Photoenzymatic catalysis enables enantioselective radical dearomative spirocyclization

Dearomatization offers a powerful route towards three-dimensional spirocyclic architectures, which are pivotal in bioactive molecules and pharmaceuticals, particularly for enantioselective construction of congested quaternary spirocenters. However, biocatalytic dearomatization towards these attractive spirocyclic frameworks under mild and green conditions remain underexplored. Here, we report a photoenzymatic platform synergizing visible-light activation with engineered nicotinamide-dependent ketoreductase (KRED) catalysis to achieve highly enantioselective dearomative spirocyclization of N-hydroxyphthalimide esters. Semi-rational engineering of KRED P2-D12 enables the synthesis of diverse chiral spirocyclohexadienones, also including the challenging ortho-cyclohexadienones, with exceptional functional group tolerance and stereocontrol (up to >99% ee). The utility of this methodology is underscored significantly by the enantioselective total synthesis of the cytotoxic natural product (+)-denobilone A (93% ee). Overall, this work establishes a chemobiocatalytic platform for the synthesis of complex and chiral spiroarchitectures with high enantioselectivity, expanding the biocatalytic toolbox in sustainable synthetic chemistry.