Postassembly Modification of Peptides by Histidine-Directed β-C(sp³)-H Arylation of Alanine at the Internal Positions: Overcoming the Inhibitory Effect of Peptide Bonds

Peptide modification by C(sp³)-H functionalization of residues at the internal positions remains underdeveloped due to the inhibitory effect of backbone amides. In this study, using histidine (His) as an endogenous directing group, we developed a novel method for the β-C(sp³)-H functionalization of alanine (Ala) at diverse positions of peptides. Through this approach, a wide range of linear peptides were modified on the side-chain of Ala adjacent to His to afford the functionalized peptides in moderate to good yield and excellent position selectivity. Furthermore, conjugation of peptides with functional molecules such as glucuronide, oleanolic acid, dipeptide, and fluorophore derivatives was achieved.