Phosphatidylinositol 3-phosphates (PIPs) are intracellular secondary messengers whose aberrant production contributes to the aggressive growth of a wide range of cancers. The fungal secondary metabolite wortmannin is a widely employed phosphatidylinositol 3-kinase (PI3K) inhibitor (IC50 4.2 nM), which represents a promising starting point for the design of isoform-selective PI3K inhibitors which are anticipated to be valuable biochemical and clinical tools for the study and regulation of PIP production. A convergent total synthesis of this structurally intriguing compound is proposed which can provide access to analogues of wortmannin suitable for the development of isoform-selective PI3K inhibitors. Key features of the proposed synthetic route include a novel Stilie coupling between an a-stannyl epoxide and a vinyl triflate and the FriedeI-Crafts alkylation of an acyl furan.
| Lanman, Brian A; Overman, Larry E; Paulini, Ralph et al. (2007) On the structure of palau'amine: evidence for the revised relative configuration from chemical synthesis. J Am Chem Soc 129:12896-900 |
