Stereocontrolled synthesis of functionalized hexahydroxanthenes

Schweinfurthins A--H were isolated in separate efforts by Beutler and co-workers at the National Cancer Institute and subsequent work by Kingston and co-workers from extracts of the plants Macaranga schweinfurthii and Macaranga alnifolia respectively. They are a family of stilbenes which, with the exception of schweinfurthin C, incorporate a hexahydroxanthene skeleton containing an oxygenated CS-position. These compounds displayed significant activity in the NCI's 60-cell line anticancer assay with mean GI50 values <1 muM, and particular potency towards some central nervous system, renal, and breast cancer cell lines. They show a pattern of activity different from any clinically used therapeutic agent which may suggest that these compounds act at a previously unrecognized target or through a novel mechanism.;This work details the synthesis of several schweinfurthin analogues with a focus on manipulation of the functional group located at the C5-position. The intention was to determine the importance of C5-substituents to the schweinfurthins' pharmacaphore. In addition studies are presented that provide a greater understanding of the mechanism governing the cascade cyclization utilized in the formation of the hexahydroxanthene core common to these compounds. Modification of the right-half of the schweinfurthins to promote greater stability towards oxidation, results from initial testing of the C5-schweinfurthin analogues, as well as progress towards the development of a third generation synthesis of 3-deoxyschweinfurthin B, also will be presented.;This investigation led to the discovery of an unprecedented reaction sequence, a Lewis acid initiated cascade cyclization of a nonracemic epoxide with tandem electrophilic aromatic substitution. The resulting products easily can be modified to allow further functionalization at the C5-position. The usefulness of this reaction is demonstrated in the total synthesis of a hexahydroxanthene-chalcone natural product isolated from the leaves of Angelica keiskei, a plant commonly used in Asian cultures to treat several ailments.