A Scalable Stereoselective Synthesis of Polysubstituted Housanes
Valentin V Veselinov1, Ayan Dasgupta1, Andreas Pielmeier1
1Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, U.K.
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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.
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