Lecture 30 - Enamine and Iminium Organocatalysis

Chem 106 E.
Kwan Lecture 34: Enamine and Iminium Organocatalysis

December 2, 2011
Enamine and Iminium Organocatalysis
Scope of Lecture
Eugene E. Kwan
Key Questions
proline aldol
reactions
enamine and iminium
organocatalysis
N
H
CO
2
H
detection of
enamines
1+rate law
analysis
List-Houk model
and alternatives
enantioselective
reduction of
iminium ions
enantioselective
Diels-Alder
reactions
cascade
organocatalysis
SOMO and photoredox
catalysis
Helpful References
1. "The Advent and Development of Organocatalysis."
Macmillan D.W.C. Nature 2008, 455, 304-307.
2. "Theory of Asymmetric Organocatalysis..." Houk, K.N. et al.
Acc. Chem. Res. 2004, 37, 558-569.
3. "Enamine Catalysis Is a Powerful Strategy..." List, B.
Acc. Chem. Res. 2004, 37, 548-557.
4. "Iminium Catalysis." Pihko, P.M. et al. Chem. Rev. 2007,
107, 5416-5470.
5. "Organocatalytic Cascade Reactions..." Enders, D. et al.
Nature Chemistry 2010, 2, 167-178.
I thank Dr. Rob Knowles and Dr. Jaclyn Henderson for
some helpful discussions and material for the preparation
of this lecture.
H
O
Br
CO
2
Et
CO
2
Et
83% yield, 95% ee
H
O
CO
2
Et
CO
2
Et
visible light
(fluorescent bulb)
organocatalyst (20 mol%)
Ru(bpy)
3
Cl
2
(0.5 mol%)
2,6-lutidine, DMF, 23 C
+
H
O
iPr
NHPMP
N
H CO
2
Et
PMP
H
O
Me
+
Me
N
H
COOH
Me
Me Me
O
O
Me H
+
Me
O
Me
OH
N
H
CO
2
H
why a
turnover?
O Me
H
O
Me
O
Cl
Cl
Cl
Cl
Cl
Cl
O
Me
O
H
Me
Cl
EtOAc, 50 C
20 mol% catalyst
+
86% yield
14:1 dr, 99% ee
(1) Proline vs. Mannich Reactions
(2) Organocascade Reactions
(3) Organo-SOMO/Photoredox Catalysis
mechanism?
mechanism?
Chem 106 E. Kwan Lecture 34: Enamine and Iminium Organocatalysis
Predicting the Future
Society: What technologies will be important in the future?
Organic Chemists: What new developments are going to
propel the field forwards?
People have been trying to predict the future of technology for
quite a while. Unfortunately, they are very bad at it. In 1977,
Ken Olson, CEO of Digital Equipment Corporation, a maker of
large mainframe computers, famously said this at a convention
of the World Future society:
"There is no reason for any individual to have a computer in
his home." ("Bill Gates: The Path to the Future." Gaitlin, J .
Perennial Currents, 1999. ISBN: 0-38080-625-8, pg 39).
But why are people so bad at it? The writer Vernor Vinge
proposes that the creation of superhuman intelligence will lead
to a breakdown in our ability to predict the future in what he
calls a "singularity." In a more restrictive usage, technological
singularities are breakthroughs beyond which technological
progress becomes so fast that it makes any predictions of the
future become impossible. Moore's Law is the classic example:
Wikipedia
Somewhat more controversial is the idea of accelerating change.
Acccording the futurist Ray Kurzweil, paradigm shifts are
occurring exponentially more frequently, and will soon lead to
"change so rapid and profound it represents a rupture in the
fabric of human history":
Now, before superintelligent AIs become our inscrutable
overlords, or the fabric of history ruptures, we will need to do
some organic chemistry. In 1990, Seebach considered the
future of organic chemistry ("Organic Synthesis--Where Now?"
ACIEE 1990 29 1320) and wrote:
"The primary center of attention for all synthetic methods will
continue to shift towards catalytic and enantioselective
variants..."
This has certainly been true. However, he also felt that:
"The discovery of truly new reactions is likely to be limited to
the realm of transition metal organic chemistry, which will
almost certainly...[deliver] miracle reagents..."
This foreshadowed things like olefin metathesis, but did not
really predict the explosion of interest in organocatalysis.
Predicting the Future
As Macmillan points out, mentions of the word "organocatalysis"
have truly exploded in the literature (ISI Web of Knowledge, ref 1):
Macmillan writes (ref 1):
"Why was organocatalysis so long overlooked as an area of
research?...One perspective worth considering is that it is
impossible to overlook a field that does not exist yet...
researchers cannot work on a problem that has not been
identified."
This may be a bit harsh, but there is a ring of truth to it. In
Seebach's defense, hardly any of the reactivity that will be
discussed in the first part of this lecture (proline aldol and
Mannich reactions, reductions of o,|-unsaturated iminium ions,
enantioselective Diels-Alder reactions) are actually new. Rather,
they are "simply" enantioselective variants of old reactions.
However, in the second part of the lecture, I will show you some
genuinely new reactivity in the context of SOMO catalysis.
The seminal work in this area came simultaneously from Hajos
and Parrish (JOC 1974 39 1615) at Hoffmann-La Roche, and
Eder, Sauer, and Weichert at Schering AG (ACIEE 1971 10
496). They reported that proline catalyzed this cyclization:
Et
O
O
O
3 mol% L-proline
(Eder and co-workers used harsher conditions involving
perchloric acid at elevated temperatures, but accomplished the
same transformation.) Other amino acids, methylated proline,
and pipecolic acid are either ineffective catalysts or give low
enantioselectivity.
As usual, these intramolecular reactions preceded the inter-
molecular versions by quite a bit. In 2000, List and Barbas
showed that intermolecular proline-catalyzed reactions can
work (JACS 2000 122 2395):
Me
OH
O
Et
OH
O
O
O
71%, 99% ee
Me
O
O
O
3 mol% L-proline
52%, 74% ee
O
O
NO
2
30 mol%
L-proline
+
NO
2
O OH
68%, 76% ee
The mechanism of these reactions is proposed to be analogous
to how type I aldolases work (Bachrach, Section 5.3):
Lys
NH
2
+
O
Lys
N
-H
2
O
Lys
NH
+
R H
O
Lys
N
H
O
R
+H
2
O
Lys
NH
2
+
O OH
R
Kinetics of Intermolecular Proline Aldol Reactions
"Kinetic and Mechanisitic Studies of Proline-Mediated Direct
Aldol Reactions." Blackmond, D.G. et al. Bioorg. & Med. Chem.
Lett. 2009, 19, 3934-2937.
"The Elusive Enamine Intermediate in Proline-Catalyzed Aldol
Reactions: NMR Detection..." Gschwind, R.M. et al. ACIE
2010, 49, 4997-5003.
Despite some recent controversy (see below), there is now little
doubt that enamines are the nucleophilic species in these
reactions and that C-C bond formation is rate-limiting.
Gschwind and co-workers have looked at the self-aldolization of
propionaldehyde under synthetically relevant conditions (20 mol%
L-proline in d
6
-DMSO at 300 K) with real-time NMR:
Me
O
H
+
Me
O
H
OH O
H
+
O
H
In agreement with previous studies, two diastereomeric aldol
addition products are formed, along with some condensation
product. Over the course of the reaction:
When the catalyst loading is raised to 100%, the total amount of
the intermediates rises from 8% to 25-30%, allowing for accurate
quantitation. As others have noted before, oxazolidinones are
detectable. But now, the enamine is detectable:
(1) The enamine is E-configured and s-trans, regardless of
[enamine]. Incidentally, this is the same conformation that
Houk predicts is reactive (see discussion below).
N
Me
CO
2
H
E
s-trans
(2) NMR exchange spectroscopy ("EXSY") is a technique that
allows the rate of interconversion between equilibrating
species to be measured, so long as the exchange rate is
suitable (for a more precise definition, you will have to wait
until Chem 117 next semester). If two peaks have a
"crosspeak" then there is exchange. The volume of the
crosspeak is related to the rate of exchange.
Here is a schematic for the exchange equilibria:
Regardless of how enamine is formed, this is the proposed
kinetic scheme for intermolecular proline aldol reactions (to
maintain consistency with previous lectures, we're using a new
set of letters to denote the various chemical species now):
O
Me
H
N
Me
CO
2
H
N
H
CO
2
H
+
N
Me
CO
2
A
I
E
N
Me
O
O
N
Me
O
O
Oa
Ob
(3) The iminium ion is spectroscopically invisible. Ob is more
stable than Oa.
(4) The dotted arrows represent crosspeaks. Note that exchange
is not found between A and E.
(5) The authors suggest that means that enamine only comes
from oxazolidinones Oa and Ob, perhaps through an E2
mechanism. To bolster their claim, they show that:
rate (Oa to A)
rate (Oa to E)
rate (Ob to A)
rate (Ob to E)
is different
than
the argument being that the partitioning to A and E should not
depend on the starting point if a common intermediate I exists.
,
?
C
CK
K
(CK)'
A
CKA
P
K
1
K
2
k
3
K
I
Q: Does this fit the observed kinetic data?
To answer this question, we need to draw a 1+rate law for this.
This is more complicated than the 1+rate laws we have
considered. For example, step 1 produces water as well as
CK and it reasonable to think that additional water would shift
this equilibrium left towards starting materials. Assuming product
release is irreversible,
Assuming that we can ignore any catalysis (perhaps by water)
of oxazolidinone formation, one can see that K
1
and K
I
will be
merged into some smaller apparent equilibrium constant K
1
'.
1 2 3 2 T
1 1 I 1 2
2
2 2 2
[H O][K][A][C]
[K] [K] [K] [A]
[H O] 1
[H O] [H O] [H O]
K K k
v
K K K K K
=
| |
+ + +
|
\ .
N
H
CO
2
H
N
CO
2
H
N
O
O
H
O
R
Me Me
O
H
2
O
N
Me
CO
2
OH
R
H
2
O
O
Me
OH
R
Me
Me
Me
1 2 3 2 T
' '
2 1 1 2
[H O][K][A][C]
[H O] [K] [K] [A]
K K k
v
K K K
=
+ +
if addition=rds,
rate is approximately
propotional to
Similarly, [H
2
O] no longer appears in the numerator, since water
will not speed up the reaction if aldol addition is rate-limiting.
Additionally, the K
2
term is small, so it does not appear in the
denominator. (1) does correspond to the power law above. To
see this for [H
2
O], hold other concentrations constant (x=[H
2
O]):
0.7 0.6 0.9
2 T
[H O] [K] [A] [C] v k

=
Note that for a multi-step reaction, the exponents do not imply
the molecularity of any particular step. Suppose the enamine
formation is rate-limiting. In that case, the reaction becomes
elementary and the rate law is (the pre-equilibrium assumption
for step 1 is no longer valid since it's now the "last" step):
T
'
2 1
[K][A][C]
[H O] [K] K +
T
'
2 1
[K][A][C] 1
[H O] [K] K x c
o
+ +
This is a bit less than negative first order in water, depending on
how big c is. Finally, let y =[K], and we get:
(1)
T
'
2 1
[K][A][C]
[H O] [K]
y
K d y
o
+ +
before the rate-determining step, slowing down the reaction.
Increasing the amount of ketone increases the amount of this
intermediate. However, because both water and ketone are
incorporated before CK goes to product in a multi-step process,
their kinetic orders have magnitudes less than one.
Further Evidence
Until a few years ago, the idea that these reactions go through
enamine intermediates was itself controversial. Even the
stoichiometry of the transition state was unclear. Here were
some of the leading proposals for the Hajos-Parrish reaction:
HO
Me
OH
N
H
CO
2
Houk model
Hajos model
N
O
Absorbing K
1
and K
I
gives this expression:
Experimentally, it has been determined that the rate can be
fitted to an approximate power law expression:
C CK / (CK)'
CKA
if enamine
formation=rds,
rate law is
Since the reaction is about first order in aldehyde, this can be
discounted. (Neither water nor aldehyde take the reaction
forwards to product, so they don't appear in the numerator.)
What if aldol addition is rate-limiting?
O
O
H
N
O
O
H
H
O
O
H
crystal surface
O
Swaminathan
model
N
Me
N
CO
2
O
H
H
R
Agami model
The Hajos and Houk models have the same stoichiometry, so
we cannot distinguish between them with kinetics. These
reactions work in compeletely homogeneous media, so the
Swaminathan model is unlikely.
Q: How can the number of prolines in the TS be determined?
O
O
1 T
[K][C] k
ee (Product)
ee (Product)
Further Evidence
The classic experiment is to examine the relationship between
catalyst enantiopurity and the product enantiopurity. This is
called a nonlinear effects experiment. Despite some initial
reports by Agami that these were involved in the Hajos-Parrish
reaction, very careful studies showed that there is no such
effect (Houk/List JACS 2003 125 16):
If the homochiral catalyst-catalyst complexes are less reactive
than heterochiral (meso) complexes, then the line would be
curved upwards (asymmetric amplification). Similarly, ee is
unchanged with dilution (more dilute =aggregation less likely):
From microscopic reversibility arguments, the fact that the retro-
aldol reaction is first-order in proline means that the forward
aldol reaction is also first-order. This also has the advantage of
definitively being related to the C-C bond forming step:
Finally, performing the reaction in
18
O-labeled water gives
incorporation of the label at the ketone. This is required by the
mechanism, which generates an iminium ion which must be
hydrolyzed by solvent (List PNAS 2004 101 5839):
Me
O
Me
O
O
25 mol%
(S)-proline
3 vol% H
2
18
O
DMSO under Ar
four days
Me
OH
N
O
2
C
Me
OH
18
O
This excludes the Hajos model, which
does not proceed via an iminium ion.
(Initial reports were to the contrary, but
careful experiments give incorporation.)
40% 50% 10%
+ +
Me
18
O
Me
N
HO
2
C
HO
Me
OH
N
H
CO
2
O O
O
O
The Houk-List Model for Stereoselectivity
All of this evidence points to a one-proline enamine mechanism.
Houk considered a variety of intermolecular reactions, both
selective and unselective, and List measured their enantio-
selectivities (JACS 2003 125 2475). One considered reaction:
Me Me
O
O
Me H
+
proline
Me
O
Me
OH
A variety of parameters were looked at:
N
HO
2
C
N
CO
2
H
syn or anti enamine
R
O
H
Re or Si face
of aldehyde
enamine-aldehyde rotamers
As it turns out, unless the carboxylic acid and the aldehyde are
engaged in hydrogen bonding, the incipient alkoxide is not
effectively stabilized, and therefore the TS is very high in energy.
The computations (B3LYP/6-31G*) led to this "metal-free"
Zimmerman-Traxler model:
O
H
N
Me
O
O
H
Me
O
H
N
H
O
O
Me
Me
favored disfavored (+1.0 kcal)
Thus, anti-enamines are preferred, as is an equatorial aldehyde.
Here are two equivalent renderings of the favored TS:
This is the lowest energy TS leading to the minor product:
Selectivity is predicted to be lower with cyclohexanone, since
this makes both the equatorial and axial aldehyde conformers
equally bad:
O
H
N
Me
O
O
H
0.0 kcal/mol +0.5 kcal/mol
O
H
N
H
O
O
Me
attraction between negatively
charged oxygen and positively
charged N-C-H hydrogen atom
0 1 2 3 4
0
2
4
6
8
p
r
e
d
i
c
t
e
d

s
e
l
e
c
t
i
v
i
t
y

(
k
c
a
l
/
m
o
l
)
observed selectivity (kcal/mol)
y =1.7 x
R =0.93
The Houk-List Model for Stereoselectivity
Of course, the computations are useless if they don't agree with
reality. In general, the correlation is good, although the predicted
selectivities are a bit too high:
The Hajos-Parrish reaction seems to work along similar lines
(Houk ACIE 2004 43 5766). The favored transition state is:
Houk also examined the uncatalyzed and Hajos pathways:
O
Me
O
O
H
uncatalyzed TS
(+10.2 kcal)
Me
OH
N
H
CO
2
OH
carbinolamine intermediate
(+12.4)
Since the carbinolamine leading up to the Hajos TS is already
higher in energy than the uncatalyzed TS, Houk concludes the
Hajos model is incorrect.
If you don't believe any of this, the results for the closely related
proline-catalyzed Mannich reactions are very compelling. Let's
apply the same model to this reaction (Houk OL 2003 5 1249):
Me Me
O
O
H
+
S-proline
Me
O
iPr
NHPMP
OMe
NH
2
+
Me
Me
E imines are more stable than Z imines, so this gives this TS:
N
H
N
H
O
O
R
Me
PMP
Indeed, this gives the correct facial selectivity and explains why
the sense of induction is turned over from the aldol reaction. Note
that for donor aldehydes, this favors syn-Mannich products:
R
N
H
N
H
O
O
R
PMP
R
H
O
CO
2
Et
NHPMP
R
So how can one obtain anti-Mannich products?
N
H CO
2
Et
PMP
H
O
R
+
90%, 93% ee
Mannich Reactions
A different catalyst turns out to be highly anti-selective:
H
O
iPr
NHPMP
70%, 94:6 anti:syn
>99% ee
N
H CO
2
Et
PMP
H
O
Me
+
Me
N
H
COOH
Me
This catalyst was designed by computations, which predicted
this transition state (Houk/Barbas JACS 2006 128 1040):
N
R
N
PMP
EtO
2
C
Me
H
O
O
Deletion of the methyl group reduces selectivity by about 1 kcal.
Oxazolidinone Intermediates?
Despite the success of the List-Houk mechanistic framework,
Seebach and Eschemenmoser have proposed an alternate
pathway that involves oxazolidinones (Helv Chim Acta 2007
90 425). Here is the List-Houk mechanism:
N
H
CO
2
H
N
CO
2
H
N
O
O
H
O
R
Me Me
O
H
2
O
N
Me
CO
2
OH
R
H
2
O
O
Me
OH
R
In that manifold, oxazolidinones are thought to be unproductive
and "parasitic." In the Seebach-Eschenmoser scheme, the
oxazolidinone can open to an enamine carboxylate, which is
proposed to be the nucleophilic species:
N
H
CO
2
H
N
CO
2
N
O
O
H
O
R
O
H
2
O
H
2
O
O OH
R
H
B:
BH
N
O
O
HO
R
Me
Me
Me
Me
B
(1) The enamine carboxylate might arise from an E2 elimination
as depicted, or perhaps by deprotonation of the iminium ion
formed from proline and acetone.
(2) The carboxylate is proposed to assist the nucleophilicity of
the enamine (similar to halolactonization):
N
H
Me
O
O
E
+
(3) From various X-ray structures and calculations, it's been
suggested that the concave/convex shape of these
structures might give rise to high stereoselectivity.
N
H
N
H
O
O
R
Me
PMP
R
Oxazolidinone Intermediates?
(4) It's been suggested that the 9-membered hydrogen
bonds required by the List-Houk model are
implausible. However, the usual proscription
against such rings is based on the transannular
interactions in medium-sized cycloalkanes.
Gellmann has shown that these H-bonds are, in fact,
quite plausible (JACS 1990, 112, 8630; CSD: PAGTIA):
N
O O
O
H
(5) However, in DMSO, a lot of these hydrogen bonds do get
disrupted (DMSO is a very good H-bond acceptor). However,
it seems plausible that in a transition state, H-bonding to an
internal donor might be feasible due to entropic effects.
Noncovalent interactions are also generally stronger in
transition states, since they're more polarized.
(6) The Seebach-Eschenmoser proposal does not take
advantage of intramolecular general acid catalysis, and so
an alkoxide is formed. Although DMSO is very polar, it is not
a hydrogen bond donor, so the alkoxide is expected to be
quite unstable. From the ground state side, the enamine
carboxylate is not expected to be very well stabilized either.
Sunoj has looked at the relative energetics of both mechanisms
computationally using a variety of methods (ACIE 2010 49 6373).
List-Houk (correct enantio- and diastereoselectivity)
Seebach-Eschenmoser (correct ee, incorrect dr)
predicted ee
B3LYP/
6-31+G**
MP2/
6-31+G**
M05-2X/
6-31+G**
predicted dr
experimental ee: 99%; dr: 4:1 anti:syn
>99 >99 98.5
5.4:1 1.2:1 1:1.7
predicted ee
predicted dr
95 >99 >99
1:3.9 1:4.6 1:2
So both models get the enantioface right, but the predictions of
diastereoselectivity are better with the List-Houk enamine model.
More compelling are the substantially higher barriers for the
Seebach oxazolidinone pathway (by about 11 kcal/mol):
Enamine vs. Iminium Activation Modes
O
H
N
Me
O
O
H
Me
Q: Why is proline a catalyst for aldol reactions?
i.e., Why does it lower the activation barrier?
(1) general acid catalysis: COOH
stabilizes forming alkoxide
(2) enamine activation
- most isolated carbonyl groups in ketones and aldehydes have
very low enol content; the catalyst increases the amount of
"enol" available
- actually, it's an enamine, not an enol; on the Mayr scale,
enamines are much more reactive
N
O
OEt OEt OEt
OEt
- enols are not available on the scale, but this shows that you
need approximately two oxygens to equal one nitrogen!
OTMS
5.41
(s=0.91)
9.81
(s=0.81)
12.06
(0.80)
3.92
(s=0.90)
4.23
(s=1.00)
If enamines are more nucleophilic, it's reasonable to expect
that iminiums ions are more electrophilic. This is similar to how
Lewis acids or hydrogen bond donors activate carbonyl groups:
O
activation
O
N N
S
H
R R
H
O
ML
n
N
R R
increasing covalency
These are all LUMO-lowering strategies. While organocatalytic
activation may not be as powerful in increasing reactivity as Lewis
acid catalysis, it can be an advantage in getting catalyst turnover.
Iminium ions are so easily hydrolyzed by water, they are
generally considered to be in equilibrium with their carbonyl
counterparts. MacMillan has taken advantage of this for Diels-
Alder reactions (JACS 2000 122 4243):
OAc
+
O
H
20 mol% cat
MeOH/H
2
O
rt
OAc
CHO
11:1 endo:exo
72%, 85% ee
N
N
H
O Me
Bn
Me
Me
cat
This also works with o,|-unsaturated ketones (JACS 2002 124
2458), but requires a different catalyst:
Me
+
O
20 mol% cat
20 mol% HClO
4
EtOH, 30 C
Me
COEt
11:1 endo:exo
72%, 85% ee
N
N
H
O
Me
Bn
cat
Me
Me
Note that, in contrast to proline aldol reactions, these occur
in protic media, where there may be some hydrophobic
acceleration. Exactly how selectivity is obtained here is still up
for debate (Houk Acc Chem Res 2004 37 558). Instead, I will
discuss what's known about models for organocatalytic transfer
hydrogenation (reviews: MacMillan Acc Chem Res 2007 40
1327; Adolfsson ACIE 2005 44 3340).
Me
O
Me
N
H
CO
2
Et EtO
2
C
Me Me
Hantzsch ester
These reactions were developed as a synthetic analog to
natural hydride reductions which occur with NADH or FADH
2
.
|,|-Disubstituted aldehydes can be reduced effectively
(MacMillan JACS 2005 127 32, List ACIE 2005 44 108) with
Hantzsch esters as the hydride source:
H H
+
NR
2
*
R
Ar
NR
2
*
R
Ar
O
H
20 mol% cat
Hantzsch ester
PhMe, 30 C
96% conv., 75% ee
N
N
H
O Me
tBu
cat
Me Ph TFA
O
H
Me Ph
Organocatalytic Hydride Reductions
The convergence of E and Z starting materials to the same
products suggests a Curtin-Hammett scenario where a
dienamine intermediate can rotate to isomerize the olefins:
Bn
An anomalous case (see below) is this tert-butyl catalyst:
O
H
20 mol% cat
Hantzsch ester
CHCl
3
, 30 C
91%, 93% ee
N
N
H
O Me
tBu
cat
Me Ph
TFA
O
H
Me Ph
Under slightly different conditions, the reaction improves:
O
H
20 mol% cat
Hantzsch ester
dioxane, 13 C
77%, 90% ee
N
N
H
O Me
tBu
cat
Me Ph TCA
O
H
Me Ph
Bn
advantages: bench-stable reagent; a good alternative to
hydrogenation (usually needs optimization) or copper-based
hydrides (unreliable); E and Z isomers converge to the same
product
disadvantages: the Hantzsch pyridine is a stoichiometric
byproduct, which must be removed by chromatography (acid-
base extraction doesn't work); the Hantzsch pyridine is quite
a large reagent for delivering just one hydrogen
An initial result:
N
CO
2
Et EtO
2
C
Me Me
byproduct
Hantzsch
pyridine
N
N
O
Me
H
Ar Me
N
N
O
Me
H
Ar
N
N
O
Me
H
Ar Me
fast
slow
O
H
Me Ar
O
H
Me Ar
Stereochemical Model
N
N
Ph
Me
O
Me
H
3
C
CH
3
CH
3
(1) In the left-hand rotamer, the bulky tert-butyl group ensures
that the benzyl group rotates over the |-face of the
electrophile, making the hydride reagent come from the
bottom.
(2) Both the attractive tt/cation-t interactions and repulsive
steric interactions (as the carbons pyramidalize) are
expected to become more important in the transition state.
What controls the stereoselectivity? Having established the
favored iminium ion geometry, we must now consider two
iminium ion rotamers:
N
N
Me
Ph
O
Me
H
3
C
CH
3
CH
3
better
than
tt or cation-t
interaction?
preferred attack
N
N
H
2
O Me
Me
Me
N
N
O Me
Me
Me
Ph
H
The ground state conformational preferences of these systems
have been studied (Tomkinson et al. OL 2009 11 133). The
X-ray structures shown below are similar to the solution phase
structures, as shown by NMR studies. Here is an X-ray
structure of a free imidazolidinone catalyst (CSD: POPRES):
Bn
Bn
Organocatalytic Hydride Reductions Calculations show the penalty for rotating the benzyl group in
the ground state of the iminium ion is about 1 kcal/mol--very
small. I doubt these ground state pictures tell us much about
the transition state; the fact that the benzyl group doesn't seem
to be covering the |-face very effectively in the X-ray structure
is meaningless.
The anomaly is that the catalyst which only has a tert-butyl
group is still very selective:
This is the X-ray structure of the corresponding iminium ion
(CSD: DOSKIG01). Note the rotation in the benzyl group:
N
N
Ph
Me
O
Me
H
3
C
CH
3
CH
3
still preferred (?)
I don't have a good explanation for this. Enones also work in
this chemistry, but with a slightly different system (MacMillan
JACS 2006 128 12662; Houk OL 2009 11 4298):
O
Bu
20 mol% cat
Et
2
O, 0 C
N
H
CO
2
tBu tBuO
2
C
Me Me
H H
+
O
Bu
82%, 90% ee
The product can be explained by this model, but it might not be
right (see the Houk paper):
N
N
Bu
O
Me
preferred attack
O
Me
Q: Why can't we make taxol in ten steps?
Organocatalytic Cascades
"Strategies to Bypass the Taxol Problem..." Walji, A.M.;
MacMillan, D.W.C. Synlett 2007, 10, 1477-1489.
Taxol is a potent anticancer agent used in the treatment of
lung, ovarian, breast, neck, and other cancers, with sales of $1.6
billion US in 2000. Until 1993, taxol had to be extracted from
the bark of the pacific yew tree and prepared via semi-synthesis.
Now, BMS uses cultured Taxus cells in a fermentation process.
Taxol is extracted and purified directly from the broth.
Analysts estimate that the world will need 1 040 kg of taxol/year
by 2012. Despite our best efforts, total synthesis is clearly not
up to the job:
Each of these groups used cutting-edge chemical methodology
and very clever synthetic logic, but none of their routes is even
remotely amenable to a large-scale process route. This problem
is certainly not unique to taxol.
Here's what I think the biggest problem is: the complexity of
molecules scales exponentially with size, but the
complexity introduced by a synthetic sequence scales even
less than linearly with its length.
MacMillan points out that the yield of a synthetic sequence also
drops exponentially with its length. A somewhat unsatisfactory,
literal explanation is that the total yield is just the product of the
yields of every step. But why don't reactions give 100% yield?
(1) The reactions are intrinsically "dirty" and give side products
which account for the remainder of the mass balance.
(2) Purification is "lossy."
J ust how lossy is purification? Hudlicky has recently done some
simple experiments (Synlett 2010 18 2701) which show that, in
general, one cannot expect more than a ca. 94% yield for any
given reaction which involves workup and chromatography.
AcO
Me
HO OBz
O
OH O
OAc O
O
OH
BzHN
H
mass recovery
filtration
aqueous extraction
fraction collection
separation
1001.7 mg
978.6 mg
985.0 mg
980.1 mg
This is bad news if you want to use a sequence of 37 steps.
The top synthesis, Wender's, already has an average yield of
85%, suggesting that there is nothing wrong with the reactions
themselves; they're simply not generating enough complexity
per step.
O
O
OH
Nicolaou
(1994)
51 steps
Me Wender
(1997)
37 steps
0.4% overall yield
H
O
Me
Kuwajima
(1998)
47 steps
NH
2
O
HO OH
Mukiyama
(1999)
38 steps O
O
Me
47 steps
Danishefsky
(1995)
Me
Me Me
Me
O
Holton
(1994)
41 steps
(1000 mg scale)
MacMillan proposes that we circumvent the defects of "stop-and-
go" synthesis by combining several steps into one step. For
example, consider this sequence (JACS 2005 127 15053):
This represents the merging of two catalytic cycles. First, the
catalyst forms an iminium ion with the aldehyde (A), which
undergoes a Friedel-Crafts alkylation. Then, the product
tautomerizes into a nucleophilic enamine (B), which is chlorinated.
(1) This reduces the number of purifications required, which is
good. However, simply performing reactions in a cascade,
rather than stop-and-go sense does not by itself improve the
intrinsic yield of a reaction.
(2) Cascade reactions are not new. In fact, we've already seen
quite a few such reactions in the course already. However,
most of them are diastereoselective in nature. For example,
this cascade reaction was discussed in Lecture 10 on page 14:
Me
Ph
Me
Ph
Me
HO
oxy-Cope/
carbonyl-ene
O Me
H
O
Me
O
Cl
Cl
Cl
Cl
Cl
Cl
O
Me
O
H
Me
Cl
EtOAc, 50 C
N
N
Me O N
Bn
tBu
20 mol% catalyst
Me
N
N
Me O N
Bn
tBu
Me
O
Me
A
B
Cl
O
Me
+
Without catalyst, one is at the mercy of the complex energy
landscape that is intrinsic to the reaction; there is no
guarantee that the desired reaction lies on the minimum
energy path. Nor is it guaranteed that there is only one
minimum energy path, such that the reaction will be "clean"
and have no other side products. So using a tunable
catalyst is a real advantage in that sense.
(3) One complaint about this chemistry is that it makes strings
of stereocenters efficiently, but is relatively ineffective at
building structural complexity. Is this true? You decide.
This area has been reviewed recently: "Organocatalytic
Cascade Reactions..." Enders, D. et al. Nature Chemistry
2010, 2, 167-178. Here is another example from the Hayashi
group for the synthesis of oseltamivir (ACIE 2009 48 1304):
86% yield
14:1 dr, 99% ee
RO
O
H
tBuO
2
C
NO
2
+
N
H
Ph
Ph
OTMS
Michael addition
Cs
2
CO
3
P CO
2
Et
O
EtO
EtO
conjugate addition/
HWE olefination
NO
2
tBuO
2
C
RO CO
2
Et
5 mol%
5:1 dr
undesired
diastereomer
The first step uses a silylated Hayashi-J orgenson diarylprolinol
catalysts. Unfortunately, the second step delivers the incorrect
stereocenter at the nitro group. (All of this occurs in one pot.)
O
H
NO
2
tBuO
2
C
RO
NO
2
tBuO
2
C
RO CO
2
Et
O Me
H
O
Me
OTMS
Me
O
O
O
Me
H
O
OH
Me
H
Me
O
H
O
Me
O
H
O
Me
O
O
O
H
O
Me
O
N
HO
2
C
Me
type I/type II
cross-metathesis
(Grubbs II)
Me
O
N
N
O Me
tBu
Ph
+
H
selective for
iminium
catalysis
three sequential
one-pot operations
Friedel-Crafts
alkylation
(imidizolidinone)
ketone aldol
(proline)
selective for
enamine
catalysis
64%, 95% ee,
5:1 dr
Fortunately, a hetero-conjugate addition/epimerization strategy,
followed by some other manipulations delivers Tamiflu in 57%
overall yield from the nitroalkene, which is pretty good. Overall,
there are nine reactions, three separate one-pot operations, and
one column chromatography purification.
TolSH
70%
NO
2
tBuO
2
C
RO CO
2
Et
STol
=
tBuO
2
C
O
2
N
RO
CO
2
Et
STol
1. TFA
2. (COCl)
2
,
cat.DMF
3. NaN
3
NO
2
RO CO
2
Et
STol
O
N
3
1. AcOH/Ac
2
O
2. Zn/TMSCl
3. NH
3
; K
2
CO
3
one-pot
one-pot
no purification
purified by
flash chromatography
NH
2
AcHN
RO CO
2
Et
oseltamivir
(82% from A)
A
(1) The second one-pot procedure sequentially cleaves the
tert-butyl ester, converts the liberated carboxylic acid into the
acyl chloride, and displaces the chloride with azide.
(2) The third one-pot procedure first converts the acyl azide into
the amine via a Curtius rearrangement. The advantage of
these conditions is that the reaction occurs at ambient
temperatures. The amine is trapped by acetic anhydride.
Zinc then reduces the nitro group. Finally, ammonia is
added to chelate the zinc, and potassium carbonate initiates
a retro-conjugate addition to generate the olefin.
Obviously, this is a very nice synthesis, but the fact that the
conjugate addition is not catalyst controlled means that its dr is
at the mercy of the various stereocenters present:
O
H
NO
2
tBuO
2
C
RO
P CO
2
Et
O
EtO
EtO
+
NO
2
tBuO
2
C
RO CO
2
Et
5:1 dr
undesired
diastereomer
A more sophisticated "cycle-specific" strategy is to use more
than one catalyst at the same time (MacMillan ACIE 2009 48
4349). This requires the catalysts be orthogonal:
Stereoselectivity in Cascades
A common feature in these cascade reactions is that they give
very high overall enantioselectivities, even if the component
reactions are not very enantioselective. How is this possible?
Consider a two-step cascade in which the first step produces an
x : 1-x enantiomeric ratio of products, where x is the mole
fraction of R configuration produced at stereocenter 1. Similarly,
step 2 has a selectivity of y:
starting
material
step 1
selectivity x
x R
1
(1-x) S
1
step 2
selectivity y
xy R
1
-R
2
x(1-y) R
1
-S
2
(1-x)y S
1
-R
2
(1-x)(1-y) S
1
-S
2
If this seems a bit abstract, maybe revisiting this example will
help:
O Me
H
O
Me
O
Cl
Cl
Cl
Cl
Cl
Cl
O
Me
O
H
Me
Cl
EtOAc, 50 C
20 mol% catalyst
+
86% yield
14:1 dr, 99% ee
stereocenter 1
stereocenter 2
The Fridel-Crafts alkylation is step 1, and has some intrinsic
enantioselectivity x. The chlorination is step 2, and has another
intrinsic selectivity y.
(1) Without a loss in generality, suppose that the R
1
-R
2
product
is the desired one. How much of it is formed? A mole
fraction of xy.
(2) Where does the enantiomer of the desired product, S
1
-S
2
,
come from? It comes from an incorrect first step, followed
by an incorrect second step. Hence, a mole fraction of
(1-x)(1-y) is formed. Since 1-x and 1-y are small fractions
(i.e., less than 1), multiplying them together gives an even
smaller number.
(3) The enantiomeric ratio of the product is therefore xy divided
by (1-x)(1-y). Division by a very small number between 0
and 1 increases the size of xy by a lot. This is why the
enantiomeric ratio of the product is very large.
(4) The enantiomeric ratio of the product can be big, even if the
enantioselectivity of the component steps is not that great.
For example, suppose steps 1 and 2 have ee's of 80%.
That would be considered good, but great. In our language,
this would mean x = y = 0.9. This gives an enantiomeric
ratio of 81:1, or an ee of 97.6% (which, for one step, would
be considered excellent).
Thus, it is relatively easy to get almost enantiopure product:
0.5 0.6 0.7 0.8 0.9
1
2
4
8
16
32
64
128
256
e
n
a
n
t
i
o
m
e
r
i
c

r
a
t
i
o

o
f

p
r
o
d
u
c
t
selectivity for second step (y)
x=0.9
x=0.8
x=0.7
x=0.6
SOMO Activation
So far, we've seen a variety of activation modes:
O
R
H
R
NR
2
enamine:
more
nucleophilic
O
R
H
R
N
iminium:
more
electrophilic
O
H-A
O
ML
n
O
R
H
O
R
H
R
M = H (acid catalysis)
M = metal (Lewis acid
catalysis)
more electrophilic
hydrogen bonding
more electrophilic
O
R
H
R
OH
R
N
RN
NHC carbonyl anion
more nucleophilic
O
R
OR
R
O
N
or R
O
R
N
RN
NHC carbonyl
pseudohalide
more electrophilic
nucleophilic catalysis
more electrophilic
or
Nuc:
O
R
OR
H
O
R
B:
base catalysis
Q: What's in between an enamine and an iminium?
"Enantioselective Catalysis Using SOMO Activation."
MacMillan et al. Science 2007, 316, 582-585.
MacMillan's clever idea is that enamines are very electron rich,
and therefore more easily oxidized than amines or iminiums:
H
O
TMS
N
H
N
O
Me
Ph
tBu
20 mol%
CAN (2 equiv.)
NaHCO
3
, DME
24h, 20 C
H
O
75% yield, 94% ee
N
R
R
O
H
+
N
H
-H
2
O
H
N
R
H
+2 e
-
9.8 eV 8.8 eV
7.2 eV
N
R
H
-1 e
-
N
R
H
N
R
H
(The ionization potentials are shown in bold; the lower the
number, the easier it is to oxidize.) Oxidation of the enamine
produces a radical cation, which is an ambident electrophile:
enamine radical cation
more reactive
In the jargon of organocatalysis, this is "SOMO activation"--
the generation of a singly occupied molecular orbital which can
undergo many subsequent reactions. One of the first examples
was an aldehyde allylation, which is very useful synthetically:
+
CAN is ceric ammonium nitrate (NH
4
)Ce(NO
3
)
6
, which is
a strong oxidant (even stronger than Cl
2
!) which reacts to
generate a chiral enamine radical cation.
H
R
R
H
O N
H
N
O
Me
Ph
tBu
20 mol%
CAN (2 equiv.), H
2
O
DTBP, acetone,
24h, 20 C
Ph
OTMS
74% yield,
93% ee
H
O
Ph
O
SOMO Activation
stereochemical model
N
N
O
Me
H
3
C
CH
3
CH
3
R
o
+
(Historical Note: This use of stoichiometric CAN for similar
reactions was previously reported by Narasaka (Chem Lett
1992 2099.)
Aldehydes can be coupled with enolate equivalents, which
produces umpolung 1,4-dioxygenated relationships (MacMillan
JACS 2007 129 7004): (DTBP =2,6-di-tert-butylpyridine)
nucleophiles
approach
from below
cationt interaction
between benzyl group
and allyl radical cation?
+
If the nucleophile is allyltrimethylsilane, then this produces:
N
R
N
R
TMS
The regioselectivity can be explained by a radical version of
the |-silicon effect; donation of the Si-C bonds into the radical
is good. (However, the |-silicon effect for radicals is much less
than for carbocations.) The radical gets oxidized to the
carbocation (which is why two equivalents of CAN are required),
and then base comes in and does a Peterson olefination.
Si
CH
3
CH
3
CH
3
|-silyl radical
stabilized by
o
SiC
to n*
C
donation
N
R
Si
CH
3
CH
3
CH
3
-1 e
-
:B
CAN
N
R
H
2
O
O
R
H H
H
H
H
(catalyst
substituents
omitted)
CN
Me
Me CN
H
H H
H O
CN
Me
Me
CN
O
N
N
O Me
Nap
tBu
Cu(OTf)
2
NaTFA/TFA
iPrCN/DME
23 C
CN
CN
Me
Me
[Ox]
- H
2
O
- 1e
-
N
N
O Me
Nap
tBu
CN
CN
Me
Me
[Ox]
- catalyst
- H
+
, - 1e
-
56%, 92% ee
A dramatic demonstration of the power of this activation mode
to produce complex architectures as well as stereodefined
arrays is this cascade polyene cyclization (MacMillan JACS
2010 132 5027):
CAN is ineffective here due to an inner-sphere nitrate transfer.
It is interesting that both the yield and ee go up when the aryl
group on the catalyst changes from phenyl to naphthyl. To me,
this strongly suggests an enhanced cation-t interaction with
a larger aromatic surface.
Cascade Reactions
In the previous examples, the radical produces by the coupling
reaction gets oxidized to a carbocation, which is then eliminated.
What happens if we intercept the carbocation with an internal
nucleophile first? Good stuff (Macmillan JACS 2010 132 10015):
Ph
OMe
+
O
H
N
H
N
O
Me
Ph
tBu
20 mol% catTFA
Fe(phen)
3
(SbF
6
)
3
Na
2
HPO
4
, THF
10 C, 12 h
OMe
O
H
Ph
First, the aldehyde is alkylated by styrene to give a stable
benzylic radical. Then, oxidative radical-polar crossover gives
a carbocation which is engaged in Friedel-Crafts alkylation:
OMe
O
H
Ph
-1 e
-
OMe
O
H
Ph
alkylation,
then
elimination
76%, >20:1 dr
94% ee
(1) The diastereoselectivity is rationalized based on a chair TS.
(2) The yield includes 7% ortho-coupled product.
(3) Because the selectivity of the second step is largely based
on the conformational preferences of the substrate, the ee
mainly reflects the enantioselectivity of the first step, while
the dr mainly reflects the diastereoselectivity of the second
step.
(4) Thus, the inherent enrichment in ee that is commonplace in
largely catalyst-controlled reactions is bypassed here.
Photoredox Catalysis
The use of stoichiometric oxidants is undesirable in terms of
atom economy, the ability of the substrate to tolerate oxidizing
conditions, purification, etc. The latest advance is to use a
photosensitized metal-ligand complex as the redox shuttle.
This is particularly convenient, as visible light can be used as
the energy source (MacMillan Science 2008 322 77):
H
O
Br
CO
2
Et
CO
2
Et
83% yield, 95% ee
H
O
CO
2
Et
CO
2
Et
visible light
(fluorescent bulb)
organocatalyst (20 mol%)
Ru(bpy)
3
Cl
2
(0.5 mol%)
2,6-lutidine, DMF, 23 C
+
N
N
O Me
Me tBu
CO
2
Et
CO
2
Et
.
N
N
O Me
Me tBu
EtO
2
C
EtO
2
C
N
N
O Me
Me tBu
EtO
2
C
EtO
2
C
*
Ru(bpy)
3
2+
Br
CO
2
Et
CO
2
Et
Ru(bpy)
3
+
Ru(bpy)
3
2+
light
SET
SET
[O]
-1 e
-
The blue cycle is started by sacrificing a few molecules of
enamine. Thereafter, it is driven by oxidation of the product
radical (A) to an iminium ion and reduction of the bromo
malonate (B) to its corresponding malonate radical. Thus,
every equivalent of product formed requires one turn of the
blue cycle.
B
A
Q: Where is chemistry going?
Looking Ahead
chemical biology
- find small molecule modulators for every cellular function
(Schreiber)
- sequence the genome of a single cell (Xie)
- find ways to visualize cellular functions; understand how
DNA controls cell funtions, cancer (Xie)
physical chemistry
- find an accurate, but cost-effective electronic structure
method (Aspuru-Guzik)
- predicting the boiling point of water (Kahne)
- protein folding (Cohen)
- determining the structure of a compound from a single
molecule (protein, DNA, etc.) (Cohen)
inorganic chemistry
catalysis:
- figure out what to do with carbon dioxide (Whitesides, Friend)
- conversion of carbon dioxide to water and CO (for syngas)
(Betley)
- new catalysts for commodity chemicals and fuels (Friend)
- metal-organic frameworks for catalysis; self-assembled
monoliths that are catalysts but don't need to support life
(Betley)
- catalysts for reducing nitrogen to ammonia
- recyclable plastics from renewable sources (Cohen)
organic chemistry
- de novo design of enzymes for new reactions (Xie)
- rational drug design (Whitesides)
- turning cellulose into food for humans (Cohen)
- "green synthesis" (J acobsen)
- cheaper and better catalysis with non-toxic first-row transition
metals; catalytic oxidations with O
2
(J acobsen)
- predicting non-covalent interactions and transition states
(J acobsen)
energy:
- materials for energy transfer, storage (Aspuru-Guzik, Friend)
- catalytic water oxidation for energy storage (Betley, Gordon)
- cheap semiconductors (Gordon)
- room temperatures superconductors (Cohen)
Where is organic chemistry going in 30 years? (speculation)
(1) Organic chemistry will not be "dead," and making small
molecule modulators will only be but one area of research.
(2) Fundamentals: We still won't be able to predict what
happens when two molecules get mixed together, but we'll
get much better at it. Strides in ultrafast spectroscopy will
allows us to probe TSs directly. Modeling of solvent effects,
ion-pairing, radicals, and dynamic effects, and electron
correlation phenomena will attain a high level of accuracy.
(2) New reactivity: Organometallic chemistry will give us much
better redox methods, but recent progress in N-heterocyclic
carbenes and SOMO activation suggests that new main
group reactivity patterns will be discovered.
(3) Methodology: Rational computer-aided catalyst design will
become common. Each catalyst will have a binding pocket
that is specifically effective for binding a particular transition
state. Thus, catalyst efficiency will improve, but substrate
scope will diminish. But that won't be seen as a problem.
Catalysts today are mostly good at functionalizations, but
future catalysts will be useful for building architecture, too.
(4) Synthesis: People will design sophisticated mixtures of
catalysts to do cycle-specific cascade sequences. Thus, it
will be much more common for drugs to have complicated
arrays of stereocenters or architectures.
Here is some of what CCB faculty have to say (Nov. 2010):

Lecture 30 - Enamine and Iminium Organocatalysis

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Chem 106 E.

Kwan Lecture 34: Enamine and Iminium Organocatalysis

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