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Synlett 2003(10): 1527-1529
DOI: 10.1055/s-2003-40824
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise Formal Synthesis of (S)-Vigabatrin Based on Nitrone Umpolung

Géraldine Masson, Walid Zeghida, Pascale Cividino, Sandrine Py*, Yannick Vallée*
LEDSS, UMR CNRS, Université Joseph Fourier, B.P.53X, 38041 Grenoble, France
Fax: +(33)476514803; e-Mail: sandrine.py@ujf-grenoble.fr;
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Publication History

Received 5 May 2003
Publication Date:
24 July 2003 (online)

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Abstract

A short, formal synthesis of (S)-vigabatrin is described, from readily available 2,3-diprotected d-glyceraldehyde (5). The key step of this synthesis involves a samarium diiodide-induced reductive coupling of the corresponding nitrone with alkyl acrylates.

Key words

asymmetric synthesis - g-amino acids - nitrones - samarium diiodide - vigabatrin

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Spectral data for compound 5a (major isomer): white solid, mp 70-71 °C; [α]D 25 +6.0 (c 2.0, CHCl3). IR (CH2Cl2): 3437, 3069, 3037, 2988, 2890, 1731, 1616, 1502, 1461, 1257, 1208, 1176 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H, CH3), 1.38 (s, 3 H, CH3), 1.89-2.00 (m, 1 H, CH2 CH 2 CHN), 2.07-2.19 (m, 1 H, CH2 CH 2 CHN), 2.50-2.61 (m, 2 H, CH 2 CH2CO), 2.65-2.71 (m, 1 H, CH2 CHN), 3.61 (s, CO2 CH 3 ), 3.74-3.81 [dd, 1 H, J = 7.4 Hz and J = 8.2 Hz, CH 2 (OC)CH(OC)CHN], 3.80 (d, 1 H, J = 13.4 Hz, NCH 2 Ph), 3.85 (d, 1 H, J = 13.4 Hz, NCH 2 Ph), 4.09-4.14 [m, 1 H, J = 6.4 Hz and J = 8.2 Hz, CH 2 (OC)CH(OC)CHN], 4.30-4.37 [m, 1 H, CH2(OC)CH(OC)CHN], 5.39 (br s, 1 H, NOH), 7.26-7.30 (m, 5 H, CHarom.). 13C NMR (75 MHz, CDCl3): δ = 22.13 (CH2 CH 2 CHN), 25.35 (CH 3 CCH3), 26.43 (CH3CCH 3 ), 31.53 (CH2 CH 2 CO), 51.42 (CO2 CH 3 ), 60.33 (NCH 2 Ph), 67.45 [CHN(OH)Bn], 68.63 [CH 2 (OC)CH(OC)CHN], 75.37 [CH2(OC)CH(OC)CHN], 108.67 (CH3 CCH3), 127.15, 128.17 and 129.09 (5 × CH arom.), 138.10 (C arom.), 174.64 (C=O). LRMS (DCI): m/z = 324 [(M + H)+], 322.1, 308.2, 220.2. Anal. Calcd for C18H27NO5: C, 63.14; H, 7.79; N, 4.33. Found: C, 63.17; H, 7.82; N, 4.33.

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Transformation of 5a to compound 6: To a solution of compound 5a (0.130 g, 0.403 mmol) in THF (100 mL) were added di-tert-butyl dicarbonate (0.100 g, 0.458 mmol) and Raney-Ni (0.510 g). This suspension was stirred under H2 (35 bar) at 60 °C overnight, and then the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and purified by chromatography on silica gel to afford compound 6 (0.090 g, 82%), which exhibited spectral data in agreement with ref. [7] : mp 85-86 °C, lit: 79-80 °C; [α]D 25
-16.0 (c 1.6, CHCl3), lit : [α]D 20 -16.0 (c 1, CHCl3). Anal. Calcd for C15H27NO6: C, 56.77; H, 8.57; N, 4.41. Found: C, 56.71; H, 8.77; N, 4.33.