Taking Cues From Nature En Route To Paclitaxel

No one is better than nature at making the cancer drug paclitaxel (Taxol). But 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. A team led by Phil S. Baran 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).