This research program (CA-19033), now in its twentieth year, embodies the principal investigator's long-term commitment to the characterization and efficient, enantioselective synthesis of architecturally challenging anticancer agents. The principal goals for the 21-24 years are: (A) to complete and then refine the P. I.'s approach to the macrolactins, highly effective inhibitors of the human immunosuppressive virus (HIV), and then to prepare multigram quantities of these materials for biomedical study; (B) to complete the total synthesis of calyculin A (22); (C) to elucidate the complete relative and absolute stereochemistries of the thiazinotrienomycins A-E (38-42), members of a new class of potent ansamycin anticancer antibiotics, as prelude to their total synthesis; (D) to devise a unified synthetic strategy for the thiazinotrienomycins, exploiting the insights gained in our trienomycin synthetic venture; and (E) to execute a viable synthesis of phorboxazoles A and B (43, 44), two extraordinarily active anticancer compounds. In conjunction with the proposed target work, he plans: (F) to further develop the bisolefination/macrocyclization protocol emanating from our trienomycin synthesis; (G) to further explore the chemo-, regio-, and stereoselective stannycupration of diynes; and (H) to exploit the Petasis-Ferrier rearrangement in the synthesis of complex pyrans. Finally, he plans: (I) to evaluate the utility of fluoro ketones as progenitors of reactive dioxiranes for the enantio- and diastereoselective oxidation of unactivated olefins and hydrocarbons. Beyond the specific synthetic objectives, a general, long-range aim of this program is the identification of the molecular architecture responsible for biological activity in these and related systems. Thus, as the P. I. develops an approach to each target structure, he will also prepare model compounds designed to permit the elucidation of structure-activity relationships. The design of new and possibly more effective agents should then be feasible.
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