A Two-Phase Approach to Terpene Total Synthesis: Demonstration of a 'Cyclase-Phase' Synthesis of the Eudesmane and Taxane Families

Terpenes are primary constituents of plant oils and have long held importance as flavors and fragrances, as well as poisons and medicines. Isolation, structural elucidation, total synthesis and occasional structural revision of these omnipresent natural products have long been conducted, providing constant challenges to chemists and thus allowing for a continuous development of the field. In particular, advances in analytical techniques and the development of retrosynthetic analysis have led to a dramatic increase in the number of isolated terpenes and the ability to execute their total synthesis. While total synthesis has conquered some extremely complex terpenes, only milligram quantities are typically prepared after many years of effort; in contrast, Nature seemingly generates terpenes with ease. Therefore, organic chemistry still needs to improve dramatically in order to match the efficiency of Nature. The main difficulty in the total synthesis of terpenes is that there are no general rules for their construction, and molecules must be retrosynthetically evaluated on a case-by-case basis. A solution to this problem perhaps lies in mimicking Nature, as the awe-inspiring efficiency of biosynthesis suggests that there might be certain advantages to conducting terpene synthesis in a similar manner. Nature creates its library of terpenes in a unified fashion by a two-phase approach: a cyclase phase that uses a small number of functional groups to cyclize and rearrange carboskeleton frameworks, and an oxidase phase that builds diversity by using a variety of cytochrome P450 enzymes to achieve C--H oxidation. Similarly, a laboratory two-phase synthesis of terpenes would involve first a "cyclase phase" with the aim to synthesize a lowly oxidized target of a particular terpene family in an enantioselective and scalable manner, followed by an "oxidase phase" that would divergently access various members of a given terpene family using C--H functionalization methods. In this thesis, two terpene families are chosen as platforms for discovery in total synthesis: the eudesmane family of sesquiterpenes and the taxane family of diterpenes. Execution of the "cyclase phase" in the eudesmane and taxane families is described through the scalable and enantioselective total syntheses of dihydrojunenol and "taxadienone".