Synthetic and mechanistic investigations of the angucycline class of antitumor agents is one objective of this proposal. An efficient enantioselective strategy to several members of the angucycline family of antitumor antibiotics is outlined. Key to the general strategy is the enantioselective assembly of the tetracyclic ring system comprising the aglycone portion of the antibiotics via a Diels-Alder cycloaddition. The diene component of the Diels-Alder reaction is efficiently prepared in optically active form starting from (-)-quinic acid. Following the construction of the ring system, novel approaches for the stereocontrolled introduction of key oxygen functionality are described. Next the synthesis of L-rhodinose a monosaccharide common to the oligosaccharide sector of many angucycline antibiotics is outlined. Methodology for the stereocontrolled assembly of oligosaccharides and its application to the synthesis of the antitumor antibiotics vineomycin B2 and PI-080 is then described. A convergent synthesis of the thymidylate synthase inhibitor BE-7585A is also outlined. Finally, experiments directed towards exploring the potential relationship of the air oxidation of the dihydroquinone form of the antibiotic aquayamycin to its antitumor activity are also discussed. The second major objective of this proposal is the total synthesis of FR- 66979, an anticancer agent which induces DNA-DNA cross-links and has undergone phase I clinical trials. Central to the success of the enantioselective synthesis of this antitumor agent is a metal-catalyzed asymmetric carbon-hydrogen insertion reaction to produce a nitrogen containing heterocycle. DNA-DNA cross-link formation reportedly occurs via a mitosene-like intermediate. A synthetic approach towards the generation of the putative alkylating species is described. Finally, experiments directed towards probing the reactivity of this intermediate is also discussed. Ultimately these investigations will lead to the development of new synthetic methodologies as well as clinical application in the development of anticancer agents.
