C–C Cross-Coupling of <i>N</i> -Terminal Glycine Dipeptides Enabled by a Cationic Pd-Phosphine Catalyst

Pd-catalyzed cross-coupling reactions are of key importance in the synthesis of C–C (linking, e.g., (hetero)aryls, alkenes, alkynes) and C–heteroatom bonds in the preparation of drug candidates. One such class of drug candidates encompasses peptides and peptidomimetics, where peptide-like motifs contribute to their biological activity. Despite its importance, direct C–C cross-coupling on the peptide backbone remains elusive. In this work, we demonstrate the utility of cationic Pd-phosphine complexes for C(sp3)–C(sp2) (hetero)arylation of protected N-terminal glycine dipeptide fragments. The underlying catalytic mechanism was elucidated via kinetic experiments, computational modeling and isotope studies, and the synthesis of up to 50 medicinally relevant dipeptide carbon scaffolds was demonstrated.