Aqueous Phase Synthesis of Complex Thiazole-Containing Peptides by Condensation of N-Acyl-α-aminonitriles and Cysteine Derivatives.

The introduction of rigid thiazole motifs into peptide backbones represents a promising strategy to enhance metabolic stability, improve cell permeability, and optimize pharmacokinetic properties. Herein, we report an epimerization-free, one-pot aqueous synthesis of thiazole-containing polypeptides from N-acyl-α-aminonitriles and cysteine derivatives. This method's broad applicability is demonstrated by synthesizing diverse polypeptides, including decapeptide 3u, antitumor mollamide F 3v', and its oxidized analogue 3v. Mechanistic studies via DFT calculations revealed that the rate-determining step proceeds through a concerted mechanism, involving simultaneous deprotonation of the amino and sulfur nucleophilic attack on the nitrile group, stabilized by a methanol solvent under mild conditions.