Overriding Intrinsic Site-Selectivity in Nickel(II)-Catalyzed Enantioselective Methylene C(sp3)-H Alkynylation

The site- and enantioselective functionalization of aliphatic C-H bonds is a pivotal challenge in organic synthesis. While directed enantioselective methyl C(sp3)-H activation is well-established, achieving analogous reactivity at methylene sites─which would enable the direct editing of molecular scaffolds─remains a formidable goal, particularly with earth-abundant 3d metals. Here, we report the first nickel(II)-catalyzed enantioselective alkynylation of β-methylene C(sp3)-H bonds. This transformation is enabled by an air-stable Ni(II) salt and a bulky chiral phosphoric acid ligand, (R)-TCYP, delivering a broad range of β-alkynylated amides in up to 98% yield and 99% ee. Notably, this system achieves preferential methylene C-H activation in the presence of methyl groups, overcoming the intrinsic selectivity of directed C(sp3)-H activation. Mechanistic studies, including the isolation and full characterization of a chiral Ni(II)-metallacyclic intermediate via X-ray diffraction, reveal that the C-H cleavage step is both the rate- and enantio-determining step.