Synthesis of the Phosphatidylinositol 3-Kinase Inhibitor

University Of California Irvine, Irvine CA

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Abstract

DESCRIPTION (provided by applicant): 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.