N‐Methylated Peptide Synthesis via Generation of an Acyl N‐Methylimidazolium Cation Accelerated by a Brønsted Acid

Abstract

AbstractThe development of a robust amide‐bond formation remains a critical aspect of N‐methylated peptide synthesis. In this study, we synthesized a variety of dipeptides in high yields, without severe racemization, from equivalent amounts of amino acids. Highly reactive N‐methylimidazolium cation species were generated in situ to accelerate the amidation. The key to success was the addition of a strong Brønsted acid. The developed amidation enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation. In addition, the amidation can be performed by using either a microflow reactor or a conventional flask. The first total synthesis of naturally occurring bulky N‐methylated peptides, pterulamides I–IV, was achieved. Based on experimental results and theoretical calculations, we speculated that a Brønsted acid would accelerate the rate‐limiting generation of acyl imidazolium cations from mixed carbonic anhydrides.