This proposal is directed towards the total synthesis of two naturally occurring diterpenes, ingenol, 1, and taxol, 2. Both of these targets are densely functionalized, complex structures that have not yet yielded to total synthesis, despite a prodigious effort directed towards the synthesis of each over the last decade. The important biological properties of 1 and 2 make their total synthesis important goals not only for synthetic organic chemistry, but also for biochemistry, pharmacology and medicine. Ingenane and phorbol esters exhibiting toxic, irritant, cocarcinogenic as well as anti-leukemic activities have been isolated from many Euphorbiaceae and Thymelaeaceae species. These substances mimic the effect of diacylglycerol, the endogenous activator of protein kinase C, an enzyme that mediates cellular signal transduction for a large class of hormones and cellular effectors that activate phosphatidylinositol 4,5-bis(phosphate) turnover. Protein phosphorylation is now recognized to be the major general mechanism by which intracellular events in mammalian tissues are controlled by external physiological stimuli. Given the biological responses induced by activators of protein kinase C, the development of inhibitors of this enzyme may lead to therapeutic agents useful in the treatment of chronic inflammatory and proliferative diseases. Dibenzoate and dipalmitate diesters of simple ingenol analogs prepared using this photochemical methodology during the first grant award period inhibit and promote protein phosphorylation, respectively, in analogy to the corresponding diesters of ingenol. According to the National Cancer Institute, the naturally occuring diterpene ester taxol is the most promising natural product lead in cancer chemotherapy in the last decade. Results presented at the NIH- sponsored June 1990 Taxol Workshop indicate that taxol shows extremely promising activity against intractable ovarian and other tumor systems. Because taxol is isolated in exceedingly low yield (,0.01%) by extracting the bark of the Pacific yew tree, a massive harvesting program has recently been undertaken to make available sufficient quantities to permit further clinical trials. However, the ecological ramifications of this harvesting program make it very undesirable. An efficient total synthesis of taxol would solve the very serious supply problem of this exciting new anti-cancer drug. However, despite a prodigious effort in several laboratories around the world, the total synthesis of taxol has yet to be achieved. This second part of this proposal is directed towards the total synthesis of taxol and congeners. Outlined herein is a highly convergent approach to the synthesis of taxol that should make possible the efficient preparation of highly functionalized taxol analogs. The goal of the studies outlined herein is not only the synthesis of these two target structures, but also the evaluation the biological activity of the ingenane and taxane analogs that are prepared during the course of the proposed synthetic efforts.
| Winkler, Jeffrey D; Rouse, Meagan B; Greaney, Michael F et al. (2002) The first total synthesis of (+/-)-ingenol. J Am Chem Soc 124:9726-8 |
