Total Synthesis and Structural Revision of Tetracyclic Diterpenoid (±)-Papililone A and (-)-Papililone A

Papililone A, a polycyclic diterpenoid isolated from Papilio species, exhibits anti-inflammatory activity and features an unprecedented fused-bridged 5/5/5/6 tetracyclic core with six contiguous stereocenters, including two adjacent all-carbon quaternary bridgehead centers. Its intricate architecture presents significant challenges for both chemical synthesis and structural assignment. Herein, we report our comprehensive efforts toward the total synthesis of (±)- and (-)-papililone A, leading to a revision of the originally proposed structure. Initial efforts using a nitrile polar-radical cyclization and a zirconium-hydride-promoted hydroiodination was hindered by inefficient fragment coupling and an unproductive stereochemical outcome in a pivotal rearrangement. A redesigned strategy using 3-bromofuran enabled efficient fragment coupling to construct a critical intermediate. Furan oxidation and base-promoted vinylogous α-ketol rearrangement then furnished the requisite 5/5 bicyclic core and contiguous all-carbon quaternary stereocenters with high selectivity. After failure of an aldol/Michael reaction, a novel tandem alkenylation/6-endo-trig cyclization was developed to rapidly construct the fused-bridged 5/5/6 tricyclic framework, delivering (±)-papililone A. Comparative NMR, nuclear overhauser effect spectroscopy (NOESY), and x-ray crystallographic data of the synthetic sample revised the C17 stereochemistry of the natural product. Absolute configuration of (-)-papililone A was confirmed by electronic circular dichroism (ECD) and optical rotation.