Site-selective modification of chemically and biologically valuable α-amino acids and peptides is of great importance for biochemical study and pharmaceutical development. Few methods based on remote C(sp 3 )-H functionalization of aliphatic side-chains of peptides has been disclosed in recent years. In this report, we developed a novel approach for γ-C(sp 3 )-H and γ-/δ-C(sp 2 )-H arylation of α-amino acids with αhydrogen by native amine-directed C−H functionalization and further realized the γ-C(sp 3 )-H arylation of N-terminally unprotected peptides.

Peptide modification by C(sp 3 )−H functionalization of internal residues remains a major challenge due to the inhibitory effect of peptide bonds. In this work, we developed a methionine-directed β-C(sp 3 )−H arylation method for internal alanine functionalization. By tuning the σ C−C bond rotation of internal Ala through head-to-tail cyclization, we overcame the inhibitory effect and functionalized a wide range of head-totail cyclic peptides with aryl iodides with excellent position selectivity.

Postassembly modification of peptides via C­(sp3)–H functionalization provides an efficient way to prepare functionalized peptides for biological study and pharmaceutical development. In this work, we developed a new method for γ-C­(sp3)–H functionalization of aliphatic side chains of N-terminus-unprotected peptides. With the N-terminal residues as directing groups, a wide range of di-, tri-, tetra-, and pentapeptides underwent C–H arylation of the residues (Val, Ile, Tle) at the +2 position from the N-terminus.