aza-annulation of enamine related substrate 18:315-386 Aza-annulation reaction asymmetric induction in 18:373-386 Aza-Claisen rearrangement 16:467 Aza-Cope reaction 16:481 Aza-Cope rearrangement Mannich directed 1:68,69 Aza-Cope-Mannich strategy 16:435 Aza-Diels-Alder approaches 16:456 Aza-[2,3]-Wittig rearrangement 19:22,45,50 Aza-Wittig reaction 1:168,169 2-Azaallyl anions by deprotonation of imines 1:344-347 by C-Si of C-Sn bond cleavages 1:344-351,353 from imines 1:344-347 from N-lithioimidazolidines 1:344,349-351 from N-metalloaziridines 1:344,348,349 generation of 1:348,350 geometry of 1:348,350 Azaallylic anions with aryl halides 4:547 Azabicyclo ketone system asymmetric cleavage of 14:571-574 cis-a, a'-disubstituted piperdine and pyrrolidines by 14:571-574 Azadiene Diels-Alder 3:311 1-Azadiene Diels-Alder cycloadditions 16:457 2-Azadienes metalloenamines from 4:7,10-14,17 2-Azahexatriene thermal cyclization of 3:395 Azetidione derivatives Mori synthesis of 13:500 Azidation reaction asymmetric 19:311 Azides dipolar cycloaddition 3:49 thermolytic cyclization of 6:429 Azido-ene reaction 16:473 Azido-olefm cyclization 13:447,448 Azidonitration 1:420,421;10:465 Aziridine from (5)-phenylglycinol 10:138,139 azomethine ylides from 1:328-331 ftised 1:189,197 nucleophilic opening 1:201,202 photochemical opening 1:328 synthesis of 1:189,197 thermal opening 1:328 Azomethine ylide cycoadditions by aziridine thermolysis 1:329,330 intramolecular 1:329,330 Azomethine ylides by 1,2-H shifts 1:331-332 formation of 1:324-344 generation of 1:324,339 preparation by aziridine opening 1:328-331 preparation by desilylation 1:324-328 preparation from a-amino acids 1:331-338

1240 Azulenes autooxidation of 14:332 electrochemical oxidation of 14:325 oxidation of 14:332-334 Backbone rearrangements 7:159,161 -166 Baeyer-Villiger rearrangement 4:647,667,139,153; 8:154,597,598 Baeyer-Villiger ring expansion 13:601 Baker's yeast 4:324,325,340,341,158,263,542,543, 552,553,410;6:13;10:410;13:58,59,309,307;20:573,59 3,818,820 Baker's yeast reduction 13:662,176 Baldwin's rule 14:792,793 Ban condensation 1:135 Bartlett demethylation 8:119 Barton oxidation 9-BBN (9-borabicyclo-[3.3.1] nonane) 13:72 Barton radical decarboxylation 18:75,340 Barton reaction 14:160 Barton reduction 12:303 Barton's modification 19:135 Barton's procedure 6:282-288,607 Barton's protocol in free radical deoxygenation 6:21 Barton's reaction 6:228,230,231 Barton-type deoxygenation 20:71 Base promoted cyclisations ofarylhalides 4:541 Base-catalyzed equilibration 14:460 Base-induced rearrangement 12:91 mechanism of 14:372-374 of hydroazulene mesylates 14:22-25 of hydronaphthalene-1,4-diol monosulfonate esters 14:356 of hydronaphthalene tosylates 14:368-370 9-BBN reduction with 4:116,117 trans-BC-ring fusion 12:205 stereochemistry of 12:205 Beaucage sulfurizating agent 13:269 Beckman fragmentation ofanti-oxime 19:486 of erythromycin-9-oxime 13:160,161 of oxacyclopentanonering 16:221 ofoxime 16:240,330 ofoxime 19:14,498 Bellus rearrangement 8:205 Benz-annulation reaction 1:505,506 Benzilic-type rearrangement 3:226 1,4-Benzoquinones enantiospecific reactions of 16:547-570 stereospecific reactions of 16:547-570 2,4-Benzoxazocine derivative by ring expansion 6:469 Benzoxazocine derivatives by ring construction 6:468-471 by ring destruction 6:468-471 by ring interconversion 6:468-471

from a-narcotine A^-oxide 6:468 synthesis of 6:468-471 1,5-Benzoxazocine N-oxide 1,6,5-benzodioxazonine from 6:472 thermolysis of 6:472 Benzoxazolidone derivative boron enolate of 12:164,166 CMlkylation by 12:164,166 stereoslective 12:164,166 2,5 -B enzoxazonine carbocation intermediate in 6:473 derivatives of 6:476,47 photosolvolysis of 6:475,476 synthesis of 6:473 A^-B enzoy Icarbamate cyclization of 14:569 from 2,3-epoxy alcohol 14:569 2-oxazolidinone from 14:569 A^-Benzoylpyrrolinone synthesis of 8:212,213 1 -Benzyl-2,6-dicyanopiperidine alkylation of 6:433 decyanation of 6:433 2,6-dialkylpiperidines from 6:433 Benzyl-4,6-0-benzylidene-3-deoxy-P-D-r/6ohexopyranoside 14:11,12 synthesis of 14:11,12 0-Benzylation 12:327 Benzylation 6:268-270,287,288 A^-Benzylation 7:41-43 of 1,4-dideoxy-1,4-imino-I-allitol 7:41-43 Benzylic hydroperoxide rearrangement 3:316-319 3,5-0-Benzylidenation 12:52,53 of (95)-9-dihydroerythronolide A 12:52,53 Benzylidene glycal 10:344 Benzylisoquinolines synthesis of 3:422 Benzyllithium alkylation of 8:6 Benzyloxycarbonylation 12:478 1 -Benzyltetrahydroisoquinoline system intramolecular oxidative coupling of 6:480 protostephanine from 6:480 rearrangement of 6:480 Benzyne 16:47 Benzyne cyclisation 4:541-551 B enzyne reaction 16:514 BF3 rearrangement 5:782,783 BF3-mediated method 11:117 Bicyclic p-lactam by Diels-Alder reaction 12:172,173 from cyclic imines carboxylic acid 12:117 from2H-4H, 1,3-dioxin derivatives 12:160,161 synthesis of 12:172,173 Bicyclo [2.2.1] heptanes 8:415 synthesis of 8:415 Bicyclo [2.2.2] octane ()-sanadaol from 6:70,71 by double Michael addition 8:422 from Li-cyclohexadienolates 8:422

1241 from a,P-unsaturated esters 8:422 synthesis of 8:412-422 Bicyclo [3.2.1] octadione synthesis of 8:161,162 Bicyclo [3.2.2] piperazinedione synthesis of 12:71 Bicyclo [3.3.1] nonanes conformation of 3:95 fragmentation of 3:74 Bicyclo [4.3.1] dec-2-en-7-one by Grob fragmentation 6:69 by intramolecular [2 + 2] photocycloaddition 6:69 synthesis of 6:69 Bicyclo [4.3.1] decanone nakaftiran-9 from 6:70 synthesis by four carbon polar annulation 6:17,21 Bicyclo [5.2.2] piperazinedione synthesis of 12:84,85 Biellmann coupling 10:6-10 Bimolecular [671+471] tropone diene cycloaddition of 12:241 (BINAP) 13:72 BINAP-Ru-catalyst in asymmetric hydrogenation 4:439 Biological Diels-Alder reaction 17:451 Biomethylation 9:47 Biomimetic cationic polyene cyclization 12:456 Biomimetic cyclization of allylic alcohol 14:681-684 Biomimetic olefin cyclization 1:671-673 Biomimetic polyene cyclisations 7:131 Birch reduction of o-toluidine 11:286 of6-methoxy-l-tetralone 12:235 of4-methoxytoluene 12:22-24 of/?-cresyl methyl ether 6:83,84 Bis (trimethylsilyl) ethylene glycol 1,3-dioxolane formation 1:584 reaction with aldehydes 1:584 reaction with ketones 1:584 Bis (trimethylsilyl)-1,2-ethanedithiol 1,3-dithiolanesfrom 1:584 reaction with aldehydes 1:584 reaction with ketones 1:584 Bischler - Napieralski reaction 3:460,93,633,790;8:291 Bischler-Napieralski condensation isokomarovine from 14:763 komarovidine from 14:763 oftryptamine 14:763 with quinoline-5-carboxylic acid 14:763 Bischler-Napieralski cyclization 4:20,23,444 Bisketene 4:349 BOC anhydride method 12:121 BOC fiinctionality deblocking with TMSOT 4:91,92 (i?)-A^-BOC-2-amino alcohols 12:435,436 with thionyl chloride 12:435,436 A^-BOC-L-threonine methyl ester from methyl trans (4S,57?)-5-methyl 3)-tert butoxycarbonyl-2-oxo-oxazolidine-4carboxylates 12:430 Boekman-Silver synthesis of(-)-P-gorgonene 6:18 Borane-methyl sulfide complex 11:360 Boration 9:366-368 Bormination of camphor 4:629,633,634,656,657 of camphor derivatives 4:629-632,633,634,636, 656-658 Bom-Oppenheimer approximation 2:155 Boron enolate of 3(y?)-3-hydroxybutanethioate 13:500 Bose reaction by 3-hydroxybutyric acid 4:440,441 by ketene-imine cycloaddition 4:440 in azetidinone formation 4:440,441 Branched amino sugars synthesis of 10:421 Branched chain nucleosides synthesis of 4:254-257 Branched decarbonucleotide [CpUpUpA(2'-pGpUpG) pUpCpA] 14:299,302 synthesis of 14:299,302 Branched hexaribonucleotide synthesis of 14:291,292 C-Branched nucleoside analogues stereoselective synthesis of 19:511-547 Branched oligoribonucleotides synthesis of 14:283-303 Branched RNAs synthesis of [A(2'-pX)pX] 14:293 synthesis of [A(2'-pY)pX] 14:293 synthesis of [A(2'-pU)pU 14:293,294 synthesis of [CpUpA(2'-pGpU) pUpC] 14:299,301 synthesis of 14:284-303 via 3'-bis(2-cyanoethoxy) phosphoryl group 14:291, 292 via 2',3'-bisphosphorylated ribonucleoside unit 14:284-290 via phosphoramidite approach 14:293,294 Branched tetrasaccharide synthesis of WA16,A11 Branched triribonucleotide synthesis of [A(2'-pA)pA] 14:294,295 synthesis of [A(2'-pG)pC] 14:289,290,297-299 synthesis of [A(2'-pG)pU] 14:290,298-300 synthesis of [A(pG)pC] 14:289,290 synthesis of [araA(2'-pU)pU] 14:294 synthesis of [GpA(2'-pG)pC] 14:295-297 synthesis of [pA(2'-pA)pA] 14:294,295 synthesis of [pppA(2'-pA)pA] 14:294,295 synthesis of [U(2'-pA)pU] 14:296,297 Branched trisaccharide synthesis of 10:476,477 Bredereck's reagent 8:262,316 Bredfsrule 12:72 Bromination 3-bromo-levoglucosenone 14:269 chemoselective 19:314 Hoye's 1:672 of(+)-3,3-dibromocamphor 16:135

1242

of levoglucosenone 14:269 withNBS 19:314 Bromination-dehydrobromination sequence 12:237 Brominative cyclization in brominated terpenoids 6:24 in glanduliferol synthesis 6:63,64 of(87?/5,9i?/5)-8-brome-9-hydroxy-(:)-bisabolene 6:62,63 Brominative rearrangement 4-Bromo-azetidinone 4:474 Bromine addition 16:336 Bromlactonisation of bromolactone 8:301 of (45)-3-methylmuconolactone 8:300,301 Bromocarbenoid procedure 1:263 Bromocarbenoid ring expansion 1:263 Bromohydrin formation 1:523 Bromolactonization 3:265,336-339,177 Brook-Rubottom-Hassner oxidation ofenolsilane 12:25,26 Brown's crotylboration 18:280 Burgess reagent 1:257,16,50,53,601,232,296 Butenylation 12:458 ()-2-Butenyldiisopinocampheylborane 13:135 3-Butenylmagnesium bromide 12:29,30 7\^-rer/-Butoxycarbonylation 12:478,479 t-Butyl acetate Claisen condensation of 11:127,129 lithiated 11:127,129 with naphthalene glutarate 11:127,129 ^Butyl hydroperoxide 12:323 tert-Buty\ hypochlorite addition to olefins 1:451 cyclization with 1:11,12 tert-Buty\ tin hydrite reduction of chlorides 1:443,444,451 reduction of dithiocarbonate 1:452,453 /er/-Butyldimethyl silyl ether 6:264,268;11:339;12:282 rerr-Butyldimethylsilyl (TBDMS) group 4:299,304 /err-Butyldimethylsilyl ketene acetal 1:465 ?er/-Butyldimethylsilylation 6:119,120 ^er/-Butyldiphenylsilyl trifluoromethanesulfonate 1:707,708 A^-I-Butyldiphenylsilyl-S-benzyl-S-methyl sulfoximine 10:686-688 rer^Butylformamidines 6:430,431 2-(t-Butylimino)-2-[(diethylamino)]-l,3dimethylperhydro-1,3,2- diazaphosphorine 12:342 Y-Butyrolactone 16:687-726 Butyrolactones 3:252-225

Cannizzaro reduction 19:536 Carbonylation palladium catalyzed 19:189,195 C-aryl glycoside stereoselective synthesis of 10:370 C-arylglycals by palladium catalyzed coupling 10:344 synthesis of 10:344 Catalytic hydrogenation 19:77 Catalytic reduction 19:76,91

C-C bond formation 6:307-349 a-C-glycosides by condensation of methylallyl tri--butylstannane 10:381 by condensation with furan 10:377 by reaction of acyl ester 10:371 from pyridyl thioglycoside 10:382 from a-tri--butyltin glycoside 10:384 stereoselectivity of 10:371 with allyltrimethylsilane 10:371 P-D-C-glycosides from 3,4,6-tri-O-t-butyIdimethylsilyl-2-deoxy D-glucopyranosyl phenylsulfone 10:383,384 C-glycosyl compounds by catalytic siloxymethylation of (9-acyIglycosides 10:373,374 by reaction with HSi R3/CO/Co2(CO)8 10:373,374 C-glycosyl-oxirans from acetobromoglucose 10:361 C-glycosylarenes by reaction of benzoylated O-alkyl glycosides 10:380 C-glycosylation of aromatic ring 10:387 of heterocyclic ring 10:387 C-glycosylcyanides from acylated bromosugars 10:355 synthesis of 10:355 Chlorination 19:61 Claisen condensation 19:35;20:740 Claisen disconnection 19:228 Claisen rearrangement 19:229;20:66,67 Clemmensen-type deoxygenation 19:18 C-linked glycosyl acetylenes from glycosylhalides 10:358 C-nucleosides 10:337,338,355,358,388-394 Collins oxidation 19:320,334,467 Cooxidants 19:270 Corey reagent 19:452 Coupling reaction 20:566 C-prostaglandins synthesis of 16:367-368 C-pyranosides synthesis of 10:340 Cram's product 19:471,476 Cram selectivity 19:473 Cram's chelation model 19:320,482 C-sucrose 11:469,470 synthesis of 11:469,470 C2-P bond analogs ofD-erythritol 6:357,358 ofD-fructofuranose 6:357,358 ofD-glucopyranoside 6:357,358 ofD-ribohexitol 6:357,358 C3-P bond analogs of D-alloftiranose 359 ofZ)-altropyranoside 6:359,360 ofD-glucofuranose 6:359,360 of Al-glyceraldehyde 6:359 ofD-xyloftiranose 6:359 C4-alkylations ofp-lactams 12:159-172

1243

with ester enolates 12:163,164 with imide enolates 12:164-168 with other nucleophiles 12:170-172 with thiolester enolates 12:168-170 C4-P bond analogs ofD-erythropentose 6:360,363,364 of A Z,-gly cero-pentopyranose 6:360,361 ofD-talopyranose 6:360 ofL-talopranoside 6:360 C5-P bond analogs of D-erythropentofUranose 6:365,366 ofD-ribofumose 6:365,366,368 ofD-xyloftiranose 6:365-367,375 ofD-xylo-hexofuranose 6:365,366,372 C6-P bond analogs of D-arabino-hexofliranose 6:376 ofD-erythro-hexofiiranose 6:376 ofZ)-galactopyranose 6:376 ofD-glucofiiranose 6:376 ofD-glucopyranose 6:376 ofD-ribo-hexofuranoside 6:376 ofD-ribo-hexofuranose 6:376 Cg-polyketide 12:290 Camphorquinone rearrangement 16:150 Capnellanes from (-)-A'^'^^-capnellene 6:42 synthesis of 4:588 Capnellene synthesis of 3:11,13,19,20,22 A^^^^^-Capnellene synthesis of 3:20 A^^'^^-Capnellene 3:7 (-)-A^(i2).Capnellene capnellanes from 6:42 by a-alkaynone cyclization 6:45 by [2+2] cycloaddition reaction 6:43,44 by [4+2] cycloaddition reaction 6:43,44 by cyclopropane sliding reaction 6:48 by Diels-Alder reaction 6:46 by inframolecular alkylation 6:42,43 by intramolecular diyl trapping reaction 6:46 by intramolecular reductive coupling 6:48 by intramolecular type I Mg ene reaction 6:45,46 by methylenation 6:46,47 by 1,2-methyl shift 6:48 by Nazarov cyclization 6:43 by photochemical annulation 6:48 by three-carbon annulation 6:42 Dreiding synthesis of 6:45 from P-diketone 6:48 from humulene 6:48 Grubb synthesis of 6:46,47 Liu-Kulkami synthesis of 6:43,44 Oppolzer-Batting synthesis of 6:45,46 Stille synthesis of 6:47 synthesis of 6:42,43 with Tebbe reagent 6:46,47 A^^'^^-Capnellene 34,35 synthesis of 13:34,35 from Capnella imbricata 13:34,35 A^^'^^-Capnellene- 3P,8p,10a -triol 3:7

A^^'^^-Capnellene- 3p,8(3,10P-14-tetrol 3:7 A^^'^^-Capnellene- 5a,8p,10a-triol 3:7 Capnellene-2p,8p,10a-triol 3:64 Capnellene-3P,8p,10a-14- tetriol 3:64 Capnellene-5a,8p, 10a-triol 3:64 A^'^-Capnellene-8p,10a-diol 3:7 A^^^^-Capnellene 2p,8p,10a-tril 3:7 Capnellenols by aldol cyclization 6:49,50 by three-carbon annulations 6:49,50 synthesis of 6:48-50 Capping reaction in oligonucleotide synthesis 4:279,280 Carba-disaccharides synthesis of 13:219-221 5a-Carba-glycosylamines synthesis of 13:195-204 5a-Carba-hexopyranoses synthesis of 13:190-207 5-Carba-levoglucosenone l,4-A:o-aducts of 14:279 3-deoxy derivative of 14:279 synthesis of 14:279 Carba-sugars (pseudo-sugars) synthesis of 13:187-255 Carbacephems synthesis of 12:121 Carbanions 1:351-353 Carbanion 16:30 Carbanion reagents 11:43 9-443 Carbanion rearrangement 16:620 Carbapenams synthesis of 8:262,263 (+)-6a-Carbaprostaglandin I2 synthesis of 1:698,699 Carbene complexes 16:406 Carbene insertion reaction 4:436,438 Carbene-diene cyclization 3:29 Carbene-olefm cyclization 3:325 Carbenoid displacement 1:259 Carbenoid insertion 13:501-503 Carbinolamides 4:57 Carbinolamine 4:57,269,270 Carboalumination with MesAl, ZrCpjClj 1:454,455,459 Carbocation intermediate in 2,5-benzoxazonines syntheses 6:474 Carbocupration reaction asymmetric induction in 14:507,508 diastereoselective 14:507,508 of C2-homochiral cyclopropenes 14:507,508 Carbocycles from palladium (+2) complexes 8:272 Carbocyclic oxetanocins synthesis of 10:608-619 Carbocyclic spiro compounds asymmetric synthesis of 14:544-546 Carbohydrate derivative synthesis of 14:659-664 via Norrish type II reaction 14:659-664

1244

Carbohydrate lactones C-glycosides from 10:385 (+)-Carbomenthone Robinson annulation of 6:547,548 Carbomethoxylation 4:36,38 ofketone 4:36,38 Carbon versus oxygen alkylation regioselectivity of 4:367 Carbon-bridged system 12:87 Carbon-tin bond conversion to carbon-silicon bond 1:352,353 Carbonolides stereoselective synthesis of 11:163-172 synthesis of 11:158-172 Carbonyl coupling reaction titanium induced 8:16-18 Carbonyl reduction diastereoselective 1:622 ofp-ketoacetals 1:622 1,2-Carbonyl transposition 3:474,485 Carbopalladation 16:374 Carboxylation (25)-methyImalony 1 CoA by 11:195 of propionyl CoA 11:195 Carboxylic acid anhydride variation of Claisen condensation 4:375 Carboxylic acid silyl esters with silylated phosphonium ylides 4:564 Carboxylic esters into aldehydes 6:334 synthesis of 6:326327 Carbylamine reaction isocyanides by 12:113 Carrol conditions 6:122 Carrol-Claisen rearrangement 6:417 Carrol rearrangement 10:58,60 D-Carvone epoxide Homer-Emmons reaction of 10:43 Lythgoe aldehyde from 10:46 Catalysts 4:302 Catalytic asymmetric aldol reaction 18:485 Catalytic deuteriation 9:476 Catalytic epoxidation 11:431,432 Catalytic hydrogenation with raney nickel 6:425 with rhodium 6:424 Catalytic hydrogenolysis 12:293,163 Catalytic osmylation 11:431,432 Catalytic receptors 18:694 Catalyzed rearrangement 16:512 Catechol borane reduction 13:562 Cationic cyclization ()-chelamine by 14:793-795 ()-chelidonine by 14:793-795 sanguinarine by 14:793-795 Cationic cyclopentannelation reactions 14:583-630 Cationic 7r-cyclization of A^-acyliminium ion 12:287 Cationic polyene polymerization 1:565 Ce (OAc)3-BF30Et2 10:572 Ceric ammonium nitrate 4:322,323,331,332 Ceric chloride 1:552

Cerium (III) chloride 14:753 Cerium ammonium nitrate (CAN) 14:780 Cerium carbanion 1:552 Cesium fluoride 1:563,564 Chan-Brownbridge procedure in (-)-pseudopterosin-A synthesis 6:74,75 Chelate model 11:268,269 Chelating transition state models 12:167 a- and (3-Chelation 11:234 Chelation 12:149,150 Chelation controlled aldol condensation 10:286 Chelation controlled Grignard reaction 1:266 Chelation-controlled addition 14:50 Chelation-controlled Sakurai reaction 12:333 Chelation directed addition 3:271 Chemoselective epoxidation 14:366 Chemoselective hydroxylation ofbicyclictriene 6:79 Chemoselective reduction with lithium tri -rer/-butoxyaluminohydride 10:85 Chiral 1,3-dioxane 14:480 Chiral 1,4-dihydropyridine isonitramine from 14:744 Chiral 1-acylpyridinium salt 12:351 Chiral 2-amino alcohol synthesis of 12:415,416 Chiral 4-hydroxyoxazolidin-2-ones 12:450 Chiral a,p-ethylenic acetals from C2-symmetric diols 14:479 with phenyl or alkenyl copper-BFs reagents 14:479 Chiral a,P-unsaturated acetals from {R, R)-{+yN, N, N', A^'-tetramethyl tartaric acid diamide 14:478,479 with organo-aluminum reagents 14:478,479 Chiral a-aldoxime-ether acetal organocerium reagents to 14:496 Chiral a-amino acetals Lewis acid-mediated reaction of 14:483 with silicon-containing nucleophiles 14:483 Chiral a-keto acetals chiral tertiary alcohol from 14:491,492 from (-)-(2/?,3i?)-2,3-butanediol 14:491 from (-)-(25,35}-l ,4-dimethoxy-2,3-butanediol 14:491 Chiral a-methyl-substituted aldehyde coupling reaction of 12:35,36 with chiral vinyl halide 12:35,36 Chiral acetals asymmetric cyclization 14:506,507 asymmetric synthesis from 14:496-516 bromination of 14:505,506 diastereoselective 14:505,506 for asymmetric bromolactonizations 4:338,339 from (-y{2S,3S)-1,4-dimethoxy-2,3-butanediol 14:496 from (2/?,4/?)-pentanediol 14:473 from (25',45)-pentanediol 14:481 from l,3-diphenylpropane-l,3-diol 14:480 from C2-symmetric diols 14:469-516

1245 from dialkyl tartarate 14:505,506 from perillene 14:506,507 nucleophilic additions of 4:330-332 preparation of 4:324 with methallyisilane 14:481 with trimethylsilyl cyanide 14:473 Chiral acetylenic acetals chirai alkoxy-allenes from 14:471 with Grignard reagent 14:480 Chiral aerylates 8:416 Chirai acyclic P-keto acetals 14:501 from (-)-(2/?,3/?)-2,3-butanediol 14:501 LiAlH4-reduction of 14:501 Chiral alcohols 14:470 Chiral alkoxy-allenes from chiral acetylenic acetals 14:480 synthesis of 14:480 Chiral alkyl (l,3-butadien-2-yl) methanols 14:474 Chiral allylboronates synthesis of 11:423,424 Chiral allylic alcohols 4:160-161 Chiral amide bases [2,3] Wittig ring contraction with 10:31-33 Chiral amines from chiral imine 14:496 Chiral aryl Grignard reagents diastereoselective addition of 14:508,509 Chiral arylaldehyde acetal chromium tricarbonyl complexes asymmetric metallation of 14:511 Chiral auxiliaries acetals as 4:327 asymmetric induction with 4:327-345 binaphthyl diols as 4:335 by (i?)-(+)-a-methyl benzylamine 4:324 by l-(-)-methyl ester 4:323 chiral diamides as 4:335 glycosides as 4:327 in asymmetric Diels-Alder reaction 4:345 in Diels-Alder reactions 4:334-336 oxazolines as 4:327,332,333 preparation of 12:416-418 prolines as 4:327 stereo-differentiating reactions 4:327 sugar as 4:334-336 thiazolidine derived 14:735 Chiral P-lactams synthesis of 12:121 Chiral boron reagent from B {0CH2)-{R,Ryi+) tartaric acid 4:609 in asymmetric Diels-Alder 4:609 Chiral building blocks from malonic acid derivatives 13:73-84 monofluorinated 13:81 preparation of 4:349-359,73-84 asymmetric synthesis of 14:551-581 via intramolecular Michael reaction 14:551-567 Chiral carbapenems 12:121 Chiral catalysts 17:479 Chiral chromatography 18:411 Chiral cyclized hemiacetal from chiral vinyl ether 14:487 Chiral cycloalkanone acetal chiral vinyl ether alcohols from 14:486 from (-)-(2/?,4/?)-2,4-pentane diol 14:486 Chiral cyclopropanation chiral pyrethroid analogues 14:401-405 ofthujone 14:401-405 Chiral dienophiles a-hydroxcarboxylic acid derivatives 8:140 cycloaddition of 14:503 isoquinolinium salt with 14:503 Chiral dienyl ether alcohol (+)-africanol from 14:487,488 cyclopropanation of 14:487,488 Chiral dioxane acetals asymmetric nucleophilic cleavage of 14:476 diastereoselective cross-aldol reaction 14:472 from (25',45)-2,4-pentanediol 14:471 from (2/?,4/?)-pentanediol 14:477,478 with organometallic reagents 14:476 with Reformatsky reagents 14:477,478 Chiral enamine asymmetric 14:553 intramolecular Michael reaction of 14:553 Chiral enol ethers asymmetric 14:489 C-N bond formation 14:489 Chiral enone acetal 14:510 Chiral epoxidizing agent diastereofacial selectivity of 4:172,173 chiral lactones 4:493 from a,p-acetylenic alcohols 4:493 from keto acids 4:493 preparation of 493 Chiral ester 14:552 Chiral fragments of amphotericine B 6:282 synthesis of 6:282 Chiral imine [2+2] cycloaddition of 12:161 from ethyl (5)-lactate 12:161 addition of organometallic reagents 14:496 chiral amine from 14:496 Chiral imine acetal with lithium enolate 14:497,498 Chiral inducer 1:73 Chiral induction 18:480 with Schoellkopf reagent 10:653,655 Chiral isoquinolines synthesis of 10:671 Chiral Lewis acids 8:140 Chiral A^-acylated 2-oxazolone 2-amino alcohol synthon from 12:419 electrophilic addition of 12:419 from camphor-derived carboxylic acid 12:419 with bromine and phenyl selenyl chloride 12:419 withDPPOx 12:419 Chiral N-glycosyl nitrones 1:370,371

1246 Chiral nitroolefination ofenolates 14:631-644 Chiral ortho ester from diethyl (Z)-tartrate 14:508 Chiral ortho ester vinyl ethers 14:503 Chiral oxazolines 4:333 Chiral piperidines synthesis of 10:671 Chiral precursors aspartic acid as 6:2989,299 (5)-3-hydroxybutyrate as 6:300,301 (/?)-methyl-p-tolylsulfoxide 6:301,302 Chiral pyrethroid analogues fromthujone 14:398-405 synthesis of 14:398-405 via chiral cyclopropanation 14:401-405 Chiral reduction 1:482 Chiral reproduction 4:346 Chiral sesquiterpenes synthesis of 14:406-425 via Robinson annulation reaction 14:406-425 Chiral shift reagent 4:326 Chiral steroid analogues synthesis of 14:431-444 Chiral steroidal acetal from (27?,4/?)-(-)-pentanediol 14:481,482 from (25',45)-(+)-pentanediol 14:481,482 with organometallic reagent 14:481,482 Chiral sulfamyloxaziridines asymmetric oxidation with 4:489 oxidation of sulfides with 4:489 Chiral sulfoxides 10:671-685 to 3,4-dihydro-6,7-dimethoxyisoquinoline 10:679-685 Chiral sulfoximines intramolecular addition to 10:671-679 to 3,4-dihydro-6,7-dimethoxyisoquinoline 10:679-685 Chiral sulfur reagents asymmetric synthesis with 10:671-689 Chiral sulphoxide (-)-sibirine from 14:747 Chiral synthesis of amino acid 12:477 of 1 -(a-hydroxyalky 1)-1,2,3,4-tetrahydroiso quinolines 12:450 of bioactive natural products 13:84-99 ofbioregulators 6:537-566 of semiochemicals 6:537-566 Chiral synthon with yeast 1:482 for 2-aminoalcohols 12:416-425 Chiral tartaric amides trans-acQtaVization of 4:338,339 Chiral template effect 12:489,500 "Chiral templates" 14:267-281 Chiral tertiary alcohols asymmetric synthesis of 14:491,492 from chiral a-keto acetals 14:491,492 Chiral titanium complexes asymmefric oxidation with 4:489 oxidation of sulfides with 4:489 Chiral vinyl ether alcohols from chiral cycloalkanone acetals 14:486 synthesis of 14:486 Chiral vinyl halide coupling reaction of 12:35,36 with chiral a-methyl-substituted aldehyde 12:35,36 Chiral vinyl sulfoxides intramolecular addition to 10:671-679 Chiral vinyllithium compounds addition reaction of 12:35-62 Chiral w-cyano alcohols from achiral a-methoxycycloalkanone oxime acetates 14:475 synthesis of 14:475 via Beckmannfragmentationreaction 14:475 Chiral ylide from L-malic acid 4:125 Chiral-o-quinodimethanes asymmetric intramolecular 14:502,503 Diels-Alder reaction of 14:502,503 with C2-symmetric acetals 14:502,503 Chiron approach Sharpless oxidation 17:211 a-Chlorinating reagent 6:310 of sulfoxides 6:310 Chlorination 6:310,340 Chloro-/rw-(triphenyphosphine) rhodium decarbonylation with 5:802 Chloroacetoxylation Pd(II)-catalysed 16:443 (a-Chloroalkyl) boronic esters synthesis of 11:409,410 Chloroamine 11:307,308 A^-Chloroamines from A^-chlorosuccinimide 6:437 Hoffmann-Loeffler photocyclization of 6:437 Chloroformate ester-induced reaction ring destruction by 6:477,486 Chloromercuric method in synthesis of 6-deoxynucleosides 4:233 (Chloromethyl) zinc reagent 14:490 A^-Chlorosuccinimide DMSO reaction with 6:310 monochlorinated sulfoxide from 6:310 //-chloroamines from 6:437 Chlorosulfonyl isocyanate cycloaddition with 4:475,477 1 -acetoxy-2-methylbutadiene with 12:150,151 [2+2] cycloaddition of 4:475;12:150,151 Chroman enantioselective synthesis of 1:644,645 Chromanes from isoprene 4:391 from phenols 4:394 in prenylation methods 4:394-396 synthesis of 4:374 Chromium (II) reagents 3:81

1247 Claisen rearrangement 13:29,30,135,142,358,417, 437,438,443,613 Claisen condensation 1:174,49,410,243,99,100 Claisen condensation, dual of dicarboxylic acid derivatives 11:114 with acetoacetate dianion 11:114 Claisen eyelization 9:341 Claisen ester enolate rearrangement 10:339 Claisen reaction in poitediol synthesis 6:36 Claisen rearrangement 1:172,173,563,180,181,230, 251,43,45,78,91,471,243,457,459;8:180;11:471; 16:260,340,439,471,623,627,703,712 [3,3]-Claisen rearrangement applications of 10:416-426 asymmetric quaternization with 10:426-428 carboxylic acid anhydride variation of 4:375 Eschenmoser modification 3:230 ester enolate procedure 3:236,240,241 in ()-9-isocyanopupukeanane synthesis 6:82,83 in ()-africanol synthesis 6:5 in ()-sinularene synthesis 6:78,79 in lactone synthesis 3:252-255 indolo [2,3-a] quinolizidines by 14:722-724 internal asymmetric induction 3:234 Ireland modification 3:77,228 modified 3:228 of 1,5-anhydro-4,6-(9-benzylidene-D-r/Z70-hex-lenitol 10:420 of allyl ester 14:738 of allyl phenyl ethers 4:368 of carbohydrate derivatives 10:416-426 of carbohydrates 3:226 of chiralallylic alcohols 10:418 of cis 2,5-disubstituted dihydrofuran 10:423,424 of dihydropyran derivative 10:425 of(3-hydroxy-l-propenyl)-(3-D-glucopyranose tetraacetate 10:422 of N,0-ketene acetals 3:232 of oxygen substituted systems 3:237-248 of silyl ketene acetals 422,423 ofvinyl ether derivative 10:420 of vinyl ketene acetals 10:234,235 ofxanthones 4:368,370-372 ortholactone procedure 3:236 regioselectivity of 4:368,368 Classical Nazarov reaction 14:612 Cleavage of olefins witht-BuOOHg/HsIOfi 1:445 withMo(CO)6 1:445 Clemensen reduction 12:279,697,698,240;15:197,198 CNBr-induced reaction 6:472-474,476,477,484,486, 488,489,491,492,495,496 Cobalt-stablized carbocations in macrocyclization 3:83,84 coculolidene 3:456,488 synthesis of 3:477,478,488,489 Collin's reagent 16:16 Collins allylic oxidation 6:27 in (-)-dictyolene synthesis 6:27 Collins oxidation 1:312,313,315,316,16,83,84,210; 6:16;11:83,84 Collins reagent 6:115,350,317,335 Collins-Wege intermediate in ()-sinularene synthesis 6:78,79 Conformational control in macrolactonization 11:152-158 Conformational effects 12:115 1,4-Conjugate addition ofelectrophile 10:405,406 to a,p-unsaturated carbocyclic aldimines 10:405, 406 Conjugate addition 3:8; 14:510 Conjugated dienes synthesis of 8:278 Conjugated ketones octant rule for 2:168 Conjugation-deconjugation epimerization 12:14 Controlled crisscross annulation 13:442 Convergent lactone synthon synthesis of 13:604 Cooke's dianion 13:594 Cope elimination 3:470,471,468,494,110 Cope reaction 13:109 Cope rearrangement 1:566,567,182,236,416;3:47,98, 372,139,190,191,249;7:216;10:236 Cope ring enlargement 12:193 Copper (I) catalyzed Grignard additions 10:180 Copper (I) trifluoromethane-sulfonate benzene complex 1:271,272 Copper acetylide 4:396,398 Copper catalyzed Grignard reaction 11:81,82 Corey's oxazaborolidme catalysts 18:182 Corey epoxide 13:568 Corey method 11:154,157 Corey procedure 6:562 Corey reagent 14:268 Corey's lactone 7:480-482 Corey-Kim oxidation 12:338 Corey-Mukaiy ama method 1:271 Corey-Myers synthesis 6:195 Corey-Nicolaou method 12:52,53 CpsZrCb. AgC104 aryl C-glycosides from 10:370 Cram {\,2-syn) coupling product 12:42,43,45,48,50,55 Cram (l,2-5y)-selective coupling reaction of chiralvinylhalide 12:35,36 with A chiral-a-methylsubstituted aldehyde 12:35, 36 Cram addition ofenolates 16:345 of2-lithiofurans 16:346 Cram rule selectivity 1:608 Cram's cyclic model 4:201,491 of 1,2-asymmetric induction 4:201 Cram's rule 14:482;16:350 Cram-selective aldol-lactonization 14:115 Cramer reaction 8:77,80 Crassin titanium-induced coupling 8:19-30

1248 p-Cresy\ methyl ether Birch reduction of 6:83,84 Criegee rearrangement 14:128 Crimmins synthesis 12:11,12 Cross coupling reactions 16:417 intramolecular 10:163 Pd-catalyzed 10:161,162 with (Z)-tributylvinyl-stannanes 10:162 Cross relaxation rates 2:60,61 Cross-aldol reaction of (7i?,8aiS)-8-hydroxy-8-methyl-7-oxoindolizidine 12:297 Cross-aldolisation 12:289,298 Cross-Claisen condensation 11:114 Cross-conjugated hydronaphthalene dienones photochemical rearrangement of 14:356 C2-symmetric diols 14:469-518 chiral acetals from 14:469-518 C2-symmetric ketene acetal 14:505 asymmetric cycloaddition of 14:505 to 3-formyl chromone 14:505 Crossed Aldol reaction asymmetric induction in 4:328,329 Crossed Cannizzaro reaction 4:17,135 Crossed Wittig reaction 4:570 Crossed-Aldol condensation diastereoselective 1:596-603 Johnson-Yamamoto mechanism 1:600 trans-Crotonamide 8:156 c/5-Crotonamide 8:156,157 Crotonates 8:410-412,427 trans-Crotomtes 8:141,147,155 ,157 c/5-Crotonates synthesis of 8:155-157 Crotonyl boronate addition 1:527 Crotyl halide in zinc dust 12:172 with 4-acetoxy P-lactam 12:172 Crotylborane reagent 12:36 Crotylboration 8:477 (-)-(E)-Crotyldiisopinocamphenyl borane 18:280,281 []-Crotylpotassium 8:477 [Z|-Crotylpotassium 8:477 "Crown ether effect" 11:234 Crystallization- induced asymmetric transformation 13:76 Cul-tributylphosphine complex tandem Michael addition with 4:556,557 Cuprate 1:456,457,459,460 Curtius reaction 12:448,458 Curtius degradation 19:145 Curtius rearrangement 1:51,6,309,637,638,19:68,79 Curtius-type reaction 13:95 Cyanide versus isocyanide formation 3:207 Cyano trapping 1:105 2-Cyano-azadiene Diels-Alder reaction 16:458 a-Cyanobenzyl alkyl ether synthesis of 14:473 Cyanoborohydride 8:205 Cyanogen bromide fragmentation of glucoamylase 2:34 Cyanohydrin cyclization of 8:198 synthesis of 8:225,226 Cyanohydrin ether alkylationof 8:177 cyclization of 8:178 Cyantions of acetals diastereoselective 1:612,613 Cyclic P-keto esters reduction with yeast 1:697-701 Cyclic dienes 8:141 Cyclic ene-dione acceptors 4:709,711 in Michael reaction 4:707-709 Cyclic enones 14:502 [2+2] photocycloaddition of 14:502 with chiral a,(3-unsaturated acetals 14:502 Cyclic hexadepsipeptides 13:533 Cyclic ketones synthesis of 6:313-315,332,333 Cyclic peroxides 5:353-355 Cyclic steroidal glycosides 15:59,60 Cyclic sulfides 8:205 Cyclic systems synthesis by modifications of 6:33-38 de novo synthesis of 6:33 Cyclic-Cram diastereoselectivity 12:297 Cyclitol derivatives 7:156,157 Cyclic halo ether compounds from marine origin 19:411-461 synthesis of 19:411-461 Cyclization (+)-(4i?)-a-terpinyI from 11:221,222 acyliminium-mediated 10:125 amide iminium ion 10:87 asymmetric 10:631-633 azido-olefin 13:447,448 bicyclic keto ester from 14:509 by C-C bond formation 10:218-231 by C-0 bond formation 10:202 by diphenyl phosphoryl azide 10:641,644,652, 10:656,657 by sodium bistrimethylsilylamide 6:540 catalytic 8:278 Dieckmann 13:445 ene 8:279 enzymatically controlled 11:287 in silver (I) triflate 12:81 intramolecular 10:631-633 intramolecular 11:253,254 intramolecular 12:156 iodotrimethylsilane mediated 11:109 Lewis acid mediated 10:87 ligase catalyzed 14:304,305 mechanism of 6:314,315 mechanism of 7:335-338,358-360 of (-)-(3/?)-linalyldiphosphate 11:221,222 of(L)-glutamicacid 6:438-440 of acyclic nucleoside derivative 10:588,592 ofallylglycidyl ether 10:588,589 of a-mono-alkoxy lated piperazinediones 12:90 of cyanohydrin ethers 8:194

1249

of epoxy alcohol 10:599,600 ofepoxy ally lie ether 10:590,591 of glucose 11:219 ofhexapeptide 10:289,290 oflycopene 7:334-354 ofneurosporene 7:334-354 ofnitroketone 6:447,448 of oligoribonucleotides 14:304,305 of vinyl sulfoxides 10:673-676 of vinyl sulfoximines 10:679 of a-diazo p-keto ester acetals 14:509 oxetane ring formation by 10:588,589 oxetanocin A synthesis by 10:588-592 palladium catalysed 1:258 reductive 8:278 regioselectivity of 6:540 Rh (Il)-catalyzed 14:509 stereochemistry of 7:338-354 stereoselective 10:110 stereoselectivity of 6:540 transannular 13:440 via SN^ displacement 11:253,254 with copper (II) perchlorate 12:85 with diphenyl phosphoryl azide 10:289,290 with Nicolaou reagent 10:121,122 with pyridinium chlorochromate 11:93,94 Cyclization of ketoesters 4:328-330 Cyclization reaction [2+2] cycloadditions 6:15,43,44 diastereoselective 14:506,507 in (+)-A^^'^^ capnellene synthesis 6:43,44 in cadinane synthesis 6:15 in elemane synthesis 6:15 in germacrane synthesis 6:15 of6-octen-l-al 14:506,507 Rh(I) catalyzed 14:506,507 Cyclized branched oligoribonucleotides 14:486,489 Cyclo-octanoid terpenes synthesis of 6:33-36 1,3-Cycloaddition 1:448,449 [2+2]-Cycloaddition 1:263,343;4:475;8:207,45,185; ll:15-20,45-47;12:l 16,150-152,160,161,173,193,416; 15:266;16:127,470,732,733 carbocyclic oxetanocins synthesis by 10:610-616 enantioselective 10:610-616 in homoerythrinan synthesis 3:481,478 ofallene 16:127 photochemical 16:12 5,469 with dichloroketene 13:6,36 synthesis of quinoline skeleton 3:385-397 [2+2]-Cycloaddition-fragmentation 12:194,195 [2+3]-Cycloaddition 4-oxo-erythrinans by 3:469 [3+2]-Cycloaddition 8:402,19:66,78,80,174,367 of 2-azaallyl fragments 1:324 ofazomethine 8:402 of azomethine ylide 19:80 intramolecular 19:367 stereospecific 19:367

[3 +2] -Cycloaddition reaction 12:155 ofnitrone 12:155 to benzyl crotonate 12:155 [3+4]-Cycloaddition 1:378,522,523 [471+271]-Cycloadditions 1:566-571 intramolecular tropone-olefm 1:568 inverse electron demand 1:566 with tropone as diene 1:566-571 [4+2]-Cycloaddition 1:282,323,420,465,8:207,45,185; 11:11,13,14,16,260-267;16:4,444,493,732;19:108109,148,221,227 acid catalyzed 4:4 base catalyzed 8,9,11,12,22,23 cycloaldolization 4:4,11,17,18,22,23 diasteroselective 12:424,425 high pressure Eu (fod)3-mediated 4:121,143 in (+)-A-^^*^^ capnellene synthesis 6:43,44 in lincosamine synthesis 4:154 in purpurosamine C synthesis 4:115 of2-alkenyltropolones 5:799 of 3-[( 1 S)-2-exo-alkoxy-1 -apocamphanecarbonyl]-2oxazolones 12:424,425 of a-amino aldehydes 4:111 of kojic acid 5:799 reverse stereoselectivity of 4:122 to dialkyl azodicarboxylates 12:424,425 transannular 5:796,797 [4+4]-Cycloaddition 11:17 [5+2]-Cycloaddition 8:160-163,16:552,553;12:260,261 [67C+471]-Cycloaddition 12:238 [6+3 ]-Cycloaddition 1:569 [6+4]-Cycloaddition intramolecular 1:571 of cyclopentadiene with tropone 1:570 ofdienes to tropone 1:569-571 of2-alkenyltropolones 5:799,800 [8+2]-Cycloaddition 1:568 Cycloaddition 16:7,47 1,3-dipolar 1:247-250 asymmetric 1:371-375;11:300 by 3-hydroxy-1-arylthiobutene 4:477 by chlorosulfonyl isocyanate 4:475 -exo-transition state 1:370,371 enolate induced 1:502-503 intramolecular [3+2] 1:247-250 intramolecular [4+1] 1:247-250 intramolecular nitrile oxide [INOC] 1:477,480,481 ionic 5:793 lanthanide catalyzed 1:413,415 MgBr2 mediated 1:474 Ni (O)-catalysed intramolecular 3:78,79 of (N-acryloyl) boman-10,2-sultam 11:307,308 ofalkene 11:468 of levoglucosenone 14:270,271 of olefmic ketone 1:693 photochemical [2+2] 1:548 stereoselection 1:370,371 TicU-catalyzed 11:307,308 with bisketene 4:349 with cyclopentadiene 11:307,308 with ethoxycarbonyl formontrile oxide 11:468 with unactivated olefins 1:338

1250

Cycloaddition processes 12:250-261 for tigliane ring system 12:250-261 Cycloaddition reaction 14:502-505,747,19:226 diastereoselective 14:502-505 with 1-trimethyl silyloxybutadiene 14:747 of quinone monoketals 5:796,797 Cycloadduct chiral synthon of 2-amino alcohol from 12:425 /ra5-4-methoxy-2-oxazolidinone from 12:425 [5+2]-Cycloadducts 16:555-559 [4+2]-Cycloadducts 16:732 [2+2] Cyclobutane formation 10:611,613 Cyclobutanes protic acid rearrangement of 16:553 rearrangements of 16:554 Cyclobutanone oxaspiropentane rearrangement by 10:618 Cyclobutanone-ring expansion 3:23,24 Cyclocondensation and///reo-selectivity 4:130,145 Lewis acid catalyzed 11:446-451 Mg Br2-catalyzed 11:451 MgBr2 catalyzed 1:415,417 with Ce(OAc)3-BF3.0Et2 1:420,421 with Danishefsky's diene 4:122,130 withEuFOD 1:420,421 with I-serinal 4:122 with A^,0-protected a-amino aldehyde 4:130 with silyloxydienes 4:113 Cyclodecadienone by [3+3]-Oxy-Cope rearrangement 8:247 by Diels-Alder reaction 8:249 photocycloaddition 8:250 Cyclodimerization withDEPC 4:92,93 of tetrahydroisoquinoline precursors 6:495 Cycloftmctionalization ofethylurethanes 6:427,428 with phenylselenyl chloride 6:427,428 Cycloheptenone enolate in perforenone synthesis 6:29,30 Robinson annulation of 6:29,30 Cyclohexane ring system annulaton of 6:5,6,29,30 1,2-Cyclohexanediones bis-Fischer indolization of 12:376,377 Cyclohexanone 8:36 aromatization of 14:637,638 by chiral lithium amides 571,572 kinetic deprotonation of 14:571,572 prochiral 4-substituted 14:571,572 Cyclohexanone aldehyde 6:61 bromochamigerene from 6:61 spiroannulation of 6:61 spiro[5.5] undecenone derivativwe from 6:61 2-Cyclohexen-1 -one aldolsfrom 11:337,338 kinetic deprotonation 11:337,338 with 4-pentenal 11:337,338 Cyclohexene derivatives synthesis of 4:581

Cyclohexene imides arcyriaflavin A from 12:378 6/5-2-chlorophenylhydrazones from 12:379 N-methylarcyriaflavin A from 12:378 trans -Cyclohexenecarboxylic acid by Diels-Alder addition 11:340,341 from ()-crotonic acid 11:340,341 from butadiene 11:340,341 deprotonation of 14:658 with lithium diisopropyl amide 14:658 Cycloisomerization of cis, c/5-3-carboxymuconic acid 8:297 Cyclopentane annulation 13:6,16 Cyclopentane ring system annulation of 6:6-8,30,31 Cyclopentanol formation of 14:647 in 5-alkoxy ketones 14:647 ring expansion of 8:245 Cyclopentanone 1-piperidenines from 6:428,429 Cyclopentene armulation 13:14 Cyclopropanation diastereoselective 14:489-491 exo 1:252,253 intramolecular 16:222 of allylic alcohol-acetal 14:490,491 of diazo ketones 3:39,40 of ten-membered enones 8:179 of unsaturated acetal 14:490 with Me3S(0)I-NaH 8:186 with oxysulfurane 8:183 Cyclopropane ring opening 1:250-253 Cyclopropanone sliding reaction 6:37,48 (+)-A-^^'^^-capnellene from 6:48 in (+)-dactylol formation 6:237 in eight-membered marine compounds 6:37 Cyclopropyl imine acid catalysed rearrangement 1:250,251,296 Cyclopropyl ketones 2:168,169 Cyclopropyl-carbinol rearrangement 3:23 Cycloreversion 4:609 Cycopentannulation 1:551,552

D-glyceraldehyde derived allylic alcohols Johnson-Claisen rearrangement of 10:436,437 D-mannono-nitriles catalytic hemihydrogenation of 10:463 Nef reaction of 10:464 (+)-Dactylol cyclopropanone sliding reaction in 6:37 Dakin reaction 9:341 Danishefsky's diene 1:460,474;4:122,130,132;8:207; 13:565;14:18,636-638;16:474,496,654 Danishefsky synthesis 12:12,13,15 of mitomycins 13:443 of avermectin Ala 12:12,13,15 Danishefsky's pyran synthesis 1:460,407 Dansylation 9:547,549 Darzens-Nenitzescu condensation 19:235

1251

Darzens reaction 17:612 DCC-HOSu procedure 6:407,409 DDQ (2,3-dichloro-4,5-dicyanobenzoquinone) 11:156, 165 DDQ 8-10,14,18 De-isopropylidenation 4:200,201 De-A^-protection via hydrogeno lysis 11:270 De-0-Acetylation 14:230,232 De-0-benzylation 12:37,38,52 Deacetylation 1:10 Deamination 1:681 of (7?)-2-aminohexadecanoic acid 1:681 Debenzylation 11:253,254;19:110,115 Debenzylidenation by Hanessian procedure 12:347 Deboronation 11:412,413 Debromination 4:336,337 Debromoaplysiatoxin 18:295,297,19:219 (2,4Z)-2,4-Decadienal 10:151 (2^,4)-2,4-Decadienal 10:151,155 /ram-Decahydro-5,8a-dimethyl-1,6-naphthalenedione derivatives 10:461 (+)-/ra5-Decahydroquinoline 219A 19:4,7 Decarboalkoxylative cyclization alkaline 14:720-722 indolo-[2,3-a] quinolizidines from 14:720-722 stereochemical course of 14:720-722 Decarbomethoxylation with MgCb/DMSO 3:473 with CaCyOMSO 3:475 Decarbonylation Rh (I)-catalysed 3:308,309 with Wilkinson's catalyst 11:263 with chloro-/r/5-(triphenyphosphine) rhodium 5:802 Decarbonylation -iminium ion cyclization 4:38,39 Decarboxylation of P-keto ester 16:371 ofanthrones 11:121 of 2-methyl-3-buten-2-yl acetate 11:130 Pd-catalyzed 11:143,144 of vinylogous P-keto acid 14:678-681 Decarboxylative condensation 11:195 Deconjugation 1:464,465 Deconjugative alkylation 4:38 Decyanation 6:431-433 Defluorination of2-fluroestradiol 5:477,453,455 Degalactosylation 7:55 Degradation ofaureol 9:31,32 of enantio-sigmoscQptreWin-A 9:28,29 ofgeraniol 7:104,105,116 ofnerol 7:105 ofa-pinene 7:106 Dehomologation 12:95 Dehydration with Burgess reagent 10:124 of A^-monosubsituted formamides 12:113 Dehydrobromination 11:341,342 Dehydrobruceantin 7:374

Dehydrogenation in CI(NO) mass spectra 2:3,4 of amines 4:54 withCMD 4:85 with DDQ 1:8,9,59 with other oxidants 4:85 with palladium black catalyzed 14:763 with p-toluene sulfmyl chloride 4:54 with selenium reagents 14:440 with sulfur catalysis 14:763 Dehydrosulfmylation 6:342 Deketalization 14:678,679 DeMayo reaction 3:74,75,102,103 Demercuration with sodium borohydride 1:671,672 Demethoxycarbonylation by Welch procedure 10:308,309 Demethylation 1:8,9 6-Deoxy-5 -enohexopyranoside Ferrier reaction of 10:510 Deoxygenation of/er/-alcohol 19:516 radical 516 withAIBN 19:516 withBujSnH 19:516 9-Deoxygoniopypyrone 19:463,19:497 1 -(2-Deoxy-a-D-ribo-hexopyranosyl) cytosine c/5-principle 4:586,587 endo-ru\Q 4:587 in biogenesis 4:615-617 intermolecular 4:587-595 intramolecular 4:595-603 inverse electron demand 4:579,580,604,605 lysergic acid by 504,605 manaomycin A by 4:591-593,609 mechanism of 4:579,580 monomorine I by 4:606 nanaomycin d by 4:591-593 nepetalactone by 4:604,605 of acylnitroso 4:606 oxazoles in 4:604 palitantinby 4:588-590 prostaglandin by 4:607 pumiliotoxin by 4:584,585 regiochemistry of 4:584-586 retro 4:609-615 solanapyrone 4:598,599 stereochemistry of 4:586,587 stereochemistry of cycloaddition 4:122,123 terramycin 4:609 tetrazines in 4:604 triazines in 4:604 triquinanes by 4:588 vemolepinby 4:584,585 volume of activation 4:112 with heterodiene systems 4:583 with ketenacetals 4:357 with modified cyclohexadienes 4:583 with N-sulfmyl dienophile 4:356 with o-quino demethone 4:583,584 with a-amino aldehydes 4:120 P-santalene by 4:607,608

1252 Deoxygenation withPBrj 1:391,392 ofD-glucose 11:219 by zinc-copper couple 4:424 by zinc-dust 4:424 of ascorbic acid 4:420-423 DEPC cyclodimerization with 4:92,93 Dephenyl thiolation 14:306 Deprotection of oligonucleotides 4:282,283 of triethyl silyl group 4:533 with tetra-A^-butylammonium fluoride 6:119-122 Deprotection of alcohol with TMSCl/Nal 1:558 Deprotonation LDA-mediated 10:425 of allylic ester 10:425 of 3-C-methyl-3-deoxy-2-ulose derivative 10:414, 415 withA^-lithio-2,2,6,6-tetramethyl-piperidine 10:414,415 asymmetric 11:241,242 azabicyclic ketone 11:241,242 Desilylation with HF-pyridine 8:263 of N-(trimethylsilyl) methyl iminium ions 1:325, 328 with cesium fluoride 1:249 Dess-Martin oxidation 19:370-371 Dess-Martin periodinate 19:357 Desulfonylation 19:77;11:349 Dethioacetalization 12:348 Detritylation 4:276-279,282,284 Di-C-alkylation 10:413 of D-mannose derivative 10:413 3,4-Dialkoxyfurans Diels-Alder cycloaddition 12:19,20 with alkyl coumalates 12:19,20 Dialkyl azodicarboxylates [4+4] cycloaddition of 12:424,425 to 3-[( 1 S)-2-exo-alkoxy-1 -apocamphanecarbonyl]2- oxazolones 12:424,425 Dialkylation 6:332,341 Dialkylboranes 9:366 Dianion alkylationof 11:284,285 condensation of 12:9,10 from4-[/er/-butyldiphenylsilyl)oxy]-2-(tributylstannyl)- ()-2-buten-l-ol 12:9,10, ofFAMSO 6:323-325 stereoselective 11:284,285 with l-TMS-2-pentyne 11:284,285 with a,(3-epoxy cyclohexanone derivative 12:9,10 Dianion aldol condensation 12:69 Diastereoconversion 12:479 Diastereolselective alkylations 1:613-616 Diastereolselectivecyclopropanations of a,p-unsaturated acetals 1:629-632 Diastereodifferentiatingisomerization 4-hydroxy-2-cyclopentenone acetal from 14:510 ofmeso-3,4-epoxycyclopentanone 14:510 Diastereofacial selection 13:62-70 Diastereofacial selectivity of chiralepoxidizing agent 4:172,173 Diastereomeric resolution 1:585-588 Diastereoselection 10:215 1,2-Diastereoselection 4:443,448,451,472,474 Diastereoselective acetylenation 611,612 Diastereoselective addition of chiral aryl Grignard reagents 14:508,509 to carbonyl compounds 14:508,509 of Grignard reagents 1:621 toketals 1:621 Diastereoselective alkylation 17:324 Diastereoselective cyanation 14:473 Diastereoselective cyclizations 1:590,591 Diastereoselective cyclopropanation 6:544,545 Diastereoselective eliminative cleavages 1:618,619 Diastereoselective halolactonization 1:620,627-629 Diastereoselective Michael addition 6:86,87,286 Diastereoselective reduction Johnson-Yamamoto rationale 1:595 ofcarbonyls 1:622 Diastereoselective synthesis of(37?,47?)-staine 12:479-481 of 2(a-hydroxyalkyl) piperidines 12:453 of4a-aryldecahydroisoquinolines 12:456-463 of 6-hydroxy-4a-phenyldecahydro 12:457 ofB/C-trans-morphinan 12:464-471 of octahydroisoquinolines 12:457 of piperidine derivatives 12:471 of pyrrolidine derivatives 12:471 Diastereoselective synthesis ofmethylphosphonate 13:276-278 ofphosphorothioate 13:276 Diastereoselectivity 11:359 Diastereotopic groups 17:481 Diastereoselectivity 16:372 Diazidation 10:465 Diazoketone cyclization 1:492 from adenosine 10:593-595 preparation of 10:593-595 Wolff rearrangement of 10:593-595 Diazoketone insertion copper mediated 1:555,556,564 cyclization 1:492 Diazomethane 1:404,405,439 esterification 1:404,405 methylation with 1:435 ring expansion with 3:12 sugar aglycone linkage cleavage by 7:155,156 Diazotization 3:325,226 DIBAH reduction 6:428;14:634;19:172 (DIBAL-H) reduction of a,p-unsaturated ester 10:428,429 DIBAL 1:177;14:529,530;19:318 reduction with 6:285,286,293,294,288,299,549,550; 11:432,457;13:456,464,465;20:67

1253 Dibutyltin oxide for stannoxane preparation 1:274 a-Dicarbonyls synthesis of 8:262 P-Dicarbonyl 10:343-348 Dicarbonyl coupling by Mukaiyama procedure 3:99 intramolecular 11:345,364-467 with TiCyLAH 3:80,81 with TiCyZn-Cu 3:80,81 Dichlorocarbene addition 10:413 Dichloroketene [2+2]cycloaddition with 13:6 (Dichloromethyl) boronic ester synthesis of 11:409,410 (Dichloromethyl) lithium 11:410 Dichloromethylenation 3:223 Dichloromethylphosphine 13:276 Dicyclohexylborane 4:116,117 Dicyclohexylcarbodiimide 12:328 Dieckmann condensation 3:289,338,339,191;8:192, 284,293 of ethyl 2-[l-(2-ethoxycarbonylmethyl) piperidinyl]proponoate 12:284 of ethyl 4-[l-(2-ethoxycarbonyl pyrrolidinyl)] butyrate 12:293 Dieckmann cyclization 1:183,340; 10:328,408,410,411; 12:126,147,279,308,445;13:546,25,26,117,131-133, 17;14:34,35 Diels Alder dimerization 2:122,128 Diels -Alder reaction asymmetric 12:26,27 cycloaddition 16:7,219,245,422 facial selectivity in 10:351 intermolecular 12:19,20,380 intramolecular 10:409;12:19,20,380;16:4,24,456 inverse electron demand 16:433 Lewis-acid catalyzed 12:26,27 of 3,4-dialkoxyfurans amides 12:19,20 of amine 16:474 of butadiene 11:340,341 of dimethyl acetylenedicarboxylate 12:379,380 of enantiomeric tetraenic acid derivative 10:409 ofenedione 16:28,34 of levoglucosenone 14:270,271 of A^-furfiiryl-P-chloroacryl amides 12:19,20 of pyranose diene 10:351 ofstyrene 16:555 precursor of 16:5,261 transition state of 16:5 with ()-crotonic acid 11:340,341 with bis (nitrophenyl) butadiene 12:379,380 with Danishefsky diene 16:10 endo Diels-Alder adduct in ()-precapnelladiene synthesis 6:33,34 Diels-Alder adduct 6:84,85,125,340,451;4:388,389 Diels-Alder chemistry of bicyclic intermediate 16:9 Diels-Alder equivalents 3:4 Diels-Alder reactions 20:769,770 "ortho" adduct formation 4:584 (+)-capnellene by 4:588 (+)-coriolin by 4:588 (+)-hirsutene by 4:588 acylnitroso 1:386 adduct 1:8,9,15 asadiene 3:311,437-441 asymmetric 4:334-336,596-598,606-609 asymmetric intramolecular 14:502,503 atomic orbital coefficients in 4:585,586 betaenoneBby 4:601,602 cadinane by 584,585 cholesterol by 4:587 coronafacic acid 4:590,591,596,597 diastereoelectivity of 4:441 dienesin 4:581-584 dienophiles in 4:584 diplodiatoxin by 4:500-602 effect of Lewis acids 4:586 Eu (fod)3-mediated 4:121,122,143 exo versus endo transition state 1:373-374 for bicyclic compounds 8:410 frenolicinby 4:591,592,594,609 gephyrotoxin 223AB by 4:606 hetero 1:478 heterodienes in 4:583 heterodienophiles 4:112,583 high pressure 4:112,121,122 imino 1:288,289;4:604,605 iminodienophile in 4:604,605 in anthracyclinone synthesis 1:502,503 in synthesis of quinolines 3:387-397 intermolecular 19:464 intramolecular 1:71,347,478,479;3:79,80; 8:403-406;10:51,52,155,156;ll:l 1,92,93, 99-108;12:253;13:108-l 15,117-141,144,149; 14:735;19:11,464 intramolecular imino 1:385-382 intramolecular nitroso 1:379-381,383 inverse electron demand 3:311 Lewis acid catalyzed 8:141 nitraramine by 14:751-754 non-catalyzed reaction 8:142 N-sulfmyl cycloaddition 22,23 odd carbon equivalent 3:419 of 1,3-butadiene 19:68 ofchiral l;3-dieneacylnitroso 19:11 of chiral o-quinodimethanes 14:502,503 of daunosamine derivative 10:375 ofenal 19:66 offuran 19:366 of furan dienes 12:253 ofimines 3:55 ofisoprene 19:226 of methyl-()-3-acetoxyacrylate 11:306,307 of A^-carbomethoxy pyrrole 19:77 of A^-substituted pyrroles 19:77,226 of optically active nitroolefin 19:144 oforthoquinodimethane 11:92,93 ofperezone 5:768 ofpyridyldienophile 19:75 regioselectivity 12:16,17 retro-Diels-Alder reaction 14:821,822 stereoselectivity 12:16,17

1254 stereospecific 19:6 with 2-azaallyl aniions 1:347 withacetal 14:502,503 with butadiene 11:356,357 with Danishefsky diene 19:144,208 with doubly activated butadienes 3:465 withisoprene 11:306,307 with ketoester 19:226 with methyl vinyl ketone 19:208 with nitroso compounds 1:359-392;12:16,17, 250,253,416 with p-quinonediimide 3:322-323 Diels-Alder sequence asymmetric 11:359 in ()-A^^'^^ capnellene synthesis 6:46 in()-12-deoxy-scalaradial 6:58 Diene dimerization 3:107 Ni(0)-catalysed 3:107 Diene isomerization 1:447,448 Diene synthesis 6:308 Diene-carbenoid addition 3:49 . a-Dienes cyclopenthesis from 3:38,39 p-Dienes synthesis of 3:38,39 Dienes 4:525 formation by reductive elimination 4:525 1,3-Dienes cyclization of 8:278,280 palladium catalyzed 8:280 Dienol disilyl ehters Lewis acid cataylzed 12:172 with 4-acetoxy-p-lactam 12:172 Dienone-phenol rearrangement 2:253,615,625,628; 19:406 Dienophiles from L-ascorbic acid derivatives 12:17 synthesis of 12:17 in Diels-Alder reactions 4:583 Diethyl amino (di-^butoxy) phosphine 14:305 Diethyl phosphorocyanidate (DEPC) 4:83 Diethylaluminum cyanide 3:213 co,0)'-Dihalides 4:560-563 1 ,(o-Dihaloalkanes 6:313,314 ketones from 6:313,314 Dihydroxylation 11:423,424 Diisobutylaliminium hydride 1:523,324,353,4:589,590 Diisobutylaluminium 6:115 Diisobutylaluminum hydride-A^-butyllithium "ATE" complex 14:595 Dilithium (cyano) dimethyl cuprate 11:361 Dilithium (cyano) divinyl cuprate 11:360,361 a-Dimethylation in (+)-brasilenol synthesis 6:8 Dimethylchlorosulfonium chloride 9:526 Dimethylsulfoxonum methylide 6:550,551 Dimsyl sodium 6:482,492,493 DIOP 13:72 - Dioxygenation 9:560,561,566,567,570,573,575 /^-Dioxygenation 9:574,575 Diphenyl phosphane chloride 9:524 Diphenyl phosphorazidate (DPPA) 4:83 Diphenylphosphoryl azide 10:289,290 ,641,644,645, 652,656,657 Diphosgene 12:113 1,3-Dipolar addition 1:230,231,291 Dipolar [3+2]cycloaddition 19:155 Dipolar cycloaddition mtramolecular 13:84-86;19:42 intermolecular 19:309 of methyl acrylate 19:309 ofalkenes 16:463 of nitrile oxide 16:464 to 3-oxidopyrazinium 10:135 1,3-Dipolar cycloaddition 1:227,278,284,285,324-344, 4:435;10:65,66,138,139,215,216,11:238-241,264,283 [3+2]Dipolar cycloaddition 13:500,191 Dipolar cycloaddition 3:223 D-(+)-DIPT 19:445,480,490 D-(-)-DIPT 19:490 DIPT 4:172-174,179,186,187 Diradical trapping 3:20 Direct cw-hydroxylation 14:183 Directed hydromagnesiation 10:29,30 Directed-aldol condensation 15:15 Dirhodium tetrakis (trifluoroacetate) 10:210 Discriminative functionalization in hexopyranoses 10:415 of geminal dimethyl groups 10:415 Disiamyl borane (bis(3-methyl-2-butyl) borane 14:183 Disiamylborane 4:116,117 Dissymmetrization enzymatic 19:45 of we^o compound 19:45 Disulfide bond 2:28,30 1,3-Dithialane system synthesis of 1:537 Divinyl cyclopropane rearrangement 12:246, 12:247 DM-CCK sonication 18:844 DMAP (4-dimethylaminopyridine) 11:154,157 DMAPP 7:98,110,11:201,202,19:520 DM AT synthase 11:202 DMDP (2,5-dihydroxymethyl-3,4-dihydroxypyrrolidines 7:13,14 DMSO 6:310,329,330 Doebher-von Miller quinoline synthesis 1:171 Double cyclization reaction 10:121,122 Double dioxygenation 9:560,561 Double indolization 1:8,9 Double Michael addition with extended acceptors 8:414,415 with substituted a,b-unsaturated esters 8:412-414 with 2-trimethylsiloxy-cyclohexadienes 8:417 with a,p-unsaturated ketones 8:418 Double Michael reaction 3:143,144,735 Edgar-Greene-Crabbe' intermediate 14:365 ' Edman degradation 2:33;9:489,499,549,551;19:797 Ehrlich products 13:300 Ehrlich's reagent 9:592;19:755 Eight-carbon sugars by epoxide route 4:172-175

1255

by osmylation 4:163-175 synthesis of 4:163-175 Eight-membered marine compounds biosynthesis of 6:37 by cyclopropanone sliding reaction 6:37;210,218220,224-226,234 Eight-membered rings by anionic oxy-Cope rearrangement 3:77 by [4+4] annulation 3:78 by dicarbonyl coupling 3:81 by Michael additions 3:83 by Nicholas reactions 3:83,84 by retroaldolization of enone-ene-photo adducts 3:74,75 by ring contractions 3:76,77 by transannular acylation 3:81,82 from allylchromium-carbonyl coupling 3:81 synthesis of 3:73-111 Electrochemical oxidation ofazulenes 14:325 ofguaiazulene 14:325,326 Electrocyclic rearrangement 6:72 Electroenzymic reactions 20:877 Electrolysis 19:35 Electromicrobial dehydrogenation 20:867 Electromicrobial reductions 20:877 Ti-Electron SCF-CI-DV MO method 17:39-40,45,47 Electron-demand 17:553 Electron mediators 20:821-824 1,4-Electrophilic addition 1:487,488 Electrophiles 19:464 Eleven-carbon sugars by osmylation 4:188 synthesis of 4:187-190 Elimination 16:366,416 P-Elimination 11:184 5y-Elimination 11:184,188 1,4-Elimination 11:187 p-Elimination antiperiplanar 12:17 of 3-mesyloxy-l-threonate 12:17 stereoselective 12:17 Hiinnig base-mediated 14:291,292 Elimination thermal 4:44,45 enantioselective epoxidation 4:29,30,343-345 by molybdenum (VI) oxodiperoxo complexes 4:344,345 by Sharpless procedure 4:29,30 of non-ftinctionalised olefins 4:344,345 Elimination 6:540 P-Elimination reaction 10:593 y-Elimination 19:165 Elimination with KN(SiMe3)2 1:440 Elimination-addition mechanism 14:457 Eliminative cleavages 1:618,619 Enamide photocyclization non-oxidative 3:404-406 reductive 3:407-410,414 Enamide-aldehyde cyclization 14:772-779 Enamidines 6:430,431 Enamine formation 1:452

Enamine related substrates 18:315-386 Enamine-aldehyde cyclization ()-corynoline by 14:785-787 ()-ll-epicorynolineby 14:785-787 ()-l 1-epiisocorynoline by 14:785-787 ()-isocorynoline by 14:785-787 Enamines acid-catalyzed 14:791-793 cyclization 14:791-793 reactions with acetylenes 3:95,96 singlet oxygen cleavage of 8:261 (3-Enamino imine substrate 18:343,366 (3-Enaminoesters cyclization of 14:738 dehydropyrrolizidines from 14:738 Enaminosulfoxides in a-ketoacid derivatives synthesis 6:317,318 Enantiofacial selection asymmetric synthesis by 13:70-73 Enantiomeric chiral auxiliary 12:342 Enantioselective epoxidation 6:445,446 fermentative reduction 6:158 hydrolysis 13:54 Michael addition 6:86 oxidation 13:54 reduction 13:54 Sharpless epoxidation 6:287 transesterification 13:53,54 Enantioselective hydrolysis with Candida cylindracea 12:337 with Pseudomonas sp. 12:337 Enantioselective reactions 16:559 Enantioselective reduction 18:288 Enantioselective synthesis of (-)-(1 R-^diS)-1 -hydroxyindolizidine 12:281 of(-)-slaframine 12:311,312 of (-)-Y-rhodomycinone 14:14-17 of (+)-(15,8a5)-1 -hydroxyindolizidine 12:281 of (+)-stoechospermol 6:39,40 of 2,5-dialkylpyprrolidine ant alkaloids 6:443 of 7,20-diisocyanoadociane 6:86,87 of epz-lupinamine 14:741,742 of kaurane-type diterpenes 14:546 oflupinamine 14:741,742 ofsolenopsinB 6:429,430 of spirovetivane-type sesquiterpene 14:546 Enantioselective yeast hydrolysis 12:338 Enantiospecific synthesis 4:625;12:313,314,317,318 Enantiotopic discrimination asymmetric synthesis by 13:60-62 Enders reagent 4:327 Endiyne antibiotic 10:154 Endoperoxide rearrangement 4:419,420 Ene cyclization 1:294,159,17 Ene reaction of 17(20) 2/pregnenes 10:59 intramolecular 11:91,108 intramolecular 16:17,246 of acryloyl chloride 16:246 of A^-sulfoxyl imines 16:17

1256 intramolecular 3:21 metallo-variant 3:21 ofmalondialdehyde 6:225,226 Ene-quinone-methide 5:744,747,749 Ene-type reactions 1:616,617 Engler synthesis 14:692-695 Enoate triol enantioselective 12:15 from (-)-quinic acid 12:15 synthesis 12:15 Enol ether reaction with azetidinone 4:437 enterobacteriaceae 4:196 triheptoses in 4:196 Enol silyl C-glycoside 10:342 Enol silyl ether (enolate) 12:160,161,163,164 3-Enol-17,21 -triacetate 9:416-418 Enol-acetate nucleosides synthesis of 4:237 Enolate alkylation 14:738 Enolate Claisen rearrangement 10:340 Enolate formation LDA-mediated 10:410,411 of Y-lactone 10:410,411 Enone 8:176-178,181,183-186,191;11:344 -Enone 8:177 Z-Enone 8:177 A2,3Enone 12:25 Enone epoxidation 10:36 Enone-alkene photocycloadditions 6:33,34 Enones 10:352-354 Enyne 8:277-281 Enyne carbocyclization 12:263 Enzymatic aldol condensation 10:535,536:11:216 Enzymatic coupling 2:392,394,396,398,399,401 Enzymatic cyclization 7:100 Enzymatic enantiotopic differentiation 13:624 Enzymatic oxidation of sulfides 14:517,518 sulfoxides from 14:517,518 Enzymatic reaction 16:108,110,111 Enzymatic reduction 12:338,58 Enzymatic synthesis of oligonucleotides 13:279,280 Enzymatic transesterification 13:55 Enzymatically controlled 11:287 Enzyme catalyzed conversion 2:372 Enzyme catalyzed reactions 7:29 Enzyme-aided enantioselective acylation 18:428 Enzyme-aided enantioselective hydrolysis 18:426-428 Enzyme-carbohydrate interactions 7:29-86 Enzyme-catalyzed acylation 12:346 Enzyme-catalyzed reactions 9:612,176 Enzymic galactosylation 10:469 Epimerization 6:558,559,367 Epoxidation enantioselective 16:571 hydroxy-directed 19:259 of allylic alcohol 16:342 ofcannabidiol 19:236 of enol 19:259 of enolsilyl ether 16:332 of ketone 8:182 oflimonene 16:229 of methyl perillate 6:545 of stigmasterol 16:334 of vinylsilane moiety 16:268 of a,(3-unsaturated ketones 16:571 of a-patchoulene 16:151 regioselective 1:436,439 Sharpless 12:236 Sharpless asymmetric 1:278,279,507,508,510 stereoselective 8:179-182;16:349;19:372 with alkaline hydrogen peroxide 16:349 witht-BuOOH-KH 8:180-182 with t-BuOOH-Ti (OPr-i)^ 3:100,101 with Vo(acac)2/t-BuOOH 1:436,439 C (2,3)-P-Epoxidation of allylic alcohols 10:39,40 Sharpless 10:39,40 with VO (acac)2-TBHP 10:39,40 Epoxide alkylation 14:746 Epoxide opening acid catalysed 1:439 cuprate mediated 1:536 organo cuprate mediated 1:536 with cuprate 1:456,457 with dimethyl cuprate 1:523 withRedal 1:538 Epoxide rearrangement 6:550,551,136 a-Epoxide reduction 4:418 Epoxide-ftiranoid rearrangement 6:162 Epoxidisation system 7:105 Epoxy allylic ether cyclization 10:590,591 fromD-ribose 10:590 synthesis of 10:589,590 a-Epoxidation 11:383 Epoxidation 11:470 Eschenmoser reaction 8:211 Eschenmoser ring contraction 9:601,602 Eschenmoser-Claisen rearrangement 10:417,419-421, 427,428 Eschweiler-Clarke methylation 10:84,165 Eschweiler-Clarke reaction 1:203,384,385 Ester enolate Claisen rearrangement. :236,246,259, 3:261-265,267-270,274-276,278-280;14:497 Ester epimerization 1:466 Ester exchange reaction 4:519 Ester type glycoside linkage 7:154,155 Esterase 13:303 Esterification 4:91,92,276,292,391,409,412,413 Etherifiction 4:718-720 Eu (fod)3-mediated [4+2] cycloaddition 4:121,122,143 Diels-Alder reaction 4:121,122 Eu(hfc)3 4:326 Eu FODTM cyclocondensation using 1:420,421 Evan's alkylation 19:62 Evan's reduction 18:253 Evan's asymmetric strategy 12:435,436 Evan's chiral auxiliaries 12:435-438

1257

Evan's rearrangement 16:296 Evan's-Cope reaction 12:193 Evan's-Cope ring expansion 12:192 Evans aldol methodology 16:483 Evans asymmetric alkylation 1:455,456,469,604 Evans asymmetric induction procedure 14:534 xo addition 8:160,161 Exo orientation 14:753 Exo-enol tautomer 14:101

7t-Facial selection 12:419-422 in methoxybromination 12:419-422 in methoxyseleny lation 12:421,422 reversed 12:419-422 Facial selectivity 10:36 FAMSO aldehyde synthesis by 6:311-313 alkylation of 6:313 allylationof 6:315,316 dianion of 6:323-325 methyl methylthiomethyl sulfoxide in 6:309-325 organic synthesis by 6:311-323 oxidation of 6:311 preparation of 6:309-311 Fast oligonucleotide deprotection (FOD) 13:266 Favorskii reaction 6:335 Favorskii rearrangement 8:225;10:410;16:242,20:69,70 Felkin-AHN model 11:234,440,474,643;12:21;19:474 Felkin-ANH conformation 3:255,134 Felkin-ANH transition state 1:402,406,423 Felkin-Nguyen (Anh) 8:213 Ferredoxin-NAD oxidoreductase 20:835 Ferrier reaction 10:347,419,510,433-437 Ferrier rearrangement 13:191,200,201,203,210 Ferrier-type reactions elimination-addition by 3:212,213 filifolone 3:40 synthesis of 3:40 Ferrous sulphate reduction 4:422,432 Fetizon oxidation 4:340,343,370 Fetizon reagent 18:28 Fetizon's intermediate 12:196,198 Fetizon's photochemical route 12:195 Fetizon's reagent 1:508,349,366,570 Fischer carbene complexes 1:505,506 Fischer indole reaction 14:845 Fischer indole synthesis 1:79,144,152,284;11:285,492 Fischer indolization 1:15,51,60 Zjw-Fischer indolization 12:376,377 Fischer projection 11:422,423 Fischer-Helferich procedure 4:222 Fischer-Kiliani synthesis 4:157-159,175,179 Fisher-Irwin test 9:386 Fitzsimmon cycloaddition 11:447 Flagpole type interaction 14:736 Flash pyrolysis 1:250 Flash vacuum pyrolysis 3:27,588 Flash vacuum thermolysis 1:337 Fluorination 13:81-83 of alkylmalonate 13:83 of chiral half-esters 13:81

of monalkylmalonic acid 13:81 with 1 -fluoro-2,4,6-trimethylpyridinumtrifluoromethane sulfonate 13:82 FOD (fast oligonucleotide deprotection) 13:267,361,268 Formylation-diazotransfer procedure 10:594,595 Four component condensation 12:11,115,117 Four-carbon polar armulation 6:17,21,29,30 Fourier transform methods 5:3 FPP 7:110,122 Fragmentation-recombination of a,P-unsaturated methoxymethyl ester 10:412 to a-hydroxymethyl unsaturated ester 10:412 Fraser-Reid synthesis 12:13,14 Free radical condensation 10:355 Free radical cyclization 3:326 Free radical deoxygenation 6:21 Friedal-Crafts acylation 8:16,13:448,18:234 Friedal-Crafts reaction 1:499-501;5:485;10:312,313; 11:140,318,319;14:7,670-676,681-684;19:306;20:692 intramolecular 10:312,313,11:140 Friedel-Crafts alkylation 6:61,62,74,75,10:376,18:231 Friedel-Crafts annulation 18:70 Friedel-Crafts products 6:309 Friedlander reaction 3:386 Fritsch-Buttenberg-Wiechell rearrangement 18:171 Fuchs synthesis 18:892-895 Funk's convergent Ireland-Claisen macrolactone Furst-Plattner effect 19:357 Fused eight-membered ring systems 6:468-474 Fused eleven-membered ring system 6:494-497 Fused lactone nucleoside synthesis 4:252 Fused nine-membered ring system 6:472-482 Fused ten-membered ring systems 6:483-493 Fusion reactions 4:236,38 Fusion technique 4:222

a-D-Galactosidation of methyl 2-0-benzyl-4,6-0-benzylidene-P-Dgalactopyranosides 14:150 P-Galactosylation 10:470 Gassman oxindole synthesis 3:320 Glycosidation bymycosamine 6:276,277 by silicon ether 6:262,276,277 in (-)-pseudopterosin-A synthesis 6:74,75 Noyori's 1:671,672 of 1-O-acetyl-oxetanose 10:603 of adenine 10:605 of amphoteronolideB 6:276,277 regioselective 6:262 stereochemistry of 3:197 with oxetanosyl chloride 10:605 with silver triflate/TMU 1:670,671 p-directing 2-bromosugars 3:202 0-Glycoside 10:344,370-380 intramolecular rearrangement 10:379 stereoselective synthesis of 10:340 Glycosyl thioformimidates from glycosyl nitriles 10:357 C-Glycosylation 1:429,430,513,514

1258

Glycosylation 6:395,397,398,400;10:470,471,472, 474-486 a-Glycosylation 13:217 1,2-cw-Glycosylation 14:209 l,2-?mra-Glycosylation 14:209 cw-Glycosylation procedures 14:202 Glycosylation reactions 14:201-259 Gomberg-Batchman-Hey reaction 20:310 Grignard addition 10:147,167,180;16:380;19:39,45, 62,541 Grignard coupling 19:45 Grignard cross coupling reaction 14:575 Grignard reaction l:261,262,533;4:330-332,353,354; 6:159,549,550;8:165,166;9:344,345,352,527;11:81,82, 248,249;14:670;18:473,630;20:571,589,592,595,599, 600,604 Grignard reagent 4:160;19:33,35-36,38,513,518;20:569, 585,596,598 Group transfer polymerization 8:409 Grubb synthesis 6:46,47

Hanessian reaction 1:511,512 Hanessian's deconjugation-epimerization of avermectin B i a derivatives 12:13 Hanessian's epimerization macrocyclization with 12:28 Hanessian's procedure from debenzylidenation 12:347 Hanessian's synthesis of avermeetinBia 12:12-15 Hanessian-Nicolau thioacetal Hantzsch synthesis racemization during 4:86 Haslinger and Michel synthesis oftaxodione 14:689-692 Heathcock's asymmetric aldol reaction 18:283 Heck arylation 19:274,19:277 Heck coupling 19:276 Heck reaction 16:367,391,400,412,416,418,427,429, 430,432,435,438,439,447;18:96;19:22,78,279,284 asymmetric 19:22 intramolecular 16:429,430,438,439 of olefin 19:279 palladium-catalyzed 19:78 Pd(0) catalyzed 16:439 silver modifaction of 16:429 with l-octen-3-one 16:391 Heck reaction conditions 19:227,279 Heck vinylation intramolecular 16:432 Henry condensation 1:408,409 Henry reaction 19:120,165,173 pyperidine-catalyzed 19:165 Hetero Diels-Alder reaction addition of 16:654 approaches 16:456 asymmetric 11:260-267 diastereoselective 12:424,425 enantioselective 11:260-267 for nepetalactone synthesis 4:604,605 for tylophorine synthesis 4:604,605

gephyrotoxin 223 AB by 4:606 gephyrotoxin by 4:606 iminodienophile in 4:604,605 intramolecular 6:449;14:757,758;19:43,223 intramolecular Lewis acid catalysed 1:553 lysergic acid by 4:604,605 monomorine I by 4:606 of2-methoxybutadiene 12:257 oxazoles in 4:604 pyran adduct from 12:257 reaction of 16:439 tetrazines in 4:604 triazines in 4:604 using nitroso dienophiles 1:378 with ethyl glyoxalate 12:257;13:69,490,625,177, 757,758,187 (3-amino acid by 12:158 Hetero-Cope rearrangement 8:205 Heterocycloaddition 1:3 5 9-3 92 Heterodienophiles in D-allo-threonimal 4:143 in Diels-Alder reaction 4:563 Heterolytic dissociation 6:307,308 Heterolytic fragmentation 13:575 Heteromercuration of carbamates 1:382 Hg(H) mediated Ritter reaction 11:281,282 High pressure technique [4+2] cycloaddition by 4:121 in Diels-Alder reaction 4:112 Hilbert-Johnson reaction 1:399,400;4:223,224,230,239 Hoffmann's cycloaddition 18:257 Hoffinann degradation 18:51 Hoffmann rearrangement 1:410,411 Hoffmann-like rearrangement 19:14 Hoffmann-Loeffler photocyclization 6:437 ofT^^-chloroamines 6:437 Hofmann degradation 6:480,4899:547,548;14:771-773, 793-795 Hofmann elimination 6:481,488;16:53 Hofmann reaction 14:868 Hofmann rearrangement 3:313 Holton's taxol synthesis 12:220 Homoaldol reaction 8:156,157 Homoallylic alcohol from epoxide 11:346,347 with vinylmagnesium bromide 11:346,347 Homoallylic coupling 10:118 Homochiral diol auxiliaries 1:579-582 Homochiral ketone auxiliaries 1:579,583,584 Homoenolate ions from allylic esters 3:217 Homologation 6:32;11:257,258,462-464;12:82;14:175 Hoppe coupling 10:15 Homer Bestmann oxidation 8:207 Homer reaction 6:285,286 Homer-Emmons condensation 1:410,411;10:13-17,19; 11:432;14:129;16:655;18:288 Homer-Emmons coupling 14:115,123 Homer-Emmons olefination 10:534,441,442,14:126, 16:460,490,18:288,633

1259
Homer-Emmons reaction 1:448,450;5:828;8:16,209, 270,271;10:43;13:175,210,570;14:593;9:356;18:481,5 86;19:14,45,62;20:567,575,580,585,588,591,595,596, 599,606 Homer-Wadsworth-Emmons condensation 19:529 Homer-Wadsworth-Emmons olefination 20:567 Homer-Wadsworth-Emmons reaction 12:30;20:72-74 Homer-Wittig olefination 10:157,159,164,16:673 Homer-Wittig reaction 9:525,6:545,546,19:448 Homer-Wittig reagents 10:164-166,20:720 Homer-Wittig-type reagent 19:452 Houk's "inside crowded" model 12:57 Houk's "outside crowded" model 12:58 Houk's concept 11:240 House procedure 10:308,309 House's conditions 12:46,47 Hoye's bromination 1:678 Hoye's procedure 6:56,57 Huang-Minion modification 14:684 Huang-Minion reduction 14:674,676,677 Hudson lactone mle 10:262 Huisgen pyrrole synthesis 13:445 Hydration mercury catalysed 4:332 of acetylenes 4:332 Hydrazine reduction with 1:20 1,4-Hydride reduction 12:154 Hydride reduction 14:153,19:372 of sulfonates 14:153 [1,2]-Hydride shift 10:216,222,19:518 Hydride shift 9:45,46 2,6-Hydride shifts 4:626,627,634,643 in camphor derivative 4:634,643 in rearrangement of camphor 4:626,627 Hydride transfer 17:486-487 6,2-Hydride-shift 4:650,651 Hydroalanafion 10:21,24,29 Hydroboration 8:470-473,475,478;10:15;ll:83,84;316, 317,319;14:456,681,682;16:472;19:367 highly stereselective 12:151,152 of allylic ethers 4:116 of olefin 12:151,152 of vinylic ethers 4:116 regioselectivity 4:116 stereoselective 19:367 to alcohol 12:151,152 Hy droboration-oxidation 14:7 7 3,7 74 Hydroformylation 16:409 Hydrogen abstraction 16:41 Hydrogen peroxide oxidation 14:324,325 Hydrogen phosphonate method of oligonucleotide synthesis 4:274-276 mechanism of 4:275 1,5-Hydrogen shift 1:327 Hydrogenation 2,3-a?/selective 12:35,36 heterogenous 12:36 homogenous 12:35,36 of double bond 19:45,19:307 of ketones 19:27 of methyl acetoacetate 13:72,73 ofpyranone 19:468 of(3-ketoester 19:29 on naphthalene-Cr (CO)3 comple 4:343,344 stereoselective 12:151,152;19:296,19:301 using Adam's catalyst 19:70 Hydrogenolysis 6:276,426,435,451,168,169,19:6,36,38, 42,104,332,362,367-368,371 Hydrolysis asymmetric 1:678,679,682 by Candida cylindracea lipase 1:685 by lipases 1:684,685 by pig liver esterase 1:685 by pig pancreatic lipase 1:685 by Pseudomonas fluorescens lipase 1:685 of N-acetyl a-amino acids 1:678,679,684,685 acid-catalyzed 11:361 enantioselective 13:54 photochemical 6:331,333 selecfive 6:285,286 Hydrolytic cleavage 12:428-430 Hydrolytic fragmentation 12:198 a-Hydroxy acids 1:446,447 as chiral building blocks 1:680,681 3-Hydroxy acids as chiral synthons 4:625 w-Hydroxy acids 8:176,233,234,236 cyclization of 8:234 intramolecular esterification of 8:176 lactonization of 8:233,234,236 Hydroxy amino acids synthesis of 12:431-438 A^-Hydroxy compounds 8:376 (R)-2-Hydroxy carboxylates dehydrogenation of 20:840-842 to 2-oxo-carboxylates 20:840-842,853 preparation of 20:842 Hydroxy dithioketal 10:203,204 Hydroxy epoxides 10:205-207 cw-Hydroxy epoxides 10:207 trans-Wydroxy epoxide cyclizafion of 10:205,206 P-Hydroxy ester from (a-bromoalkyl) boronic ester 11:425 synthesis of 11:425 p-Hydroxy esters as chiral building blocks 1:689-701 Hydroxy ketones syn selectivity of 10:205 4-(3-Hydroxy-1 -propenyl) derivatives Johnson-Claisen rearrangement 10:436-438 3-Hydroxy-4-pentenyl amines stereoselective cyclization of 14:568 to pyrrolidines 14:568 Hydroxy-directed epoxidation of trifluoracetate salt of 12:300 (3i?)-3 -Hydroxybutanethioate boron enolate of 13:500 (7?)-3-Hydroxybutanoic acid acetals diasteroselective allylafion of 1:610 3 -Hy droxybutyrates a//-products formation 4:439

1260

in thienamycin synthesis 4:431 P-lactam formation 4:446 lithio dianions of 4: 441 3-Hydroxybutyric acid 4:431,438,440,465,471,479,480 acid chlorides of 4:471 in thienamicin synthesis of 4:438-440 R, .S-4-Hydroxycyclopentenones absolute configuration 6:315 asymmetric synthesis 6:315 from A^-tataric acid 6:315 Hydroxyl inversion 1:204,205 Hydroxyl removal 1:454,456 trans-Rydroxylation of olefin 1:413,414 withHjOj 1:260 withWOs 1:260 Hydroxylation 5:827 by stereospecific double bond 11:464 cw-Hydroxy lation 1:413,415 stereoselective 1:413,415;4:511 stereospecific 4:503,504 Whiteside's procedure 1:668 with Ba(CL03)2 1:260 with CUCI2/CU/O2 5:827 with osmium tetroxide 4:508,509 withOS04 1:260 12(3-Hydroxylation 13:663 a-Hydroxylation 4:331,333;13:43 d5-Hydroxylation 4:45,145,204,205,344 lincosamine derivafive from 4:145 ofacrylates 4:45 of E-allylie alcohol 4:204 of Z-allylic alcohol 4:205 with Os04-chiral base 4:344 o-Hydroxylation of 2-alkylbenzoic acids 5:826 C-3 Hydroxylation 7:359-361 liP-Hydroxylation 9:417

Ichikawa synthesis 616-618 Imine [2+2] cycloaddition of 12:173 azaally 1 anions from 1:3 31 -3 44 CIS reduction of 6:428 deprotonation of 1:331 -344 preparafion by Standinger reaction 1:352-353 trans reduction of 6:428 ^/-a5-3-acetyl-P-lactam from 12:173 withdiketene 12:173 ylides from 1:331-334 Iminium 'A' 2:390,2:398,402 Iminium 'B' 2:390,390 Iminium cyclization 1:243 Iminium ion cyclization to vinylsilanes 1:286,287 Iminium ion-vinylsilane 19:52 Iminium ion-vinylsilane cyclization 12:454 p-Imino carboxylic acid 8:384 2-Imino cyclic ethers synthesis of 10:215 Imino Diels-Alder approach 14:732,733

Imino Diels-Alder reaction 4:36,37,604 y^-Imino sulfoxide subsfrate 18:382 5,8-Imino-7-0-mesyl-2,3,5,8-tetradeoxy-Dglucooctano-1,4-lactone 12:325 Iminodienophile in Diels-Alder reaction 4:604 Indole N-/^r/-butyloxycarbonyl 3:309,310 thermolyfic deprotection 3:309,310 Indoles, synthesis of Fischer 1:79,144,152 Smith 1:360,365 Indolizidine alkaloids 7:11-13,453-502 synthesis of l:360-365;10:556,561;16:453-502 Indolizidone cross-aldolisation of 12:298 from L-proline thioester 12:297 3 -Indolyl-acetonitrile Ritter reaction of 11:281,282 with (-)-p-pinene 11:281,282 Indolylmagnesium iodide 1:7 Inhoffen-Lythgoe diol 1:591,592 synthesis of 1:592 INOC reaction 1:480,481 Inouye's photochemical route 12:198 Intermolecular aldol condensation 10:318-320 Intermolecular cationic [5+2] cycloaddition 8:160,161 Intermolecular cyclization spirosystems construction by 6:59 Intermolecular Diels-Alder reacfion 6:549,550 Intermolecular Michael reaction enantioselective 14:552 Intermolecular 0-alkylafion 8:198,199 Internal aldolization in (+)-2-isocyanopupukeanane synthesis 6:81 Internal alkylation 6:74 in (+)-9-isocyanopupukeanane synthesis 6:80 Internal Diels-Alder reaction 6:86,87 Intramolecular reaction (2+2) cycloaddition 11:45-47 [4+4] cycloaddition 11:17 1,3-dipolar cycloaddition 11:283-285 aldehyde-ketophosphonate condensation 6:264,265 aldol condensation 11:90,108,113,115 aldol condensafion 12:82 aldol condensation 183,303,306,318,329,330 alkylation of 8:176,177 amidoalkylation 10:108 amidomercuration 12:281 aminolysis 12:279 annulation 10:407 asymmetric hydrosilylation 13:72 azido-olefin cyclization 13:447,448 Biellmann coupling 10:6-10 C-C bond formation 12:65 cross coupling reacfion 10:163 cross-aldolisation 12:289 cyclization 10:631-633;12:281,327 dicarbonyl coupling 11:345,364-367 Diels-Alder reaction 10:51,52,155,409;11:11,92,93, 99,108;13:108-115,111;14:745 double cyclization 10:83

1261 displacement 12:347 ene reaction 11:91-108 epoxide alkylation 14:746 esterification of 8:176 etherification 12:65 Friedal-Crafts acylation 10:131 Friedal-Crafts reaction 10:312,313 hetero Diels-Alder reaction 6:449 Homer-Emmons condensation 10:13-17 imino Diels-Alder approach 14:732,733 Michael addition 11:312;14:736 Michael reaction 9:435,437;10:51,52;13:180-443 mixed Claisen condensation 12:104 Mukaiyama condensation 10:181,182 N-acyliminium ion cyclization 11:284,285 nitrile oxide cyclization 14:745 nitrone cycloaddition 14:744 0-C bond formation 12:83 Pi-allyl Pd alkylation 10:10-13 photocycloaddition 11:20 photoreduction 12:283 proton transfer 12:102 Pummerer reaction 10:682 rhodium II mediated 10:407 ring contraction 11:42,43 ring-opening 12:83 Sakurai reaction 10:182 S-alkylation 13:145 SE'additions 10:17-25 SN2 cyclization 12:85 SN'-process 11:323 stereoselective cyclization 10:92 translactonization 13:159 trans-sulfenylation 12:69,72 Ulmann reaction 10:640 Wadsworth-Emmons reaction 12:328 Wittig Homer reaction 11:152,153 Wittig reaction 13:601 Wittig-Homer cyclization 12:292 Wittig-type reaction 12:147 a-diazo-p-keto ester synthesis 10:407 Intramolecular [2+1] cycloaddition 6:52 Intramolecular [2+2] cycloaddition 12:193 Intramolecular [2+2] photoaddition 12:210 Intramolecular [2+2] photocycloaddition 6:69 Intramolecular [4+1] pyrroline annulation 1:250 Intramolecular [4+2] cycloaddition 5:166-168,182 olefin tropolone 5:799 Intramolecular [4+2] cycloaddition in ()-sinularene synthesis 6:85 in 7,20-diisocyanoadociane synthesis 6:86,87 Intramolecular 1,3-dipolar cycloaddition 12:318 Intramolecular acetalization 14:60 Intramolecular acylinitroso Diels-Alder reaction 1:386 Intramolecular addition to chiral sulfoximines 10:3-11 to chiral vinyl sulfoxides 10:3-11 Intramolecular Alder ene reaction 10:222,224 Intramolecular aldol condensation 6:549,550,231; 15:235,269,297 Intramolecular aldol cyclization 6:36,66,67;18:633 in poitediol synthesis 6:36 in (-)-upial synthesis 6:66,77 Intramolecular alkylation 6:42,43;8:225-233,540,558 Intramolecular amidoalkylation 1:246 Intramolecular aminomercuration 10:532,540;12:333 Intramolecular ary lation 12:447-452 Intramolecular base-induced rearrangement 14:374 Intramolecular carbenoid displacement 1:259 Intramolecular chelation 14:53 Intramolecular Claisen condensation 18:299 Intramolecular coupling 6:546,547 Intramolecular cyclization nickel-catalyzed 2:282 spirosystems construction by 6:59 in ()-9-isocyanopupukeanane synthesis 6:82,83 Intramolecular cycloalkylation 6:6 in ()-amjitrienol synthesis 6:53 in tricyclic natural products synthesis 6:74 Intramolecular cyclopropanation 6:73,74 Intramolecular Diels-Alder reaction betaenoneBby 4:601,602 betaenone C by 602-604 coronafacic acid by 4:596,597 diplodiatoxin by 4:600-602 endomlQ 4:18 fused versus bridged product 4:565 in biosynthesis 4:616,621 kinetic selectivity 4:601 solanapyrone A by 4:598 stereoselectivity 4:595,596 Intramolecular displacement reaction 12:311,344 Intramolecular diyl trapping reaction 6:46 Intramolecular double Michael addition 8:418 Intramolecular glycosylation 14:236 Intramolecular heteroene reaction 12:295 Intramolecular Homer-Emmons condensation 12:341 Intramolecular Michael addition in ()-sanadaol ((3-crenutal) synthesis 6:70,71 Intramolecular Michael cyclization of an acyclic compound 14:552 Intramolecular Michael reaction 6:178,184,196 asymmetric 14:551-567 by chiral enamine 14:551-567 enantioselective 14:551-567 Intramolecular oxidative coupling 6:480 Intramolecular 71-alkylation 6:184,185 Intramolecular photocycloaddition 6:34,35,54 in ()-ep/-precapnelladiene synthesis 6:34,35 in isoamijiol synthesis 6:54 Intramolecular Pinner reaction 15:415 Intramolecular reduction 14:153 Intramolecular reductive amination 12:316 Intramolecular reductive coupling 6:48,52,54 in ()-A^^'^^ capnellene synthesis 6:48 indolasta-1 (15),7,9-trien-14-ol synthesis 6:52 in isoamijiol synthesis 6:54 Intramolecular ring closure reaction 6:492 Intramolecular /ra5-ketalization 10:211 Intramolecular type I-"Mg-ene" reaction 6:45,46,76-78 in ()-A^^^^^ capnellene synthesis 6:45,46 in (+)-sinularene synthesis 6:76,77

1262

Intramolecular Wittig reaction 1:234,235,573 Inverse electron demand in Diels-Alder reaction 4:579,580,604 using enamines 4:604 using enols 4:604 using ketone dithioacetal 4:604 Inversion of alcohol center 1:204,205,456,457,459 Mitsunobu protocol 1:459 Iodine pentoxide 1:51 oxidation of indoles to 2 acylindoles 1:151 Iodine-catalyzed 6:139-141,153,154 stereomutation mixtures 6:139-141,154 isomerization 6:141,153,154 lodocyclisation ofalkene 10:391 lodocyclocarbamation 4:126 lodoetherification 10:21,24 lodolactone 8:153,154 lodolactonization 1:526,254,199,204-206;13:208,622 by Aw-chloroperbenzoic acid 11:358,359 by iodine 11:358,359 lodomagnesium salt 14:750 lodomethylphenyl sulfide 4:463 alkylation with 4:462 lodotrimethyl silane 1:390;11:528 cyclization with 11:109 Ion-exchange column chromatography 19:519 Ionic cycloaddition 5:793 IpcjBCl as chiral reducing agent 8:476 IpcBH2 as chiral reducing agent 8:475,476 (-)-Ireland alcohol synthesis of 14:119,120 Ireland approach 12:16,17 Ireland-Claisen rearrangement 3:614,268;10:416,417, 424-425,429;18:230,231,259;20:67 in nonactic acid synthesis 3:228 of allylicglycolate esters 10:437 of silylketene acetal 10:423 Iron pentacarbonyl 14:689,690 Iron tricarbonyl derivatives acylationof 1:572 oftropone 1:572 Isocyanides by alkylation of silver cyanide 12:113 by carbylamine reaction 12:113 by dehydration of N-minosubstituted formamides 12:113 from diphosgene 12:113 from phosgene 12:113 from triphosgene 12:113 Isodendrocrepine 12:286 from dendrocrepine 12:286 /?,5 Isomerization 6:141 trans, cis Isomerization 6:141,142 cw-Isomerization 6:153,162 Isoprenylation by 4-(Y,y-dimethylallyl) tryptophan synthase 11:200 of tryptophan 11:200

Ito cyclization 10:6

Jenkins's synthesis 12:185,186 Johnson synthesis oftaxodione 14:681-684 Johnson-Claisen rearrangement of allylic alcohols 10:428-438 ofaldoheptofiiranoses 10:432-436 of D-glyceraldehyde derived allylic alcohols 10:436,437 of 4-(3 -hydroxy-1 -propeny 1) derivatives 10:436-438 of L-lyxofuranose derivatives 10:431,432 Jone's oxidation 19:252,19:304,19:320-321 Jones reagent 19:173,19:428 Johnson-Lemieux reaction 3:328 Jone's reagent 14:818 Jones oxidation 4:456,50,465,470,490-492;16:323,29, 30,595,248,235,514,627,641,72,551,558 Jones reagent 6:17,25,55,78,509,515,461;12:466,508, 613 reaction with stypodiol methyl ether 6:55 Joullie method 10:283 Jourdan-UUman condensation 13:353-355 Ju-Fang synthesis of (+)-polygodial 6:14 of(-)-polygodial 6:14 of()-polygodial 6:14 Julia coupling 1:457,458,461-464 Julia olefmation reaction 16:230 Julia reaction 1:454,456 Julia sulfone 1:463 Julia synthesis 9:356 of aglycon of 22,23-dihydroavermectin Bib 12:17-19

Kato's synthesis of^eco-taxane 12:181,182 Katsuki-Sharpless epoxidation 12:324,481 Kedde reagent 19:753 Ketalization 6:73,82,83,85 regioselective 11:41,42 /ram-Ketalization acid catalyzed 4:8,9 Ketalized Diels-Alder type adducts 17:458 Keten acetals Diels-Alder reaction with 4:357 Ketene complex 16:406 Ketene dithioacetal derivative preparation of 12:156,157 Ketene dithioacetal S,S-diozides 6:733 synthesis of 6:33,334 Ketene silyl acetals 4:463,464 Ketene-imine cycloaddition 4:440,470-472,474 1,2-diastereoselection 4:472 in Bose reaction 4:440,470 Keteny 1 idene-triphenyIphosphorane 4:569,572 P-Keto acetals addition of organometallic reagents to 14:497-499

1263
diastereoselective 14:497,498 from {+y{2R,3Ry 1,4-dimethoxy-2,3-butanediol 14:497-500 from (i?,/?)-2,4-pentanediol 14:497,499 LiAIH4-reduction of 14:499,500 NaBH4-reduction of 14:500 a-Keto acetals from (-)-(25,35)-1,4-dimethoxy-2,3-butanediol LiAIH4-reduction of 14:500,501 Michael addition of 14:500,501 with methyl addition of 14:510 p-Keto esters 4:436,439 in asymmetric hydrogenation 4:439 P-Keto thioester reduction of 11:195 4-Keto-5 -methyl-/ra5-decalins 9:30 P-Keto-acid 8:384 decarboxylation of 8:297 a-Keto-P,Y-unsaturated acetal addition of Grignard reagents 14:496 5-Keto-imine intermediate benzodiazonin-3-one from 6:480,481 a-Ketoacetals diastereoselective reduction 1:622 3-Ketoadociaquinone A 17:33 a-Ketoamide from aminoketal 11:286 p-Ketoamide asymmetric hydrogenation of 12:162 4-unsubstituted P-lactam from 12:162 P-Ketoester enolization 14:734 a-Ketol rearrangement 11:53,54 Ketone formation by epoxide rearrangement 5:782,783 Ketone reduction Luche's conditions 1:415,417 stereoselective 1:415,417 to equatorial alcohol 1:415,417 with axial hydride attack 1:413,415 withNaBH4-CeCl3 1:413,419 Ketosugars Grignard reactions with 4:353,354 P-Ketosulfoxides reaction with enolate anions 4:502 reduction 4:502-504 synthesis of carbohydrates 4:504-512 synthesis of macrolides 4:513-512 Kinetic resolution 1:508,698,3:23,19:478 by Sharpless epoxidation 4:342 of secondary 2-furylcarbinols 19:478 under Sharpless epoxidation conditions 19:478 Kirk-Petrow reaction 10:409 Kishi synthesis 13:436-442,443,457,458,461 ofmitomycins 13:4-10,25,26,29 Kishi's rule 1:404,130,163,167,168,171,175;4:178, 181,183,184,188,197,202,203,705 Kishi's-model 4:503,504 Klemer fragmentation 3:201,202 Klemer-Plhodomeyer reaction 1:510,511 Klyne-Hudson rule 15:207 Knoevenagel condensation 6:67,68,316,320,328,331, 334,53 in \4-epi-up[a\ synthesis 6:67,68 Knoevenagel condition 11:140 Knoevenagel cyclisation 9:341 Knoevenagel reaction 13:109 Knoevenagel-type reaction 7:475 Kocienski-Lythgoe condensation 4:602,603 Kocienski-Lythgoe-Julia olefmation reaction 11:393-395 Kodo-cytochalasin-1 and2 15:353 Koenigs-Knorr reaction 6:395 Koenigs-Knorr condensation 3:199 modification of 3:199 Koenigs-Knorr coupling (Ag2C03-AgCL04) 1:419,420 Koenigs-Knorr procedure 10:571 Koenigs-Knorr reaction 8:359,363,206,258 Koenigs-Knorr synthesis 10:466 Koga's method ofasymmetrization 11:241,242 of a-symmetric ketones 11:241,242 Kolbe reaction 9:371 Konevenagel-type reaction 11:139 Kozikowski's retrosynthetic analysis 13:588 Kozikowski approach for avermectin oxahydrindene subunit 12:20-22 Kozikowski's nitrile oxide 12:21,22 Krapcho decarboxylation 18:246 Kraus method 6:225,226 Kraus's method 11:129 Krebs cycle 7:112,117,387 Krebs cycle enzymes 11:197 Krebs tricarboxylic acid cycle 6:252 Krohnke' s procedure 6:513 Krohncke reaction 20:602 Kuehne's synthesis of vinblastine 14:831-849 of vincristine 14:831-849 Kuhn-Roth oxidation 11:210 Kutney's synthesis of vinblastine 14:806-821 of vincristine 14:806-821 Kuwajima's B-ring cyclization route 12:190 Lactam carbonyl selective reduction 3:474 p-Lactam compounds from p-amino acid 12:155-159 synthesis of 12:155-159 Lactam sulfoxide cyclization of 3:109 Lactone hydrogenation of 19:469 methylation of 19:469 y-Lactone reduction of 19:470 (45,55)-Lactone 8:296 5-Lactone 8:298,306 syn addition of 8:306 (4/?)-Lactone anti addition of 8:305,306 Lactone annulation 13:29-31 Lactone Claisen rearrangement 13:544,596

1264 Lactone methyl-isomerase 8:300 Lactone rearrangement fragmentation 3:96 Lactone synthesis 13:615-626 asymmetric synthesis of 13:621,622 Lactone triflate ring contraction reaction 10:605 to oxetane-2-carboxylate 10:605 Lactone unit construction of 11:345-347 model studies on 11:345-347 of compactin and mevinoline 11:345-347 Lactonisation acid-catalyzed 12:157,158 by Gerlach's procedure 6:542,543 of A^-acetyl muramic acid 6:389,390,395 ofw-hydroxy-acids 8:233 with pyridinium acetate 11:84,85 Lauryl chloride protection with 6:429 Lead tetraacetate oxidation of diol 1:439 oxidation of ring C of yohimbine 1:158,439 glucuronide linkage cleavage by 7:156-158 Lead tetraacetate oxidation 5:788 Lemieuix oxidation 18:171 Lemieuix-Johnson oxidation 4:592,593;10:591-592; 13:613;18:81 Lemieux-Nagabhushan reaction 14:145 Lexitropsins 5:567,578 Ley synthesis ofavermectinBia 12:22-24 Ley's procedure in ()-polygodial synthesis 6:13 Lithiated trimethylsilylacetonitrile 1:311,312 Lithiation of 2-methoxy-//,7^-diethylbenzamide 5:827 of 3-methoxy-A^, A^-dimethylbenzylamine 5:828, 5:829 with ^ec-butyllithium 5:827,828 1- Lithio glycals by direct lithiation 10:345 from tributyltin 10:345 2-Lithio-2-phenyl-6-heptene synthesis of 8:7,8 2-Lithio-3,3-diethoxy-l-propene 12:36,40,43 Lithiodianion-imine condensation 4:433,443-448,450, 464 Lithioglycal 10:346 N-Lithioimidazolidines anionic cycloreversion of 1:349-351 2-azaallyl anions from 1:349-351 Lithium /4,4'-di (tert. butyl) biphenyl (DTBBP) 11:309 Lithium di (a-ethoxyvinyl) cuprate addition of 12:25 BF3 0Et2 promoted 12:25 toA^'^enone 12:25 Lithium isopropylcyclohexylamide (LICA) 10:410 Lithium methylcrotyl aluminate condensation with 6:298,299 Lithium organocuprates 1,4-addition 4:555,556 Lithium organyls 1,2-addition 4:556-558 Lithium tri-sec butylborohydride (L-Selectride) 11:234 Lithium triethyl borohydride 11:423 reduction with 11:83,84 Liu-Kulkami synthesis 6:43,44 Lombardo methylenation 6:209 Lombardo reagent methylenation with 11:40,41 Low-valent titanium from reductive elimination 4:521-535 Low-valent titanium reagent keto aldehydes with 11:364 preparation of 11:364 Luche reaction 1:474 Luche reduction 14:126,19:372-373 Luche-type reduction with a,P-unsaturated ketone 4:130 Macrocarbocyclic rings synthesis by titanium 8:16-18 with TiCl3/Zn-Cu 8:16-18 Macrocyclic [2,3]-Wittig rearrangements 8:196 Macrocyclic reaction 8:175-201 Macrocyclic transannular reaction 8:187-201 conformational control in 11:152-163 of geranyl geranyl pyrophosphate 11:24 with Hanessian's epi-merization 12:28 Macrocyclization 4:591;8:21;11:24,152,158, 163;12:28 by ally chromium species 3:81 by dicarbonyl coupling 3:80 by Michael additions 3:83 by Nicholas reactions 3:83,84 by transannular acylation 3:81 for synthesis for 8-membered rings 3:80-84 polymer supported 3:82-83 transition metal mediated 3:80,83 Macroheterocyclization palladium mediated 16:423 Macrolactonization 1:445,452,453,461,462,464,465; 8:233-242;9:246,247,290;12:244;13:115,20 Madelung reaction 1:52 Magnus's synthesis of vinblastine analogues 14:821-830 of vincristine analogues 14:821-830 Maillard reaction 13:317-319 Majetich synthesis ofperforenone 6:32,33 Mallory stilbene photocyclization 3:305 Mannich base methiodide condensation of 14:406-408 with thujone 14:406-408 Mannich condensation in ()-stoechospermol synthesis 6:39 Mannich reaction 1:244;6:39;9:332;13:473;16:481 intramolecular 14:746 of dimethyl a-ethylmalonate 14:850 with diethylamine 14:850 with vitamin 4:715 Mannich-Aldol condensation 12:293

1265 Marfat-Helquist annulation 13:11,12 Marschalk condensation 1:595 Marschalk reaction 4:346,347,350,352;14:5,12 Marshall synthesis 6:73 of(-)-dictyolene 6:27 of dihydrospiniferin-1 derivative 6:72,73 Martin reagent 13:601 Martin sulflirane reagent 6:204,205 McFayden-Stevens reduction 8:273 McLafferty rearrangement 2:6 McMurry coupling 11:337,354 intramolecular 11:343,363,364 McMurry cyclization 11:27 McMurry reaction 9:250,255 intramolecular 11:337 McMurry reagent 13:601 MCPBA oxidation 8:216 Mechanics 6:316,320 of acetal derivatives formation 6:335,336 of cyclization 6:314,345 Mechanism of C (8) bromination of camphor 4:638,639 of C(9) bromination of camphor 4:633,634 of biomimetic olefin cyclization l:671-674of cyclization 7:335-338,358-360 of Diels-Alder reaction 4:579,580 of hydrogen phosphite method 4:277 of lithio dianion-imine condensation 4:444-447 of phosphite method 4:272 of phosphotriester method 4:270 Medium ring ethers biological activity of 10:201 synthesis of 10:201-239 Meerwein's reagent 8:205;12:289,20:426 Meerwein's salt 12:300,305,320 Meerwein-Pondorf-Verley-Oppenauer reaction intramolecular 14:481 Meisenheimer rearrangement of allocryptopine TV-oxide 6:468 of cw-()-laudanosine N-oxide 6:468 [l,2]-oxaza ring formation by 6:472 MEM protection with 6:558,559 MEM ethers 1:558 deprotection TMSCl/Nal 1:558 for alcohol protection 1:558 MEM-directed organometallic addition 12:201 Mercaptolysis 6:279,280,282-286 Mercaptomethylation 6:323-325 Merck method 12:135 Merck procedure for carbapenem formation 4:453 mercuric salt method 4:22 for nucleoside synthesis 4:22 Mercuric acetate 1:125 oxidative cyclization 1:133 Mercuric amidation 14:568 Mercury (II) triflate formation of 1:657 Mercury (II) triflate/A';7V-dimethylaniline complex 1:657,658 Mercury (II) trifluoromethanesulfonate cationic olefin cyclization 1:656 Mercury group 1:659 replacement by OH group 1:659 Mesylate elimination 1:477 Mesylation 4:16,126,442;6:9,10,71,76,77,229,289; 6:290,390,548-550;10:322,323;19:147,371 axial 1:415,417 ofalcohol 19:494 of allylic alcohols 4:16 of primary alcohol 19:477 Metal acetates 11:116 Metal complexes of ascorbic acid 4:720-722 Metal enolates 3:409 contact ion pair 14:497 from a,a-disubstituted ethyl ester 14:497 Metal reduction of v/c-phenyl thiobenzoate 6:541,542 with sodium naphthalenide 6:541,542 Metalated arenes 11:140 Metalated sugar 11:140 Metallation with n-butyllithium 5:822,823 Metallation reactions in basic media 4:386-389 A^,A^-disubstituted amides with 4:389 A',A^-disubstituted benzyl amines with 4:389 Metallo-ene reaction 3:21;16:418,437 intramolecular 16:437 A^-Metalloaziridines 2-azaallyl anions from 1:348,349 ring opening of 1:348,349 Metalloenamines 4:5-7,22 from 2-azadienes 4:7,10-14,17 Metalloorganic addition to a-amino aldehydes 4:124 P-Methallyltriphenylstannane 12:478 p-Methallytri-n-butylstannane 12:478 Methane sulphonate DBU reaction with 6:126,127 Methanesulfonyl chloride 8:27-30 Methaniminium methylide 1:336,337 Methanolysis 6:276,390-395;19:42,442 acid-catalyzed 14:563,564 alkoxyacrylate from 14:563,564 Methoxybrominations diastereoselecfive 12:419-421 of 3-[(IS)-2-exo-alkoxy-1 -apocamphanecarbonyl]-2oxazolones 12:420,421 of3[(IS)-ketopinyl]-2-oxazolone 12:420,421 Methoxycarbonyl as activating group 6:540 Methoxylation anodic 1:247 Methoxymercuration-demercuration 1:510 Methoxymethyl group protection with 6:282,283 Methoxyselenylations of 3 [IS)-2-exo-alkoxy-1 -apocamphanecarbonyl-2oxazolone diastereoselective 12:421,422

1266

Methyl ketones Claisen condensation of 11:130 from ester 11:130 synthesis of 11:130 Methyl phosphonates 13:271-281,287,290 by phosphoramidite method 13:272 by phosphotriester method 13:272 diastereoselective synthesis of 13:279,280 Methylation 19:134 chemoselective 19:92, deoxygenative 19:519 Hakamori method 2:336 of 3-oxovincadifformine with sodium hexamethyl disilazide (NaHMDS) 13:63 with trimethyl orthoformate 1:448,449 A^-Methylation 19:321 ;6:478,491,492 ofindolines 4:79 of 1,4-dideoxy-1,4-imino-I-allitol 7:41 -43 O-Methylation 6:76,77 ofcoumarins 5:516-520, oflignans 5:525-532 in ()-sinularene synthesis 6:76,77 C-Methylation in Artemisia austriaca 7:207 P-Methylation 8:192,193 a-Methylenation 8:21,29;10:13,17,25;13:33 Methylenation 8:26,29,30 with Lombardo reagent 11:40,41 Michael (1,4-addition) reaction 147-199 Michael acceptors 16:650;18:315,329,334,339,369 a,|3-unsaturated orthoesters 3:146 Michael addition 5:181,182;6:5-7,7,74,75,8:224,277; 9:343,347;10:61,164,183,412;11:96,97,123;14:5,37, 39,42,118,274;15:272;16:30,155, 424,582,700; 18:10,63,81,333,343,355,374,378,369 2-amino alcohol by 12:411,413 asymmetric 14:510 base catalyzed 14:521 carbocycles 8:409-428 diastereoselective 11:286 enantiospecific 16:221,262,613 in the synthesis of 8:409-428 intermolecular 14:524 intramolecular 3:83;10:51;11:312;12:17;14:521, 523,524,736;16:695 natural products 8:410-412 of alcohol 16:104 ofalkoxides 12:411,413 ofdiene 16:548,595 ofenolates 10:407 oflevoglucosenone 14:271,272 of methyl group 10:414,415 ofMT-sulfone 6:337,347 of nitroalkane dianion 1:311,312, of trimethylsilyl ketene acetal 10:353 of a-ethylidene-y-lactone 10:405,406 of a-formyl-a-phenyl acetic acid 10:408 of a-keto acetal 14:510 stereoselective 1:489,490 Stork modification of 10:185 tandem 4:556,557

to nitro olefins 10:407;12:411,413 to p-methylated enone 10:414,415 with methyl vinyl ketone 14:510 Michael cyclization 16:437 intramolecular 14:552 Michael reaction 6:70,71;9:435,437,516;11:31,38,39, 41,42;13:29,30,180,398,404-406,417,418,437,440, 448,458,609,618;16:494 aliphatic acceptors 4:705,706 alkenoylcyanide acceptors 4:709-711 asymmetric 14:551-567 chiral building block from 14:551-567 cyclic ene-dione acceptors 4:709 cyclic enone acceptors 4:707-709 intramolecular 14:551-567 reaction mechanism of 14:551-567 with quinone methides 4:712 withvitamicC 4:705-715 Michael type addition 18:65,269,302,303,305,307,309 of nucleophilic glycosyl radical 11:464 P-amino ketone 8:286 Michael-Aldol reaction 3:132-143 Michael-Arbuzov transformation 13:273 Michael-induced cyclization 14:755,756 Michael-Michael construction 12:203 Michael-type acceptors 12:99 Michael-type addition 8:286 Michaelis-Arbuzov reaction 4:68 Microbial hydroxylation 9:416 Microbial oxidation ofarenes 18:430-432 Microbial reduction of keto acids 4:493 by Baker's yeast 6:13 of Kloeckera magna 6:13 Microbial transformation 9:416;13:298 oflimonene 16:208 Microbiological reduction 13:556 of racemic dione 13:556 Microsomal oxidation 19:188 Microozonolysis 6:455 Mitsonubu activation 3:328 Mitsonubu alkylation 3:313 Mitsunobu condensation 18:88 Mitsunobu conditions 16:461 Mitsunobu coupling of 3,4-dimethoxyphenethyl alcohol 12:448 of l-methyloxazolidien-2,4-dione 12:453 Mitsunobu displacement reaction 12:281 Mitsunobu inversion 1:695,697,698;4:449,459;6:553, 554;13:499,502;18:7,237,246,259,281,470,893,903 Mitsunobu procedure 1:456; 14:182 ring closure by 11:10 Mitsunobu reaction 1:205;4:86,456,457,478,515,519; 6:294,295;10:603;11:404;12:305,312,319,468; 13:201,443,485;14:15,275;16:79,350;18:174,217, 235,471 with phthalimide 11:236 Modified Eschenmoser method 3:482 Modified Eschweiler-Clarke conditions 6:476 Modified Schollkopf s procedure 15:443 Moffatt oxidation 12:325,335;14:814,815

1267
Molecular rearrangements ofperezone 5:792-794 of sesquiterpenes 5:794-800 of grandiflurenic acid 19:389-410 Monoalkylation 6:341 ofMT-sulfone 6:330,331,339, Monobenzylation 11:253,254 Monochlorinated sulfoxide a-alkoxysulfoxide from 6:310 chemcial reactions of 6:310 epoxysulfoxide from 6:310 from A^-chlorosuccinimide 6:310 from sulfoxides 6:310 Mori synthesis of azitidinone derivative 13:500 Mori-Matsui synthesis totaxodione 14:667-670 Mosher ester 11:361;12:478 absolute configuration of 13:77 Mosher's (+)-MIPA ester 1:370,371 Mosher's method 15:76;17:264,271,276 MT-sulfone acidity of 6:329 alkylation of 6:334 dialkylation of 6:332 fromDMSO 6:329,330 Michael addition of 6:337-339 monoalkylation of 6:330,331,339 organic synthesis with 6:329,330 properties of 6:329 synthesis of 6:329,330 Mukaiyama ADD reagent 10:23,24 Mukaiyama aldol process 19:203 Mukaiyama aldol reaction 18:292 Mukaiyama condensation 10:187 intramolecular 10:181,182,218 Mukaiyama conditions 12:244 Mukaiyama's protocol 11:289,296,297 Mukaiyama-Michael aldol condensation 16:664 7V-Acylation with Cbz-L-alanine 16:22 A^-Acyliminium ion cyclization 11:290 intramolecular 11:284,285 A^-Alkylation reductive 16:99,104 with Z)-glyceraldehyde 16:99,104 with L-glyceraldehyde 16:99 A^-BOC-tyrosine photooxygenation of 16:609 A^-Glycosidation oxetanocin-A synthesis by 10:595-607 with 1-0-acyl-oxetanose 10:597-604 with oxetanosyl derivative 10:595-607 with oxetanosyl halide 10:604-607 A^-sulfonation of 3-indolyacetic acid 11:291 Nagata hydrocyanation 11:87 Nagata's reagent 16:13 Nazarov cyclizations 3:11 ;13:34,35 BF3-OEt2 mediated 10:412 in ()-A^^'^^ capnellene synthesis 6:43 of(+)-limonene 10:412 withBF3-Et20 8:242 Nazarov reaction 14:592,611 Nazarov's reagent 14:734 Nef reaction 10:464;14:39,;19:120,141,146,152,153, 173 reductive 14:633,634 Neighboring group participation acetamide assisted displacement 1:204,205 for hydroxy 1 inversion 1:427,428 Nicholas reactions 3:83,84 Nichora's method 12:175 Nickel boride desulfiirization with 3:472 Nine-carbon sugars by ascent of sugar series 4:179 osmylation 4:180-182 synthesis of 4:179 Wittig olefmation of 4:180 Nine-membered rings by Claisen rearrangement 3:77 by intramolecular Diels-Alder/ozonolysis 3:79,80 by ring expansions 3:76 from 1,3-diolmonotosylates 3:73,74 synthesis of 3:73,111;6:472-482 by ring contraction 6:474-482 of ring destruction 6:475,482 by ring interconversion 6:472-482 Nishimura's catalyst 6:80,81 Nishizawa complex 16:665 Nitrene insertion 1:8,9,167 Nitrile oxide cyclization intramolecular 12:20-22 isonitramine by 14-745 Nitro-olefins alkoxides 12:411,413 2-amino alcohols from 12:411,413 Michael additions of Nitroaldol condensation 19:159 Nitroaldol (Henry) condensation 1:408,409,417418 KF catalysed 1:417,418 Nitroaldol reaction 1:427,428 Nitroblue tetrazolium reduction 20:515 Nitronate addition 1:505 Nitrone 1,3-dipolar cycloaddition of 1:230,254,277; dibenz [c,g] azonine derivative from 6:474,475 from cis (trans) canadine N-oxide 6:474,475 photolysis of 6:474,475 synthesis of 1:230 Nitrone cyclization procedure 14:737 Nitrone cycloaddition 1:282,283,37-375;12:290,291 asymmefric 1:374,375 intramolecular 14:744 nitramine synthesis by 14:744 Nitrone-based synthesis 6:442 Nitrone-olefm 1,3-dipolar cycloaddition of 11:283 intramolecular 11:283 [4+2] Nitroso cycloaddition 1:378

1268 Nitroso Diels-Alder reaction 1:378,380,381,383 intramolecular 1:385-392 reaction with alkenes 2:6 reactions with hydrocarbons 2:4,5 Norrish type 1 photo-cleavage upon UV irradiation 19:35 Norrish cleavage of alkylphenacyl sulfides 8:207 Norrish reaction 20:74 Norrish II reaction of gibberellin aldehyde ester 8:128-131 Norrish II process 7:147 Norrish type II photocyclization 14:659-664 Norrish type II photofragmentation 14:659-664 in carbohydrate 14:659-664 Norrish type II reaction 4:419,420; 14:645-665 Noyori BINAL-H reagents 10:22-24,37 Noyori procedure 11:96 Noyori Ru-BINAP catalyst 13:503 Nozaki reaction intramolecular 12:13 Nozaki's reagent 14:637 Nozaki-Oshima methylenation 6:185 Nozaki-Oshima reagent deuterated 6:189 Nucleophile 16:399 Schollkopftype 16:403 Nucleophilic addition intramolecular 16:439 Nucleophilic addition 16:439;19:527 2-amino alcohol by 12:411,413 of 2-lithio-3,3-diethoxy-l-propen with N bulc 12:36 ofketonucleosides 19:527 of organolithium reagents 12:411,413 of a-alkoxydimethyl hydrazones 12:411,413 to a-amino aldehydes 12:411,414 to carbonyl compounds 12:36 by allyltin derivatives 11:442,443 by carbanion reagents 11:439-443 by vinyl carbanions 11:440,441 of chiral a-keto acetals 4:330-332 of nonylmagnesium bromide 19:493 Nucleophilic agents 19:121 Nucleophilic conjugate addition to 2-(r-hydroxyethyl) propenoates 4:479 Nucleophilic epoxidation 19:167 Nucleophilic displacement 19:68,191 intramolecular 16:426 of allylic acetate 16:426 Nucleophilic substitution 14:438-445 Lewis acid-mediated 14:484 of acetals 14:484 Octalin coupling reagent 13:586 Ohno's cyclization method 4:466,467 Ohno's lactone synthesis of 8:148,149 Ohtsuk-Tahara synthesis oftaxodione 14:677,678 Oishi's macrocyclic lactam contraction 12:187 Olefin reduction of 12:151,152 with high stereoselectivity 12:151,152 c/5-Olefin benzylation of 14:569 from propargyl alcohol 14:569 trans-Olefm ^-allylic alcohol from 14:570 benzylation of 14:570 Olefin conjugation withDBU 1:442 Olefin cyclization biomimetic 1:655-673 using mercury (II) triflate/amine complex 1:655673 Olefin isomerizadon of ally 1 acetates 4:49 with Pd (MeCN)2 CI2 4:49 Olefin metathesis 3:18 Olefin stain 12:207 Olefin-arene photocyclization 3:28 Olefin-ketocarbene cyclization reaction in ()-isocycloeudesmol synthesis 6:41 Olefinic dioxolane acetal cyclizafionof 14:471 from (2/?,3/?)-2,3-butanediol 14:471 Olefins 1:451,453,4:503,504,7:390,9:315,13:313 conversion to chlorohydrins 1:451 isomerization 1:453 with Rh (PPh3)3 CI 1:453 Oligomerization 12:189 base-catalyzed 14:271,272,274 oflevoglucosenone 14:271,272,274 ofPBG 9:595 Oligoribonucleotide synthesis by phosphite method 4:303 by H-phosphonate method 4:304,305 by phosphotriester method 4:301-303 protecting group for 2'-hydroxy 4:296 One-carbon homologafion of allylic alcohols 3:238 Oppenauer oxidation 13:451,20:749 Oppolzer-Battig synthesis of()-A^^'^^capnellene 6:45,46 Oppolzer's aldehyde ()-vincamine from 14:726 Oppolzer's chiral acryloyl sultam 19:314 Oppolzer's chiral auxiliary from (+)-camphorsulfonyl chloride 11:307,308 preparation of 11:307,308 with ()-3-chloroacryloyl chloride 11:307,308 Oppolzer's acryloyl sultams 10:138 Optically active sulfoxides synthesis of 4:489-491 Organic synthesis by 1,3-dithiane 6:301-303 withFAMSO 6:311-323 with MT-sulfone 6:330-340 Organoboranes 8:472,473,478 Organocopper reagents addition to a, p-unsaturated acetals and ketals 1:626,627

1269
Organocuprate reagent conjugated addition of 14:509 to enones 14:509 Organolithium reagents 2-amino alcohol by 12:411,413 to a-alkoxydimethylhydrazones 12:411,413 nucleophilic addition of 12:411,413 Organometallic addition to A^, (9-protected Z)-a//o-threoninal 4:142 Organometallic reactions in prenylation methods 4:396,398 Organometallic reagents nucleophilic additions of 4:328-333 Organometallic tropone derivatives addition of Gringard reagent 1:573 addition of organolithium reagents 1:573 Organopalladium reactions 16:367 Organoselenium technology 13:5 Organosilicon compounds 13:473-518 Orthoester Claisen rearrangement 1:446,447,598 Ortholactone formation 457 Orthometallation 14:684,686 Orthoquinodimethanes synthesis of 3:434 Osmium (III) chloride 12:162 Osmium tetraoxide 4:169,178 hydroxylation with 4:508,509 in cw-bishydroxylation 4:160,163 selectivity of 4:160-162,172,180 Osmylation 1:413,141,441;4:160,162,175-185;6:182; 13:400,401;16:323,324,326,329,332;19:226-275 (3//-stereoselective 4:161,162,167,170,171,178 in synthesis of eight-carbon sugars 4:163-172 in synthesis of eleven-carbon sugars 4:188 in synthesis of nine-carbon sugars 4:180-182 in synthesis of seven-carbon sugars 4:175-179 in synthesis often-carbon sugars 4:192-185 Kishi's rules 1:413,414 of allylic ethers 1:413,414 ofchiral ally lie alcohols 4:160 of bis-allylically substituted cyclopentenes 19:355 ^yw-stereoselective 19:355 Overman synthesis of(+)-elaeokanine B 13:487,488 of(+)-streptazoline 13:514,515 Oxabicycles synthesis of 10:214 Oxahydrindene subunit of avermectins Barrett's approaches for 12:9-11 Crimmins synthesis of 12:11,12 Danishefsky synthesis of 12:12,13 Fraser-Reid synthesis of 12:13,14 Hanessian synthesis of 12:14,15 Hirama synthesis of 12:15,16 Ireland approach for 12:15,16 Julia synthesis of 12:19,20 Jung synthesis of 12:19,20 Kozikowski approach 12:20-22 Ley synthesis of 12:25,26 Smith synthesis of 12:25,26 vang synthesis of 12:26,27 White synthesis of 12:27,28 Williams approach for 12:28-30 [l,2]-0xaza ring formation by Meisenheimer rearrangement 6:472 2-Oxazolidinone 3-acetyl-2-oxazolone from 12:411,415 acyclic amino alcohol from 12:428-430 acyclic A^-boc amino alcohols from 12:428-430 from 1,35-tris (2-hydroxyethyl) cyanuric acid 12:411,415 TV-protection of 12:428-430 2-oxazolone from 12:411,415 ring opening of 12:428-430 with di-/er/-butyl dicarbonate [B0C)20] 12:428-430 debenzylation of 14:569 from 7V-benzoylcarbamate 14:569 pyrrolidine derivative from 14:569 Oxazolidinone auxiliaries 18:161 2-Oxazolidinone ring 4-methoxy group on 12:428-430 substitution of 12:428-430 2-Oxazolidone derivatives synthesis of 12:166 A-2-Oxazoline from D-threonine 4:140,141 with furfurylithium 4:140,141 Oxazoline 10:474-477 as chiral auxiliary 4:327,332,333 of2-acetamido-2-deoxy-Z)-glucose 6:399 in the synthesis of Li substances 10:473 in the synthesis lacto-A^-biose 10:473 Oxazoline derivative 6:399 Oxazoline method 6:393 Oxazoline rings synthesis of 4:86 Oxazolo [4,3-a] decahydroisoquinolines 12:464 2-Oxazolone from 2-oxazolidione 12:411,415 preparation of 12:411,415 A^-acety 1 derivative 12:411,415 Oxepan-4-ones 10:219 Oxepane synthesis of 10:202,205-207,209-212,214,215, 224-226 cw-Oxepane 10:211,212 bis-OxepauQ 10:205 trans-OxQpanQ synthesis of 10:211,212 Oxepanols synthesis of 10:230 3-Oxepanols synthesis of 10:231 Oxepanone 10:205,209 3-Oxepanones 10:209,210 Oxepins synthesis of 10:236 Oxetanocin synthesis of 10:585-627 OxetanosinA 19:511 Oxidation

1270

aerial 16:66 by ninhydrin 16:83 by Sharpless procedure 8:23 enantioselective 13:54 enzymatic 13:58 in vitro 6:138 in vivo 6:138 Lemieux-Johnson, 4:592,593 nitrotoketo 1:417,418 of(-)-bomeol 16:124 of (+)-5-methoxylaudanosine 16:506 of(+)-camphor 16:149,153 of (+)-laudanosine 16:506 of l,r-methylene bis (3,7-diisopropylazulene) 14:340,341 of l,3diinethylazulene 14:336,337 of 1,5-diisopropylazulene 14:337,338 of 1-isopropylazulene 14:336 of2-ethyl-5-pentylpyrrolidine 6:444 of 2-furycarbinol 19:473 of 3,3'-methylene bis (guaiazulene) 14:343-345 of 3,3'-methylene bis (guaiazulene) 14:344 of4,6,8-trimethylazulene 14:341,342 of alcohol 16:40,350 of alcohols to ketones 4:331 ofaldehyde 16:294;19:210 ofalkene 16:459 of allylic alcohol 16:296 of amides 1:10 of aromatic compounds 6:509 of azulenic hydrocarbons 14:313-354 of benzylic alcohol 19:225 of bromonaphthol 16:48 of cholesterol 17:207 ofconjugateddienes 16:420 of dimethyl 2-amino-1,3-azulenedicarboxylate 14:339 of di-substituted azulenes 14:336,337 of ellipticine 6:509 of enol acetate 19:207 of enol ether 16:85 ofenolate 16:474 ofFAMSO 6:326 of formaldehyde dimethyldithioacetal 6:326 offriedelin 7:160,161 ofgenipin 16:313 of guaiazulene 14:313-354 ofhemiacetal 1:453,454 ofhydrazide 16:473 oflactol 19:473 of oleananetriterpenoids 7:159-161 of olefin 10:111 of olefins to ketones 4:333 ofphenolate 19:233 ofphenylsulfide 16:296 of phosphite linkage 4:280 of phosphonate linkage 4:280 ofphosphoniumylides 4:558,559 of secondary hydroxyl group 19:489 of sulfide to sulfone 1:454,456 oftaraxerone 7:160,161 of tertiary allylic alcohol 19:262 oftetrahydroisoquinolinols 16:519

of tetra-substituted azulenes 14:343-345 of tri-substituted azulenes 14:339-342 of unactivated carbons 2:90-103 of a, p-unsaturated aldehyde functionality 214 of a,p-unsaturated ketones 4:100 Pd (II) catalysed 4:100 photochemical 1:159 regioselective 19:262 Swem 1:453,454 using Kelly procedure 10:111 with AC2O-ACOH 8:160,162 with Attenburrow-Mn04 8:119 with benzeneselenic anhydride 4:40,41,52 with eerie ammonium nitrate 4:331,332;6:472 with eerie sulphate 1:159 with Collin's reagent 1:360,363,367 withDDQ 8:169;19:473 with H202-aq. NaOH, 8:163 withHgO/l2 1:454,456 with iodine 1:126,138 with Jones reagent 19:136 with KMn04-NaOtBu 1:417 with/wCPBA 2:90-103 with manganic acetate 4:72 withmCPBA 19:71 withMn02 8:198;16:294 with N(n-Prop)4 RUO4 8:150-152 with o-chloranil 1:131,132,135,137 with osmium tetraoxide 10:111 withOs04 8:23;16:292 with oxone (KHSO5) 1:454,456 with palladium 1:131,133 withPb(0Ac)4 8:165 withPCC 19:62,19:473,19:541 withPDC 19:145,19:265 with Ph I (OCOCF3)2 4:73 withPPC 1:440 with pyridinium chlorochromate (PCC) 8:22,23, 163;11:401 with pyridinium chlorochromate 1:208;6:117 with pyridinium dichromate 4:331 withRu04 1:404,405;8:150-152 with Ru04-NaI04, 8:162 with Se02/t-BuOOH 8:2,3 with silver carbonate 1:453,454 with silver oxide 11:86 with sodium chlorite 16:83 with sodium metaperiodate 4:50; 19:354 with sodium periodate 16:293 with Swem oxidant 6:119,120 with tetrapropylammonium metaperiodate 1:379,380 with thallium acetate 4:72 with thallium nitrate 4:338;8:166,167,169 Oxidation-Wittig homologation 13:612,613 stereospecific 9:255,256 Oxidative conversion 19:484 Oxidative coupling reaction olefin 8:160 of phenol 8:160 Oxidative Nef conditions 19:73 Oxidative cyclization ofdavanones 9:533

1271
Oxidative phenolic coupling in biosynthesis of 20:291-293 natural products by 20:263-315 Oxidative decarboxylation 1:536 of a-keto acids 1:536 Oxidative degradation of fatty acids 13:303-306 of ilimaquinone 9:31 Oxidative demethylation 5:769 Oxidative elimination of arylselenide 3:260 Oxidative hydroboration 12:318,322,344,14:460,461 Oxidative olefination 4:448 Oxidative rearrangement 16:650 Oxidative transformations 7:159-168 Oxidative-degradation system 7:105 Oxidising action of NO in CI (NO) mass spectra 2:3 Oxidizing agents 19:120 Oxidizing enzymes in Strychnos dinklagei 6:520 Oxidopyridinium ions 1,3-dipolar cycloadditions of 1:340 Oxirane opening influence of a-OH 1:560,561 reaction with lithiated nucleophile 1:157 regiospecifity of 1:560,561 with dilithioacetate 1:558,560,561 Oxirans 2-amino alcohol by 12:411,413 ring opening of 12:411,413 with nitrogen nucleophiles 12:465 0x0 reaction 3:223,4:255 Oxocarbenium ion 16:94,95,108 formation of 16:94 Oxocene oxidation of 10:204 synthesis of 10:203,204,211,218,224,225 unsaturated 10:231 Oxocenones synthesis from 5-lactones 10:217 Oxy-Cope rearrangnement 3:96;6:28,29,36,538-540; 7:216;8:179,234,246,249;10:61,416;ll:43,45-49, 627;18:17 anion assisted 16:459 anionic 4:591;16:127;16:127;19:6 in the synthesis of macrocycles 8:245 of tertiary alkoxide 16:127 suprafacial 16:12 Oxyallyl zwitterion 14:587 Oxyaminations 2-amino alcohol by 12:411,413 ofalkenes 12:411,413 Oxygen-containing heterocycles by cyclization of mixed acetals 10:220,221 from Lewis acid catalyzed reaction 10:220,221 Oxymercuration 10:67,324,185 Oxymercuration cyclization 1:423,425 Oxymercuration-demercuration procedure 14:538,539 Ozone-triphenylphosphine adduct 4:554 oxidation of ylides with 4:558,559 Ozonization 1:264,265 of olefin 1:439 of()-dihydrolimonene 6:541 Ozonization reaction with thuj one 14:416,417 Ozonolysis 4:523;5:590;6:137,298,299;8:139;9:338, 359,525,527;11:337,338,369;12:81;14:101;16:495,64 9,712;20:409 cardanol methylether by 9:338 ofalkene 16:462 ofdiacetate 5:599 of diacetylirumamycin 5:599 of enol ether 16:495 ofenyne 16:384 ofergosterol 16:336 of olefins 10:565 of seleno ether 16:7 ofstigmasterol 16:324,336 of streptolydigin 14:101 reductive 4:523 Ozonolytic cleavage 13:604,258 of(+)-A^-carene 16:258 Ozonolytic degradafion 6:137 of 19'-hexanoylfiicoxanthin 6:137 ofperidinin 6:137 Palladium (II) acetate 10:344 Palladium (0) for macrocyclization 3:82,83 Palladium (0) catalyzed cyclization of allylic acetates 8:228 Palladium (O)-catalyzed condensation 12:300 Palladium acetate coupling with 1:19 Palladium black as catalyst 14:763 Palladium catalysed acetalization 1:584 Palladium catalysed coupling 3:258 with [PdCl2(PPh3)-Cu I) 1:532 Palladium catalyzed rearrangement 14:625 Palladium dehydrogenation 1:129,130 Palladium mediated coupling regiospecificity of 10:341 stereochemistry of 10:342 stereospecificity of 10:341 Palladium mediated oxidation 12:241 Palladium-induced indolizidine ring formation 12:299 Palladium-promoted reaction of vinylic bromide 16:367 Parikh oxidation 12:305 Parikh-Doering oxidation 14:60 Parsons approach for hexahydrobenzofuran component 12:24 ofavermectins 12:24 Partial synthesis of acetylenic carotenoids 6:157-160 ofanguidine 6:225,226 of carotenoid sulfates 6:150 ofgibberellins 6:186-194 Passerini reaction 12:131,138 Paterno-Buchi photocycloaddition 10:440

1272
Pattende's synthesis ofverticillene 12:180,181 Paulsen method 6:357 Pauly's reagent 17:396 Pauson-Khand cyclization 3:83,84 Payne rearrangement 4:173,179,186,344;11:10,36,38; 12:209 PCC Oxidation 6:545 Pd-(0)-catalyzed carbonylation 10:29 Pd-catalyzed cross coupUng reactions 10:161 -163 PDC oxidation 16:23 Pellegata oxidation 19:226 Pentasaccharides by glycosylation 10:475,476 synthesis of 10:475,476 Pentenylation 12:466 Peracid oxidation ofguaiazulene 14:320-324 Perhydrogenation of (3/?,3/?')-zeaxanthin 6:149 [2CT+2CT+27i]-Pericyclic reaction 16:621 [27i+2a+27r]-Pericyclic reaction 16:628 Pericyclic reactions ofarynes 3:418 Pen interaction 1:386 Periodate 2:346 oxidation of glucoamylase 2:346 perrottetianal 2:278,280 Periodate-nitromethane procedure for purine synthesis 4:240 trans-anti-Periplanar fashion 11:301,302 Perkin condensation intramolecular 12:381 Permethylation 5:199 Peterson olefmation 3:202;8:247,248;11:10,11;19:374 in p-dictyopterol synthesis 6:189,19 Phenolic a-diazoketone bromochammigrene from 6:60,61 spiroannulation of 6:60,61 Phenolic coupling reactions 16:504 Phenols 17:586 anodic oxidation of 8:159-172 chemoselective protection of 19:304 chromanes from 4:394 oxidation with TI (03)3 (TTN) 8:166,169 photosenstized oxygenation of 16:582 Phensulfmylation 19:470 a-Phenyl selenide in P-dictyopterol precursor synthesis 6:16 v/c-Phenyl thiobenzoate metal reduction of 6:541-542 1-Phenyl-2-buten-1-one reaction with silyl enol ether 3:129 a-Phenyl-y-lactone derivative alkylationof 10:410,411 stereoselective 10:410,411 Pheny lacetaldehyde 6:312 synthesis of 6:312 Phenylacetic acid derivatives synthesis of 6:320-322 Phenylation of aldehyde 19:497 chemoselective 19:497 3 -Pheny ley clohexanone sulfenylation of 12:25 Phenyiselenyl bromide in quinolizidine formation 14:737 Phenylselenylation 1:242,248 1-(PhenyIsulfonyl) indole 6:509,510 regiospecific lithiation of Phenyiselenyl chloride cyclofiinctionalization with 6:426-428 Phosgene isocyanides from 12:113 Phosphite method for oligonucleotide synthesis 4:271-274,4:280 in oligoribonucleotide synthesis 4:303 mechanism 4:272 oxidation reaction 4:280 Phosphitylating agents 4:272,273;13:276 Phosphitylation 8:388,389 Phosphonate condensation 19:83 Phosphoniosilylation ofenones 3:79,80 Phosphonium mercaptides 4:554 Phosphonium ylides 4:553-578 acylation with thioesters 4:554 acylation with trimethylsily esters 4:564 oxidation 4:558,553 Phosphoramidite 8:373 synthesis of 8:388-390 Phosphoramidite in coupling reactions 4:306 Phosphoramidite method 13:270 methylphosphonates by 13:270 Phosphoramidites 13:265,267,268,269,270;18:398 Phosphorodichloridate 8:83 Phosphorodithioates 13:268,269,270,271,274 from thiophosphoramidites 13:272,273 Phosphoroimidazolidate 8:90 Phosphorothioates 13:263,268,269 diastereoselective synthesis of 13:276 Phosphorus oxychloride 8:72,73 with diisopropylamine 12:113 Phosphorylation 8:97,100;9:391;12:384;18:395, 397-402 dihydrogen phosphate 8:105 methylphosphonates by 13:272 of alcohols 8:80 ofcitronellol 8:76 of-geraniol 8:76 of mevalonic acid 7:322 ofprenols 8:75,80 with tetra--butylammonium Phosphotriester method 13:271,272 methylphosphonates by 13:272 Phosphotriester method 4:268-271,301-303 for oligodeoxyribonucleotides synthesis 4:268-271, 301-303 in oligoribonucleotide synthesis 4:301-303 reaction mechanism 4:270 using polymer support 4:271

1273

Phosphotriesters 13:263,271 synthesis of 13:272 Photo-Fries rearrangement 499 Photo-induced annulation of A^-alkylated pyrrolidinones 12:293 Photo-induced deoxygenation process 14:166 Photo-induced electron-transfer 14:166 Photo-induced reduction of esters 14:166,167 Photo-initiated radical allylation 12:487 Photoaddition 3:102,103 Photoautotrophic cell lines 7:9 A^-phthalylaspartic acid 7:10 Photochemical hydrolysis 6:331,333 Photochemical [2+2] cycloaddition 1:548 Photochemical acyl migration 1:51 Photochemical annulation in (+)-A^^^^^-capnellene synthesis ofp-diketone 6:48 Photochemical decarboxylation of allylic carboxyls 3:487 Photochemical olefin isomerization 1:413,414 Photochemical oxidation 1:159 Photochemical reaction 6:330,331 Photochemical rearrangement l:547;14:356-360 Photochemical synthesis 20:302,303 Photochemical transformation protoberberine 1:218,219 spirobenzylisoquinoline 1:218,219 Photochemical valence isomerization 1:189 Photocyclization 3:14-17,19,20,309,414;14:651 non-oxidative 3:403-406 ofenamides 3:401-403 reductive 3:402,407,407-410,414 Photocyclization 1:45,52,63,141;6:32; of oxopropyl ester 8:131 of phenacyl ester 8:133 Photocycloaddition 11:20;16:651 Photocycloaddition [2+2]-Photocycloaddition 3:97;6:39;8:251;10:405,406; 16:264 diastereoselective 14:502 of cyclic enones 14:502 with chiral a,p-unsaturated acetals 14:502 [67i+27r]Photocycloadditions intramolecular 1:568,569 ofalkenyltropones 1:568,569 Photodeoxygenation 3:199 Photodiode array detection 9:462 Photoisomerization 3-oxo-4,5-oxido steroids 12:236 Photolactone 8:134 Photolithography 13:646 Photolysis of ()-laudanosine methiodide 6:475,476 of(-)-orientalinone 16:512 of(4-oxopentyl)D-glycoside 10:420 of carbohydrate derivatives 14:649,650 ofenamine 16:469 ofA^-alkenylbenzotriazoles 13:445,446 ofnitrone 6:474,477

of phthalimide derivatives 14:649,650 of/raw-canadineA^-oxide 6:474 ofp-ketoester 14:652 Photooxidation 6:472,491,492,16:604 Photooxygenation 1:190,214;4:419-421,424;14:597, 601 ofcoptisine 1:191 ofpalmatine 1:191 of protoberberine 1:203 Photorearrangement 16:512 Photoreduction intramolecular 1:257 Photosensitized oxidation 6:138,142 Photosolvolysis of2,5-benzoxazonine 6:475,476 ring destruction by 6:475,476 Photosolvolytic reactions 6:472,475,477,484 Pictet-Spengler condensation 1:72;14:633 Pictet-Spengler cyclization 8:265,266,288,289;19:301 Pictet-Spengler reaction 1:139,140;4:13,16,17,23, 10:87;13:408-410;14:633,759,761,763 (+)-eJo-6-bromocamphor fi^om 4:644 Pictet-Spengler type reaction oftryptamines 19:91 Piers annulation of methylene cyclophexane 6:21,22 Piers synthesis ofpalauolide 6:22 Pig liver esterase (PLE) 13:56 asymmetric hydrolysis with 1:685 Pinacol coupling 18:443 Pinacol rearrangement ll:52-54;14:360-362; 15:500; 18:174;19:397 of hydronaphthalene-l,10-diol monosulfonate esters 14:356 of 9p-hydroxy-l 1-oxoderivative 19:399 Pinacol-pinacolone rearrangement ofdiol 16:127 Pinacol-type derivatives 8:4 Pinner reaction 5:557,558,561,566,574 Pirkle reagent 9:241 Pivaloyl group 6:292,293 protection with 6:264,268,276,282,283 Pivaloylation 13:32 Polyene cyclization acid catalyzed 8:188 Polonovski reaction 1:105-110,112;14:715-746,811, 815,816,857,858,869-872 modified 4:31 Polonovski-Pofier-Husson reaction 1:79,80 Polonvski-Potier reaction 1:49 Polycondensafion 7:458 Polycycles synthesis of 8:278 Polycyclic aromatic compounds 7:8-10 polyfunctionalized 11:113 synthesis of 11:119-127 via aromatic p,P,5,5'-tetraoxo-alkanedioates 11:119-127 Polycyclic arenes 11:113 functionalization of 11:113

1274 Polyene acetal tetracyclization of 14:471 Polyene synthesis 20:571 Polyene cyclization biomimetic 14:740 initiators 1:656 steroids from 14:740 Polymer support synthesis 4:274,277-283 protecting groups 4:276 protocol for oligonucleotide synthesis 4:288 Polymer supports for macrocyclization 3:82,83 Polyphenylalanine synthesis 7:386 Polyphosphoric acid cyclization 1:58 Polyphosphoric acid trimethyl silyl ester (PPSE) 12:377 Polyprenyl diphosphate sugars 8:63,64,68-106 deacetylation of 8:88 from phosphorobenzimidazolidate 8:90 from phosphoroimidazolidates 8:89,107,108 synthesis of 8:68-70,86-92 Polyprenyl monophosphate sugars from glycosylcation 8:82 from glycosyl-oxyanion 8:83 from phosphoroamidates 8:80,81,107 synthesis of 8:68,69,82-86 synthesis with prenyl cation 8:69 synthesis with prenyl halides 8:69 synthesis with tosylates 8:69 Polyprenyl phosphates from prenyl trichloroacetimidates 8:70,71 synthesis of 8:68-72 Polypropionates 17:25,26;18:155 Pomeranz-Fritsch isoquinoline synthesis 129 Pomeranz-Fritsch reaction 16:510 Ponaras reagent 13:16 Pondorf-Meerwein-Verley method 17:605 Potassium graphite (CgK) 11:366,367 Potassium tri (seco-buty\) borohydride 1:261 Potier's synthesis ofvinblastine 14:869-873 Prelog-Djerassi lactone 3:227,225-257;10:423 synthesis of 3:227,255-257;16:711 Prelog-Djerassi lactonic acid synthesis of 14:267 Prenylation methods 4:367-402 by alkali metals 4:386-400 bychromanes 4:394-396 by Friedel-Crafts alkylations 4:391,394 by organometallic reactions 4:396,398 by silver oxide method 4:386 by trimethylsilyl intermediates 4:394 in basic media 4:386-391 of2,6-dihydroxy-4-methoxy-acetophenone 4:386, 387 of 1,3-dimethoxybenzene 4:89 cw-Principle 4:584,585 in Diels-Alder reactions 4:584,585 Prins cyclization 18:174 Prins reaction 13:41,42;18:882,891 Prochiral carbonyl groups asymmetric addition to 4:332,333 Prochiral ketones chiral alchohols from 1:689 reduction with yeast 1:689 Prochiral naphthalene rings asymmetric additions to 4:332 Prochiral sulfides asymmetric oxidation 14:517,518 Prolines as chiral auxiliaries 4:327 /-Prolinol as chiral auxiliary 14:743-747 Prolycopene 7:330-335 Propane-1,3-diols asymmetric synthesis of 13:53-105 enantioselective 13:53-55 enzymatic 13:55 transesterification of 13:53-55 (5)-Propargyl alcohol 13:585 Propargyl alcohol cw-olefm from 14:569 pyrrolidine derivative from 14:569,570 Propargylic alcohols synthesis of 14:473 Propargylic titanium reagent fromalkyne 12:24 with methacrolein 12:24 Yamamoto condensation of 12:24 Protecting groups acid labile 4:299 anilido 4:286 base labile 4:299 benzyl 4:299 2'-0-t-butyldimethylsilyl (TBDMS) 4:299 1 -[(2-chloro-4-methyl) phenyl]-4-methoxypiperidin-4-yl (CTMP) 4:299 5-chloro-8-quinolyl 4:286 2-cyano-l,l-dimethylethyl 4:285 2-cyanoethyl group 4:285 dimethoxytrityloxyethyl sulfonyl ethyl 4:285 for 2'-hydroxyl 4:296 for 5'-hydroxyl 297 for intemucleotidic phosphate group 4:268 for phosphomonoester formation 4:285 in polymer support synthesis 4:276 p-methoxybenzyl (MBn)) 4:300 3-methoxy-1,5-dicarbomethoxypentanyl (MDMP) 4:300 methoxytetrahydropyranyl 4:297 (1-methyl-1-methoxy) ethyl (MME) 4:300 monomethoxytrityloxyethylamino 4:289 o-nitrobenzyl (NB) 4:300,301 /7-nitrophenylethyl 4:285 e/-pseudoguaianolide intermediate 4:675 2-(2-pyridyl) ethyl 4:286 tetrahydroftiranyl 4:297 tetrahydropyranyl 4:297 trihaloalkyl 4:285 3,4,5-trimethoxybenzoyl 4:299 Protection with cyclocarbonate group 6:284,285 with lauryl chloride 6:429 with MEM 6:558,559

1275

with methoxyethoxy group 6:298,299 with methoxymethyl group 6:282,283 with O-isopropyHdene 6:269,270 with pivaloyl ester 6:264,268 with propanedithiol 6:300,301 with /er/-butyldimethyl silyl ether 6:264,268 with tetrahydropyranyl ether 6:264,268 Protection of alcohol with tert-Bu MesSiOCHjCOCl, 1:440,442,443 Protection of inositols 18:403-421 Protection/deoxygenation procedures regioselective 14:744 Pschorr reaction 20:301;16:504 Pschorr-type diazo-couplings 20:301,302 Pummerer intermediate 3:461 ;14:646 Pummerer reaction 1:63-65;4:139,464;10:678,682; 11:326,327;14:539-546,747;19:14 Pummerer rearrangement 4:36-39,496,505,506,510; 6:317-319,321,328,335;12:160,161,324;14:539; 16:230,671 Pyridinium acetate lactonization with 11:84,85 Pyridinium chlorochromate 7:478;11:93,94;12:492 oxidation with 4:117,118;6:116,118 Pyridinium methylides cycloaddition with 1:334,335 Pyridinium salts reduction with dithionite 1:91 Pyrolysis 14:268;17:455 levoglucosenone from 14:268 of isoquinoline A^-oxide 6:468 ofA^-acyllactams 6:430,431 of A^-lauryl-6-methyl-2-piperidone 6:430,431 of acid-treated cellulose 14:268 ofprotopineA^-oxide 6:494 of microgranular cellulose 14:268

Quaternary carbon 8:3-14,14:631-644 asymmetric 10:405-412,426-428 asymmetric induction of 10:412 chiral construction of 4:4-27;14:631-644 synthesis of 8:3-14 through addition elimination process 14:631-644 Quatemization 6:513,514 by 4 -nitrobenzy 1 bromide 6:513,514 Quinone-Diels-Alder adducts 16:548 Quinone-styrene reaction 16:547,551-552,559,560,564, 565 Lewis-acid promoted 16:565

Radical chemistry 16:30 "Radical clock" 9:568 Radical coupling reactions 11:464,465 Radical cyclization 1:256-258,292 ofhaloolefms 3:13 of phenylselenyl derivative 3:462 of tertiary alcohol 16:235 stereoselective 19:54 thermal 16:41 tin mediated 1:483,490

with R3 SnH 3:38 Radical induced deoxygenations of carbohydrates 14:157-162 Radical mechanism 14:166 Radical Michael addition 12:281 Radical olefin cyclization 3:327 Radical polymerization 6:541,542 Radical reduction 2-deoxy-1 -hydroxysugars from 11:141 ofdithiocarbonates 3:475 Radical spirocyclization 16:28,33,35,41,51,53,63 thermal 16:55 Radical-alkene cyclization 3:327,328 Ramberg-Backlund olefination 18:205,206 Ramberg-Backlund reaction 8:208 Random Bi-Bi process 11:201 Raney nickel 6:150,151 desulfiirization 11:357 catalytic hydrogenation with 6:425 Raney nickel desulfiirization 1:66;14:736,828 Reaction mechanism of asymmetric intramolecular Michael reaction 14:561,562 Rearranged quinone-methide 5:744,745 [3,3]-Rearrangement 10:236 1,2-Rearrangement 10:412 of P,Y-epoxy alcohols 10:412 Rearrangement 3:467,342,480,355-387;10:233-236 in C-glucoside synthesis 3:225-228 intramolecular 3:226-228 of substituted hydronaphthalene 14:355-387 of [4.3.1 ]-bicyclodecanes 14:355 anionic 3:467 of sulfonyl group 6:342 of 1-benzyl tetrahydroisoquinoline system 6:480 reductive 3:227 Rearrangement of camphor 2,6-hydride shifts in 4:626,627 2,3-ejco-methyl shifts in 4:626,627,633,634 1,2-Rearrangement reaction from pyranosides 10:592,593 pinacoltype 10:592,593 Red-Al 19:482 reduction with 6:289,290 Reducing agents 19:120 Reduction 1:10,131,315,316,3 86,592-595,698-701,2830,33,155-159,165,166;3:253,237,339-345,358,590, 660,718;6:115,116,119,124,126,129,229,285,286,288, 289,292,295,296,298,299,428,426,509,511-515; 8:6,7,19,23,34,162,163,165,181,322,323,388,8184,87,91-93,98-100,103-106,288;ll:364-366;12:151, 152,281,283,283,287,290,297,300,301,411,414; 13:54,58,72,499-502,19,45;16:155,294,295, 301,307,348 2-amino alcohol by 12:411,414 acetal/ketal cleavage 1:591-595 asymmetric 4:339-345 baker's yeast 19:129 by Ueno method 10:322,323 catalytic 19:475 chelation controlled 3:253

1276
chemoselective 16:307;19:299,19:329 diastereoselective 1:591-595;14:499-502;19:334 during FAB mass spectra 2:28-30,33,35 enantioselective 13:54 enzymatic 13:58 H-H-C-Relayed '^C-^H correlation spectrum 2:101 intramolecular 12:283 ;16:420 1-selectride 11:365,366 of()-2-oxoindolizine 12:284 of (-)-camphorquinone 4:660 of 17-oxoellipticine 6:509,511 of 1-piperideines 6:426 of2-enals 20:831-839 of2-enoates 20:824 of2-methylseleno-2-phenyl-6-heptene 8:7 of 2-0X0 carboxylates 20:840-842 of 3-ketotrichothecene 6:229 of7-oxoindolizidine 12:286,287 of 8-azido-l-/7-menthene 11:288 of allyl alcohol 20:831-839 of allylic alcohol 16:348 of amide 19:145 ofazide 16:19 of carbonyl group 19:226,229 ofC-C double bond 20:824 of conjugated double bond 16:155 ofC-Sebond 8:7 ofcuparenones 8:6 of cyclic P-keto esters 1:697-701 of cyclopropane carbonitrile 12:287 ofenamines 1:386 of exocyclic double bond 19:53 of exo-methylene-y-lactone carbonyl 1:315,316 offamesal 8:19 offumarates 20:831-839 ofhalide 11:364 ofimines 6:426,428 of indolizomycin 12:301 of isoxazolidine 12:290 of keto group 16:348 of keto lactone 16:301 of ketones 1:131 of kingiside-aglycone-O-silyl ether 16:307 of lactone to lactol 1:315,316 of A^-p-oxy-17-oxoellipticine 6:511 of primary mesylate 16:19 of symmetrical diketones 19:129 ofTiCl3(DME) 8:19 of titanium trichloride 11:364 of a,p-acetylenic ketones 13:72 of a-amino ketones 12:411,414 of a-halo ketones 19:193 regioselective 6:288,289;16:135 selective 19:119,228 stereoselective 11:91;12:151,152;19:259, 473-474, 476 stereospecific 11:98 //2reo-selective of 12:300 under Luche conditions 12:297;19:357 with (5)-Alpine-hydride 19:158 with Baker's yeast 12:281 withBH3-Me2S 12:281 withBujAlH 8:163 with Bu3SnCl-NaBH4 1:512 with Clostridium formicoaceticum 20:831-839 with Clostridium thermoaceticum 20:861 withDIBAH 6:426 withDIBAL 6:285,286;8:165;16:295 with diisobutyl aluminium hydride 1:315,326;4:589, 590;6:115,116;11:105,106 with EtsSiH/BFs 10:388 with hydrazine 1:131 with K-selectride 12:151,152 withLAH 19:475 withLiAlH4 8:23,162,163,181 with lithium aluminum hydride 11:364 with lithium triethylborohydride 11:83,84 with I-Selectride 6:2989,299;19:147 withNaBHsCN, 8:162 with NaBH4 16:348 withNaBH4/Mo03 4:237 with NaBH4/NiCl2 4:237 withNaCNBH3 1:386 withNiCl3-NaBH4 3:165,253 withPh3P 12:281 withRaneyNi 16:294 withREDAL 6:288,289 with Selectride 8:181 with sodium borohydride 19:296 with sodium cyanoborohydride 11:87 with sodium dithionite 16:45 with sodium hydrotelluride 11:81,82,92,93 withTiCU 1:591-595 with trialkyl aluminium 6:426 with tributyl tin hydride 4:718 with tri-A^-butyltin hydride 8:34 with yeast 1:697-701 with zinc/copper couple 11:3 64 Reductive elimination 19:6 Reduction of substrate 17:495 Reductive acetylation 4:232,324 Reductive alkylation of a(phenylthio) methyl enone 10:409 Reductive amination 1:253,289,290,301;11:302,350, 429,437,438,445,446,450" with acetone/cyanoborohydride 11:3 01,3 02 of 1,4-diketones 6:437,438 of ketones 6:429 triketones 6:445,446 2,6,9-undecatrione 6:450 Reductive aminocyclization ofalkane-2,6-diones 6:433,434 Reductive cleavage withLAH 1:439 Reductive cyclization 1:106,279,281 indolizidine from 11:241,242 of ketones 11:241,242 Reductive decyanation of 2,6-dialy-2-cyanopiperidines 6:431,432 Reductive demercuration 14:185 Reductive desulfurization 12:81,167,307-309,319 Reductive elimination of acyloxysulfones 4:522 of allylic radicals 4:525

1277 with low valent titanium 4:521-535 with zinc copper couple 4:119 Reductive hydrolysis 19:155 Reductive methylation 4:55;6:553,554 Reductive A^-methylation in ant alkaloids synthesis 6:435,443 Reductive opening with Et3AlCl-CH2Cl2/Et3SiH 1:519 Reductive oxygenation withNaBH4-DMF-02 10:532 Reductive ozonolysis 4:523 Reductive rearrangement 3:253 of3,4,6-tri-0-acetyl-i)-glucal 3:253 Reductive transposition in ()-pachydictyol-A synthesis 6:11 Reformatsky reaction 1:312,313,520,41;8:232;14:478, 727;20:569 of ethyl bromodifluoroacetate 16:727 of chiral 2-bromopropionic acid derivative 12:166 p-selectivity of 12:167 with 4-acetoxy p-lactam 12:166 vinylogous 3:38,39 Regio-pyranocoumarins 18:993 Regioselective ketalization 11:315,316 oxymercuration 11:324 ring expansion 11:280,281 Regioselective acylation 12:346,404 Regioselective alkylation 6:546,547 Regioselective aza-annulation 18:319,327 Regioselective p-glycosylation 10:477 Regioselective dehydration 13:561 Regioselective Diels-Alder reaction 14:48 Regioselective glycosidation 6:262 Regioselective hydroboration 13:130 Regioselective Michael addition 18:319 Regioselective nucleophilic substitution 18:406 Regioselective phosphorylation 18:399 Regioselective reduction 6:289,290 Regioselective tosylation 12:218 Regioselectivity 4:372,373,391118,142 in Diels-Alder reactions 4:584-586 of C-aryl glycoside 11:142 of 2-substituted 1,2,3,4-tetrahydronaphthalene acetate 11:118 of Claisen rearrangement 4:368,369 ofFriedel-Craftsalkylations 4:391 of hydroboration 4:116 Regiospecific cleavage ofoxiranering 11:267,268 Regiospecific enolization 12:84 Regiospecific lithiation of l-(phenylsulfonyl) indole 6:509,510 Regiospecific oxidation ofellipticine 6:508 17-oxoellipticine from 6:508 Regiospecific sulphonation of camphor 4:633 Regiospecificity ofFriedel-Craftsallylations 4:391 Reimer-Tiemann reaction '^C-Relaxation measurements 2:67,68 H-Relaxation measurements 2:67,68 ofphenol 8:33,34 Retro-Michael elimination 12:490 Retro[2+2]cycloadition 19:221 Retro Diels-Alder cleavage 5:634;9:295,300 Retro Diels-Alder fragmentation to secodine 4:40,41 Retro Diels-Alder reaction synthesis of actinidine 4:614,615 synthesis of a-caryopterone 4:612-614 synthesis of crotepoxide 4:162 synthesis of epiepoformine 4:612,613 synthesis of epiepoxydon 4:610 synthesis of epoformine 4:612 synthesis of epoxydon 4:610 synthesis of ligularone 4:615 synthesis of petasalbine 4:615 synthesis of phyllostine 4:610 Retro Michael reaction 14:748 Retro-aldol reaction 7:286,288,291;10:168,303,329; 18:284,285 Retro-aldolisation 14:180 Retro aldol process 19:194 Retro-ene reaction 11:46,47,16:246 Retro-Mannich reaction 1:157,158;6:497;10:682,99, 333;11:55,56;13:181,397,423,460;18:18 of 0-quinol acetate 16:521 Retro-Prins reaction of 16:248 Retro-Wittig reaction 18:78,176 Retro-Aldol degradation 12:216 Retro-Aldol fragmentation 12:212 Retroaldolization 4:4,7,56 Retrograde aldol reaction 6:78 Retrograde Michael reaction 6:173,187,199,200 Reverse Michael addition 3:473,25 Rh (Il)-catalyzed carbenoid insertion 13:501,502 Rhodium catalytic hydrogenation with 6:424 Rhodium (1) decarbonylation by 1:177-179 Rhodium catalyst in carbene insertion reaction 4:436 Rhodium catalyzed isomerization 4:22,23 Rieke'szinc 13:146 Ring cleavage 16:139 of(+)-9,10-dibromocamphor 16:139 Ring cleavage reactions of camphor 4:667-673 of camphor derivatives 4:667-673 Ring closure by Mitsunobu procedure 11:10 Ring construction 3:226,310;6:482,474,475 by diazotization 3:225,226 in benzazocine derivative synthesis 6:468-471 in benzoxazocine derivative synthesis 6:468-477 intramolecular 11:42,43 nine-membered rings from 6:474,475 of furanosyl nucleoside 10:592-595 of lactone triflate 10:605 oxetanocin A synthesis by 10:592-595 thermal 3:310 to eight-membered rings 3:67,77

1278 to nine-membered rings 3:76 to oxetane-2-carboxylate 10:605 Ring destruction 6:468-471,475-497 by CNBR-induced reaction 6:476,477,484,486 by chloroformate ester-induced reaction 6:477 by photosolvolysis 6:475,476 in benzazocine derivative synthesis 6:468-471 in benzoxazocine derivative synthesis 6:468-471 nine-membered rings formation by 6:468-471 of tetrahydroisoquinoline systems 6:477 Ring enlargement by migration 10:232,233 by rearrangements 10:232,233 Ring expansion 6:468,472,477,478;ll:6,7,28-31,109 regioselective 11:6,7 2,4-benzoxazocine derivatives from 6:469 in aporphine alkaloids 6:469 in()-spiniferin-l synthesis 6:73,74 of erythrinan-3-one 6:477,478 of a-narcotine//-oxide 6:468 Ring interconversion 6:468-475,478,482-497 in benzoxazocine derivative synthesis 6:468-471 in benzoxazocine derivative synthesis 6:468-471 nine-membered rings from 6:468-471 Ring opening 12:411,413 2-amino alcohol by 12:411,413 ofoxirans 12:411,413 with nitrogen nucleophiles 12:411,413 Ring transformation 10:303-336 Ring transposition procedure 6:374,375 Ritter reaction Hg(II)-mediated 11:281,282 Robinson annelation 1:81,446,478,17-21,29;6:30, 18,57,58,55,56,148,182;11:78,93-96,108,678,679,33 bicyclic enone from 14:678,679 of()-carbomenthone 6:547,548 of2-carboethoxycyclohexanone 14:678,679 of ethyl vinyl ketone 14:678,679 of cycloheptenone enolate 6:29,30 of ethyl vinyl ketone 6:19 of 2-methy 1-1,3-eyelohexadione 6:19 trimethyl decalone by 6:19,20 Robinson annulation reaction 13: chiral sesquiterpenes from 14:406-425 Robinson-Schopf condensation 1:294,295 Rubottom epoxidation 11:75 Rubottom oxidation 12:215 Ruthenium (III) chloride 12:162 Ruthenium tetraoxide 1:27,28 Ruthenium-catalyzed oxidation 12:175 Rydon bromination 6:287,288 Rylander oxidation 12:198 Samarium iodide mediated cyclization 8:232 Saponification 6:146,162,445,447,19:322 Sarett oxidation 14:635 Sarett reagent 4:434;6:27,28 Saucy-Marbet rearrangement 10:417 Schill's synthesis ofvinblastine 14:861,862 Schlosser-Wittig reaction 16:482 Schmidt reaction intramolecular 16:472 Schmidt rearrangement 13:95;16:472 Schoellkopf reagent chiral induction with 10:653,655 Schollkopf system 4:125 Schollkopf s isocyanides a-metalated 10:88 Schotten-Baumann acylation with 2,2,3-trimethylethanolamine 10:131 Schotten-Baumann reaction 11:448 Z-Selective Wittig olefmation of 4:125 Selective acylation 12:346;13:586;14:163 Selective aldehyde reduction 13:579 Selective antitumor activity 15:355 Selective benzoylation 13:557;14:244 Selective cleavage ofbisdesmosides 7:155 of ester type glycoside linkage 7:154,155 of glucuronide linkage 7:156-158 of sugar aglycone linkage 7:154-158 Selective cytotoxicity 13:648 Selective deoxygenation of maltose 14:160 Selective deoxygenations of primary alcohol 16:348 Selective deprotection 12:345 p-Selective glucosylation 15:28 Selective heteronuclear J-resolved spectroscopy 2:147 Selective hydrogenation in ()-9-isocyanopupukeanane synthesis of 6:83 with iridium black 6:83,85 Selective hydrolysis 12:343;13:571 Selective J-resolved spectra 2:115 2D Selective ketalization 6:33 Selective mesylation 12:326,335 Selective monotosylation 13:620 Selective O-methylation 12:485 Selective reaction acylation 6:282,283 esterification 6:276 formation of cw-5-oxo-l-indanones 6:558 hydrolysis 6:285,286 Selective redox reaction chiral synthesis by 20:817-881 Selective reduction of methyl 4,6-0-benzylidene-2,3-di-(9tosyl-a-Z)-glucopyranoside 14:145 Selective silylation 12:330 K-selectride 12:475 oftriol 4:184 Selective skeletal rearrangement 14:377 Selective synthesis of5-lactams 18:315-386 ofpyridones 18:315-386 a-Selective thermal glycosidation of cyclooligosaccharide 8:367 ofcyclo-I-rhamnohexaose 8:367 a-Selective thermal rhamnosylation 15:28

1279

Selective thiocarbonylation of sucrose derivative 14:162 with thiocarbonyl diimidazole 14:162 5y-Selectivity to (2/?)-methyl aldehyde 12:58 //?reo-Selectivity in cyclocondensation 4:130,145 in A^-protected alaninals 4:122 erythro-SQlQCtWity 4:143 e^T^o-Selectivity (f/Z-addition) 6:549,550;8:411, 415-417 K-Selectride 14:179 anhydride reduction with 3:489 in stereoselective reduction 4:437,459 L-Selectride 16:454;19:72,419,478,494,629 reduction with 4:470,516;6:38,39;14:378,379; 18:235 Selenation-oxidation in (-)-pseudopterosin-A synthesis 6:74,75 Selenium dioxide for allylic oxidation 1:549,550 Selenium dioxide oxidation 1:74 Seleno-lactonization 13:622,623 a-Selenoalkyllithiums 8:5,11 as key intermediates 8:3 a-Selenobenzyllithiums 8:3,5,11 Selenocyclization 11:98,99,101,102 Selenoetherification 10:207;11:109 Selenoxide-based elimination 1:248 Selenylation 1:452;6:70 Sepulchre's method 19:367 Sequential Homer-Emmons condensation 13:608 Sequestration 17:93,104 "Serendipitous" deconjugation 12:28 "Serial" Michael additions 14:756 Shapiro reaction 13:509,578 Shapiro reaction, modified 1:460,461 Shapiro synthesis 11:84 Sharpless asymmetric dihydroxylation 18:197;16:332; 20:592 Sharpless asymmetric epoxidation 1:265,266,487,488, 507,508,510,532,538;4:496;10:534,598,599;12:11,18; 13:621;14:568-571,828;16:296,342;16:492;18:217; 19:431,435,443,478;20:450 diastereofacial-selective manner 19:492 dihydroxylation of 19:246 of2-ethyl-2-propen-l-ol 14:828 of2-heptenol 19:61 of allylic alcohol 10:534 of allylic alcohol 12:11 of allylic alcohol 19:45 ofgeraniol 19:139 osmium-catalyzed 19:246 pyrrolidines from 14:568-571 regioselective manner 19:492 Sharpless epoxidation 4:173,174,179,186,187,203,339345,506,514,516;6:268,269,287,289;10:39,40,66; 11:7,8,59,60,83,93,94,267,268;14:746;18:197,204, 205,244 (+)-nitramine by 14:746 enantioselective 4:343,344;6:287 of 1-cyclohexenyl alcohol 14:746

of allylic alcohols 4:312,516 kinetic resolution by 4:342 Sharpless method in thienaycin synthesis 4:483 Sharpless hydroxylation 12:218 Sharpless kinetic resolution 10:236 of ()-A^-benzy loxycarbony 1-3 -hydroxy-4pentenylamine 12:281 Sharpless oxidation 4:602;10:289;12:353;16:296,342; 19:463 of P-hydroxyl olefin 16:296 with diethyl Z-(+)-tartrate 16:342 in ()-precapnelladiene synthesis 6:34 Sharpless reaction 13:203,204;19:375 Sharpless vicinal hydroxyamination 12:219 [1,5]-Shift of cw-alkyl vinylcyclopropanes 3:34 1,2-H Shifts 1:331,332 Shine-Dalgamo sequence 13:262 [ 1,2]-Sigmatropic (Stevens) rearrangement 6:315 2,3-Sigmatropic rearrangement [l,3]-Sigmatropic rearrangement 16:254,617 [l,5]-Sigmatropic rearrangement 4:333;11:27,3:289 [2,3]-Sigmatropic rearrangement 1:401,560;3:354; 6:316;8:209;11:15,16,24,30,326,327,45,46,48,49,188; 12:93,95,467;13:418,519,589,72;14:533,534;16:255, 173,621,622-623,627;19:259 for C-S to C-0 conversion 1:560 of allylic sulfonium ylide 16:255 of sulfoxides 1:560 of allylic sulfoxides 11:326,327 of 6-alkenyl-4-oxapyran-2-ones 10:460 of allylic (alkyl) ketene acetal 10:417 of allylic azides 10:418 of allylic thiocyanates 10:418 of allylic trichloroacetimidates 10:421 of allylic sulfoxides 11:326,327 suprafacial 16:627 [3,3]-Sigmatropic rearrangement 1:53,228,401;3:228; 4:522;6:222,224,225;8:245,251;10:333,416-420; 11:15,16,45,46,48,49,188;12:95,193,249;13:418,519, 589;14:625;19:6 Sigmatropic rearrangement 12:246-250;13:420,564; 16:340 Sigmatropic migration phenylselenium 19:208 Sigmatropic 1,3-H-migration 18:166 [2,3]-Sigmatropic elimination 12:11 ofPhSeOH 12:11 [l,5]-SigmatropicH shift 10:70 [l,7]-Sigmatropic shift 2:128 [l,5]-Sigmatropic shift of hydrogen 12:182 [3,3]-Sigmatropy 10:235 Sih's compactin synthesis 13:593 Silicon ethers in glycosidation 6:262 Silicon-containing nucleophiles 14:472 Siloxane bridged oligonucleotides 13:271 [l,3]-Siloxy-Cope ring expansion 8:246 p-Siloxyacetals with organometallic reagent 14:483

1280 Siloxydiene 4:334 asymmetric Diels-Alder reaction with 4:34 Silver (II) oxide oxidative demethylation with 5:769 Silver cyanide allyl isocyanide from 12:113 Silver oxide oxidation with 11:86 Silver oxide method in prenylation methods 4:386 Silver staining 17:396 Silver sulphamate 9:433 Silver triflate in C-glucosidation 3:216 Silver trifluoroethane sulphonate method 4:323,324 Silylated phosphonium ylides reaction with acid silyl esters 4:546 synthesis of 4:563 Silyl enol ether reaction with l-phenyl-2-buten-l-one 3:129 reaction with unsaturated ketones 3:129 Silyl enolate Claisen rearrangement 1:563;2:685 Silyl group removal with n-Bu4 NF 1:452,453 Silyl ketene acetals Claisen rearrangement of 10:422,423 0-Silyl ketene acetals in Claisen rearrangemment 3:243 Silyl Pummerer rearrangement 4:550 Silyl-Wittig reaction 14:461,463,464 Silylacetylenic reagents 14:473 Silylation 6:16,19,20,25,26,30-33,39-41;ll:338,369; 19:518 Silylenol ethers 4:475-477 a'-Silyloxy ()-enone 19:59 co-Silyloxy propargylsilanes by exocyclic ring closure 10:227 synthesis of 10:227 Silyloxydienes in cyclocondensation 4:113 Silymarin 5:496;13:660 Silyvinylalane 12:295 Simmons-Smith cyclopropanation 6:72;11:29,30; 16:703 Simmons-Smith reaction 6:5,234,235;8:34;14:490 annulationby 6:5 diastereoselective 14:487-489 of chiral vinyl ether alcohols 14:487,488 of a,P-unsaturated acetals 14:489-491 Simmons-Smith reagent 14:490 chelation controlled delivery 1:637 cyclopropanation with 1:631,632 Singlet oxygen addition to isoquinolines 3:439,440 asdienophile 4:612 Six-membered ring 8:175 Six-membered cyclic ethers by rhodium carbenoid mediated cyclization of hydroxy a-diazo-P-keto esters 10:209 Skeletal rearrangements 7:159-168 Smith degradation 1:436,439;5:197 Smith indole synthesis 1:155 Smith reaction 7:270 Smith synthesis of avermectin oxahydrindene subunit 12:25,26 SnAr reaction 20:410 SN'-process 11:323 intramolecular 11:323 SN'-products 11:319,320 SN^ reaction 11:207;14:747;16:296 oftriflate 16:296 SN^ type cyclocarbamation 12:479 SN^-alkylation 13:585 SN^-displacement 14:156;13:589 SN -nucleophiles 16:415 SN^-type condensation 14:147 SN^-type reaction 14:269 Sodium amalgam desulfonylation with 11:349 Sodium artesunate 13:657 Sodium bistrimethylsilylamide cyclization by 6:540 Sodium borohydride 8:468-470 Sodium cyanoborohydride reduction with 11:87 Sodium hexamethyl disilazide (NaHMDS) methylation with 13:63 Sodium hydrotelluride reduction with 11:81,82,92,93 Sodium methanethiolate 6:340 Sodium naphthalene 11:371 Sodium naphthalenide 6:541,542 Sodium phenylselenide reaction with ()-canadine 6:489,490 Soft acids/bases 3:409 Sowden method in L-glycero-D-mannoheptose synthesis 4:197,203 Spiro [5.5] undecane group 6:59-65 construction of 6:59 Spiro systems construction 6:60-65 by intermolecular cyclization 6:59 Spiro-dehydration reaction 12:64 Spiro-rearrangement 12:99 Spiroannelation 4:7,12;14:546 in bromochamigrene synthesis 6:60,61 of cyclohexanone aldehyde 6:61 of phenolic a-diazoketone 6:60,61 Spirocyclic systems 6:59-65,85 Spirocyclization 10:170;14:649,755;16:28 enantioselective 14:750 Spiroethers synthesis of 18:269-309 Spiroketal enol ethers 7:220 Spiroketal reduction withDIBAH 18:276,277 with Silane-Lewis acid 18:277,278 Spiroketals 9:530;13:60 diaxial configuration 1:476 stereoselective synthesis of 14:519-521 Spiroketone 8:288 from ketolactam 8:287 Splicing reaction 13:261;13:290 Squalene cyclization 1:655 TT-Stacking model 4:609
2

1281 Standinger reaction 1:352,353 Stereo-controlled syn aldol reaction 13:546 Stereochemical inversion 6:178 Stereochemical revision of methyl nuapapuanoate 9:19 Stereochemistry of cycloaddition in Diels-Alder reaction 4:122,123 Stereocontrol methods 1:578 Stereodifferentiating reactions 16:399 using chiral auxiliaries 4:327-345 Stereoselective arylation C-glycosidation 10:345 Stereoselective a-hydroxylation 9:518 Stereoselective addition 19:33 in Z)-glycero-Z)-galactoheptose synthesis 4:198,199 Stereoselective aldol condensation 6:264,268 Stereoselective construction of withanolide D-type side chain 19:470 Stereoselective C-glycosylations 10:373 Stereoselective epoxidation 4:505;6:553,554;11:165, 166,172;14:366 of tetracyclic intermediates 14:148-150 Stereoselective glycosidation 8:359 Stereoselective hydrogenation 10:551,552 Stereoselective intramolecular reductive alkylation 10:541 Stereoselective ketone reduction 13:600 Stereoselective Michael addiction 13:619 Stereoselective pinacol-type rearrangement 15:509 Stereoselective reduction 10:537;11:91,99,100,103; 11:104,170-172;12:337;14:72,378,529 by 1,3-asymmetric induction double bond hydrogenation 14:147 ofazetidinone 4:437 ofbrasilenone 6:7,8 of chiral p-keto sulfoxide 14:529 of penicillinates 4:437 of p-ketoester 6:429,430 with diisopropylamine borane 4:437 with Dipodascus sp. 12:337 with K-Selectride 4:437 with NaBH4 CeCls 3:483-485 with tetrabutylammonium borohydride 3:483-485 Stereoselective ring opening 12:346 Stereoselective synthesis cis cyclopentane 8:9 of ()-dolasta-l (15),8-dien- 14p-ol 6:54 of ()-eremophilone 15:243 of (-)-swainsonine 12:330 of (+)-castanospermine 12:353,354 of3,7-octadien-l-ol- 12:467,468 of acetogenins 18:193-227 of bicarbocyclic fused systems 6:5-38 ofcarbonolides 11:163-172 of cw-2,6-dialkylpiperidines 6:431,432 of doxorubicin 14:3-46 of forsythide aglycone dimethyl ester 16:294 of leuconolides 11:163-172 ofmaridonolides 11:163-172 of methyl cyclopentanoid monoterpenes 20:41 -46 of natural products 12:445-498 of oligonucleotides 13:275-281 ofspiroketals 14:519-521 oftetraponerine-8 6:452 of threo-2-mvmo alcohols 12:489-493 of ^/'a5-2,6-dialkylpiperidines 6:431,432 of vitamin D 10:43-75 of p-oxygenated y-amino acids 12:476- 489 trans cyclopentane 8:9 Stereoselective Wittig reaction 12:312 p-Stereoselectivity 10:466 Stereoselectivity of oxazolo [4,3-a] isoquinolines 12:452 of (Z)-conjugate esters 4:177,178 of C(3)-monosubstitution reactions 4:653 of (^-nonenopyranuronate 4:180,181 ofosmylation 4:161,162,167,168,170-172,175,178, 183,188 of Wittig reaction 4:175 e^o-Stereoselectivity 4:657,659 Stereospecific iminium ion-vinylsilane cyclization 12:298 reduction 11:98 Stereospecific cationic cyclization 12:456 Stereospecific deuteration 20:839 Stereospecific hydroxylation withOs04 1:404,405 Stereospecific intramolecular-Diels-Alder cycloaddition in 7,20-diisocyanoadociane synthesis 6:86,87 Stereospecific oxidation/reduction 17:484 Stereospecific preparation of(3)-3,7-octadien-l-ol 12:466,467 of 6-oxygenated 4a-aryldecahydroisoquinolines 12:457,458 Stereospecific reduction ofketonucleosides 4:234 Stereospecific synthesis from chiral pool 18:197-202 Stereospecificity of glycosylation reactions 14:201-259 Stetter thiazolium salt method 6:437-438 Stevens [l,2]-sigmatropic rearrangement 6:315 Stevens and Bisacchi synthesis oftaxodione 14:684-686 Stevens condensation 3:463 Stevens rearrangement 6:497;16:470-471 of ring C-homoberberine analogue 6:496 Still olefmation 10:157;12:46,47 Still procedure 13:88 Still rearrangement 13:22 Still synthesis of()-A^^'^^-capnellene 6:47 ofasperdiol 10:18 Still's product 6:542 Stille-type Pd (0) catalysis 16:435 Stork modification of Michael addition 10:185 Stork's vinyl radical cyclization 12:15 Stork-Boeckmann enone 12:262 Stowell's iodide 8:146,147 Strecker reaction 6:312 intramolecular 19:36 Strecker-type reaction 10:463

1282 Stubenrauch's technique 4:414 Styrene-quinone reactions 16:551-552 Styrenes cycloaddition reactions of 16:561 polymerization of 16:551 Styryl azide thermolysis 3:314,315 Sugar aglycone linkage 7:154,157,158 cleavage by diazomethane 7:155,156 Sugar-epoxide reductive cleavage of 14:168 a-Sulfenylacetamide cyclization to erythrinans 3:461 trans-Su\{Qny\ation intramolecular 12:73,76 Sulfide contraction reaction 6:438,439 Sulfidopeptide lipoxins 9:576 Sulfmates 4:490 Sulfmyl carbanion 1:451 a-Sulfmylesters in Aldol type condensations 4:491-494 synthesis of 490,491 Sulfonation 16:127 of endo-3 -bromocamphor 16:127 Sulfone anion addition to epoxide 1:471 Sulfone coupling reaction 4:526,528 Sulfones 17:91 Sulfonium ion-induced cyclocarbamation 12:487 Sulfonyl group 6:342 1,3-rearrangement of 6:342 0-Sulfonylation 12:338 Sulforhodamin B 20:524,537 Sulfoxides optically active 489-491 preparation of 14:517-519 monochlorinated sulfoxide from 6:310 synthesis of 4:489-491 Sulfur analogue by Pummerer rearrangement 12:160,161 from (/?)-2-methyl-l,3-butanediol 12:160,161 Sulftir-assisted C-C bond formation 6:308 Sulfur stablized carbanions 3:81,82 Sulpheno-cycloamination 1:228 Sulphonation 4:628,633,634 of camphor 4:628 of (+)-edfo-3-bromocamphor 4:628 regiospecific 4:633,634 Sulphonium ylids 13:144 sigmatropic rearrangement of 13:144 Sulphurisation 9:371,372 of4-t-nonylphenol 9:372 Super-hydride reduction with 3:279 Suzuki coupling of organoboronic acids 16:435 Suzuki reaction 20:300 Suzuki-type coupling 20:445 Swem method 19:452 Swem oxidant 6:119,120 oxidation with 6:119,120 with oxalyl chloride 8:25 Swem oxidation 1:451, 4:19,200,210,418,425; 5:822,20,21,254-257,447,449,3 86,497,705-708,821 824,826;6:11,13,21,25,57,58,62,66,67,74,75,129,192, 193;8:3-59,64,65,68,69,81,82,115-135,139--157,159172,175-201,205-217,219-256,261,274,277-282,283292,315-350,359-370,373-392,395-406,409-428,433463,466,467,478,25,50;9:37,224,225,228,241-243, 248,343-369,434;10:3-42,51,52,59,65,69,70,77145,155,156,159,166,167,168,171,180,188,241302,307-311,315-317,320-323,330,331,350,351, 386,414,418,419,421,423-428,436,437,439-448,457493,507-511,514-516,585-627,629-669,682685,15,16,20,24,34,38,47,289,290,532,534,551,552,5 61,589,590,597;11:3-69,71-111,117,119-144,151172,229-275,277-377,379-425,429-480,85,86,105, 106,156,233,236,249,267,268,365-367,421;12:933,35-62,65-95,113-135,145-177,181-225,233274,275-363,375-383,411-444,445-498,15,88,321, 324,331,336,343,465,468,469;13:3-52,84,108120,165,187-255,264-281,288,289,328,353-367,383471,473-518,22,125,132,138,139,142,416,420,422, 487,488;18:91,176-178,198,201,210,260,282,283,297, 475,623,633,641;19:22,33,42,45,62,207,238,296,304, 307,341,373,426,452,473,497-498;20:50,75, 592 in synthesis of (-)-warburganal 4:418,425 of ()-10-O-methyl-18,19-dihydrohunter-bumine 14:706-708 of()-ll-epiambinine 14:790,791 of()-ll-epicorynoline 14:785-787 of ()-11 -epiisocorynoline 14:785-787 of ()-16-hydroxy dihydrocleavamine 14:850-853 of ()-18,19-dihydroantirhine 14:406-408 of ()-18,19-dihydrohunterbumine 14:406-408 of ()-3-epi-18,19-dihydroantirhine 14:707,708 of()-3-epicorynantheidol 14:790,791 of()-5-ep/-nardol 14:374,375 of()-alloaromadendrane-4b,10a-diol 14:379-384 of()-alloaromadendrane-4a,10a-diol 14:379-384 of()-alloyohimbane 14:710,711 of()-ambinine 14:788-791 of()-bulnesol 14:365 of()-chelamine 14:793-795 of()-chelidonine 14:793-795 of()-confertin 14:362 of()-corynanthediol 14:709,710 of()-corynoline 14:785-787 of ()-ebumamonine 14:72 8 of ()-epialloyohimbane 14:710,711 of ()-homochelidonine 14:796 of()-isocorynoline 14:785-787 of ()-tirandamycin A 14:120-123,129-132,134-138 of()-tirandamycinB 14:123-126 of()-vincamine 14:726 of()-a-bulnesene 14:364,365 of(-)-(10i?)-hydroxydihydroquinine 14:564,565 of (-)-7-deoxydaunomycinone 14:493,494 of(-)-ajmalicine 14:563,564 of(-)-a//o-yohimbane 14:267,277,278

1283 of(-)-ambrox 14:420-425 of(-)-chokol 14:490 of(-)-eburunamenine 14:636 of(-)-eldanolide 14:272,273 of (-)-e/7/-ambrox 14:420-425 of(-)-eserethole 14:636-638 of(-)-esermethole 14:639 of (-)-Ireland alcohol 14:119,120 of(-)-lardolure 14:487 of (-)-7V-acetylamphetamine 14:496,497 of (-)-ochropposinine 14:565 of (-)-physostigmine 14:636-638 of(-)-polygodial 14:413-421 of (-)-selin-l l-en-4a-ol 14:456-465 of(-)-talaromycinB 14:538,539 of(-)-tirandamycin A 14:114-117 of (-)-/r5-cognac lactone 14:272-273 of (-)-/ram-whisky lactone 14:272,273 of(-)-warburganal 14:413-421 of(-)-a-selinene 14:406-413 of(-)-5-multistriatin 14:273,274 of(+)-africanol 14:487,488 of(+)-arborescin 14:365,366 of (+)-carissone 14:406-413 of(+)-dihydropinidine 14:572,573 of(+)-ebumamine 14:636 of(+)-isoambrox 14:420-425 of(+)-multistriatin 14:267 of(+)-pedamine 14:499 of(+)-PS-5 14:497,498 of (+)-streptolic acid 14:112-114 of (+)-tirandamycic acid 14:110-112,127-129 of(+)-yohimbine 14:566,567 of(+)-zaluzanin 14:366,367 of(+)-a-eudesmol 14:406-413 of(+)-P-eudesmol 14:490 of ()-olefinic alcohol 19:452 of (I)-a-santonin 14:406-413 of (7?)-(-)/(5)-(+)-3 -methoxy-4'-0-methy 1 joubertiamine 14:501,502 of (5)-2-(6-methoxy-2-naphthyl) propanoic acid 14:473 of (5)-5-hydroxy-2-penten-4-olide 14:273,274 of {S)-trans-g-butQny\ 14:473 of (5)-Y-acetylenic-Y-aminobutyric acid (GABA) 14:473 of 1,2,4,6-tetra-0-acetyl-2,3-didehydro-3-deoxy-aZ)-threo-hexopyranose 14:173 of 1,2,4,6-tetra-0-acetyl-3-deoxy-a-Z)-/yxohexopyranose 14:173 of 1,2-dehydroaspidospermidine 14:635,636 of 1,3-diols 16:11 of 10-hydroxy corynanthediol 14:709,710 of 13-methyltetrahydroprotoberberine 14:790 of 16-carbomethoxyvelbanamine 14:831,832 of 16'-demethoxycarbonyl-16'-e!/7/-deoxy vinblastine 14:850-852 of 2-methyl-l,6-dioxaspiro [4.5] decane 14:526-531 of 2'-phosphorylated ribonucleotides 14:304-312 of2-pyrrolidones 14:560,561 of 3,4-anhydro-a-Z)-altropyranoside 14:170 of 3-arylisoquinoline alkaloids 14:796-799 of 3-deoxy-1,2:5,6-di-0-isopropylidene-Z)-xy/ohexofuranose 14:172 of 3 -deoxy-1,2:5,6-di-0-isopropylidene-a-Z)-ribohexofliranose 14:168-171 of 3 -deoxy-D-r/6o-hexofuranoside 14:164 of 3 -deoxy-D-r/^o-hexose derivative 14:163 of3-deoxy-hexoses 14:143-200 of 3'-deoxykanamycin A 14:145 of 4-deoxy-Z),i^-^/o-hexopyranose 14:178 of 4-deoxy-Z)-/yxo-hexose 14:158 of 4-deoxy-Z)-r/Z>o-hexopyranoside 14:164 of4-deoxy-hexoses 14:143-200 of 5,6-methanoleukotriene 14:489,490 of 5-carba-levoglucosenone 14:279 of 5-e/7/-paradisiol 14:454,456-465 of 7,8-demethylene sanguinarine 14:783,784 of adriamycin 14:474,475 ofaflatoxinMz 14:651-657 of alcohol 16:313,480 of alkaloids 14:632-639 of allylic alcohol 16:261 of ambergris fragrances 14:420-425 ofaminocyclitol 14:147 ofamiteol 14:456-465 of anthracyclines 14:271 ofapovincamine 14:635,636 ofaspidospermidine 14:632-636 of benzyl 4,6-0-benzylidene-3-deoxy-P-Z)-nZ70hexopyranoside 14:153,154 of branched RNAs 14:284-303 ofbulgecinine 14:193 of calabarbean alkaloids 14:636-638 of carbohydrate derivatives 14:659-664 ofcardenolide 14:440-444 of catharinine 14:847 of chelamidine 14:796 ofchelerythrine 14:773-775,796 ofchelirubine 14:777,778 of chiralalkoxy-allenes 14:480 of chiral sesquiterpenes 14:406-425 of chiral steroid analogues 14:431-444 of chiral vinyl ether alcohol 14:486 of c/5-a,a'-disubstituted pyrrolidines and piperidine 14:571-574 of cleavamine 14:810 ofcorydaline 14:790 of damascones 14:425-431 ofZ)-andI-lividosamine 14:186-193 of daunomycin 14:474,475 ofdaunomycinone 14:5-8,24-42 of desepoxymethylenomycin 14:602 of dihydrobenzofuranol 14:651 ofdihydrochelerythrine 14:773-775,796 ofdihydronitraraine 14:765

1284

of dihydrosanguinarine 14:793-795 of diterpenoids 14:63 9-642 of fl^/-carbomethoxydihydrocleavamine 14:831 -833 ofi//-coronaridine 14:847,850-853 ofdl-dihydrocatharanthine 14:850-853 ofebumamonine 14:632-636 of emetine 14:565 ofepilupinine 14:704-709 of epivincadine 14:635,636 ofeudesm-ll-en-4-ols 14:449-467 offagaronine 14:775-777 of guaiani alcohol 14:374 of homoallylic aleohol 19:238 of hydroazulene sesquiterpenes 14:355-387 ofibophyllidine 14:847 of iboxyphylline 14:847 of indole alkaloids 14:632-636,703-730 of insect juvenile hormone analogues 14:391-397 ofintermedeol 14:452,453,456-465 of isoebumamine 14:635,636 of isokomarovine 14:763 of isolevoglucosenone 14:279 ofisonitramine 14:543,743-747 of isoretronecanol 14:737 of isovelbanamine 14:865-869 of isovincadifformine 14:850-853 ofkomarovicine 14:763 ofkomarovidine 14:763 ofkomarovine 14:763 ofkomarovinine 14:763 of lambertic acid 14:640-642 ofleurosine 14:811 of lupine alkaloids 14:731-768 oflupinine 14:737,738 ofmacarpine 14:781-783 of methyl 2,3,6-tri-(9-benzoyl-4-deoxy-D-A:>'/ohexopyranoside 14:158,159 of methyl 2,3-di-0-benzyl-4-deoxy-a-Z)-xj^/ohexopyranoside 14:153 of methyl 3-deoxy-4,6-0-benzylidene-Z)-/yxohexopyranoside 14:167 of methy 1-2,3,6-tri-0-benzoyl-4-(9-(trifluoromethane sulfonyl)-P-Z)-galactopyranoside 4:164 ofminovine 14:635,636 ofmodhephane 14:490 of monomorine I 14:575 of iV-acetyl-Z)-lividosamine 14:188,191 of naphtho [2.3.c] pyran-5,10-quinone antibiotics 14:271 ofnaproxene 14:505 ofneointermedeol 14:453,454,456-465 ofnitidine 14:775-777 ofnitramine 14:743-747 ofnitrarine 14:765 ofnitraramine 14:751-754 of M / m n a alkaloids 14:731-768 of A^-methyl decarine 14:783,784 ofoligoribonucleotides 14:283-312 of oxaunomycin 14:493-495

ofoxychelerythrine 14:773-775 ofoxyterihanine 14:775-777 ofpandoline 14:831-833 ofparadisiol 14:453,456-465 ofpenta-(9-acetyl-Z)-glucopyranose 14:659-664 ofpenta-0-acetyl-Z)-isopyranose 14:659-664 ofpiperidine 14:553-559 of piperidine derivative 14:572 of podocarpic acid 14:639-642 of polysaccharides 14:201-259 of Prelog-Djerassi lactoic acid 14:267 of primary alcohol function 19:42 of propargylic alcohols 14:473 ofpunctatin 14:646,647 of purpurosamine C 14:268 of pyrethrin analogues 14:391-397 ofpyrrolidine 14:553-559,568-571 ofquebrachamine 14:632-636 of quinolizidine alkaloids 14:731-768 ofreserpine 14:267 of rose oil components 14:425-431 ofsanguilutine 14:777,778,780,781 ofsanguinarine 14:793-795 of secodehydroabietane 14:642 of securinine alkaloids 14:657-659 ofserricomin 14:267,275 ofsibirine 14:744 ofsibirinine 14:742,743 of spiro [4.5] decane 14:544-546 of stereoisomers of eudesm-ll-en-4-ols 14:456-465 of streptolydigin phosphonate tetramic acid 14:117,118,132-134 oftaxodione 14:667-702 oftetrahydroalstonine 14:563,564 oftetrahydrocorysamine 14:790 of tetramic acid 14:110 oftetrodotoxin 14:267,276,277 ofthalictricavine 14:790 ofvelbanamine 14:810,865-869 ofvinblastine 14:805-884 of vincadifformine 14:635,636 ofvincadine 14:635,636 ofvincamine 14:635,636 ofvincaminorine 14:635,636 ofvitaminEandK 14:478,479 of a-cyanobenzyl alkyl ether 14:473 of a-linked 3'-deoxy cyclitol 14:147 of p-adrenergic blocking agents 14:473 ofp-cyperone 14:406-413 of P-damascenone 14:430-432 ofp-elemol 14:406-413 ofy-citromycinone 14:8-10 of v|/-tabersonine 14:847 Swem reaction 4:425,6:125,9:526,11:90 Swem-Wittig protocol 19:22 Syn elimination ofselenoxide 16:335 oftrifluroacetate 16:357 Syn-QnoatQ 8:140

1285 5iv-epoxidation 16:442 5y-isomerization metal ion-assisted 11:220,221 tertiary allylic isomer from 11:220,221 Syn hydrostannation 19:62 Synthesis of () HON 13:512-513 of()-l-ep/-slaframine 12:309 of()-l-oxoindolizidine 12:279,280 of()-2-oxoindolizine 12:283,284 of ()-5-epipumiliotoxin 18:340 of()-6-demethylstatine 13:514 of()-6-e/7/-slaframine 12:311,312 of ()-apovincamine 18:331 of()-cathenamine 13:490,491 of {ycis-1 -hydroxy indolizidine 12:279 of()-dihydroanatoxin-A 13:494 of()-elacokanineC 12:289-293 of ()-elaeokanine A 12:289 of()-elaeokanineA,C 13:487 of()-epilupinine 13:483,484 of()-eremophilone 15:243 of()-gabaculine 13:509,510 of()-indolyzomycin 12:301-330 of ()-isoretronecanol 13:483,484 of()-mesembrine 13:492,493 of ()-A^a-benzyl-20-desethylaspidospermidine 18:323 of ()-nanaomycin-A 11:127-130 of()-nupharolutine 13:488,489 of ()-0-methylpallidinine 12:470,471 of()-pleuromutilin 8:418 of()-semivioxanthin 11:130,131 of()-seychellene 8:412,423-425 of()-slaframine 12:307-312 of()-statine 12:432,433 of ()-tashiromine 18:353 of()-tetrahydroalstonine 13:490,491 of ()-tetrangomycin 11:135-139 of ()-a-allokainic acid 13:508,516 of()-6-coniceine 13:486,487 of(-)-(l/?,8aS)-l-hydroxyindolizidine 12:281 of(-)-(15,2/?,8a^-indolizidine-l,2-diol 12:303,305 of(-)-l,8a-e/7/-slaframine 12:312 of(-)-l-e/7/-castanospermine 12:333-335,344 of(-)-(15,2/?,8a/?)-indolizidine-l,2-diol 12:303,304 of (-)-8,8a-di-ep/-swainsonine 12:329-332 of (-)-8a-6:/7/-swainsonine 12:328,329 of (-)-8-g/?/-castanospermine 12:344 of(-)-8-e/7/-swainsonine 12:328 of(-)-alstonerine 13:383 of(-)-anatoxin-A 13:493,494 of(-)-aristeromycin 8:148,149 of(-)--P-santalene 8:145,146 of(-)--P-santalol 8:145,146 of(-)-hobartine 11:280-283 of(-)-muscone 10:330,331 of(-)-patchoulol 8:423-425 of (-)-peduncularine 11:284,285;13:491,492 of(-)-periplanoneB 8:227 of(-)-phoracantholideI 10:320-323 of(-)-specionin 10:425,426 of(-)-Z-P-santalol 8:145,146 of(-)-P-santalene 8:145,146 of(-)-P-turmerone 8:51-54 of (+)-(155)-prostaglandin A2 10:418 of(+)-(15,8aS)-l-hydroxyindolizidine 12:281 of {+)-(6R,7S,SS,SaR)- trihydroxyindolizidine 12:347 of (+y(6S,7R,SR,SsLRy trihydroxyindolizidine 12:347,348 of(+)-l,8a-di-e/7/-castanospermine 12:335,336 of (+)-6,7-di-e/7/-castanospermine 12:342-344 of (+)-6-deoxycastanospermine 12:337,338 of (+)-6-erp/-castanospermine 12:342-344 of(+)-acetomycin 10:443-448 of (+)-allopumiliotoxins 267A 12:297 of (+)-allopumiliotoxins 339B 12:298-300 of (+)-and (-)-indolizidine alkaloids 11:246-267 of (+)-aristofruticosine 11:323-325 of (+)-aristoserratine 11:296 of(+)-aristoteline 11:280-283 of(+)-asteltoxin 10:439-442 of(+)-biotin 13:514-516 of (+)-castanospermine 11:267-271 of(+)-castanospermine 12:321,332-342,353,354 of(+)-compactin 11:335-377 of(+)-compactin 13:555-615 of (+)-hastanencine 12:472 of(+)-heliotridine 12:472-474 of (+)-isoeremolactone 8:423,425-428 of(+)-makomakine 11:280-283 of(+)-mevinolin 11:335-377 of(+)-mevinolin 13:561 of (+)-monomorine I 11:231 -244 of(+)-picrasinB 11:76,77 of(+)-pseudoephedrine 12:479,480 of(+)-quassin 11:76,77 of(+)-streptazoline 13:514,515 of(+)-thienamycin 13:498-504 of(+)-A^'^picrasinB 11:76,77 of (+)-a-homonojirimycin 11:431,432 of(+)-a-santalol 8:145,146 of (l^l)-aldosyl aldoside 8:317-327 of (l->2) aldosyl ketoside thiodissacharide 8:324 of (l->2) linked thiodisaccharides 8:327,328 of (l->4) linked thiodisaccharides 8:331-338 of (2/?,3/?)-3-hydroxyglutamic acid 12:477 of (2S',3/?)-3-amino-2-hydroxy-4-phenylbutyric acid (AHPBA) 12:433,434 of (25,3/?)-P-hydroxy-L-glutamic acid 12:431,432 of (3i?)-Y-amino-p- hydroxybutyric acid 12:434 of (3/?,45)-4-methyl-3-heptanol 11:415,416 of(35,3/?)-3-amino-2-hydroxy-5-methylhexanoic acid(AHMHA) 12:433,434 of(35,4/?)-statine 12:480 of(35,4i?)-statine 13:513 of(35,45)-4-methyl-3-heptanol 11:412,413,415

1286 ofWO-bulnesol 10:310,311 of(J,/)-trichodiene 10:307-309 of(^/)-acorenone 10:315-317 of (//)-a-cuparenone 8:3,4 of ()-3-bromoacrylates 8:150,151 of (E)-trans-1 -hydroxy-10-vinyl-2-cyclodecene 8:196 of (,)-diallylic ether 8:176 of (,Z)-2,6-cyclodecadiene 8:177 of(,Z)-2,6-cyclodecadiene 8:177 of(/?)-(-)-homolaudanosin 13:494 of (i?)-(+)-tetrahydro-palmatine 10:682,683 of(7?)/(5)-homoproline 13:513,514 of(5)-pinanediol 11:410 of {Z)-trans-1 -hydroxy-10-viny 1-2-cyclodecene 8:196 of (a-chloroalkyl) boronic ester 11:410 of (a-haloalkyl) boronic ester 11:425 of 1,2-disaccharide 8:362,366 of l,3,5-trihydroxyacridin-9-one 13:357,358 of l,3-dihydroxyacridin-9-one 13:355 of 1,5-diepoxy l,5-imino-D-g/yce/'o-D-a//o-heptitol 11:461,462 of l,5-dihydroxy-2,3-dimethoxy- 10-methylacridin9-one 13:354,355 of 11-hydroxynoracronycine 13:356-358 of 15-tritiatedGA3 8:128,129 of 19,10-thio-3-g/?/-gibberellin Ai 8:125,126 of 19,10-thiogibberellins 8:125 of 19,20-dehydrotalcarpine 13:411,427,428 of 1-aldo-C-glycosides 10:350,351 of 1-aryl bicyclo [3,10] hexane derivatives 8:12 of l-aryl-2-methyl cyclohexane 8:9 of l-aryl-2-methyl cyclopentane 8:9 of 1-deoxynojirimycin 12:332 of 1 -methyl-1 -phenyl-2-(methylseleno)methyl cyclopentane 8:7,8 of 1-O-acetyl oxetanose 10:597-604 of 1-thio analog of sucrose (P-Z)-fructofuranosyl 1thio-a-D-glucopyranoside) 8:324 of 1-thiosucrose 8:326 of 1 -thio-a,a-trehalose 8:318 of la,24/?-dihydroxy vitamin D3 11:384,385 of 1 a,245-dihydroxy vitamin D3 11:3 84,3 85 of 1 a,25-dihydroxy-(24/?)-fluorocholecalciferol 10:69 of la,25-dihydroxycholecalciferol 26,23(S)-lactone 10:59 of la,25-dihydroxyvitamin D2 11:393-395 of la,25-dihydroxy vitamin D3 11:384,385 of la,255,26-trihydroxycholecalciferol 10:69 of la,3(3-diacetoxy-23,24-dinorchola-5,7-dien-22-al 11:398-402 of la,3p-diacetoxy-23,24-dinorchola-5,7-dien-22ol 11:398-402 of la,3P-diacetoxychola-5,7-dien-24-al 11:398402 of la,3P-diacetoxychola-5,7-dien-24-ol 11:398402 of la-hydroxy vitamin D3 10:59 of 1 a-hydroxyvitamin D2 11:381 -383 of 1 a-hydroxyvitamin D2 (IS-hydroxycalciol) 11:380,381 of 1 |3-hydroxy vitamin D2 11:402-404 of 1 P-hydroxy vitamin D3 11:402-404 of 1 P-methylcarbapenem 13:84 of Ip-methylcarbapenems 12:145-177 of 2-(a-hydroxyalkyl) piperidines 12:453-456 of 2-(a-hydroxyalkyl) pyrrolidines 12:473 of 2,3,4,5-substituted tetrahydroflirans 11:433 of 2,3,4,6-tetra-O-acety 1-1 -5-acetyl-1 -thio-a-Dglucopyranose 8:316,318 of 2,3-unsaturated 1-thioglycosides 8:346 of2,6,7-trideox-2,6-imino-Z)-glycero-Z)-mannoheptitol 11:467 of2,6,7-trideoxy-2,6-imino-)-glycero-Z)-glucoheptitol 11:467 of 22,23-dihydro-1 a,25-dihydroxyvitamin D2 11:395-398 of 24,24-dihomo-la,25-dihydroxy vitamin D3 11:385-387 of24-epiteasterone 18:515 of24-epityphasterol 18:515 of 25,26-hydroxy vitamin D2 10:65,69 of 25-hydroxy vitamin D2 10:69 of 25-hydroxy vitamin D3 11:388-393 of2-allylphenol 8:169 of 2-amino alcohols 12:411 -444 of2-deoxy-24-epibrassinolide 18:515 of 2-deoxy-2-desmethylene bicylomycin 12:87 of 2-deoxy-3,24-diepibrassinolide 18:515 of2-flurorostradiol 5:447,449 of 2-hydroxy-6-methylbenzoic acid 9:347,350 of2-hydroxyindolizidines 12:283,284 of2-isocephems 12:126,127 of2-iso-oxacephems 12:128,129 of 2-lithio-2-phenyl-6-heptene 8:7,8 of 2-methylseleno-2-phenyl 6-heptene 8:7 of3,13-diacetyl-GA3 8:122,123 of 3,13-diacetyl-GA3 phenacyl ester 8:133 of 3,4-dihydroisoquinoline 8:230 of 3,5-disubstituted indolizidine alkaloids 11:245259 of 30-methyloscillatoxin D 18:294-309 of 3-amino-5-hydroxybenzoic acid 9:434 of 3 -cyanocephem derivative 12:135 of3-dehydro-24-epiteasterone 18:512,513 of3-dehydroteasterone 18:512,513 of 3-deoxy-la,25-dihydroxy vitamin D3 10:70 of 3 -deoxyrosaranolide 11:164 of 3-hydroxy-2-hydroxymethyl-6-substituted piperidines 12:474 of 3 -nocardinic acid 12:118 of 3-thioxylobiose 8:329 of 4 5-P-Z)-galactopyranosyl 4-thio-Z)-galactose 8:339 of 4a-arylisoquinoline ring system 12:457,458 of4-acetoxy-P-lactam 12:160-162 of 4-aryl-1,2,3,4-tetrahydroisoquinoline derivative 12:451

1287 of 4-aryltetralin-type lignan 18:586-588 of4-5'-D-xylopyranosyl 4-thio-D-xylose 8:338,339 of 4-5-a-D-glucopyranosy 14-thio-Z)-glucose 8:331,332 of 4-5'-p-D-galactopyranosyl 4-thio-D-glucose 8:335 of 4-iS'-p-D-gIucopyranosyl 4-thio-Z)-glucose 8:336,337 of 5,8-disubstituted indolizidine alkaloids 11:260267 of 5-amino-7-methoxy-2,2-dimethyl chroman 13:358,359 of 5-demethylene-6-deoxy-bicyclomycin 12:75,76 of 5a-carbahexopyronoses 13:190-207 of 6(^-alkylidene-8-hydroxy-8-methylindolizidines 12:294,295 of 6(Z)-aIkylidene-8-hydroxy-8-methyIindolizidines 12:295,296 of 6,78-trihydroxy indolizidine 12:348 of 6,7-dihydroxyindolizidine 12:348 of 6-acetamido-6-deoxy-castanosperimine 12:345,346 of 6-deoxy-24-e/7/-castasterone 18:512,513 of 6-hydroxy-4a-aryl-cw-decahydro- isoquinoline 12:458,459 of 6-hydroxyindolizidines 12:285,286 of 6-0-methylerythromycin A 166 of 6-iS'-P-D-galactopyranosyl 6-thio-Z)-glucose 8:339 of 6-iS'-p-Z)-glucopyranosyl 6-thio-Z)-glucose 8:339 of 7-hydroxy-3-oxoindolizidine 12:287,288 of 7-hydroxy-7-methyl-5-oxoindolizidine 12:289 of 7-hydroxyindolizidines 12:286-289 of 7-methyl-2-methylseleno-2-phenyl-6-octene 8:9,10 of 7-oxoindolizidine 12:286,287 of7-thiogibberellinA3 8:123-127 of 8-(3,5-dimethoxyphenyl) octan-1-ol 9:339 of8,14-cedranoxide 8:163-165 of 8-fIuoroerythromycin A 166 of 8-hydroxyindolizidines 12:293 of 9-hydroxyanthracene 11:119 of a( 1 -^4)-linked 4,4'-dithiotrisaccharides 8:344,345 of A-62232 8:400 of A-65265 8:399,400 of A-65638 8:400 of abscisic acid 10:167 ofacarbose 10:511,515 of acoragermacrone 8:178 of acridin-9-one derivatives 13:353-361 of ACRL toxin 18:178-185 ofacyclic amino acids 13:512-516 of acyclic bastadins 10:629-631,634,635 ofadiposin-1 10:514,515 ofadiposin-2 10:514,515 ofagelasphin-9b 18:467-469 of AI-77-B 15:412-418 ofaklavinone 11:121,122 of alkaloids 8:283-292 of a//o-aristoteline 11:318-322 ofallopumiliotoxins 12:297-300 of alstonerine 13:383,408,411,416,-423 of aluminum borohydride 8:467 ofambrucitin 10:386 of amino acids 11:417;13:507-516 of amino sugars 13:190-207 of amino-5a-carba-deoxyhexopyranoses 13:203-207 of aminoacy Iheptoglycosides 11:433-435 ofamylostatin 10:507-509 ofamylostatinXG 10:507,510,511 of anacardic acids 5:826 of Aniba neolignans 8:159-161 of anisomelic acid 10:13-17 of antisense oligonucleotides 13:264-281 ofarcyriacyaninA 12:382,383 ofarcyriaflavin-A 12:376-379 ofarcyriaflavin-B 12:379 ofarcyriarubin-A 12:375,376 ofarcyriarubin-B 12:375,376 of arcyrin/arcyrinin model compounds 12:383 ofaristolasicone 11:315-317 of aristotelia alkaloids 11:277-334 of aromatic selenoacetals 8:5 ofasatone 8:168 ofaspochalasin C 13:131,132,134 of aspochalasin B 13:142,143 ofatisirene 10:180 of avermectins 12:9-33 of aziridinomitosenes 13:444 ofazocine 8:207 ofbastadin-6 10:636-638 of benz[a] anthracene antibiotics 11:134-144 ofbenzalmalonates 9:224,225 ofbenzyllithuim 8:5 of beryllium borohydride 8:467 of bicyclo [2.2.2] octanes 8:412-417,419,422,423 of bicyclo [3.2.2] piperazinedione 12:71 of bicyclo [5.2.2] piperazinedione 12:84,85 ofbicyclohumulenone 8:161-166 ofbicyclomycin 12:65-95 ofbilobol 9:354 ofbinaphthaleneterol 8:221-223 of bioactive natural products 13:473-518 ofbisabolones 8:39-59 of Z)/5-indolymaleimides 12:375-383 of blood group I active oligosaccharides 10:457493 of blood group i active oligosaccharides 10:457493 ofboromycin 10:414 of branched amino sugar 10:421 of branched pentasaccharide 10:476,477 of branched tetraacetate 10:476,477 of branched trisaccharide 10:474-476 ofbrasilenol 9:249 ofbrassinosteroids 18:507-520 ofbruceantin 11:71-73,79-95 ofbutenolides 11:453 of Ci8-desmethylcytochalasin D 8:212-217 of calamanenenes 15:251 of calichemicin 12:283

1288 of carbacepham 8:262 of carba-disaccharides 13:219-221 of carbapenam 8:262 ofcarba-sugars 13:187-255 ofcarbocycles 8:410-422 of carbocyclic oxetanocins 10:608-619 of carbohydrates 11:420-422 ofcarbonolide 11:158-172 of carbonolide A 11:165,166 of carcinogenic adducts 8:373-392 ofcardolmonoene 9:354 of carotenoids 20:561 ofcarpanone 8:168 of carpetimycins 12:135 ofcasbene 8:16,17 of castelanolide 11:74-76 ofcembranes 10:3-42 of cembranoid 8:18-32 of cembranolide 8:16,17 ofcembrene 8:15,16 of cembrene diterpenes 8:15,32 ofcephalostatins 18:900-902 of cepham derivatives 12:131-133 of C-glycopyranosyl-a-amino acid 11:470-472 ofC-glycosides 11:139-144 of chiral allyl boronates 11:393,394 of chiral (3-lactams 12:121 ofcholesta-5,7-diene-la,3p,25-triol 11:390-393 ofchroman 13:359,360 ofcivetone 8:224 ofcodeinone 10:180 of conjugated dienes 8:275 of convergent lactone synthon 13:604 ofcostunolide 8:175-181 of coumarinolignanpropacin 5:497 ofcrassin 8:19-32 of crassin acetate 10:6,7 ofC-sucrose 11:469,470 ofcuanzin 8:283-292 ofcubitene 8:221,230 ofcuparene 8:6 ofcuparene analogue 8:6 ofcyanocycline A 10:108-115 ofcyanohydrin 8:225,226 ofcyclaradine 8:148,149 ofcyclic amino acids 13:507-512 of cyclodextrins 8:367 of cyclo-I-rhamnohexaose 8:359-370 ofcyclooctenone 8:35 ofcyclooligosacharides 8:359-370 of cyclopropane derivatives 8:11,12 of cyclosarkomycin 8:150 of cycloundecenones 8:214 ofcytochalasin B 10:166;13:116,117 ofcytochalasin C 13:148,199 ofcytochalasin D 13:134-139 ofcytochalasin G 13:130,131 ofcytochalasin H 13:125-129 ofcytochalasins 8:213 of^,/-chaparrinone 11:105,106 of D-allo-a-amino acid 11:460,461 of dendrobatid alkaloids 11:244-267 of deoxybouvardin 10:640-642 of deoxybouvardin methyl ether 10:640-642 of desmethoxycuanzine 8:2 8 5 -292 of des-//-methylnoracronycine 13:355,356 of desoxyasperdiol 10:29,30 ofZ)-g/>'ce/'o-D-talo-L-/a/o-undecosepentaacetonide 11:455-458 ofdiacetoxybinaphthyl 8:222,223 of dibenzylbutryrolactone lignans 5:486 ofdiborane 8:466-468 ofdidemnin-A 10:275,276,281 ofdidemnin-B 10:276,281 ofdidemnin-C 10:276,281 ofdihydroacarbose 10:508 of dihydromevinolin 13:575,608,609 ofdihydronapthalene 8:402 ofdihydropyrrole 10:112,113 ofdihydrothiopyrone 8:207 of diisopropyl (bromomethyl) boronate 11:425 ofdiquinanes 13:3-52 ofdisaccharides 11:469 of diterpenes (tumor-promoting) 12:233-274 of JZ-camptothecin 12:283 ofDNA 8:373-392 ofdolaisoleucine 12:477,483-486 of dracaenones 5:20,21 ofZ)-a-aminouronicacid 11:459,460 ofebumamonine 8:264 of elaeocanine 12:454 ofeldanolide 11:414 ofenone 8:279 of e^4-oxo-2,33-dihydrosolamin 18:197 ofent-brefeldin A 8:148,149 ofer-brefeldin A 8:148,149 of e/7^rolIiniastatin-l 18:210,211 of e/-rolliniastatin-2 18:208,209 ofenyne 8:280 of enzymes 8:315 of e/7/-corrossoline 18:200 ofepigloeosporone 9:241,242 of epimeric 2,3-epoxy brassinosteroids 18:512 of epipodophyllotoxin 18:5 97-601 of epoxyallylic ether 10:589,590 of epoxysesquiphellanhdrene 8:57,58 ofequisetin 13:545-547 of eremophilone 10:436,437 of erythromycin A 12:48-54 oferythronolideA 11:152, ll:153,157;12:46-54 of erythronolide A seco acid 11:154-156 of ethyl 2-methoxy-6-methylbenzoate 9:345,346 of e^ro-bre vicomin 11:413,414 offlexibilene 8:16,17 offreelingyne 10:167 of fruticosonine 11:286 offutoenone 8:159 offiitoquinol 8:169 ofgangliosides 18:486-488 ofgermacrone 8:178 of gibberellic acid 8:119 ofgibberellins 8:115-135

1289 ofgibberellinsGA4 8:115,119 ofgibberellinsGAss 8:119,121 of gibberellins GA57 8:121-123 ofgibberellinsGAfio 8:119,121-123 of gibberellins GA7 8:115,119 ofginkgolicacid 9:355 ofglaucarubinone 11:79,80,105 ofgloeosporone 9:228,241 of glutamic acid 11:419 of glycerol 11:392,393 of glycosyl ester 8:66 ofglyfoline 13:361-367,375-380 ofguggultetrols 5:707 ofguianin 8:159 ofhaageanolide 8:175-181 ofhelminthosporal 8:162,163 ofhemandin 18:579-584 of heteroatom mediated 8:205-217 of hexalin alcohol 13:601 of hexepi-u\a.ncm 18:207-216 of higher carbon sugars 11:429-480 of hobartine derivatives 11:309,310 ofhobartine-19-ol 11:309 ofhomothienamycin 8:262 ofhumulene 8:156 ofhydroxy amino acid 12:431-438 of hydroxylated indolizidines 12:275-263 of I-active oligosaccharide containing lactose 10:477-479 of I-active oligosaccharide containing lactose 10:477-479 of li-active oligosaccharide containing mannose 10:477-479 of indolizidine alkaloids 11:229-275 of indolo [2,3-a] carbazoles 12:375-383 ofingenol 12:233-345 of inositol phosphates 18:391-451 ofionophoreX-14547A 10:425 ofipsenol 10:188 of isocyanides 12:113 of isodeoxybouvardin 10:644,645 of isodeoxybouvardin methyl ether 10:644,645 of isodihydrofutoquinol 8:169,170 of isodityrosine 10:630 of isoindolone 8:212 ofisoingenol 12:234-245 ofisolobophytolide 10:10-13 ofisolobophytolide 8:205-217 of isomaltoside 11:469-471 of isomitomycin A 13:35-37 of isopeduncularine 11:284,285 of isoquinoline quinone antibiotics 10:77-145 ofisosilybin 5:486 ofjatrophone 10:155,156 of K-252C (staurosporinone) 12:379-381 ofketophosphonate 13:560 of kidamycin "aglycone" 11:135-139 ofklaineanone 11:74-76 oflacto-7V-bioseI 10:467,468 of lactone synthon 13:615-628 of lactosamine 10:461-467 of Z,-a//o-a-amino acid 11:460,461 of large ring compounds 8:19-32 oflasalocidA 10:424 ofleukotrieneBs 10:159 ofleukotrieneB4 10:168 oflignans 18:551-606 oflignarenones A,B 10:167,171 of lithium borohydride 8:467 of longipinene 8:33,36,37 ofl-ribose 11:390,391 ofZ-xy/o-guggultetrol 5:705-708 ofL-jcy/o-octadecane-l,2,3,4-tetrol 5:707 of I-a-aminouronic acid 11:459,460 of macrocarbocyclic 8:16-18 ofmacrocycleA 10:280,281 of macrocyclic cytochalasans 13:108-120 of macrocyclic semiochemicals 8:219-256 ofmacrolide 8:176;10:423 of macrolide antibiotics 12:35-62 ofmacroline 13:383,411,423,424 of macroline-related alkaloids 13:383-432 ofmaesanin 5:821-824 of melicopicine 13:353,354 of methoxybipyrrole aldehyde 8:273 of methyl (2,4)-2,4-nonadienoate 10:166 of methyl epijasmonate 8:152-157 of methyl jasmonate 8:152-157 of methyl-a-peracetylhikosaminide 11:449-451 ofmethynolide 11:158-163 of methyomycin 11:151 of mevinicacid 13:553-625 ofmevinoline 13:605 of mitomycin A 13:439-442 of mitomycin B 13:439,441 of mitomycin C 13:440 of mitomycins 13:433-471 of monocyclic p-lactams 12:120,121 of monosaccharides 13:207-212 of morphine 18:56-98 ofmukulol 8:178 ofmuscone 8:242,243 ofmycinolide 11:393,394 ofmyoporone 15:228 ofA',7V-dimethyl-4-desmethylenebicyclomycin 12:68-70 ofA^-acetyllactosamine 10:461-467 of 7V-alkyl analogues 8:211 of naphthopyran antibiotics 11:127-133 of natural products 8:175-201,409-428 of A^-benzoyl-iso-serinate 12:223,225 ofyV-benzoylpyrrolinone 8:212 ofneolignans 8:159-172 ofneopinone 10:180 ofnitrosterene 8:230,232 of A^-methylcyriaflavin A 12:377-379 ofnocardicineA 12:118,119 of nonactic acid 10:423,424 of nonactic acid 18:229-268 ofnonactin 18:260-265 ofnonitol 11:464 ofnonofliranose 11:458

1290 ofnordidemnin-B 10:294-298 of norepinephrine 8:395-406 of octahydroindolizidine-8-ols 12:293 ofoctahydroindolizine-2-ols 12:283,284 of octahydroindolizine-6-ols 12:285,286 of octahydroindolizine-7-ols 12:286-289 of octa-0-acetyl 1 -thio-mannosyl disaccharide 8:320 of octose derivatives 11:462-464 of Ohno's lactone 8:148,149 ofoligomericDNA 8:373 of oligopeptides 10:629-669 of oligosaccharides 8:316 of oligostatins 10:516 of 0-methylancistrocladine 8:228,229 ofoscillatoxinD 18:269-309 ofotonecine 8:211 ofoxetanocinA 10:587-608 ofoxetanocins 10:585-627 of oxetanosyl chloride 10:604-607 of oxycyclopropane 8:34,35 of pantolactone homologue 10:442,443 ofpapaveraldine 8:263 ofpenamcarboxylic acid 12:127-129 ofpenems 8:262 of penicillin derivatives 12:129-131 of penicillins 12:115,116 of pentacenequinone 11:121,122 of pentacyclic diterpenoids 8:418 ofpentalenene 13:6-8 ofpepstatin 12:476 of periplanone B 8:156,179-182,226,227 of permethyl cyclohexanone 8:4,5 ofpermethylcyclopentanone 8:4,5 of persoonol dimethylether 9:355 ofpetrosterol 9:37 of phenolic lipids 9:343-369 of phenylalanine 11:417,418 ofphenyllactate 12:223 ofpheromones 9:351 ofphorbol 12:245-272 ofphosphatidylinositols 18:445-450 ofphosphoramidite 8:388,389 of phosphorylated polprenols 8:64,65 ofphosphotriesters 13:272,273 ofphyllanthocin 8:280 ofphytosphingolipids 18:457-490 ofpicrotoxinin 8:279 ofpikronolide 11:158-163 ofpiperazinomycin 10:638-640 ofpodophyllotoxin 18:597-601 of polene synthons 20:571,573 ofpolycycles 8:278 of polycyclic aromatic compounds 11:119-127 of poly-A^-acetyllactosamine 10:323 of polyprenyl diphosphates 8:65,68,69,81 of polyprenyl monophosphates 8:65,68,69,82 ofpolysiloxanes 13:328 ofporfiromycin 13:440 ofprezizanol 15:248 of protein 8:315 ofproxiphomin 13:122,123 ofpseudo-disaccharides 13:212-216 of pseudomonic acid 10:425 ofpseudo-NANA 13:210 ofpseudo-oligosaccharides 13:235-246 of pseudo-trisaccharides 13:212-216 ofptilostemonol 8:45,47 of ptilostemonol acetate 8:47 ofpumiliotoxin 12:294,296 ofpumiliotoxin251D 12:294,295 of putative epoxyenone intermediate of estradiol metabolism 5:449 ofpyrazines 5:254 of pyrrole formation 8:269 ofquassimarin 11:79,80 ofquassin 11:73-76 of quassinoids 11:1-111 of quaternary carbons 8:3-14 of quinocarcin 10:125-141 ofquinocarcinol 10:120-124 ofR (-)-muscone 8:224,225 of7?-(+)-/?-carvomenthene 8:49 of racemic compactin 13:562,563 ofrecifeiolide 8:176 ofrenieramycin A 10:97-100 ofrifamycinS 12:37,38 ofrifamycinW 12:39-47 ofritterazineK 18:900-902 ofRNA 13:284,285 ofrosaranolide 11:164 ofsafi-amycinA 10:84-87,92-96 ofsaframycinB 10:88-93 of saframycins 10:83-100 ofsarcophytolB 8:18,19 ofsecasterone 18:512 ofseco-taxane 12:179,180,201 of serine 11:420 of shikimicacid 13:188 ofsildydianin 8:166,167 ofsilphinene 8:165,166 ofsilybin 5:486 ofsinefungin 11:437,438 of sodium trimethoxyborohydride 8:467 ofsorelline 11:326,327 ofspiroethers 18:269-309 ofsterepolide 8:280 of steroid 8:167-174 ofsuaveoline 13:383,408,411-417 ofsupensolide 8:222,234,236 ofswinholideA 18:178-185 oftalcarpine 13:383,411,424-426 oftautomycin 18:269-309 oftaxane 12:181-216 oftaxanes 11:3-69 oftaxol 12:217-221 oftaxusin 11:55-59 oftaxusin 12:200,221 ofterpenes 8:33-37 of terpenoid alkaloids 8:418 of tetracyclic diterpenoids 8:418

1291 oftetramethoxyturriane 8:228,229 of tetraoxoalkanedioates 11:117 oftetrols 5:708 ofthiodisaccharides 8:316-330,339,342,343,346 ofthiolactone 8:205-207 of thiooligosaccharides 8:316,317-330 ofthiotrisaccharides 8:340 of//zre<9-(45',55)-4-benzylamino-5-hydroxy-2methyl-6-phenylhex-1 -ene 12:478,479 of thromboxane B2 10:419 of thymosin a 1 8:437-446 of thymosin ttii 8:447 of thymosin p4 8:447-453 of thymosins 8:437-454 of thymosins Bg 8:456,457 of tjipanazoie D 12:382 of tjipanazole E 12:382 of fra?i5-7-formyloxy-8a-methylindolizidine 12:288 of trans-hydrindanQ 10:51 oftricarbonyls 8:261-274 of triquinane terpenes 10:426-428 oftriquinanes 13:3-52 of tunicamycins 11:446-449 of uranium (iv) borohdride 8:467 of urdamycinone B 11:134,135,142-144 of uridine diphosphate-galactose 10:468 ofvalidamine 13:190 ofvalidamycin A-H 13:228-232 ofvalienamine 10:507 ofvalienamine 13:199 of valine 11:418,419 ofvaliolamine 13:201 of vancomycin 10:661-669 ofverrucarol 10:426-428 ofverticillene 12:182,183 ofvillalstonine 13:405 of vinblastine 14:805-884 of vincristine 14:805-884 ofvinylsilanes 8:242,243 of vitamin D 11:379-408 of vitamin D aldehyde 10:52 ofxylosides 8:362 ofZ,Z-l,4-dienicmacrolides 8:242 of zearalenone 13:536-543 ofzeralenone 8:176,177 ofzygosporin E 13:146,147 of Z-p-y-unsaturated macrolide 8:222,232 of Z-y-unsaturated carboxylic acids 8:239 of A^'^-unsaturated brassinosteroids 18:515-520 of A^-7-oxygenated brassinosteroid 18:515-520 of A^^'^^-capnellene 13:34,13:35 of A-benzyl-1,2,3,4-tetrahydro-isoquinolone alkaloids 10:683-685 of a dicarbonyls 8:261-274 of a-l,4-disccharide 8:369 ofa-aminoacid 12:435-438 ofa-copaene 8:33-36 of a-cyclodextrins 8:367,368 of a-D-fructofiiranosyl-1 -thio-p-Z)-glucopyranoside 8:325,327 of a-enamino derivative 8:262 of a-halomethyIcycloheptane 8:35-37 of a-hydroxy-p-amino acid 12:493 of a-longipinene 8:33,36,37 of a-mono-alkoxylated piperzinediones 12:84 of P (1^4) linked 4,4'-dithiotrisaccarides 8:347,349 ofp,P-trehalose 8:317,318 ofp-copaene 8:33-36 of P-galactosidase 8:315,316 of P-hydroxy ester 11:395 of P-hydroxy macrolides 8:231,232 ofp-longipinene 8:33,36,37 of P-necrodol 8:279 of p-sesquiphellandrene 8:45,46,51,55 ofp-turmerone 8:51,52 ofy-allenyl-GABA 13:514 of y-aminobutyric acid (GABA) 13:514 of y-dehydro-a-amino acid 11:471,472 reaction with lead tetraacetate 5:21 reaction with tristrifluoroacetate (TTFA) 21 via phenolic oxidative coupling 5:21 Synthetic approaches to vinblastine 14:805-884 to vincristine 14:805-884 to purpurosamine B 4:120 to 6-e/7/-purpurosaine B 4:120 ofmicrocystins 20:899-902 ofnodularins 20:899-902 Synthetic methods ofbiaryls 20:294-307 of diarylethers 20:307 Synthetic reagents dithioacetal S-oxides as 6:307-349 dithioacetal S'.^-dioxides as 6:307-349 Synthetic studies of humantenine-type oxindole alkaloids 15:493-500 of koumine-type alkaloids 15:500-503 of sarpagine-type alkaloids 15:487-493 Synthetic substrate analogues in enzyme-carbohydrate interactions 7:29-86 Takano's reaction ofenoate 12:26,27 with cyclopentadiene 12:26,27 Takano's synthesis of vinblastine 14:865-867 of vincristine 14:865-867 Tandem Grignard reaction 19:11 Tandem Michael addition 4:556,557 with Cu (I)-tributylphosphine 4:556,557 Tandem Michael-aldol reaction 3:138-143 Tandem process (two-stage coupling process) mechanistic consideration of 12:55-58 TBDMSCi protection 4:388,389 in (+)-5-(9-methyllicoricidin synthesis 4:388,389 Tebbe olefmation 3:270 Tebbe rearrangemet in ()-A^^^^^-capnellene synthesis 6:46,47 Tebbe's reagent 14:119;16:226 Telomerizations 12:416

1292 Template selectivity 1:608 Ten-carbon sugars by epoxide route 4:182-187 by osmylation 4:182-187 Ter^butoxycarbonylation 12:488 A^-/er^butyloxycarbonyl groups thermolytic removal 3:356 Tetra-A^-propylammonium perruthenate 12:312 Tetra-iV-butylammonium fluoride deprotection with 6:119-121 Tetra-substituted azulenes oxidation of 14:343-345 Tetrabutyl ammonium fluoride 11:369 Tetrahydropyran from Claisen ester enolate rearrangement 10:339 Tetrahydropyrans enantioselective synthesis of 1:637 Tetrahydropyranyl ether protection with 6:264,268 Tetrahydropyranylation 14:694,695 Tetrazole-catalyzed reaction 14:288 Tetrazolium blue reagent 19:755 Thallium nitrate 4:338 oxidation with 4:338 Thallium (III) compounds 20:305,306 Thallium nitrate (TTN) oxidation 10:631-635,637,638, 640,641,644-647,653,654,661,662,666,667 Thallium triacetate 4:72-72 oxidation of 17-hydroxyaspidospermidines 4:74 oxidation of 3-oxo-tabersonine 4:72 oxidation with 4:70-76 Thermal glycosidation (metal free) of allyl glucoside 8:365,366 of allylrhamnoside 8:365,366 of(+)-baiyunol 8:362 of cholestanol 8:365,366 of cholesterol 8:361,362,365,366 ofdecanol 8:362,365 of dihydrolanosterol 8:362,365,366 ofgeraniol 8:362,365 of glucoside 8:362,365,366 of glucosyl chloride 8:361,362 of mannosyl chloride 8:361,362 of methanol 8:365 of 1-methylcyclohexanol 8:365,366 of methyl glucoside 8:365 of rhamnosyl chlorides 8:361,362 of xylosyl chlorides 8:361 Thermal [4+2] addition 8:412 Thermal fragmentation of [2'-(phenylselenyl) ethyl] glycoside 10:420 Thermal mannosidation 8:359,369,370 Thermal rhamnosidation 8:359,369,370 Thermally-induced rearrangement 6:468 of (3-hydrastine A^-oxide 6:468 of a-narcotine//-oxide derivative 6:468 Thermolysis 3:314,315 of 1,5-benzoxazocine A^-oxide 6:472 of 2-benzazocine //-oxide derivative 6:472 of camphor-10-sulphonyl bromide 4:626,627 of()-laudanosine A^-oxide 6:472 of styrylazides 3:314,315 Thermolytic cyclization alkenyl azides 6:429 ofazides 6:429 Thiele acetylation 10:120,121 Thio-Claisen rearrangement l:53;14:865-867 isovelbanamine from 14:865-867 velbanamine from 14:865-867 5-Thio-D-glucose 6:351 5 -Thio-Z)-mannopyranose 6:351 2-Thio-hexopyranose-4-ulose nucleosides synthesis of 4:252 5-Thio-Z,-rhamnose 6:351 Thio-oligonucleotide 13:283 Thio-oligosaccharides reaction with enzymes 8:315 synthesis of 8:316-346 4'-Thio-toyokamycin 6:351 Thioacetal hydrolysis of 14:660,661 with cadmium carbonate 14:660 with mercury (II) chloride 14:660 Thioaldehyde cycloaddition 8:207-217 Thioaldehyde Diels-Alder reaction 8:207,210,213 6-Thioallolactitol 8:353 6-Thioallolactose 8:338,339 Thioallolactose 8:339,342,353 a-Thiocarbocation 1:240 Thiocarbonate 1:442,443 pyrolytic elimination of 1:442,443 4-Thiocello-oligosaccharides 8:348,349 4-Thiocellobiose 8:332,333,351,352 Thiocyanates 8:316 4-Thiodisaccharide 8:330,332 1 -Thiodisaccharides 8:317-326 synthesis of 8:317-326 \,2-trans 1-Thiodisaccharides 8:317,318 Thiodisaccharides (1^-4) linkage 8:329 Thiodisaccharides synthesis of 8:317-340 Thiodisaccharides (l->-2) linkage 8:327 Thiodisaccharides (1-^3) linkage 8:329 Thiodisaccharides (1-^6) linkage 8:338 Thiodisaccharides (6^6) linkage 8:340 Thioesters acylation of phosphonium ylides 4:554 1-Thioglycosides 8:315-317 Thioglycosides synthesis of 1:429,430 Thioglycosidic linkage 16:114 Thioketalization 14:680,681 Thiolactone synthesis of 8:206,207 Thiolester with triethyl phosphite 12:147 Thiolester enolates 4-acetoxy-(3-lactam with 12:167-170 C4-alkylation with 12:167-170 Thiolesters 8:316 Thiomercury derivatives 8:316 Thionolactones by macrolactonization 10:208

1293 desulphurization of 10:208 synthesis of 10:208 Thiophene C-glycosides from glycals 10:349 2-Thiophenecarbaldehyde (2-thienyl)-acetic acid from 6:322 Thiophenol 6:542;14:750 elimination of 6:540 Thiophenolate complex non-chelating 14:750 Thiophenyl-glycosides 10:381 allylation of 3:222 Thiophosphoramidites phosphorodithioates from 13:269,270 Thiosugars 8:315 Thiotrisaccharides 8:340,341 3-Thioxovincadifformine 19:103 2-Thioxylobiose synthesis of 8:328 3-Thioxylobiose 8:329 4-Thioxylobiose 8:336 4-Thioxylobioside 8:349 4-Thioxylooligosaccharides 8:348,349 1-Thioxylose 8:336 Thorpe-Ziegler reaction 10:328 Three component reaction 4:572,573 Three-carbon annulations 6:42,49,50,52,74,75 in ()-A^^'^^ capnellene synthesis 6:42 in capnellenol synthesis 6:48,50 in dolasta-1 (15), 7,9-trien-14-ol synthesis 6:52 Three-carbon ring expansion (-)-muscone by 10:330,331 Three-dimensional structure ofmicrocystins 20:903-907 ofnodularins 20:903-907 Threo-2-ammo alcohols interconversion of 12:430,431 stereoselective synthesis of 12:489-493 to erythro-2-ammo alcohol 12:430,431 Threo-erythro interconversion 12:430,431 of 2-amino alcohol 12:430,431 r/ireo-selective reduction 12:300 Tin (II) enolate of achiral thiazolidin-2-thione derivative 12:166 with tin triflate 12:164 Tin a-alkoxyanions Z-trisubstituted olefins from 3:281 Tin acetylide palladium mediated acylation 1:475 Tin enolate from ketone 12:170 with 4-acetoxy-P-lactam 12:170 with high (3-selectivity 12:170 Tin hydride reduction 12:271 Tin(II) enolates thiazolidines from 14:735 Titanium reductive elimination with 4:421-535 Titanium (IV) catalyzed cyclization 12:241 Titanium (O) by titanium trichloride 11:366,367 preparation of 11:366,367 with potassium graphite 11:366,367 Titanium reagent application of 11:371 discovery of 11:366,367 Titanium tetrachloride 11:358 Titanium tetrachloride catalyzed reaction 8:141-43, 146,151 of aery late 8:142 Titanium tetrachloride method 4:252 for 6-deoxynucleoside synthesis 4:232 Titanium tetraisopropoxide 4:505 in stereoselective epoxidation 4:505 Titanium trichloride titanium (O) from 11:366,367 with potassium graphite 11:366,367 Titanium-induced carbonyl coupling reactions 8:15,25,31 Titanium-induced coupling 11:345,368 Titanium-induced intramolecular pinacol coupling 8:18 Titanium reagents in dicarbonyl coupling 3:80,81 Titanocene dichloride 10:30 TMAO-urea complex 18:678 2-TMP (2-thiazolyl methylene triphenyl phosphorate) 11:443,444 TMS enol ether 4:8,10,36,38 formmation from ketone 4:8,10 TMS triflate 1:514 TMSOF (2-(trimethylsiloxy) friran) 11:451,453 TMSOTF 1:308 TMSOTf 4:91,92 deblocking of BOC 91,92 2-TNO (2-thiazolylcarbonitrile A^-oxide) 11:443,444 (/?)-Tolbinap-ruthenium (II) complex 12:153 (5)-Tolbinap-ruthenium (II) complex 12:153 Tollens oxidation withAgNOs 8:25 (p-Toluenesulfonyl) methyl isocyanide(TOSMIC) 3:321,322 double addition of 3:321,322 Tosylation 6:287,288,11:359,19:518 of nucleosides 19:516 2'-0-Tosyl-5'-0-trityladenosine 19:519 co-Tosyloxy-a-phenylthiocrylontriles 6:540 Total synthesis of 25-oxa-25-phospha-vitamin D3 9:509-528 of destomicacid 4:130 of erythromycin A 12:53,54 of erythronolide A 12:46-53 ofgalantinicacid 4:127 ofkoumidine 15:493 ofA^a-Methyl-D^^-isokoumidine 15:493 ofphorbol 12:265-272 of purpurosamine C 4:123 ofrifamycinW 12:46,47 of vitamin D3 9:510 TPSTe as condensing agent 4:269

1294

Trans-Rydroxylation of olefinic double bond 16:16 Transacetalation 8:287,288;11:82,83,109 acid-catalyzed 14:654 intramolecular 14:654;11:109 Transannular [2,3]-Wittig rearrangement synthesis of costunolide 8:195-201 synthesis of haageanolide 8:195-201 Transannular [4+2] cycoaddition 5:796,797 Transannular acylation of sulfur stablized carbanions 3:81,82 medium ring formation by 3:81,82 Transannular cyclization 13:440 Transannular deprotonation 10:222 Transannular Diels-Alder reaction 8:187-195 Transannular ketal cyclization 11:59 Transannular reaction 8:175,19:66,418 Transannular SN^ cyclization 15:500 Transcription initiation 5:580 Transesterification 1:267,8:288,292 enantioselective 1:685;13:53,54 enzymatic 13:55 of tricyclic lactones 12:30 of propane-1,3-diols 13:53-55 Transformation biomimetic 11:292-295 hobartine-aristoteline 11:292-295 of bile alcohols 17:217 ofoxetanocin A 10:586,587 ofquinocarcin 10:119,120 ofsaframycins 10:101-103 Transglycosylation 7:54,55,61 Transketalization 1:415,417,457 Translactonization 8:21,29 intramolecular 13:159 Transmethylation 2:53 in FAB spectra 2:53 Transmethylation inhibition of 1:408 1,3-Transposition of allylic system 4:165 Transylidation 4:560,563,564 2'-/3'-Trialkyl silyl ribonucleosides silyl migration in 14:285 Trialkylaluminium compounds addition to a,p-alkynyl acetals 1:624,625 addition to a,(3-unsaturated acetals 1:624,625 diastereoselective addition of 1:624,625 Trialkylalumnium 6:428 Trianion of indole-3 -acetic acid 1:13 Tribenzo[a,c,e] cycloheptatrien-5-one from diethyl 2,2'-Bi-l-benzoate 11:125 synthesis of 11:125 Tribenzotropone 11:125 Tributyltin radical addition to olefin 1:490 (Z)-Tributylvinylstannanes cross coupling reactions with 10:162 Tricarbocyclic bridged systems 6:74-86

Tricarbocyclic epoxide by Saegusa ring expansion 6:37,38 ()-dactylol from 6:37 synthesis of 6:37,38 Tricarbocyclic fused systems stereoselective synthesis of 6:38-58 Tricarbonyl (diene) iron complex 12:280 Trichloroacetamidate from Z)-glucose 6:276,277 3-Trichloroacetamido-3-C-vinyl-derivative 10:421 Trichloroacetimidate method condensation of 4:207-209 in oligoheptose synthesis 205,206 Trichloroacetimidate method 6:402 a-Trichloroacetimidates 14:212,213 (3-Trichloroacetimidates 14:212,213 Trichloroethyl carbamate 1:71 Trideoxynucleosides synthesis of 4:525 Triethyl silane reduction of hemiketal 3:218 Triethylammmonium formate Pd2 catalysed reduction 3:184 Triethylsilyl silyl ethers 11:339 bis (Triethylsilylacetylene) 10:249 Triethylsilylation 11:363,364 Trifluoroacetoxy-selenylation 12:473 3-Trifluoroacetyl-allohobartine from allohobartine 11:318,319 A^-Trifluoroacetyl-I-acosamine synthesis of 4:150,151 iV-Trifluoroacetyl-L-daunosamine synthesis of 4:150,151 Trifluoromethanesulfonates 8:316 4-(9-Triflylgalactoside derivative synthesis of 8:330,331 5-eA:o-Trigaryl radical-alkene cyclization 3:327,328 14-endo-Trig cyclization 13:589 Triglycosides 7:270,273,275,286,287 Trihaloalkyl protecting group removal of 4:286 2,4,6-Triisopropylbenzenesulfonyl chloride as condensing agent 4:269 2,4,6-Triisopropylbenzenesulfonyl-4-nitro-imidazole TPSNI as condensing agent 4:269 Trimethyl decalone by Robinson annulation 6:19,20 from ethyl vinyl ketone 6:19 from 2-methyl-1,2-cyclohexadione 6:19 in euryfuran synthesis 6:20 in pallescensin-A synthesis 6:20 synthesis of 6:19,20 Trimethyl orthoformate methylation with 1:448,449 Trimethyl silyl enolate ozonolysis of 14:572,573 piperidine derivative from 14:572,573 Trimethylsilyl cyanide 1:156 in glycosylcyanide synthesis, 3:210-212 Trimethylsilyl derivative 4:223 in nucleosides synthesis 4:223

1295 Trimethylsilyl esters acylation of phosphonium ylides 4:564 Trimethylsilyl intermediates in prenylation methods 4:394 A^-Trimethylsilyl iodohydrin 1:277 Trimethylsilylmethylation 1:249 Trimethylsilyl triflate (TMSOT) 12:419,420 bis-(Trimethylsilyl) hydrogen phosphate 8:69 2,3-^w-[(Trimethylsilyl)oxy butadiene 1 ,2-ZJw-phenyIhydrazone from 12:377 with maleimide 12:377 A^-TrimethyIsily 1-3 -(trimethyIsily) propynal-dimine 4:457 Trimethylsilyl-3-butyn-1 -ol 12:473 2-Trimethylsilyl-l,3-dithiane 12:156 2-(Trimethylsilyl)oxy] butadiene 12:377 Trimethylsilylation 1:272,273 3-e<io-Trimethylsilylcamphor 4:663,664 Trimethylsilyldiazomethane esterification of 4:91,92 Trimethylsilylisocyanate 3:309 A'^-acylation of indoline 3:309 Trimethylsilyloxy butadiene with methylene glutarimide 14:751,752 4-(Trimethylsilyloxy)-p-lactam from enolsily 1 ether 12:160,161 2-Trimethylsilyloxybutadienes in Diels-Alder reactions 4:581 2-Trimethylsilylthiazole (2-TST) 11:443,444 Trimethylsilyvinylalanate reagent 12:295 Triol 4:166 selective silylation of 4:184 Triphenylmethyl phosphonium permanganate 3:182 Tripheny Iphosphine 11:3 42 Tripheny Iphosphonium methy lide 11:351,352 deprotonation of 11:351,352 with sec butyllithium 11:351,352 A^-(Triphenylphosphoranylidene)-(3- alanine methyl ester 12:301 Triphenyltin hydride in reductive of selenides 6:427,428 Triphosgene isocyanides from 12:113 Triquinane angular 13:3-25 diterpenes 13:3-52 linear 13:34-56 sesquiterpenes 13:3-52 sesterterpenes 13:3-52 synthesis of 13:3-52 Triquinane 6:33,34 precapnelladiene from 6:33,34 synthesis of 6:33,34, Triquinane derivatives 7:216 Triquinane terpenes Claisen rearrangement by 10:426-428 synthesis of 10:426-428 Triquinanes angular 3:5-7 linear 3:5 synthesis of 3:5-48 Tris (4,5-dichlorophthalimido) trityl bromide (CPTrBr) 14:288 Trisubstituted olefins synthesis of 4:565 Triton B 6:320-322;12:244 Trityl-cyanoethylidene condensation 14:219-226 polysaccharides by 14:228 Tritylation 6:282,284,292,293 Tritylperchlorate as catalyst 4:236 Tropolones 1:340 synthesis of 1:340 Tropone 1:549,554-573;10:178;13:624 1,8-addition of lithio tert butyl acetate 1:554 addition to enolates 1:554,555 as diene in [47i + 27r] cycloadditions 1:566,571 c/5-hydroazulene from 12:251 diazoketone insertion 1:555 for perhydroazulene synthesis of 1:549-556 iron tricarbonyl complexes 1:572 organometallic derivatives of 1:572,573 photochemical electrocyclic closure 1:549 vinyl sulfide cycloaddition 1:567 Trost cyclization of allylic acetate 16:423 TTN (thallium nitrate oxidation) 10:631-635,637,638, 640,641,644-647,653,654,661,662,666,667 Two-stage coupling process (tandem process) 12:35-62 Uang synthesis avermectin oxahydrindene subunit 12:26,27 (7-hydroxystaurospermines) 12:26,27 Ueno method reduction by 10:322,323 Ugi reaction 12:114-138 Ullmann biaryl synthesis 20:294-301 Ullmann diarylether synthesis 20:307-310 Ullmann macrocyclization 20:308 Ulmann reaction 10:629-631,641,644,646-653,655, 661,667;13:353,354,364;20:294,296,297 intramolecular 10:640 Umpolung 10:160,167 Umpolung-Michael-Addition 8:46 Uncatalyzed thermal cycloaddition reaction 12:425 2,3-Unsaturated 1-thioglycosides synthesis of 8:343 a,p-Unsaturated acetal cyclic enones with 14:502 from dialkyl tartrates 14:489-491 photocycloaddition of 14:502 Simmons-Smith reaction of 14:489-491 Unsaturated acetals cyclopropanation of 14:490 from (-)-(25',35)-1,4-dibenzyloxy-2,3-butanediol 14:490 2,3-Unsaturated allyl glycoside preparation of 10:420 A^'^-Unsaturatedbrassinosteroids synthesis of 18:515-520

1296 a,p-Unsaturated butyrolactones 11:453 Unsaturated C-18 fatty acids 1:528-533 2,3-Unsaturated C-glycofuranosyl by Claisen reaction 10:341 fromglycal 10:341 Unsaturated C-glycopyranoside from pyranoid glycals 10:345 synthesis of 10:345 2,3-Unsaturated C-glycoside 10:346,349,350 from Claisen rearrangement 10:338 from lithioglycal 10:312 from peracety lated glycals 10:350 regioselectivity of 10:350 stereoselectivity of 10:350 synthesis of 10:350 Unsaturated C-glycoside alkylation with dibenzylidene acetal bis (diphenylphosphino) ethane 10:343 alkylation with trifluoroacetate ester 10:343 by palladium (0)- 10:354,355 (3-dicarbonyl C-glycoside 10:348 from glycosyl fluoride 10:368 from peracety lated glycols 10:343 1,2-Unsaturated C-glycoside 10:349 2,3-Unsaturated C-nucleoside 10:341,342 by reaction of furanose-glycals 10:341 synthesis of 10:341 with pyrimidine-mercury/palladium acetate 10:341 a,P-Unsaturated carbonyl compounds oxidation of 4:46 (^-a,P-Unsaturated ester 13:89 5,6-Unsaturatedhexopyranosyltheophylline synthesis of 4:237 a,P-Unsaturated imide 12:162 asymmetric aldol reaction of 12:162 4-unsubstituted p-lactam from 12:162 a,p-Unsaturated ketone 4:129 in Luche-type reduction 4:130 reduction of 4:382,383 a,p-Unsaturated ketone ^H-NMR spectrum of 12:46 NOE experiments of 12:46 stereochemistry of 12:46 a,p-Unsaturated ketones 14:438,753 with 2-methyl-6-vinylpyridine 14:438 a, p-Unsaturated ketones reaction with silyl enol ethers 3:126,127,129 a, P-Unsaturated ketones synthesis of 6:339,340 Unsaturated ketonucleosides synthesis of 4:248,253 tumor inhibition by 4:253 A-8,9-Unsaturated lactol in endoperoxide rearrangement 4:420,421 Z-p,Y-Unsaturated macrolide synthesis of 8:232 a, P-Unsaturated methoxymethylester fragmentation-recombination of 10:412 a,P-Unsaturated nitroolefms 14:636-638 2,3-Unsaturated nucleosides 1,3-intramolecular shift of 4:223 2-Unsaturated nucleosides 4:225 Unsaturated nucleosides 4:235-237 synthesis of 4:235-237 Unsaturated O-glycosides 10:354,355 a,p-Unsaturated orthoesters Michael acceptors 3:146-149 A'^-Unsaturated oxepene 10:221 A'^-Unsaturated oxocenes 10:223 2,3-Unsaturated pentose fromD-xylal 10:425 Unsubstituted 2-oxazolidone derivative low P-selectivity of 12:166 with 4-acetoxy p-lactam 12:164,166 4-Unsubstituted P-lactam 4-acetoxy p-lactam from 12:162 by asymmetric aldol reaction 12:162 by asymmetric hydrogenation 12:162 of P-keto amide 12:162 of a,p-unsaturated imide 12:162 oxidation of 12:162 withperacids 12:162 Unsymmetrical chiral biaryls 20:410 Unsymmetrical onoceranoid triterpene synthesis of 1:543 Unsymmetrical pyrazines 18:887-892 ()-Upial from Dysideafragilis 6:65 synthesis of 6:65,66 Urethane cyclization of 14:566,567 Uridine diphosphate A^-acetylglucosamine 1:399 Uridine diphosphate-galactose (UDP-gal) synthesis of 10:468 Uronolactones 14:192 Urushiols (catechols) 9:318,325,328,329,331,334,338, 352-354,356,358-360,:364 from anacardic acid 9:341 VandeWalle approach in P-dictyopterol synthesis 6:16 in dictyopterone synthesis 6:16 Vedejs reagent 11:80,81 Vicinal oxyamination reaction 11:61 1,2,3-Vicinal tricarbonyl unit synthesis of 8:261-274 Vicinal tricarbonyls 8:261-274 Vilsmeier reaction 6:322 Vilsmeier formylation 1:507,508;18:233 Vinamidine 2:389,390,398 Vinblastine 2:370,372,287,389,390;4:29;8:283;12:179; 13:633;14:805-884;19:748;20:458 3'-0X0vinblastine from 14:813 anticancer activity of 14:805 Atta-ur-Rahman's synthesis of 14:850-859 biosynthesis of 4:31 Buchi's synthesis of 14:868,869 deacetylvindoline from 14:862,863

1297
first synthesis of 4:32 jfrom anhydrovinblastine 14:820,821,871 from catharanthine 14:854-858 from Catharanthus roseus 8:283;14:805 fromleurosine 14:860 Gorman's synthesis of 14:862-864 Kuehne's synthesis of 14:831-849 Kutney's synthesis of 14:806-821 Magnus's synthesis of 14:821-830 Potier's synthesis of 14:869-873 Schill's synthesis of 14:861,862 synthesis of 5:185-187 synthetic approaches to 14:805-884 Takano's synthesis of 14:865-867 velbanamine from 14:862,863 Vincristine 2:390,398;9:387;11:5,12:396;13:633; 20:458 anticancer activity of 14:805 Atta-ur-Rahman's first synthesis of 14:850-859 biosynthesis of 4:31 Buchi's synthesis of 14:868,869 first synthesis of 4:32 from catharanthine 14:854-858 from Catharanthus roseus 8:283;14:805 Gorman's synthesis of 14:862-864 Kuehne's synthesis of 14:831-849 Kutney's synthesis of 14:805-821 Magnus's synthesis of 14:821-830 A^-demethyl deacetylvindoline from 14:862,863 Potier's synthesis of 14:869-873 Schill's synthesis of 14:861,862 synthetic approaches to 14:805-884 synthesis of 5:187-189 Takano's synthesis of 14:865-867 velbanamine from 14:862,863 Vinyl acetate reaction with methyl lithium 1:562,563 Vinyl azides preparation of 1:165 Vinyl carbanions nucleophilic addition with 11:440,441 Vinyl cuprate addition 3:189,190,195,196 Vinyl ether 14:487,488 from(35',55)-2,6-dimethyl-3,5-heptanediol 14:487,488 from (2/?,4i?)-2,4-pentanediol 14:487,488 Vinyl iodide 12:48-53 fromD-glucose 12:37,38 from 1,2,5,6-Di-O-isopropylideneD-glucose 12:41 fromD-ribose 12:50 Vinyl palladation of4-cyclopentene-l,3-diols 16:371 Vinyl radical cyclization 12:24 Vinyl stannane synthesis of 1:490 from tributyltin/acetylene 1:490 Vinyl sulfoxides cyclization of 10:673-676 Vinyl sulfoximines 10:679 cyclization of 10:679 Vinyl tricarbonyl hydrate 8:267-272 Vinylaziridine cleavage of 3:50 Vinyl carbene 3:27 Vinylacetyl chloride condensation of 14:453,454 with 9-chloro-l-/7-menthene 14:453,454 Vinylallenes 4:522 sigmatropic rearrangement 4:522 Vinylation in 7,20-diisocyanoadociane synthesis 6:86,87 in 14-e/7/-upial synthesis 6:67,68 of olefins 16:416 Vinylaziridination 3:55 [2+3] 3:55 [4+1] 3:55 Vinylcyclobutane rearrangement of 3:465,466 Vinylcyclopropane isomerization 3:15 Vinylcyclopropane-cyclopentene rearrangement 3:38,44,47 Vinylcyclopropanes from 1,4-dienes 3:34-36 pyrolysis of 3:34 via ally lie SN^ process 3:47 Vinylcyclopropylcarbene 14:627 Vinylic anions inversion of 4:497 Vinylic ethers hydroboration 4:116 Vinylic sulfoxides for synthesis of esterone 4:501,502 for synthesis of vitamin E 4:494-501 Vinylketene acetals asymmetric Diels-Alder reaction of 14:503,504 Vinylnitrene cyclization 1:178-180 Vinylogous amide susbtrates 18:376,386 Vinylogous carbamate substrates 18:344,377 Vinylogous urea substrates 18:363 Vinyloxetane 10:588,589 Vinyloxiranes synthesis of dihydrofiirans 3:55-58 Vinyloxyborane-imine reaction 4:465,466 carbapenem precursors by 4:469 stereochemistry of 4:467,468 Vinylpicoline 14:437,438 bis-annelating agent 14:437,438 Violaxanthin 20:575,727 Viologen oxidoreductase 20:840,858 Vinylpyridine 14:438 Vinylsilane AICI3 catalyzed Friedel-Crafts acylation 8:242 synthesis of 8:242 Vinylsilane-medicated bicyclization 13:615 Vilsmeier's reagent 9:422-424 V0-(acac)2-TBHP 10:39,40 epoxidation with 10:39,40 of allylic alcohols 10:39,40 Von Braun degradation 18:51

1298
Wacker oxidation 10:308,309,316;13:494;14:560,561, 584;16:481;18:633,273,283;19:29 in ()-brasilenol synthesis 6:7 Wacker process 11:238,241,246,16:85 Wadsworth-Emmons chain extension 13:596 Wadsworth-Emmons condensation 1:52,60,13:573 Wadsworth-Emmons reaction 1:176,177;7:480;11:89; 12:328;16:349;18:897 intramolecular 11:108 Wadsworth-Emmons-Homer reduction 20:450 Wadsworth-Homer-Emmons reaction 1:401,402 Wagner- Meerwein rearrangement 4:38,39,626628,633,634,637,643;6:181,149,52;12:245,37,356,363 -368,131,147,236,248 of end-6-silyloxy-isobomeol 16:147 of (+)-isoepicmpherenol 16:131 1,2-Wagner-Meerwein shift 18:882 Wallenberg's procedure 6:298,299 warburganal 6:108 Warren procedure 3:257 Wartski imine Diels-Alder reaction 16:458 Watt synthesis oftaxodione 14:678-681 Weiler's reaction 11:115 Weiss - Cook condensation 3:23,24 Weiss reaction 18:286 Welch procedure demethoxycarbonylation by 10:308,309 Welch synthesis ofisozonarol 6:17 ofzonarol 6:17 Wender synthesis of7-methoxymitosene 13:445,446 Wender's [4+4] cycloaddition strategy 12:189 Wenkert's enamine 1:113 synthesis of 14:727 Wenkert-type enamine 8:284,285 Wessley-Moser rearrangement 2:133,665 Western blotting analysis 15:449 Wharton reaction 10:47 Wharton rearrangement 10:36,37 Whistler method 6:367 White synthesis of avermectin Bu aglycone 12:15,27,28 Wieland-Gumlich aldehyde 9:183 Wieland-Gumlich diol 1:38,39 Wieland-Miescher ketone endesmanes from 6:18,19 endesmanolides from 6:18 synthesis of 6:18,19 (+)-Wieland-Miescher ketone 10:409 Wieland-Miescher ketone 11:16-18,50,51,53;17:608,29 absolute configuration of 17:53 Wierenga intramolecular alkylative closure 3:325,326 Wildman procedure 4:19,22 Wilkinson catalyst 6:10,11;9:459,474;10:39;11:354, 363;12:8,35,37,38,40,50,267,311;13:564;18:207; 19:500 for decarbonylation 16:340,345,350 Wilkinson complex decarbonylation with 11:363 Willgerodt reaction 14:681,682 Williams approach for avermectin oxahydrindene subunit 12:28-30 Williams enantioselective synthesis of (-)-zonarene 6:15 Williamson ether synthesis 6:386 Wilson synthesis 10:48 Winstein spirocyclization 3:325 Winterfeldt synthesis \ of K252c (staurosporinone) 12:381 Witkop photocyclization 1:52 Wittig condensation 3:4to;12:281;13:620;14:112; 19:59;20:582 \ { of olefin 5:708 in ()-sinularene synthesis 6:85 Wittig coupling 10:9,15,13:617 in 7,20-diisocyanoadoci^e synthesis 6:86,87 Wittig homologation 3:268,269;11:100,101;18:196,216 Wittig methylenation 6:185,165;19:42;18:177 Wittig olefination 1:460,461,473,487,488;4:252,123, 163,164,169,176,279,280,285,286;8:413 ;10:429; 12:327,330;13:604;14:129,132,460,461;16:377,378,38 8,484,18:8;19:22;137 for fiised lactone nucleoside synthesis 4:254 in ()-precapnelladiene synthesis 6:39 in ()-stoechospermol synthesis 6:39 in nakafuran-9 synthesis 6:70 in nine-carbon sugars synthesis 4:180 of amino aldehyde 16:490 of Z)-galacto-hexodialdopyranose 4:163,4:164 of Z)-lyxo-pentodialdofiiranoside 4:176 of heptodialdopyranose derivative 4:180,181 of hexodialdopyranoside derivative 4:169 ofpentodialdofiiranose 4:190 of /-butyl 2-C-methyl-2,3,4,7-tetradeoxyhept-6ulopyranoside 10:414 with 7V-pentylidene triphenylphosphorane 5:822 Z-selective 4:125 Wittig reaction 1:221,399,400,447,448,531,533,535, 538;3:258,288,488,4:126,150,175,202,553-578; 5:828;6:16-19,21,61,68,125,157,158,225,226,269, 279,281,285,286,301,302,425,558,559;8:46,146,147,1 61-164,223,224;9:351,352,354,356,358,360,362; 10:48,55,68,166,308,309,389-392,510;11:367; 12:319,321,350,488;13:32,35,37,125,141,175,200,208 ,482,508,594;16:4,39,60,85,248,352,702;18:178,233,2 34,255,256,288,297,618;19:10,20,43,72,267,367,373, 396495;20:563,566,567,571,572,578,584,586592,594,599,601,602,606,759 C-glycosides by 3:218-220 hydroxyl directed 1:406,407 intramolecular 4:573,575 iodide 14:556,557 of aldehyde 8:163,164,223,224,19:495 ofglutarimide 14:560 of ketone 8:162 of pyrrolidine derivative 14:556,557 stereoselective 12:12 stereoselectivity 4:175 unstabilized 1:406,407 with Corey reagent 19:452 with ethyl (triphenylphosphoranylidene) acetate 14:553,554

1299
with formyulmethylene triphenylphosphorane 1:535,536,538 with glutaric dialdehyde 14:560 with heptylidene triphenylphosphorane 5:828 with hexyhdenetriphenylphosphorane 19:495 with methyl triphenyl phosphonium with sugars 3:218-220 Wittig reagent 4:126;158;11:78;6:71,72;10:63,16:64; 19:57 conformational models 3:248,252 in lactone synthesis 3:252,255 in synthesis of higher-carbon sugars 4:158 of secondary allylic ethers 3:249 of tertiary allylic ethers 3:251 of zirconium enolates 3:241 of a-allyloxy anions 3:248-250 stereochemical induction 3:248-252 [2,3]Wittig ring contraction 10:34-42 by chiral amide bases 10:31-33 [2,3]-Wittig sigmatropic rearrangement 10:61,62 Wittig ylide 6:181,183 Wittig-Homer condensation 11:159,298 Wittig-Homer cyclization intramolecular 12:292 Wittig-Homer homologation 18:333 Wittig-Homer olefination 11:431-435 Wittig-Homer reaction 4:602,603;7:484;10:673; 12:324,462;18:247,623;19:256 Wittig-Homer reagent 19:84 Wittig-methylenation ofZ-mannose 10:413 Wolff rearrangement 19:18 ofdiazoketone 10:593-595 oxetane ring formation 10:592,593 Wolff ring contraction 6:178,179 Wolff-Kishner cyclization 1:58 Wolff-Kishner reaction Huang-Minion modification of 14:684 Wolff-Kishner reduction 2:235;4:416;6:6,17,509;8:164, 165;13:6,11,12,21-23,403;14:277,278,359,417,419, 452,453,728;15:231;19:135;18:35 Woodchuck hepatitis vims 20:535 Woodward reaction 19:363 Woodward reagent K 6:238,247,405 Woodward-Hofmann rule 2:128,3:401 Wortmannin 6:219,220 Wurtz coupling 9:344 Xylitol pentaacetate synthesis of 4:509 D-Xylo-hexofuranose 6:365,367,372 C5-P bond analogs of 6:365,367,372 Xylosides synthesis of 8:362 Xylosyl chlorides 8:359-362 Yamada's synthesis 12:203 Yamaguchi method 11:154,157,158 Yamaguchi reagent 11:157 Yamamoto condensation of propargylic titanium reagent 12:2 regioselective 12:24 stereoselective 12:24 Yeast reduction 1:482;13:560 Yeasts for asymmetric reduction 1:689 Ylides acylation of 4:554-556 Yu-Lin-Wu synthesis of()-polygodial 6:14 (-)-polygodial 6:14 (Z)-zinc (II) enolate 12:166 Z-Diene 16:4 Z-Enediones 16:648 Z-Enolate 16:661 Zaitev reaction 1:318,517,518 Zemple'n conditions 6:409 Zemple'n 0-deacetylation 6:412 Zemple'n reaction 6:411 Zemplen de-(9-acetylation 12:348 Zincke'ssalt 19:38 Zimmerman-Traxler transition state 4:445 Zinc (II) iodide 12:164 Zinc borohydride reduction with 1:261;4:348 Zinc bound alkoxide 17:481 Zinc clathridine 17:18 Zinc mediated coupling 1:264;265 Zinc-copper couple in deoxygenation 4:424 in reductive elimination 4:165 Zinc-dust 12:166 in deoxygenation 4:424 Zinc (II) chloride 1,4-dehydro-p-lactam from 12:172,173 with 4-acetoxy-P-lactam 12:172,173 Zirconium (IV) enolate 12:168 Zirconium derivatives 9:453 as fluorescence-inducing reagent 9:453 Zirconium enolate of phenylthio ester 13:506 Zirconium enolates 3:249 [2,3]-Wittig rearrangement of 3:249 Zwitterionic aza-Claisen rearrangement 16:466

1300

CUMULATIVE PHARMACOLOGICAL ACTIVITY INDEX

VOLUMES 1-20
Acarbose as a-amylase inhibitor 13:3 as a-glucosidase inhibitors 7:47 as antihyperglycemic drug 10:505 as antihyperlipoproteinaemic drug 10:505 (-)-Acetomycin antimicrobial activity of 10:443 antitumor activity of 10:444,447 (+)-5-epi-Acetomycin antitumor activity of 10:447 Acetylcholine receptor 18:863 (3-( 1 -6)-A^-Acetylglucosaminyltransferase in biosynthesis of I-antigens 10:486 (+)-Acetylphomalactone antifimgal activity of 19:479 antitumor activity of 19:479 insect antifeedant activity of 19:479 plant growth inhibitory effect of 19:479 Aciclovir (9-[2-hydroxyethoxy methyl] guanine) antiviral activity of 10:585 Acronycine antitumor activity of 13:365-375 (+)-Actinobolin antineoplastic activity of 16:3 dental cariostatic activity of 16:3 immunosuppressive activity of 16:3 microbial antitumor antibiotics 16:3 Acute leukemia in children 14:805 vinblastine for 14:805 vincristine for 14:805 Adenocarcinoma of colon 1:276 Adipokinetic hormones 9:487,489 Adiposin-1 and 2 inhibitory activity against a-amylases 10:514 Adiposins antibacterial activity of 10:514 a-glucosidase inhibitors of 10:513 (3-Adrenergic blocking agents synthesis of 14:473 Adriamycin 4-demethoxy analogs of 14:474 synthesis of 14:474,475 Agglutination inhibitors 2:308,309 Aggregation pheromone of Gnathotrichus 1:692 Aggreticin platelet aggregating inhibitor 5:597 a2-Agonists 8:396-298 AIDS 2:421-426 Aids virus 12:245 Alarm pheromone n-undecane in 6:453,454 Aldose reductase inhibition 6:20 by (+)-dysideapalaunic acid 6:20 Alkaloids molluscicidal activity of 7:427 Alkenyl phenols molluscicidal activity of 7:427 AUamandicin antifungal activity of 16:299 antileukemic activity 16:299 antimicrobial activity 16:299 cytotoxic activity 16:299 Allamdin antifungal activity of 16:299 antileukemic activity of 16:299 cytotoxic activity of 16:299 Allelochemicals 9:387 Allelopathic activities 20:391 Allergenic dermatitis 2:277,280-281 Allergy inhibitors 5:759 Altholactone biological activity of 19:498 Alzheimer's diseases (-)-physostigmine for 14:637 Amastatin [(25',3/?)-3-amino-2-hydroxy-5-methyl hexanoyl-L-valyl-L-valyl-L-asparticacid)] leucine aminopeptides A inhibitor of 12:434 leucine aminopeptidase inhibitor of 12:434 Amebicidal activity of emetine 6:485 of 1,2-secoemetine derivatives 6:485 (3i?)-Y-Amino-(3-hydroxybutyric acid biological activity of 12:434 central inhibitory transmitter 12:434 Aminocyclitol inhibitors 10:517-524 Aminoglycopyranoses p-glactosidase inhibition with 7:47 2-Aminooxetanocin A antiviral activity of 10:619,620 Aminoquinone immunosuppressive effect 5:437 Aminotransferase activity 19:650 Amoebicides 7:398 Amphidinolide M cytotoxicity of 19:566 Amphidinolide Q cytotoxicity of 19:560 Amphotericin B 2:421,422,446;4:513-520;6:261-306; 10:150;17:245 a-Amylase inhibitor acarbose as 13:189 Amylostatins GXG inhibitory activity of 10:509 Amylostatins GXGG inhibitory activity of 10:509 Amylostatins GXGGG inhibitory activity of 10:509 Amylostatins XG inhibitory activity of 10:509 synthesis of 10:507-511 Amylostatins XGG inhibitory activity of 10:509

1301 Amylostatins XGGG inhibitory activity of 10:509 Analgesic 17:633 Ant repellant neoxanthinas 6:142 Antagonistic activity 20:515 Anthelmintic activity 1:408,5:552 Anthelmintic agents 12:3 Anthracycline antibiotics antitumor activity of 14:492 Anthracyclinones biological activity 4:318 cardiotoxicity 4:318 Anti-AIDS agent (+)-castanospermine 11:267 Anti-digoxin antibodies 15:374 Anti-feedant activity 2:277 Anti-fertility action ofplumbagin 2:229-231 of Plumbago zeylanica 2:229,231 ofisoshinanolone 2:229-231 Anti-hepatitis B agents 20:527 Anti-HIV-activity 19:511,748 Anti-HIV-assay 20:535,536 Anti-HIV-screening 13:665 Anti-i-antibody 10:480 Anti-inflammatory activity 13:647 Anti-inflammatory agent 7:397,14:315 Anti-leukemic activity 1:305 Anti-malarial agents 20:516-521 Anti-microbial activity of sesquiterpenes 2:287,288 Anti-stress activity 20:646 Antibacterial activity 20:245,712 Anti-tubercular activity 5:752,753 Anti-tubercular agents 5:751 Anti-tumor activity 1:275,316-320-408 Anti-tumor agent 1:180,268,269 Anti-tumor antibiotics synthesis of 1:498-721 Anti-tumor metabolites 1:239 Anti-venom alkaloid oxidation 1:239 Anti-vitamin activity of 25-aza-vitamin D3 9:519 Antiallergic activity 18:674 Antiallergic effect ofK-252a 12:398 of staurosporine 12:398 Antibacterial activity of3',4'-dideoxykanamycin 14:145 ofacteoside 5:512 of P-hydroxyacteoside 5:512 of benz [a] anthracene antibiotics 11:134 ofcelastrol 5:747 offorsythiaside 5:512 ofphenylpropanoids 5:512 ofsaframycins 10:78 of staurosporine 12:398 ofsuspensaside 5:512 oftetrazomine 10:117 ofthienamycin 12:147 Antibacterial agent aplasmomycin 5:377 aurantinins 5:601 chimeramycin 5:613 Antibacterial macrolide 5:613,747 Antibiotic activity of2-isocephems 12:192 of 2-iso-oxacephems 12:192 of semivioxanthin 11:130 ofthienamycin 12:188 Antibiotic activity of macrolide 17:283 Antibiotic potency ofimipenem 4:432 of 1-P-methylthienamycin analogue 4:432 Antibiotic T-1384 5:549 Antibiotics ansamycin 9:431-445 bio-organic chemistry of 9:431-445 biosynthesis of 11:207-213 from microorganisms 5:589 isoquinolinequinones 10:77-145 mitomycin 9:431-445 relative configuration of 6:261 shikimic acid derived 11:182-191 sugar components of 11:213-222 Antibiotics A 26771 B by Penicillium turbatum 11:194 Antibodies 2:345-348,7:29 Anticancer activity DNA-damaging natural products with 20:457-500 ofvinblastine 14:805 of vincristine 14:805 Anticancer agents 19:511 Anticancer compounds 13:347-382 Anticandidal activity 20:485 Anticaries activity 18:673 Anticholinergic agents 17:395 Anticoccidium agent 4:591 Antidiabetic agents 7:47 Antidote for scorpion sting 5:751 for snake bite 5:751 Antidysenteric agent 5:758 Antiedema activity of staurosporine 12:384 Antifeedant 17:153,234,237 Antifeedant activity of (-)-specionin 10:425 Antifeedant assays 18:771-774 Antifeedants 7:395-397 Antifertility activity 5:754 Antifouling 17:93,98 Antifungal agents 17:239 activity of 17:378 macrolide 17:16 sesquiterpene dialdehydes 17:233 Antifungal activity of alga 5:342 ofcoelenterate 5:342,368 ofcordigol 7:408 ofcordigone 7:408

1302
offlavolol 3-methyl ether 7:414 offlavonoids 7:413 ofgarcigerrin 7:423 of hydroquinone uncinatone 7:408 ofmollusk 5:342 ofnanaomycins 11:127 ofnaphthoxirene 7:423 ofpterocarpans 7:414 of semivioxanthin 11:130 of sesquiterpenes 2:287 of sponge 5:342,368 of tunicate 5:342 ofurdamycin 11:134 ofxanthones 7:410 Antifungal agents 4:513 Antifungal antibiotic cerulenin 5:613 irumamycin 5:597 phhoamycin 5:607 Antifungal compounds 7:406,408,415 Antifungal flavones 7:413 0-Antigen from Salmonella anatum 6:262 synthesis of 6:262 I-Antigenic determinant 10:483 O-Antigenic polysaccharide from Pseudomonas aeruginosa 14:236 from Salmonella newington 14:233 from Shigella flexnert 14:233 Antigenic specificity 4:197 I Antigens 10:457-461 II Antigens 10:457,461 Antihormones 20:515 Antihepatotoxic activity 17:377 Antiherpes activity 5:565 Antihyperglycemic activity 18:672;19:351 Antihypertensive activity of Forsythia suspensa 5:513 ofK-252a 12:398 of staurosporine 12:384 of suspensaside 5:513 Antihypoxic activity 18:373 Antiinflammatory activity 5:367;17:137,376;18:775 Antiinflammatory agent 5:753 Antiinflammatory drug 17:130 Antiinflammatory effects ofK-252a 12:398 of staurosporine 12:398 Antileukemic activity 4:232;7:382-387,390;17:348 Antimalarial activity of acetylvismione D 7:424 ofartemisinin 7:424 of 3-geranyloxy-6-methyl-1,8-dihydroxy anthraquinone 7:424 of 3-geranyloxy-6-methyl-1,8-dihydroxyanthrone 7:424 ofquassinoids 7:391-394 of quinine 7:424 ofvismioneD 7:20 Antimalarial agents 8:391-394,351 Antimetastatic effect of 16:93 Antimicrobial activity against Candida albicans 5:752 against Clostridium difficile 5:601 against Clostridium perfringens 5:601 against Proteus mirabilis 5:752 against Proteus vulgaris 5:752 against Staphylococcus aureus 5:752 of(-)-acetomycin 10:443 of amphibian venoms 15:327-339 ofcryptolepine 5:752 ofdimertriterpenes 18:776-778 of medrrhodine A and B 5:618 oftriterpenes 18:776-778 Antimicrobial agent 5:753 Antimitotic activity oflignans 5:461 ofgigantecin 9:396 Antimycine A antifungal agent 16:694 Antimycoplasmal activity ofnanaomycins 11:127 Antimetastatic agents 19:351 Antineoplastic activity 4:29 Antineoplastic glycoproteins 7:285 Antioxidant 4:495;9:371,372 Antiperiplanar orientation 14:457 Antiphlogistic 17:451 Antipredation 17:93 Antiplasmodial activity 19:587 Antiplasmodial agents 20:525 Antiproliferative activity 7:419,422,245,515;16:93 Antiproliferative effect against HL-60 cells 12:393 against T cells 12:393 BALB/C mouse 3T3 cells 12:393 bovine brain cortex capillary 12:393 cis-platin 12:390 endothelial cells 12:393 human breast cancer 2R-75 cells 12:393 human myeloid progenitor cells 12:393 in walker rat carcinoma cell 12:390 L2CB lymphocytes 12:393 mouse isolated microglia 12:393 NIH/3T3 fibroblasts 12:393 of anticancer drug 12:390 of staurosporine 12:393 Antipyretic activity 18:775 Antirachitic factors 17:623 Antisweet activity of gymnemic acid 18:671,672 Antituberculous activity 20:712 Antitumor 17:17 Antitumor activity of (+)-5-epi-acetomycin 10:447 of (-)-acetomycin 10:444,447 ofacronycine 13:365-382 of benz[a] anthracene antibiotics 11:134 ofcyanocycline A 10:103 ofdidemnins 10:254-257 of diphyllin 5:462 ofglyfoline 13:375-380 of indolo [2,3-a] carbazole alkaloids 12:390-396 ofK-252a 12:394,395

1303 oflignans 5:461 of naphthocyanidine 10:104 ofnogalamycin 4:335 ofpristimerin 5:747 ofquinocarcin 10:117 ofrebeccamycin 12:394 ofsaframycins 10:78 ofstaurosporine 12:390-394 oftaxol 12:180 oftetrazomine 10:117 ofUCN-01,UCN-02 12:395 ofurdamycin 11:134 ofstaurosporine 5:275 Antitumor agents 3:301,383;9:383,385 Antitumor antibiotic 5:592,593;19:118 Antitumor bioassay 9:383,386,401 Antitumor polyethers 5:377 Antitussive 17:633 Antiviral activities Herpes simplex virus 17:146 HIV-2 17:146 of(-)-aristeromycin 10:609 of (+)-C-2'-ara-fluoroguanosine 10:609 of2-aminooxetanocin-A 10:620,621 of 3'-azido-3'-deoxythymidine 10:585 of aciclovir (9-[2-hydroxyethoxy)methyl] guanine 10:585 of carbocyclic oxetanocin A and G 10:620,621 ofcarbovir 10:608,609 of D-2'-deoxycarbocyclic guanosine 10:608,609 ofdidemnins 10:253,254 offlavonoids 17:145 of imidazole analogues 5:566 oflignans 5:461 of marine organisms 5:359,364 of mycalamide A 5:366 of spermidine 5:563 of oleanolic acid derivatives 17:135 of oxetanocin A 10:608,619,620 of oxetanocin G 10:619,620 of quinovic acid derivatives 17:134 of Theonella sp. 5:364 Antiviral agents 19:351,511 Antiviral protein 13:655 Aplyronines A-C cytotoxic activities of 19:609 Aplysinopsine cytotoxic activity of 5:410 (-)-Aplysistatin antineoplastic agent 16:705 Arenarone cytotoxic activity of 5:438 (-)-Aristeromycin antiviral activity of 10:609 Arrow poisons 12:233 Asperdiol 10:18 activity against lymphocytic leukemia 8:15 growth inhibition of KB, PS and LE Cell lines 8:15 Aspergillosis 2:422,425 Astringent 5:751,754 Atherosclerosis 11:335;12:399 Aureolic acid antitumor antibiotics 3:173-206 Autoimmunodeficiency syndrome 18:908 Auxins effect on root culture growth 17:424 indoleacetic acid as 7:90 naphthaleneacetic acid as 7:90 Avermectin biological activity of 12:709 structure-activity relationship of 12:8 Avermectin Bi insecticidal activity of 12:9 Avermectin Bia synthesis of 1:463-465 Avian hemoglobin allosteric regulator binding sites 5:849 Avidinphosphatase assay 4:284 Bacterial growth inhibitors 17:101 Bactobolin antibacterial activity of 16:3 antitumor antibiotic 16:3 BAP (6-benzylaminopurine) as cytokinin 7:90,94 Bayogenin molluscicidal activity of 7:432 BE-13793C 12:366,370,396 antitumor activity of 12:396 topoisomerase I and II inhibitors of 12:370 Benz [a] anthracene antibiotics antibacterial activity of 11:134 antitumor activity of 11:134 Benzo [a] pyrene carcinogenicity of 7:8 Bicyclomycin antibiotic activity of 12:63 antimicrobial activity of 12:41 toxicity of 12:63 KB Bioassay 2:404,405,9:230,231,238,220-222 Biogenic amines 15:328 Bioinsecticides 15:381 Biological activities chiralityin 7:3-28 isolation of 4:243 of(+)-compactin 11:335,336 of(-i-)-mevinolin 11:335,336 of (-)-selin-l l-en-4a-ol 14:450,451 of amicoumacins 15:410-412 ofavermectms 12:7-9 ofbaciphelacin 15:409,410 of ^w-indolyl maleimides 12:384-399,133,91 of erythromycin 13:155-185 of indolo [2,3-a] carbazole alkaloids 12:384-399 of intermedeol 14:450,451 of ivermectin 12:8,9 of macrolactone 155-185 of microcystins 20:896,897 of natural products 7:3-29 ofneointermedeol 14:450,451 ofnocamycin 14:110 ofnodularins 20:896,897 of PI turnover inhibitors 15:461,462 of polyene macrolides 6:261

1304

of self-inhibitors 9:222,238 of spatanediterpenoids 6:39 ofspatol 6:39 ofsphingolipids 18:459,460 of staturosporine 12:399 ofstreptolydigin 14:108,109 oftaxanes 11:4-6 oftaxodione 14:667 of tetramic acid 14:107-110 of tyrosine kinase inhibitors 15:447,449 ofxenocoumacins 15:408,409 Biological properties ofdidemnins 10:241-302 oflipo-gastrin 18:857-863 oflipo-CCK 18:857-863 Biologically active compounds 17:153 Bioregulators studies with 2:377-386 chiral synthesis of 6:537-566 Black vomit 1:679,680 Boll weevil pheromone 1:693 Botanical juvenile hormones 18:498 Bradykinin 9:296,298 Brassinolide antiecdysteroid activity of 16:321 plant growth promoter 16:321 biological activity of 19:245,281 Brassinosteroids biological activity of 19:473 Brine shrimp lethality bioassay of 9:385,387-400 Brine shrimp toxicity of Goniothalamus giganteus 9:395 Bronchodilators in treatment of asthma 5:759 Bryostatin as anticancer drugs 19:550,572 pharmacological aspects of 19:572

Cannabinoid receptor (CBi) 19:186 Cannabis sativa as an intoxicant 19:186 Carcinogenesis 20:512,513 Colon 26 carcinoma 19:609 Calcium effects of staurosporine 12:397 Calcium/calmodulin-dependent protein kinase 12:389 Calmodulin inhibitory activity 2:282,284 Camptothecin as anticancer agent 13:654 Cancer 17:137 Cancer chemotherapy by substituted benzo [c] phenanthridines 4:544 Candidiasis 2:332,425,432 Candidoses polyene macrolides in 6:261 Carbapenem as asparenomycins 4:434 as carpetimycins 4:434 as KA-antibiotics 4:434 as nor-thienamycin 4:434

as OA-antibiotics 4:434 as pharmacophore 4:434 as pluradomycins 4:434 Carbapenem antibiotics 13:495-507 Carbocyclic nucleoside antibiotic activity of 8:148 antitumor activity of 8:148 antiviral activity of 8:148 Carbocyclic oxetanocin A,G antiviral activity of 10:620,621 Carbohydrate transporting proteins 7:29 (-)-Carbovir antiviral activity of 10:608,609 Carinogenesis 9:583 Carcinogenesis research 15:439 Carcinogenic activity of fumonisins 13:532 Carcinogenicity of benzo [1] pyrene 7:8,9 Carcinomycin 1:498 Cardiac depressant 5:750 Cardiac glycosides 9:293 Cardiotonic constituent 17:33 Cardiotonic peptides 5:403 (+)-Castanosperime inhibitory activity of 12:332 insect antifeedant activity of 12:332 plant growth regulating activity of 12:332 Castanospermine as anti-aids agent 11:267 a-glucosidase inhibition by 7:12 p-glucosidases inhibition by 7:12 CC-1065 antitumor activity of 3:310,302 DNA sequence selectivity 3:304 toxicology 3:302 CCK hormone 18:834 CCK-A antagonist 18:863 CCK-B antagonist 18:863 Cecropia }u\Qm\Q hormone synthesis of 3:271 Cembranoids anticancer activity of 8:15 Cerbinal antifungal activity of 16:302-304 CGP-41251 cyclic AMP-dependent protein kinase inbitor 12:388 S6 kinase inhibitor of 12:388 tyrosine specific protein kinase inhibitor of 12:388 Chagas disease 2:293,302 Chalcones molluscicidal activity of 7:427 p-Chamydosporol toxicity of 13:543 Chemical-induced edema 12:398 a-Chlamydosporol toxicity of 13:543 Choriocarcinoma vinblastine for 14:805 vincristine for 14:805 ep/-8-Chromozonarol antimicrobial activity of 5:437

1305 Chrysosplenol-D antimicrobial activity of 7:413 Cichoriin inhibitor of dehydropeptidase (DHP-1) 12:145 Cinnamoyl ester of crassin antileukemic activity of 8:15 Cocarcinogen 1:547 Coccidiomycosis 2:422 (+)-Compactin biological activity of 11:335,336 Competitive inhibitors 7:40,56,69,70 Comutagenic effect of estrogens 5:477 Coprotoxins 18:698 Crassin antitumor activity 8:15,19 Crassin acetate antibiotic activity 8:15 Crown gall tumors 9:386 (CT) Chymotrypsin synergistic effects 13:536 toxicity 13:536 Cuanzin 8:283,284,289,293 antiarrhytmic activity of 8:283 antihypertensive activity of 8:283 Cubitermes sp defence secretion of 8:220 Cyanobacterial hepatotoxins 9:496-499 Cyanocycline A antitumor activity of 10:103 (-)-Cyclizidine biological activity 12:305,306 Cytochrome P-450 inhibitor 4:621 Cytokinins 4:227-229,7:89,90,94,20:531 Cytopathogenicity 15:76 Cytopathic "activity" 20:442 Cytostatic activity 18:775-778,20:796 Cytotoxic agents 19:601 Cytotoxic against human neurablastomaNB-1 cells 12:390 staurosporine 12:390 Cytotoxic activity of9-methoxycamptothecine 5:84 of Acalycgorgia 5:368,369 of alga 5:342,346 of camptotheeine 5:84 ofcoclenterate 5:342 of cyclic peptides 4:101,102 of mollusk 5:342 of sponge 5:342-346,353 of tunicate 5:342 ofulithiacyclamide 4:101 Cytotoxic agent 2:404,293-303,653 savinin 13:653 from Nerium oleander 9:293-303 Cytotoxic hydrophilic taxol derivatives 12:221 Cytotoxic peptides 4:83,110 Cytotoxicity of p-alaninookadaic acid 5:388 of y-aminobutyrokadaic acid 5:388 of 5-aminovalcrookadaic acid 5:388 ofamphidinolideB 5:396 of glycookadaic acid 5:384,385 ofhalichondrin B 5:378,380 of halichondrin C 5:380 ofhomohalichondrin A 5:380 ofhomohalichondrin B 5:380 of norhalichondrin A 5:378,380,383,384 ofokadaicacid 5:384,385,389 of taurookadaic acidf 5:388 of tumour necrosis factor 5:387 Dendrodoine cytotoxic activity of 5:412 Denticulatin A and B antimicrobial activity of 17:24 Denudatin antifeeding activity of 8:160 6-Deoxy-6-fluoro-sucrose as competitive inhibitors 7:69 14-Deoxy-taondiol methyl ether from (+)-manool 6:55 synthesis of 6:55 Deoxytedanolide antitumor activity of 19:558 Deoxymannoj irimycin a-mannosidase inhibitor of 10:539 P-mannosidase inhibitor of 10:539 Deoxymannoj irimycin a-mannosidase inhibition by 7:15,41,42 1-Dexoynoj irimycin 10:543-546,549 antihyperglycemic activity of 10:526 antiviral activity of 10:529 (-)-8,8a-Di-epi-swainsonine inhibitory activity of 12:331,332 Diarylheptanoids activity of 17:375 Didemnin-B (isodidenmin-I) 10:251-258,262,263,266272,276,277,281,285,291 Didemnin B antitumor activity of 5:421 antiviral activity of 5:421 immunosuppressive activity of 5:421 Didemnins antitumor activity of 5:421,254-257 antiviral activity of 5:421,253,254 biological properties of 10:241-302 cytotoxic activity of 5:421 immunosuppressive activity of 10:257,258 Diemenensin A antibacterial activity of 17:24 24,24-Dihomo-la,25-dihydroxy vitamin D3 pharmacological activity of 11:385,386 9,10-Dihydroxy-7-methoxynaphtho [2,3-c] pyran-1 (IH)-one (semivioxanthin) antibiotic activity of 11:130 antifungal activity of 11:130 2i?,5/?-Dihydroxymethyl-3i?,4/?-dihydroxypyrrolidine almond emulsin p-glucosidase inhibitor of 10:545 yeast invertase inhibitor of 10:545 yeast a-glucosidase inhibitor of 10:545 Diuretic activity 12:398

1306 DNA-damaging activity 20:467 DNA-damaging agents 20:460,20:461 DNA-damaging natural products 20:457-500 Dolastatin 12:10,477,485,486;5:421 Dolastatin 3 synthesis of 4:87-89 Doxorubicin (adriamycin) 4:317-319 Duct cell carcinoma of breast 1:276 Dyspepsia 5:754 Ecklonialactone A cytotoxic activity of 19:554 Ehrlich carcinoma 19:609 Elastase inhibitor from Streptomyces noboritoensis KM-2753 5:590 ()-Emetine 18:330 amebicidal activity of 6:485 Endosymbiosis 6:134 Enzymatic hydrolysis 6:150;7:268,270;13:54,56,57; 16:291 ofgeniposide 16:291 of diacetylenic a//o-xanthin 6:150 of soya bean flour 9:412,413 Enzyme activity 2:389,390,2:392,394,396,399 Enzyme-inhibitory properties 7:14 Erythromycin A 11:196,197 biological activity of 12:48 Estrogen hormones 9:411 Estrogen responsive kidney 5:447 Ethnopharmacology 13:640 Expectorant 17:451 Fatty acid antileukemic activity of 7:24 Fertility regulation 13:658 Fertility-regulating agent 13:658 Feverfew 13:660 Flavors analysis of 13:322-345 biogeneration of 13:295-345 Food mutagens 8:378,388,389 Forskolin 10:183;13:659 Fragrant odor of liverworts 2:278 Fredericamycin A antitumor agent 16:27 antitumor antibiotic 16:27 synthesis of 16:27-74 Fungal toxin synthesis of 1:289 Fungicidal activity 17:243 Fungicidal saponins 7:433 Fungicides 9:226 Fusarium ioxms 9:201-208 (3-Galactosidase inactivation by P-galactoside analogue 7:40 inhibition by aminoglycopyranoses 7:47 inhibition by conduritol C c/5-epoxide 7:38 inhibition by conduritol C /ra5-epoxide 7:38 inhibition by (3-galactosyl amines 7:44 inhibition by nitrophyenylthiogalactoside 7:48 Galactostain 7:41,42,267 mammalian P-galactosidase inhibitor of 10:542 St-4 Gastric carcinoma 19:298 Gastritis 17:137 Gastrointestinal cancer 1:275 Gaucher's disease 7:39 Gene experession control 5:580,581 Gene expression byantisense RNA 13:257-261 natural regulation of 13:257-261 Gibberellenic acid growth effect on root culture 17:425 Ginseng 13:660 a-Glucosidase inhibitors 7:46,48;13:235-246;10:496 P-Glucosidase inhibitor 19:369 P-Glucosidase 2:379,352,514,526,567;10:568,249,250; 19:357,365,369 3,8-diepialexine inhibition with 7:14 6-e/?/-castanospermine inhibition with 7:12 australine inhibition with 7:15 castanospermine inhibition with 7:12 DMDP inhibition with 7:15 inhibition by 2-deoxy-2-fluoro-P-D-glucopyranoside 7:36 inhibition by acarbose 7:47 inhibition by conduritol B epoxide 7:38,39 inhibition by nojirimycin heptitol derivative 7:43 inhibition by validamycin 7:47 Glycoalkaloids molluscicidal activity of 7:427 Glycopeptide antibiotics 10:657-669 Glycosyl pyridinium salts p-glycosidases inhibition by 7:57 Glyfoline antitumor activity of 13:375-380 GoniodominA 19:578 antifungal activity 19:578 antifungal metabolite 19:578 (6i?)-(+)-Goniothalamin antifungal activity of 19:479 antitumor activity of 19:479 insect antifeedant activity of 19:479 isolation of 19:481 plant growth inhibitory effect of 19:479 Growth inhibition 17:142 Growth-inhibitory activity 7:407,416-419,423 Guaiazulene 5:363,369 as an anti-inflammatory agent 14:315 Gugulipid 5:715,716 Gymnemic acids biological activity of 18:670-674 Gyrostroma missouriense 15:351,383 Haemagglutinin-based inhibitors 16:111 Halichondride antitumor activity of 5:378,380 Haliclona sp. 5:346,347,459

1307
Halitunal antiviral activity of 16:302 HBV infection 20:528-530 Hederagenin 7:134,135,429,431-433,9:61,62 molluscicidal activity of 7:432 Helenanes antiinflammatory activity of 16:664 antileukemic activity of 16:664 cyctotoxic activity of 16:664 Helichrysum nitens 5: 413 antifungal flavonoids from 5:651 (Z)-Heneicos-6-en-l 1-one sex pheromone of 19:124,126 Heparanase activity in malignant cells 16:90 Hepatitis B surface antigen 20:537 Hepatitis B virus 20:227,20:528 Hepatoprotective activity 20:116 Hepatotoxic cyclic peptides of cyanobacterial origin 20:887-913 Hepatotoxins cyanobacterial 9:496-499 Herbasterol antimicrobial activity of 5:410 ichtyotoxic activity of 5:410 Herbicidal antibiotic 5:592,607 Herbicides 7:398,383,384,387 Herbimycin as an antitumor antibiotic 5:592 as herbicidal agent 5:592 Heroin 18:48 HIV (human immuno deficiency virus) 7:12 HIV whole cell assay 19:757 HIV-assay 19:757 Hodgkin's disease 4:29 vinblastine for 14:805 vincristine for 14:805 Hormones 18:819-866;19:627-687 bioactive conformations of 18:819-866 HSV-2-Virus antiviral activity against 4:237 Co-3-Human colon carcinoma 19:289 Human growth hormone 4:271 Human immunodeficiency virus (HIV) 7:12,396 Human leukemia cells 18:269 Human leukocyte elastase inhibitor of 16:727 Human nasopharyngeal KB staurosporine activity against 12:390 Human neuroblastoma NB-1 cells cytotoxic against staurosporine 12:390 Human neuroblastoma nbla-N-5 cells tamoxifen activity against 12:390 Human neuroblastoma SH-SY-5Y cells 12:390 Human neutrophils 12:390 Human neutropil protein kmase C 12:389 Human onchocerciasis ivermectin for 12:9 Human platelets study of protein kinase C in 12:390 by staurosporine 12:390 Human xenografted carcinomas 19:330 Hydroperoxides cyctotoxic activity of 5:409 10-Hydroxyellipticine anticancer activity of 6:507 la-Hydroxylase inhibitors of 9:515 Hypericin retroviral activity of 7:421 Hypocholesterolemic agent 13:554 Hypocholesterolemic drug 5:195 Hypoglycemic activity 18:672 Hypoglycemic effects 17:139 Hypotensive activities 17:451 ofcryptolepine 5:752 Hypotensive alkaloid 5:751,752 Ichthyotoxicity 17:24;18:607,716 Ilimaquinone 5:430;15:291,314 antimicrobial activity of 5:434,437 Imidazolone 5:412 cytotoxic activity of 5:413,415 Imipenem antibiotic potency of 4:432 PBP-2 affinity for 4:433 Immunosuppressant agents 16:561 Immunosuppressive activity 18:739,921 ofdidemnins 10:257,258 Immunosuppressive therapy 20:528 bis-lndiO\y\ maleimides 12:365,372,375-383 biological activity of 12:384-399 protein kinase activity of 12:389 Inflammatory activity 20:531 Inhibitins 7:119 of aminoglycopyranoses 7:47 of 1 thio p-Z)-galactopyranosides 7:48 Inhibition 7:47,48;9:581 Inhibitors of enzymes 9:515 of vitamin-D-metobolism 9:515 Inhibitory activity of(+)-castanospermine 12:332 of(-)-swainsonine 12:327 of (-)-(8,8a-di-e/7/-swainsonine 12:325 ofbenzalmalonates 9:225-227 Insect antifeedant 2:288 Insect juvenile hormone analogues fromthujone 14:391-397 Insect pheromones via diisopropylethanediol esters 11:415-417 Insect repellant 5:757 Insecticidal activity 18:229,704 Insecticides 7:395-397 Interferon 4:273 LPS induction of 4:199 Interferon-a-P and Y 20:531-533 Interferon production by human cell cultures 12:390 protein kinase in 12:390 InterleukinI 5:388

1308
Interleukin I induction 4:197 by LPS 4:197 (+)-Intermedeol biological activity of 14:450,451 lonophore activity 4:93 lonophoretic activity 18:857 Iridoids analgesic activity of 7:490 antidote for a-amanitin poisoning 7:490 antileukemic activity of 7:490 antiphlogistic activity of 7:490 antitumor activity of 7:490 biological activity of 7:490 diuretic activity of 7:490 hepatoprotectivity of 7:490 hypotensive activity of 7:490 uterine contracting activity of 7:490 Irreversible cytotoxicity 15:447 Irreversible inhibitors (suicide substrates) 7:36-40 2-Iso-oxacephems antibiotic activity of 12:126 2-Isocephems antibiotic activity of 12:126 Isofraxidin 5:515,520,7:117,120,204,224 anticancer activity of 5:521 sedative activity of 5:521 Isoindoline 8:397-403 as a2 agonists 8:397-403 Isolobophytolide antitumor activity 8:15,19-32 Isopulmericin antifungal activity of 16:299 antileukemic activity of 16:299 cytotoxic activity of 16:299 Isoquinolinequinones 10:77-145 antibiotics 10:77-145 Ivermectin (22,23-dihydroavermectin Bi) biological activity of 12:8,9 Jaspamide (jasplakinolide) anthelmintic activity of 5:429 antifungal activity of 5:428 insecticidal activity of 5:428 Jaspisamides A-C cytotoxic macrolides 613 Juvenile hormone (JHI) synthesis of 1:704-707 Juvenile hormone III synthesis of 1:704,705 K-252a C'SF-2370") 12:366,368 K-252b protein kinase C inhibitor of 12:384 K-252C (staurosporinone) protein kinase inhibitor of 12:386 K-252d 12:366,368,369,386 protein kinase inhibitor of 12:386 K-25a 12:366,368,369,384,390,395,396,398,399 antaillergic effect of 12:398 anihypettensive activity of 12:398 antiinflammatory effect of 12:398 antitumor activity of 12:395 effect on nerve growth factor 12:396 protein kinase A inhibitor of 12:384 prostaglandin production by 12:399 porcine spleen protein kinases inhibitor of 12:390 protein kinase C inhibitor of 12:384,390 protein kinase G inhibitor of 12:384 KA-antibiotcs in carbapenem 4:434 Kala-azar 2:302 Ketonucleosides 4:234,253,19:512 biological activity in 4:253 Kidamycin "aglycone" antitumor antibiotics 11:136 KT-5926 myosin inhibitor of 12:388 protein kinase inhibitor of 12:385,386 Lardoglyphus konoi pheromoneof 1:696 Larvotoxic 17:102 Leaf spot disease 4:601 Leech repellent 5:745 Leishmania adleria 2:311,313 immunity against kala-azar 2:313 Leishmaniases 2:293 Lemmatoxin molluscicidal activity of 7:428 Lemmatoxin-C molluscicidal activity of 7:428 Lentinan 5:279 antitumor activity of 5:317 Lethality bioassay of brine shrimp 9:385,387,388,399,400 Leukemia 1:275 Leukotrienes 1:528 Leukemia P388 19:558 Leukoencephalmalacia 9:215 Leukopenia 5:135 Leurocristine from Catharanthus roseus 13:655 Lewis jung carcinoma 19:609 Libinia emarginata juvenile hormone from 1:704 Lignans 5:9,459,503, 753,754,311;17:313,441; 20:108-113,273,613 biological activity of 5:505,544,545 Lipid peroxidation inhibitor of 4:495 Lipid storage disease (phytoesterolemia) 9:478 Lipo-CCK biological properties of 18:857-863 Lipo-gastrin physical properties of 18:844-848 biological properties of 18:844-848 Lipophilicity 4:369

1309 Lipoxygenase catalysis products of 9:559-589 5-Lipoxygenase inhibitory activity 2:282,284,335 Lipozyme activity 20:845 Liver cancer 20:528 (LPLC) 7:407,408,410,415,418 antigenic specificity of 4:195 6-deoxy-D-mannoheptose in 4:195 interleukin I induction by 4:197 T-Lymphoblast cells 19:556 Lymphatic filariasis 12:9 Lymphocytes 15:369 Lymphocytic leukemia system 18:696 Lymphoid leukemia 4:723 Lyngbya majuscula lyngbyatoxin from 11:278 Lyngbya toxin A. 5:412 cytotoxic activity of 5:411 Lyngbyatoxin fvom Lyngbya majuscula 11:278 Macrolides 3:277-281;4:513-520;5:609,356,357,6:272277;9:246,247,290;8:175-201,222;16:658-662 Macrolide antibiotics 3:277-281;5:606,609,613;195; 13:155-185,664 acetySpiramycin 5:609 difficidin 5:609 erythromycin 5:609 oleandomycin 5:609 oxydifficidin 5:609 (-)-Malyngolide 19:463 antimicrobial activity of 19:492 Mammary carcinoma 1:275 Mannosidase inhibitor of 19:356 mannojirimycin inhibition by 7:41 a-Mannosidase inhibitor synthesis of 1:331 Mannostatins A & B 10:523,524 a,D-mannosidase inhibitors 10:523 Manoalide 3:157,158; 18:717 antibacterial activity of 16:666 inflammatory activity of 16:666 inhibitory activity of 16:666 Marine invertebrates neuropeptide from 9:493-495 Marine macrolide antifungal activity of 19:549 antitumor activity of 19:549 antiviral activity of 19:549 bioactive 19:549-626 cytotoxic activity of 19:549 immunomodulatory activity of 19:549 Melanine pigment physiological role of 16:615 Melanoma 1:275 Melanoma cells 16:90 Meningitis due to Candida neoformans 2:422 Metastasis of tumors 19:351 Metastatic cells 16:76 Methyl aplysinopsin antidepressant activity 5:410 Methyl epijasmonate 6:558-559,8:152-155 plant growth inhibitor 8:140 (-)-Methylenolactocin antitutmor antibiotic 16:699 2-Methylheptadecane pheromoneof 19:125 Methylmalonyl CoA 11:194,195 with macrolide antibiotic 11:195 7-co-0-Methylnogarol 14:47,78,79 antitumor activity of 14:48 (+)-Mevinolin biological activity of 11:335,336 reductase inhibitor of 11:335,336 Microbial secondary metabolites screening of oncogene function inhibitor from 15:439-463 Mildiomycin 4:241, activity of 4:245 Mitomycin 1:340;4:573;5:439,440; 16:573 Mitomycin A 13:434,435,445-447,460,467 Mitomycins 13:439 Mitotic activity of the cells 2:380 Mixed inhibitors 7:40 Molluscicide 7:425-427 Moloney sarcoma virus 5:565 Monoclonal anti-I biosynthesis of 10:484 I-antigenic determinant of 10:480,481 Monomorium species 6:443 pyrrolidine venom alkaloids in 6:436 Multidrug-resistant human cancer cell staurosporine activity against 12:390 Mutagenic activity of estrogen 5:447 offumonisins 13:532 Mutagenicity 7:9 Naphthalen eacetic acid as auxin 7:90,94 Naphthocyanidine 10:106 antitumor activity of 10:104 Naphthoquinones 4:388,389;7:435 biosynthesis of 2:226 with isovaleraldehyde 4:396,398 synthesis of 3:450,451 Naphthyridinomycin 10:108-115 antitumor activity of 10:107 Naphtooxirene derivatives antifungal activity of 7:407 cytotoxicity of 7:407 Naproxene antiinflammatory drug 14:505 Narburgia stuhlmanni antifeedant from 1:701,702 Natural inhibitors of phosphatases 20:889

1310

Natural regulation of gene expression 13:257-261 by antisense RNA 13:257-261 NCI assay 18:878 Nematocidal activity against Bursaphelenchus lignicolus 12:396 Nematodes activity against 1:435 Neolaulimalide cytoxicityof 19:569 Neoplastic transformation 5:448 of subclone A-31-1-13 ofBALB/c3T3 cells 5:452 Neoxanthin 6:133,136,141,146;7:98,320,321 as ant repellant 6:142 Nerium oleander cyctotoxic agents from 9:293-315 Nerve growth factor effect of K-252a on 12:394 effect of staurosporine on 12:3 94 Netropsin binding of DNA 5:575 Neuraminidase 16:75,93,105,106,107 from viruses 16:108 inhibitor of 16:95,111 of bacteria 16:112 Neuropeptides from marine invertebrates 9:493-495 Neurotoxin alkaloids 1:385 Neurotoxins 17:3 Nicotinic toxins 18:697-699 Nigeran 5:299,310 antitumor activity of 5:317 Nitidine 4:544;13:656;14:770 antileukemic activity of 14:769 Nitraraine cardiovascular activity 14:764 Nitrarine 14:731 biological activity of 14:759 Nitrogen sugar inhibitors 7:41-48 Nitrophenyl thiogalactoside P-galactoside inhibition with 7:48 3-Nitropropanoic acid biological activity of 19:117 Nodularins 9:498,18:269 biological activities of 20:896,897 inhibition of protein phosphatases by 20:903 Nodusmicin activity against Staphylococcus aureus 17:290 Nogalamycin congeners antitumor activity of 14:76 Nogalamycines synthesis of 4:330 Nojirimycin 6:351;42,50;11:267 glucoamylase inhibitors of 10:525 a-glucosidase inhibitors of 10:526 p-glucosidase inhibitors of 10:526 glucosidases inhibiton with 7:41 invertase inhibitors of 10:526 takadiastase inhibitors of 10:525 trehalase inhibitors of 10:526 Nojirimycin analogues 7:70 sialidases inhibition by 7:42

Nojirimycin hiptitol derivatives 7:42 a-glucosidase inhibition with 7:43 Nucleoside antibiotics synthesis of 1:397-431

OA-antibiotics incarbapenem 4:434 Oat carcinoma of lung 1:276 Old world cutaneous leishmaniansis 2:314 cause of 2:312 9'-01eanoglycotoxin-A molluscicidal activity of 7:428 Oleanolic acid 2:129,7:134,154,189,429,430,432,434; 9:51,55,57,293;20:6 antiviral activity of 17:135 Oligostatins 10:517 amylase inhibitor of 10:516 antibacterial activity of 10:516 mammalian a-amylase inhibitors 10:516 Onchocerciasis (river blindness) treatment of 1:435 Oncogene function inhibitor from microbial secondary metabolites 15:439-463 screening of 15:463 Oncogenesis 19:351 Oncogenic viruses 15:439 Onychine anticandidal activity of 2:443,443 Z,-Omithine nitro derivative condensation of 11:437 Ornithine decarboxylase 20:513 by staurosporine 12:393 induction of 12:393 Oviposition attractant pheromone 3:157-157 Oxetanocin A antiviral activity of 10:619,620 Oxetanocin G 10:586,587 antiviral activity of 10:619,620

P388 mouse leukaemia staurosperine activity against 12:390 Pachyman 5:288,317 antitumor activity of 5:317 Pancreatic acinar cells 18:857 Pancreatic acini from rat and mouse 12:394 2-Pectenotoxin cytoxic activity of 19:580 Pendolmycin 15:456,462 tumour promoter activity of 15:462 Penduletin 7:227 Penems 4:448,476 absolute stereochemistry of 4:435 by azetidinone synthesis 4:437 synthesis 8:262 Phenethylisoquinoline derivative 6:487 Penicillin 6:385;9:413 Penicillin derivatives synthesis of 12:129-131

1311 Penicillinates stereoselective reduction 4:437 Penicillins 4:432,433,435,442;17:614-617 biosynthesis of 11:211-213 cephalosporin C from 11:211-213 chemical shifts of 4:442 from5-(Z,-a-aminoadipoly)-Z-cycteinyl-Z)-valine (LLD-ACV) 11:211-213 semi synthesis of 17:614-617 Penicillium alladadense 5:300 Penicillium atrovenetum 19:117 Penicillium brefeldianum 11:192 Penicillium brevicompactum 5:299,17:475,19:168 Penicillium calaviforme 5:300 Penicillium caseiculum 13:305 Penicillium charlesii 5:296,299 Penicillium chrysogenum 5:299,300,15:351,17:616 Penicillium citrinum 5:300,13:553,19:168 Penicillium digitatum 12:103 Penicillium erythromellis 5:300 Penicillium expansum 5:299,7:13,14 Penicilliumfrequentans 4:588 Penicillium grisofulvium 9:341 Penicillium islandicum 5:299,300 Penicillium javanicum 5:299 Penicillium luteum 5:299 Penicillium madriti 11:198 Penicillium notatum 7:71;17:615 glucose oxidase from 7:71 Penicillium ochrochloron 5:300 Penicillium palitans 4:588-590 Penicillium patulum 5:300,11:198 Penicillium raistrickii 5:300 Penicillium roqueforti 13:305 Penicillium rugulosum 10:646 Penicillium scleriotorum 5:299 Penicillium sp. 5:299,301,325,326;17:475 Penicillium turbatum antibiotic A 26771B by 11:194 Penicillium varians 5:300 Penicillium zacinthae 5:300 Penicillus dumetosus 18:688 Pennogenin 2:445 Pentafiibalol 20:273 Penstemide 7:441 activity against P-388 lymphocytic leukemia 16:295 Pentane in lipid autoxidation 9:564 Peptide antagonists 18:863-865 5 a, 8 a-Peroxycholesterol cytotoxic activity of 5:406 Pestalotan polyol 5:319-321 antitumor activity of 5:391,320 Pestalotia sp. 5:307,308 antitumor activity of 5:319 Pesticidal activity 18:196 of staurosperine 12:397 Pesticides 9:383,391 Pharmacological activity ofquinocarins 10:115-117 Pharmacophore incarbapenem 4:434 Pharmacophore models 12:264 Phenylpropanoids 5:419,420,426,427;15:29 biological activity of 5:505 Pheromone of California red scale 16:138 Pheromonal function 6:458 Pheromonal specificity 7:6 Pheromones 1:276,389,682-684,695;7:193;19:122 fire ant 1:682,683 from Pharoah ants 1:389 from pharaoh ants 4:606 macrocyclic 8:219 of cigaratte beetle 1:695 of Vespa orientalis 1:684 oriental hornet 1:684 Pheromone activity 7:6 Phorbol ester-induced activation inhibition of 12:389 Phorboxazole A antifringal activity of 19:600 2',5' -Phosphodiester antiviral activity of 14:283 Phototoxic 17:378 Phytoalexin 4:391,392;7:119,184;9:221;13:637 antimicrobial properties of 16:564 Phytohormones 8:115-135,227 Phytosphingolipids biological activities of 18:459,460 Phytosterolemia (lipid storage disease) 9:478 Phytotoxic activity 15:345 Phytotoxicity 15:479 Phytotoxins 6:554-556;15:342;17:475 PI turnover inhibitors 15: 452 biological activity of 15:461,462 Piclavine A antibacterial activiy of 16:453 antifringal activity of 16:453 Piscicidal activity offrullanolide 2:289 of liverwort terpenes 2:289 ofplagiochiline A 2:289 ofpolygodial 2:289 ofsacculatal 2:289 Plant growth regulation 1:545 Plant growth regulatory activity of liverwort terpenes 2:289 ofpolygodial 2:289 Plant growth stimulants 9:383,384 Platelet aggregation inhibition of 12:397 Platelet aggregation inhibitor 1:4 Platelet-activating factor by inhibiting phospholipase A2 12:397 Platelet-activating factor 17:326 Platelet-derived growth factor 15:441 Plicacetin activity of 4:244 Polycavemoside A toxicity of 19:572 Polyenal macrolides biological activity of 6:261 incandidoses 6:261 in tumor therapy 6:261

1312 Polygodial 1:467,468;2:278,279,286,289;6:108;7:103, 110,121-123;17:235,244 piscicidal activity of 2:289 Polymixin B protein kinase inhibitor of 12:387 Polyoxins 1:404 antifungal action of 1:399 chitin synthetase inhibition 1:399 Polyphenols 7:409;17:421,427-429 antifungal activity of 7:408 Polyprenols (dolichols) as antiinflammatory agents 8:64 Polysaccharides 5:275-340;7:31-33,72;8:315;9:296,297 antigenicity of 19:689-745 as antitumor agent 5:315 as cell-surface antigens 5:322 Potato disc bioassay 9:399,401,402 Potato discs crown gall tumors on 9:399 Pretazettine 15:135 physiological properties of 4:13 Prostaglandin l:686,687;5:377,815-833;7:483;9:290, 559,571;13:659;17:642;19:550 anticancer clavulones 16:366 Prostaglandin synthetase inhibitors 5:815-833 Protein kinase C inhibitor 4 Protein-tyrosine kinases (PTK) inhibition by piceatannol 9:390,391 Pseudobersana mossambicensis 20:478 bioactive steroids from 20:476 Pseudo-oligosaccharide inhibitors 10:503 Pseudohypericin retroviral activity of 7:421 Pseudolaric acid B as fertility-regulating agent 13:653 Psychotropic activity 7:7 Pulmericin antifungal activity of 16:299 antileukemic activity of 16:299 cytotoxic activity 16:299 Pulmonary colonization 19:370 Pumiliotoxin B activity of 12:294 Pungency 17:379 (-)-Pyrenophorin antifungal antiobiotic 19:154-155 Pyrethrin analogues 14:397-405 insecticidal activity of 14:398 Pyrimidine phosphorylase inhibition of 4:230 Pyrrolidines glycosidase inhibitors of 10:524 Quassinoids antileukaemic activity of 7:382-387 antimalarial activity of 7:391-394 antitumor 11:71-111 toxicity of 7:388,389 Quinocarcin antitumor activity of 10:117 inhibitor of DNA 19:290 (-)-Quinocarcin antimicrobial activity of 19:289 antitumor activity of 19:289 Quinones molluscicidal activity of 7:427 Ras function inhibitors compactin 15:450,451 oxanosine 15:449 Rebeccamycin 5:55,56 antitumor activity 1:394 Reversible inhibitors glycosidase inhibitors as 7:40 Rice blast disease 1:404,529 Rocaglamide antileukaemic activity of 16:565 Saframycin antibacterial activity of 10:78 antitumor activity of 10:78 Saponins 1:305;9:50-64,402;7:155,156,190,426432,434,435;18:649,650 molluscicidal activity of 7:427,428 Sarcophytol B antileukemic activity 8:18 Sarkomycin as antitumor agent 8:150 synthesis of 8:150 Savinin as cytotoxic agent 13:653 Schistosomiasis (Bilharzia) 7:405,408,425,426,435 Schistosomicidal activity 1:545 Scopoletin 5:515,520;7:117,120,204,205,224 analgesic activity of 5:521 hypertensive activity of 5:521 1,2-Secoemetine derivatives amoebicidal activity of 6:485 Selective antitumor activity 15:355 Selective cytotoxicity 13:648 Self-inhibitors bioassay of 9:230,231 biological activity of 9:222,237 (-)-Selin-ll-en-4a-ol biological activity of 14:450,451 Semiochemicals chiral synthesis of 6:537-566 synthesis of 8:219-256 ()-Semivioxanthin(9,10-dihydroxy-7-methoxynaphtho-[2,3,c] pyran-1 (IH)-one) antibiotic activity of 11:130 antifungal activity of 11:130 Serotonin secretion inhibition by K-252a 12:390 Sesquiterpene lactone 7:426;8:195-201 molluscicidal activity of 7:427 Sesquiterpene quinones antimicrobial activity of 5:429 cytotoxic activity of 5:429 Sex pheromone synthesis of 6:537-546

1313 Shigella flexnert 0-antigenic polysaccharide from 14:233 Shikimicacid I0:45;ll:182-191 antibiotics 11:182-191 Sialyltransferase activity 16:81 Silydianin as antihepatotoxic agent 8:166 Sindbis virus 17:135 Skin cancer 5:747 SKK Moth juvenile hormone from 1:704-706 (-)-Slaframine 18:386 activity of 12:306 Sleeping sickness 2:293,302 Smenoquinone antimicrobial activity of 5:434,425 Smenorthoquinone 5:431,432;15:291,292 antimicrobial activity of 5:434,435 Smenospongine antimicrobial activity of 5:434,435 cytotoxic activity of 5:435 Spasmolytics 17:395 Spatol biological activities of 6:39 (-)-Specionin antifeedant activity of 10:425 Sphinxolide 10:153;17:17 antitumor activity of 17:17 Spider mite hatching inhibitor 1:702 Steroid saponins 7:426;15:27-29 molluscicidal activity of 7:427 Steroidal amines 7:16-24 teratogenic metabolites of 7:21-24 toxic 7:16-24 Steroidal lactones 14:439,20:135-148 cardiac active steroids 14:439 Structure-activity profile oftaxol 12:220,221 Substituted benzo[c] phenanthridines in cancer chemotherapy 4:544 5,6-Substituted tetralin a-adrenergic activity of 8:396 Suicide inhibitors 9:593 Suicide substrates (irreversible inhibitors) 7:36-40 Suspensaside antihypertensive activity of 5:513 Suspension cultures 7:92,93 Swainsonine 7:32,44,112 immunomodulation by 7:16 a-mannosidase inhibition by 7:11 Sympathomimetic amines 12:411 T-2 toxin from Fusarium sporotrichioides 13:522 Tachykinin 9:318 Tar cancer 7:8 Taste principles hot and bitter 2:278-280 Taxane biological activity of 11:4-6 Taxodione 19:405,20:712 biological activity of 14:667 Taxol antitumor activity of 12:180 biological activity of 12:179,180 Taxotere biological activity of 12:179,180 Teratogenic metabolites of steroidal amines 7:21-24 Teratogenicity 7:19-22,24 Termite soldiers defensive secretion of 14:451 Terpenes 5:403;7:208-219;8:219;17:4,15,613,642 as antihealants 14:451 as glues 14:451 as irritants 14:451 as repellents 14:451 Tetrahydroanthracenes (vismiones) 7:418-420 antiproliferative activity 7:419 Tetrahydrocannabinol 7:7 psychotropic activity of 7:7 Tetramic acid antibiotics 14:97-141 biological activity of 14:107-110 Tetrazomine 10:117,19:289-290 antibacterial activity of 10:117 antitumor activity of 10:117;19:290 antimicrobial activity of 19:290 cytotoxicity of 19:290 TG-1 anti-fungal activity of 2:445,446 TG-11 anti-fimgal activity of 2:446 Thienamycin antibacterial activity of 4:431,432;12:145 antibiotic activity of 12:122 P-lactamase inhibition by 12:145 (+)-Thienamycin synthesis of 13:498-504 Totipotency of cell cultures 7:94-96 Toxicity of asterosaponins 7:303 offumonisine 13:532 ofholothurins 7:279-282 ofquassinoids 7:388,389 Toxigenic moulds 9:201-203 T-2 Toxin 9:28,210 Toxin 5:403,404,411;9:9-11,209-211 of echinoderms 7:265-316 T-2 Toxin analogues 6:242 Trichommonasfoetus 2:293 staurosporine against 12:397 Trillium glycosides antifimgal activity of 2:443 Tuberculosis rifampicin for 12:37 Tumor necrosis factor staurosporine effect on 12:396 Tumor necrosis factor 5:385,387 Tumor promoters 2:286,287

1314

Tumor therapy polyene macrolides in 6:261 Tumor-promoting diterpenes 12:233-274 synthesis of 12:233-274 Tumour-inhibiting activity 17:341 ;20:408 Tumour-promoter activity ofpendolmycin 15:462 Tyrosine-specific kinase inhibitor of 19:178 Tyrosine kinase 12:394 Tyrosine kinase activity 15:441 Tyrosine kinase inhibitors biological activity of 15:447-449

Xenobiotics and cooxidation 9:582,583 Xenochemicals 18:680;18:680,681 Xenocoumacins 15:381-472 biological activities of 15:408-412

UCN-Ol-UCN-02 12:386 antitumor activity of 12:395 protein kmase inhibitor of 12:386 Udoteatrial 16:312-316 antimicrobial activity of 16:312,315-316 Ulapualides A antifungal activity of 19:609 Ulicyclamide 5:419,420;10:242 cytotoxic activity of 5:419 Ulithiacyclamide 5:419;10:242 cytotoxic activity 4:101,102;5:419 Unsaturated ketonucleosides tumor inhibition by 4:253 Urdamycin A antifungal activity of 11:134 antitumor activity of 11:134

Valepotriates from Valeriana officinalis 13:660 Validamycin as a-glucosidase inhibitors 7:47 Valienamine 13:189,195,198 a-glucosidase inhibitors of 7:46;10:518 yeast a-glucosidase inhibitor of 10:518 Valiolamine 13:189,195 yeast a-glucosidase inhibitor of 10:518 Vesicant activity 1:365 Vinblastine 2:370,372,287,389,390;4:29;8:283;12:179; 13:633;14:805-884;19:748;20:458 anticancer activity of 14:805 Vincristine 2:390,398;9:387;11:5,12:396;13:633; 20:458 anticancer activity of 14:805 Vismione D antimalarial activity of 7:424 antiproliferative activity of 7:419

(-)-Warburganal antifeedant properties 14:413 -421 Withanolide 19:463,470 antitumor activity of 19:470 biological activities of 19:470 insect antifeedant properties of 19:470

1315

CUMULATIVE BIOLOGICAL SOURCE INDEX

VOLUMES 1-20
Abies koreana 20:619 A bies mariestii 20:619 Abrus Jruticulosus 15:26 Abrus precatorius 7:152,15:25 Acacia astringens I'All Acacia nilotica 7:427 Acacia tomentosa lAll Acalycigorigia inermis 5:370 Acalycigorigia sp. 5:368,369 A canthaster planci acanthaglycosides A-D,F from 7:288 marthasteroside A from 7:288 thomasteroside A from 7:288 Acanthella klethra 20:525 Acanthodris nanaimoensis 19:139 Acanthomyops claviger 6:454 A canthoscelides obtectus 10:160 A canthus ebracteatus 7:176 Acanthus illicifolius 7:176,179,181,182,189-191,193 Acetobacter suboxydans 17:636-637 Achantaster planci 15:45 A chillea m illefolium 10:151 Achillea nana 10:151 Acilius sulcatus 5:700 A cinetobacter calcoaceticus 12:103 Acnistus arborescens 20:247 Acnistus breviflorus 20:234 Aconitum napellus 20:19 Acrasiomycetes 9:220 Acronychia baueri 13:347,349;20:789 Acronychia oigophylebeia 13:348,350 oligophylidine from 13:348,350 A croscyphus sphaerophoides 5:310 Actinidia polygama Miq. 16:290,291 Actinogyra muelenbergii 5:311-313 Actinomadura melliaura AT 2433-Ai and A2 from 12:366,368 AT 2433-Biand Bj from 12:366,368 Actinomadura sp. 5:55 Actinomadura sp. SF-2370 K-252a (SF-2370) from 12:366,368 Actinoplanes coloradoensis 17:283 Actinopyga agassizi holothurins from 7:267,269 Actinopyga echinites echinoside A&B from 7:269 Actinopyga mauritiana 7:281 Adocia species 7,20-diisocyanoadociane 6:86 Aedes aegypti 9:299 Aegiceras comiculatium 7:\16-178,180,185,195 A egiceras floridium 7:176-178 Aeridoteres tristis hemogloin components of 5:837 A erobacter aerogenes 11:183 Aeromonas hydrophila 4:197 Aeromonas salmonicida 4:197 Aesculus glabrus 15:191 A escuius hippocastanum 7:142,143 Aesculus indica aesculosides A,B from 7:142 triterpenes of 7:142,143 Aesculus sdcpomns 15:191 Afzelia bipendensis bipendensis from 9:256 Agave cantala 7:427 Agelas mauritianus agelasphins from 18:460,467 Agelas nakamurai agelasin-B from 6:28 Agelas species agelasins from 6:28 Agelenopsis aperta 19:675 Ageratina adenophora 5:28 Ageratum fastigiatum 5:728 Aglaopheniapluma 5:353 Agratis ipsilon 7:397 Agrobacterium rhizogenes 15:376,377;17:395,421 Agrobacterium sp. 7:76 Agrobacterium tumefaciens 9:386,388 Ailanthus altissima 7:392,394 A ilanthus grandis 7:369,381 Alcaligenes eutrophus 1:690;4:39;8:299 Alcaligenesfaecalis \ar.myxogenes 5:314 Alcyonidium gelatinosum 18:695 Alectoria sarmentosa 5:310,311 Alectoria sulcata 5:310,311 Alexa leiopetala (+)-castanospermine from 12:332 (+)-6-e;7/-castanosperime 12:342 (15',65,7/?,8/?,8a/?)-tetrahydroxyindolizidine from 12:332 Alexa leiopetale (+)-castanospermine from 11:267 Alexandrium fundyense 18:703 Alexandrium ostenfeldii 18:703 Alexandrium tamarebnsuis 7:703 Alexandrium tamarensis 17:4;18:703 Allomyces macrogynus 5:276,6:544 Allomyces sp. 5:276 Alnusfirma 17:359,364 Alnus glutinosa 19:246 Alnushirsuta 17:360-361 Alnus japonica 17:360,368 Alnus rubra 17:359 Alnus serrulatoides 17:359-360 Alnus species 17:358-359,368,375 Alpinia katsumadai 17:362,375 Alpinia officinarum 17:362-363,375 Alpinia oxyphylla 17:362,375,379 Alpinia sieboldiana 17:362 Alpinia species 17:358 Alstonia augustifolia 13:422 Alstonia scholaris 5:135,137,138,13:383 Alstonia constricta 1:125,214-217,219,2:369 Alstonia macrophylla 5:135,154-157

1316

Alstonia venenata 1:125 Altemaria solani 598 Altermaria mali 12:400 Altemaria 9:203 Alternaria cinerariae dehydrocurvularin by 11:194 Altemaria kikuchiana 5:598 Altemaria kikuchiana tanaka 15:385 Altemaria solani altersolanol A from 15:346 Altemaria tannius 9:300 Alutera scripta 5:390 Amanita agaricus 9:203 Amantia phalloides 5:496 Amata sp. 5:225,252 Amathia altemata 17:85 Amathia convoluta 17:75,18:715 Amathia genus 17:82 Amathia wilsoni 17:92,95,97,101,18:693 Amauromis phoenicurus hemoglobin components of 5:83 Ambrosia maritima lAll Ambrosia peruviana 14:379 (+)-Alloaromadendrane-4,10-diol from 14:379 Amenanthus retroflexus 7:398 Amitermes evuncifer evuncifer ether from 14:452,463 Amitermes excellens amiteolfrom 14:450-452 Amitermes messinae evuncifer ether from 14:452 Ammania baccifera sesquiterpenes from 9:65 Ammophilafemaldi 5:224,232,253 Ammophila nigricans 5:224,232,252 Ammophilaprocera 5:225,232,252 Ammophila urnaria 5:223,224,232,252 Amphidinium species 5:396,19:559 Amphiscolops sp. 5:396 Amsonia elliptica 1:125 A nacardium giganteum 9:316 Anacardium occidentale 7:427,17:645,34,9:75,316, 318,323,329,9:332,9:335,337,338,340,347 Anacardium semecarpus 9:318 Anacyckus pyrethrum pellitorine from 10:162 Anagasta kueniella 9:322 Anas platyrhynchos hemoglobin components of 5:836 Anastrepha suspensa Anchusa officinalis 17:126 Ancistrocerus antilope 5:223,232,253 Ancistrocerus campestris 5:224,252 Ancistrocerus sp. 5:251 Ancistrocladus abbreviatus ancistrobrevin B from 20:447 Ancistrocladus alkaloids 20:408,437 Ancistrocladus korupensis 20:442,447 korupensamines A and B 20:442 korupensamines C 20:447 michellamines from 20:442 Andrena haemorrhoa 19:129,131-132 Andrena ocreata 19:129

Andrena ovatula 19:129 Andrena wilkella 19:129 Andrena wilkella mandibular gland secretion 1:692 Andrographispaniculata 5:678,7:117,17:472 Androsace saxifragifolia saxifragifolins A and B from 15:200 Anemia mexicana antheridiogens from 6:195,202,208 Anemia phyllitidis antheridiogen from 6:194,202 Anethum graveolens 7:108,109 Aniba sp. neolignans from 8:159 Aniba canellila 19:117 Aniba neolignans total synthesis of 8:159-163 Anigozanthos 17:372 Annona bullata 9:396,397;18:221 Annona densicoma annonacin from 9:395 Annona muricata 17:277;18:213 Annona squamosa 9:398 Anochertus sedilloti 5:223-225,238,254 A nthem is saguram ica 10:15 3,162 Anthocidaris crassispina ganglioside GM5 from 18:486 Anthonomus grandis 1:693,7:187,190 Anthopleura elegantissima 2:306,9:493-495 Anthricus sylvestins anthricinfrom 18:555 Anthrobacter citreus 20:234 Anthrobacter simplex 20:234 Anthrobacter ureafaciens 16:87 Anthrotaxis spp. 3:456 Apaenogaster rudis 5:254,255 Apergillus oryzae 18:807 monohexosylceramides from 18:807 Aphaenogaster longiceps 5:252 Aphelasterias japonica 15:69 Aphomia melleus 15:387 Aphomiaoniki 15:383 Aphom ia sociella 15:3 84 Aplidium californicum 10:248;18:716 Aplidium cavernosa 10:248 Aplidium constellatum 10:248 Aplidium sp. 5:440,617;10:244,248 Aplinia species 17:358 Aplysia brasiliana 6:6;9:249;18:625 Aplysia dactylomela 5:368;6:35;17:7,8,430 Aplysia faciata 17:6 Aplysia Juliana 17:6 Aplysia kurodai 6:24,56;17:4,6 Aplysia punctata 17:9 Aplysia sp. 5:368 Aplysilla glacialis 17:14,15 Aplysilla rosea 6:107 Aplysilla sulphurea 17:11 Aplysina fistularis 17:103 Apuleia leiocarpa 5:679,680 Arabidopsis thaliana 18:721 Arachniodes exilis 15:33 Arachniodes sporadosora 15:33

1317

Araliopsis tabouensis 2:121 Araucaria cookii 17:36 Araucaha cunninghamii 17:36 Arbacia lixula 15:104 Arbaciapunctulata 7:303 Archaster typicus 7:304-306; 15:74,84 Arctium lappa 5:497 Arcyria denudata arcyriaflavin-B from 12:366,370 arcyriaflavin-C from 12:366,370 arcyriarubin A from 12:366,370 arcyriarubin B from 12:366,372 arcyriarubin C from 12:366,372 arcyriaverdin C from 12:366,372 arcyoxepin A from 12:367,373 arcyroxepin B from 12:367,373 arcyroxindole A from 12:367,372 arcyroxocin B from 12:367,372 dihydroarcyriarubin B from 12:366,370 Arcyria denudata 5:55 Arcyria feruginea arcyriarubin C from 12:366,372 Arcyria natans arcyriacyanin A from 12:366,372 arcyriaflavin-A from 12:366,370 arcyrioxocin A from 12:367,472 dihydroarcyriacyanin A from 12:367,372 Arcyria sp. arcyrinAfrom 12:367,373 arcyrinBfrom 12:367,373 Ardeola ibis hemoglobin components of 5:837 Ardisiajaponica 13:660;17:117,127 Areca catechu arecoline from 13:660 Arelia cordota 20:690 Arenaria kansuensis 18:721 Argogorytesfargei 5:225,250,253 Argogorytes mystaceus 5:225,231,252,253 Aristolochia argentina 19:494 Aristotelia alkaloid (-)-peduncularine synthesis of 13:491,492 Aristotelia alkaloids biosynthesis of 11:278,279 nomenclature of 11:331 numbering system of 11:331 synthesis of 11:277-334 Aristotelia australasica allo-aristoteline {epi-11 -aristoteline) from 11:317 aristolasicone from 11:312 (+)-aristoserratenine from 11:293 3-e/7/-aristoserratenine from 11:293 Aristotelia fruticos a (+)-aristofruticosine from 11:324 (+)-fruticosonine from 11:278 Aristotelia serrata (-)-aristomakine from 11:301 (-)-aristomakinine from 11:301 (+)-aristoserratenine from 11:293 (+)-aristoserratine from 11:296 (-)-hobartine from 11:278

Armillaria mellea 5:289,290 Artabotrys zeylanicus dioxoaporphines of 20:480 Artemia salina 9:385,387 Artemisia abrotanum 7:205,218,240 coumarin-sesquiterpene ethers in 7:205 Artemisia absinthium 7:215,219,220,240 absinthinfrom 7:215 Artemisia annua artemisinin from 13:657;20:518 arteannuin B from 7:217 candinane derivatives from 7:217 Artemisia anomala 7:215,240 aurantimide acetate from 7:220 simiarenol from 7:218 Artemisia aragonensis (A. herb alba) 7:212 Artemisia arbuscula 7:208 arbusculone from 7:208 Artemisia argyi 7:218 simiarenol from 7:218 Artemisia aucheri 7:208,241 Artemisia austriaca 7:241 C-methylflavone m 7:207 Artemisia californica 20:4 Artemisia cantabrica 1'2\ 6,242 Artemisia capillaris 7:220,242 Artemisia carvifolia 7:206,242 Artemisia compacta 7:205,243 Artemisia douglasiana 7:203,204,217,218,243 Artemisia dracunculus 7:220,243 Artemisia feddei filifolide A from 7:208 filifolone from 7:208 Artemisiafragrans 7:208,244 Artemisia glutinosa 7:220,244 Artemisia gypsacea 7:211,245 Artemisia herba alba (A. aragonensis) 7:212,217, 7:245 Artemisia herba-alba 17:475 Artemisia hispanica elemanolide from 7:216 2a-hydroxyartemorin from 7:211 tamaulipin A from 7:211 Artemisia inculta 7:217,245 Artemisia iridentata ssp. rothrockii 7:208,252 Artemisiajudaica 7:211,216,217,246 Artemisia ketone 7:100,101,202,203,208,221;9:530, 536 Artemisia klotzchiana 7:214,246 Artemisia koidzumii 7:218,246 Artemisia laciflora 7:203,218,246 Artemisia laciniata 7:215,216,246;9:529,531,533-535 Artemisia lanata 7:214,246 Artemisia latifolia 7:219,247 Artemisia leucodes 7:215,247 Artemisia longloba 7:218,247 Artemisia ludoviciana 7:203,247 Artemisia maritima 7:217,427;13:660 Artemisia marschalliana 7:220,248 Artemisia molinieri 7:218,248 Artemisia monosperma 7:204,220,248 Artemisia moorcroftiana 9:529,530,534 Artemisiapallens 7:217,249

1318

Artemisiapallens 9:531 Artemisia palustris 7:207,220,249 Artemisia pectinata 7:214,216,249 Artemisiapersica 7:217,249 Artemisia roxburghiana 7:219,250 Artem isia rupestris 7:218,2 5 0 Artemisia rutifolia 7:215,250 Artemisia salsolodes 9:529-531,533,534 Artemisia santolina 7:212,250 Artemisia santonicum 7:212,250 Artemisia schmidtiana eudesm-11 -en-4-ols from 14:450 neointermedeol from 14:450 Artemisia selengensis 7:203,204,215,251 Artemisia sp. 7:201-263;9:529-536 Artemisia szowitziana 7:216,251 Artemisia toumefortiana 7:212,252 Artemisia umbelliformis 7:215,253 Artemisia valentina 7:213,218 Artemisia vulgaris 7:120,208,215,218,253 Artemisia xanthochroa 7:215,253 Arthrobacter globiformis 9:418 Arthrobacter simplex 9:418,427,428 Artocarpus nobilis l.l'iX Ascidia nigra 10:241 Asclepias curassavica 5:249 Asclepiasfruticosa 5:248,249 Ascobolusfurfuraceus 5:279 Asimina tiloba 9:391 Asltonia macrophylla 13:383,422 Asltonia muelleriana 13:383,399,422 Asparagopsis sandfordiana marine sterols from 9:83-85 Asparagus cochinchinensis 17:116-117,130.132 Asparagus curillus 7:427 Asparagus plumosus I'All Asparagus spec'iQS 17:130 Aspergillus acylase 1:678 Aspergillus alleaceus 20:792 Aspergillus awamori 2:322,341,353 Aspergillus brevipus 12:400 Aspergillus caespitosus 19:480 Aspergillus duricaulis 15:343,345 Aspergillusflavus 2:446;5:296;9:300;15:386,245; 18:711 Aspergillusfumigatus 5:295-298,322,326;7:65;9:300; 12:400;18:469,807,809 Aspergillus melleus 15:383 Aspergillus nidulans 5:295,296 Aspergillus niger a-L-rhamnosidase from 7:70 p-glucosides from 7:51,52,55,56,65-67 cycloisomerase from 8:296 glucoamylase from 7:62 isozyme I from 2:322,341 lactone from 8:300 Aspergillus ochraceus ochratoxins from 15:387 Aspergillus ochraceus wilhelm 15:384 Aspergillus orizae 13:304 Aspergillus oryzae 1:697,117;2:322,341;5:295; 6:551,552

Aspergillus parasiticus averufinby 11:194 Aspergillus terreus 19:168 Aspergillus sp. 5:276,278,294,301,325, 5:326,328,368,370 Aspergillus spp. 2:323;9:203,300 glucoamylase from 2:322 Aspergillus stellatus (+)-asteltoxin from 10:439 Aspergillus terreus 5:296,730;15:385 Aspergillus versicolor 18:807,809 Aspergillus wentii 7:56,64;9:300 Asphaenogaster rudis 5:226,243-245 Aspidosperma alkaloids 4:27,275,411 Aspidosperma cyclindocarpon 19:112 Aspidosperma marogravianum 1:124 Aspidosperma oblongum 1:124,125 Asteriapectinifera I'.l^il Asterias amurensis 7:286-298,303;15:44 Asterias amurensis vesicolor asterosaponin-1 from 7:287 thomasteroside A from 7:287 versicosides (A-C) from 7:287 Asteriasforbesi 7:288;15:58,69 Asterias rubens 6:151,152,156,161;7:288,294,304,306; 15:48 Asterias vulgaris 7:288,291,304;15:59 Asterinapectinifera 7:289;15:44,48,55 Astichopus multifidus 7:272,273,281 astichoposide C from 7:273 Astragalus emoryanus (-)-swainsonine from 12:313 Astragalus lentiginosis 7:11,486 Astragalus lentiginosus (-)-swainsonine from 12:313 Astragalus mister 19:118 Astragalus sp. 7:23 Astropecten aurantiacus 15:104; 15:61 Astropecten indicus 5:214;7:299 Astropecten latespinosus 7:288;15:48 Astropecten polyacanthus 7:306;18:725 Astropecten scoparilis 15:68 Atalantia ceylanica 1,5-dihydroxy-3-methoxy-10-methylacridin-9-one from 13:348,350 ll-hydroxynoracronycine from 13:348,349, 13:356 11-0-methylatalphilidine from 13:348,349 A^-methylatalphyllinine from 13:348,349 Atalantia monophylla atalphyllidine from 13:348,349 atalphylline from 13:350 atalphyllinine from 13:349 A^-methylatalphylline from 13:350 Atractylis gummifera 20:8 Atropa belladona 20:135 Atropa gQmxs 17:395 Atta cepholotes 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Atta sexdens rubropilosa 2,5-dimethyl-3-ethyl-pyrazines of 5:222

1319
Atta sex dens sex dens 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Attatexana 5:234,125 Aulacohorafemoralis chinensis 18:771 Aureobasidium pullulans 5:307,308,314 Aureobasidium sp. 5:307 Auricularia sp. 5:287,317,320 Austrocedru chilensis 19:405 Avena sativa 9:220 Avicennia alba 7:176,181,182,189,195 Avicennia germinas 7:175 Avicennia marina 7:176,180,183,184,194,195 Avicennia officinalis 7:176,181,182,189,195 Avicennia resinifera 7:193 Avicennia sp. 7:176 Avicennia tomentosa 7:189 Axinella canabina axamide-1 from 6:5 axisonitriIe-1 from 6:5 Azadirachta indica 9:293-311 ;13:644;15:384 Azomonas macrocytogenes 19:814 Azospirillum lipoferum 4:197 bartogenic acid from 7:132 19-e/7/-bartogenic acid from 7:132 Basidiomycetes 9:220,317 Begonia plebeha 19:764 Betemnitella species 13:330 Berberis cell cultures j atorrhizine from 11:201 -204 Berberis koetineana 11:202 Berberis sp. 7:88 berberine from 7:88 Berberis stolomifera 20:292 Berberis vulgaris 13:660 Beta vulgaris 15:3;20:721,731,740 Betula pendula 17:361,366 B etui a platyphylla 17:361 Betula species 17:358.361 Betulaceae 17:358,359,364,366 Bicyrtes ventralis 5:223,224,253 Biflustra perfragilis 17:81,89,91 Bifurcaria bifurcata 18:713 Biomphalaria glabrata 7:432-435 Bipolaris sorokiniana 4:647;9:238 Bixaorellana 20:721,733,59 Blaberus discoidalis 9:488,489 Blastocladiella emersonii 5:276 Blastomyces dermatiditis 5:307 Blastomyces sp. 5:325,328 Blattella germanica 6:53;9:488,489 Blatta orientalis 9:488,489 Bledius mandibularis 4:494 Bledius spectabilis 4:494 Bleekeria vitiensis 1:125 Blighia welwitschii 15:205 Blumea malcomii 5:678 Bohadschia argus bivittoside B,C from 7:270 Bohadschia bivittata bivittosides A, B, C and D from 15:91 Bohadschia graffei holothurins A,B from 7:269 holothurin A2 from 7:269 Bohadschia marmorata bivittoside B,C from 7:270 Bohadschia tenuissima bivittoside B,C from 7:270 Bohadschia vitensis bivittoside B,C from 7:270 Bolbostemma paniculatum (tu-bei-Mu) tubeimoside I from 7:143,144 Boletinus cavipes 20:26 Boletus edulis 5:289 Bombyx mori 5:832;19:647 Borreria capitata borrecarpin from 11:278 Bothriochloa bladhi eudesm-1 l-en-4-ols from 14:450 (+)-intermedeol from 14:450 neointermedeol from 14:450 Bothriochloa glabra eudesm-1 l-en-4-ols from 14:450 (+)-intermedeol from 14:450 neointermedeol from 14:450

Babylonia japonica 11:724 Baccharis articulata 15:22 Baccharis gaudichaudiana arabinoside gaudichaudioside A from 15:21 Baccharis timer a lAll Bacillus antharacis 12:400 Bacillus aurantinus 5:601 Bacillus cereus 7:413 Bacillus megaterium 10:585;12:104 Bacillus pumilis 7:70,308,390 Bacillus sp.TA 12:104 Bacillus sp. 12:103 Bacillus subtilis 5:302,304,368,418,308,353;8:353; 10:117,104,400,345,692,290,556,559;18:778 Bacillus thiaminolyticus baciphelacin from 15:390 Bacterium pseudomonas 9:322 Bacteroides fragilis 14:107 Bai-yun-shen baiyuoside from 1:666 Balanites aegyptiaca 7:426 Balanophora japonica balanophonin from 20:642 Balsamodendron mukul 5:695 Banksia grandis 19:246 Barbilophzia hatcheri 5:730 Barbilophzia lycopodioides 5:730 Barringtonia acutangula barrigenic acid from 7:132 barringtonic acid from 7:132 barrinic acid from 7:132 tangulic acid from 7:132 Barringtonia racemosa barringtogenic acid from 7:132 Barringtonia sp. triterpenes of 7:132,133 Barringtonia speciosa anhydrobartogenic acid from 7:132

1320

Bothhochloa grasses intermedeol from 14:450,451 neointermedeol from 14:450,451 Bothriochloa imculpta eudesm-1 l-en-4-ols from 14:450 (+)-intermedeol from 14:450 neointermedeol from 14:450 Bothriochloa intermedia eudesm-1 l-en-4-ols from 14:449- 451 intermedeol from 14:450,451 neointermedeol from 14:450,451 Botryotiniafuckeliana 12:400 Botrytis 4:246 Botrytis cinerea 5:598 Botrytisfabae 2:434 Bouvardia ternifolia bouvardins from 10:640 Brachyponera sennaarensis 5:224,225,254 Brackenridgea zanguebarica 7:408 Brassica compestris L. 19:246 Brassica napus 18:495,498;19:245 Bredius mandebularis 1:684 Bredius spectabilis 1:684 Brettanomyces anomalus 5:283 Brettanomyces bruxellensis 5:283 Brettanomyces dublinensis 5:283 Brettanomycesmyces lambicus 5:283 Brevibacterium ammoniagenes 20:32 Brevibacterium divaricatum 6:385 Brickellia veronicaefolia 5:680 Brucea antidysenterica quassinoids from 7:374-376 Brucea javanica bruceoside-A from 7:371 bruceoside-B from 7:377 quassinoids from 7:377-379 Brucea sumatorana 7:391 Bruguiera conjugata 7:193,194 Bruguiera cylindrica 7:176,193,194 Bruguiera exaristata 7:191 Bruguiera gymorhiza 7:176,180-182,188,195 Bruguieraparviflora 7:180,195 Bruguiera sexangula 7:176,191 Bruguiera sp. 7:176 Bryonia alba 20:13 Bryonia dioica 15:24;20:13 Bryum argenteum 2:277 Buddleja davaidii buddlenol A from 20:644 Bufo regularis 2:310,804 Bugula dentata 17:88 Bugula neritina 5:394,395,153,75,77,89,92, 18:715,716,573-574,576 Bugula trubinata 17:102 Bugula turrita 17:80 Bugularia dissimilis 17:95,101 Bulinus 7:426,432 Bulinus globosus 7:432,434 Bullerasp. 5:291 Bupalus piniarius 4:566 Bupleurum fruticosum 17:117,127 Bursaphelenchus lignicolus 12:398

Bursera ariensis 17:317 Bursera m icrophylla 17:330 Bursera schlechtendalii 18:556 Burseraceae 18:558;17:370 Buxus alkaloids 2:175,205 Buxus papilosa 2:175

Cacaliahastata 19:149 Caesalpina braziliensis 19:776 Caesalpinia pulcheriime 20:475 Callinectes sapidus 19:647,672 Camellia sinensis 20:735 Candida albicans 19:578;20:712 Candida ytast 20:868 Candida lactom 20:474 Cannabis sativa as an intoxicant 19:186 Cantharellus cinnabarinus 20:721 Capsicum annuum 20:586 Capsicum frutescens 20:135 Carcinus maenas 19:628 Carissa edulis 20:619 Cassia leptophylla 20:486,487 Castanea crenata 19:246 Catharanthus roseus 19:246 Celastruspaniculatus 20:521 Celuxpipens 19:481 Cephalotaxus species 19:141 Charybdis japonica 62)1 Chenopodium ambrosioides 20:12 Chenopodium anthelminticum 20:12 Chiloscyphus rivularis 20:472 Chiococca alba 175 Chrysanthemum golden 20:246 Cinachyra sp. 19:581 Cistrus hirusutum 19:246 Citrullus colocynthis 20:13 Cladosporium herbarum 20:245 Clematis hexapetala 19:125 Clematis sinensis 20:539,540 Clerodendron inerme 20:539,540 Clitocybe acrom elalga 19:163 Clivia miniata 20:351 Clostridiumformicoaceticum 20:821,824,861 -862,867, 869,870,871,873-879,881 Clostridium kluyveri 20:821, 824,831,834 Clostridium thermoaceticum 20:821,824,861-863,867, 869,870,871 Clostridium tyrobutyricum 20:821, 824,829,830,834839,863,873-877 Coleusforskohlii 19:137 Cortex eucommia 20:646 Coryneb acterium poinsettiae 20:594 Crescentia cujeta fiiranoaphthoquinones from 20:494 Crinum oliganthum 20:234 mesembrenol from 20:234 Crotalaria species 19:499 Croton tiglium 20:19 Cryptocarya caloneura 19:481 Cryptolestes ferrugineus 19:154

1321

Cryptomeriajaponica 19:246 Cadabafarinosa sesquiterpenes from 9:64,65 Cadlina luteomarginata 9:6 Caesalpinia sappan 5:17 Calderiella species macrocyclic lipids from 11:464 Galeaprunifolia 5:728 Calendula arvensis 17:126 Calendula officinalis lutein from 7:361 Callosobruclus analis 9:299 Calomyrmex sp. 5:223,224,230,253 Caloscyphafulgens p,y-carotene from 7:338 Calpurina aurea I'All Calyx nicaeensis calysterol from 9:38 dihydrocalysterol from 9:37,44 (237?,24/?)-23,24-methylenecholesterol from 9:37 nicasterol from 9:37 Calyx podatypa 9:38,45 Campnospermum auriculata 9:323 Candida albicans 2:422,428,438-440,292,5:323,324, 342,356,369,282,400,233 ;7:282 Candida bogoriensis 5:294 Candida curvata 5:292 Candida cylindracea 12:337;18:429 Candida cylindracea lipase (CCL) 1:658,55,57 Candida guillermondii 2:422 Candida humicola 5:292 Candida krusei 12:400 Candida lipolytica 5:292,308 Candida lusitana 5:292 Candida lusitaniae 5:283 Candida obtusas 5:283,292 Candidaparapsilosis 5:292,323,324 Candida patens 2:441 Candida pseudotropicalis 12:400 Candida rugosa 1:694,306 Candida sp. 5:291,292,328 Candida tropicalis 2:422,400 Candida utilis 7:69,302,235 Canella winter ana I'AAl Cannabis I'.l Cantharellus cibarius 5:289 Capnella imbricata A^^'^^-capnellene from 13:34 capnellanes from 6:42 precapnelladiene from 6:33 Capparis decidua alkaloids from 9:73-75,77 Capraria biflora 15:259 Capsicum annum 13:320 Capsicum sp. capsaicin from 7:93 Caralluma tuberculata saponins from 5:212;9:62-64 Carapaabovaa 7:189 Carausius morosus 9:492 Cardwellia sublimis 9:320 Carpinus cor data 17:369 Carpinus species 17:369

Carthamus lanatus eudesm-1 l-en-4-ols from 14:450 intermedeol from 14:450,451 Caryopteris clandonensis 4:612 Cassia siamea 1:174,3 85 Cassine balae (Elaeodendron balae) S:1A2),1AAJA1; 7:149,150 friedo-olenenes from 7:149,150 triterpene quinone methides from 7:149,150 Cassipourea gerrardii 7:192 Cassipourea gummiflura 7:192 Castanopsis saponins 15:191 Castanospermine australe australine from 10:567 Castanospermum austale (+)-6-e/7/-castanosperime from 12:342,343 (+)-castanospermine from 11:267 (15,65,7/?,8^,8a/?)-tetrahydroxyindolizidinefrom 12:332 6-e/7/-castanospermine from 7:13 australine from 7:13 castanospermine from 12:332 Casuarianjunghuhniana 17:371 Casuarianaceae 17:371 Catharanthus roseus alkaloid production 2:370-391 alkaloids of 7:416 catharanthine from 13:663;14:855 growth inhibitory activity of 7:416 leurosine from 14:860 vinblastine from 8:283;14:805 vincristine from 8:283;14:805 vindoline from 14:805 Caulerpa racemosa 18:689,714 Caulerpalean algae 18:688 Caulocyctis cephalornithos 15:386 Cecropia ]\xwQm\Q hormone synthesis of 3:271 Celastrjus 18:741,753 Celastrus angulatus 18:771 Celastruspaniculatus S\1A?),1AA,1A1 Cellcfria pilosa 17:95,101 Cellaria species 17:89,92 Cellulomonas dehydrogenans decapenoxanthin from 7:69 Centrolobium paraense 17:367 Centrolobium robustum 17:367 Centrolobium sclerophyllum 11:367 Centrolobium species 17:358,366 Centrolobium tomentosum 17:367 Cephalodiscus gilchristi 18:875,876,901,902 Cephalosporium acremonium 11:211,619 Cephalosporium caerulens 5:613 Cephalothrix linearis 18:725 Ceratitis capitata 2,5-dimethyl-3-ethyl-pyrazines of 5:223 Ceratocystis brunnea 5:306 Ceratocystisfimbrata 5:305,306,351 Ceratocystis minor 15:385 Ceratocystis paradoxa 5:3 06,3 07 Ceratocystis sp. 5:296,305,309,325 Ceratocystis stenocerus 5:305

1322

Ceratocystis ulmi 5:305 Cerbera mangmas 7:176 Cerbera odollum 7:195 Cercospora beticola 15:351 Cercospora taiwanensis 15:383 Cereale secale 9:328 Cerebrotendinous xanthomatosis 17:207 Ceriops decentra 7:192 Ceriops sp. 7:176 Ceriops tagal 7:176,180,195 Cerotoma trifurcata 9:392 Cetraria islandica 5:309,310,322 Cetraria richardsonii 5:310,311 Chaetomium 5:730,203 Chara globularis charamin from 18:677 3-azelidinol from 18:677 4-azoniaspiro [3,3] heptane-2,6-diol 18:677 Charania lampas glycosidase of 7:286,288 Charonia lampas 15:58,88 Charonia sauliae 7:306,724 Chartella papyracea 17:85,86,89,92,692 Chelaner antarcticus pyrrolidine venom alkaloids in 6:436 pyrrolizidine alkaloids in 6:445 Chelynotus semperi 17:23 Chenopodium album 7:398 Chenopodium quinoe 9:402 Chilomonas Paramecium 2:294 Chiloscyphuspolyanthos 2:278,279;18:609 Chlamydia trachomatis 13:183 Chloropseudomonas ethylica 7:363 Chondodendrum tomentosum 13:631 Chondria armata 17:21 Chondria oppositiclada 6:40 cycloeudesmol from 6:40 Chondrilla sp. 18:718 Chondrococcus hornemanni 5:343 Chondrosia collectrix 18:719 Choriaster granulatus 7:299 Chromatogaster scutellaris cenom 6:455-458 Chromodoris cavae 9:4,13 Chromodoris funarea 17:9,10 Chromodoris lachii 17:13 Chromodoris macfarlandi 17:11 Chromodoris maridadilus 6:69 Chromodoris norrisi 17:12 Chromodoris species 17:12,14 Chrysanthemum frutescens 9:317 Chrysanthemum sp. 7:427 Chrysochromulina species 6:135 Chrysomma sinensis hemoglobin components of 5:837 Chrysoplenium pseudofauriei 5:678 Chrysosplenium americanum 5:682 Chrysospleniumflagelliferum 5:682 Chrysosplenium grayanum 5:682 Chukrasia tabularis 9:105 Cicer arietinum 18:719 Cinnamomm osmophloeum 15:29 Cinnamomum sieboldii 15:33

Cinnamonium camphola (-)-dimethylmatairesinol 18:558 Cioclapta species 17:16 Ciona intestinalis 5:405,408,249 Citeromyces matritensis 5:283 Citeromyces sp. 5:280 Citrullus colocynthis 5:750 Citrus buxifolia atalfoline from 13:350 Citrus aurantium 15:5 Citrus decumna 13:348,349 Citrus depressa citracridones I,II from 13:348 citpressine I from 13: Citrus grandis baiyumine A from 13:348,349 baiyumine B from 13:350 butanine from 13:350 citpressin II from 13:350 grandisines I,II from 13:350 grandisinine from 13:350 honyumine from 13:348,349 prenyl-citpressine from 13:350 Citrus junos junosidine from 13:348,349 Citrus natsudaidai natsucitrines I,II from 13:350 Citrus paradisi eudesm-1 l-en-4-ols from 14:450 (+)-intermedeol from 14:450 Citrus sinensis citbrasine from 13:350 citrusinines I,II from 13:348,350 Citrus sp. 5:651 Citrus unshiu 18:682 Cladonia alpestris 5:310,313 Cladonia confusa 5:310,313 Cladonia crispata 5:310 Cladonia mitis 5:310 Cladonia rangiferina 5:310 Cladonia sp. 5:310 Cladonia squamosa 5:310 Cladophorafascicularis 5:367 Cladosporin cladosporiodes 11:193;15:386,193 Cladosporium cucumerium 7:406,409,411,413;15:64, 415,421,433,64 Cladosporium herbarum 5:302 Cladosporium sp. 5:301,325,328,370 Cladosporium suaveolens 13:309-311,313,315 Cladosporium wemeckii 5:301 Cladosporum herbanum 7:119 Cladrastis lutea 5:678,683 Clathapalustris 7:427 Clathria pyram ida 6:351 Clausena harmandiana 9:400 Clausena heptaphylla 2:118 Clausena indica 2:118 Clausena pentaphylla 2:118 Clavelina picta 10:249 Claviceps eurotium 9:203 Clavicepsfusiformis 5:278 Claviceps purpurea 13:631 Claviceps sp. 5:278;11:200

1323

Clavicipitales 9:203 Clavularia inflata (+)-12-acetoxysinularene from 6:77 Cleistopholis patens 2:340 Cleome icosandra 18:28 Cleome viscosa 18:28 Clerodendrum uncinatum 7:408,417,423 Clionacelata 5:411 Clitocybe geotropa 18:813,814 Clitocybe nebularis 18:813,814 Clostridium 13:303 Clostridium difficile 5:601 Clostridium perfringens 5:601,71,81,86,87,16:108 Clostridium tetanomorphim 9:598,601 Clostridium themoaceticum 9:606 Cocculus spp. 3:456,478 Cocculus trilobus 3:488 Colaphellus loweringi 18:771 Colaptes auantus 5:836 Colchicum autumnale 5:46 Coleus forskolii forskoline from 13:659 Coleus sp. 7:96,118 Collectotrichum lagenarium 16:302 Colletotrichum dematium 9:230,238,239 Colletotrichum gloeosporiodes f ^p.yussiaea 9:288, 229,231-235,238-241 Colletotrichum gloeosporioides (Glomerella cingulaa) 9:228,230,232,238-240 Colletotrichum gloeosporioides f sp. aeschynomene 9:230,238,239 Colletotrichum graminicola 9:230,238,239 Colletotrichum lagenarium 12:400 Colletotrichum lindemuthianum 9:230,239 Colletotrichum malvalum 9:230,231,238,239 Colletotrichum species 9:228,230,239,247 Collisella limatula 17:26 Colocynthis vulgris 5:743,744,750 Comantheria briareus 7:266 Comantheria perplexa 7:266 polyketide sulfates of 7:266 Comanthula pectinata polyketide sulfates of 7:266 Comanthus parvicirrus 7:266 Commiphora mukul 5:695,700,701 Conocephalum conicum 2:273,277,278;9:249 Conopeum seuratum 17:79 Convolvulus arvensis 15:341 Convorvolus microphyllus 13:312 Conyza odentophylla (Pluchea arguta) sesquiterpenes from 9:65-68 Coprinus mcrorhizus var. microsporus 5:288 Copsychus saularis hemoglobin components of 5:837 Cora islandica 5:313 Corapavonia 5:313 Cora silandica synthesis of 5:128 Coracias benghulensis hemoglobin components of 5:837 Coracina novachollandiae 5:837 hemoglobin components of 5:837

Cor chorus acutangulus 18:650 23-hydroxylongispinogenin from 18:650 3 p, 16p,23,28-tetrahydroxyolean-12-ene from 18:650 Cordia goetzei 7:408,409 Cordiceps ophioglossoides 5:279,318,320 Cordiceps sinensis 5:279 Coreopsis parvifolia 5:800 Coriaria nepalensis 13:311 Cornitermes ovatus 15:384 Cornitermes pugnax 15:384 Cornus florida 1:427 Corona virus 5:360 Corpora cardiaca 2:90,93,94,99,106,112;9:487,490 Corticium caeruleum 18:712 Corvus splendens 5:837 Corymbellus aureus 6:135 Corynebacterium bovis 12:400 Corynebacterium glutammicum 13:320 Corynebacterium poinsettiae 7:357 Cosciansterias tenuispina cosicinasteroside D from 7:298 Coscinasterias tenuispina 15:46,51,52 Costaticella hasta harman from 18:726 pavettine from 18:726 Costaticella hastata 17:90 Crataeva nurvals 5:209 Crematogaster ants 6:454,455 Crematogaster deformis mellein 15:383 Crematogaster lineolata 6:454 Crematogaster scutellaris 6:422,453,455 Cribricellina cribraria 17:79,89-90 Cribrocalina vasculum dihydrocalysterol from 9:37 petrosterol from 9:37 Crinum asiaticum 18:687 Crithidia deanei polysaccharides in 2:296-298 Crithidiafasciculata 2:295-297,577 Crithidia guilhermei 18:791,792 Crithidia harmosa 2:298 Crithidia luciliae 2:298,791,792 Crithidia oncopelti 791 Crossasterpapposa 7:298,299;15:61,69 Crossopteryxfebrifuga 7:417,425 Croton 9:265 Croton macrostachys 4:612 Croton tiglium 12:233 Crypthecodinium cohnii 9:47 Cryptocarya pleurosperma 1:365 Cryptococcus albidus 4-thioxylobiose from 8:336,352 Cryptococcus albidus 5:292,328 Cryptococcusflavescens 5:294 Cryptococcus laurentii 5:292,294,328 Cryptococcus neoformans 2:428,446,292,322,5:326328,400,408 Cryptococcus sp. 5:291,292,294,328 Cryptolepine 5:751,752 Cryptolepis sanguinolenta 5:751 Cryptolestesferrugineus 8:227 Cryptomeriajaponica 2:402

1324

Cubitermes sp defence secretion of 8:220 Cubitermes umbratus cubitene from 8:230 Cuculus micropterus hemoglobin components of 5:837 Cucumaria echinata 15:94 Cucumariafraudatrix cucumariosides Gi, Ci and C2 from 15:87,92 Cucumaria frondos a frondogenin from 7:277 Cucumaria japonica cucumarioside A2-2 from 7:275;15:87 Cucumaria lefevrei 15:92 Culcia novaeguinea 7:298,15:69 Culex pipiens fatigans 3:157 Cunninghamella echinulata 20:792 Cunninghamella elegans 20:214 Curculigo Iat ifo Ha 15:36 Curcuma longa 8:52,13:660,17:363,373,377,379, 20:734 CwrcMwa species 17:358 Curcuma tinctoria 17:357 Curcuma xanthorrhiza 17:3 64 Curvularia lunata 9:412,417,418 Cussonia barteri I'All Cussonia spicata 7:427,435 Cybister tripunctatus 5:700 Cyclea atjehensis 20:552 Cyclea barbata 20:522 Cymbopogon flexuosus eudesm-1 l-en-4-ols from 14:450 intermedeol from 14:450,451 Cynara scholaris 13:660 Cystodytes dellechiajei 10:250 Cystophora torulosa 9:322 Cystoseira balaerica 20:35 Cystoseira crinita 20:25,28,35 Cystoseira elegans 18:712,713 Cystoseira spinosa (var. squarrosa) 9:321 Cytisus scoparius (-)-3,13a-dihydroxylupanine from 15:525 Cyttaria hariotti 5:278

Dacrydium cuprassinum 13:19-22 Dacrydium cupressinum 3:117 Dacrydium intermedium 20:619 Dactylopius coccus 20:734 Dacus cucumis 2,5-dimethyl-3-,6-dimetyl pyrazines of 5:225 Dacus cucurbitae 2,5-dimethyl-3-methylpyrazines of 5:225 methylpyrazines of 5:222 Dacus dorsalis 2,5-dimethy 1-3-methylpyrazines of 5:222 Dacus occfipitalis 2,5-dimethyl-3-ethylpyrazines of 5:222,223 Dacus oleae 4:571,222;14:521,19:131 Dam aliscus dorcas 19:122 Danaus gilippus danaidonefrom 8:223

Daphna genkwa yuanhuacine from 13:660 Daphne mezereum 20:22 Dasytricha 2:294 Datisca cannabina 5:678,682 Datura gtmxs 17:395 Datura stramonium 20:135 Datura tatura daturataturin A and B from 20:194 Datura innoxia 11:204 Daucus carota 5:721,730 Debaryomyces castelli 5:283 Debaryomyces hansenii 5:282,283 Debaryomyces kloeckeri 5:283 Debaryomyces phaffi 5:283 Debaryomyces subglobosus 5:283 Delesseria sanguinea 4:712 Delphinium spQc'iQS 20:19 Dendrobates histrionicus (+)-indolizidine from 11:294 Dendrobates pumilio Panamanian population of 19:4 pumiliotoxin B from 12:294 Dendrobates speciosus A^-oxides of allopumiliotoxin 267 A from 12:294 iV-oxides of pumiliotoxin 323 A from 12:294 Dendrobates tricolor pumiliotoxin 251 D from 12:294 Dendrobatid alkaloids synthesis of 11:244-267 biology of 10:3 chemistry of 19:3 pharmacology of 19:3 synthesis of 19:3-88 Dendrobatid speciousus mdolizidines from 11:266 Dendrobium crepidatum crepidamine from 12:285 crepidinefrom 12:285 dendrocrepine from 12:285 Dendrocotonus brevicomis exo-brevicomin from 11:413 Dendrodoa grossularia 5:412;10:245 Dendrodoris grandiflora 17:28 Dendrodoris limbata 17:28 Dendropanax trifidus dendropanoxide from 2:98-103 Dendryphiella salina 10:152 Dentroctonus brevicomin 19:126 Dermasterias imbricata 2,4-di-0-methyl-(3-D-quinovopyranosyl-(l2)-5O- sulphate-p-D-fticofiiranosyl from 15:66 imbricatine from 7:306 Derris araripensis 7:177,193 Derrisnicou 7:177,193 Derris sericea 7:177,193 Derris trifoliata 7:176-178 Derris ulignosa 7:181,182 Derris urucu 7:177,193 Desmia sp. (red alga) 5:343

1325
Dianthus sp. acylated anthocyanins 5:659 malic acid in 5:659 Diaperoecia californica \1.90,92 Diaporte helianthi 15:345 Dichroafebrifuga 20:522 Dictydiaethalium plumbeum arcyriaflavin-D from 12:366,370 Dictyoceratida 6:107,111 ;19:568 Dictyodendrilla cavernosa 18:718 Dictyopteris divaricata dictyopterone from 6:16 P-dictyopterol from 6:16,18 (-)-zonarene from 6:15 Dictyopteris undulata isozonarol from 6:17 zonarolfrom 6:17 Dictyopteris zonaroides (-)-zonarene from 6:15 Dictyostelium 9:220 Dictyostelium discoideum 5:275,384 Dictyota 9:78,79,86 Dictyota acutiloba (-)-dictyolene from 6:27 Dictyota crenulata 5:370,70;6:70 Dictyota dichotoma 9:86,88 Dictyota divaricata 6:52 Dictyota indicia 9:78-81 Dictyota linearis (+)-amijitienol from 6:52 dolasta-1 (15)-7,9-trien-14-olfrom 6:52 isoamijiol from 6:53 Dictyota spinulosa 5:370 Dictyotaceae dolastanes from 6:52 marine diterpenes from 6:52 Didemnum chartcium 17:22 Didemnum species 10:244 Didemnum voeltzkowi 10:244 Digitalis 2:402,439 Digitalis lanata 15:367,375,377 Digitalis purpurea steroidal lactones from 14:439 digitoxin from 5:505 Dinophysis acuminata 5:384 Dinophysis fortii 17:20 Dinoponera grandis 5:223,224,229,254 Diospyros 7:406,423 . Diospyros abssinica 7:417 Diospyros canaiculata 2:224 Diospyros kaki Thunb 19:246 Diospyros maritima 2:231,22,754 Diospyros usambarensis 7:427,435 Diospyros zombensis I'A 17,427,429 Diphylleia cymosa 5:492 Diplodia maydis 4:600 synthesis of 4:230 Diplophyllum albicans 2:278 Diplorhoptrum alkaloids 6:422,423 Dipodascus sp. 12:337 Distemonanthus benthamianus 5:676-681 Distolasteria nipon 7:299;15:55 Dodonea sdt^onms 15:191 Dodonea viscosa 7:139,427 Dolabella auricularia 19:557,19:601 Dolabella auricularia 4:87,420,421 Dolichodenis clarkii 5:224,253 Dolichos lablab L 19:247 Dolichos kilimandscharicus 7:432,433 Dolichos marginata ssp.erecta 7:413,414 Dracaena loureiri 5:17 Drechslera gigantea 6:555 Drimys species 4:404 Drimys winteriYoYsX 4:418 Drosophila melanogaster 18:698 Duasmodactyla kurilensis 7:279,91,153 Duboisia gQnus 17:395 Duguetia panamensis 9:402 Dunalia austral is 20:191,194 Dysideaavara 5:433,438 Dysideafragilis nakafiiran-9 from 6:69 (+)-upial from 6:65 Dysidea genus 17:10,11 Dysidea herbacea 4:404 (22/?,23/?)-22,23-methylene cholesterol from 9:37 Dysoxylum lenticellare 6:487 Dysoxylum spp 3:456 Dytiscus marginalis 5:700

E. coli 18:921 -co//BFrATPase 10:439 Ecbeallium elaterium 20:13 Echinaster brasiliensis 15:55 Echinaster luzonicus 7:294 Echinaster sepositus 7:294,298;15:59 Echinocystis macrocarpa 7:330 Echinophora lamellosa echinolactones A,B from 7:136 glycyrrhetic acid from 7:136 smilagenin from 7:136 Echium piantagineum 19:247 Eciton hamatum 5:250 Ecklonia stolonifera 19:553 Egregia menziessi 19:554 Ehrlich arcitis 20:245 Eimeria tenella 17:376 Ekebergia senegalensis 2:117,2:118,120,2:269 Elaeocarpus alkaloids general synthetic route to 1:283,284 biogenesis of 12:292 Elaeodendron balae (Cassine balae) 149,150 Elaeodendron glaucum 5:757,152 Elaodendrum 18:741 Eldana saccharina 11:414 eldanolide from 3:168;11:414 synthesis of 3:168 Eleutherococcus senticosus Harms (Acanthopanax senticosus) 5:505,514,515,521,523,524,544 Elsinoe leucospila 5:278 Empidonnax hammondii 5:836 Endomyces spp. 2:323 Endomycopsisfibuliger 5:280,282 Engelhardtia chrysolepis 15:31

1326

Entada saponins 15:191,214 Entamoeba histolytica 6:485,398 Entandrophragma 9:102 Entandrophragma utile 9:95 Enterobacter cloacae 12:63 Enterococcus faecalis 10:117,400,20:712 Epeolus cruciger 5:223,224,231,253 Epeolus variegatus 5:223,224,231,253 Ephedra sinica Stapf 5:505 Epilachna varibestis 7:396 Epipedobates tricolor 19:66,19:146 Eremanthus glomerulatus I'All Eremmophla aureonontata 5:223,225,253 Eremophila 15:225-282 Eremophila abietina 15:227 Eremophila alternifolia 15:225,232 Eremophila caerulea (+)-fenchone from 15:227 oleanolic acid from 15:281 ursolic acid from 15:281 Eremophila clarkei 15:253 Eremophila cuneifolia 15:227,248 Eremophila dalyana 15:225,227 Eremophila decipiens 15:263 Eremophila dempsteri 15:227,254 Eremophila drummondii (+)-calamenene from 15:244 serrulatane from 15:259 (+)-spathulenol from 15:248 Eremophila duttonii 15:225 Eremophila elderi 15:225 Eremophila exilifolia 15:252 Eremophila foliosissima 15:255 Eremophila fraserii 15:248,252,271 Eremophila freelingii eremolactone from 15:252,271 freelingyne from 15:233 Eremophila georgei 15:269,271 Eremophila gilessi 15:225 Eremophila g/utinosa 15:252 Eremophila granitica 15:254 Eremophila inflate 15:229 Eremophila interstans 15:245,247 Eremophila latrobei 15:229,232,258 biflorinfrom 15:258 Eremophila longifolia 15:225 Eremophila maculata 15:226,229 Eremophila miniata 15:229 Eremophila mitchelli 15:226,281 Eremophila paisley 15:248 Eremophila petrophila 15:252 Eremophila platycalyx 15:281 Eremophila racemosa (+)-spathuIenol from 15:248 Eremophila rotundifolia freelingyne from 15:233 Eremophila scoparia 15:227,232,244 Eremophila serrulata 15:257,259 Eremophila spp. (+)-isoeremo lactone 8:423 Eremophila virgata 15:245 Eremophila viscida 15:260 Eriobotryajaponica 17:115,118-119;19:247

Erythrina bur ana 20:496 Ervatamia coronaria 5:135,136,158,171,172 Erwinia herbicola 17:637 Envinia species 4:434 Erythrina alkaloids 3:455-493 Erythrina arborescens synthesis of 3:455-493 Erythrina berteroana I'AXl Erythrina crysta - galli L. 3:476 Erythrina lithosperma 3:479 Erythrina ty^Q 11:229 rv//2/'o compounds 12:415,416 Escherichia coli 4:433;5:367,429,434;7:39,44,46, 50,52,54;9:293,308,537,592,593,596,603,604,606; 8:102;11:182,214;12:63,95-109;13:157,162,164,261, 262,283;17:378;18:709,722,727;18:921;19:601; 20:712 Escherichia coli BFi-ATPase 10:439 Eubacterium saburreum 4:195 Eucalyptus calophylla 19:247 Eucalyptus marinata 19:247 Eucalyptus spathulata (+)-spathulenol from 15:248 Eucommia ulmoides oliv. 5:505,521-525,530,544 Eucommia ulmoides 20:613,647-648 Eudistoma cf. rigid 10:247 Eudistoma glaucus 5:353 Eudistoma olivaceum 5:417,418,246,100 Eudistoma sp. 12:366,370,10:247 Eudynamis scolopacea 5:837 Euginia uniflora 14:450 Euglena viridis 6:150 Eumenesfl-aternus 5:224,225,232,253 Eumycota 9:202 Eunicea spQc'iQS 10:9 Eunicia succinea 10:7 Eunicea tourneforti 20:492 Euodynrusfiiscus 5:224,253 Euonomynus 18:741 Eupatorium adenophorum 5:28 Eupatorium maculatum 20:145 Eupatorium trapezoideum 15:247 Eupentactafi-audatrise (Cucumariafl-audatrix) 7/275,276 Euphorbia 12:233,234 Euphorbia acaulis 9:265,267,288 Euphorbia caudicifolia 9:265 Euphorbia fidjiana 15:385 Euphorbiafidjiana 9:265-292 Euphorbia helioscopia 9:265 Euphorbiajolkinii 9:265 Euphorbia lagascae 9:391 Euphorbia laterifolia 2:262 Euphorbia milii 5:678 Euphorbia nerifolia 7:152-154 Euphorbiapallasii 9:265,288 Euphorbia poisonii 2:261 Euphorbia species 9:265,267,20:19 Euphorbia triaculeata 9:265 Euplaxaura erecta 14:315 Euponerasp. 5:224 Euretaster insignis 7:304,94,45

1327
Europhthalma alkaloids 6:422-434 Europium sp. 5:325 Eurycomma longifolia 7:393 Euryspongia species 4:404 Everniaprunastri 5:310-312,322 Excoecaha agalloccha 7:176-178,180,183,195 Fusarium crookwellense 13:526 fiisarin C from 13:526 Fusarium crookwellese 9:205 Fusarium culmorum 13:519,520,526 Fusarium culmorum 4:648,250,204-208,212 Fusarium equisete 9:204 Fusarium equiseti 13:543,545 Fusarium graminearum 9:204-208,216,524,543 Fusarium larvarum 15:381,386 Fusarium lini 18:807 monohexosylceramides from 18:807 Fusarium merismoides 9:204 Fusarium moniliforme 9:203-205,214,215;13:524 Fusarium moniliforms 13:524,526,530 Fusarium nygamai 13:530 Fusarium oxysporum 9:204 Fusarium oxysporum f. sp. cucumerinum 9:238 Fusarium poae 9:204,314,315,526 Fusarium proliferatum 13:530 Fusarium roseum 13:543 Fusarium sambucinum 13:526,543 Fusarium sambucinum 9:204 Fusarium semitectum 9:204 Fusarium solani 9:204 monohexosylceramides from 18:807 Fusarium species 6:219-259,201-218 Fusarium sporotrichioides 13:526 Fusarium sporotrichioides 6:247,204,205,208-213 Fusarium subglutinans 13:530 Fusarium toxins 9:201-208 Fusarium tricinctum 9:205 Fusicoccum amygdali 15:385 Fusobacterium nucleatum 4:195

Fagar a macrophylla 7:427 Fascaplysinopsis sp. 5:411 Fasciospongia rimosa 19:568 Ferula akitschkensis 5:723 Ferula communis subs.communis 8:57;5:723 Ferula elaeochytris 5:723 Ferula galbaniflua 19:157-158 Ferulajaeschkeana 5:725 Ferula karatavika 1:660 Ferula lancerottensis 5:725,727 Ferula lapidosa 5:723 Ferula linkii 5:725,734 Ferula pallida 5:723 Ferula rubicaulis 19:158 Ferula sp. 5:721,732 Ferula tenuisecta 5:723 Ferula tingitana 5:723 Ficus costata 2:231 Ficus diversiformis 2:231 F/CW5 elastica 8:66 Ficus fergusoni 2:231 Ficus pyrifolia 20:522 Flammulina velutipes 5:289 Flavobacter dehydrogenans 9:417,418 Flavobacterium sp. 7:330,336,341-345,347-351,358, 360,363 Flexibacter elegans 9:323 Flustrafoliacea 17:80,85,87,102,103;18:689,692, 693,708,725 Flustra papyracea 17:86 Foeniculum vulgare 5:473 Fogs grandifolia 5:472 Forsythia suspensa warfortunei 5:475 Forsythia intermedia 5:489-491,492,494 Forsythia mandshurica Rupr. \ar. Japonica Maxim 5:505,514-516,520,523-525,531 Forsythia sp. 5:511-513,521 Forsythia suspensa 5:489,506,522,592,616 Forsythia viridissima Lindley 5:505,506,514,522 Fraxinusjaponica Blume 5:505,514,515,520,521,523525,531 Fraxinus rhyncehophyllus 13:660 Fromia monilis 15:60 Frullania dilatata 2:280,607 Frullania nisquallensis 2:280,471 Frullania tamarisci 2:278,280;9:254;18:607,614,623 Fulica atra 5:837 FMWCO oreganus 5:836 Fusarium 13:519,524-529 Fusarium acuminatum 13:535 Fusarium acuminatum 9:204,213 Fusarium avenaceum 13:526,535 Fusarium avenaceum 9:204,205,213,214 Fusarium compactum 13:536

Galium species 4:400 Garcinia I'.AAA Garcinia gerrardii 7:444,445,457 Garcinia mancostana 4:382,384 Garcinia spicata 5:757,758 Garcinia thwaitesii 5:757,758 Gardenia cramerii 5:756,757 Gardeniafosbergii 5:756,757 Gardenia jasminoides Ellis 16:298 Gardenia sp. 5:756,757 Gardneria nutans 15:491 Garrya diterpene alkaloids 6:174 Garuga gamblei 17:370, Garuga pinnata 17:370,375-376 Garwga species 17:375 Ge/gma species 20:10 Geigeria burkei 14:450 Geissospermum laeve 1:124 Geissospermum vellosii 1:124 Gelonium multiflorum 9:265 Gelsemium aXkaXoxds 15:465-515 Gelsemium elegans akuammidine from 15:466 gelsemamide from 15:472,473 humantenine from 15:472 koumine from 15:475,476 11-methoxygelsemamide from 15:472,473 16-e/7/-voacarpine 15:469

1328

Gelsemium rankinii 15:465 Gelsemium sempervirens 1:125,465-467 Gentianasp. 5:651 Geothelphusa dehaai 19:647 Geothricum penicillatum 13:3 02 Geranium macrorhizum 5:679 Geranium thunbergii 17:421,428,433 Gibberellafujikuroi 8:115,117 Gibbons ia elegans 17:94 Gingko biloba 9:317,321,323,659,660 Gleditsiajaponica 15:195 Gleditsia saponins 15:191 Gleosporium fructigenum 18:715 Glococladium sp. 5:370 Gloeosporium lacticolor 15:351 Glomerella cingulata 5:278,415,228,230,240 Glomerellafructigene 9:230,239 Glomerella glycines 9:230,239 Glomerella gossypii 9:230,239 Glomerella species 9:228,230,239 Glomerella tucumanensis 9:230,239 Gloria superba 5:47 Glutarenghas 9:319 Glycine max soyasaponin A3 15:196 Glycosmis bilocularis 13:348,350,355 Glycosmis citrifolia cycloglycofoline from 13:348,349 glycocitrine I from 13:348,350 glycofoline from 13:348,349,361 pyranofoline from 13:348,350 Gly coxy Ion huberi 15:31 Glycyphylla smilax 15:31 Glycyrrhiza glabra 15:5 Glycyrrhiza inflata 15:26 Gmelina arborea 17:332 Gnetum ula 9:258,263 Gobius criniger 18:48 Gomophia watsoni 15:61 Goniothalamas giganteus 19:498 Goniothalamus giganteus 9:393,395;18:221,222 Goniothalamus sesquipedalis 9:393 Gonomia kamassi 1:124 Gonystylus keithii 19:764 Gonyaulax tamarensis 17:4 Gorgoniaflabellum 9:37 23-demethylgorgosterol from 9:37 Gorgonia ventilina 9:37 23-demthylgorgosterol from 9:37 Gorytes campestris 5:251 Gorytes mystaceu 5:251 Gracilaria edulis 19:570 Gracilaria verrucosa 19:571 Gracula religiosa 5:837 Graphium sp. 5:307,309,325 Grapholitha molest a 15:3 84 Guidongnin 15:142,150,159,174 *^C-nmrof 15:159 from Rabdosia rubes cens 15:174 'H-nmrof 15:150 Grapholitla molesta 6:557 Grevillea banskii 9:319,320 Grevillea hilliana 9:320

Grevillea pteridifolia 9:320 Grevilleapyramidalis 9:319,354 Grevillea robusta 9:320 Grevillea species 9:329 Grifolafrondosa 5:287 Grifolaumberllata 5:287,317 Gromphadorhina portentosa 9:488,489 Gryllus bimaculatus 9:492 Guaiacum officinale 5:197,139,319,324;9:51-59 Guettarda platypada 17:116,125 Guttiferae 7:409-411,417,418,420-423,19:768 Gundelia toumefortii 1:427 Gutierrezia grandis 5:680 Gutierrezia microcephala 5:680,681 Gutierrezia texana 5:679 Gutierrezia-xanthocephahum complex 5:676 Gym.galatheanum 6:76-D 6:135 Gyminda 18:741 Gymnema sylvestre 15:36;18:649,650,653,661,671,673 Gymnocolea inflata 2:280 Gymnodium breve 19:430 Gymnodinium breve 17:20 Gymnomitrion obtusum 13:39 Gymnosperma glutinosum 5:679-681 Gymnotroches axillaris 7:192 Gynostemma pentaphyllum 18:662 Gyrophora aureolum 6:135 Gyrophora esculenta 5:311,322 Gyrostroma missouriense 15:351,383

Hacelia attenuata 7:290,295,304-306,61;15:61 Haematoxylon campechainum 15:34,20:776 Haemodoraceae 17:372 Haemophilus influenzae 4:195 Hakea amplexicaulis 9:320 Hakea persihana 9:320 Hakea trifurcata 9:320 Halcyon smyrnensis 5:837 Halichondriajaponica 18:475 Halichondria melanodocia 5:387 Halichondria okadai 5:378,379,383,384 Halichondria panicea 17:719 Halichondria species 17:17 Haliclona sp. 5:346,347,459 Halimeda incrassata 18:689 Halimeda tuna 689 Halityle regularis halityloside D and I from 15:61 gomophioside A from 15:61 halitylosides A,B,D,E,F,H,I from 7:297 Halobacterium sp. bacterioruberin from 7:355 Halocynthia roretzi halocynthiaxanthin from 6:152 mytiloxanthinone from 6:152 Halymenia porphyroides marine A^-acylsphingosine from 9:85,86,88 Hannoa klaineana 18:726 Hanseniaspora osmophila 5:283 Hansenula beijerinkii 5:287 Hansenula bimundalis var. americana 5:287 Hansenula capsulata 5:280,284,315

1329

Hansenula ciferii 5:287 Hansenulafabianii 5:287 Hansenula minuta 5:315 Hansenula mrakii 5:287 Hansenula saturnus 5:287 Hansenula sp. 5:281,282,315 mannans from 5:282 Hansenula subpelliculosa 5:282 Hansenula wingei 5:282 Hapalochlaena maculosa 18:724 Hapalosiphon fontinalis hapalindoles from 11:278 Haplophyllum dauricum 17:335 Hasnenula holstii 5:280,285,315 Hedera helix 7:427,20:6 Heinsia crinata 151 Helenium amarum 20:10 Helenium microce 20:10 Heliathus annuus L. 19:247 Helicacus kanaloanus 15:383 Helichrysum nitens 5: 413 antifiingal flavonoids from 5:651 Helicobacter pylori 13:183 Helicondria species petrosterol from 9:37 Heliconius pachinus macrolide from 8:222 Heliocidaris erythrogramma 17:95 Heliopsis buphthalmoides 17:319 Heliopsis helianthoide 5:728,334 hemoglobin components of 5:836-839 in bird species 5:836-839 Heliopsis longipes lAll Heliothis virescens 7:395 Heliotropium strygosum 19:145 Heliotropium-Arten. 19:145 Helix promatia 18:655;19:636 Helminthosporin teres 2:434 Helminthosporium oryzae 9:237 Helminthosporium sativum 4:23,24 Helvella gyomitra 9:203 Hemophilus influenzae 13:162,177,181 Henricia laeviuscola henricioside from 15:48,55 Heritiera littoralis 7:176,177,180,181,185,187,190 Hernandia cordigera 5:485,561 5'-methoxypodorhizolfrom 18:561 Hernandia ovigera 5:485 Hernandia ovigera L. hemandion from 18:600 isohemandion from 18:600 isohemandion from 18:600 desoxypicropodophyllin from 18:600 epiaschantin from 18:600 epimagnolin from 18:600 Hernandiapeltata 20:522 Hernandiaceae 18:558 Herpes simplex 5:418 Herpes simplex type 12:366 Herpetomonas curzi 2:298 Herpetomonas mmuscarum 2:298,301 Herpetomonas samuelpessoai 2:298 polysaccharides in 2:299-301

Hesperiphona vespertina hemoglobin components of 5:836 ofa-cedrene 5:790 ofartemisinin 5:25,26 of angelic acid 5:778 oftiglicacid 5:778 of 7-hydroxyfrullanolide 9:152 spectra of 8:151,152 Heteromorpha trifoliata 7:415 Heteronema halopuupehenones from 6:23 puupehenones from 6:23 Heteropora alaskensis 17:90,92 Heterotropa takaoi 17:348 Hexabranchus sanguineus 17:16,19:609 Heynea trijuga 2:267 Hibiscus rosa-chinensis 7:180,183,195 Hibiscus tiliaceus 7:185 Himerometra robustipinna 7:266 Hincksinoflustra denticulata 17:85,88 Hippocratea 18:741,754 Hippocratea indica 5:749 Hippocrepis balearica 19:117 Hippocrepis comosa 117 Hippodiplosia insculpta 17:90,92 Hippospongia metachromia 5:430 Hippospongia sp. 5:432 Hiptagam adablota 19:117 Histoplasma capsulatum 5:307 Histoplasma duboisii 5:307 Histoplasmafarcinosum 5:307 Histoplasma sp. 5:325,328 Holothuria atra holothurin A from 7:269 holothurin B from 7:269 holothurin B, from 7:269 Holothuria edulis holothurin A2 from 7:269 Holothuria floridana holothurin Ai from 7:269 holothurin A2 from 7:269 holothurin Bi from 7:269 Holothuria grisea holothurin Ai from 7:269 Holothuria leucospilota 15:87 Holothuria leucospilota holothurin A from 7:268 holothurin B from 7:268 holothurin from 7:268 Holothuria lubrica holothurin A from 7:269 holothurin B from 7:269 Holothuria mexicana 7:281 Holothuria pervicax 15:92 Holothuria scabra 7:210 Holothuria squamiera holothurin A from 7:269 holothurin B from 7:269 Holothuria tubulosa 15:104;17:134 Holothuria vagabunda 7:267,268 Homarus americanus 19:668 Homo sapiens 18:705

1330

Homoerythrina alkaloids biosynthesis of 6:487 Hormodendrum sp. 5:325 Horsfieldia iryaghedhi 5:753 Hortia arborea 4:400 ftiranocoumarin from 4:398 Hoslundia opposita 2:129 Hovenia dulcis 15:36 Humicola spp. 2:323 Humulus hupulus P-famesene from 7:121 eudesm-1 l-en-4-ols from 14:450 (-)-selin-l l-en-4a-ol from 14:450 Hunteria indole alkaloids 13:70,93 Hura crepitans 20:19 Hyalodendron pyrium 5:305 Hyalodendron sp. 5:305 Hyalophora oecropia 1:206 Hydnocarpus wightiana 5:496 Hydractinia echinata 18:701 Hydrangea macrophylla phyllodulcin from 13:660 Hydrangea macrophylla 15:5,30,387 phylloduclin from 15:30 Hydroangea macrophylla 2:286 Hydrodictyon reticulatu 19:247 Hydrodictyon reticulatum 18:495,507 Hydrogenomonas eutropha 4:439 Hym enoxys turneri 15:32 Hyoscyamus albus 17:398 Hyoscyamus genus 17:395 Hyoscyamus niger 13:631 Hypericum 7:409 Hypericum annulatum 7:417 Hypericum calycinum 7:422 Hypericum chinense 7:422 Hypericum japonicum 5:758 Hypericum mys or ens e 5:758,759 Hypericum perforatum 5:758,656 Hypericum revolutum 7:409,410,417,420-422 Hypoponera opacior 5:224,230,254 Hypselodoris californensis curyfiiran from 6:20 Hypselodoris godefroyana 6:69 curyftiran from 6:20 nakafriran-9 from 6:29 Hypselodoris porterae 6:20 Hyrtios eubamma 6:23 puupehenone from 6:23 Hysselodoris califomiensis 4:404 Hysselodoris porterae 4:404 Hyssopus officinalis 7:119

Inula cappa 5:678 Inula crithmoides 5:728 Inula nervosa 19:125 Ipomoea alba alkaloids of 1:362 Ipomoea muricata 1:362 Ircinia wistarii ircinianin from 6:8 wistarin from 6:8 Iridomyrmex humilis 5:223,225,240,241,245,253 Iridomyrmex nitidus 5:222-224,233,253 Iridomyrmexpurpureus 5:222,224,233,253 2,5-dimethyl-3-ethyl pyrazines of 5:222 Iridomyrmex purpureus sanguineus 5:224,233,253 Iridomyrmex rufoniger sp.gr. 5:223,237,253 Iris germinica 10:152 Isoopalanoids 6:108 from (+)-labda 8(20),13-diene-15-oic acid 6:57 synthesis of 6:119-122 Isoptera 19:118 Isotricha 2:294 Itersonilia tilletiopsis 5:291 Iva xanthifolia 5:728

Jaborosa bergii 20:180 Jacaranda acutifolia 5:682 Janua bioticus 17:100 Jasminum officinale 7:218,222,223 Jasminum sp. 7:218,219 Jasminum grandiflorum 19:152,158-159 Jaspis 19:580 Jaspis s\>Qc\QS 5:428,19:613 Jatropha gossypilifolia 10:152 Juniperus communis 20:16 Juniperus sabina 20:16 Juniperus virginiana 20:16 Jungermannia infusca 2:280 Juniperus virginiana 15:346 Juniperus communis 5:485 Juniperus foetidissma 8,14-cedranoxidefrom 8:163 Jusiaea decurrens 9:214 Justicia procumbens 17:333 Justicia prostata 17:335

Iberisamara 19:762,20:12 Ilex aquifolium 20:6 Ilex lactone 20:6 Ilex paraguariensis 20:6 Ilex verticillata 9:402 Ilybiusfenestratus 5:780 Indigofera endecaphylla 19:117 Indigofera swaziensis 7:417

Kadsura species 17:346 Khaya grandifoliola 5:700 Kigelia africana 7:406 Klebsiella 12:63 Klebsiella pneumoniae 5:325,308,308,106,12:400; 20:712 Kloeckera africana 5:283 Kloeckera magna 1:701,283,13 in microbial reduction 6:13 Kluyveromices species 13:302 Kokoona zeylanica 5:743-745 D:A-friedo oleananes from 7:147-149 phenolic triterpenes from 7:147-149 triterpene quinone methide from 7:147-149

1331

Lachnanthes tinctoria 4:618 Laciniatafuranone 9:532,533 Lactarius camphoratus 17:156 Lactarius chrysorrheus 17:196 Lactarius circellatus 17:197 Lactarius controversus 17:198 Lactarius deceptivus 17:198 Lactarius deliciosus 17:198 Lactarius deterrimus 17:198 Lactarius flavidulus 17:198,201 Lactarius fuliginosus 17:153,201 Lactarius fulvissimus 17:200 Lactarius genus 17:153,156 sesquiterpenes from 17:159 biogenesis of sesquiterpenes from 17:159 Lactarius glaucescens 17:198 Lactarius glutinopallens 17:199 Lactarius glyciosmus 17:199 Lactarius helvus 17:199 Lactarius indigo 17:199 Lactarius lignyotus 17:200 Lactarius mitissimus 17:200 Lactarius necator 17:199 Lactarius pergamenus 17:198 Lactarius picinus 196,201 Lactarius piperatus 17:197,198 Lactarius quietus 17:196 Lactarius rufus 17:199 Lactarius scrobiculatus 17:153,196,197 Lactarius subvellereus 17:198 Lactarius thejogalus 17:200 Lactarius torminosus 17:196,197 Lactarius vellereus 17:153,196,197 Lactarius, metabolites 17:154 Lactobacillus helveticus 13:319 Lactuca virosa 20:8 Lagerstroemia subcostata Koehne 1:368 Laguncularia racemosa 7:175 Lamellariidae 17:21,22 Lansium domesticum 1:658 Lanthella basta 10:632 bastaxanthins from 6:150 Lardoglyphus konoi pheromoneof 1:696 (-)-lardolure from 14:487 Larix decidua 17:332 Larix leptolepis 20:613 Larrea divaricata 17:315 Larrea tridentata 5:9 Larus asrgentatus hemoglobin components of 5:837 Larus Philadelphia hemoglobin components of 5:837 Lasalliapapulosa 5:311 Lasallia pensylvania 5:311 Laserpitium halleri subsp. halleri 5:728 Laserpitium latifolium 5:725,727 Lasiantheaefruticosa 5:728 Lasioderma serricorne (cigarette beetle) 1:695,275 serricomin from 14:275 Lasiodiplodia theobromae 6:557,290,477 Lasioglossumze phyrum 8:222

Lasius niger 6:454 Latrinculia brevis trunculin-A,B from 9:20 Latrunculia apialis 18:716 Latrunculin magnifica 17:14 Laurencia concinna concinnidiol from 6:24 Laurencia glandulifera glanduliferol from 6:63 Laurencia implicata brasilane sesquiterpene from 18:633 Laurencia majuscula bromochamigrene from 6:60 Laurencia nipponica 6:41,63 (-)-(2;?,65,95)-2,8-dibromo-9-hydroxy-achamigrene from 6:63 ()-isocycloeudesomol from 6:41 Laurencia obtusa 5:363;8:625 brasilenol from 6:6 brasilenol acetate from 6:6 brasilenol from 6:6 e/?/-brasitenol from 6:6 Laurencia okamurai 19:454 Laurencia pacifica (+)-2-bromo-p-chamigrene from 6:63 Laurencia perforata 6:29,30,56 Laurenciapinnata 6:9,26 Laurenciapinnatifida 5:216,363,81 -8 marine sesquiterpenes from 9:81-83 Laurencia poitei poitediol from 6:35 Laurencia snyderae 6:6,30 epiguadalupol from 6:30 guadalupol from 6:30 isoconcinndiol from 6:30 Laurencia sp. 5:361-363,368,370 Laurencia specie 6:24,59,60;9:8;10:231 (-)-aplysin-20 from 6:24 10-bromo-a-chamigrene from 6:60 spirobicarbocyclic chamigranes from 6:59 eye lie ethers from 10:213 Laurencia subopposita 6:10 oppositol from 6:9 prepinnaterpene from 6:9 Laurencia venusia 5:361 Lavandula angustifolia 7:94,95,108,109,118,119,125, 126 Lavandula sp. 7:125 Ledum palustre 20:17 Legionella pneumophila 13:155 Leishma braziliensis 2:311 Leishmania 18:791,793,794 Leishmania adleria 2:311,313 immunity against kala-azar 2:313 Leishmania amazonensis 2:298,794 Leishmania donovani glycopetidophosphophingolipid 2:312 polysaccharides of 2:311,312 Leishmania enrietti carbohydrates in 2:314 Leishmania mexicana amazonensis 2:314 carbohydrates in 2:314

1332

Leishmania spp. glycocomplexes of 2:311-314 polysaccharides of 2:311-314 Leishmania tarentolae 2:298,311 carbohydrates in 2:311,314 Leishmania tropica major polysaccharides in 2:314 Lemna bioassay 9:386,387,389,390;15:344 Lemna minor (duckweed) 9:383,384,386,387,389,390 Lentinus edodes 5:287,288,316 Leontice leontopetalum 9:153 Lepidoptera 9:322,772 Leptochilus acolhuus 5:223,224,253 Leptogenys diminuta (3/?,45)-4-methyl-3-heptanol from 11:415 Leptogorgia virgulata 17:99 Leptomonas collosoma 2:301 Leptomonas samueli 2:298 polysaccharides of 2:301 Lesquerella spcc'iQS 13:310 Letharia vulpina 5:310,311,313 Lethasterias nanimensis chelifera 15:59 Leucadendron 4:712 Leucetta chagosensis 17:17 Leucocyclies formosies 10:151 Leucojum aestivum 20:359 Leucojum vernum 20:359 Leuconostoc measenteroides 2:350,314,325,69;7:69 Leucophaea maderae 9:488,489 Libinia emarginata juvenile hormone from 1:704 Li Hum longifolium teasterone myristate from 18:507 teasterone 3-myristate from 18:495,522 Limonia acidissima 20:497 Linckia guildingi 7:298 Linckia laevigata 7:290,295,46,61 laevigatoside from 7:290 maculatoside from 7:290 marthasteroside Al from 7:290 ophidianoside F from 7:290 thomasteroside A from 7:290 Lineus fuscoviridis 18:725 Lippia nodiflora 5:647,648,655 Lippiasp. 7:427 L ipria dulcis 15:14 Liriodendron tulipifera 5:476 Lissoclinum bistratum 10:243 Lissoclinum patella 4:89,93,99,5:419,420,10:242,243 Lissoclinum perforatum 10:244 Lissoclinum vareau 10:243 Lissodendoryx isodactyalis 5:395,13:168,18:715,716 Lithospermum erythrorhizon shikonin from 7:88 Lituaria austral as iae 19:596 Lobaria retigera (-)-retigeranic acid from 13:22 Lobophylum crassum 8:11 isolobophytolide from 8:20 Lochnera (Vinca) rosea 1:125 Locusta 9:489 Locusta migratoria manilensis 18:771

Locusta migratoria migratorides 7:395,18:771 Lonchura malabarica hemoglobin components of 5:837 Lonchura malacca hemoglobin components 5:837 Lonchura punctulata 5:837 hemoglobin components 5:837 Lonicera nigra 7:427 Lophozozymus pictor 5:393 Lotus uliginous 19:117 Luffariella variabilis 17:10 Luffariella variabilius 18:717 Luidia maculata 7:303-306,15:46 luidiaglycosides A-D from 7:288 maculatoside from 7:289 marthasterosides from 7:289 thomasteroside A from 7:289 Lumnitzera sp. 7:176 Lupeol 7:189 Lupine alkaloids synthesis of 14:731-768 Lupinus hirsutus 15:521 Lupinus luteus (-)-(/ra5-4'-P-D-glucopyranosyloxy-cinnamoyl) lupininefrom 15:521 (-)-(rraM5-4'-P-D-glucopyranosyloxy-3'methoxycinnamoyl) lupinine from 15:521 (-)-(/ra5-4'-hydroxy-cinnamoyl) lupinine from 15:521 (-)-(/ra5-4'-rhamnosyloxy-cinnamoyl) lupinine from 15:521 {-)-{trans-A' -rhamnosy loxy-3' -methoxy-cinnamoy 1) lupinine from 15:521 Lupinus termis 15:524,525 (-)-A^-dehydroalbine from 15:524 (-)-A^-dehydromultiflorine from 15:525 Lychnophora sellowii bisabolone from 8:48 Lycoris incarnata incartinefrom 20:351 Lyngbia gracillis 19:586 Lyngbia majuscula 19:492,587 Lycopersicon esculentum 18:523,529,532,533 Lycopodium alkaloids 16:456;18:341 Lycopodium magellanicum 18:3 Lycopodium paniculatum 18:3 Lyngbya gracilis 17:4 Lyngbya majuscula lyngbyatoxin from 11:278 Lyngbya majuscula 5:411 ;18:294 Lyngby a XoxmK 5:412 cytotoxic activity of 5:411 Lytechinus variegatus 7:285;15:104 lytechinastatin from 7:285

Maackia amurensis (+)-13p-hydroxymamanine from 15:522 (-)-lusitanine from 15:521 Maackia tashiroi 15:523 tashiromine from 15:523 Macrophiotrix longipeda 7:309 Macrophom is phaseolina 6:555

1333

Maesa lanceolate 5:819;17:240 Magnifera indica 9:321 Magnolia salicifolia 17:348 Magnolia sp. neolignans from 8:159 Majidea foster i maj ideagenin from 7:141 triterpenoids of 7:139,141 Mammea africana 7:417 Mammea americana coumarins from 4:389,391 i-yMammea B/BB 390,391 synthesis of 4:390,391 Mammea longifolia coumarins from 4:389,391 saranginBfrom 4:391 Mandragora officinarum 13:631 Mandshurin manica bradleyi 5:250 Manduca sexta juvenile hormone from 1:704 Manica bradlyi 5:250 Manica hunteri 5:250 Manica mutica 5:250 Manica rubida 5:235,254 2,5-dimethyl-3-methyl-pyrazines of 5:222 2,5-dimethyl-3-methyl-pyrazines of 5:222 methyl pyrazine of 5:222 Mar chant ia paleaceae 2:281 Marchantia palmata 2:283 Marchantia tosana 2:281 Marjoram hortensis (sweet marjoram) cyclase from 11:221 Marshallia tenufolia 10:442,443 Marthasterias glacialis 7:289,299;15:48,104 glacialosides A,B from 7:299 Massoia lactone 3:157,158 Maytenus boaria 18:752,775 Maytenus buchanii tissue culture of 7:146 triterpenes of 7:146 Maytenus bnxifolia 18:757 Maytenus diversifolia maytensifolic acid from 7:152 maytensifolia A,B from 7:152 maytensifoliol from 7:152 triterpenoids of 7:152 Maytenus genus 18:739,740 Maytenus ovatus 4:492 Maytenus rigida wilfordinfrom 18:771 Medicago saliva 15:202,20:734 Megalobulimus paranaqnensis 2:306 Melaleuca leucadendron phyllodulcin from 15:387 Melannorrhea usitata 9:319 Meleagris gallopavo hemoglobin components of 5:836 Melia azedarach 9:502 Melissa officinalis callus cultres of 2:404 Melodienone 9:400 Melodium fruticosum 10:152

Melodorum fruticosum 9:399 Melospiza lincolnii hemoglobin components of 5:837 Melospiza melodia hemoglobin components of 5:837 Membranipora membranacea 17:93 Membranipora perfragilis 17:91 Menippe mercenatia 19:628 Mentella genus 19:4 Mentha 7:124,126 Mentha longifolia 7:119 Mentha spicata cv. lacinata 7:119 Mercurialis annua 17:117 Me/-M//M5 species 9:317,327,350 Mesoponera castanea 5:224-227,229,245,247,254 Mesoponera castaneicolor 5:224-227,229,245,257,254 Mesoponera sp. 5:224-227,245,247,254 Mesuaferrea 4:768 coumarins from 4:389,391 Me^wa genus 19:768 Metarhizium anisopliae 19:486 Mesua thwaitesii coumarins from 4:389,391 Metarhizium anisopliae (-)-swainsonine from 12:313 Metatrichia vesparium arcyrialflavin B from 12:366,370 arcyrialflavin C from 12:366,370 Methanobacterium thermoautotrophicum 9:606 Metridium illicifolia 18:665 Metridium loesner 18:757 Metridium senile 18:813 Micrococcus flavus 12:400 Micrococcus leuteus 12:400;13:283;15:389 Microcystis 9:496 Microsporum canis 12:400 Microsporum guinckeanum 5:294 Microsporum gypseum 12:400 Millingtonia hortensis 5:14 Milius banacea exoaporphines of 20:483 Mimulus species mimulaxanthin in 6:137 Minoyobates bombetes 19:81 Monascus ruber 19:168 Moniliaspip. 2:323 5:278 Moniliniafructigena Monodora tenuifolia 2-dimethylallylindole from 2:446 Monohba quadridens 5:225,231,253 Monom irium fori cola pyrrolidine venom alkaloids in 6:436 Monomorium carbonarium pyrrolidine venom alkaloids in 6:436 Monomorium cyaneum pyrrolidine venom alkaloids in 6:436 Monomorium ebeninum pyrrolidine venom alkaloids in 6:436 Monomorium latinode 16:441 pyrrolidine venom alkaloids in 6:436 Monomorium minimum pyrrolidine venom alkaloids in 6:436

1334

Monomohum minutum pyrrolidine venom alkaloids in 6:436 Monomorium near emersoni pyrrolidine venom alkaloids in 6:436 Monomorium near metoecus pyrrolidine venom alkaloids in 6:436 Monomoriumpharaonis L. 1:389;6:336,445,454; 14:575 indolizidine alkaloids in 6:445 pyrrolidine venom alkaloids in 6:436 (+)-monomorine I from 11:231 Monomorium species 6:443 2,5-dialkylpyrrolines in 6:434,443 rram-2,5-dialkylpyrrolidines in 6:434 pyrrolidine venom alkaloids in 6:436 Monomorium subopacum 6:436 Monomorium viridum 6:3436 Montanoa tomentosa 389 Morinda lucida 1:421 Mortierella ram annianus 19:578 Mortaniapalmeri 5:678 Mortonia greggi 18:751 Morusalba 17:47,451,465 cell cultures 17:471 polyprenols from 8:36 Morus alba Linne moracenin A and B from 4:618,619 Moschus moschiferus muscone from 8:219 Mucor miehi 13:303 Mucor rhizopus 9:203 Mucor rouxii 5:276 Mucor spp 2:323 Mugil cephalus 18:486 Mugil umbelata 18:665 Murray a 1:172 Musca domestica 18:698,19:124 Mutatis mutandis 15:262 Mycale adhaerens 15:386,19:558,613 Mycalesp. 5:366;9:19,22,24 Mycelia sterilia 9:203 Mycobactericum tuberculosis H37R 4:244 Mycobacterium avium 13:183 Mycobacterium aviumintracellulare 2:424 Mycobacterium intracellulare 2:428 Mycobacterium leprae 9:322 Mycobacterium phlei 12:103 Mycobacterium smegmatis 12:400 Mycobacterium sp (all ) phytoene from 7:327 Mycobacterium tuberculosis 12:398;18:351 Mycobacterium vaccae 9:411 Mycoplasma sp. 12:48 Mycosphaerellapinode 5:278 Myoporum bontioides 15:229 Myoporum deserti 15:228,229 Myoporum laetum (-)-ngaione from 15:236 Myoporum montanum 15:229 Myoporum species 15:227 Myriapora truncata 11:11 Myricanagi 17:371 Myrica rubra 17:371

A ^ n c ^ species 17:375 Myriogloia sciurus marine sterols from 9:83,84 Myrmecia gulosa 5:223,233,254 Myrmecocystus testaceus 15:383 Myrmica 6:454 Myrmica afracticornis 5:250 Myrmica americana 5:250 Myrmica brevispinosa 5:250 Myrmica emergana 5:250 Myrmica lobicomis 5:233,235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica rubra 5:235,250,254 2,5-dimethyl-3-methyl-pyrazines of 5:222 2,5-dimethyl pyrazines of 5:222 methyl pyrazines of 5:222 Myrmica ruginodis 5:235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica rugulosa 5:235,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica sabuleti 5:235,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica scabrinodis 5:235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 2,5-dimethyl-3-methyl-pyrazines of 5:222 2,5-dimethyl pyrazines of 5:222 Myrmica schencki 5:235,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica sp. 5:233,235,236,250,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmica sulcinodis 5:235,236,254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Myrmicinae 6:421,422,454,455 Myrrhis odorata 15:29 Myrsine africana 9:400 Mytilus edulis 6:142,143,156;17:21 Myxococcus xanthus 10:78,79 Myxoderma platiacanthum 15:58,75,81 3b,5,6b, 15a-tefrahydroxy-5a-stigmastan-29-oic acid from 15:81

Nadsoniafulvescens 5:290 Narburgia stuhlmanni antifeedant from 1:701,702 Narcissus alkaloids 20:233 Narcissus pallidulus mesembrenone from 20:234 Narcissuspseudonarcissus 20:353,359,391 lycorine from 20:233 Nardoa gomophia 15:46 Nardoa novaecale donia halityklosides A,B,D from 7:298 Nardoa tuber colata 15:71 Nardostachys jatamansi guaiane alcohol from 14:375 (-)-nardol from 14:374 Nasutitermes exitiosus 5:702 Nauphoeta cinere 9:488,489 Navanax inermis 10:152;17:28 Nectandra salicifolia 20:522 Nectriafuckeliana 15:383 Nectria gibberella 9:203

1335

Nectria haematococca 18:709 Neisosperma glomerata 1:124 Neisseria 12:63 Neisseria meningitides diheptosesin 4:196,206 Neisseria perflava 7:69 Nematospiroides dubius 12:3 Neorautaneniapseudopachyrrhiza lAXl Neosiphonia superstes 19:596,19:607 Neosm ilaster georgianus 15:58 Neothyone gibbosa neothyoside A from 15:92 Neothyonidium magnum neothyonidioside from 7:278 Nepeta cataria 4:604;6:522 Neptunia antiqua 7:4 Neptunia contraria I'A Nerine bowdenii 20:352 Nerinejonquilia 20:391 Nerinepapyraceus 20:391 Nerine poeticus 20:391 Nerine tazetta 20:391 Nerium oleander cyctotoxic agents from 9:293-315 Netschnikowia reukaufii 5:282 Neurospora crassa 5:277-279,8:297 Nicandra physalolides 20:24 8 Nicandra steroids 20:180,182 Nicandrenone 20:181 Nicandria physaloides 20:238 Nicotiana glutinosa 7:101,110 sclareol from 7:121 Nicotiana setchelli 1:662 Nicotiana tobaccum 20:135 Nicotiana tabacum 1:671 Mco/masp. 7:124,126 nicotine synthase from 11:204,206 Nigroporus durus 13:305 Nitraria alkaloids synthesis of 14:731-768 Nitraria indole alkaloids 14:758-765 Nitraria komarovii isokomarovine from 14:762 komaroine from 14:762 komarovicine from 14:762 komarovidine from 14:762 komarovine from 14:762 komarovinine from 14:762 nitramarine from 14:762 tetrahydro-komarovinine from 14:762 tetrahydronitramarine from 14:762 tetramethylene tetrahydro-b-carboline from 14:758 Nitraria schoberi 1:125 isonitrarine from 14:759 nazlininfrom 14:758 nitramidine from 14:759 nitraramine from 14:750 nitrarine from 14:759 schoberine from 14:757 schoberidine from 14:759 spiroalkaloids from 14:742 Nitraria sibirica isonitramine from 14:541

nitramine from 14:541 (-)-s ibirine from 14:541 spiroalkaloids from 14:542 Nitraria species 14:742-765 Nitraria spiro alkaloids 14:742-765 Nitraria tripiperidine alkaloids 14:757,758 Nitzschia palea 18:698 Nocardia aerocolonigenes 5:55 Nocardia aeroligenes 1:3 Nocardia interforma 10:587 Nocardia mediterranei 9:431,433,435,440,441 rifamycin S from 12:37 rifamycin W from 12:39 Nocardia species 9:433,434 Nocardia uniformis monocyclic p-lactams from 12:118 Nocardioides 17:285 Nocardiopsis dassonvillei TAN-999from 12:366,367 Nocardiopsis sp. 5:55 Nocardiopsis sp. K-252 1:4 Nocardiopsis sp. K-252a K-252afrom 12:366,368 Nocardiopsis sp. K-290 K-252bfrom 12:366,368 K-252cfrom 12:366,368 K-252dfrom 12:366,368 Nocardiopsis syringae nocamycinfrom 14:97,98 Noctiluca m iIliar is 5:353 Noctuidae 18:772 Nodular ia species nodularin from 9:496 Nodularia spumigena 20:894,896 Nomamyrmex esembecki 5:250 Nopalea coccinellifera 20:734 Norcardia argentisis 17:283 Norcardia spQCiQS 10:153 Nostoc linckia 19:587 Nostoc sp. 9:496-499 Nostoc sphaericum indolo [2,3 a] carbazoles from 12:366,370 Notholaena affinis 5:678-680 Notholaena aschenborniana 5:676,681 Notholaena californica 5:677-679 Nothomyrmecia macrops 5:233 Notodoris citrina 17:17 Notodoris gar diner i 17:18 Notoncus ectatommoides 5:224,230,254 Numida meleagrus hemoglobin components of 5:836 Nypafruticans 7:176 Nysson spinosus 5:225,231,251,253

Ochrosia elliptica epchrosine from 6:521 Ocimum basilicum 5:473,474,7:108,109 Octotea pretiosa 19:117 Odontomachus brunneus 5:223-225,237,254 Odontomachus clarus 5:224,228,254 Odontomachus hastatus 5:224,228,254

1336

Odontomachus sp. 5:221,232,225,228,237,238 Odontomachus troglodytes 5:223-225,237,238,254 Oestrogenic activity 20:659 Oleacapensis 5:514 Olea europa 3:254 Olea europaea L 5:505,515,521,523,524,531,7:427,477 Oleum chenopodii 20:12 Oligocerus hemorrhages 17:14 Oligosporic actinomycete 14:98 Omphalea diandra 11:431 Onchidella benneyi 17:27 Oncomelania 7:425 Oncosperma tigillaria 7:176 Ononis natrix 6,8-dihydroxy-3 -undecyl-3,4-dihydroisocoumarin from 15:386 Onychopetalum amazonicum 2:442 Oochromonas malhamensis 2:293 Ophiarachna incrassata 7:308,309 Ophiarthrum elegans 7:308,309;15:96 Ophidiaster ophidianus 7:290; 18:460 Ophiocoma dentata 7:308,309;15:96 Ophiocomina nigra 15:100 Ophioderma longicaudum 7:309,96 longicaudoside A and B from 7:94,308 Ophiodiaster ophidianus 15:46 Ophiolepis superba 15:84,96 Ophiomastix annulosa 15:99 Ophiorachna incrassata 15:96 Ophiorrhizajaponica 1:125 Ophiosparte gigas 15:99 Ophiura sarsi cholest-5-ene-3 a,4p,21 -triol-3,21 -disulphate from 15:98 Opisthiolopis heterophylla 9:320 Orconecttes limosus 19:628,668 Oreaster reticulatus 7:3 04-3 06,15:61 asterosaponin P, from 7:297,300 Oricia renieri 2:121 Oriola xanthornus hemoglobin components of 5:837 Ornithopus sativus 18:514,520,523,529-533 castasterone from 18:503 24-epicastasterone from 18:503 Orthoscuticella ventricosa 17:90,95,101 Orthosphenia 18:754 Orthosphenia mexicana 7:756,758 netzahualcoyon from 7:147 orthosphenic acid from 7:147 triterpenes of 7:147 Orygyia pseudotsugata 20:124 Oryzasativa 1:529,522,20:247 Oscillatoria nigroviridis 18:294 Oscillatoria species 19:567 Oscillatoria nigroviridis 19:586 Ostryajaponica 17:369 O^/rya species 17:369 Oudemansiella mucida 3:257 Ourouparia gambir 1:25 Oxytropis sericea Ozoroa mucronata 5:824,830;9:316,327

Pachiclavularia violacea 17:610 Pachodynerus erynnis 5:223 Pachydictyon coriaceum ()-pachydictyol A from 6:11,70 sanadaol (P-crenutal) from 6:70 Pachygrapsus crassiples 628 Pachystima 18:741 Pacifigorgia adamsii 18:614,615 pacifigorgiol from 9:254 Pacifigoria adamsii 6:10 Paecilomyces varioti 2:341;12:103 Palythoa toxica 5:390 Palythoa tuberculosa 5:390,391,393 Panax ginseng 10:153 Pancratium maritimum A^,0-dimethylnorbelladine from 20:359 Pandalus sp. 19:672 Pandaros acanthifolium 5:3 84 Papaver somniferum 17:633 ;18:45,54;20:292 Papilio xuthus 18:682 Paprika oleoresin 20:721 Paracaudina ransonetii caudinoside A from 7:278 Paracentrotus lividus 15:104 Paracoccidioides brasiliensis 5:307,323,326 Paracoccidioides sp. 5:307,325,328 Paramuricea camaleon 6:72 Parancistrocerusfulvipes 5:223-225 Parancistrocerus perennis 5:224 Parancistrocerus rufovestis 5:224 Parancistrocerus sp. A 5:224 Parancistrocerus sp. B 5:224 Pararespula vulgaris 19:130 Parastichopus californicus holotoxins A, Aj, B and Bi from 15:87 Parathyona sp. parathyonoside R from 7:277 parathyonoside T from 7:277 Paravespula vulgaris 2-methyl-l,6-Dioxaspiro [4.5] decane from 14:526 Parmelia sulcata 5:313 Parus gambeli hemoglobin components of 5:836 Paspalum scrobiculatum 15:352-356 Passeer domesticus hemoglobin components of 5:836 Pasteurella multocida 4:196 riheptosesin 4:196 Patinopectin yessoensis 17:20 Patinopecten yessoensis 19:5 79 Patiria miniata 15:55 miniatoside A and B from 15:61 patirioside A from 15:48 Patiriapectinifera 7:297,302;15:61 Pectinophora gossypiella 20:25,20:28 Peganum harmala 2:369 PEL {Pseudomonas fluorescens lipase) 13:54,55 Pelagococcus subviridis 6:135 Pelargonium fragrans 7:112 Pelargonium graveloens 7:100,101 Pelargonium sp. 7:95,96,100,112 Pellia endiviifolia 2:278,279 Pellia sp. 2:90

1337

Pellina sp. 5:419 Peltigera aphtosa 5:313 Penaeus vannamei 19:628 Penares sp. 18:460 Penicillium alladadense 5:300 Penicillium atrovenetum 19:117 Penicillium brefeldianum 11:192 Penicillium brevicompactum 5:299,13:553;17:475; 19:168 Penicillium calaviforme 5:300 Penicillium caseiculum 13:305 Penicillium charlesii 5:296,299 Penicillium chrysogenum 5:299,300,15:351,17:616 Penicillium citrinum 5:300,13:553,19:168 Penicillium digitatum 12:103 Penicillium erythromellis 5:300 Penicillium expansum 5:299,7:13,14 Penicilliumfrequentans 4:588 Penicillium grisofulvium 9:341 Penicillium islandicum 5:299,300 Penicillium javanicum 5:299 Penicillium luteum 5:299 Penicillium madriti 11:198 Penicillium notatum 7:71;17:615 glucose oxidase from 7:71 Penicillium ochrochloron 5:300 Penicillium palitans 4:588-590 Penicillium patulum 5:300,11:198 Penicillium raistrickii 5:300 Penicillium roqueforti 13:305 Penicillium rugulosum 10:646 Penicillium scleriotorum 5:299 Penicillium sp. 5:299,301,325,326;17:475 Penicillium turbatum antibiotic A 26771B by 11:194 Penicillium vavians 5:300 Penicillium zacinthae 5:300 Penicillus dumetosus 18:688 Pentaceraster alveolatus 7:290,304-306;15:46,61 6-g/7/-nodosides from 7:34 nodososide from 7:298 Pentacta australis DS-penaustrosides A and B from 15:91 Pentapora fas data 18:715 Pentaspadon motleyic 9:316 Pentaspadon officinalis 9:316 Periandra dulcis 15:26 periandrins from 7:142 Periandra mediterranea 15:26 PmV/a alcohol 19:214 Perillafrutescens 15:5 Periplaneta americana 6:538;8:182,221 ;9:488-490 Periplaneta bunnea 8:182 Periplanetajaponica 8:182 Peritassa 18:754 Persea major 9:402 Persoona elliptica 9:320,355 Pestalotia sp. 5:307,308 antitumor activity of 5:319 Petchia ceylanica 5:135,140,147,149,173 Petrosiaficiformis 9:42 26-dehydro-25-epiaplysterol from 9:40

dihydrocalysterol from 9:37 (23R,24R)-23,24-methylenecholesterol from 9:37 Petrosia hebes dihydrocalysterol from 9:37 hobesterol from 9:37 petrosterol from 9:37 Peziza vesiculosa 5:277 Pfaffiia baniculata pfaffic acid from 7:135 pfaffosides A-F from 7:135 Phaeocystis spQcxQS 6:135 Phaeolus vulgaris L. 19:247 Phqffia rhodozyma 7:361 (3/?,3'/?)-astoxanthinfrom 7:321 Phalacrocorax niger hemoglobin components of 5:837 Phallusia manillata 10:249 Phanerochaete chrysosporium 13:309 Pharbitis purpurea 19:247 Phaseolus vulgaris 19:268 23-0-P-Z)-glucopyranosyl-2-epi-25-methyldolichosteronfrom 18:495,522 cell suspension of 2:369 isozymes from 9:563 Phasianus colchius hemoglobin components of 5:836 Pheidolepallida (minors) 5:254 2,5-dimethyl-3-ethyl-pyrazines of 5:222 Pheidolepallidula 5:235,236 Phelline comosa 3:484 Phelline spp. 3:456 P hellinus gQims 19:351 Phellinus tremulae 19:171 Phenylobacterium immobile Kj triheptoses in 4:196 Phidolopora pacifica 17:92 Philanthus triangulum 5:223,224,231,251,253 Philodendron scandens 9:317,321 Phlomis betonicoides 1:666;15:20 Phoenix dactylifera 18:507 Phoenix paludosa 7:189 Pholacantha synonyma 10:320 Phoma betae 4:601 Phoma destructiva 6:555 Phoma exigna var. indoxi dabilis 6:555 Phomopsis 9:203 Phomopsis citri 15:341 Phomopsis convolvulus 15:341-345 Phomopsis helianthi 15:341,345,346 Phomopsis juniperovora 15:346 Phomopsis leptostromiformis 15:341,347 Phomopsis longicolla 15:341 Phomopsis oblonga 15:383,388-392 5-methylmellein from 15:385 Phomopsis paspalli 15:352 Phomopsis phaseoli 15:341 Phomopsis viticola 15:341 Phoracantha synonyma 6:542;8:222 macrocycles from 8:221 Phorbassp. 19:601 Phycomyces blakeslearus 18:806 Phycomyces sp. 5:276,294

1338

Phycomyces blakesleeanus (15Z)-phytoenefrom 7:327 Phyllanthus niruri 5:49;17:317,343,421,441,443 Phyllidia bourguini 17:16 Phyllidia species 2-isocyanopupukeanene from 6:80 Phyllidia varicosa 6:79,17:15 2-isocyanopupukeanene from 6:79 Physalis acnes 20:32 Physalis alkekengi 20:182,189,191,247 physalinAfrom 20:182 physalinBfrom 20:182 physalinCfrom 20:182 physalinLfrom 20:189 physagulius E from 20:194 physagulins G from 20:194 Physalis angulata 20:180,182,194,247 Physalis berghei 20:522,524 Physalis cordeana 20:470 Physalis cubeba 20:619 Physalis lancifolia 20:182 Physalis minima 20:234,238,247 A'*,6-hydroxyphysalin from 20:189 Physalis mirabilis 20:859 Physalis peruviana 20:247 Physalis pubescens 20:180,189,191,247 physapubescin from 20:189 physapubenolide from 20:189 pubescenin from 20:191 Physalis vulgaris 20:845,849,851,853,854,857 Physalis yoelii 20:521 Physalis alkekengii zeaxanthin from 7:360 Physarium sp. 5:275 Physarium polycephalum 5:275,276 Phytolacca acinosa triterpenoids of 7:144,145 Phytolacca americana 13:655 Phytolacca dodecandra 7:427,428,430,434 Phytophthora parasitica 5:607 Phytophthora sp. 5:276;7:183;9:203 Phytophthora infestans 5:276 Pica pica hemoglobin components of 5:836 Piceaabies 18:498 Picea sitchenesi 19:247 Picha strasssburgensis 5:287 Pichia bovis 5:287 Pichiafarinosa 5:283 Pichia ohmeri 5:283 Pichia past or is 5:283 Pichia sp. 5:281,297 Pichia terricola reduction with 1:706 Pichia totetana 5:283 Pichia vanriji 5:283 Picicularia oryzae 5:287,598 Picrasma ailantholides 7:369,385 Picrasma quassioides 1:126 Picrolemmapseudocoffea 7:369,381 Pier is rapae 18:771 Pierreodendrom kerstingii 7:369,379,398 Pimpenella anisum 5:473

Pinna muricata 19:616 Pinus koraensis 5:701,702 Pinus radiata 7:99,101,105,106,108,109 Pinus sp. 7:106 Pinus silverstris 17:604,19:247 Pinus thunbergii 19:247,18:498 Piophocarpus tetragonolobus 19:247 Piper clusii 20:619 Piper guineense 17:317 Piper methysticum kawain from 13:660 Piper nigrum 10:152 Piper officinarium 10:151 Piper sumatranum 17:348 Piptocalyx moorie Oliv. 4:709 Piricularia oryzae 2:434 Pisaster brevispinus pisasteroside A from 15:61 Pisaster giganteus 15:66 Pisaster ochraceus pisasteroside A from 15:61 Pisidium guajava eudesm-ll-en-4-olsfrom 14:450 (-)-selin-ll-en-4a-ol 14:450 Pisittacula cyanocephela hemoglobin components of 5:837 Pistachia wera 9:316,327,339 Pisum sativum 17:402,18:708,710,19:247 Pityophthorus pityographus 1:692 Pityrosporium species 13:309 Plactranthus caninus 7:119 Plagiochila acanthophylla 2:81,280 Plagiochila hattoriana 2:280 Plagiochilayokogurensis 2:280 Plakortis angulospiculatus 18: 719 Plakortis halichondroides 18:719 Plakortis lita 5:353,354;18:718,719 Planaxis sulcatus 17:22,28 Planotortaix excessan 7:193 Planotortaix leafroller 7:193 Plasmodium 7:424 Plasmodium genus 19:587 Plasmodium falciparum 20:516,517,519-522 Plasmodium malariae 20:516,517 Plasmodium ovale 20:516 Plasmodium vivax 20:516 Plasmodium berghei 7:391,394,395 Plasmodium falciparum 7:391,392-394,424;13:656 antimalarial activity of 7:424 Pleiocarpa mutica 1:124 Pleiocarpa talbotii 13:397,424 Pleisopermium alatum 13:351,20:497 Pleraplysilla spinifera spiniferin 1 from 6:72 Pleurotus ostreatus 5:288 Plexaura homomalla 9:570 Plocam ium cartilagineaum 18:714 Plocamium coccineum 17:9 Pluchea arguta 5:202,204;9:65 Pluchea species sesquiterpenes from 9:65-68 Plumbago scandens 2:225

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Plumbago zeylanica 2:215,226 quinonesof 2:212-231 Pneumocystis carina 2:421 Podocarpus dacrydioides (-)-selin-ll-en-4a-ol from 14:449,450 Podochaenium eminens 7:416 Podophyllum emodi 17:341 podorhizol from 18:556 Podophyllum hexandrum 5:474,477,480,482,483,485497,488,493,494 Podophyllumpeltatum 5:480,483-485,493;17:341; 18:557 podorhizol from 18:556,557 podophyllotoxin derivatives of 7:416 Podophyllum sp. 5:461,477,481,483,485,489,493 Poecillastra species 19:580 Pogonomyrmex barbatus 5:250 Pogonopus speciosus 9:401 Pogonopus tubulosus 9:401 Pogostemon purpurascens 5:681 Pogostemon sp. (-)-patchoulol from 8:423 (-)-seychellen from 8:423 Polyandrocarpa species 10:248 Poly cavernosa tsudai 19:570 Polyfibrospongia species 19:577 Polygalafruticosa 7:415 Polygala polygama 17:341 Polygonum hydropirer 7:100,101,103,110,121;17:237 sesquiterpene from 1:701,702 Polygonum nodosum 7:427 Polygonum senegalense 7:427 Polymastia sp. 18:716 Polyorchis penicillans 9:493,494 Polypodium glycyrrhiza 15:28 Polypodium vulgare 15:28 Polyponus circinatus 5:288,308 Polyporus betulinus 5:288 Polyporusfomentarius 5:289 Polyporus giganteus 5:288 Polyporus igniarius 5:289 Polyporus tumulosus 5:288,290 Polyscias 7:435 Polysiphonia lanosa 4:712 Polytomella coeca 2:294 Ponerapennsylvanica 5:224,230,254 Populus maximowiczii 20:627 Poraniapulvillus 7:298 poranoside A from 7:299,301 P or aster superbus 7:299 Porella perrottetian 2:280 Porellasp 2:90 Porella cordeana 20:469 Poria cocos 5:288 Porthetria dispar 19:481 Porteresia coarctata 7:189 Prianos species muqubilinfrom 9:15 Primula denticulata 5:211 Primula obconica I'All Primula viscosa 20:740 Procambarus bouvieri 19:665 Procambarus clarkii 19:627 Propionibacterium shemanii 9:598,600-604;ll:182 Prorhinotermes simplex 19:118 Prorocentrum lima 5:384,17:20,19:617 Prosopisjuliflora 5:211 ;9:68-73 alkaloids from 9:70-73,290 terpenoid diketone from 9:68,69 Proteus 12:63 Proteus mirabilis 12:400;20:712,837,840,842,853, 855,858 Proteus vulgaris 9:308;12:103,400;20:831,837,839, 840,859,879 Protoreaster nodosus 7:290,304-306;15:46,60 5a-cholestan-3p,6a,8,15a,16p,25-hexol from 15:77 nodosocide from 7:295 Prunus cerasus 20:721 Psalliota bispora 13:310,304 Psalliota campestris 5:289 Psathyrotes ramosissima 7:427 Psendom onas aureginosa 20:712 PseudaminyssasptcxQS 9:38 Pseudobersana mossambicensis 20:478 bioactive steroids from 20:476 Pseudodistoma kanoko 10:249 Pseudodoynerus quadrisectus 5:224,232 Pseudomonas aerginosa 1:370,377;3:302;5:434; 9:308,537,540,553,555;12:63,103,401;14:144,236; 19:601 Pseudomonas aureofanines 9:527 Pseudomonas cepacia 4:432 Pseudomonas chloroaphis 9:537 Pseudomonas cichoriae 9:537 Pseudomonas coriacea 12:294 Pseudomonas denitrificans 9:600,603,604,606 Pseudomonasfluorescens 3:263;9:537,553; 10:78 Pseudomonas fluorescens lipase 1:685;13:54,55 Pseudomonas gQnus 19:791 Pseudomonas lipase PSL 13:55 Pseudomonas maltophilia 4:432 Pseudomonas morganii 5:434 Pseudomonas perolens 13:320 Pseudomonasputida 4:647;8:296,298,303,305,309; 9:537;13:58,299;18:430 Pseudomonas sorghi 9:220 Pseudomonas species 5:434;9:37;18:429,430 papakusterol (glaucasterol) from 9:37 for enantioselective hydrolysis 12:337 Pseudomonas striiformis 9:220 Pseudomonas syringae 4:590;9:537 Pseudomonas taetrolens 13:320 Pseudomyrmecine species 6:421,422 Pseudophryne coriacea 725 Pseudophryne genus 19:52 Pseudophryne guentheri 726 Pseudophryne Occident alls 18:726 Pseudoplexaura crucis 8:20 Pseudoplexauraflagellosa 8:20 Pseudoplexaura porosa (Plexaura crassa) crassin acetate from 8:20 Pseudoplexaura wagenaari crassin acetate from 8:20 Pseudopterogorgia americana (-)-p-gorgonene from 6:18,27

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Pseudopterogorgia elisabethae 15:259 pseudopterosins A-D 6:74 Pseudostichopus trachus pseudostichoposide A from 15:94 Pseudosuberites hyalinus 18:696 Psiadia 7:411 Psiadia trinervia 7:411-413 Psittacula krameri hemoglobin components of 5:837 PSL {Pseudomonas lipase) 13:55 Psolus fabricii 15:89 Psolusfabricii 7:278,279 Psoriasis 9:514,517 Psorospermumfebrifugum I'A 17-420,424 psoprspermin from 13:368 Pteridium aquilinum 6:194 Pterocarpus santalinus 20:774 Pterogyne nitenes 20:489 guanidine alkaloids from 20:488 Pterogorgia citrina 17:99 Ptychodiscus brevis 6:135 Puccinia 9:203,220,222 Puccinia antirrhini 9:220 Puccinia arachidis 9:220 Puccinia coronata 9:220,226 Puccinia coronata f.sp. avenae 9:220-223,228 Puccinia coronata f.sp.festucae 9:221 Puccinia graminis 9:220,226 Puccinia graminisf.sp. tritici 9:220,221,228 Puccinia helianthi 9:220 Pulchea indica 7:185 Purpurea glycoside A 15:362 Purpurea glycoside B 15:362 Pycnonotus cafer hemoglobin components of 5:837 Pycnonotusjocosus 5:837 hemoglobin components of 5:837 Pycnopodia heliantoides 15:46 pycnopodiosides A,B and C from 15:61 Pyicularia oryzae 12:401 Pyrenophora avenae 19:154 Pyricularia oryzae 1:404;4:598;15:385 Pyricularia sp 16:302 Pythium acanthicum 5:276 Pythiumsp. 5:276 Pythium ultimum 7:183,190 Pytophthora cinnamomi 5:276 Rabdosia Rabdosia Rabdosia Rabdosia Rabdosia Rabdosia laxiflora 15:176 lophanthoides 15:167 macrophylla 15:167 occidentalis 15:176 parvifolia 15:167 shikokiana 15:162,176

Quassi excelsia 7:124 Quassia amara quassin from 7:392 Quassia amora 7:124

Rabdosia amethystoides 15:167 Rabdosia diterpenoids classification of 15:112 Rabdosia eriocalyx 15:176 Rabdosia gerardiana 15:167 Rabdosia glutinosa 15:167 Rabdosia japonica 15:111

rabdoepigibberellolide from 15:112 Rabdosia species diterpenoids from 15:111-185 Rabdosia stracheyl 15:167 Rabdosia trichocarpa 15:135,176 Radula complanata 2:283 Radula kojana 2:283 Radulaperrottetii 2:283 Ramalina usnea 5:310,313 Rapanea laetevirens 9:321 Raphanus sativus 19:247 homoteasterone from 18:507 Ratibida columnifera 19:771 Rauwolfia alkaloids 14:553,19:748 Rauwolfia heterophylla 1:125 Rauwolfia nitida 1:125,126 Rauwolfia sellowii 1:125 Rauwolfia serpentina 1:125,126,283,390;2:369;13:629, 660;19:748 deserpidine from 8:283 reserpine from 8:283 Rauwolfia suaveolens 13:390,411 Rauwolfia tetraphylla 1:126 Rauwolfia verticil lata 13:391 Rauwolfia vomitoria 1:125,427 Rhazya stricta 5:135,140-144,150,152,153,165,167, 169,176,178 Rheum palmatum 17:421,439 Rhipocephalus phoenix 18:689 Rhizocotonia solani 7:190 Rhizoctonia leguminicola 7:11 ;19:468 (-)-(15,2/?,8aS)-indolizidine-l,2-diol from 12:303 slaframine from 12:306 (-)-swainsonine from 12:313 Rhizoctonia solani 13:233,234 Rhizophora apiculata 7:180-182,189,194,195 Rhizophora mangle 7:175 Rhizophora mucronata 7:176,180,188,189,192,194,195 Rhizophora sp. 7:176 Rhizophora stylosa 7:179-181,193 Rhizopus arrhizus 17:629 Rhizopus delemar 2:322,341 Rhizopus nigricans 17:629 Rhizopus niveus 2:322,341 glucoamylase from 7:49 Rhizopus sp. 2:322,323,276 glucoamylase from 2:341 Rhodoccus rhodocrous 8:299,302,303,312 muconolactone methyl isomerase from 8:307 Rhododendron chrysanthum 20:17 Rhododendron ferrugineum 20:17 Rhododendron hirsutum 20:17 Rhododendron luteum 20:17 Rhododendron molle rhomitoxin from 13:660 Rhododendron ponticum 20:17

1341

Rhododendron simsa 20:17 Rhodophida bifida 20:356 Rhodophyllis membranacera 5:410 Rhodotorula glutinis 5:292,309 Rhodotorula lactosa IF01424 13:233 Rhodotorula minuta 5:292,299 Rhodotorula peneaus 5:292 Rhodotorula rubra torularhodin from 7:340 Rhodotorula sp. 5:291,292 Rhus species 9:337 Rhus succendanea 9:319 Rhus toxicodendron 9:318,328,339 Rhus toxicodendron diversilobum 9:318 Rhus toxicodendron radicans 9:318 Rhus vernicifera 9:318,328,329,331,339 Rhytidoponera aciculata 5:224,229,254 Rhytidoponera chalybaea 5:224,225,229,246,254 Rhytidoponera metallica 5:224,226,229,243-247,251, 252,254,255,262,266,15:384 Rhytidoponera sp. 5:230,247 Rhytidoponera victoriae 5:223,224,229,251,254 Ribes nigrum 20:721 Ritterella sigilloides 5:253 Ritterella tokioka 18:881,882 Rodobyrum giganteum 2:277 Roemeria si^QCiQS 2:253 Rollinia mucosa rolliniastatin from 18:208 Rollinia sylvatica 9:399 Romalea microptera 9:488,489 Rosa damascena 14:425 a-damascenone from 14:425 P-damascenone from 14:425 y-damascenone from 14:425 a-damascone from 14:425 p-damascone from 14:425 y-damascone from 14:425 5-damascone from 14:425 Rosa damascena cv. trigintipentalla 7:125 Rosa damascena 7:104,107,109-112,125 Rosasx^. 7:102,105,107,108,125 Rubia cordifolia 10:640,19:776 Rubus fructicosus 20:721 Rubus ideans 20:721 Rubus suavissimus 15:16,18 desglucosylstevioside from 15:14 rubusoside from 15:14 Russula spQcies 17:153 Ruta chalepensis 7:427 Rzedowskia tolantonguensis 18:756,764

Saccharomyces bailii 8:238 Saccharomyces carls bergens is 19:601 Saccharomyces bailii 1:689 Saccharomyces cerevisiae 1:689,694;2:353,390;3:302, 5:418;10:526;12:103;13:302,307,312;17:241; 18:721, 722,727;20:470 dimethyl allyldiphosphate isomerase from 11:201 Saccharomyces dobzhanskii 5:287 Saccharomyces drosophila 5:287

Saccharomyces lactis 5:287 Saccharomyces lodderi 5:283 Saccharomyces microellipsodes 5:283 Saccharomyces phaseolosporus 5:287 Saccharomyces pretoriensis 5:283 Saccharomyces rosei 5:283 Saccharomyces sake 12:401 Saccharomyces sociasi 5:287 Saccharomyces sp. 5:279 Saccharomyces vager 5:283 Saccharomyces wieckerhamii 5:287 Saccharothrix bromorebeccamycin from 12:366,368 11-dechlorobeccamycin from 12:366,368 rebeccamycin from 12:366,368 Saccharothrix mutabilis 19:290 Saccharothrix mutabilis subsp. chichijimaensis 10:117 Saccharum officinarum 15:3 SdigQ {Salvia officinalis) 11:220 Salacia 18:741 Salacia macrosperma salaspermic acid from 7:150 Salix pet-susu 20:627 Salix sachalinensis 20:613,627,628,631,641,645 Salmonella 12:63 Salmonella anatum 0-antigen from 6:262 Salmonella enteritidis 12:401 Salmonella monteyideo 8:102 Salmonella newington 8:101 ;14:233 0-antigenic polysaccharide from 14:233 Salmonella paratyphi 9:308 Salmonella schottmuelleri 9:308 Salmonella thompson 8:102 Salmonella typhi 9:308,12:401 Salmonella typhimurium 5:440;9:214,606;12:401; 20:512 Salmonella typhosa 12:401 Salvia acetobulosa hormonone from 20:673 1-oxoferruginol from 20:673 3-oxoferruginol from 20:673 18-oxoferruginolfrom 20:673 ^isiferalfrom 20:673 sempervirol from 20:673 Salvia candidissima 11 -hydroxy-12-methylabieta-8,11,13-triene 11 P-hydroxymanoyl oxide from 20:691 14-oxoisopimaric acid from 20:688 1-oxoethiopinonefrom 20:680 1-oxosalvipisonefrom 20:680 3-oxosalvipisone from 20:680 7-acetyhorminone from 20:660 7p-hydroxysandracopimaric acid from 20:688 8,13-di-e/7/-manoyl oxide from 20:691 candidissiol from 20:680 cryptanol from 20:660 crysoeriol from 20:712 diosmetinfrom 20:712 ferruginol from 20:660 horminone from 20:660 isopimaric acid from 20:688

1342

manoyl oxide from 20:691 microstegiol from 20:680 montbretyl-12-methyl ether 20:661 salvipisone from 20:680 Salvia divaricata 6-horminone-18-oic acid from 20:661 6-0X0-12-methylroyleanone-18-oic acid from 20:661 P-sitosterol from 20:702 oleanolic acids from 20:702 oxoroyleanone-18-oic acid from 20:661 salvinine from 20:660 ursolic acid from 20:702 Salviaforskahlei 20:672,20:710 Salvia glutinosa 3-acetoxy-olean-9,ll-diene from 20:707 a-amyrin acetate from 20:707 ll-cholest-5-ene-3P,7a-diol-l-one from 20:707 erithrodiol 28-acetate from 20:707 3(3-hydroxy-ll-oxo-oleana-12-ene from 20:707 3p-hydroxy-ll-oxo-ursa-12-ene from 20:707 7a-hydroxysitosterol from 20:707 lupeolfrom 20:707 l-oxo-7a-hydroxysitosterol from 20:707 oxo-a-amyrin from 20:707 11-oxo-P-amyrin from 20:707 oleanolic acid from 20:707 stigmasterol from 20:707 sitosterol from 20:707 ursolic acid from 20:707 Salvia heldreichiana 7-0X0-13-^p/-pimara-8,15-diene-18-oic acid from 20:690 7p-hydroxy sandracopimaric acid from 20:690 di (4,4'-hexyloxy-carbonylphenyl) ether from 20:709 heldrichinic acid from 20:670 isopimaric acid from 20:690 salvigenin from 20:711 Salvia hierosolymitana forskalinone from 20:672 Salvia leucophylla 20:4 Salvia limabata abieta-8,11,13-triene from 20:673 a-amyrin from 20:702 dehydrosalvilimbinol from 20:683 eupatilinfrom 20:712 ferruginol from 20:673 12-hydroxysapriparaquinone from 20:683 3,12-hydroxysapriparaquinone from 20:683 2-hydroxysaprorthoquinone from 20:683 limbinol from 20:683 luteolinfrom 20:712 manool from 20:691 pectolinarigenin from 20:712 quercetin-3-methyl ether from 20:712 salvilimbinol from 20:683 stigmasterol from 20:702 vergatic acid from 20:702 Salvia montbretii 2^:666,61^,1X2,10A a-amyrin from 20:704 apigenin from 20:712

7,7'-bistaxodione from 20:678 cirsitiolfrom 20:712 3p-0-?ram-p-coumroylmonogynol A from 20:704 3p-0-/ra5-cw-coumaroyImonogynol A from 20:704 11,11 '-didehydroxy-7,7'-dihydroxytaxodione from 20:678 demethyleryptojaponol from 20:666 ferruginol from 20:666 ferruginyl 12-methyl ether from 20:666 hypargenin F from 20:666 6-hydroxy-salvinolone from 20:666 7-hydroxy-axodione from 20:666 14-hydroxyferruginol from 20:666 luteolinfrom 20:712 lupeolfrom 20:704 monogynol A from 20:704 oleanolic acid from 20:704 salvinolone from 20:666 salvinolonyl-12-methyl ether from 20:666 P-sitosterol from 20:704 taxodione from 20:666 ursolic acid from 20:704 Salvia multicaulis 7(3-hydroxy-3,11 -dioxo-pimara-8( 14), 15-diene from 20:690 horminone from 20:673 12-methy 1-5-dehydrohorminone 20:676 12-methy 1-5-dehydroacetythorminone 20:676 1-oxoferruginolfrom 20:673 3-oxoferruginol from 20:673 18-oxoferruginol from 20:673 pisiferal from 20:673 sempervirol from 20:673 salvipimarone from 20:690 Salvia napifolia 20:670 acetyl-horminone from 20:670 cryptanol from 20:670 cryptojaponol from 20:670 ll,12-dioxoabieta-8,13-diene from 20:670 7,20-epoxyroyleanone from 20:670 ferruginol from 20:670 horminone from 20:670 1-oxoferruginol from 20:670 6-oxoferruginol from 20:670 pachystazone from 20:670 sugiol from 20:670 6,12,14-trihydroxyabieta-6,8,11,13-tetraene from 20:670 Salvia nemorosa apigenin from 20:712 a-amyrin from 20:702 2a,14-dihydroxydehydroabietic acid from 20:669 eupatilinfrom 20:712 luteolinfrom 20:712 24-methylenecycloartenol from 20:702 nemorosine from 20:669 oleanolic acid from 20:702 salvipisone from 20:683 salvinemoral from 20:702

1343

p-sitosterol from 20:702 stigmast-7-en-3-one from 20:702 stigmast-4-ene-3-one from 20:702 stigmast-7-en-3-ol from 20:702 ursolic acid from 20:702 Salvia miltiorrhiza Cell suspension cultures of 2:402 Salvia officinalis 7:119;11:220 Salvia pomifera a-amyrin from 20:702 erithrodiol from 20:705 ferruginyl 12-methyl ether from 20:663 23-hydroxygermanicone from 20:705 18-Hydroxyabieta-8,ll,13-triene-7-one from 20:663 lupeolfrom 20:702 moradiol from 20:705 moronic acid from 20:705 pomiferin A-G from 20:663 P-sitosterol from 20:702 taraxasterol from 20:702 Salvia potentillifolia 20:660 Salvia prionitis 5:31,33,36 Salvia sclarea 7:101,103,110,123;20:660,669,633,691, 712 sclareolfrom 7:121 Salvia species biological investigations of 20:659 chemical investigations of 20:659 Salvia splendens 5:646 Salvia tchihatcheffii 3-acetylerythrodiol from 20:707 28-acetylerythrodiol from 20:707 3-acetyloleanolicaldehyde from 20:707 3P-acetylolean-12-en-28-al from 20:707 salvitchitatine from 20:676 tchitatine from 20:676 Salvia tomentosa ferruginol from 20:667 horminone from 20:667 1 -oxo-abieta-8,11,13-triene-18-oic acid from 20:9 Salvia triloba salvigenin from 20:711 Salvia wiedemanni 7p-hydroxysandracopimaric acid from 20:688 isopimaric acid from 20:688 14-oxoisopimaric acid from 20:688 salvigenin from 20:711 Salvia yosgadensis ambrenolide from 20:692 apigenin-7-methyl ether from 20:712 apigenin-4-methyl ether from 20:712 apigenin-7,4-dimethyl ether from 20:712 apigenin-6,4-dimethyl ether from 20:712 apigenin from 20:712 6a, 14-dihydroxymanoy 1 oxide-15,17-diene16,19-olidefrom 20:697 6a, 16-dihydroxymanoyl oxide-14,17-diene16,19-olidsfrom 20:697 6a-hydroxyambrenolide from 20:692 6 a -hydroxynorambrenolide from 20:692 6 a -hydroxy-8a-acetoxy-13,14,15,16-

tetranorlabdane-12-oic acid 20:692 kaempferol-3-methyl ether from 20:712 luteolinfrom 20:712 norlabdane diterpenoids from 20:692 norambrenolide from 20:692 yosgadensonol from 20:696 13-e/7/-yosgadensonol from 20:696 yosgandensolide A and B from 696 Sanguisorba officinalis 17:421,423 polyphenols 17:423 Santalum album (3-santalol from 8:145 Santolina chamaecyparissus 7:100,101 Sapium indicum 7:188 4a-sapinine from 7:187 Saprolegniaparasitica 9:577,578 Saprophyton glaucum papkusterol (glaucasterol) from 9:37 Sarcinalutea 12:401 Sarcomelicepe agyrophylla 20:807 Sarcomelicepe simplieifolia 20:807 Sarcomelicope dogniensis 20:806 Sarcomelicope glauce 20:806 Sarcocapnos enneaphylla 3:428 Sarcophyton glaucum 8:18 Sargassum tortile 20:25-27,29,34-36 Sarotherodon nilotica 7:184 Saururus cernuus 17:319 Saussurea lactonQ 7:216,237 Saxicola insignis hemoglobin components of 5:837 Saxidomus gigantius 5:3 Scaevola racemigera strychnovoline from 6:522 Sceletium alkaloids synthesis of 4:4,5,8-12 Schaefferia cuneifolia 18:761 Schelhammera spp. 3:455,483 Schelhammmerapedunculata 3:484,486 Schistocerca 9:498 Schistochila appendiculata 2:280281 Schistosoma haematobium 7:425 Schistosomajaponicum I'AIS Schistosoma mansoni 7:425,428 Schizandra sp. 5:462 Schizophyllum commune cellulase from 8:352 Schizophyllum commune fruiting body formation of 1:680,681 Schizophyllum commune 5:288,316;18:460,813,814 Schizosaccharomyces octosoporus 5:280,286,293 Schizosaccharomycespombe 5:280,286;12:398;18:721 Schizothrix calcicola 18:294,20:586 Schlerochiton ilicifolius 15:335 Schwanniomyces alluvius 5:283 Schwanniomyces castelli 5:283 Schweinfurthia papilionaceae alkaloids from 9:75,76,78 Scidopitys verticillata 20:107 Sclerotinia 4:246 Sclerotinia cinera 12:401 Sclerotiniafructicola 6:546,547 sclerosporin from 6:546

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Sclerotinia sclerotiorum 15:385;18:269 Sclerotinin A and B 15:385 Sclerotium cerevisiae 5:279-282,285,323 Sclerotium fermenti 5:280 Sclerotium fragilis 5:280,282 Sclerotium glucani 5:277 Sclerotium glucanicum 5:314 Sclerotium libertiana 5:277 Sclerotium rolfsii 5:314 Sclerotium rouxii 5:282 Scolytus multistriatis (elm-bark beetle) multistriatin from 14:274 Scolytus multistriatus 19:127 (35',45)-4-methyl-3-heptanol from 11:412 Scolytus multistriatus 15:348 Scolytus scolytus 15:348,349 Scopolia genus 17:395 Scopoliajaponica Maxim. atropine from 5:505 Scorpiurus muricatus 19:117 Scripus maritimus 9:391 Scrophularia canina I'Ald Scutellaria tenax 5:678 ^cy/Zo-inositol from a-glucosidases 7:37,38 ^cy/Zo-nitrocyclitols 7:157 Scyphyphora hydrophyllaceae 7:176 Scytonemasp. 5:429 Secale cereale 18:500,502,512,19:247 Securiflustra securifrons 18:691 Securinega alkaloids 5:49 Securinega species 10:153 Securinine alkaloids synthesis of 14:657-659 via Norrish type II reaction 14:657-659 Selinum vaginatium 5:728 Selligueafeei 15:33 Semecarpus heterophylla 9:319 Semecarpus vernicifera 9:319 Senecio amplexicaulus endesm-1 l-en-14-ols from 14:450 (+)-intermedeol from 14:450 Senecio oxyodontus senoxydene from 13:13 Senecio toxicosis 7:23 Seratia marcescens 12:103 Serratia marcescens 12:401 Serratia marcescens 9:308 5err/msp. 4:434;12:103 Sesamum angolense 7:407,417,423 Sesbania drummondii 1:305,514 Sesbania punicea 1:305 Sesbania sesban 7:427,432,433 Sesbania vesicaria 1:305 Shigella sp. 12:63 Shigella flexnert 0-antigenic polysaccharide from 14:233 Shigella dysenteriae 9:308 Shigella sonnei 9:308;12:401 Shizandra chinensis B 18:589 Shodoptera littorolides 20:245 Sida acuta 5:751

Sida carpinifolia 5:752 Sida cordifolia 5:75 Sida rhombifolia 5:751 Sida sp. 5:751 Sideritis sp. 5:658 Silphinium perfoliatum silphinene from 8:165 Silphium perfoliatum silphinene from 13:8 (-)-silphiperfol-6-ene from 13:8,11 Silybum marianum 5:496 silymarin from 13:660 Simabaamara 7:369,381 Simabacedron 7:392 Simaba cuspidata 7:369,381 Simaba multiflora 7:369,380,396 Simalikalactone-D 7:391,392,395,396,398;11:72,79 Simarouba glauca glaucarubin from 13:660 Siphonaria atra 17:25 Siphonaria baconi 17:25,28 Siphonaria diemenesis 17:24 Siphonaria laciniosa 17:25 Siphonaria maura 17:25,26 Siphonaria normalis 17:25,27 Siphonaria species 17:23,26,28 Siphonaria zelandica 17:25 Siphonoborgia species 9:37 (22i?,23/?)-22,23-methylene cholesterol from 9:317 Sir aitia grosvenorii 15:5,22 Siraitia siamensis 15:24 Sitophilus granarius 18:698 Sitophilus oryzae 9:299 5/Yw ketalization 11:361 Slum latifolium 5:724,728,20:6 Sium latijugum 5:728 Smenospongia aurea 5:437 8-epichromazonaral from 15:291 Smenospongia sp. 5:429,43-0,432-434,439 Sodoptera littorals 18:772 Solanum 2\k3i\o\&s 7:17,19,21,22,24 Solanum duleamara 20:135 Solanum eleagnifolium 7:19 Solanum ^ycodXkaXoids 1\\1 Solanum indicum 20:135 Solanum mammosum I'All Solanum melongena 20:135 Solanum ridellii 7:23 Solanum sp. 7:21,22 Solanum tuberosum 7:20,22;20:135 Solanum umbelliferum steroidal alkaloids from 20:489 Solanum xanthocarpum 20:135 Solaster borealis solasteroside from 15:55 Solenopis aurea piperidine venom alkaloids in 6:423 Solenopsis (fire ants) 6:422 SolenopsisA 1:389,390 Solenopsis carolinensis piperidine venom alkaloids in 6:423

1345

Solenopsis conjurata indolizidine alkaloids in 6:450 piperidine venom akkaloids in 6:423 Solenopsis eduardi piperidine venom alkaloids in 6:423 Solenopsis fugax piperidine venom alkaloids in 6:436 Solenopsis geminata piperidine venom alkaloids in 6:423 Solenopsis invicta pheromone synthesis 1:682 Solenopsis invicta 3:273;5:228 piperidine venom alkaloids in 6:423 Solenopsis littoralis 6:423 piperidine venom alkaloids in 6:423 Solenopsis molesta 6:436 pyrrolidine venom alkaloids in 6:436 Solenopsis pergandei piperidine venom alkaloids in 6:423 Solenopsis punctaticeps pyrrolidine venom alkaloids in 6:423 Solenopsis richteri 6:423 piperidine venom alkaloids in 6:423 Solenopsis saevissima piperidine venom alkaloids in 6:423 Solenopsis sp. arthropod alkaloids from 11:231 Solenopsis species 6:450,454 alkyl-1-piperideine in 6:422 Solenopsis texanas 6:436 pyrrolidine venom alkaloids in 6:436 Solenopsis xyloni 6:422,423 2-methyl-6-alkyl-l-piperideine in 6:422 piperidine venom alkaloids in 6:422,423 Solidago altissima 19:247 Solidago saponins 15:191 Solidago species kolavenic acid from 6:28 Solmonella anatum 8:101,103 Sonneratia alba 7:176,194,195 Sonneratia apetala 7:188 Sonneratia caseolaris 7:176 Sonneratia grift ithie 7:195 Sonneratia ovata l:\76 Sonneratia sp. 7:176 Sophora chrysophylla 15:522 Sophoraflavescens 9:148 Sophora griffithii 9:149 Sophora tomentosa (-)-epilamprolobine from 15:522 (+)-epilamprolobine A^-oxide from 15:522 5-(3 '-methoxycarbonylbutyroyl) aminomethyl/ram-quinolizidine A^-oxide from 15:522 Sorghum bicolor 9:322,344 Sorocea bonplandii 17:458 Soulamea soulameoides 7:396 Soulamea tomentosa 7:369,381 Sphaerantnus indicus 9:145 Sphaerechinus granular is 15:104 Sphaereophorus globosus 5:310 Sphaerodiscus placenta 7:3 04-3 06 22-dehydrohaIitylosides D,E from 7:298

halitylosides A,B,E from 7:298 placentoside A from 7:298 Sphaerophorin cetraria 9:317 Spheciospongia vagabunda (245,255)-24-26-cyclocholesterol from 9:37 Spilanthes alba 10:152 Spinus tristis hemoglobin components of 5:836 Spizella arborea hemoglobin components of 5:837 Spizella passerina hemoglobin components of 5:837 Spodoptera frugiperda (army worm) 14:451 Spodoptera eridania 7:396 Spodoptera littoralis 18:772,20:245 Spongia hispida 15:312 Spongia mycofijiensis 19:568 Spongia nitens 17:10 Spongia officialis 17:10 Spongia officinalis isoagatholactone 6:56,107,108 Spongia sp. 5:371 ;6:107,111 Sporobolomyces odorus 13:309,312 Sporobolomyces reseus 5:291 Sporobolomyces sp. 5:291 ;13:315 Sporomia fimgi 6-methoxymellein from 15:384 Sporothrix curviconia 5:304 Sporothrix inflata 5:304 Sporothrix schenckii 5:302-305,322,325 monohexosylceramides 18:807 Sporothrix schenckii var. luriei 5:304 Sporothrix sp. 5:302,304,325,328 Sporotrichum dimorphosporum 8:349 xylanase A 8:349 xylanaseB 8:349 Sporotrichum thermophile 2:323 Sprekeliaformosissima 20:356 Staphylococcus aureus 3:302;5:368,370;505,511;7:282, 304,309;9:308,500;8:102;10:117;12:401;13:162,164,1 73,181,183;17:285;18:777,778;19:556,601,712; 20:30,32 Staphylococcus citerus 9:308 Staphylococcus epidermidis 9:308;12:401;13:164,173; 20:712 amylopectin in 7:32 amylose in 7:32 enzymatic conversion to glucose 2:321 enzymatic hydrolysis of 10:496-503 Steganotaenia araliaceae 17:346 Stelospongia conulata 15:312 Stemphylium radicinum 19:154 Stenodynerusfloridans 5:223,253 Stenodynerusfulvipes 5:223,224,232,253 Stephania erecta 20:522 Stephaniajaponica protostephanine in 6:480 Stephaniapierrei 20:522 (+)Stephania venosa 2:253 Steracaulon ramulosum 5:310,311 Stereocaulonjaponicum 5:310 Stevia phlebophylla 15:16

1346

Stevia purpurea 1-bisasolones from 8:44-46 Stevia rebaudiana 15:4,5 Stichopus chloronotus stichlorosides A,, B,, Cj and A2, B2, C2 15:87 Stichopus chloronotus 7:272 Stichopusjaponicus 7:277 holotoxins A, Ai, B and Bi, 15:87 Stichopus sp. 7:282 Stichopus variegatus 7:2 72,2 82 stichoposide D from 7:273 Stillingia lineata 7:417 Stomphia coccinea 15:66 Stongylocentrotus purpuratus 9:575 Streotpmyces lysosuperficus 1:417 Streptococcal carbohydrates 19:696 Streptococcus bovis 19:696 Streptococcus faecalis 12:401,19:696 Streptococcusfaecium 4:432,12:103,401 Streptococcus mutans 7:69;18:673,20:32,34,36 Streptococcus pneumoniae capsular polysaccharide 14:233 Streptococcus pyogenes 5:601,9:308,10:117,13:162, 173,181,183,19:492 Streptococcus sanguis 7:69 dextransucrase from 7:41 Streptococcus sp. 5:325;16:108 Streptomyces actuosus staurosporin ("NB-2025") from 12:365 Streptomyces aizunensis aizumycin from 12:63 Streptomyces amakusaensis 19:178 Streptomyces ambofaciens 5:613,614 Streptomyces antibioticus 11:214,215 chlorothricin producer 11:214,215 Streptomyces aureus 5:429,434 Streptomyces avermitilis 1:435 avermectins from 12:3 Streptomyces azureus thiostrepton from 11:209 Streptomyces bikiniensis 18:700 Streptomyces cacoi war. asoensis 1:399 Streptomyces caespitosus 9:431;13:434 albomitomycin A from 13:433 isomitomycin A from 13:433 mitomycins A-C from 13:433 Streptomyces cattleya thienamycin from 11:210;12:145 Streptomyces cellulosae 12:103,54 Streptomyces chrysomallus 8:102 Streptomyces cinnamonensis 11:197 Streptomyces coelicolor 5:617,618 Streptomyces collinus ansatrienin (mycotrienin) from 11:189 enoyl CoA reductase from 11:190-191 Streptomyces diastatochromogenes staurosporine from 12:366 Streptomyces distallicus 5:551 Streptomyces erythreus 13:166 Streptomyces Jlaveolus tirandamycin A from 14:98 tirandamycin B from 14:97,98

Streptomyces flavogriseus 10:103 Streptomyces fradiae 5:591 urdamycin from 11:134 Streptomyces gougerotti 4:242 Streptomyces griseochromogenes 18:269 Streptomyces griseochroogenes 4:242 Streptomyces griseoflavus 12:63 ;19:165,167 Streptomyces griseolavendus 15:445 Streptomyces griseolus 1:408 Streptomyces griseoplanus 10:104 Streptomyces griseus 1:514;7:388;18:700;19:587 Streptomyces griseoflaus 19:165,177 Streptomyces grisline indolizomycin from 12:300 Streptomyces hygroscopicus subsp limoneus 13:223 Streptomyces incarnatus 19:177 Streptomyces lavendulae 10:77-80 Streptomyces lusitanus 10:103 Streptomyces lydicus 14:105 streptolydigin from 14:97,98,100 Streptomyces matensis 11:113 vineomycin A1 from 11:113 Streptomyces matensis subsp. vineus 5:594 Streptomyces mediocidicum telocidines from 11:278 Streptomyces melanovinaceus 10:115,19:289,340 Streptomyces miharaensis 1:404 Streptomyces mobaraensis 15:457 Streptomyces morookaensis 4:242 Streptomyces noboritoensis 5:590 Streptomyces nodosus 4:513 amphotericin B from 6:261 Streptomyces nodosus var. asukaensis asukamycin from 11:189 Streptomyces nogalater nogalamycin from 14:47 Streptomyces novoguineensis 1:404 Streptomyces OM-4842 5:597 Streptomyces oxamicetus 4:234 Streptomyces pactum 15:457 Streptomyces phaeochromogenes 18:10 Streptomyces phaeochromogenes 5:553 Streptomycesplicatus 4:243,244 Streptomyces ramulosus (-)-acetomycin from 10:443 Streptomyces rhishiriensis ansatrienin (mycotrienin) from 11:189 Streptomyces rimoss tetrangomycin from 11:135 tetrangulol from 11:135 Streptomyces rosa var. OS-3966 11:127 Streptomyces sandaenis 13:434 Streptomyces sapporonensis bicyclomycin from 12:63 Streptomyces sp. 5:35,55,377,607,615-618 Streptomyces sp. C-71799 staurosporin from 12:366,367 Streptomyces sp. M-193 12:365 Streptomyces sp.^-\26 12:366,368 Streptomyces sp. PK-286C staurosporine from 12:366

1347

Streptomyces sp. RK-286 RK-286Cfrom 12:366 Streptomyces species 9:433-435;ll:189;18:229 validamycin A from 13:189 Streptomyces spectabilicus 20:796 Streptomyces spiroverticillatus tautomycin from 18:269 Streptomyces staurosporeus 1:3; 5:5 5; staurosporine ("AM-2228") from 12:365 BMY-41950from 12:366,368 Streptomyces subflavus subsp. irumaensis 5:597 Streptomyces tanashiensis 5:618 Streptomyces teryimanensis indolizomycin from 12:300 Streptomyces tirandis 3:270; tirandalydigin from 14:97,98 tirandamycin A from 14:98 Streptomyces venezuelae 5:552 Streptomyces verticillatus 9:433-434 Streptomyces violaceoniger 4:255 Streptomyces violaceoruber granaticin producer 11:214,215 Streptomyces viridosporus 15:441 Streptomyces zelensis 1:180 ;3:310 Streptopelia chinensis suratensis hemoglobin components of 5:837 Streptopelia orientalis hemoglobin components of 5:837 Streptoverticilium rimofaciens B98891 4:245 Streptoverticillium ardum porfiromycin from 13:433 Streptoverticillium mobaraense BE-13793 C from 12:366,370 Streptoverticillium olivoreticuli subsp. neoenacticus 10:638 Streptoverticillium verticillus 19:351 Striga asiatica 5:823;9:364 Stronglyophora hartm ani 15:312 Strongylocentrotus droebachiensis 7:285; 15:104 Strongylocentrotus intrmedius sulfated sterols from 7:285 Strongylocentrotus purpuratus 15:104 Strurnus vulgaris hemoglobin components 5:836 Strychnos species 6:503 Strychnos alkaloids 16:435 from 2-pyiTolidones 14:560,561 nomenclature of 1:33 numbering of 1:33 synthesis of 14:560,561 Strychnos dinklagei 6:503-536 alkaloids of 6:503-506 brafouedine from 6:503-506 cantleyine from 6:503-506 dinklageine from 6:522 ellipticine from 6:506 gentianine from 6:529 10-hydroxyellipticine from 6:509 18-hydroxyellipticine from 6:513 isobrafouedine from 6:503-506 8-methoxy-8,10-dihydrogentianine from 6:529 7-0-[4-methyl-5-( 1 -hydroxyethyl) nicotinoyl]

strychnovoline from 6:522,527 monoterpene alkaloids from 6:522-527 oxidizing enzymes in 6:520 A^-b-oxy-17-oxoelipticine from 6:513,515 strellidimine from 6:516 venoterpine from 6:527 Strychnos gossweileri 1:125 Strychnos longicaudata 1:124 Strychnos melinoniana 1:124,125 Strychnos ngouniensis 1:124 Strychnos nux-vomica cantleyine from 6:503 Strychnos usambarensis 1:124,126 Strychnos vacacoua bakankoside from 6:503 Sturmus pagodarun 5:837 hemoglobin components of 5:836 Stylocheilus longicauda 17:4,104,19:549 Stypopodium zonale 5:439;6:54 stypodiol from 6:54 stypoldione from 6:54 Styracaster caroli carolisterol A-C 15:75,76 Subergorgia suberosa 13:26 Subulitermes bailey eudesm-1 l-en-4-ols from 14:451 neointermedeol from 14:451,452 Subulitermes oculatissimus neointermedeol from 14:451 Subulitermes parvellus neointermedeol from 14:451 Swainsona canescens (-)-swainsonine from 12:313 Swainsona species 7:11 ;10:558 Swartzia madagascariensis 1:417,427,429,431,432 Swartzia simplex 7:427,429 Symphytum officinale 9:60-62 saponins from 9:60-62 Synechocystis trididemni 10:251

Trypanasoma dionisii 18:801-804 Trypanasoma verpertillionis 18:801,804 Tabebuia avellandeae 5:16;15:385 Tabernaemontana ciliata 5:83 Tabernaemontana divaricata 9:166-168 Tabernaemontana eglandulosa 5:109 Tabernaemontana orientalis 5:70 Tabernaemontana pachysiphon 5:110 Tabernaemontana rigida 5:107 Tabernaemontana sp. 5:69-70,83,84,86,89,93 indole alkaloids 5:69-134 Tabernaemontana spQciQS 9:164,165 Tachytes guatemalensis 5:223,253 Taiwania cryptomeroides 17:333 Talaromyces stipitatus talaromycin A and B from 14:531 Talinum tenuissimum 7:427,435 Tamus communis 17:130,132 Tanacetrum vulgare 7:94,95,98,101,102,108,109, 112,120 Tanacetum parthenium 7:119,120

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Tanacetum vulgare 11:221 Taonia atomaria taondiol from 6:54 Tararomycin stipitatus 3:262 Targionia hypophylla 2:278 Taricha torosa 18:724 Taxodium distichum 14:667 taxodione from 14:667 Tethys fimbria 19:552 nudibranch 19:551 Taxopneustes pileolus 7:283-285 Taxusbaccata 11:61,20,79,80,112,116,118 10-deacetyIbaccatin III from 11:61 abscessic acid from 10:118 betuloside from 20:111 escholtzxanthine 20:118 isotaxiresinol from 20:108 secoisolariciresinol from 20:108 taxiresinol from 20:108 taxicatinfrom 20:116 Taxus brevifolia taxolfrom 11:5,12:180 diterpenesof 7:416 Taxus brevifolia 20:140 Taxus canadensis canadensiene from 20:107 Taxus chinensis 20:107 Taxus cuspidata 20:80 Taxusfloridata 20:81 Taxus mariei a-conidendrine from 20:108 kojic acid from 20:118 Taxus media 20:81 Taxus species chemical constituents of 20:79-123 Taxus wallichiana wallifoliol from 20:107 Tebebuia chrysantha naphthopyrans from 4:388 Tecona grandis naphthopyrons from 4:388 Tedania ignis 19:558 Teleogryllus commodus 5:815,830,831 Telesto riisei punaglandin from 1:687 Terminalia alata {Terminalia tomentosa) arjunolic acid from 7:134 maslinic acid from 7:134 maslinic lactone from 7:134 oleanolic acid from 7:134 terminolic acid from 7:134 Terminalia arjuna arjunosides I-IV from 7:133 terminic acid from 7:133 terminoic acid from 7:133 Terminalia siricia siricic acid methyl ester from 7:132 Terminalia tomentosa {Terminalia alata) 7:134 Terminalis sp. triterpenes of 7:133-135 Terron phoenicoptera hemoglobin components of 5:837

Tessaria dodoneifolia 15:31 Tetrahymena pyriformis 2:294 Tetrahymena thermmphila 2:306 Tetrahymena thermophilas 4:268 l(2,3,4,6-tetra-0-benzoyl-P-glucopyranosyl)-2pyriidine 4:224 Tetramorium caespitum 5:235,254 2,5-dimethyl-3-ethyl-pyrazines from 5:223 2,5-dimethyl pyrazines of 5:222 methyl pyrazines from 5:222 Tetramorium impurum 5:235,254 2,5-dimethyl-3-ethyl-pyrazines from 5:223 2,5-dimethyl pyrazines of 5:222 methyl pyrazines from 5:222 Tetranychus urticae 1:702 Tetraplaura tetraptera l'A2>A Tetraponera alkaloids 6:451-454 Tetraponera species 6:451 Teucrium fruticans 7:119 Thadiantha grosvenorii 15:22 Thapsia villosa 18:685 Thaumatococcus daniellii 15:5 Thea sinensis 19:247 Thelenota ananas 7:272 thelothurin A from 7:273 theothurin B from 7:273 Theonella sp. 5:355,364 Theonella swinfoei 5:356,396,20:894,896,589 Therioaphis maculata germacrene-A from 8:221 Thermopsis chinensis 15:523 (+)-5,6-dehydrolupanine from 15:523 Thermopsis lupinoides 15:523 (+)-lupanine A^-oxide from 15:523 Thladiantha grosvenorii 15:5 Thorecta choanoides 15:312 Thorectasp. 5:410 Thorectandra excavatus 18:717 Thromidia catalai 7:299;15:46 thomasteroside A from 15:45 Thuja occidentalis 2:402,20:16 Thuja oriental is 20:16 Thuja plicata thujonefrom 14:389,390 Thuja plicata 5:476 Thuja plicata D.Don 16:269 Thuja plicata Don 17:338 Thujia orientalis 8:3 essential oil from 8:3 Tilapia mossambica 5:370 Tilapia nilotica 7:183,185,187 Tilletiopsis sp. 5:291 Tiphia sp. 5:225,253 Torpedo califronica 18:721 Torulopsis colliculosa 5:283,292 Torulopsis gropengiesseri 5:293 Torulopsis lactis-condensi 5:293 Torulopsis magnoliae 5:293 Torulopsis sp. 5:292 Toxocara canis 17:379 Toxoplasma gondii 13:183 Toxotrypana curvicauda 5:239,252 2-methyl 6-vinyl-pyrazines of 5:222

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Trachelospermum asiaticum Nakai var intermedium 5:505,515,521,526,545 Tremella mesenterica 5:288,289,307 Tremella sp. 5:288 Tribolium castaneum 9:299 Tricellaria ternata 17:92 Trichilia emetica 20:492,493 Trichocolea tomentella 2:278 Trichocoleopsis sacculata 2:278,279 Trichocoleopsis sp 2:90 Trichoderma harzianium 4-thiocellobiose from 8:352 Trichoderma lignorum xylanases from 8:352 Trichoderma reesei cellobiohydrolases from 8:348,351 cellobiohydrolase A from 8:351 cellobiohydrolase B from 8:351 Trichoderma sp. 5:368;7:406 Trichoderma viride 4-thiocellobiose from 8:352 Trichommonasfoetus 2:293 staurosporine against 12:397 Trichomonas gallinae 2:294 Trichophyton granulosum 5:294 Trichophyton interdigitale 5:294,298,598;12:401 Trichophyton mentagrophytes 2:446; 12:401 ;20:28, 30,31 Trichophyton rubrum 5:294,236,12:401 Trichophyton schonleinii 5:294 Trichophyton sp. 5:294,328 Trichophyton tonsurans 12:401 Trichoplusia ni 5:832 Trichosanthes kirilowii 13:655,660 Trichosporon aculeatum 5:283,292 Trichosporon cutaneum 5:292,294 Trichosporonfermentans 5:292 Trichosporon inkin 5:294 Trichosporon sericeum 5:294 Trichosporon sp. 5:292 Trichosporon undulatum 5:294 Trichothecium roseum 10:307 Tricophyto mentagrophytes 9:297 Tridedemnum sp. didemnine A from 12:477 didemnine B from 12::303 Trididemnum cyanophorum 4:102;5:427,428;10:244, 250,251,252,262,294 Trididemnum palmae 10:252 Trididemnum solidum 10:245,250,252,253 Trididemnum solidum 4:102 Trididemnum species 10:245 Trididemum sp. (cf. olidum) 5:422 Tridiemnum genus 17:23 Trillium glycosides antifimgal activity of 2:443 Trillium grandiflorum 2:443 Trillium tschonoskii 2:443 Trimusculus reticulatus 17:27 Tripneustes gratilla 7:283,284

Tripterygium wilfordii 2:403,404,414,416;7:146 tissue culture of 7:146 triterpenes of 7:146 Triticum 9:321 Triticum aestivum 18:503,512,520,19:247 3-dehydroteasteron from 18:500 Triticum vulgare 9:321 Trypamosoma 18:791,793 Trypanosoma burcei 18:448,449 polysaccharides of 2:310 Trypanosoma conorhini 2:311 Trypanosoma cruzi 18:796-802 glycosphingolipids 18:796-802 glycocomplexes of 2:302-309 Trypanosoma mega 18:804 glycocomplexes of 2:310,311 polysaccharides of 2:310,311 Trypanosoma spp. glycocomplexes of 2:301-310 polysaccharides of 2:301-310 Trypterigium sp. 18:753 Trypterigium wilfordii 18:771 Tubastraea aurea 5:359 Tubastrea micrantha 5:360 Tulip a gesneriana 19:247 Tubulanus punctatus 18:725 Turbo connutus mixed glucosidase from 7:270 Turdoides somerville hemoglobin components of 5:837 Turus migratorius hemoglobin components of 5:836 Tutufa lissostoma 18:724 Tylophora hirsuta phenanthroindolizidine alkaloids from 12:300 Tylophora spQc'iQS 1:360 Typha latifolia 19:247

Ucapugilator 19:628 Udoteaflabellum 16:312 Ulmus thomasii 17:338 Ulvalactuca 7:338 (65',6'5)-8,8-carotene from 7:338 Umbilicaria angulata 5:311 Umbilicaria caroliniana 5:311 Umbilicaria polyphylla 5:311 Uncaria gQmxs 17:122 Uncaria guaianensis 17:116,124 Uncaria tomentosa 116,118,124 Uromyces phaseoli 9:220 Usnea rubescens 5:310 Usnea sp. 5:311,313 Ustilago species 9:203 Uvaria accuminata 17:251 uvaricin from 18:193 Uvaria narum isodencetyl uvaricin from 18:221

Valeriana officinalis monoterpep'* alkaloids from 6:524

1350

Valsa ceratosperma 5-methylmellein from 15:385 Vellozia Candida rosane diterpenoids of 20:474 Velocitermes velox 14:451,452 (+)-intermedeol from 14:451,452 Vepris lousii 2:121 Veratrum alkaloids 7:16,20-22 Veratrum califormicum steroidal alkaloids from 7:16 Verbesina rupestris 16:131 Vernonia galpinii 5:728 Verongia species 10:632 Verongia spengelii 5:410 Vespa orientalis 4:494,19:133 Vibrio cholerae 4:195 Vibrio ordalii tetraheptoses in 4:195 Vibum ium dilatatum 4:712 ViciafabaL. 19:247 Vigna radiata 23-(9-P-Z)-glucopyranosyl brassinolide from 18:522 Vinca major elegantissima 1:124 Vinca minor 2:370 (-)-ebumamonine from 8:283 (+)-vineamine from 8:283 Virola elongata 17:319 Virola sebifera 18:726 Vismia decipiens 4:378 Vitis vinifera 20:721,723,724,731 Viverra civetta 8:219 Volvariella volvacea 5:287,288,290,316,320

Xenor habdus spp. 15:381 Xeromphis spinosa I'All Xestospongia exigua 15:312;17:33 Xestospongia sapra 15:312;17:33 Xestospongia sp. 5:350,353;18:718 (22/?,23/?)-22,23-methylenecholesterol from 9:37 Xiphidium 17:372 Xylocarpus grantum 7:190,191,195 Xylocarpus moluccensis 7:176,191,195 xylomollin from 7:185 Xylocarpus sp. 7:176 Xylopia aethiopica 20:484 oxoaporphines of 20:483

Yarrowia lipolytica (Candida lipolytica) 13:308,312, 313 Yersinia 4:195

Wachendorfia 17:372 Warbugia stuhlmannii 17:234 Warbugia ugandensis 17:234 Warburgia stuhlmanii 4:403,427 Warburgia ugandensis 4:403,427 Wedelia asperrima 20:8 Wedelia glauca 20:8 Wedelia scaberrima I'All Wiesnerella denudata 2:280 Withania coagulans 20:238 Withania somnifera 20:13 8,180,181,234,238,241,246, 247 Wurmbea species synthesis of 6:158 Xanthophils 6:158

Zamthaxylum americanum 9:402 Zanthoxylum ailanthoides 10:152 ZeamaysL. 19:247 Zelus leucogrammus 2:299,301 Zeuxis siquizorensis 18:724 Zingiber officinale 9:321 ;17:365 sesquiterpene from 8:52 Zingiber offiicinarum 17:378 Zingiber species 17:365 Zinziber cassumar 17:365 Zinziber officinale 17:365 Ziziphus jujuba 15:36,18:671 Ziziphus mauritiana 20:507 Zonotrichia leucophyrys hemoglobin components of 5:837 Zoobotryon verticillatum 17:85 Zoogloea ramigera 1:689,690 Zygophyllum propinquum saponins from 9:59-62 Zygosporium masonii 15:356

Xanthoceras sorbifolia triterpenoids of 7:139,141 Xanthomonas campestris 5:314;12:401 Xanthomonas oryzae carboxylate against 12:398 Xenopus laevis 8:435 (3-thymosin from 8:435 thymosin P4xen 8:435 Xenopus oocyte 15:451 Xenorhabdus nematophilus xenocoumacins from 15:389