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 ingenanes6-8 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.

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Total syntheses of the complex, highly oxygenated sesquiterpenes thapsigargin (1) and nortrilobolide (2) are presented. Access to analogues of these promising bioactive natural products has been limited to tedious isolation and semisynthetic efforts. Elegant prior total syntheses demonstrated the feasibility of creating these entitites in 36–42 step processes. The currently reported route proceeds in a scalable and more concise fashion by utilizing two-phase terpene synthesis logic. Salient features of the work include application of the classic photosantonin rearrangement and precisely choreographed installation of the multiple oxygenations present on the guaianolide skeleton.

The intriguing structure of tagetitoxin (1), a long-standing challenge in natural product synthesis, has been the subject of multiple revisions and has been confirmed through total synthesis. The route commences from a renewable furan starting material and features a number of unusual transformations (such as rearrangements, bromocyclization, and P(V)-based phosphate installation) to arrive at the target in 15 steps. As the route was designed to enable access to both enantiomers, the absolute configuration of the natural product could be assigned using a bioassay on (+)-1 and (−)-1.