Abstract
The nitroaromatic scaffold has been a cornerstone for prodrugs used in cancer and infectious disease. After initiating prodrug activation, an electrophilic azaquinone methide intermediate is formed and can react with essential biomolecules, such as protein residues (e.g. lysine), glutathione, and DNA, to convey toxicity. The Gamble group has previously implemented a nucleophilic handle appended to the nitroaromatic scaffold, which can quench the azaquinone methide in a self-immobilising cyclisation. Previous research has been limited to six-membered ring formations of tetrahydroisoquinolines (THIQs) and phenanthridines. However, recent research has expanded to investigate the formation of seven-membered rings for the formation of benzodiazepine-type scaffolds. This thesis expands upon the synthesis of benzodiazepine scaffolds and biaryl-derived phenanthridines through the generation of (aza)quinone methides using Zn/AcOH as the model reductant of nitroaromatic to the self-eliminating aniline.
In Chapter 2, the synthesis of benzodiazepine analogues through the reduction of nitroaromatic-amino acid conjugates and a 7-endo-trig cyclisation of an amine with the generated azaquinone methide was investigated. Three amino acids (valine, phenylalanine, and N-phenylglycine) were used to synthesise three benzodiazepine analogues, and their cyclisation was supported by crude NMR and HRMS data. However, NMR did not provide conclusive evidence as the crude spectra obscured the key benzylic peak. Future work will focus on improving the purification of these polar 1,4-benzodiazepine-type compounds through reverse-phase flash chromatography.
In Chapter 3, acyclic biaryl-based precursors were utilised to investigate the nucleophilicity of aniline in generating polycyclic (tricyclic) compounds via a 6-endo-trig cyclisation. The di-nitro-substituted biaryl precursor was synthesised via a Suzuki-Miyaura cross-coupling. Synthesis of a pyridine-derived phenanthridine was attempted, yielding the 5,6-dihydrophenanthridine in ~16%. Previous work demonstrated oxidation to the full aromatic phenanthridine upon exposure to air; therefore, the more electron-deficient pyridine scaffold likely hinders this oxidation step. When compared to previous aniline nucleophiles, apparent inefficiency in yield was demonstrated (~16% vs ~80%), likely because of inductive and mesmeric effects of the pyridine.
Overall, this thesis expanded the application of in situ azaquinone methide generation and self-immobilisation to novel 7-endo-trig (benzodiazepines) or 6-endo-trig (phenanthridine) cyclisation products. The structures of benzodiazepine analogues were not confirmed, with future work focused on improving purification methods to ensure clean NMR spectra. In contrast, the polycycle was confirmed via 2D NMR and HRMS, providing insight into the relative efficiency of nucleophilic aniline handles. This work demonstrates the potential of this methodology and opens new avenues, including diverse substitution patterns, larger fused systems, and alternative applications (e.g. click chemistry).