The broad scope of the work proposed involves the development of the chemistry of Fischer carbene complexes to the field of organic synthesis and to the synthesis of organic compounds of importance in human health. The reactions of Fischer carbene complexes with alkynes will be examined for the synthesis of the platelet activating factor antagonist phomactin D and for the synthesis of colchicine and allocolchicinoids that have been investigated for the treatment of gout, familial Mediterranean fever and liver cirrhosis. Asymmetric versions of this reaction will also be used to prepare aS,7S and aR,7S isomers of 1 2 - methylcolchinyl methyl ether to test an unresolved issue regarding the stereochemical requirements for binding of colchicine and allocolchicinoids to tubulin. A new strategy for the synthesis of the new anticancer agent eluetherobin will be explored which involves an intramolecular exo-selective Diels-Alder reaction as a key step. The aldol reaction of Fischer carbene complexes will be utilized in the first synthesis of the anticancer agent fostriecin and analogs of fostriecin which are more stable and thus more useful in the clinic. The reaction of Fischer carbene complexes with 1,6-enynes will be explored as a method for rapid access to the taxol family of antitumor agents. The the cyclopropanation reactions of chiral carbene complexes will be examined for the synthesis of aminocyclopropanes and for a synthesis of the antitumor agent helenalin which involves a tandem cyclopropanation/Cope rearrangement sequence.
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