By: Zongbin Jia, Hugo A. Salazar, Yixuan Ma, Olivia L. Coyle, Eric Crossley, Ricardo Alvarado, Yuzuru Kanda, Noelle Williams, Shuming Chen, Tian Qin
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.
