Enantioselective [2+2] Cross-Photocycloaddition Enabled by a Chiral Cage Reactor via Multilevel-Selectivity Control

In the recently burgeoning field of asymmetric [2 + 2] photocycloaddition, a challenging hurdle lies in achieving a multilevel control of chemo-, regio-, diastereo-, and enantioselectivities in cross-coupling photoreactions, which often result in chaotic outcomes when partners show similar electronic and optical properties. Here, we introduce a biomimetic cage-pocket confined photocatalytic protocol that can effectively realize bimolecular recognition and manipulate excited triplet-state dynamics through stereochemical confinement. This approach allows for highly selective synthesis of heterocoupled [2 + 2] syn-HH (head-to-head) enantiomers from two photoactive α,β-unsaturated carbonyl compounds, which are typically difficult to access via conventional strategies due to competitive pathways. We find that the cooperative heteromolecular binding dynamics plays a critical role in initial chemoselective and successive stereoselective photoreactions. Notably, the open pockets of the cage reactor display tolerable guest–host match but products–host mismatch for a wide scope of substrates, overcoming common limitations associated with enzyme-mimicking cage reactors such as guest specificity and product inhibition against catalytic generality and turnover.