Electrochemical synthesis of peptide aldehydes via C‒N bond cleavage of cyclic amines

Peptide aldehydes are crucial biomolecules essential to various biological systems, driving a continuous demand for efficient synthesis methods. Herein, we develop a metal-free, facile, and biocompatible strategy for direct electrochemical synthesis of unnatural peptide aldehydes. This electro-oxidative approach enabled a step- and atom-economical ring-opening via C‒N bond cleavage, allowing for homoproline-specific peptide diversification and expansion of substrate scope to include amides, esters, and cyclic amines of various sizes. The remarkable efficacy of the electro-synthetic protocol set the stage for the efficient modification and assembly of linear and macrocyclic peptides using a concise synthetic sequence with racemization-free conditions. Moreover, the combination of experiments and density functional theory (DFT) calculations indicates that different N -acyl groups play a decisive role in the reaction activity. Peptide aldehydes are an important class of biomolecules, playing essential roles in various living systems, and there is an ongoing demand for the efficient synthesis of peptide aldehydes. Herein, the authors report the electrooxidative ring-opening reaction via C‒N bond cleavage for the synthesis of unnatural peptide aldehydes.