Chiral Phosphoric Acid-Catalyzed Asymmetric Hydrogenolysis of C-O Bonds

The combination of chiral phosphoric acid with a biomimetic hydrogen source (Hantzsch esters) constitutes a powerful system for asymmetric reduction of unsaturated compounds. In contrast, asymmetric hydrogenolysis of C-O single bonds remains an elusive challenge owing to the high C-O bond energy and the weak intermolecular affinity between the substrate and the catalyst. In this study, we report a hydrogen-bond-activation strategy, driven by aromatization, for asymmetric hydrogenolysis of C-O bonds using the chiral phosphoric acid/Hantzsch ester system. This protocol enables kinetic resolution of o-quinone monoketals, affording axially chiral compounds and chiral spirocycles with selectivity factors up to 1773. Moreover, this methodology provides an efficient route to axially chiral cannabidiol (axCBD) analogs. Preliminary mechanistic experiments and DFT calculations suggested that asymmetric hydrogenolysis proceeded via an enantioselective 1,4-transfer hydrogenation initiation step, followed by an aromatization-driven remote proton transfer and skeletal rearrangement.