A bio-inspired approach to proline-derived 2,4-disubstituted oxazoles

Abstract

A convenient four-step approach to the synthesis of (S)-4-alkyl-2-(pyrrolidin-2-yl)oxazoles starting from l-Boc-proline inspired by naturally occurring oxazole-containing peptidomimetics is described. The key step is the cyclization of 1-Boc-N-(1-oxoalkan-2-yl)pyrrolidine-2-carboxamides - aldehyde intermediates which demonstrate low to moderate stability - under Appel reaction conditions. This method furnishes the target compounds with more than 98% ee and in a 17-51% overall yield and has been used at up to a 45-g scale.