Concise synthesis and strain-release diversification of bridgehead-substituted [2]-ladderanes
Abstract
Strained hydrocarbons offer privileged platforms for accessing otherwise elusive reactivity and molecular architectures. Among these, [2]-ladderane scaffolds hold considerable promise, yet modular access to diversely functionalized derivatives remains a major challenge. Here we report a concise and scalable strategy for the efficient synthesis of bridgehead-substituted [2]-ladderanes from readily available precursors. The resulting ladderanes serve as versatile intermediates for programmable, regioselective bridgehead functionalization and strain-release cycloadditions with electron-deficient alkenes, granting access to a broad array of multisubstituted bicyclo[2.2.2]octanes (BCOs). Furthermore, BCO scaffolds were leveraged for site-selective diversification and as saturated isosteres for benzene rings in pharmaceutically relevant molecules, leading to enhanced three-dimensionality and tunable physicochemical properties. Collectively, this work overcomes long-standing synthetic limitations and establishes bridgehead-substituted [2]-ladderanes and BCOs as modular platforms for complex molecule construction and rational molecular design.
Repository Citation
Jia, Zongbin, Hugo A. Salazar, Jet Tsien, et al. 2026. "Concise synthesis and strain-release diversification of bridgehead-substituted [2]-ladderanes." Nature Chemistry 18: 1404-1412.
Publisher
Nature Portfolio
Publication Date
6-26-2026
Publication Title
Nature Chemistry
Department
Chemistry and Biochemistry
Document Type
Article
DOI
http://dx.doi.org/10.1038/s41557-026-02196-5
Language
English
Format
text
