3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Application of biocatalysts in the synthesis of anti-tuberculosis compounds and analogues(2022) Maphupha, Mudzuli MaxwellThe current advancements in genomic engineering and DNA technology have expanded the range and applications of enzymes in synthetic organic chemistry. Biocatalytic transformations continue to replace traditional chemical methods at an exponential rate. With the world now faced with various sustainability and climate change challenges, synthetic chemists need to rethink how we might prepare important target molecules in the future. In this thesis, we present an overview of the design, investigation, and application of enzyme biocatalysts towards the synthesis of important active pharmaceutical ingredients, placing a particular interest in anti-tuberculosis drugs. The target molecules in this work include benzimidazole and benzothiazole fused to triazole rings (part one) and quinazolinone derivatives (part two). The enzymes of focus in this study include commercially available biocatalysts—Laccases (EC1.10.3.2), Nitrile hydratases (EC 4.2.1.84), and Lipases (E.C. 3.1.1.3). The synthesis of hydroxy 2-aryl-1H-benzimidazoles and 2-arylbenzothiazoles from the cyclisation and oxidation reaction of arylamines and hydroxy benzaldehydes was investigated using laccase as an oxidant. Subsequently, the obtained hydroxy heterocycles were treated with potassium carbonate and propargyl bromide in acetone to form 2-aryl-1H-benzimidazole and 2-arylbenzothiazole ether alkynes in decent yields. A novel approach for synthesising triazole rings through the laccase-catalysed 1,3- dipolar cycloaddition reaction between alkynes and azide derivatives was outlined. By treating the obtained 2-aryl-1H-benzimidazole and 2-arylbenzothiazole alkynes with phenyl-azides in the presence of a catalytic amount of laccase (Trametes versicolor), target benzothiazole and benzimidazole fused 1,2,3-triazole derivatives were achieved. Our method effectively catalysed the condensation reaction for a broad range of substrates, yielding both the 1,4-Disubstituted-1H-1,2,3-triazoles and the 1,5- disubstituted-1H-1,2,3-triazoles in adequate to moderate yields. For the first time, we present a novel multistep biocatalytic process for the synthesis of novel quinazolinone derivatives. We effectively catalysed the hydrolysis of nitriles to amides using whole cells containing nitrile hydratase. This is then followed by a condensation reaction between the obtained amides with aldehyde esters using microwave irradiation and a novel laccase/DMSO oxidation to obtain quinazolinone esters in excellent yields. Subsequently, we hydrolysed the quinazolinone esters to acids using immobilised lipase (CAL B). Finally, using HBTU as a coupling reagent, we effectively catalysed the direct amidation reaction of the quinazolinone acid to obtain the target quinazolinone amide derivatives in excellent yields.Item Application of laccase enzymes in organic synthesis(2018) Maphupha, Mudzuli MaxwellThe use of enzymes as catalysts in various synthetic procedures appears to be an economical and profound way of providing selective processes in synthetic organic chemistry. Enzymes provide alternative and sustainable processes and have helped to avoid limitations encountered when using traditional heterogeneous and homogeneous catalysts; this includes the use of toxic substances, use of expensive heavy metals, extensive use of harmful organic solvents, harsh reaction conditions, and also poor selectivity of many catalysts. Laccases are oxidoreductase enzymes capable of catalysing oxidation reactions of several low molecular weight organic compounds such as polyphenols, aminophenols, methoxyphenols, polyamines, and lignin-related molecules. The catalytic process of these enzymes occurs though a one-electron oxidation and water is released as the only by-product. In this project we investigated the range and limitations of applications of laccase enzymes in organic synthesis. The project focus was on method development for cross-coupling reactions of Carbon, Nitrogen, Oxygen, and Sulphur substituted aromatic compounds. The laccase facilitated synthesis of five classes of compounds; biaryl compounds, benzoxazoles, benzimidazoles, benzothiazoles, and aminobenzoquinones, was investigated. The research explored the synthesis of biaryl compounds from simple substituted phenol substrates. The optimal reaction conditions for the synthesis of biaryl compounds from simple phenols were investigated. A condensation reaction between 2-aminophenol and aryl aldehyde derivatives was performed with the aim of synthesising 2-arylbenzoxazole derivatives; however various aminophenol derivatives were formed as the phenolic Schiff base failed to cyclise. Alternatively, when including the laccase-mediator ABTS, dimerization of 2-aminophenol to 2-amino-3H-phenoxazin-3-one (4) occurred. A chemo-selective method for the synthesis of 2-aryl-1H-benzimidazoles from condensation of 2-phenelynediamine and aryl aldehydes was developed using laccase as an oxidising catalyst. Optimal conditions for synthesising 2-aryl-1H-benzimidazoles were identified while using acetate buffer (0.1 M, pH 4.5), acetonitrile as a co-solvent and the commercial laccase preparation Novoprime base 268. A modern and practical laccase-catalysed route suitable for the synthesis of 2-arylbenzothiazoles was developed. To the best of our knowledge, the laccase catalysed method for preparation of 2-arylbenzothiazole derivatives derived from condensation–dehydration reaction of 2-aminothiophenol with aryl-aldehydes has not been reported before. The method described is green, effective and simply requires a facile work-up routine, utilising solvents such as acetonitrile and DMF as co-solvents. Finally, factors limiting yields for the synthesis of aminobenzoquinones were investigated by varying the reaction conditions. The laccase catalysed nuclear diamination of aromatic hydrobenzoquinones with aliphatic and aromatic amine molecules was investigated under mild reaction conditions using commercial laccases from Novozymes (Suberase®, Denilite® II Base, and Novoprime Base 268). Conducting the reactions under dilute conditions, sequential addition of enzyme and substrate over time and using Novoprime Base 268 as our laccase increased the yields to up to 100%.