A Scalable Stereoselective Synthesis of Polysubstituted Housanes

Journal article

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.

Authors: Veselinov, VV; Dasgupta, A; Pielmeier, A; López-Francés, A; Haraldsdóttir, H

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Organic Letters
• Volume: 28
• Issue: 23
• Pages: 7279-7284
• Publication date: 2026-06-04
• Acceptance date: 2026-06-02
• DOI: 10.1021/acs.orglett.6c01751
• EISSN: 1523-7052
• ISSN: 1523-7060
• Language: English
• Keywords: Cyclopropane; Stereoselectivity; Enantioselective synthesis; Metalation; Stereospecificity; Stereoisomerism; Bicyclic molecule