- This research program is broadly directed to investigate fundamental advances for the chemical synthesis of biologically active marine natural products. Part I. Marine Antitumor Macrolides. Section A. A plan for the highly efficient, convergent, and enantiocontrolled synthesis of laulimalide will be executed. Laulimalide displays comparable potency to taxol with IC50 concentrations in the 0.01-0.05 mico/mL range against a broad selection of tumor cell lines. High cytotoxicity was registered toward KB lines (IC50 = 0.015 mico/mL). Significantly laulimalide retains activity in multi-drug resistant SKVLB-1 cultures. Section B. Strategies for the synthesis of peloruside will explore issues of stereoselectivity and efficiency for the assembly of this highly oxygenated hemiketal. With key structural features and macrocyclic rigidity, which address important proposals and research concerning the nature of the antitumor activity of the bryostatins (NCI; phase II trials), peloruside A studies are designed to offer a significant chemical advance for probing the nature of the pharmacophore and the mechanisms of biological activity for this family of molecules. Our chemical studies toward these target molecules will develop asymmetric allylation reactions. Bidirectional, divergent asymmetric allylation strategies are examined. Direct formation of new homochiral allylborane species will be pursued via cross coupling reactions with organozinc reagents. Part II. Zoanthamines. Our investigations of this novel class of marine alkaloids describe challenging issues of chemical synthesis toward densely functionalized, polycyclic systems. Members of this class have exhibited important antitumor and anti-inflammatory activities, and norzoanthamine is considered to be a promising osteoporotic candidate. Part III. Australifungin. This unique natural product is a potent antifungal which is the first nonsphingosine-based inhibitor of sphingolipid biosynthesis. It functions as a selective inhibitor of sphinganine N-acyl transferase, and may have an important role in lipid signal transduction, cell differentiation, and apoptosis. Our plans toward zoanthamines and australifungin will explore asymmetric induction in conjugate addition reactions and intramolecular Michael-based cyclizations. The intramolecular (4+2) cycloadditions of nitroalkene precursors will provide facile construction of trans-decalins. .
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