The Total Synthesis of Leucascandrolide A

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DESCRIPTION (provided by applicant): Leucascandrolide A is a novel doubly bridged 18-membered macrolide isolated from the calcareous sponge Leucascandra caveolata along the coast of New Caldonia, Coral Sea. The compound is a highly bioactive molecule, showing strong cytotoxic activity towards KB and P388 cells as well as excellent inhibition of Candida albicans, a pathogenic yeast that attacks AIDS patients. The approach is highly flexible and amenable to the construction of synthetic variants. The use of stereodefined glycosyl anions will provide a rapid synthesis of the macrolide core. The center piece of the synthesis of the leucascandrolide A side chain will be the development of a novel dihalooxazole and its use in two highly selective palladium-catalyzed cross coupling reactions to install the two alkyl side chains. The development of this novel precursor for palladium reactions will not only facilitate the synthesis of the side chain, but should open new routes for the synthesis of functionally more elaborate oxazole systems which are becoming increasingly important due to their discovery in a variety of natural products.