Synthesis of Novel Cytotoxic Marine Macrolides

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This Research Planning Grant is supported by the Organic and Macromolecular Chemistry Program. Prof. Horacio F. Olivo of the University of Iowa will synthesize the aglycone moiety of the natural product, callipeltoside, a natural product recently isolated from a lithistid sponge. Callipeltoside is a 14-membered macrocyclic halogenated lactone. The synthesis involves Cr(II)-mediated coupling of two key fragments, the synthesis of which involves whole-cell systems and isolated enzymes. A biocatalytic method will be used to introduce the two stereogenic centers present in the chlorocyclopropane side chain. The non-racemic synthesis of the first intermediate involve the desymmetrization of a meso-cyclopropane using an esterase. The second fragment will be prepared via a Baeyer-Villiger oxidation using an engineered Baker's yeast. During the eighteen-month grant period, the PI will prepare these two key intermediates in racemic form and investigate their chemistry. He will investigate stereo- and regio-controlled ring openings of bicyclic oxiranes derived from cyclopentadiene to provide new methods for the elaboration of substituted hemiketal oxane rings. Prof. Olivo will also explore the use of palladium and chromium coupling reactions in an effort to develop new synthetic methods. Most of the 2500 naturally occurring organohalogen compounds known have had their structure elucidated in the last decade and a half. Several cytotoxic and/or antitumor macrolides have been encountered in marine sponges. One form of callipeltoside appears promising as an anti-HIV agent and as a chemotherapeutic agent.