The broad aim of this research program continues to be the discovery and application of new strategies in synthetic organic chemistry which can facilitate the acquisition of bioactive molecules through laboratory synthesis. The particular chemical structures towards which this synthetic effort is directed are naturally occurring macrocyclic lactones (macrolides), all of which possess striking biological properties of potential chemotherapeutic value. The specific targets identified for synthesis are (a) rhizoxin, a 16-membered macrolide, with promising anticancer activity; (b) rapamycin, a 29-membered macrolide, with powerful immunosuppressant properties; (c) antillatoxin, a neurotoxic substance which exhibits potent effects on the central nervous system in fish; (d) polycavernoside A, a marine macrolide which has been found to have an effect on the central nervous system in humans similar to ciguatera; (e) epothilone B, a recently discovered 16-membered macrolide with remarkable antitumor activity, especially against taxol-resistant cell lines; (f) cochleamycin A, a highly unusual lactone which exhibits antileukemic properties; and (g) phorboxazole A, a 21-membered macrolactone with extremely potent in-vitro activity against tumor cell lines. Plans are presented for synthesis of each of these compounds in which construction of subunits sets the stage for their final assembly into the complete macrolide. A necessary prerequisite for chemical synthesis at this level of complexity is a practical design which leads to implementation of efficient convergent routes to the target. These pathways, regardless of whether they are successful, must also serve as paradigms for accessing other potentially useful chemotherapeutic agents of equal or greater complexity.
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