Date of Award

6-2011

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry/Green Chemistry

First Advisor

Bela Torok

Second Advisor

Jonathan Rochford

Third Advisor

Marianna Torok

Abstract

Heterocyclic and organofluorine compounds play a crucial role in human life, since they have exceptional biological activities. The traditional methods for their synthesis usually do not comply contemporary safety and environmental regulations. The goal of this work was to design new, safer and environmentally benign methods for synthesis of heterocyclic and organofluorine compounds for biological applications.

Initially work was focused on using solid acid catalysis for the synthesis of heterocyclic compounds. A new method was developed for the diastereoselective preparation of cis-aziridines from imines and ethyl diazoacetate using K-10 as catalyst. The reaction provided the products in excellent yields and exclusive selectivity. The same K-10 catalyst with combination of microwave irradiation was applied for the cyclocondensation of alkylhydrazines to alk-3-yn-1-ones leading to 1,3,5-trisubstituted pyrazoles in excellent yields. In both reactions the catalyst could be recycled and used in subsequent reactions without significant loss of activity.

Then we developed environmentally benign methods for the synthesis of organofluorine compounds. We designed a new method for synthesis of aryl-3,3,3-trifluoropropenes by Wittig olefination of ylides with trifluoroacetaldehyde ethyl hemiacetal. We also developed the first asymmetric synthetic preparation of trifluoro-1-(indol-3-yl)ethanols by an enantioselective hydroquinine-catalyzed reaction from indoles and inexpensive trifluoroacetaldehyde methyl hemiacetal. Trifluoro-1-(indol-3-yl)ethanols were produced in excellent yields and good enantioselectivities.

In the next two projects we worked on the biological applications of heterocyclic and organofluorine compounds. A highly diastereoselective microwave-assisted multicomponent synthesis of azabicyclo[2.2.2]octan-5-ones by a silicotungstic acid-catalyzed aza-Diels-Alder cyclization has been developed. The focus was on using a green catalyst and alternative source of energy. Preliminary assays were performed to determine the activity of the products in acetylcholinesterase enzyme as well as in amyloid beta self-assembly.

Finally the molecular docking of a broad variety of pyrrole, indole and pyrazole-based fructose 1,6-bisphosphatase inhibitors has been carried out and the potential of these compounds has been evaluated. 5 heterocyclic and organofluorine compounds were selected, synthesized and tested in the inhibition of the FBPase enzyme. The best inhibitor showed an IC50 value that was better than that of AMP, the natural inhibitor of FBPase, by over two orders of magnitude.

Comments

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