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.

Free amino group-directed C­(sp3)–H functionalization of aliphatic amines is a fundamental challenge in synthetic organic chemistry. Also, the NH2-directed C­(sp3)–H functionalization of α-amino acids and their derivatives remains barely explored. With palladium as the catalyst and Ag2O as the additive, we developed the first NH2-directed γ-C­(sp3)–H arylation of α-amino esters with diaryliodonium triflates for the construction of synthetically useful γ-aryl-α-amino esters, and the result of the KIE study suggested that the catalytic reaction involved an irreversible C–H cleavage as the rate-determining step.

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