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

Alan Armstrong; Nicola J. Convine; Matthew E. Popkin

doi:10.1055/s-2006-941584

LETTER

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

Alan Armstrong*^a, Nicola J. Convine^a, Matthew E. Popkin^b
^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

Abstract

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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.

Key words

conjugate addition - cyanide - samarium - oxazolidinone

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Referenzen

References and Notes

1a Review of conjugate addition of cyanide: Nagata W. Nozaki H. Org. React. 1977, 25: 255

1b For cyanide group manipulations, see: North M. Tetrahedron: Asymmetry 2003, 14: 147 ; and references therein

1c For a review of stereoselective conjugate addition, see: Armstrong A. Convine NJ. In Comprehensive Organic Functional Group Transformations II Vol. 1: Katritzky AR. Taylor RJK. Cossy J. Elsevier Pergamon; Oxford: 2005. p.287 ; and references therein

2a Sammis GM. Jacobsen EN. J. Am. Chem. Soc. 2003, 125: 4442

2b Sammis GM. Danjo H. Jacobsen EN. J. Am. Chem. Soc. 2004, 126: 9928

3 Mita T. Sasaki K. Kanai M. Shibasaki M. J. Am. Chem. Soc. 2005, 127: 514

For selected diastereoselective approaches, see:

4a Dahuron N. Langlois N. Synlett 1996, 51

4b Garcia Ruano JL. Cifuentes Garcia M. Laso NM. Martin Castro AM. Rodriguez Ramos JH. Angew. Chem. Int. Ed. 2001, 40: 2507

4c Acherki H. Alvarez-Ibarra C. Dios A. Quiroga ML. Tetrahedron 2002, 58: 3217

4d Benedetti F. Berti F. Garau G. Martinuzzi I. Norbedo S. Eur. J. Org. Chem. 2003, 1973

4e Steurer S. Podlech J. Eur. J. Org. Chem. 2002, 899

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6 Evans DA. Chapman KT. Bisaha J. J. Am. Chem. Soc. 1988, 110: 1238

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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: ν_max = 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.

9a Hoekstra MS. Sobieray DM. Schwindt MA. Mulhern TA. Grote TM. Huckabee BK. Hendrickson VS. Franklin LC. Granger EJ. Karrick GL. Org. Process Res. Dev. 1997, 1: 26

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9e Brenner M. Seebach D. Helv. Chim. Acta 1999, 82: 2365

9f

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

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