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;
Further Information

Publication History

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

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.

    References

  • 1 Delgado-Escueta AV. Ward AA. Woodbury DM. Porter RJ. Basic Mechanisms of the Epilepsies   Raven Press; New York: 1986.  p.365 
  • 2a Lippert B. Metcalf BW. Jung MJ. Casara P. Eur. J. Biochem.  1977,  74:  441 
  • 2b Nanavati SM. Silverman RB. J. Am. Chem. Soc  1991,  113:  9341 
  • 3 Kwon TW. Keusenkothen PF. Smith MB. J. Org. Chem.  1992,  57:  6169 
  • 4 Margolin AL. Tetrahedron Lett.  1993,  34:  1239 
  • 5a Wei ZY. Knaus EE. J. Org. Chem.  1993,  58:  1586 
  • 5b Wei ZY. Knaus EE. Synlett  1993,  295 
  • 5c Wei ZY. Knaus EE. Synlett  1994,  345 
  • 5d Wei Z.-Y. Knaus EE. Tetrahedron  1994,  50:  5569 
  • 6 Trost BM. Lemonine RC. Tetrahedron Lett.  1996,  37:  9161 
  • 7 Alcon M. Poch M. Moyano A. Pericas MA. Riera A. Tetrahedron: Asymmetry  1997,  8:  2967 
  • 8 Chandrasekhar S. Mohapatra S. Tetrahedron Lett.  1998,  39:  6415 
  • 9 Dagoneau C. Tomassini A. Denis J.-N. Vallée Y. Synthesis  2001,  150 
  • 10 Masson G. Py S. Vallée Y. Angew. Chem. Int. Ed.  2002,  41:  1772 
  • 11 Masson G. Cividino P. Py S. Vallée Y. Angew. Chem. Int. Ed.  2003,  42:  2265 
  • 12 Riber D. Skrydstrup T. Org. Lett.  2003,  5:  229 
  • 13 Debost JL. Gelas J. Horton D. J. Org. Chem.  1983,  48:  1381 
  • 14 Schmid CR. Bryant JD. Dowlatzedah M. Phillips JL. Prather DE. Schantz RD. Sear NL. Vianco CS. J. Org. Chem.  1991,  56:  4056 
  • 15 DeShong P. Dicken CM. Leginus JM. Whittle RR. J. Am. Chem. Soc.  1984,  106:  5598 
  • 16 Dondoni A. Franco S. Junquera F. Merchan F. Merino P. Tejero T. Synth. Commun.  1994,  24:  2537 
  • 18a Girard P. Namy JL. Kagan HB. J. Am. Chem. Soc.  1980,  102:  2693 
  • 18b Kagan HB. Namy JL. Girard P. Tetrahedron, Suppl.  1981,  175 
  • 18c Hasegawa E. Curran DP. J. Org. Chem.  1993,  58:  5008 
  • 20 Merino P. Castillo E. Franco S. Merchan FL. Tejero T. Tetrahedron: Asymmetry  1998,  9:  1759 
17

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.

19

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.