Graduation Semester and Year
Fall 2025
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Carl J. Lovely
Second Advisor
Junha Jeon
Third Advisor
He Dong
Fourth Advisor
Peter Kroll
Abstract
This dissertation reports the progress toward a convergent total synthesis of a marine natural product ceratinadin B. The synthesis is centered around the union of two key fragments: an unusual bis heterocyclic and novel imidazolyl-quinolone framework and a more common spiroisoxazoline. Also, described in this dissertation is the synthesis of several thiazolidine-based analogs exhibiting diverse biological activities and the synthesis, isomerization studies, characterization, and identification of the two constitutional 4H-chromene-based isomers formed through a multi-component one-pot reaction.
Chapter 1 provides an overview of prior efforts toward the total syntheses of a bromotyrosine-derived imidazolyl-quinolone containing alkaloid, ceratinadin B. It commences with a brief background to bromotyrosine alkaloids and ceratinadin B itself, followed by a review of previously attempted synthetic approaches towards the total synthesis of ceratinadin B.
These prior efforts resulted in a rather steppy route and intensive protecting group strategies toward the imidazolyl-quinolone fragment which inspired us to develop a more concise route as discussed in Chapter 2. The connection between the imidazole and the quinolone is quite unique in natural products and its construction is a key step. An initial approach via a Sonogashira cross-coupling reaction followed by hydration of alkyne provided an aryl ketone. Alternatively, a shorter approach to this ketone has been established by Friedel-Crafts acylation reaction. Subsequent alpha bromination followed by a Hantzsch-like cyclization installed the 2-aminoimidazole successfully along with variable traces of a net oxidation product, 2-iminoimidazole. To circumvent the byproduct formation, the incorporation of an imidazolyl-pyrimidine moiety was ultimately successful. Further, nitration and reduction afforded an aniline derivative which was used in a Gould-Jacobs reaction for construction of the quinolone which although showing promise requires further optimizing. Spiroisoxazoline construction was accomplished in thirteen steps starting from resorcinol. Finally, acid activation and condensation will lead to the total synthesis of ceratinadin B. Chapter 3 serves as a repository of experimental details supporting the studies discussed in Chapter 2.
Chapter 4 outlines the synthesis of several new thiazolidine-derived analogs via ene reactions of thiazolidine scaffolds and different enophiles such as nitrosobenzene, benzyne, ethyl glyoxylate and N-phenylmaleimide under thermal conditions. Additionally, two previously unreported methylidene thiazolidines have been prepared in this study and were employed in ene reactions utilizing same set of enophiles. Although, the pericyclic reaction could successfully afford several ene adducts with satisfactory yields, not all the methylidenes in the series were successful with benzyne and ethyl glyoxylate.
In Chapter 5, the synthesis and characterization of several chiral tetrahydro-4H-chromene derivatives as racemic mixtures of two constitutional isomers through a commonly used one-pot multicomponent reactions (MCRs). Although substantial research on 4H-chromene synthesis via MCR’s has been conducted, the formation and characterization of the structural isomers from diketones lacking a vertical plane of symmetry have likely been overlooked in prior studies. The existence of isomeric product pairs was evident from HPLC and HMBC results. Further kinetic analysis revealed the isomerization of these product pairs in aqueous environments, suggesting a similar interconversion may occur under physiological pH, therefore careful analysis is essential in related MCRs where multiple reaction pathway exists.
Keywords
Organic chemistry, Total synthesis, Heterocyclic chemistry, Marine natural products, Imidazolyl-quinolone alkaloid, Ceratinadin B, Gould-Jacobs reaction, Thiazolidines, Ene reactions, Tetrahydro-4H-chromene derivatives
Disciplines
Organic Chemistry
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Ghorai, Anasuya, "Studies Toward a Total Synthesis of Marine-Derived Imidazolyl-Quinolone Alkaloid Ceratinadin B and Access to Novel Thiazolidine-Based Analogs via Ene Reactions" (2025). Chemistry & Biochemistry Dissertations. 294.
https://mavmatrix.uta.edu/chemistry_dissertations/294