Probing enantioinduction in confined chiral spaces through asymmetric oxime reductions

Abstract

Enzyme-like enantiopure supramolecular hosts leverage non-covalent and electrostatic interactions to engage substrates in a chiral environment without direct coordination. Elucidating the mechanistic underpinnings of enantioinduction in these systems is critical to the success of this nascent field. We report herein an enantiopure Ga₄L₆¹²⁻ host-catalyzed asymmetric reduction of aromatic, heteroaromatic, and aliphatic oximes to hydroxylamines, without N–O bond cleavage, using pyridine borane as a reductant cofactor. The reaction scope and mechanistic study, in combination with data science analysis, showcase that guest recognition and enantioinduction are highly sensitive to both steric and electronic effects. Optimization of interactions between the host, oxime, and reductant within the host cavity enabled highly enantioselective reactivity (>99% ee) for even previously unreported pyridine oximes. The emergent principles outlined herein lay the foundation for future applications of these promising catalytic scaffolds toward challenging synthetic targets.