Synthesis of Peptides by Silver-Promoted Coupling of Carboxylates and Thioamides: Mechanistic Insight from Computational Studies

Abstract

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.The mechanism of the recently described N→C direction peptide synthesis through silver-promoted coupling of N-protected amino acids with thioacetylated amino esters was explored by using density functional theory. Calculation of the potential energy surfaces for various pathways revealed that the reaction proceeds through silver-assisted addition of the carboxylate to the thioamide, which is followed by deprotonation and silver-mediated extrusion of sulfur as Ag2 S. The resulting isoimide is the key intermediate, which subsequently rearranges to an imide through a concerted pericyclic [1,3]-acyl shift (O-sp(2) N 1,3-acyl migration). The propo..