Synthetic organic chemistry makes new compounds available for all fields of science, and synthetic chemists develop the tools to assemble chemical compounds more effectively. This proposal focuses on syntheses in four different classes of natural products. Synthesis of candidin and rimocidin, both polyene macrolides with potent antifungal properties, will be completed. The principle remaining challenge is attachment of the B-mycosamine sugar to the aglycones, and several new strategies have been developed to address this problem. The second compound of interest is SCH 351448, a complex macrolide that is the first small molecule activator of the LDL receptor promoter. This activity suggests a new therapeutic approach to controlling serum cholesterol levels. It will be synthesized using the 4-acetoxy-1,3-dioxane synthons developed in the previous grant period. Apicularen A is the third target. It is a very potent inhibitor of human cancer cell lines. Its preparation features a cyanohydrin acetonide coupling and a formal benzylic anion addition to an oxocarbenium ion. The final natural product is amphidinol 3. It has potent antifungal activity, and its structural assignment is provocative and worth investigating. Our proposed synthesis features a number of unusual convergent coupling strategies. The synthetic targets are challenging and interesting, and the new methods developed in these projects will be applicable to many other structures of contemporary interest.
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