Head-to-Tail Peptide Cyclization of N -Aryl Peptide Hydrazides

Abstract

A novel method for the macrocyclization of unprotected peptides is presented, featuring in situ oxidation of N-aryl peptide hydrazides and chemoselective hydrazone bond formation. A series of >50 macrocyclic peptides were accessed with a variety of sequences, ring sizes (16–25 atoms), and substitution at the site of ligation. Analogs of Gramicidin S and Cilengitide were also synthesized. The resulting stable keto-hydrazone linkages can be used in chemoselective postligation modifications such as reductions and isomerizations.