Taxol® is widely regarded as amongst the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically-guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural-(plant material) or biosynthetically-derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol®. File list (2) download file view on ChemRxiv Manuscript.pdf (1.42 MiB) download file view on ChemRxiv Supporting Information.pdf (67.60 MiB)

This Perspective goes into the fine details of our laboratory’s quest to answer a longstanding fundamental question: Could any new approach to terpene synthesis, perhaps one patterned on biosynthesis, enable a divergent synthetic approach to the taxane family of natural products? We targeted Taxol, the flagship taxane, as the upper limit of chemical complexity and employed two-phase terpene synthesis logic as the guiding strategy. The first synthesis target was taxadiene, the lowest oxidized member of the taxane family, followed by three site-selective allylic oxidations at C5, C10, and C13, which led to the two-phase synthesis of taxuyunnanine D. Successful C9 oxidation enabled access to a wider range of taxanes, which was demonstrated by the two-phase synthesis of decinnamoyltaxinine E and taxabaccatin III. The final two sp3 C–H oxidations at C1 and C7 were attained by dioxirane-mediated C–H oxidation and an oxidation relay based on judicious substrate design, culminating in a two-phase synthesis of Taxol. The purpose of this Perspective is to articulate strategies and tactics developed for the two-phase synthesis of taxanes, whose lessons can be potentially extrapolated to medicinal chemistry endeavors in the taxane family, as well as to the synthesis of other terpene families.