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.
Liu et al. (Tue,) studied this question.