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.