FURAN-CARBONYL PHOTOCYCLOADDITIONS IN ORGANIC SYNTHESIS

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This grant application details our plans to utilize a chemical process based on the photocyloaddition of carbonyl containing compounds onto electron rich hetecrocycles such as furan. The reaction provides bicyclic photoadducts with excellent stereochemical control. These products can be converted to highly oxygenated target systems by subsequent functionalization procedures that have been developed during the current funding period. Our objectives for the research outlined in this proposal are: (1) to attempt new permutations of the reaction process that have been designed on the basis of a mechanistic hypothesis, (2) to apply the overall synthesis strategy to the preparation of several natural and unnatural products, the latter which (on the basis of a pharmacophore hypothesis) serve as potential drug candidates for treatment of arthritis, asthma, pepticulceration, and shock, and (3) to evaluate the predictive capabilities of these hypotheses by interpreting the results of mechanistic and synthetic studies and testing the biological properties of the drug candidates. On the basis of mechanistic considerations and preliminary findings the intramolecular photocycloaddition of 2-substituted furans is expected to result in an efficient route to highly unusual tricyclic ring systems. These materials will be converted to carbocycles with substitution patterns that are common in the natural products domain. Other specific aims include the identification of stereocontrol elements that will provide increased levels of chemo- and enantioselectivity in the photoaddition. Several applications of this strategy will be undertaken that are directed towards highly oxygenated members of the ginkgolide, alkaloid, germacranolide, and cembranolide classes. The structural homology of natural and unnatural platelet activating factor (paf) receptor antagonists is suggestive of a pharmacophore requirement for biological activity. Molecular modeling facilitates the design of new structures that may exhibit paf receptor antagonism. Such compounds are likely candidates for membership to the important class of nonsteroidal antiinflammatory agents. The furan-carbonyl photocyclo-addition reaction based strategy is central to our plans for the preparation of these new materials.