SYNTHESIS OF BRIDGED AND POLYCYCLIC ANTITUMOR AGENTS

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The long-term objectives of our research are to discover new chemical strategies and tactics for the synthesis of complex natural products. Our focus is on the synthesis of structures known or likely to have in vivo anticancer activity. We propose to carry out the first total synthesis of a natural taxane diterpene, taxusin, and to construct close analogs of the clinical anticancer drug taxol. We outline a novel synthesis of the drug Fredericamycin A (currently under development by NCI) and of the antimitotic agent colchicine, both employing radical coupling cyclizations. Also proposed are chiral syntheses of the new antitumor antibiotics oxazolomycin and neooxazolomycin. We described a stereocontrolled chiral approach to the in vivo antitumor macrocyclic antibiotic Lankacidin C based on the intramolecular rearrangement of an optically active Beta-lactam intermediate. Applications of the thermal and Pd (II)-mediated cycloalkenylation methodologies developed in our group are tested in proposed syntheses of the terpenes hirsutic acid, patchoulenone and sanadaol. General syntheses of Gelsemium aldaloids, in particular gelsedine and gelsemine, are anticipated based on recent results from our laboratories involving the stereocontrolled intramolecular cyclizations of acetal derivatives of N-methoxy oxindoles.