Accessing three-dimensional molecular diversity through benzylic C–H cross-coupling

Pharmaceutical discovery efforts rely on robust synthetic methods that rapidly access diverse molecules. Cross-coupling reactions are the most widely used reactions, but these methods typically form bonds with C(sp2)-hybridized atoms and lead to a prevalence of 'flat' molecules with suboptimal physicochemical and topological properties. Benzylic C(sp3)–H cross-coupling offers an appealing strategy to address this limitation, as emerging methods exhibit synthetic versatility that rivals conventional cross-coupling to access drug-like products. Here we use a virtual library of benzylic ethers and ureas derived from benzylic C–H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized centres affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. These concepts are validated through an informatics-guided synthesis and high-throughput experimentation to prepare three-dimensional products that are broadly distributed across drug-like chemical space. Cross-coupling reactions are among the most widely used synthetic methods in medicinal chemistry; however, they typically form bonds with C(sp2)-hybridized atoms. The resulting molecules often have suboptimal physicochemical and topological properties. Here virtual and experimental libraries of products from benzylic C(sp3)–H cross-coupling are shown to access underpopulated 3D chemical space.