Studies toward the total synthesis of the tedanolides: Total synthesis of 13-deoxytedanolide.

Tedanolide and 13-deoxytedanolide are highly cytotoxic marine macrolides that exhibit antitumor activity at nanomolar concentrations in various cancer cell lines. The combination of potent biological activity and structural complexity has stimulated considerable interest by the synthetic organic community. This dissertation describes a total synthesis of 13-deoxytedanolide. The synthesis features a highly stereoselective fragment assembly aldol reaction of the C(1)-C(12) methyl ketone and C(13)-C(23) aldehyde fragment to establish the complete carbon skeleton of the tedanolides. The facile formation of a remarkably stable hemiketal intermediate, which proved unreactive with respect to oxidation of the acyclic delta-hydroxy ketone form to the C(11,15)-dione, thwarted attempts to elaborate the aldol product to tedanolide. However, deoxygenation of the C(13)-hydroxyl of the hemiketal intermediate provided the 13-deoxyhemiketal that was smoothly advanced to 13-deoxytedanolide. In our continuing efforts toward tedanolide, we have proposed that inversion of the stereochemistry at C(15) should sufficiently destabilize the unreactive hemiketal form to allow for oxidation to the C(11,15)-dione. Our preliminary results addressing this hypothesis are described.PhDOrganic chemistryPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125113/2/3186660.pd