Concise synthesis and strain-release diversification of bridgehead-substituted [2]-ladderanes.

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.