Divergent Annulations and Applications of Imidazo-Fused Azines and 2-Aminoimidazoles
Violette 210
Title: “Divergent Annulations and Applications of Imidazo-Fused Azines and 2-Aminoimidazoles”
Advisor: Dr. Sivappa Rasapalli, Chemistry & Biochemistry Dept., University of Massachusetts Dartmouth
Committee Members: Dr. Catherine Neto, Chemistry & Biochemistry Dept., University of Massachusetts Dartmouth & Dr. Akbar Ali, Biochemistry and Molecular Biotechnology Dept., UMass Chan Medical School
Abstract: The 2-aminoimidazole (2-AI) motif is the structural core of the pyrrole-imidazole marine alkaloids, including oroidin, sceptrin, and ageliferin. Its high polarity, tautomeric instability, and crowded nitrogen framework make regioselective synthesis and late-stage modification difficult. Beyond natural products, imidazoles and imidazo-fused azines are also common structural features in approved drugs and clinical candidates, adding practical motivation to solve this synthetic problem. This dissertation proposes a synthetic platform built around a 2-aminopyri(mi)dine bearing a carbon-based reactive handle (imine, formimidine, acetamidine, guanidine, etc.). This handle enables an ionic annulation through an ammonium ylide intermediate to form imidazo[1,2-a]azines. These bicyclic products are a stable, storable form of the target molecules, effectively a masked version of 2-aminoimidazoles. A Dimroth ring-opening reaction later releases the free, active 2-aminoimidazole on demand. Notably, the same carbon handle is shared across three distinct cyclization pathways, namely, ionic, radical-polar crossover (RPC), and hydrogen-atom-transfer (HAT). This dissertation work is divided into three Chapters/Aims.
Chapter/Aim 1 establishes the annulation pathways on azines such as pyrimidines and pyridines and defines their mechanistic limits. Chapter/Aim 2 applies the resulting building blocks to the synthesis of natural-product targets. The primary objectives are oroidin-type congeners, strepimidazoles, sceptrin, and ageliferin, while more ambitious extensions toward grossularines, dragmacidin cores, and ceratamine are pursued only after specific milestones are met. Chapter/Aim 3 evaluates matched pairs of fused and unmasked 2-AI compounds through three collaborative biological screening efforts: antibacterial and antibiofilm activity, anti-Naegleria fowleri activity with follow-up informed by the Arp2/3 pathway, and antifungal activity. Computational studies support all three aims as needed, guiding reaction design, helping distinguish between competing mechanisms, modeling/designing the leads, and analyzing the structure-activity relationships. The expected outcome is a dissertation that unites mechanistic methodology development, natural-product synthesis, and biological evaluation into a single coherent body of work.