Ligand-Controlled Stereodivergent α-Vinylation and α-Arylation of Peptide Backbones

The stereoselective modulations of peptide backbone α-carbons at internal sites present a longstanding synthetic challenge. To the best of our knowledge, transition metal-catalyzed C-C cross-coupling chemistry has not been employed to address this issue. Herein, we report that a racemic α-C-tosyl glycinyl unit (TsG), readily installed at a defined site within the peptide backbone, serves as an excellent electrophile for Ni-catalyzed reductive vinylation and arylation with vinyl and aryl triflates or halides, delivering α-C(sp²)-modified peptides with outstanding diastereoselectivity. Catalyst control dominates stereoselectivity, enabling stereodivergent modification at internal peptide backbone sites by tuning ligand chirality─a rare achievement compared with most contemporary studies focusing primarily on <i>N</i>-terminal α-carbons. The peptide scope was broad, encompassing decapeptides and cyclic pentapeptides. This study is expected to inspire broad interest in late-stage peptide backbone modification through cross-coupling strategies.