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.