School of Chemistry - Theses

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    The Development of Methods to Install and Diversify Carbonyl Derivatives via Radical Intermediates
    Guan, Xiaocong ( 2023-10)
    Alkyl carboxylic acids play a crucial role as pharmacophores in drug molecules. The current method for obtaining alkyl carboxylic acids primarily limited to the hydroxylation of carboxylic acid derivatives. Therefore, developing innovative approaches to directly install carboxylic acid is very meaningful for pharmaceutical molecular synthesis. The most efficient way to incorporate this motif is through direct carboxylation of the substrate. Traditionally approach involves preparing highly reactive Grignard reagents from alkyl halides, which had limitations in terms of functional group tolerance. Previous work by the Polyzos group demonstrated that transition metals such as palladium could selectively activate C(sp3)-H bonds by forming palladacycle complexes with the assistance of directing groups. However, the insertion of CO2 into the palladacycle was found to be unfavourable. Therefore, CO2 surrogate was employed to explore direct C(sp3)-H carboxylation based on the palladacycle complex. Another approach to construct alkyl carboxylic acids is through the hydrocarboxylation of double-bond systems, which can be achieved by using umpolung strategy. Although reaction systems utilizing photochemistry and electrochemistry have been reported for the hydrocarboxylation of double bonds, these methods are specific to certain double bond system, and most electrochemical methods require sacrificial anodes to stabilize the carboxylic anion. Chapter 1 is a literature review, in which two direct carboxylic acid installation approaches, C(sp3)-H carboxylation and hydrocarboxylation of double bond systems, are introduced. The challenges of C(sp3)-H carboxylation and limitations of current hydrocarboxylation examples were highlighted. Next, the principles of photocatalysis, electrochemistry and continuous flow chemistry are discussed. Finally, the general objectives of this PhD thesis are subsequently elaborated. Chapter 2 explores direct C(sp3)-H carboxylation using carbon tetrabromide as a CO2 surrogate. This approach builds upon previous work by the Polyzos group on auxiliary-directed C(sp3)-H arylation through synergistic photoredox and palladium catalysis. To check the feasibility of this reaction design, the exploration was started with the palladacycle, which is the key intermediate for the previous arylation reaction. During the exploratory studies, both carboxylation and carbonylation product were obtained under the photoredox reaction system. Although the selectivity issue was eliminated by adopting a direct excitation of the palladacycle complex, which favours the annulation pathway, only moderate yield was obtained. Chapter 3 investigates the hydrocarboxylation of double bonds to access alkyl carboxylic acid construction. Electrochemical approach was employed to address the challenging reduction of the double bonds. Furthermore, due to the CO2 gas was employed as the carboxylation source, the continuous flow technology was incorporated to better manage the multiphase reaction, which could also potentially circumvent the decarboxylation issue by precisely control the residence time. Following optimization, the reaction exhibits excellent functional group tolerance and this hydrocarboxylation procedure broadly covers C=N, C=O, C=C systems. Mechanistic study indicates the carboxylic acids are primarily formed through the nucleophilic attack of the carbanion on the CO2. In Chapter 4, a chemoselective reduction procedure of carbonyl compounds in continuous flow was developed, based on the disparities observed in the primary byproducts during the hydrocarboxylation process of C=N and C=O bonds described in Chapter 3. The umpolung strategy, wherein the ketyl undergoes the radical polar crossover under specific flow-electrochemical conditions, is employed to solve the homocoupling issue in the carbonyl reduction process. Both aromatic or aliphatic ketones and aldehydes, are viably reduced to the corresponding alcohols in good to excellent yields with broad functional group tolerance. Quantitative deuterium incorporation indicates the radical polar crossover was effectively achieved. Chapter 5 provides detailed experimental procedures and spectroscopic data for all isolated compounds throughout the thesis.
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    Synthesis of histrionicotoxin analogues using coventional and continuous flow approaches
    Johnson, Brian A. ( 2011)
    The histrionicotoxins are a family of alkaloids, originally isolated from the skin extracts of the amphibian Dendrobatidae histrionicus, that display non-competitive inhibition of the nicotinic acetylcholine receptor. The biological activity of these compounds, combined with a protected natural source, has given rise to considerable interest from a synthetic chemistry standpoint. This manuscript describes the synthesis of 6,6,5-isoxazolidine scaffolds of the histrionicotoxin spirocycles, from bis-α,β-unsaturated nitrile intermediates of well defined stereochemistry, using both conventional batch-type and continuous flow techniques. A library of both racemic and enantiomeric examples of perhydrohistrionicotoxin and its conformationally restricted precursors has been synthesised. Additionally, analogues of perhydrohistrionicotoxin, one example bearing an epimeric centre and other species furnished with pendant side chains of increased length have been synthesised.