Exploration of N‐Arylation of Backbone Amides as a Novel Tool for Conformational Modification in Peptides

Abstract

AbstractA set of 15 cyclic‐hexaalanine and 10 cyclic‐pentaalanine peptides containing one or two backbone N‐aryl amide bonds were synthesized by following a combination of solution‐phase and solid‐phase peptide synthesis. NMR‐based conformation studies of these N‐aryl cyclic‐hexaalanine peptides revealed five distinct template conformations with an antiparallel β‐sheet structure; for N‐aryl cyclic‐pentaalanine peptides three template structures were revealed. All the template structures have distinct peptide‐turn features. The conformations in these N‐aryl peptides were compared to those in the commonly studied N‐methyl peptide analogues. We observed that the N‐aryl peptides exhibit a considerable conformational homogeneity, and their conformations differ significantly from those in N‐methyl analogues. We anticipate that the N‐arylation of backbone amides has the potential for application as a novel tool for conformation and physicochemical modification in peptides.