Synthesis and reactivity of enediynes
Hecnar, Tiffany Rose
Master of Science
Nitrogenous aromatic enediynes
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The discovery of a class natural products with anti-cancer properties, the enediynes, has stimulated interest in their research. Due to their cytotoxicity, these compounds are not feasible for use in cancer treatment, however, synthetic work has centered around improved stability, reduced toxicity and elucidation of the mechanism of the Bergman cyclization reaction. Protocols utilizing palladium-catalysed cross coupling reactions have been used extensively in the synthesis of enediyne analogues. Little work to date has investigated the effect of heteroatoms on the success of coupling reactions, thermal Bergman cyclizations and photochemically induced cyclizations. In this thesis, a synthetic study involving the coupling reactions o f nitrogenous aromatic halides, halotriflates and a series of alkynes will be presented. Several enediyne analogues were synthesized in moderate to high yields, isolated and characterized. In general, it was observed that nitrogen heteroatoms increase the reactivity toward Sonogashira coupling reactions. In order to examine the effect o f resonance and inductive effects on the reactivity under Sonogashira conditions, a series o f competitive reactions between m- or p-substituted aryl iodides and iodobenzene were performed. In general, electron withdrawing substituents in the m- or p-positions increased the reactivity, while electron donating substituents decreased it. It was observed that resonance effects have a larger effect on reactivity than inductive effects. Thermal and photochemical cyclization studies were performed for the nitrogenous aromatic enediynes synthesized. None o f the enediynes were observed to cyclize thermally, while only the TMS- and phenyl-substituted enediynes were observed to photochemically cyclize.