Highly Oxygenated Diterpenoids Associated to the Central Nervous System: Syntheses of Salvinorin and Forskolin

Abstract

Total synthesis of salvinorin A (1), a densely functionalized neoclerodane diterpenoid, having the most potent hallucinogenic activity and a selective κ–opioid agonist, has been completed in 20 steps starting from enantiomerically–pure Wieland–Miescher ketone derivative 23. Subsequently, alternative total synthesis of salvinorin A (1) has been developed via palladium–catalyzed double carbonylation to bis–enol triflate followed by samarium diiodide–mediated double conjugate reduction in 13 steps. Forskolin (2), a highly oxygenated labdane diterpenoid and an activator of adenylate cyclase, has been synthesized in 12 steps and 12% overall yield from ptychantin A (62), which has been isolated from liverwort Ptychanthus striatus in sufficient yield. Tuning of the synthetic pathway enabled more expedient synthesis of forskolin (2) in 11 steps with 17% overall yield from ptychantins A (62) and B (63). In addition, synthesis of 1,9–dideoxyforskolin (3), an inhibitor of glucose transporter, has been accomplished in 8 steps and 37% overall yield from ptychantin A (62).