Enantioselective [2π+2σ] Cycloaddition to Bicyclo[2.1.1]hexanes Enabled by an Artificial Photoenzyme

Bicyclo[2.1.1]hexanes (BCHs) are valuable bioisosteres, yet efficient catalytic methods for their asymmetric construction remain limited. We report an artificial photoenzyme system that enables highly enantioselective intermolecular [2π+2σ] cycloadditions between quinolin-2(1H)-ones and monosubstituted bicyclobutanes (BCBs). Central to this platform is MeO-BpAD, a rationally designed photoactive NAD+ analogue that operates under 400 nm irradiation to suppress background reactivity while maintaining specific binding to NAD+-dependent proteins. In combination with an engineered Rr12αHSDH-M4 mutant, this artificial photoenzyme delivers chiral BCHs in moderate to high yields and up to 94% ee across a broad range of BCB substrates. Photophysical studies show that the protein scaffold stabilizes the MeO-BpAD excited state, whereas MD simulations and QM/MM calculations reveal the key exciplex intermediate and indicate that stereocontrol arises from defined noncovalent interactions within the active site. These results underscore the versatility of NAD+-analogue-based artificial photoenzymes in enabling stereocontrolled transformations that remain challenging for conventional methods.