Formal Remote Stereodifferentiation of Minimally Distinct Groups in the Enantioselective Desymmetrization of meso -Epoxides

Achieving high enantioselectivity in reactions involving substrates bearing remotely positioned substituents with nearly identical steric and electronic properties represents an outstanding challenge in asymmetric catalysis. Herein, we describe a local stereocontrol strategy mediated by a confined chiral Brønsted acid catalyst that exerts precise stereodifferentiation at the prochiral epoxide center, resulting in the formal stereodifferentiation of minimally distinct remote substituents, such as methyl vs ethyl or C6D5 vs C6H5, located up to nine bonds away from the reactive center. Computational studies reveal that localized stereorecognition at the reaction site translates into significant energy differences between diastereomeric transition states, rationalizing the high stereoselectivity. Beyond introducing a novel paradigm for achieving enantioselectivity through formal remote stereodifferentiation, this method also establishes a catalytic asymmetric route to donor-acceptor type chiral spirofluorenes, which exhibit promising properties as solvatochromic probes, live-cell imaging agents, and circularly polarized luminescence emitters.