Continuous-Flow Synthesis of N-Methylated Peptides via Generation of an Acyl N-Methylimidazolium Cation

Abstract

A detailed protocol is described for the continuous-flow synthesis of N-methylated peptides. N-Methylated peptides are very important class of bioactive compounds compared with normal peptides because they can enhance oral bioavailability, cell membrane permeability, and stability against enzymatic degradation. In our developed flow synthesis, a variety of N-methylated dipeptides is obtained in high yields without severe racemization from equivalent amounts of amino acids. The addition of a strong Brønsted acid is critical to generate the highly reactive N-methylimidazolium cation species to accelerate the amidation. The developed approach enabled the synthesis of a bulky peptide with a higher yield in a shorter amount of time compared with the results of conventional amidation.

Keywords: Acyl N-methylimidazolium cation; Acylation; Amino acids; Anhydrides; Continuous flow; Peptides.