Access to EnantiopureSpiropyridines Enabled by Enantio-RelayDouble [2 + 2 + 2] Cycloaddition and Kinetic Resolution [2 + 2 + 2]Cycloaddition of Alkynes and Nitriles

The synthesis of enantiopure and structurally unique spiro-type molecules is of utmost significance in catalysis, synthetic chemistry, and related fields. We present here a general solution, a nickel-catalyzed [2 + 2 + 2] cycloaddition, for accessing enantioenriched spiropyridines from readily available nitriles and alkynes in a single synthetic step, including (1) enantio-relay double [2 + 2 + 2] cycloaddition of malononitriles with alkynes and (2) kinetic resolution [2 + 2 + 2] cycloaddition of racemic pyridine-containing nitriles with alkynes. Both strategies feature a broad substrate scope and exclusive regioselectivities, and are scalable to multigram. Remarkably, the double [2 + 2 + 2] cycloaddition integrates enantio-induction by desymmetrizing dinitriles during the initial catalytic cycle with additional enantio-enhancement during the second cycloaddition (enantio-relay), yielding excellent enantioselectivities (>99% ee for all examined examples). Furthermore, the highly efficient kinetic resolution strategy enables the achievement of exceptionally high enantioselectivities without compromising yields (<i>s</i> > 200 for most examples), overcoming the general challenges of kinetic resolution toward yield and enantioselectivity. The ability to construct previously inaccessible spiro structures lays the groundwork for advancing spiropyridine derivatives, especially the multinitrogen-containing compounds as potential ligands. Due to the perpendicular molecular orientation and inherent rigidity of the architectures obtained, we anticipate significant promise of the presented synthetic approaches for enhancing efforts in synthesis and catalysis.