Nineteen-step total synthesis of (+)-phorbol

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Abstract
Enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene is demonstrated using a two-phase terpene synthesis strategy. Tigliane diterpenes, particularly phorbol esters, are seen as promising leads in many different medicinal applications. These molecules are remarkably complex and access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Now Phil Baran and colleagues report the enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The authors envisage their two-phase terpene synthesis strategy not as a replacement for isolation/semisynthesis as a means to generate the natural product, but rather as a route to analogues containing unique oxidation patterns that are otherwise inaccessible. Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters1. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes2, germacrenes3, taxanes4,5 and ingenanes6,7,8 have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C–C bond constructions and C–H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.

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