Catalytic asymmetric epoxidation of α-branched enals

Article abstract of DOI:10.1021/ja1037935

An asymmetric catalytic epoxidation of α-branched, α,β-unsaturated aldehydes is presented. A highly synergistic combination of a primary cinchona-based amine and a chiral phosphoric acid was found to promote the reaction with excellent enantiocontrol for α-monosubstituted and α,β-disubstituted enals.

Full text of DOI:10.1021/ja1037935

Published on Web 07/12/2010
Catalytic Asymmetric Epoxidation of r-Branched Enals
Olga Lifchits, Corinna M. Reisinger, and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mu¨lheim an der Ruhr, Germany
Received May 4, 2010; E-mail: list@mpi-muelheim.mpg.de
Table 1. Catalyst Screeninga
Abstract: An asymmetric catalytic epoxidation of R-branched,
R,ꢀ-unsaturated aldehydes is presented. A highly synergistic
combination of a primary cinchona-based amine and a chiral
phosphoric acid was found to promote the reaction with excellent
enantiocontrol for R-monosubstituted and R,ꢀ-disubstituted enals.
Ever since Sharpless’s pioneering studies on the enantioselective
epoxidation of allylic alcohols in the 1980s,1 advances in catalytic
olefin epoxidation have defined the current state of the art in
asymmetric synthesis. Breakthrough discoveries have not only
tackled important substrate classes such as unfunctionalized olefins
but also identified entirely new catalyst motifs.2 Very recently,
initiated by a seminal finding by Jørgensen et al.,3 aminocatalysis
has provided powerful methodologies for the epoxidation of R,ꢀ-
unsaturated aldehydes and ketones, including substrate classes that
had been inaccessible to enantioselective epoxidation catalysis
before.4 Despite these advances, however, a general method for
the direct catalytic asymmetric epoxidation of R-branched, R,ꢀ-
unsaturated aldehydes is still lacking.5 Such a reaction would
provide enantioenriched R-substituted epoxyaldehydes, which find
numerous and specific applications in organic synthesis.6 Herein
we describe a general solution to this problem. We have identified
new salts that consist of a chiral primary ammonium cation and a
chiral phosphate anion that catalyze the epoxidation of a variety of
branched enals with superb enantioselectivity.
While several approaches exist for the generation of racemic
R-substituted, R,ꢀ-epoxyaldehydes,7 catalytic enantioselective vari-
ants invariably utilize substrates of higher or lower oxidation state.8
For example, one of the most widely used routes to R-substituted,
R,ꢀ-epoxyaldehydes is based on the Sharpless epoxidation of allylic
alcohols.1 However, since the starting material is commonly at the
carbonyl or carboxyl oxidation level, this approach suffers from
moderate step, atom, and redox economy9 (eq 1).
entry
catalyst
conv (%)b
drb
erc
1
2
3
4
5
6d
7
8
9
1a
1b
1c
1d
1e
1e
1f
38
58
50
35
84
100
25
32
2
75:25
87:13
94:6
74:26
96:4
92:8
75:25
81:19
93:7
95:5
99.5:0.5
36:64
99.5:0.5
98.5:1.5e
14:86
6.5:93.5
0
1g
1h
a See Supporting Information for full details. b Determined by GC.
c Determined by GC analysis on a chiral stationary phase. d With THF
as solvent and 5 equiv of H2O2. e The absolute configuration (2R,3S) of
4a was assigned by comparing the optical rotation of the corresponding
alcohol to the literature value.15
salt 1a and aqueous hydrogen peroxide (Table 1, entry 1). The
desired product was obtained with moderate conversion as a 25:75
cis/trans mixture of diastereomers but with an encouraging enan-
tiomer ratio (er) of 93:7 for the major trans-diastereomer. A screen
of acid cocatalysts (see Supporting Information (SI)) showed that
an achiral phosphoric acid had a positive influence on conversion
and selectivity (entry 2). Cognizant of the potential role of an
asymmetric counterion in such systems,4b-d,10,13 we tested the
chiral phosphoric acid (R)-2a (TRIP) as the cocatalyst. This resulted
in a dramatic case of “matched” chiral induction, whereby the major
diastereomer was generated in essentially enantiopure form (er )
99.5:0.5, entry 3). Notably, this synergism was lost when the
opposite enantiomer of the phosphoric acid (S)-TRIP was used:
catalyst salt 1d furnished the product with completely reversed but
only modest enantioselectivity (entry 4). A further screen of
phosphoric acids 2, bearing various 3,3′-substituents, identified the
bis-phenyl-substituted analogue 2b as the optimal cocatalyst in terms
of both activity and stereoselectivity (entry 5). Using the most
effective catalyst 1e, we further optimized the reaction parameters
to achieve full conversion (entry 6). We also tested various simpler
achiral and chiral amines in combination with TRIP,14 including
the chiral catalyst pair that we employed for the epoxidation of
cyclic enones4c (entries 7 and 8), but none of the combinations
provided satisfactory levels of enantiocontrol. Similarly, our previ-
Encouraged by our previous success in establishing primary
amine salts in asymmetric iminium ion catalysis,10 we have recently
introduced cinchona alkaloid-derived primary ammonium salts as
powerful catalysts for the epoxidation of cyclic and acyclic
enones.4c,d,11 Recent reports7a,12 have furthermore demonstrated
the utility of primary aminocatalysis also for the activation of
R-branched enals. With this background in mind, we became
interested in exploring our previously used catalyst system consist-
ing of a primary cinchona alkaloid-derived amine and trifluoroacetic
acid (1a) in the epoxidation of R-branched, R,ꢀ-unsaturated
aldehydes.
We began our investigation by testing the epoxidation of
commercially available (E)-2-methylpent-2-enal (3a) with catalyst
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C O M M U N I C A T I O N S
ous system utilizing a secondary amine catalyst4b failed to give
any conversion (entry 9).
no reports describing a direct enantioselective epoxidation for this
substrate class, although Pihko et al. have recently developed a
very useful non-asymmetric version.7a The combination of two
chiral catalysts proved essential in this case, as achiral acid
cocatalysts gave very poor enantioselectivity (er up to 63:37 for
6a).14 In comparison, catalyst pair 1e afforded the epoxide 6a with
91:9 er. Gratifyingly, the enantioselectivity could be further
improved by using catalyst salt 1c, which contains (R)-TRIP as a
bulkier phosphoric acid (Table 3, entries 1-3). This catalyst salt
could also be applied to the kinetic resolution of ꢀ′-substituted enal
5d (entry 4). After 53% conversion under the reaction conditions,
the (R)-enantiomer underwent a highly enantioselective epoxidation,
while the (S)-enantiomer was recovered with a 97:3 er.
With the optimal conditions in hand, we examined the scope of
our new epoxidation (Table 2). It is noteworthy that the required
(E)-configured R,ꢀ-disubstituted enals 3 could be easily prepared
via redox-neutral9 methodologies from aldehyde precursors via
Grubbs olefin cross-metathesis16 and aldol condensation.17 We were
pleased to find excellent enantioselectivity regardless of the
R-substituent (entries 1-3). The same level of enantiocontrol was
seen for cyclic substrate 3d (entry 4) and enals bearing different
functional groups (entries 5 and 6). In all cases, the trans-
diastereomer was favored with good to excellent selectivity.
Tetrasubstituted olefins appear to be a current limitation of our
method, as enal 3g (entry 7) did not afford the desired product,
giving decomposition products via Baeyer-Villiger reaction instead.
We also tested (Z)-3e in the reaction. This starting material also
gave preferentially the trans-product, although the reaction rate and
selectivity were compromised (entry 8, see SI for further details).
Intriguingly, the current catalyst system proved unsuitable for
R-unbranched, R,ꢀ-unsaturated aldehydes (entry 9). While we
currently do not have an explanation for this reactivity, the result
underscores the intricate complementarity that must be achieved
between the steric and electronic requirements of the substrate and
those of the catalyst to obtain a viable catalytic system.
Table 3. Substrate Scope of the Epoxidation of R-Monosubstituted
Enals
Table 2. Substrate Scope of the Epoxidation of R,ꢀ-Disubstituted
Enals
a Isolated yield after reduction with NaBH4. b Determined by GC on a
chiral stationary phase. c Isolated yield of the aldehyde. d Using 1b as
the catalyst. e The absolute configuration (R) of 6c was assigned by
comparing the optical rotation of the corresponding alcohol to the
literature value.18 f Determined by GC analysis of the crude reaction
mixture. g Refers to the major diastereomer; er (minor diastereomer) )
87:13.
Mechanistically, we believe that the primary cinchona-derived
amine activates the enal substrates via iminium ion A, which
undergoes conjugate addition by hydrogen peroxide and ring closure
via enamine intermediate B (eq 2). Importantly, the chiral phos-
phoric acid provides additional enantiodiscrimination in both steps
as a chiral counterion in A and as a Brønsted acid in B. This is
supported by the dramatic match/mismatch observed when using
the phosphoric acids (R)-TRIP and (S)-TRIP in the epoxidation
of enals 3 (Table 1, entries 3 and 4), as well as the strong influence
of the acid cocatalyst on the enantioselectivity of epoxidation of
enals 5 (Table 3, entry 1).
a Isolated yield after reduction with NaBH4. b Determined by NMR or
GC analysis of the crude reaction mixture. c Determined by GC or
HPLC analysis on a chiral stationary phase. d Complete conversion and
no side products were observed; the reduced yield reflects the high
volatility of the product. e E/Z ratio of the substrate )96:4. f GC yield.
g E/Z ratio of the substrate )5:95.
In summary, we have developed a highly enantioselective
catalytic epoxidation of R-branched, R,ꢀ-unsaturated aldehydes.
Crucial to the success was the combination of a chiral primary
cinchona-based amine and a chiral phosphoric acid. Employing the
catalyst pair not only provided excellent enantiocontrol due to the
We next turned our attention to the epoxidation of R-substituted
terminal enals 5 (Table 3). To the best of our knowledge, there are
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C O M M U N I C A T I O N S
Schweizer, W. B.; Senn, H. M.; Gilmour, R. Angew. Chem., Int. Ed. 2009,
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exceptional synergism of its two components but also allowed for
rapid optimization for different substrates owing to its modular
nature. The utility of our methodology is underscored by the
numerous synthetic applications described for R-branched, R,ꢀ-
epoxyaldehydes, which can now be accessed in a single step from
readily available precursors.
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Acknowledgment. We thank our GC and HPLC departments
for their support, and Natascha Wippich, Simone Marcus, and
Marianne Hannappel for technical assistance. The Max-Planck-
Society, the DFG (Priority Program Organocatalysis SPP1179), and
the Fond der Chemischen Industrie (Kekule´ fellowship to C.M.R.
and Award to B.L.) are gratefully acknowledged.
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Supporting Information Available: Experimental procedures,
compound characterization, and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
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