Post-Assembly Modification of Peptides by Ligand-Enabled β-C(sp³)-H Arylation of Alanine at the C-Terminus: Overcoming the Inhibition Effect of Peptide Bonds

Postassembly modification of peptides via C(sp3)-H functionalization on aliphatic side chains provides a straightforward approach to access functionalized peptides as therapeutics. However, C(sp3)-H functionalization of C-terminal residues remains underdeveloped due to the inhibition effect of secondary amides in the backbone. Herein, we report a ligand-enabled, bidentate auxiliary-assisted β-C(sp3)-H arylation method, which is well tolerant of secondary amides. A wide range of peptides (tri- to dodecapeptides) underwent position-specific modification of alanine at the C-terminus.