A highly enantioselective chiral Lewis base-catalyzed asymmetric cyanation of ketones [2]

Full text of DOI:10.1021/ja010690m

J. Am. Chem. Soc. 2001, 123, 6195-6196
Scheme 1. Decomposition of Secondary Amines to
6195
A Highly Enantioselective Chiral Lewis
Carbamates 7
Base-Catalyzed Asymmetric Cyanation of Ketones
Shi-Kai Tian and Li Deng*
Department of Chemistry, Brandeis UniVersity
Waltham, Massachusetts 02454-9110
ReceiVed March 15, 2001
The control of absolute configuration of quaternary stereo-
1-3
centers represents a great challenge in asymmetric catalysis.
A conceptually direct and attractive approach is to transform
prochiral ketones to chiral building blocks containing a quaternary
stereocenter by a catalytic asymmetric C-C bond formation. The
realization of this approach, however, has proven to be a
formidable task.1
,2d,3
Achieving synthetically useful enantiose-
lectivity with unconjugated aliphatic ketones is particularly
challenging since the two alkyl substituents of the ketone closely
resemble each other both electronically and sterically. We describe
here the development of a highly enantioselective cyanation of
dialkyl ketones catalyzed by an organic chiral Lewis base.
Guided by our recent discovery that readily available modified
cinchona alkaloids are highly effective chiral Lewis base catalysts
Figure 1. Structures of modified cinchona alkaloids.
Scheme 2. Proposed Catalytic Cycle for a Tertiary Chiral
Amine-Catalyzed Asymmetric Cyanation of Ketones
4
for desymmetrization of cyclic anhydrides, we undertook the
development of a chiral Lewis base-catalyzed asymmetric cya-
nation of ketones in view of its significance in asymmetric
5
synthesis. Our investigation started with the development of an
efficient amine-catalyzed cyanation of ketones. Poirier reported
that the treatment of unconjugated aliphatic ketones 1 with 20
4
equiv of diisopropylamine (3, R ) i-Pr) and 5-10 equiv of
3
methyl cyanoformate (4, R ) Me) afforded tertiary cyanohydrin
3
6
carbonates 2 (R ) Me) in good yield. A large excess secondary
amine 3 was used, presumably because deprotonation of 5 or 6
by a second equivalent of 3 will decompose 3 to carbamate 7
(Scheme 1). However, in principle, the reaction could be catalytic
in a tertiary amine, which cannot undergo this proton transfer.
3
Although, Poirer reported that excess Et N was much less effective
than diisopropylamine in promoting the conversion of 1 to 2,6
we observed at 25 °C that cyanation of 2-heptanone with 10 mol
%
amine and 1.5 equiv of NCCO
2
Me in THF proceeded in 35-
40% conversion with Et N, and the conversion was further
3
improved to 84% with DABCO.
Encouraged by these results, we turned to the enantioselective
conversion of 1 to 2 catalyzed by a tertiary chiral amine, such as
natural and modified cinchona alkaloids (Figure 1), as shown in
the proposed catalytic cycle (Scheme 2). Asymmetric cyanation
quinidine (66%, 2.6% ee), DHQD-CLB (63%, 17% ee), QHQD-
PHN (83%, 27% ee), (DHQD) PYR (86%, 11% ee), (DHQD)
PHAL (80%, 22% ee), (DHQD) AQN (94%, 27% ee). With
DHQD) AQN as the catalyst, the enantioselectivity of the
asymmetric cyanation can be improved from 27% ee to 40% ee
by employing ethyl cyanoformate and performing the reaction at
2
2
-
2
(
2
of 2-heptanone (1a) with 1.2 equiv of methyl cyanoformate and
1
1
0 mol % of the chiral amine in CHCl
3
at 25 °C gave 2 (R )
2
3
5
n-C H11, R ) R ) Me) in the following conversion and ee:
-
24 °C. The substitution of ethyl cyanoformate with benzyl
*
To whom correspondence should be addressed.
cyanoformate or the employment of other common organic
solvents such as dichloromethane, ether, toluene, and acetonitrile
resulted in deteriorated enantioselectivity for the asymmetric
cyanation of 2-heptanone (see Supporting Information for details).
Most importantly, a variety of acyclic and cyclic dialkyl
ketones, both R-substituted and R,R-disubstituted, are transformed
to tertiary cyanohydrin carbonates in good to excellent enantio-
selectivity and in synthetically useful yield with either DHQD-
(
1) For excellent reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388. (b) Fuji, K. Chem. ReV. 1993, 93, 2037.
2) For recent examples of catalytic creation of quaternary stereocenters
see: (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
(
2
000, 122, 5228. (b) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (c)
Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. (d) Dosa, P. I.;
Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445.
(3) While this manuscript was in preparation, Shibasaki and co-workers
reported the first highly enantioselective cyanosilylation of ketones catalyzed
by transition metal complexes prepared via a multistep synthesis from D-glucal.
See: (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000,
2
PHN or (DHQD) AQN as the catalyst (Table 1). Enantioselective
1
22, 7412. (b) Hamashima Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
001, 42, 691.
cyanation of the sterically hindered R,R-disubstituted ketones has
been reported previously only once with tert-butyl methyl ketone
using an enzymatic method.7 Particularly noteworthy is that, for
the first time, a catalytic asymmetric cyanation of a cyclic ketone
2
(
4) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542.
5) For reviews, see: (a) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649. (b)
,8
(
Effenberger, F. Angew. Chem., Int. Ed. 1994, 33, 1555. (c) North, M. Synlett
1
993, 807.
6) (a) Poirier, D.; Berthiaume, D.; Boivin, R. P. Synlett 1999, 1423. (b)
Berthiaume, D.; Poirier D. Terahedron 2000, 56, 5995.
(
(7) Griengl, H.; Klempier, N.; P o¨ chlauer, P.; Schmidt, M.; Shi, N.;
Zabelinskaja-Mackova, A. A. Tetrahedron 1998, 54, 14477.
1
0.1021/ja010690m CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/05/2001

6196 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Communications to the Editor
Table 1. Catalytic Asymmetric Cyanation of Unconjugated
duced in a 10 mmol scale reaction from which the catalyst,
DHQD-PHN, was recovered quantitatively using a simple extrac-
tive procedure. Although an extended reaction time was required
with a reduced catalyst loading, the reaction can be carried out
by simply allowing the reaction mixture in a vial to stand in a
freezer without stirring and any special precaution to exclude
moisture and air. Modified cinchona alkaloids derived from
quinine and quinidine have been shown to furnish highly
enantioselective access to both enantiomers of the tertiary
cyanohydrin carbonates (entries 1,2, 3,4, and 8,9, Table 1), thus
Ketones with Modified Cinchona Alkaloidsa,b
establishing themselves as the only class of synthetic catalysts to
9
do so. Furthermore, LiAlH
4
cleanly reduces the optically active
cyanohydrin carbonates (2b and 2i) to the synthetically and
8
biologically important chiral amino alcohols without any deteri-
oration in ee.10
As found in the reaction with 2-heptanone (1a), the ee of the
cyanohydrin carbonate generated from reactions involving simple
dialkyl ketones started to decrease noticeably when the conversion
of the reaction proceeded over 55% (entries 14-15, Table 1).
However, the ee variation of the product is significantly less
pronounced in reactions employing R,R-dialkoxy cyclic and
acyclic ketones, which allows the generation of the corresponding
cyanohydrin carbonates in excellent enantioselectivity and good
to excellent isolated yield (entries 8-12). As shown in Scheme
2, the enantioselectivity of the reaction may originate from the
enantioselective addition of the cyanide, as part of a chiral ion
complex (10), to ketone 1. Alternatively the ee of the cyanohydrin
carbonates (2) can be determined by a dynamic kinetic resolution
of cyanoalkoxides 10A and 10B (k
asymmetric alkoxycarbonylation (10 to 2), which provides a
a
> k
b
or k
a
b
< k ) via an
plausible explanation for the observed ee change of cyanocar-
bonates 2 during the reaction course.
a
11,12
The reaction was performed by treatment of the ketone (0.2 mmol)
b
with ethyl cyanoformate (1-3 equiv) in chloroform (0.2-0.3 mL). The
catalyst was recovered in quantitative yield. See Supporting Informa-
tion for details to ee analysis. Determined by GC analysis using an
In summary, we have developed a highly enantioselective
cyanation of prochiral ketones promoted by a metal-free organic
catalyst. The reaction is mechanistically interesting as the first
efficient asymmetric cyanation of simple ketones realized with a
chiral Lewis base approach. Importantly, the reaction complements
known enzyme- and transition metal-based methods3 in substrate
scope via its unique ability to transform cyclic and sterically
hindered dialkyl ketones in highly enantioselective manner.
Additional notable features of the reaction are the utilization of
easily accessible and fully recyclable catalysts and the employ-
ment of a simple experimental protocol. These features should
render the reaction a useful catalytic entry for the asymmetric
creation of quaternary stereocenters via prochiral ketones.
c
d
e
f
internal standard. Isolated yields. Yields in parentheses are based on
the conversion of ketones. g The opposite enantiomer is generated. h The
absolute configuration of the major enantiomer was determined to be
R (see Supporting Information for detials).
,5
is realized with excellent enantioselectivity to give the tertiary
cyanohydrin derivative in greater than 90% ee (entries 1-4 and
-11, Table 1). Since it is catalyzed by a chiral Lewis base, the
reaction tolerates acid-sensitive functionality as shown by the
successful cyanation of acyclic and cyclic ketones bearing either
an acetal or ketal functionality that affords functionalized tertiary
cyanohydrin products in excellent enantioselectivity (entries 8-13,
Table 1).
8
Acknowledgment. We gratefully acknowledge the financial support
of Research Corporation (RI-0311), the Harcourt General Charitable
Foundation and Daiso Inc.
The modified cinchona alkaloid-catalyzed asymmetric cyana-
tion proceeded cleanly to consistently afford the chiral tertiary
cyanohydrin carbonates in >95% yield based on converted ketone
Supporting Information Available: Complete experimental details
(
Table 1). The reactions were usually quenched after 2-5 days
(PDF). This material is available free of charge via the Internet at
when they reached a conversion between 55 and 97% to provide
the desired products in 52-96% isolated yields. It should be noted
that the catalyst loading could be reduced substantially without
any significant adverse effect on the enantioselectivity and yield
of the reaction. For example, the nearly quantitative yield and
excellent ee obtained from the cyanation of ketone 1g (entry 9,
Table 1) using 20 mol % catalyst can be also realized by using
http://pubs.acs.org.
JA010690M
(
9) As reviewed in ref 5, both enantiomers of certain chiral cyanohydrins
are accessible from methods based on (R)- or (S)-oxynitrilase, respectively.
(
(
10) See Supporting Information.
11) According to the quantitative expression described by Noyori and co-
12
workers for a dynamic kinetic resolution, the ee of the cyanohydrin carbonate
is expected to decrease at high conversion if the rate of epimerization of the
quaternary carbon stereocenter in intermediates 10A and 10B, via ketone 1,
is slower than the rate of the kinetic resolution step.
10 mol % catalyst. These results have been successfully repro-
(
8) For a recently reported diastereoselective cyanation of sterically hindered
ketones, see: Wilkinson, H. S.; Grover, P. T.; Vandenbossche, C. P.; Bakale,
(12) (a) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993,
115, 144. (b) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn.
1995, 68, 36.
R. P.; Bhongle, N. N.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2001, 3,
53.
5