Total Synthesis of Hyperforin

A 10-step total synthesis of the polycyclic polyprenylated acylphloroglucinol (PPAP) natural product hyperforin from 2-methylcydopent-2-en-l-one is reported. This route was enabled by a diketene annulation reaction and an oxidative ring expansion strategy designed to complement the presumed biosynthesis of this complex meroterpene. The described work enables the preparation of a highly substituted bicyclo[3.3.1]nonane-1,3,5-trione motif in only six steps and thus serves as a platform for the construction of easily synthesized, highly diverse PPAPs modifiable at every position.