Rh-Catalyzed Asymmetric Transfer Hydrogenation of Cubane-Containing Ketones to Access Bioisomers of Diaryl Alcohols

The enantioselective synthesis of chiral diaryl alcohols, crucial pharmaceutical intermediates, remains challenging due to the poor stereochemical differentiation between similar aryl groups. We address this by reporting a highly enantioselective Rh-catalyzed transfer hydrogenation of cubane-aryl ketones. Leveraging the three-dimensional cubane as a sterically distinct surrogate for a flat aryl group, this method provides chiral cubane-aryl alcohol bioisosteres in excellent yield (up to 99%) and enantioselectivity (up to >99% ee). DFT studies implicate key noncovalent C-H···π interactions in the stereocontrol. Gram-scale synthesis and a TON of 5000 establish the method's practical utility for accessing valuable, stereodefined scaffolds in drug discovery.