π-π interaction-directed asymmetric hydrogenation of sterically unbiased aromatic ketones

Abstract

Transition metal-catalyzed asymmetric hydrogenation of ketones has been well established; however, the asymmetric hydrogenation of sterically unbiased ketones remains a major challenge, primarily due to difficulties in controlling enantioselectivity. Here, we report a highly practical and efficient protocol for the asymmetric hydrogenation of such substrates, delivering chiral cyclic diaryl alcohols (including the baloxavir intermediate) in up to a 99% yield and 99% enantiomer excess (ee). Mechanistic studies show that [Ir(cod)Cl]₂ undergoes intramolecular oxidative C–H activation with an oxa-spirocyclic ligand, forming a rigid, butterfly-shaped Ir–PNNC complex, as confirmed by single-crystal X-ray diffraction. In our understanding, this tetradentate binding both prevents catalyst poisoning by sulfur-containing substrates and maximizes enantioselectivity, aided by crucial π-π interactions (as revealed by density functional theory [DFT] and non-covalent bond interaction [NCI] analyses). The synthetic practicality is demonstrated by gram-scale hydrogenation with excellent stereocontrol, underscoring the potential of this approach for the efficient preparation of valuable enantiopure compounds.