Nineteen-Step Total Synthesis of (+)-Phorbol

Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from scores of chemists and biologists due to its intriguing chemical structure and the medicinal potential of phorbol esters.(1) Access to useful quantities of phorbol and related analogs has relied upon isolation from natural sources and semisynthesis. Despite relentless efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies due to its sheer complexity and unusual oxidation pattern. In fact, purely synthetic enantiopure phorbol has remained elusive and efforts on the synthetic biology side have not led to even the simplest members of this terpene family. Recently the chemical syntheses of eudesmanes,(2) germacrenes,(3) taxanes,(4,5) and ingenanes(6-8) have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis where powerful C–C bond constructions and C–H bond oxidations go hand in hand. In this manuscript, we show how a two-phase terpene synthesis strategy can be enlisted to achieve the first enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this route is not to displace isolation/semisynthesis as a means to generate the natural product per se, but rather to enable access to analogs containing unique oxidation patterns that are otherwise inaccessible.