Ring expansion of bicyclo[1.1.0]butyl ketones to bicyclo[2.1.1]hexenes using ketone as both activating and reacting groups

Junjie Ge, Lihang Cao, Kun Lin, Chenhao Ruan, Xinyi Ye, Xiaoze Bao, Zhikun Yang (), Hong Wang () and Hua Chen ()
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Junjie Ge: Zhejiang University of Technology
Lihang Cao: Zhejiang University of Technology
Kun Lin: Zhejiang University of Technology
Chenhao Ruan: Zhejiang University of Technology
Xinyi Ye: Zhejiang University of Technology
Xiaoze Bao: Zhejiang University of Technology
Zhikun Yang: Zhejiang University of Technology
Hong Wang: Zhejiang University of Technology
Hua Chen: Zhejiang University of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract Bicyclo[n.1.1]alkyl skeletons are of significant interest as bioisosteres of phenyl groups for lead drug modification. Common strategies for their synthesis utilize bicyclo[1.1.0]butanes, wherein the electron-withdrawing groups serve solely as activating groups to facilitate the cleavage of the bridged σ bond, leading to ring expansion by an insertion manner. In this work, we utilize ketones in bicyclo[1.1.0]butane as both activating and reacting groups, promoting a tandem nucleophilic addition/intramolecular Horner-Wadsworth-Emmons olefination process by a distinct exo-cyclic annulation manner. The approach enables the synthesis of diverse bicyclo[2.1.1]hexenes (52 examples, up to 96% yield). A series of transformations have been carried out on bicyclo[2.1.1]hexenes to synthesize bicyclo[2.1.1]hexane/hexene analogues of sonidegib, and the physicochemical properties and anti-tumor activities of these analogues have been investigated. In addition, this approach enables the discovery of aggregation-induced emission properties in this distinctive ring skeleton.

Date: 2025
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DOI: 10.1038/s41467-025-64226-z

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