| This dissertation details chemical work directed towards the total synthesis of iejimalides A and B, two marine macrolides possessing significant cytotoxic activity.; As part of this goal, all of the necessary subunits required by our retrosynthetic analysis were successfully prepared in homochiral form. Of significance, the C17 stereocenter was established via an asymmetric Horner-Wadsworth-Emmons reaction, employing a parallel kinetic resolution, followed by a regio- and diastereoselective palladium-catalyzed allylic etherification reaction. Paterson's asymmetric anti selective propionate aldol reaction proved highly effective for establishing the required stereochemistry at C22 -C23.; The preparation of the C24-C29 diene prompted the investigation of several palladium-catalyzed cross-coupling reactions. Both Suzuki and Heck couplings proved superior to the Stille coupling for generation of this key fragment, with the Heck coupling being the most efficient overall.; Attempts to from the C5-C6 double bond prompted the investigation of the Julia olefination reaction. Both the traditional and modified versions of the Julia olefination were studied with the former providing better results than the latter. On the other hand, the modified version proved more effective for generating the C11-C12 double bond.; Investigation of the biological activity of iejimalides A and B has also been pursued. Iejimalides A and B have displayed significant cytotoxicities against a range of tumor cell lines. Further evaluation suggests that iejimalide B is slightly more potent than iejimalide A against certain cells and that iejimalide B also displays some selective toxicity. Mechanistically, it has been determined that iejimalide B has a negligible effect on microtubule formation. There is some indication that iejimalide B causes arrest in the G2/M phase of cell replication. |
