Intracellular Mediators: Synthesis of l-α-Phosphatidyl-d-myo-inositol 3,4,5-Trisphosphate and Glyceryl Ether Analogs

L-α-Phosphatidyl-d-myo-inositol 3,4,5-trisphosphate (3,4,5-PIP₃), the most prominent member of a new class of intracellular second messengers, and two ether analogs were conveniently prepared from the differentially functionalized d-myo-inositol intermediate 7 which was ultimately derived from the unique cyclitol precursor dehydroshikimic acid (1). Critical transformations included the stereoselective hydride reduction of the shikimate ketone, exclusive osmylation from the α-face to give 3, controlled enolization of 4, and dioxirane epoxidation with in situ rearrangement affording ketone 5. Dioctanoyl 3,4,5-PIP₃ (9a) and its dioctyl ether analog 9b selectively activated the δ, ∈, and η-isotypes of protein kinase C (PKC).