Convergent Total Synthesis of Papililone A via Pd-Catalyzed Alkenylation/Cyclization Cascade

Papililone A is a unique polycyclic diterpenoid with <i>anti</i>-inflammatory activity, characterized by its intricate fused-bridged 5/5/5/6 tetracyclic skeleton and six contiguous stereocenters, including two adjacent bridgehead all-carbon quaternary centers, which pose significant challenges to chemical synthesis. Herein we describe the first total synthesis of papililone A in a nine-step longest linear sequence (LLS) from commercial materials without the use of a protecting group, achieved through a cyclization cascade strategy. The strained fused-bridged 5/5/6 tricyclic framework and the two contiguous stereocenters were efficiently constructed in a single step via an unprecedented Pd-catalyzed alkenylation/6-endo-trig cyclization, while the fused 5/5 bicyclic ring system and the vicinal all-carbon quaternary stereocenters were rapidly forged through a combination of a polar-radical cyclization cascade, a convergent fragment coupling, and a vinylogous α-ketol rearrangement in a highly stereoselective manner. This concise approach establishes the β-methyl configuration at C17 as the authentic stereochemistry of naturally occurring papililone A, resolving previous computational ambiguities and facilitating future biological studies.