Asymmetric Synthesis of Strained Multichiral Spirocyclobutanes through Cage-Confined Cross [2 + 2] Photocycloaddition.

Chiral spirocycles possess the ability to undergo diverse modifications in three-dimensional space, offering advantages in terms of physicochemical property and structural variability over conventional organic scaffolds and holding promising potential for the design of biologically active molecules and drugs. Among them, highly strained spirocyclobutanes with multiple chiral center-containing four-membered rings have attracted significant attention, but their viable and efficient synthesis poses a great challenge. By virtue of cage-confined asymmetric photocatalysis, we successfully construct spirocycle and bispirocycle compounds containing multiple quaternary and tertiary chiral carbon centers in cyclobutane rings through cross [2 + 2] photocycloaddition with visible-light-induced and mild reactions. The mechanistic studies unveil that the chiral open pockets of a cage photoreactor facilitate dynamic bimolecular recognition to render preferential heteromolecular cross-cycloaddition with enhanced reactivity, unconventional enantioselectivity, and good substrate tolerance, providing a promising direction for enzyme-mimetic catalyst design for challenging asymmetric photochemical transformations.