Electronic effects on Bergman cyclization and synthesis of novel enediyne analogues as potential DNA selective cleavage molecules for anticancer agents

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)

First Committee Member

Keith C. Russell - Committee Chair


The first part of this thesis (chapters 1--5) demonstrates electronic effects on Bergman cyclization and its utilization, and the second part (chapter 6) describes our research pursuits toward the synthesis of 5,6-diethynyluridine. More closely, chapter 1 details the chemistry of Bergman cyclization and naturally occurring enediynes. Existence of electronic effects on Bergman cyclization has been confirmed via introduction of electron negative atoms, nitrogen(s) in several arenediynes in chapter 2, and its dependency of solvent is demonstrated in chapter 3. Furthermore, in chapter 4, the electronic effects are more closely examined by a linear free energy correlation using the Hammet Equation and the Swain-Lupton model. The experimental data in these three chapters clearly support the hypothesis that electronic effects are an important factor to determine Bergman cyclization reactivities, thus, providing additional useful tools to researchers in the field of enediyne-based prodrug research. Then, in chapter 5, tautomerization was utilized as a triggering mechanism for the Bergman cyclization of 5,6-diethynyluracil as a part of an effort to incorporate such electronic effects into the development of simple enediyne prodrugs.Additionally, detailed discussions of the complete kinetic models for Bergman cyclization are included. Experiments demonstrate that the Bergman cyclization of 26 and 67 were independent of the 1,4-CHD concentration, suggesting the benzannellation is not important for the tautomer analogues studied in this thesis. These results are discussed with respect to the known kinetic models.Finally, synthesis of 5,6-bis(trimethylsilylacetyl)-2',3 '-O-isopropylidne-5'- O-tert-butyldimethysilyluridine, the first diethynyluridine is described. This work is compared to a route later reported by Robins et al. (Tetrahedron Lett. 2000, 41, 8741--8745).


Chemistry, Organic

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