You are on page 1of 7

Supporting Materials

Using Curved Arrows for Retrosynthetic Analysis


John W. Keller
Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK 99775-6160

1. Table S1. Using curved arrows for retrosynthetic analysis: ten examples
2. Table S2. Example retrosynthesis problems and solutions

Table S1. Using curved arrows for retrosynthetic analysis: ten examples
No.

Forward
reaction

Reverse mechanism

Stepwise algorithm
Carbonyl condensations

Aldol
condensation B

H
O

H
O

Aldol
dehydration

a. Add hydroxide ion back to the


-carbon of the ,-unsaturated
aldol dehydration product, putting
the , -bond electron pair onto
the -carbon to form an enolate.
b. Protonate the enolate -carbon
with solvent.

HO
H

RO
3

H
B

OH

OH

RO

Claisen
RO
condensation
O

RO O

RO

H
RO

RO

a. Base removal of the aldol OH


proton to form an alkoxide.
b. Make the carbonyl bond of the
reactant ketone or aldehyde, and
detach an enolate ion.
c. Protonate the enolate -carbon.

a. Add alkoxide back to one


carbonyl of the 1,3-dicarbonyl
compound to form a tetrahedral
intermediate.
b. Make the ester carbonyl bond
and detach an enolate ion.
c. Protonate the enolate -carbon.

Michael
condensation

RO

RO

H
O

a. Remove a proton from an


interior -carbon of the product
1,5-dicarbonyl product.
b. Form the ,-C=C bond and
detach an enolate ion.
c. Protonate the enolate -carbon.

H
RO

RO

Carbonyl addition
5

Hydride
reduction or
Grignard
addition

BH
H

O
R'

H
R

R'

R'

R'

c
H

R'
O

NaBH4

c
R

R'
O

c
R'

RMgBr

R'MgBr

a. Remove a proton from product


alcohol to generate the alkoxide
intermediate.
b. Form the reactant ketone or
aldehyde carbonyl bond, and
detach hydride (H).
c. Regenerate a hydride reagent
such as sodium borohydride
NaBH4.
OR
b. Form the reactant ketone or
aldehyde carbonyl bond, and
detach a carbanion (R).
c. Regenerate the Grignard by
adding MgBr.
OR
b. Detach other alkyl group as a
carbanion.

Other additions
6

Diels-Alder*

H3C

H3C

Reductive
amination

Wittig

H
H3C

CH3
F
H

O
a

PPh3

H2N

PPh3

H2O
c

CH3

BH

H3C

NaBH4

PPh3

b
B

H
c

H
B

PPh3

a. Align the Diels-Alder product


with the C=C on the left. Move
the -bond CW or CCW. Move
the 3rd & 5th bonds CW or CCW.
b. Re-draw the s-cis diene by
placing the upper atoms or groups
cis to the former C=C. Re-draw
the dienophile with the upper
atoms or groups cis on the
dienophile C=C.
a. Remove a proton from the
product amine N-H.
b. Form the imine C=N bond and
detach a hydride (H) ion.
c. Hydrolyze the imine to amine
and ketone or aldehyde.
d. Regenerate a hydride reagent
such as NaBH4.
a. Put triphenylphosphine oxide
O=PPh3 back onto the Wittig
product alkene (either orientation)
to form an oxaphosphetane
intermediate.
b. Fragment the oxaphosphetane
to form the reactant carbonyl
bond, and detach the Wittig
reagent.
c. Protonate the Wittig carbanion
to form the phosphonium Wittig
precursor.

*Also illustrated in [1].

Nucleophilic substitution
9

Acetylide
Substitution#

B
a
RCH2

CH

B
C

RCH2

CH

RCH2 H

10

Williamson
ether
synthesis

a
R'CH2

b
R'CH2

O
R

a. Break the single bond on the


sp-carbon to form a carbanion
and a carbocation synthon.
CH
b. Protonate the acetylide, and
neutralize the + charge by adding
a halide ion.

O
R

R'CH2

O
R

a. Break the C-O bond on the


side of a methyl or primary
carbon to form an alkoxide ion
and a methyl or primary
carbocation synthon.
b. Protonate the alkoxide to form
and alcohol, and neutralize the +
charge by adding a halide ion.

Also illustrated in [2].

References
1.
2.

Smith, J. G. Organic Chemistry, 1st Ed.; McGraw-Hill: New York, 2007; p 593.
Solomons, T. W. G.; Fryle, C. B. Organic Chemistry; 9th ed.; Wiley: Hoboken, 2007; p 348.

Table S2. Example retrosynthesis problems and solutions


One step

Q: Suggest a one-step synthesis of 1-phenylethanol from smaller


precursors.
A: (1) Identify the appropriate synthesis reaction. Alcohols can be synthesized
by alkene hydration, reduction of carbonyl compounds, hydrolysis of esters,
SN1 or SN2 substitution, Grignard addition, and others. Only Grignard additions
involve C-C bond formation.
(2) Apply the stepwise curved arrow retrosynthetic analysis beginning with
deprotonation of the OH.

:B

H
HB

O
CH3

CH3

CH3

MgBr

(3) Write the synthetic reaction in the forward direction:


O

1.PhMgBr,ether

H
CH3

Multi-step

2.H3O+

OH
CH3

Q: Show how the following compound can be synthesized using Stork


enamine and Robinson annulation reactions [1,2]. O
H3C

CH3

A. (1) Reversing the Robinson annulation requires sequential retro-aldol


dehydration, retro-aldol condensation, and retro-Michael condensation steps.
The retro-aldol dehydration and retro-aldol condensation:

BH

O
H3C

H3C

CH3

CH3

H3C

HO

CH3

HO

HO
B
BH

H3C

H3C

CH3

CH3
O

The retro-Michael condensation:


O
H3C

B
H

CH3

H3C

BH

H3C

CH3
O

CH3

CH2

(2) Reconstruct the enamine equivalent of the enolate:

(3) Finally, write the synthetic reaction in the forward direction:


O
O
H3C

N
+

CH3

1.orga ni cs ol vent,hea t
H3C
2.OH,H2O

CH3
+

CH2

N
H

References
1.
Boeckman, R. K., Jr.; Bershas, J. P.; Clardy, J.; Solheim, B. J. Org. Chem. 1977, 42,
3630-3633: DOI: 10.1021/jo00442a043.
2.

Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc.
1963, 85, 207-222: DOI: 10.1021/ja00885a021.
7

You might also like