Studies towards the synthesis of tricyclic alkaloid scaffolds for potential medicinal applications

Abstract

Polycyclic alkaloids are valued, diverse medicinal targets which are sought after in drug discovery for their bulky nature and their wide range of pharmaceutical applications. Their rigid, three-dimensional frameworks can support selective interactions with biological targets. Many naturally occurring members of this broad class display antimicrobial, antifungal, or antitumor activity. Yet conventional syntheses of complex polycyclic frameworks often require long sequences and may provide limited access to analogues. This thesis therefore examines several strategies for converting nitrogen-containing alkaloid precursors into more complex tricyclic heterocycles. Three ring-closing strategies were examined across benzimidazole-, indole-, and imidazo[1,2-α]pyrimidine-based substrate families. Acid-promoted aza-Nazarov cyclization was evaluated with conjugated enones or α-ketoamides designed to act as double-bond equivalents. Bromine-induced cyclization through a halonium-ion intermediate and hypervalent iodine (III) reagent-mediated carbon–nitrogen bond formation through a nitrenium-ion pathway were also investigated. Structures and reaction outcomes were assessed by nuclear magnetic resonance spectroscopy and, where available, X-ray crystallography. Under the conditions tested, none of the three approaches gave confirmed spectroscopic evidence of the intended ring-closed tricyclic product. Instead, the experiments defined substrate-dependent limitations: bromination favored a dibrominated product, acid-promoted reactions generally returned starting material, and the PIFA reaction remained inconclusive because the isolated material was impure. These results establish the accessible precursor chemistry, identify likely barriers to annulation, and provide a documented basis for further condition development without overstating the extent of cyclization achieved. Chapter 1 describes the medicinal relevance of these three heterocyclic families, followed by a literature review on Aza-Nazarov cyclization, halide-induced intramolecular cyclization, and carbon-nitrogen coupling through nitrenium ions. Chapter 2 describes the preparation of benzimidazole-chalcones and evaluates three approaches to ring closure. Because the unprotected scaffold had resisted aza-Nazarov cyclization, N-tosyl protection was examined to alter protonation and activation. The conditions attempted returned starting material. Bromine-induced cyclization and PIFA-mediated nitrenium-ion coupling were tested as mechanistically distinct alternatives. Bromination led to dibrominated products, meanwhile with the addition of PIFA, a product was spotted on the TLC but due to impurities, could not be determined by NMR. Chapter 3 examines indole-derived α-ketoamides as nonclassical aza-Nazarov precursors. Acid screening returned starting material, and N-tosyl protection was introduced to probe whether the indole nitrogen contributed to the lack of reactivity. Finally, chapter 4 extends the study to imidazo[1,2-α]pyrimidine-chalcones and documents their preparation and behavior under several Brønsted- and Lewis-acid conditions, which have so far returned starting material. Bromine-induced cyclization was also attempted, yielding dibrominated structures rather than tricyclic products.