Cytotoxic Nitrogen Heterocycles

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This program will explore the synthesis of complex heterocyclic structures related to important experimental anticancer agents including FK317, FR900482, mitomycin C, telomestatin, and diazonamide A. In the FK317/FR900482, a synthesis of the intermediate proposed to cause DMA crosslink formation will be completed, and its role in DMA alkylation will be evaluated. Related structures will be prepared to test their role as possible late stage intermediates in the biosynthesis of mitomycin C or FR900482 in collaboration with Prof. D.H. Sherman. A synthesis of polyoxazoles related to the telomerase inhibitor telomestatin will be initiated. Our focus will be to develop methods for connecting simple oxazole units in a repeating chain. A synthesis of diazonamide A will be completed, following a route that has accessed the key aminal and macrocycle subunits, and has developed techniques for controlling configuration at a quaternary carbon in an oxindole. The approach allows late stage introduction and modification of the macrocyclic peptide ring. Advances in methodology will be pursued, including further studies of lithiated aziridines, oxazole activation, aryl triflate coupling to assemble amino acids in a complex setting, enolate amination, and macrocyclic peptide ring closure.