Chenchen Qi, L Liu, Xiangsheng Xu, Xiaoqing Li
Herein, we report a method for peptide bond formation via anhydride exchange‐mediated in situ generation of N‐methylimidazolium cations using trimethylacetic anhydride (Piv 2 O) and catalytic N‐methylimidazole (NMI). It tolerates diverse amino acid side chains (e.g., −OH, indole NH) with no detectable racemization/epimerization even when dipeptides serve as electrophiles. Convergent synthesis of protected Leu‐enkephalin underscores its utility, expanding the toolbox for peptide bond formation.