ORGANIC
LETTERS
2001
Vol. 3, No. 4
553-556
A New Lithium Alkoxide Accelerated
Diastereoselective Cyanation of Ketones
H. Scott Wilkinson, Paul T. Grover, Charles P. Vandenbossche, Roger P. Bakale,
Nandkumar N. Bhongle, Stephen A. Wald, and Chris H. Senanayake*
Chemical Research and DeVelopment, Sepracor Inc., 111 Locke DriVe,
Marlborough, Massachusetts 01752
Received December 5, 2000
ABSTRACT
A remarkably general lithium heteroatom assisted TMSCN or TBSCN addition to aldehydes and ketones has been discovered. The process
provides excellent selectivities and high rates. Conformationally constrained ketones such as camphor, fenchone, and nopinone give excellent
diastereoselectivities with TMSCN. Reduction of 2 provided diastereopure amino alcohol 3 in good yield. r- and â-Methyl cyclohexanones
with TBSCN−LiOR afford high diastereoselectivities and yields.
The development of practical technology for the preparation
of R-hydroxy-R-substituted acids, ketones, aldehydes, and
â-hydroxy amines from readily available carbonyl com-
pounds is an extremely important area of organic chemistry.
One of the most straightforward entries to the above-
mentioned building blocks is via cyanohydrins.1 Preparation
of cyanohydrins from ketones is well documented, and
limited enantioselective methods are available.2 The most
commonly used method is through the use of the Lewis acid
catalyzed addition of TMSCN to ketones.3 However, general,
mild, high-yielding, and selective processes for cyanation
of hindered carbonyl groups are still lacking.
In our efforts to synthesize conformationally constrained,
enantiomerically pure amino alcohols for use in asymmetric
synthesis, we required a practical procedure for the prepara-
tion of camphor-derived amino alcohol 3. We envisaged that
compound 2, derived from a selective cyanide addition would
provide an easy access to the desired amino alcohols.4 Herein,
we disclose the development of a new and neutral diastereo-
selective cyanation process for the generation of the silyl
ethers of cyanohydrins from ketones using cyanosilanes and
a lithium heteroatom catalyst. The method is applied to the
synthesis of enantiomerically pure amino alcohol 3 in a
convenient, high yielding procedure.
(1) (a) Matthews, B. R.; Gountzos, H.; Jackson, W. R.; Watson, K. G.
Tetrahedron Lett. 1989, 30, 5157. (b) Jackson, W. R.; Jacobs, H. A.;
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2045. (c) Jackson, W. R.; Jacobs, H. A.; Matthews, B. R.; Jayatilake, G.
S.; Watson, K. G. Tetrahedron Lett. 1990, 31, 1447. (d) Ziegler, T.; Horsch,
B.; Effenberger, F. Synthesis 1990, 575. (e) Effenberger, F.; Stelzer, U.
Angew. Chem., Int. Ed. Engl. 1991, 30, 873. (f) Zandbergen, P.; Brussee,
J.; Van der Gen, A.; Kruse, C. G. Tetrahedron: Asymmetry 1992, 3, 769.
(g) For a recent review: North, M. Synlett 1993, 807 and references therein.
(f) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649.
(2) (a) Choi, M. C. K.; Chan, S. S.; Matsumoto, K. Tetrahedron Lett.
1997, 38, 6669. (b) Belokon, Y. N.; Green, B.; Ikonnikov, N.; North, M.;
Tararov, V. Tetrahedron Lett. 1999, 40, 6105. (c) Hamashima, Y.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412.
Scheme 1
(3) (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Chem. Soc.,
Chem. Commun. 1973, 55. (b) Gassman, P. G.; Talley, J. J. Tetrahedron
Lett. 1978, 19, 3773. (c) Noyori, R.; Murato, S.; Suzuki, M. Tetrahedron
1981, 37, 3899. (d) Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif, W.
Tetrahedron Lett. 1988, 29, 3295. (e) Singh, V. K.; Saravanan, P.; Anand,
R. V. Tetrahedron Lett. 1998, 39, 3823 and references therein.
10.1021/ol0069608 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/30/2001