Enantioselective Access to Complex [4.1.1] Scaffolds with All-Carbon Quaternary Stereocenters via Catalytic Asymmetric [4 + 3] Cycloaddition of Bicyclo[1.1.0]butanes

Cycloaddition of bicyclo[1.1.0]butanes (BCBs) has emerged as a powerful strategy for assembling diverse molecular architectures; however, its application has predominantly been limited to the synthesis of bicyclo[n.1.1]alkanes (n = 2 or 3). Expanding this strategy to access structurally intricate bicyclo[4.1.1]octanes (BCOs) remains a formidable challenge. Here, we report a palladium-catalyzed asymmetric [4 + 3] cycloaddition of γ-methylidene-δ-valerolactones and BCBs under mild conditions, enabling the enantioselective construction of all-carbon BCOs with broad substrate scope and high functional group tolerance. This strategy delivers 39 examples with excellent stereocontrol (up to 98% ee), generating strained polycyclic [4.1.1] scaffolds bearing two quaternary stereocenters. The chiral BCOs possess versatile functional handles, enabling late-stage derivatization into more complex 3D frameworks. Additionally, computational studies offer key insights into the stereoselective cycloaddition pathway, further elucidating the reaction mechanism.