The specific aim of the proposed research is to develop an efficient, convergent, asymmetric total synthesis of the cytotoxic natural product fijianolide D, which has shown promising biological activity, and the production of synthetic material will allow for further testing of its anticancer activities. Organometallic chemists have developed many powerful methodologies for the stereo, regio, and chemeoselective formation of complex organic molecules. The synthetic strategy use in the proposed synthesis of fijianolide D utilizes both well established and relatively new methodologies;additionally, it as a scaffold to showcase the versatility of several transition-metal catalyzed methods for the rapid assembly of this complex 20-membered macrolide. It especially highlights the a Ru-catalyzed Alder-ene reaction for regioselective macrocyclization.
Many biologically active natural products are only available from nature in very small amounts;for example, only 6 mg of fijianolide D was isolated from over a kilogram of sea sponges. The production of synthetic material allows for additional screening of biological activity and once a synthetic route is established, analogs can be made for structure-activity relationship (SAR) studies. This process aids greatly in the discovery of new pharmaceutical agents.
| Trost, Barry M; Stivala, Craig E; Fandrick, Daniel R et al. (2016) Total Synthesis of (-)-Lasonolide A. J Am Chem Soc 138:11690-701 |
| Trost, Barry M; Stivala, Craig E; Hull, Kami L et al. (2014) A concise synthesis of (-)-lasonolide A. J Am Chem Soc 136:88-91 |
