A Scalable Stereoselective Synthesis of Polysubstituted Housanes

High Resolution Image Download MS PowerPoint Slide 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.