Design, synthesis and study of Bergman cyclization of novel enediyne analogues

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)



First Committee Member

K. C. Russell - Committee Chair


Ever since the discovery of the naturally occurring enediyne. anticancer antibiotics, there have been many reports of potential mimics of enediyne natural products. This dissertation has been focused on the design, synthesis and study of Bergman cyclization of novel enediyne analogues.In order to examine the detailed electronic contributions to Bergman cyclization, a series of 4-substituted-1,2-diethylnylbenzenes were prepared and subjected to Bergman cyclization. Kinetic experiments showed a linear free energy relationship between the cyclization rate and the Hammett a substituent parameters. Lumazine derivatives appended with ethynyl groups in C7 and C8 positions were synthesized and examined for their ability to undergo Bergman cyclization. The lactam tautomer showed a shorter half life than the lactim tautomer. The synthesis of alkynyl-flavins is described. The reduction potentials of these compounds are in good agreement with the values expected based on the Hammett substituent parameters.In order to improve the DNA cleaving activity while retaining synthetic simplicity of the designed enediynes, simple cyclic enediynes have been prepared. Novel 10-membered pyrimidine-enediynol and -enediynone were synthesized, and compared for their abilities to undergo Bergman cyclization either thermally or photochemically. The pyrimidine-enediynol readily cyclized both thermally and photochemically. On the other hand, the pyrimidine-enediynone thermally cyclized with a reasonable rate at 40°C, but did not undergo efficient photochemical cyclization. The pyrimidine-enediynol showed better DNA cleavage than -enediynone under photochemical conditions, while the enediynone showed better DNA cleavage under thermal conditions. The novel 10-membered uracil-enediynol was also synthesized and compared for its ability to undergo Bergman cyclization with 10-membered pyrimidine-enediynol under thermal conditions. Uracil-enediynol showed a shorter half-life and better DNA cleavage ability than pyrimidine-enediynol under thermal conditions. The activation energies of uracil-enediynol and pyrimidine-enediynol were determined under the different dependency on radical trapping agent (1,4-CHD). Benzannelation effect between non-aromatic enediyne (uracil-enediynol) and aromatic enediyne (pyrimidine-enediynol) was studied at several concentrations of radical traping agent. The uracil-enediynol was independent on the concentration of 1,4-CHD while pyrimidine-enediynol was dependent.


Chemistry, Biochemistry; Chemistry, Organic

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