Graduation Semester and Year
2022
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Carl J Lovely
Abstract
Natural products have inspired researchers over the years due to their complexity and biological activity. Organic chemists have made great efforts to investigate new unambiguous methodologies toward the synthesis of these complex structures. Moreover, the synergy between total chemical synthesis and medicinal applications to evaluate the biological activity of the isolated compounds significantly raised the desire for discovery of novel synthetic approaches. The research described in this dissertation focuses on oxidative dearomatization reactions as a key reaction to construct natural products. The three specific aims are as follows: Aim 1: investigation of the applications of oxidative dearomatization reactions for different classes of molecules using environmentally benign hypervalent iodine reagents and electrochemical oxidation conditions. Aim 2: investigating an oxidative dearomatization reaction to construct the core scaffold of the tris guanidine natural product, KB343. Aim 3: studying the validation of our developed synthetic method towards thiazolidine and benzothiazole structures and investigating their biological activity as antiproliferative and GABA regulator agents, respectively. The dissertation contains two parts. The first part discusses the oxidative dearomatization reactions of urea, thiourea and guanidine derivatives, while the second part focuses on developing novel stable thiazolidines and their antiproliferative activity. Chapter one describes and summarizes the oxidative dearomatization literature. Chapter two focuses on the development of oxidative spirocyclizations of N-aryl urea, N-aryl thiourea and guanidine derivatives, and includes a DFT investigation of the putative cyclization mechanisms. Oxidative dearomatization reactions of nonphenolic thiourea derivatives produce benzothiazole derivatives, which serve as a novel synthetic methodology for this intriguing ring system. Chapter three discusses how electrochemical oxidations are considered a realistic solution to solve issues observed by the conventional hypervalent iodine oxidations. In addition, it discusses an investigation of the stabilizing effect of N-alkoxy group on the nitrenium ion formation, which resulted in improving the isolated yields and the chemoselectivity of C-X bond transformations. In chapter four, we evaluate “oxidative dearomatization methods” to construct the KB343 core structure on vinyl guanidine candidates. The key Grignard reaction towards synthesis the targeted guanidine is still ongoing. Also, new synthetic methodology towards N-methoxy hydantoin construction is uncovered via three-component reaction. Chapter five discusses the biological activity of the synthesized benzothiazoles as a potential antiepileptic agent. The second part of the dissertation reports the development of novel thiazolidine derivatives and investigating their antiproliferative activity as presented in chapters six, seven, and eight. We further validated our previously reported solid support methodology with substituted propargyl amines and a series of aryl isothiocyanate derivatives to isolate chemically stable anticancer candidates. The progress of this portion discusses the synthesis of three thiazolidine libraries and the third group was the most chemically stable which is discussed in chapter eight. Three different carcinomic cells were utilized for testing the anti-proliferative activity including breast, colon, and esophageal cell lines. Investigation of the apoptotic mechanism revealed that the thiazolidines probably block the phosphorylation of extracellular signal-regulated kinases (ERK).
Keywords
Oxidative dearomatization, KB343 natural product, Thiazolidines, Benzothiazoles, Hydantoin construction, GABA receptor, Computational techniques, Molecular docking, Medicinal chemistry
Disciplines
Chemistry | Physical Sciences and Mathematics
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Awadalla, Marian, "Synthetic studies on oxidative dearomatization reactions and applications in synthesis of the KB343 core structure, and investigation of bioactive thiazolidines" (2022). Chemistry & Biochemistry Dissertations. 216.
https://mavmatrix.uta.edu/chemistry_dissertations/216
Comments
Degree granted by The University of Texas at Arlington