Synlett 2004(14): 2609-2611  
DOI: 10.1055/s-2004-834823
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Expedient Entry into the α-Mercaptodiketopiperazine Nucleus

Stephen T. Hiltona, William B. Motherwell*a, David L. Selwoodb
a Chemistry Department, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London, WC1H OAJ, UK
b The Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, UK
Fax: +44(20)76797524; e-Mail: w.b.motherwell@ucl.ac.uk;
Further Information

Publication History

Received 5 August 2004
Publication Date:
20 October 2004 (online)

Abstract

A novel approach to the α-mercaptodiketopiperazine ­nucleus is reported, which involved a three-component reaction of a number of amines with ethyl glyoxalate and para-methoxy­benzylmercaptan. The subsequent products were readily elaborated to the monothiodiketopiperazine core structure.

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19

Representative Procedure: Benzylamine (2.75 mL, 2.70 g, 25.22 mmol) was added to a solution of ethyl glyoxalate (5.00 mL of a 50% solution in toluene, 25.22 mmol) in toluene (40 mL). This was followed 2 min afterwards by the addition of p-methoxybenzylmercaptan (3.51 mL, 3.89 g, 25.22 mmol) and the resulting cloudy solution left to stir at r.t. for 2 h. Organic solvent was removed by rotary evaporation at a bath temperature of less than 55 °C to give a yellow oil that was purified by flash column chromatography to give the protected α-mercapto amino acid ester as a colourless oil (8.01 g, 92%). MS (FAB+): C19H24NO3S requires [M + H]: 346.14819. Found: [M+] 346.14768. IR (film): νmax = 3347.2, 1732.0, 1511.1, 1301.9,1250.8, 1175.5, 1032.8 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.31 (3 H, t, J = 7.2 Hz, CO2CH2CH 3), 3.72 (1 H, d, J = 13.1 Hz, SCH 2), 3.75 (2 H, m, NHCH 2), 3.79 (3 H, s, OCH 3), 3.87 (1 H, d, J = 13.1 Hz, SCH 2), 4.22 (2 H, q, J = 7.2 Hz, CO2CH 2CH3), 4.35 (1 H, s, CH), 6.84 (2 H, d, J = 8.7 Hz, Ar-H), 7.23-7.29 (7 H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δ = 14.15 (CO2CH2 CH3), 33.23 (SCH2), 49.22 (NHCH2), 55.28 (OCH3), 61.41 (CO2 CH2CH3), 63.71 (CH), 114.00 (Ar-C-H), 127.19 (Ar-C-H), 128.41 (Ar-C-H), 128.48 (Ar-C-H), 130.07 (Ar-C-H), 130.07 (quaternary C), 138.79 (quaternary C), 158.76 (quaternary C), 169.97 (CO2CH2CH3). MS: m/z (%) = 346 (49) [M + H], 214 (31), 192 (100), 165 (30).