Coordination Cage-Confined Chirality of Non-precious Metals for Enantioselective C-C and C-N Bond Formation.

Self-assembled cages have emerged as nanoscopic reactors that emulate enzymatic pockets, where confined cavities preorganize substrates, stabilize intermediates, and modulate transition states through supramolecular interactions. Here we harness this confined effect to address the long-standing challenge of enantioselective catalysis with nonprecious metals. We report a robust tetrahedral metal-organic cage built from six carboxyl-anchored BINAP-derived ligands and four Cp3Zr3 clusters, enabling site-isolated incorporation of Ni and Cu. The resulting chiral cages, validated by single-crystal X-ray diffraction, Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), and complementary techniques, provide well-defined confined nanospaces for asymmetric transformations. Postassembly metalation furnishes catalysts for C-C and C-N bond-forming reactions, including asymmetric alkylations and alkynyl aminations, achieving up to 99.9% ee with broad substrate scope, recyclability, and gram-scale applicability exemplified by the efficient synthesis of the antiepileptic drug lacosamide. Remarkably, these cage-based catalysts operate at low metal loadings (0.5% for Ni and 0.1% for Cu), an order of magnitude lower than the 2-10% typically required for homogeneous analogues. While their confined cavities suppress deactivation, enrich substrates, and amplify enantioselectivity through cooperative host-guest interactions. This work establishes a generalizable strategy merging nonprecious metals with chiral supramolecular confinement, providing a blueprint for sustainable asymmetric catalysis.