Synlett 2003(10): 1536-1538
DOI: 10.1055/s-2003-40846
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

First Examples of a Highly Stereoselective Passerini Reaction: A New Access to Enantiopure Mandelamides

Raymond Freya, Stuart G. Galbraitha,, Sandro Guelfia, Clemens Lamberth*a, Martin Zellerb
a Syngenta AG, Research Department, Optimisation Chemistry, Schwarzwaldallee 215, 4002 Basel, Switzerland
Fax: +41(61)3238529; e-Mail: clemens.lamberth@syngenta.com;
b Syngenta AG, Process Development, Breitenloh 5, 4333 Muenchwilen, Switzerland
Further Information

Publication History

Received 2 June 2003
Publication Date:
24 July 2003 (online)

Abstract

Achiral benzaldehydes and isocyanides could be transformed enantioselectively in a Passerini three-component reaction to chiral mandelamides by using a galacturonic acid derivative as chiral inducer.

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1

Current address: Department of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh, EH9 3JJ, UK.

15

A typical experimental procedure is as follows: A mixture of benzaldehyde (3, 6 mmol), 2-(3,4-dimethoxyphenyl)ethyl isocyanide [12] (4, 6 mmol) and 1,2,3,4-tetra-O-acetyl-α-d-galacturonic acid [13] (5d, 6 mmol) in 15 mL of acetonitrile was stirred for 16 h at r.t. Subsequently, the reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4 and evaporated. The residue was taken up in a mixture of 1 N NaOH (5 mL) and dioxane (10 mL). This mixture was stirred for 1 h at r.t., acidified to pH 2 with 2 N HCl and extracted with EtOAc. The combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel (EtOAc/hexane 7:3) to obtain colourless crystals of predominantly (S)-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-phenylacetamide (7, 1.2 g, 3.8 mmol, 63%). 1H NMR (300 MHz, CDCl3): δ = 2.74 (q, 2 H, NCH2), 3.49-3.60 (m, 3 H, PhCH2, OH), 3.83 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.01 (s, 1 H, CHO), 6.06 (br s, 1 H, NH), 6.57-7.39 (m, 8 H, aromatic H). MS (70 eV): m/z = 315 (M+), 316 (M+ + 1). Mp: 91-92 °C (Lit. [16] 92-93.5 °C).