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

作者：Jinsi Li, Ping Du, Tai-Ping Zhou, Wei Hu, Hui Li, Binju Wang, Hui‐Jie Pan · 发表于：Journal of the American Chemical Society · 年份：2026 · DOI：10.1021/jacs.5c20918 · 被引用次数：5 · 研究领域：Radical Photochemical Reactions、Cyclopropane Reaction Mechanisms、Organic Chemistry Cycloaddition Reactions

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.