SYNTHESIS OF THE ANTITUMOR AGENT (+)-SUPERSTOLID

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The proposed research is a convergent, enantiospecific synthesis of the highly cytotoxic macrolide antitumor agent (+)-superstolide A (1). Isolated from a marine sponge, 1 has very high in vitro cytotoxicity toward various cancer cell lines. A synthetic route is necessary to obtain sufficient quantities of 1 and analogs for further testing. The essential first steps in exploring the potential of 1 and analogs as clinically useful cancer therapeutics are the following specific aims of this proposed research: * A convergent, enantiospecific synthesis of 1, adaptable to synthesis of analogs, will be developed. * The structure and absolute configuration of 1 will be verified by synthesis and X- ray crystallography. The synthetic strategy proposed includes a) an intramolecular Diels-Alder reaction to define the configuration of four stereocenters of the functionalized decalin system and b) iterative double asymmetric crotylboronation to form the C19-C26 propionate-derived segment. An additional benefit of this research is the likelihood of significant new insights regarding the synthesis of complex macrolide natural products.