Chiral Boron Complex-Catalyzed Asymmetric [2π+2σ] Cycloaddition of β-Fluoroalkyl-α,β-Unsaturated Ketones with Bicyclo[1.1.0]butanes

Abstract Bicyclo[2.1.1]hexanes (BCHs), three-dimensional benzene bioisosteres characterized by high sp3 carbon content, hold great promise for diverse applications in medicinal chemistry. While racemic BCH synthesis has advanced significantly, highly enantioselective approaches are still comparatively scarce. Here, we report an enantioselective [2π+2σ] cycloaddition of β-fluoroalkyl-α,β-unsaturated ketones with bicyclo[1.1.0]butanes (BCBs) catalyzed by a chiral (R)-3,3′-(3,5-(CF3)2-C6H3)2-BINOL–boron complex. This approach overcomes major limitations of existing metal-catalyzed and photochemical methods. This transformation provides BCH derivatives featuring CF3- or C2F5-bearing stereocenters in moderate to high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). This mild catalytic protocol exhibits a broad substrate scope and enables the rapid construction of complex fluoroalkyl-containing BCH scaffolds.