Electrochemical Site-Selective C(sp3 )-H Heteroarylation of Proline-Containing Peptides

Abstract

The site-selective modification of aliphatic C(sp 3 )-H bonds within peptides represents a significant synthetic challenge, crucial for advancing peptide-based therapeutics. Current strategies largely depend on transition-metal catalysts, directing groups and stoichiometric oxidants, which limit functional group tolerance and biocompatibility. Here, we report an unprecedented electrochemical strategy that enables the mild and precise heteroarylation of the inert α-(C5)-H bond in proline-containing peptides. This strategy employs a hydrogen atom transfer (HAT) process, using electricity as the sole redox agent, thereby eliminating the need for precious metals, directing groups and stoichiometric oxidants. The reaction demonstrates exceptional regioselectivity and broad compatibility across a wide range of heteroarenes and peptide sequences (dipeptides to hexamers), including those containing oxidation-sensitive amino acid residues. This work establishes a versatile and sustainable platform for the late-stage diversification of complex peptides.