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

Abstract A 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.