A Convenient Preparation of Diastereomerically Pure, Diversely Substituted Piperazine-2,5-diones from N-Protected α-Amino Acids

Abstract

The products of the Ugi reaction of various N-tert-butoxycarbonyl-protected a-amino acids, aldehydes, amines and tert-butyl isocyanide, after tert-butoxycarbonyl deprotection, undergo efficient microwave-assisted cyclization in acetic acid to give diastereomerically pure, racemic piperazine-2,5-diones. The formation of a single diastereomer is rationalized via an enolization equilibration process in acetic acid at high temperature which enriches the product mixture in the more stable diastereomer. The relative stereochemistry of the products are confirmed by NOESY experiments and are consistent with molecular mechanics calculations.