Pd-Catalyzed Geminal Coupling for the Construction of Fused Polycycles and Natural Product Synthesis

Densely functionalized 6/5/6 polycycles are prevalent in bioactive natural products, yet their efficient assembly remains a persistent synthetic challenge. Here, we report a palladium-catalyzed autotandem cascade that merges Suzuki-Miyaura coupling with an underexplored oxidative cyclometalation to effect C═C-conserving geminal heterocoupling, thereby enabling rapid construction of fused 6/5/6 scaffolds from readily prepared bicyclic precursors and alkenyl boronates. The transformation proceeds under operationally simple conditions, tolerates broad substrate variation, and is scalable to decagram quantities. Its synthetic utility is demonstrated in a formal synthesis of gracilamine and the total syntheses of GA₁₈ methyl ester and xiamycin E, where the geminal heterocoupling forges the fused tricyclic core and provides advanced intermediates for subsequent target-oriented elaboration. Mechanistic studies support an autotandem pathway involving initial cross-coupling followed by oxidative cyclometalation. Collectively, these studies establish a useful method for the modular construction of fused 6/5/6 polycycles.