Late-Stage N-Heteroarylation of Peptides Via α-C-H Functionalization of Glycine Residues by Shono-Type Oxidation

The Shono oxidation stands as a premier electrochemical method for the α-C-H functionalization of amines. While glycine esters serve as ideal substrates with immense synthetic potential, their electrochemical derivatization has historically been restricted primarily to C-C and C-P bond formation. Herein, we report the first electrochemical strategy for the direct N-heteroarylation of α-C-H bonds in Gly-containing natural products, drug molecules, and peptides via a controllable anodic oxidation pathway under transition-metal-free conditions. At the same time, modified target product 3x exhibited good inhibitory activities toward the SKOV3 and MDA-MB-231 cell lines, with IC₅₀ values of 9.94 ± 1.46 and 17.11 ± 3.67, respectively, far superior to the antitumor activities of unmodified substrate 1a (IC₅₀ > 50). Therefore, besides synthetic applications, this method also provides new possibilities for discovering potentially bioactive molecules.