A short stereocontrolled synthesis of hydroxyethylene dipeptide isosteres

Abstract

A stereocontrolled synthesis of protected hydroxyethylene dipeptide isosteres 14 and 16 is described. It provides the 2R,4S,5S epimers required for the preparation of aspartic proteinase inhibitors. The choice of a benzene ring as a precursor to the carboxylic acid function has enabled us to use the readily accessible chiral Grignard reagent 3 which reach with the protected α-amino aldehyde 8 stereoselectively. Kilogram quantities of 16 have been produced by this route in a satisfactory overall yield. The combination of N- and O-protecting groups employed facilitates the incorporation of 14 or 16 into peptide-based enzyme inhibitors