Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from a,β-unsaturated aldehydes for enantioselective Diels-Alder reactions

Article abstract of DOI:10.1073/pnas.1007469107

The catalytic generation of chiral ester enolate equivalents from α,β-unsaturated aldehydes with chiral N-hetereocyclic carbene catalysts makes possible highly enantioselective hetero-Diels- Alder reactions. The reactions proceed under simple, mild condit

Full text of DOI:10.1073/pnas.1007469107

Chiral N-heterocyclic carbene-catalyzed generation
of ester enolate equivalents from α,β-unsaturated
aldehydes for enantioselective Diels–Alder reactions
Juthanat Kaeobamrung1,2, Marisa C. Kozlowski1, and Jeffrey W. Bode1,2,3
Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule-Zürich, Zürich 8093, Switzerland
Edited by David W. C. MacMillan, Princeton University, Princeton, NJ, and accepted by the Editorial Board September 5, 2010 (received for review May 28, 2010)
The catalytic generation of chiral ester enolate equivalents from
α,β-unsaturated aldehydes with chiral N-hetereocyclic carbene
catalysts makes possible highly enantioselective hetero-Diels–
Alder reactions. The reactions proceed under simple, mild condi-
tions with both aliphatic and aromatic substituted enals as sub-
strates. Previous attempts to employ these starting materials as
enolate precursors gave structurally different products via cataly-
tically generated homoenolate equivalents. Critical to the success
of the enolate generation was the strength of the catalytic base
used to generate the active N-heterocyclic carbene catalyst. To
complement these studies, we have investigated the enolate
Fig. 1. Starting materials for catalytically generated enolate equivalents
structure using computational methods and find that it prefers
conformations perpendicular to the triazolium core.
using NHC catalysts.
enantioselective carbon–carbon bond-forming reactions (Fig. 1).
We have applied this approach to the generation of enolate
equivalents from α-chloroaldehydes and their surrogates for
highly enantioselective inverse-electron demand Diels–Alder
reactions of enones togive enantiopure dihydropyranone products
(23). We have likewise used the protonation of electron-deficient
α,β-unsaturated aldehydes to generate such enolates and trapped
these with N-sulfonyl, α,β-unsaturated imines to afford dihydro-
pyridinone products (18). Similar enolates can also be generated
from the corresponding stable ketenes, and the research group of
Smith and Ye have documented several elegant applications of this
chemistry (24–27). Most recently, Scheidt and co-workers have
used enolates generated from α-aryloxy aldehydes for enantiose-
lective Mannich reactions (28).
All of these catalytic reactions proceed from starting materials
that are either unstable or require several steps for their prepara-
tion. For example, the α-chloro aldehydes used in our own work
have a modest shelf life, although they can be conveniently
prepared and used as their corresponding bisulfite adducts
(29). The use of isolated ketenes and α-aryloxy aldehydes adds
several steps to the preparation of the starting materials. We
therefore sought to use α,β-unsaturated aldehydes as substrates,
as these compounds are widely employed in a variety of enantio-
selective organocatalytic reactions and they are increasingly com-
mercially available or readily prepared by improved methods
(30). Although this has proven possible in carefully designed
intramolecular systems, such as those reported by Scheidt and
asymmetric synthesis ∣ catalysis ∣ reaction mechanism
he catalytic generation of uniquely reactive chemical species
Tfrom simple, inert starting materials makes possible synthetic
access to complex, stereochemically rich organic molecules. This
concept differs from the equally important and successful concept
of substrate activation, in which a catalyst such as a Lewis acid or
organocatalyst enhances the inherent reactivity of a substrate
such as an aldehyde or electron-deficient olefin. Although great
success in the generation of uniquely reactive species such as
metallocarbenes or carbon nucleophiles is common in transition
metal-mediated reactions, this mode of catalysis is less well
established in the emerging area of organocatalysis.
An exception to this generalization is the rich chemistry of azo-
lium-catalyzed reactions, exemplified by the long known benzoin
dimerization of aldehydes promoted by the cofactor thiamine and
its derivatives (1, 2). The catalysts derived from these azolium
salts, typically categorized as N-heterocyclic carbenes (NHC) (3),
undergo reactions with aldehydes that lead to catalytic generation
of acyl anion equivalents. These species have long been known
to act as nucleophiles in reactions with a range of electrophilic
partners including aldehydes, electron-deficient olefins (Stetter
reactions) (4), imines (5), and oxidants (6, 7). As we and Glorius
first demonstrated in 2004 (8, 9), the use of α,β-unsaturated
aldehydes and suitable catalysts makes possible the catalytic gen-
eration of homoenolate equivalents for the synthesis of γ-lactones,
γ-lactams (10, 11), cyclopentenes (12, 13), and numerous catalytic
cascades (14, 15) often with high levels of enantioselectivity.
Beyond acyl anion and homoenolate equivalents, the combina-
tion of N-heterocyclic carbenes and α-functionalized aldehydes
also makes possible the catalytic generation of two other impor-
tant species: acyl azoliums (16, 17), which serve as activated
carboxylic acids, and ester enolate equivalents (18). Since the
initial disclosures of this possibility in 2004 by our group (19),
and that of Rovis (20), these concepts have been widely employed
and developed into an impressive range of unique reactions,
often with high levels of diastereoselectivity or enantioselectivity
(21, 22) under mild, simple reaction conditions.
Author contributions: J.K. and J.W.B. designed research; J.K. performed
research; M.C.K. designed and performed computational studies; J.K. analyzed data
and prepared SI Appendix; and J.W.B. wrote the paper.
The authors declare no conflict of interest.
This article is
a PNAS Direct Submission. D.W.C.M. is a guest editor invited by the
Editorial Board.
1This work was performed at: Department of Chemistry, University of Pennsylvania,
Philadelphia, PA 19104.
2Present address: Laboratorium für Organische Chemie, ETH-Zürich, Zürich 8093,
Switzerland.
3To whom correspondence may be addressed. E-mail: bode@org.chem.ethz.ch.
Among the most exciting of these discoveries has been the
catalytic generation of chiral ester enolate equivalents for highly
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1007469107/-/DCSupplemental.
www.pnas.org/cgi/doi/10.1073/pnas.1007469107
PNAS ∣ November 30, 2010 ∣ vol. 107 ∣ no. 48 ∣ 20661–20665

Table 2. NHC-catalyzed reactions of alpha-hydroxy ketoenone
Entry
R1
¼
% yield*
d.r.†
% ee‡
1
2
3
4
5
6
Ph
93
93
92
85
96
89
>20∶1
>20∶1
>20∶1
>20∶1
>20∶1
>20∶1
99
99
99
99
99
99
p-BrC6H4
p-MeOC6H4
2-furyl
p-CHOC6H4
H
*Isolated yield following chromatography.
†Determined by 1H NMR of unpurified reaction mixtures.
‡Determined by SFC analysis on chiral stationary phases. SFC, supercritical
fluid chromatography.
In this paper, we document the successful use of α,β-unsatu-
rated aldehydes as starting materials for the catalytic generation
of chiral ester enolate equivalents and their use in inverse-elec-
tron demand Diels–Alder reaction with enones. Remarkably, a
change in the cocatalytic amine base employed in these reactions
can completely shift the reaction pathway to the hetero-Diels–
Alder reaction, which proceeds via a catalytically generated
enolate, to the complete exclusion of an alternative pathway that
occurs via a fomal homoenolate equivalent (Scheme 1). The same
chiral triazolium catalyst affords the hetero-Diels–Alder products
in outstanding yield and enantioselectivity. These conditions
are successful for a range of α,β-unsaturated aldehyde enolate
precurors and various electron-deficient enones.
Scheme 1.
co-workers (31), the use of simple α,β-unsaturated aldehydes
as ester enolate precursors has not been achieved. Attempts to
date have resulted in dramatically different reactivity as the
homoenolate pathway dominates (Scheme 1) (12, 13). This
can be exploited for highly enantioselective cascade reactions
but not for the desirable intermolecular reactions of catalytically
generated ester enolate equivalents.
Results and Discussion
In 2009, we disclosed a highly enantioselective cascade reaction
of α,β-unsaturated aldehydes and α′-hydroxyenone 2 to give
cyclopentyl lactone 4 as a mixture of isomers (14, 15). During
optimization of this reaction, we observed that weaker amine
bases led to the formation of the hetero-Diels–Alder product 3.
Although we had previously obtained such products using
α-chloroaldehydes as starting materials, prior attempts to gener-
ate and trap enolate intermediates from simple enals were unsuc-
cessful. Using enone 2 and cinnamaldehyde as substrates, we
further investigated conditions that favored the formation of
the Diels–Alder product (Table 1).
Table 1. Conditions for catalytically generation of enolate
equivalents from cinnamaldehyde for hetero-Diels–Alder
reactions*
Three factors were found to be beneficial for favoring the
desired Diels–Alder reaction. First, the use of weak amine bases
was crucial; DMAP (conjugate acid pKa ¼ 9.2)and N-methyl mor-
pholine (NMM, conjugate acid pKa ¼ 7.4) gave the best results.
A stronger base such as DBU (conjugate acid pKa ¼ 12) or excess
Entry
Conditions
Base
Ratio 3∶4†
1
2
3
0.1 M THF, RT
0.1 M EtOH, RT
0.1 M DCE, RT
0.1 M Tol, RT
25% DBU
25% DBU
25% DBU
25% DBU
25% DIPEA
1∶1
No annulation products
1∶1
Table 3. NHC-catalyzed reactions of N-Cbz protected ketoenone
1∶5
8
1∶0
(side products
observed)‡
9
10
25% DMAP
1 equivalent DBU
1.5 equivalent NEt3
25% DBU
1∶0
0∶1
1∶5
11
12
13
0.1 M Tol, 40 °C
0.1 M CH2Cl2, 40 °C
1∶10
Entry
R1
¼
% yield*
d.r.†
% ee‡
15% DMAP
15% NMM
1∶0 (10∶1 d.r., 99% ee)
1∶0 (>20∶1 d.r., 99% ee)
1
2
3
4
5
Ph
98%
98%
79%
98%
80%
>20∶1
>20∶1
>20∶1
20∶1
99
99
99
99
99
p-BrC6H4
p-MeOC6H4
2-furyl
*Reaction time: 18–24 h. DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP,
N,N-4-dimethylaminopyridine; NMM, N-methylmorpholine; DIPEA.
diisopropylethylamine RT, room temperature; d.r., diastereomeric ratio;
ee, enantiomeric excess.
n-C3H7
>20∶1
†Product ratios determined by 1H NMR of unpurified reaction mixtures. Minor
cyclopentane-derived isomers also observed, see refs. 14 and 15 for details.
‡Side products include substrate decomposition or unidentified materials.
*Isolated yield following chromatography.
†Determined by 1H NMR of unpurified reaction mixtures.
‡Determined by SFC analysis on chiral stationary phases.
20662
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www.pnas.org/cgi/doi/10.1073/pnas.1007469107
Kaeobamrung et al.

Table 4. NHC-catalyzed reactions of para-methoxyphenyl
ketoenone
Table 6. NHC-catalyzed reactions of alpha-ketoenone
Entry
R1
¼
R2
¼
% yield*
% ee†,‡
Entry
R1
¼
% yield*
d.r.†
% ee‡
1
2
3
4
5
Ph
Me
Me
cyclo-Hex
cyclo-Hex
iso-C3H7
85
51
79
49
91
98
99
98
99
96
1
2
3
4
Ph
p-BrC6H4
H
62
70
54
60
>20∶1
>20∶1
>20∶1
>20∶1
99
99
99
99
H
n-C3H7
H
n-C3H7
Ph
*Isolated yield following chromatography.
*Isolated yield following chromatography.
†Determined by 1H NMR of unpurified reaction mixtures.
‡Determined by SFC analysis on chiral stationary phases.
†All products >20∶1 dr as determined by 1H NMR of unpurified mixtures.
‡Determined by SFC analysis on chiral stationary phases.
of moderate bases such as NEt3 (conjugate acid pKa ¼ 10.8) gave
predominantly cyclopentane products (entries 1 and 2). Toluene
and CH2Cl2 were the preferred solvents; selectivity decreased
with THF or 1,2-dichloroethane. Finally, slightly elevated tem-
peratures (40 °C) gave cleaner reactions. Although the reaction
times and yields were similar with either DMAP or NMM (entries
12 and 13), better diastereoselectivities were observed with the
less basic NMM. For reactions where epimerization is not an
issue, either base may be used.
As the catalytic generation of the reactive enolate equivalent
occurs via protonation of the β-position of the extended Breslow
intermediate (32), we anticipated that this reaction might be
limited to a narrow range of enals. This fear proved to be un-
founded, and the conditions identified in Table 2 were applicable
to electron-rich and electron-deficient cinnamaldehyde deriva-
tives (Entries 1–5). Remarkably, the reaction tolerates an unpro-
tected aromatic aldehyde without competing benzoin or oxidation
reactions (entry 5). Acrolein is also a viable substrate (entry 6).
Although not investigated in this series, simple aliphatic enals
such as 2-hexenal are excellent substrates for the Diels–Alder
reactions vide infra.
ing that these enones are less electrophilic than the correspond-
ing alcohols.
Our original work on NHC-catalyzed Diels–Alder reactions
via catalytically generated enolates employed electron-deficient
enones as substrates. With some limitations the optimized condi-
tions from Table 1 were also applicable to these substrate classes.
γ-Ketoenones bearing either electron-rich aromatic substituents
(Table 4) or aliphatic (Table 5) gave products in good yields
and outstanding stereoselectivies. Methyl-substituted enones
required higher concentrations and longer reaction times to reach
full conversion, but these changes did not compromise the high
levels of stereoselectivity. With more electron-deficient variants,
the formation of cyclopentane derivatives via the alternative
annulation pathway became important (Eq. 1).
[1]
In addition to the use of synthetically versatile enone 2, we
have also applied this catalyst and conditions to annulations
with three other classes of enones. N-Cbz protected enone 5 is
also an outstanding substrate and gave the expected products
in excellent yield and enantiopurity using DMAP as the catalytic
base (Table 3). In contrast to enone 2, the formation of cyclopen-
tane derivatives was never observed as side products. It is not
clear if this should be attributed to the reduced electrophilicity
of 5, or the possibility that the amide N-H acts to protonate
the conjugated Breslow intermediate, leading exclusively to the
hetero-Diels–Alder pathway. When DBU was employed as the
catalytic base, no cyclopentane products were observed, suggest-
In light of these findings, we were somewhat surprised to find
that α-keto-β,γ-unsaturated esters were excellent substrates
(Table 6). This makes possible the synthesis of synthetic challen-
ging vicinal dialkyl stereocenters in excellent yield and with ortho-
gonal synthetic handles for further elaboration. Although the use
of acrolein in this reaction gave somewhat lower yields (entries 2
and 4), it provides access to important stereochemical arrays
including erythro-dimethyl building blocks that have been the sub-
ject of recent efforts by several groups (33, 34). With α-keto-β-γ-
enones bearing aromatic substituents, the reactions gave complex
product mixtures under these conditions and further optimization
has not yet been explored*.
In seeking to rationalize the high levels of enantioselectivity
observed across several classes of enones and N-sulfonyl imines,
we have revisited our initially proposed stereochemical model
for the hetero-Diels–Alder cycloadditions. Our original analysis
suggested that the intermediate azolium-enolate complex formed
a conjugated, planar structure between the azolium and the
enolate olefin. Upon conformational searching, we have found
that the two lowest-lying enolate structures are ones in which the
triazolium moiety and the enolate are nearly perpendicular. (For
computational studies on the azolium catalyzed benzoin and
Stetter reactions, see ref. 35.) These two conformers differ in
the orientation of the enolate, with the lowest-lying structure
positioning the enolate oxygen on the same face as the indene
ring. The N-mesityl group blocks the approach of the oxodiene,
Table 5. NHC-catalyzed reactions of methyl ketoenone
Entry
R1
¼
% yield*
d.r.†
% ee‡
1
2
3
4
5
6
Ph
94
70
54
88
63
95
>20∶1
>20∶1
>20∶1
>20∶1
>20∶1
>20∶1
99
99
99
99
99
94
p-MeOC6H4
2-furyl
p-BrC6H4
H
n-C3H7
*Isolated yield following chromatography.
*This probably reflects the higher electrophilicity of these substrates, leading to
competing reactions. High yields of the identical Diels–Alder adducts can be obtained
with these substrates with chiral enolates generated from α-halo aldehydes.
†Determined by 1H NMR of unpurified reaction mixtures.
‡Determined by SFC analysis on chiral stationary phases.
Kaeobamrung et al.
PNAS
∣
November 30, 2010
∣
vol. 107
∣
no. 48
∣
20663

Fig. 2. The two lowest energy conformers from geometry optimization with HF 6-31G*. Initial conformers were identified via Monte Carlo conformational
searches using the Merck Force Field Model (MFFM). Four other low-lying conformational isomers were also optimized and found to be higher in energy
(see SI Appendix).
providing a rationalization for the necessity of this substitutent in
highly enantioselective annulations catalyzed by chiral N-hetero-
cyclic carbenes. Approach of the oxodiene toward the open face
of this enolate conformation via an endo transition state gives the
observed absolute stereochemistry of the products. We therefore
believe that an enolate with the structure shown in Fig. 2A is
the operative nucleophile in these hetero-Diels–Alder reactions
and in the several other unique reactions that invoke them as
intermediates.
Although not the focus of this study, the structure and electro-
nics of the N-heterocyclic carbene catalyst also play a crucial role
in determining the product outcome. We have previously demon-
strated that more electronic-rich imidazolium-derived catalysts
favor the homoenolate pathways, whereas triazolium-derived
structures enhance protonation and lead to the enolate and
activated carboxylates (36). The exceptions occur with very good
electrophiles, such as enones 2 and 11, particularly when stronger
amine bases, such as DBU, that give weaker conjugate acids are
employed.
Discussion
The catalytic generation of chiral enolates and their use in this
hetero-Diels–Alder pathways highlights the impressive ability
of a single catalyst and substrate combination to access multiple,
nonobvious reactive species by subtle changes in the reaction
conditions. As shown in Fig. 3, the combination of an α,β-unsa-
turated aldehyde and an N-heterocyclic carbene can lead to the
formation of four discrete reactive intermediates: (i) acyl anion
equivalents, (ii) homoenolate equivalents, (iii) ester enolate
equivalents, and (iv) activated carboxylates. Both the structure
of the azolium precatalyst and the nature of cocatalytic amine
base determine the reaction pathway. Remarkable selectivity,
often completely favoring one pathway to the exclusion of the
other three, can be obtained in NHC-catalyzed reactions of alde-
hydes. In the present case, selectivity between the homoenolate
and enolate pathways is determined by the fate of conjugated
Breslow-intermediate i. If the conjugate acid of the catalytic
base, generated by deprotonation of the azolium salt, is acidic
enough to protonate the Breslow intermediate at the β-position,
the formation of enolate equivalent iii occurs. Provided that the
enone reactant is sufficiently electrophilic, annulation occurs to
give the hetero-Diels–Alder products. The success of the reac-
tions, and the product distribution, is therefore determined by
the relative rates of C ─ C bond formation from the reactive in-
termediates and the two protonation steps.
Conclusion
In summary, we have identified conditions for the selective gen-
eration of NHC-bound enolates from α,β-unsaturated aldehydes
and their use in highly enantioselective hetero-Diels–Alder reac-
tions with electron-deficient enones. These reactions occur under
mild, simple conditions and afford synthetically valuable products
in excellent yield with outstanding stereoselectivities using a
single catalyst precursor. These studies reinforce the remarkable
range of reactivities available to α,β-unsaturated aldehydes, which
in this study serve as precursors to nucleophilic ester enolates
rather than their more traditional roles as C1 or C3 electrophiles,
and the versatility of N-heterocyclic carbenes in generating and
controlling uniquely reactive intermediates. Further efforts to
explore the utility of these catalytically generated intermediates
and unique catalysts to enhance their reactivity are ongoing.
ACKNOWLEDGMENTS. We are grateful to National Institute of General
Medical Sciences (National Institutes of Health, GM–079339), the National
Science Foundation (CHE-0449587), Bristol–Myers Squibb, and Roche for
support of this research. J.K. is a graduate fellow of the Royal Thai Govern-
ment. Instrumentation support for computing was provided by the National
Science Foundation Chemistry Research Instrumentation and Facilities
program (CHE0131132).
Fig. 3. Catalytically generated reactive species from α,β-unsaturated aldehydes with N-heterocyclic carbene catalysts.
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Kaeobamrung et al.

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