Peptide Cyclization by the Use of Acylammonium Species
Otoka Shamoto, Keiji Komuro, Naoto Sugisawa, Ting‐Ho Chen, Hiroyuki Nakamura, Shinichiro Fuse
Abstract
Abstract Although cyclic peptides have become increasingly important as drugs, the most conventional peptide cyclization method using moderately active coupling agents suffers from a lot of waste and high cost as well as long reaction times and burdensome purification. Herein, we report an unconventional approach to peptide cyclization that uses acylammonium species generated from inexpensive and less wasteful Me 2 NBn and ClCO 2 i ‐Pr. Using this approach, we observed the desired rapid activation of the C‐terminus of cyclization precursors by an acylammonium ion for rapid and epimerization/dimerization‐free cyclization of synthetically challenging peptides, including a difficult cyclization involving N ‐methyl amide bond formation. The ease of purification, productivities, and reaction mass efficiencies of our approach were significantly superior to those in previous reports. We synthesized a previously reported versicotide D analogue, and our data indicated that its assigned stereostructure should be revised.