Graduation Semester and Year
Fall 2025
Language
English
Document Type
Thesis
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Prof. Carl J. Lovely
Second Advisor
Prof. Purnendu Dasgupta
Third Advisor
Dr. Frank W. Foss
Fourth Advisor
Dr. Jongyun Heo
Abstract
This dissertation describes an exploration of the chemistry of heterocyclic building blocks directed towards the total synthesis of members of the oroidin alkaloids. The oroidin alkaloids are secondary metabolites that naturally occur in deep-water marine sponges and consists of two distinct heterocyclic frameworks, imidazole and pyrrole, hence, they are classified as pyrrole–imidazole alkaloids. The first section describes approaches to the oroidin dimer, ageliferin, an amino-imidazole-fused six-membered carbocycle with three contiguous stereocenters through a bioinspired [4+2] cycloaddition. The second part of this dissertation describes a novel approach leveraging thioacid-azide chemistry to access the basic oroidin monomers. This approach is unique and chemoselective that can be harnessed for the total synthesis of more complex pyrrole-imidazole natural products.
Chapter 1 provides an overview of prior total syntheses of the pyrrole–imidazole alkaloid ageliferin. It begins with an introduction to pyrrole–imidazole alkaloids and ageliferin itself, followed by a review of previously accomplished total synthesis of ageliferin by several research groups.
Despite several successful efforts, the collective process was inefficient in terms of yield, complexity, and scalability. To address these issues, our group initially hypothesized few strategies, discussed in Chapter 2, which are refered to as our first-generation approaches based on a putative biosynthesis. These attempts successfully led to the formation of advanced bis-imidazole intermediates. However, conversion of these intermediates into the natural product was not achieved. Although, highlighting the key challenges and limitations encountered in each pathway, the insights gained from these preliminary studies proved invaluable in shaping the design of our current synthetic strategy.
Integrating the insights from the first-generation approaches, we adopted new strategies, referred to as the second-generation approaches, discussed in Chapter 3. This effectively overcomes the limitations encountered in the first-generation routes, and we achieved the synthesis of very late stage ester mediates en route to ageliferin. The current route is strategically designed to minimize the number of steps and reduce overall synthetic complexity. In this strategy, the intramolecular Diels–Alder (IMDA) reactions of both 4-vinylimidazoles (containing different types of electron donating and electron withdrawing groups) and imidazopyrimidine systems were explored, leading to the successful and a stereoselective formation of a tetrahydrobenzimidazole core containing an N–N bonded framework, along with the development of various methods for its reduction. Overall, this work highlights methodological advancements and the establishment of advanced intermediates that can be further utilized for the synthesis of other complex pyrrole–imidazole family of natural products.
While working on the total synthesis, we realized that the late-stage introduction of the pyrrole–carboxamide can be challenging, especially when the substrate is more complex. To address this issue, our group introduce a novel method for late-stage pyrrole–carboxamide bond formation in Chapter 4. Notably, the thioacid-azide ligation (TAL) reaction is well established for the formation of carboxamide bonds in simple aliphatic and aromatic systems. We harnessed TAL-chemistry on a range of imidazole substrates, resulting in successful thioacid-azide ligation to 4-vinylimidazole derivatives. While this ligation was effective for accessing simple pyrrole–imidazole monomers, it was not achievable in a single step and required two distinct thioacid precursors, thereby reducing overall efficiency.
To circumvent the shortcomings of harnessing TAL-chemistry to achieve the pyrrole-carboxamide bond formation in a single step, we introduce an imidazopyrimidine precursor, discussed in Chapter 5. Here we illustrate the TAL-chemistry on vinyl imidazopyrimidine substrates which deliver oroidin congeners with a single thioacid-azide ligation, thereby underscoring its broader potential in natural product synthesis.
Keywords
Natural Products, Pyrrole - Imidazole Alkaloids, Total Synthesis, Ageliferin, Thioacid - Azide Ligation, Oroidin monomer, hymenidine, Imidazopyrimidine, N-N reduction, Nagelamide C
Disciplines
Heterocyclic Compounds | Organic Chemicals | Pharmaceutical Preparations | Polycyclic Compounds
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Dey, Nilakshi, "Studies Towards a Total Synthesis of Ageliferin and Construction of Fundamental Building Blocks of Pyrrole-Imidazole Alkaloids Using Thioacid-Azide Ligation" (2025). Chemistry & Biochemistry Dissertations. 295.
https://mavmatrix.uta.edu/chemistry_dissertations/295
Included in
Heterocyclic Compounds Commons, Organic Chemicals Commons, Pharmaceutical Preparations Commons, Polycyclic Compounds Commons