Discovery of Oxazole Byproduct Formation in the Modified Dakin–West Reaction and Efficient Synthesis of Diastereomeric α-Ketoamide Cysteine Protease Inhibitors

Abstract

α-Ketoamide derivatives are the most widely used chemical class of cysteine protease inhibitors. α-Ketoamide cysteine protease inhibitors have typically been developed as diastereomeric mixtures because the electrophilic carbonyl group adjacent to the chiral center, a common feature of α-ketoamide derivatives, causes epimerization. However, owing to several low-yielding steps in the diastereomeric synthetic route of α-ketoamides, these inhibitors, particularly calpain inhibitors, are typically synthesized via the single-enantiomer synthetic route using a dl-amino acid. Herein, we report the formation of oxazole byproducts during the modified Dakin–West reaction and the subsequent amidation reaction. Furthermore, we successfully synthesized a diastereomeric mixture of α-ketoamide cysteine protease inhibitors, reducing oxazole byproducts by optimizing the solvent selection in the modified Dakin–West reaction and the reaction conditions of the subsequent amidation reaction.