Synlett 2006(10): 1589-1591  
DOI: 10.1055/s-2006-941584
LETTER
© Georg Thieme Verlag Stuttgart · New York

Diastereoselective Conjugate Addition of Cyanide to α,β-Unsaturated ­Oxazolidinones: Enantioselective Synthesis of ent-Pregabalin and Baclofen

Alan Armstrong*a, Nicola J. Convinea, Matthew E. Popkinb
a Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Fax: +44(20)75945804; e-Mail: A.Armstrong@imperial.ac.uk;
b Chemical Development, GSK Tonbridge, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK
Further Information

Publication History

Received 9 March 2006
Publication Date:
12 June 2006 (online)

Abstract

Conjugate addition of cyanide to chiral α,β-unsaturated oxazolidinones catalyzed by samarium(III) isopropoxide proceeds with good diastereoselectivity. The addition products can be ­converted into the biologically active targets ent-pregabalin and ­baclofen.

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Typical Procedure.
The substrate 3 (1 mmol) in toluene (1 mL) was added to Sm(Oi-Pr)3 (0.1 mmol) under N2 at 0 °C followed by commercial acetone cyanohydrin (2 mmol). The reaction mixture was warmed to r.t. and stirred for the indicated time. Upon completion, wet Et2O (5 mL) was added and the reaction mixture filtered through Celite®, washing with Et2O and CH2Cl2. The filtrate was concentrated in vacuo and the resulting crude material purified by silica flash column chromatography to yield the separated diastereomers of 4. Major diastereomer of 4a (132 mg, 59%) isolated as a colourless oil; [α]D 20 +60 (c 1, CHCl3). IR: νmax = 2965, 2243, 1779, 1703, 1390, 1209 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.89 (d, J = 7.0 Hz, 3 H, MeCHMe), 0.93 (d, J = 7.0 Hz, 3 H, MeCHMe), 1.41 (d, J = 7.0 Hz, 3 H, Me), 2.41 (sept of d, J = 7.0, 4.0 Hz, 1 H, MeCHMe), 3.07-3.24 (m, 2 H, NCCHCH 2), 3.41 (m, 1 H, NCCHCH 2), 4.25 (dd, J = 9.2, 3.4 Hz, 1 H, OCH 2), 4.31 (dd, J = 9.2, 7.9 Hz, 1 H, OCH 2), 4.46 (dt, J = 7.9, 3.7 Hz, 1 H, NCH). 13C NMR (62.5 MHz, CDCl3): δ = 14.7 (CH3, MeCHMe), 17.7 (CH3), 17.8 (CH3), 21.1 (CH, NCC), 28.3 (CH, MeCHMe), 39.6 (CH2, COCH2), 58.4 (CH, NCH), 63.8 (CH2, OCH2), 122.1 (C, CN), 154.0 [C, NC(O)O], 169.0 (C, COCH2). MS (CI):
m/z (%) = 242 (100) [M + NH4 +]. HRMS: m/z calcd for C11H20N3O3: 242.1505; found: 242.1498.

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Details will be provided in a full account of this work. We thank Dr. A. J. P. White, Dept. of Chemistry, Imperial College London, for this structure determination.