Catalytic asymmetric cyanosilylation of ketones with chiral Lewis base

Article abstract of DOI:10.1021/ja036222p

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (α,α-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions. Copyright

Full text of DOI:10.1021/ja036222p

Published on Web 07/26/2003
Catalytic Asymmetric Cyanosilylation of Ketones with Chiral Lewis Base
Shi-Kai Tian, Ran Hong, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received May 19, 2003; E-mail: deng@brandeis.edu
Scheme 1. A General Approach for Catalytic Enantioselective
Construction of Quaternary Stereocenters
Catalytic asymmetric cyanation of prochiral ketones provides an
attractive enantioselective approach toward chiral building blocks
containing a quaternary center via optically active tertiary cyano-
hydrins.1,2 Enantioselective cyanosilylation and cyanocarbonation
of ketones with chiral metal-based Lewis acids3-6 and organic
bases,7 respectively, have been reported. These reactions provide
useful methods for the enantioselective creation of quaternary
stereocenters bearing two electronically or sterically different
substituents (R1 and R2).8 However, a broadly applicable catalytic
approach for the construction of quaternary stereocenters, especially
those bearing two electronically and sterically analogous substit-
uents, remains a desirable yet challenging goal. Herein, we describe
an advance toward this goal via the realization of the first highly
enantioselective cyanosilylation of ketones with an organic chiral
Lewis base.
Scheme 2. DABCO-Catalyzed Cyanosilylation of Ketones
Table 1. (DHQ)2AQN-Catalyzed Asymmetric Cyanosilylation of
a
PhCOCHX2
Our strategy involves a catalytic enantioselective cyanation of
ketones bearing a versatile functional group, followed by transfor-
mations of the versatile functional groups into a wide range of other
structures (Scheme 1). For such an approach to become broadly
useful, ketones 1 should be readily accessible and the catalytic
cyanation must be highly enantioselective and extremely general
with respect to the R1 group of ketone 1. These desirable properties
should be, ideally, attained with readily available catalysts.
Of particular interest to us was to explore this approach via the
development of a metal-free catalytic enantioselective cyanation
of ketones 1 with the readily accessible modified cinchona
alkaloids,9 in light of the ability of modified cinchona alkaloids to
function as broadly effective organic chiral Lewis base and
nucleophilic catalysts.7,10-15 The implementation of the strategy
illustrated in Scheme 1 with catalysts based on a cinchona alkaloid
skeleton requires an amine-catalyzed cyanation that is effective for
both conjugated and unconjugated ketones. Unfortunately, the
recently reported modified cinchona alkaloid-catalyzed cyano-
carbonation of ketones is ineffective with conjugated ketones.7
Although only sporadic examples of amine-catalyzed cyanosilyla-
tions have been reported for cyclohexanone,16 1,1,1-trifluoro-4-
ethoxybut-3-en-2-one,17 and acetophenone,18 they nevertheless
indicate that an amine may be able to efficiently catalyze the
cyanosilylation of both conjugated and unconjugated ketones.
Indeed, our initial catalyst screening studies revealed that
DABCO is an effective catalyst for both conjugated and unconju-
gated ketones (Scheme 2). High-yielding cyanosilylation can be
achieved even with the sterically hindered pinacolone (4b).
Moreover, cyanosilylation of chalcone (4d) afforded exclusively
the corresponding 1,2-addition product.
c
d
entry ketone
X
cat./mol% T/°C time/h conv/% ee/%
1
4c
6a
6b
6c
7a
7a
H
10
10
10
10
10
2
-24
-24
-24
-24
-24
-50
16
7
7
7
7
91
100
100
100
100
100
31
57
63
73
74
90
2
3
Oc-C6H11
OCH2CHdCH2
On-C8H17
OEt
4
5
6b
OEt
19
a Unless specified, the reaction was run with 4.0 equiv of TMSCN and
the catalyst in chloroform. b Three equivalents of TMSCN was used.
c Determined by GC analysis. d Determined by HPLC analysis.
Cyanosilylations of acetal ketones 6a-c, 7a with various cinchona
alkaloid derivatives were performed, and at -24 °C in the presence
of (DHQ)2AQN they were found to proceed with increased rate
and enantioselectivity relative to the cyanosilylation of acetophenone
4c (entries 2-5 vs entry 1, Table 1). Importantly, the cyanosilylation
of acetal ketone 7a at -50 °C was found to proceed in complete
conversion and 90% ee with 2 mol % of (DHQ)2AQN (entry 6,
Table 1).
As summarized in Table 2, excellent enantioselectivity and yield
is obtained with acetal ketones 7 bearing a broad range of aryl,
alkenyl, alkynyl, and alkyl substituents.20 Even acetal ketone 7m,
in which both the R- and the R′-carbon are disubstituted, is
converted to the corresponding ketone cyanohydrin in 94% ee (entry
17, Table 2). Interestingly, (DHQ)2AQN in chloroform and
(DHQD)2PHAL in ethyl acetate afford the highest ee for the
formation of the two enantiomers of the product (8), respectively
(entries 3-4, 6-7, 10-11, 13-14, Table 2). The cyanosilylation
of acetal ketone 7j was performed on a 0.10 mol scale (Scheme
3). Both the isolation of product 8j (92% ee) and the recovery of
the (DHQ)2AQN were achieved in quantitative yield using a simple
extractive procedure.21 These results were duplicated with the
recovered (DHQ)2AQN.
We next focused on the cyanosilylation of ketones with modified
cinchona alkaloids. We were especially interested in the asymmetric
cyanosilylation of the readily accessible R,R-dialkoxy ketones
(acetal ketones).19 We reasoned that, in addition to serving as a
versatile handle for synthetic elaborations of the product, ketone
cyanohydrin, the acetal group should also enhance the activity of
the ketone toward the nucleophilic enantioselective cyanosilylation.
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J. AM. CHEM. SOC. 2003, 125, 9900-9901
10.1021/ja036222p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Modified Cinchona Alkaloid-Catalyzed Asymmetric
versatility of the acetal functionality, this reaction provides a new,
practical, and broadly applicable approach toward chiral building
blocks bearing quaternary stereocenters. Although, to our knowl-
edge, previously unexplored in asymmetric synthesis, acetal ketones
7 demonstrate unusual reactivity and selectivity toward the enan-
tioselective cyanosilylation, thereby suggesting that they may be
interesting substrates for other catalytic enantioselective reactions.
Cyanosilylation of Acetal Ketonesa
Acknowledgment. We are grateful for the generous financial
support from NIH (GM-61591), Daiso, and an Alfred P. Sloan
research fellowship (L.D.).
Supporting Information Available: Experimental procedures and
characterization of the products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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a Unless specified, the reaction was performed by treatment of the ketone
(0.20 mmol) with TMSCN (3.0 equiv) and the catalyst in chloroform (0.20
mL). b The reaction was run with 2.0 equiv of TMSCN in ethyl acetate.
c Isolated yield. d Determined by HPLC or GC analysis as described in the
Supporting Information. e The absolute configuration is determined to be
R as described in the Supporting Information.
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Scheme 3. Catalytic Enantioselective Synthesis of Amino Alcohols
Bearing Quaternary Stereocenters
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We have applied this cyanosilylation to the synthesis of several
optically active multifunctional chiral building blocks bearing a
quaternary stereocenter (10-12j, 12d, Scheme 3). Especially
noteworthy is the synthesis of 12d, which contains a quaternary
stereocenter bearing two substituents that are highly analogous to
each other in terms of both steric and electronic properties.
In summary, we have developed the first highly enantioselective
cyanosilylation of ketones catalyzed by a chiral Lewis base. The
reaction employs commercially available and fully recyclable
catalysts, involves a simple experimental procedure, and is exceed-
ingly general for acetal ketone 7. Coupled with the synthetic
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(19) As described in the Supporting Information, a wide variety of R,R-dialkoxy
ketones (6a-c, 7a-m) can be prepared from commercially available
reagents such as R,R-dialkoxyacetonitrile, arylglyoxal monohydrate, and
1,3-dihydroxyacetone dimer in one or two steps.
(20) Simple ketones afford generally modest enantioselectivity (10-76% ee).
(21) For experimental details, see the Supporting Information.
JA036222P
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J. AM. CHEM. SOC. VOL. 125, NO. 33, 2003 9901