Metal‐catalyzed C–N cross‐coupling generally forms C−N bonds by reductive elimination from metal complexes bearing covalent C‐ and N‐ligands. We have identified a Cu‐mediated C–N cross‐coupling that uses a dative N‐ligand in the bond‐forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a Cu^IIcomplex bearing neutral N‐ligands, such as nitriles or N‐heterocycles. Subsequent generation of a putative Cu^IIIcomplex enables the oxidative C–N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp²) precursors and can be applied to drug synthesis and late‐stage N‐arylation, and the limitations in the methodology are mechanistically evidenced.

The first total syntheses of cyclic depsipeptides colletopeptide A and colletotrichamide A, have been accomplished. The key advanced intermediate, a cyclic tridepsipeptide derivative, was constructed using a sequence of transformations that features asymmetric Brown crotylation, cross metathesis, Yamaguchi esterification, ozonolysis, and macrolactamization. A late-stage incorporation of the mannose fragment completed the synthesis of colletotrichamide A, and the desilylation of the common intermediate gave rise to colletopeptide A, which led to unambiguous confirmation of the absolute stereochemistry of the aforementioned natural products.

Chemoselective control of a multi-reactive system allows two sequential C–C bond formations via two distinct reactivity modes, accessing pharmaceutical and natural product scaffolds.