A Scalable Stereoselective Synthesis of Polysubstituted Housanes

Small ring bicyclic carbocycles are valuable building blocks in medicinal chemistry due to their rigid structures and useful physicochemical properties. Bicyclo[2.1.0]pentanes (housanes) have received relatively little attention, and methods for their late-stage diversification remain limited. Here we report a straightforward directed metalation approach enabling the synthesis of di- and trisubstituted housanes with excellent regio- and diastereoselectivity via sequential bridgehead and cyclopropane bridge functionalization. We also explore housanes as isosteres of ortho-substituted benzene rings using computational and X-ray crystallographic analysis, and describe a stereospecific boron-mediated 1,2-metalate rearrangement that affords a highly substituted cyclopentaneboronic ester. Finally, we disclose an enantioselective synthesis of a housane, enabling access to enantioenriched polysubstituted housane scaffolds.