The goals of the proposed research involves the development of new strategies for synthesis as well as new methodologies. These investigations are conducted in the context of studies directed toward the synthesis of natural products. In this particular program we focus on natural products with interesting and potentially useful profiles of biological action. Our target structures are organized around biological goals and chemical themes. The biological goals include HIV suppression, MDR inhibition, antifungal agents, immunosuppression and antimitotic properties. The latter arise from interference with tubulin processing or inhibition of topoisomerase I - DNA interactions. The natural product lead systems around which the program is organized are (I) cyanobacterial sulfolipid, (II) cyanobacterial sulfolipid, (III) N- acetylardeemin, (IV) cyclindricene, (V) Sch 38516, (VI) acarbose, (VII) cell surface tumor antigens, (VIII) taxol, (IX) camptothecin and (X) rapamycin. In some instances we are studying the total synthesis of the natural product for the first time in our lab. In other cases we are following up from a successful total synthesis. The main chemical themes to be explored pursuant to these goals are: synthesis of alpha-glycosides from glycals, glycopeptide synthesis, stereochemical transmission in the SN2' reaction of organometallic reagents, the stereoelectronic requirements of the classical SN2' displacement reaction with heteronucleophiles, the generation and use of complex organometallic nucleophiles in highly functionalized systems, intramolecular olefin metathesis of intramolecular Heck reactions, heterosubstituted alkenes, intramolecular Diels Alder reactions, intramolecular imino Diels Alder reactions, charge-driven Claisen rearrangements, and, enantioselective synthesis of pyruvates.
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