ASYMMETRIC SYNTHESIS OF ANTITUMOR POLYKETIDES

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The specific objectives of the proposed research are to establish the relateive and absolute configuration and to execute a synthesis of the extremely potent antitumor agent spongistatin. Ultimately, perhaps less complex derivatives of this potent antitumor agent with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and spiroketal containing natural products will be developed. This methodology can also be applied to the antitumor agent bryostatin 11. Spongistatin 1 has been found to be extra ordinarily effective against a variety of highly chemoresistant tumor types which comprise the NCI panel of 60 human cancer cell lines. Human melanoma, lung, brain, and coon cancers were found to be especially sensitive to spongistatin. The activity of spongistatin correlates well with the class of microtubule interactive antimitotics. Because of the extremely limited availability of spongistatin from natural sources [400kg wet weight of Spongia sp. provided only 13.8 mg (3.4 x 10-7% yield) of spongistatin] synthesis may be essential for providing adequate quantities of the substance for biological studies, structure-activity relationships and even to assist in the elucidation of the complete relative and absolute stereochemistry of this important compound. The bryostatins including bryostatin 11 have also been shown to possess significant antitumor activity including activity against lymphocytic leukemia and carcinosarcoma. The asymmetric approaches to polyacetate fragments described herein should find application in the synthesis of a variety of biologically important compounds. These methods can also be extended to allow the preparation of polypropionate fragments by the incorporation of additional methyl substitution in combination with equilibration strategies. The asymmetric polyketide fragments within spongistatin and bryostatin and will be constructed utilizing spiroketal templates to control much of the stereochemistry. The spiroketal enones to be used as stereochemical control elements will be constructed by nucleophilic addition of metallated pyrones to aldehydes. The resulting delta-hydroxypyrones can be cyclized to spiroketals under acid catalysis. Selective spiroketal ring cleavage reactions will also be developed in the context of these syntheses.