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

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

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 
• 5 Kawasaki Y. Fujii A. Nakano Y. Sakaguchi S. Ishii Y. J. Org. Chem.  1999,  64:  4214 
• 6 Evans DA. Chapman KT. Bisaha J. J. Am. Chem. Soc.  1988,  110:  1238 
• 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 
• 9b Burk MJ. de Koning PD. Grote TM. Hoekstra MS. Hoge G. Jennings RA. Kissel WS. Le TV. Lennon IC. Mulhern TA. Ramsden JA. Wade RA. J. Org. Chem.  2003,  68:  5731 
• 9c Burk MJ, Goel OP, Hoekstra MS, Mich TF, Mulhern TA, and Ramsden JA. inventors; WO01  55090. 
• 9d Hoge G. J. Am. Chem. Soc.  2003,  125:  10219 
• 9e Brenner M. Seebach D. Helv. Chim. Acta  1999,  82:  2365 
• 9f

  See also ref. 2a and 3.

• For selected approaches to (R)-baclofen employing conjugate addition as the key step, see:
• 10a Corey EJ. Zhang F.-Y. Org. Lett.  2000,  2:  4257 
• 10b Baldoli C. Maiorana S. Licandro E. Perdicchia D. Vandoni B. Tetrahedron: Asymmetry  2000,  11:  2007 
• 10c Licandro E. Maiorana S. Baldoli C. Capella L. Perdicchia D. Tetrahedron: Asymmetry  2000,  11:  975 
• 10d Meyer O. Becht J.-M. Helmchen G. Synlett  2003,  1539 
• 10e Becht J.-M. Meyer O. Helmchen G. Synthesis  2003,  2805 
• 11 Olpe H.-R. Demieville H. Baltzer WL. Koella WP. Wolf P. Hass HL. Eur. J. Pharmacol.  1978,  52:  133 
• 12 Puetz C, and Przewosny MT. inventors; WO03  062185. 
• 13a Thakur VV. Nikalje MD. Sudalai A. Tetrahedron: Asymmetry  2003,  14:  581 
• 13b Caddick S. Judd DB. de Lewis AKK. Reich MT. Williams MRV. Tetrahedron  2003,  59:  5417 

7

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.

8

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.