ACS Meeting News: Taking Cues From Nature En Route To Taxol

No one is better than nature at making the cancer drug paclitaxel (Taxol). Cumulatively, chemists have been able to produce only small amounts of the stuff, but a plant cell fermentation process can churn out metric tons of the compound.

Synthetic chemists would like to learn from nature. By mimicking the early steps in paclitaxel’s biosynthesis, a team at Scripps Research Institute, La Jolla, Calif., has potentially come up with a way to create analogs of paclitaxel that are unavailable via bioengineering. These could turn out to be powerful drugs as well. Phil S. Baran, who spearheaded the research, spoke about the work on Tuesday at the American Chemical Society meeting in Dallas, in the Division of Organic Chemistry.

First, Baran’s team synthesized the natural product (–)-taxuyunnanine D in just five steps from taxadiene. The transformation mimics the first three of eight oxidations that occur biosynthetically when taxadiene is converted to paclitaxel. Taxuyunnanine D, Baran said, could ultimately be used as an intermediate en route to paclitaxel.

The challenge for Baran’s group was to control the order of the three oxidations. It’s a tough task, Baran explained, because taxadiene is a strained, doubly unsaturated hydrocarbon that is “spring loaded” for oxidation at several spots at once. Through computational modeling, developing a seldom-used chromium reagent, and conducting hundreds of reactions, Baran’s team executed the early steps of paclitaxel’s biosynthesis (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja501782r).

“His approach is very innovative,” commented Guangbin Dong, an expert in organic synthesis at the University of Texas, Austin. Dong was particularly impressed with Baran’s use of the unusual chromium compound for one of the oxidations. “I think it’s going to inspire others to realize the value of using that reagent,” he said.