Thesis (M. Sc.)--University of Hong Kong, 1964. / Typewritten.

The central focus of this dissertation pertains to the synthesis and study of novel N-Heterocyclic carbene architectures. This pursuit has led to advances in carbine structure and bonding, and application of NHCs in materials chemistry in the role of monomer and catalyst / text

Ricin is a potent cyctotoxin with no known antidote. Chapter 1 provides background and context for this thesis, which is primarily focused on probing the active site of Ricin toxin A (RTA). Relevant information about Ricin, its use, method of action, and noteworthy contributions towards the discovery of Ricin A chain inhibitors are provided. Furthermore, a brief description of the assays used by our collaborators to monitor RTA inhibition is provided. Additionally, a great deal of this thesis pertains to a particular heterocycle, pterin, and thus the remainder of Chapter 1 is dedicated to pterins, their physical properties, biological relevance, and selected reports of pterin chemistry. Chapter 2 details preliminary research focused on the use of nucleic acid-based platforms as RTA inhibitors. Two specific nucleic acids were chosen, adenine and guanine, and the chapter is split to address them individually. Rational for their use is provided, as well as the synthetic strategies investigated. Both platforms showed significant interference with the analysis assay, most pronounced for the adenine series. A primary goal throughout this thesis is the identification of a simple, rapid method to provide a library of new compounds. To this end, discussion of improved synthetic routes are provided within the section dedicated to guanines. Initial investigation into pterins as a platform for RTA inhibitors is provided in Chapter 3. Much of this chapter is concerned with hurtles encountered while dealing with the poor solubility of pterins, purification, and limits in reaction scope. Finally this chapter details a significant discovery in pterin's utility, both in terms of synthetic ease and preference towards one regioisomer over another. A variety of amides are initially used to probe the active site for significant interactions to the pterin pendents. Chapter 4 builds off the discoveries detailed within the previous chapter. Efforts to optimize the preliminary amide series from Chapter 3 are described, leading to a significant enhancement in activity. Additionally, Chapter 4 describes a synthetic breakthrough which greatly enhanced the speed of synthesis and complexity of the designed pterin inhibitors. Building upon the goal to map the RTA active site, a description of various peptide conjugated pterins is provided, as well as efforts to arrive at optimized isosteres of the most promising peptide derivatives. / text

published_or_final_version / Chemistry / Master / Master of Science

Not available / text

A unifying theme of the chemistry presented is the synthesis, study, and application of a novel N-heterocyclic carbenes. Pursuit of these materials has resulted in new advances in carbene structure and bonding, the discovery of highly-efficient reactions, and the development of new polymers with unusual properties. / text

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The synthesis of 1-methyl-promazine, 4-hydroxymethyl-iminodibenzyl, and 4-bromo-5-trimethylsilyl-iminodibenzyl via dilithiation and ¹H-NMR's are described. Molecular modeling was done for the latter compound. The heat of dissociation was 30.6 kcal/mole for the lowest energy conformer. Rotational energies were examined for three bonds. The IC₅₀ values for inhibition of neurotransmitter uptake by rat brain synaptosomes were determined for a series of 1-substituted promazines, and 4-substituted imipramines. 1-Substituted promazines were fair inhibitors of serotonin uptake with an average IC₅₀ of 2000 nm. Their potency for inhibiting norepinephrine uptake was difficult to assess due to poor assay reproducibility, and the average IC₅₀ was estimated at 200 to 1700 nm. Serotonin, but not norepinephrine, uptake inhibition was increased with additional ring substitution at C(2) with a trifluoromethyl group. The 4-substituted imipramines were equal or slightly decreased in potency to unsubstituted imipramine for uptake inhibition of both neurotransmitters. IC₅₀'s were also reported for imipramine and desipramine.

A summary of tin hydride mediated reactions in generating radicals in organic synthesis is presented, together with some of the many alternative methods now available for conducting radical reactions. Particular attention has been given to the iminyl radical and the development of tin-free organic radical precursors. This introduction is followed by three chapters describing research on the development of two new sources of iminyl radicals and their application in syntheses of aza- heterocyles. O-Phenyl oxime ethers are the first iminyl radical precursors described in the thesis. Microwave thermolyses of oxime ethers released iminyl and phenoxyl radicals under comparatively mild conditions and with short reaction times. Few microwave-assisted synthetic methods, based around radical intermediates, are known. The mild and neutral conditions associated with radical chemistry, and the ability of radicals to perform intramolecular cyclisations, together with the virtues of MAOS, make their combination a very useful tool in syntheses of aza-heterocycles. A comprehensive study of intramolecular additions of iminyl radicals onto several radical acceptors, alkenes, alkynes, phenyl rings and indoles, is described. Furthermore, a wide range of nitrogen heterocyles with potential biological activity was prepared making use of this methodology. Intramolecular iminyl radical cyclisation onto imines via microwave irradiation was another process extensively studied. Microwave assisted syntheses of dihydroquinazolines and quinazolines are described. The precursor O-phenyl oxime ethers enable imine formation to be assimilated with iminyl radical generation before subsequent cyclisation. Clean, fast and high yielding methodology was therefore developed for the syntheses of these highly interesting heterocycles which form the basis of many pharmaceutical products. Dioxime oxalates were the second type of precursor investigated as sources of iminyl radicals. Homolytic cleavage of their N-O oxime bonds occurred on photolysis releasing two molecules of CO₂ and two iminyl radicals in a clean and atom-efficient process. A facile route to dioxime oxalates with a range of radical acceptors in suitable positions is described. ESR spectroscopy was used to demonstrate that dioxime oxalates dissociate on photolysis to give iminyl radicals in the presence of photosensitizer. This technique also confirmed the proposed mechanisms of radical cyclisation onto double bonds and several 2-azacyclopentylmethyl radicals were characterized by ESR spectroscopy. In several instances both the uncyclized iminyl radical, and the cyclised C-radical, could be simultaneously detected, and their concentrations determined. ESR spectroscopy was then profitably used to determine 5-exo-cyclization rate constants of iminyl radicals onto double bonds. Finally, the syntheses of several heterocycles from dioxime oxalates are described. Photolytic dissociation of dioxime oxalates containing alkenyl groups yielded iminyl radicals that ring closed to 3,4-dihydro-2H-pyrroles in toluene solution. The syntheses of phenanthridines, and the natural product trisphaeridine, were also accomplished by UV irradiation of dioxime oxalates containing aromatic rings as the radical acceptor.

No description available.