Scripps Institute researchers describe synthetic pathway for generating gram quantities of taxadienone and taxadiene.
Scientists have developed a scalable biosynthetic route to generating a range of natural and unnatural taxane-based compounds and derivatives for drug discovery. Reporting in Nature Chemistry, Scripps Research Institute researchers claim their approach allows the production of gram quantities of taxadienone and taxadiene in just a few steps from commercially available starting materials. Phil S. Baran, Ph.D., Abraham Mendoza, Ph.D., and Yoshihiro Ishihara, Ph.D., describe their method in paper titled “Scalable enantioselective total synthesis of taxanes.” They claim the amount of taxadiene generated using their synthetic approach is “the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form.”
Taxol (paclitaxel) is a widely used diterpene anticancer drug in the taxane family of terpenes, which was originally derived from the bark of the yew tree. The drug is now produced commercially using a plant cell culture technology through a collaboration between Bristol-Myers Squibb (BMS) and Phyton Biotech, the authors explain.
Taxanes actually represent a large family of terpenes that comprise over 350 natural products, and a strategy for synthetic production of these molecules in a laboratory setting would not only give researchers an alternative route to producing Taxol itself, but also related taxanes. Since the early 1990s seven alternative synthetic routes to generating Taxol have been developed, but as well as being incredibly complex, none of these approaches has managed to generate more than 30 mg of the drug, which is required commercially at the tonnes scale, the Scripps team continues.
In 2007 the Scripps Institute established its own research program focused on generating a synthetic pathway that mimics the way terpenes are synthesized in nature. The two-phase process involves an initial biogenetic phase (the cyclase phase), in which linear hydrocarbon building blocks are brought together and cyclized efficiently, and a second, oxidase phase in which the carbon-carbon triple bonds and C–H bonds are oxidized to generate structural diversity. “The goal is to divergently access all ‘pre-taxol’ compounds (both natural and unnatural), and to unveil new insights into their chemical reactivity during an ‘oxidative ascent’ of the taxane pyramid,” the team comments.
The process builds on earlier work in which the team generated a Taxol relative, eudesmane. The eudesmane molecule represented the basis for devising a retrosynthesis pyramid, in which the target compound is at the top, and the lower levels comprise molecules that could theoretically be modified using the cyclic and oxidase phases to reach the levels above. This approach allowed the scientists to devise a synthetic route for generating gram quantities of taxadienone, and also significant quantities of taxadiene and its (+) enantiomer, a compound that represents a significant milestone along the road to generating Taxol itself.
This was a significant achievement, the team notes: “taxadiene is produced in negligible amounts in nature (less than 1 mg can be obtained from 750 kg of tree bark from T. brevifolia) and therefore its optical rotation has never been recorded.” And importantly, while current methods for synthesizing taxadiene are inefficient and involve 26 steps, the Scripps group’s method involves just 10 steps, and generates much larger quantities of the compound.
The team is now continuing to modify the chemical groups on taxadienone in order to create a pyramid-like library of both natural and unnatural taxanes en route to Taxol. “This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself,” they conclude.