School of Chemistry (ETDs)

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Browsing School of Chemistry (ETDs) by Author "Bode, Moira L."

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    Diastereoselective conjugate addition reactions using diverse nucleophiles on a variety of Morita-Baylis-Hillman (MBH) adducts
    (University of the Witwatersrand, Johannesburg, 2023-09) Bhom, Nafisa; Bode, Moira L.
    The Morita-Baylis-Hillman (MBH) reaction involves the formation of a new carbon-carbon bond, generating an MBH adduct. These MBH adducts are multi-functional molecules, which can be used as synthons for the generation of complex and diverse compounds. The first part of the work described here involved the synthesis of a series of diverse ester and nitrile MBH adducts obtained as racemic mixtures. The MBH adducts were protected using different protecting groups, which could potentially control the diastereoselectivity and the formation of alternative products in the subsequent conjugate addition reaction. Conjugate addition reactions were performed on the protected MBH adducts using different nucleophiles to obtain the product as diastereomers. These reactions were monitored to detect whether diastereomers were obtained or not. The diastereomeric ratios obtained using different substrates, protecting groups and nucleophiles were determined. The best diastereomeric ratio was 3:1, obtained for the piperidine and benzylamine addition on the TBDMS protected nitrile adducts 192a/b and 196a/b. The addition of sulfur nucleophiles gave the conjugate addition product only and the addition of nitrogen nucleophiles gave both conjugate addition and allylic substitution products. It was found that the protecting groups did not have an effect on the diastereomeric ratio obtained, nor on the formation of alternative products. The last step performed in the sequence was the deprotection of the conjugate addition products. The configuration of the major and the minor diastereomers were determined, the major product was assigned as the syn diastereomer. The major:minor diastereomeric ratio for compound 208a/b was 3:1 and for compound 209a/b, a ratio of 2:1 was obtained. The next part of the work involved the synthesis of MBH adducts with amide as the electron withdrawing group. The originally proposed route involved the synthesis of MBH esters and their conversion into amides. The conjugate addition reactions were attempted on these amide adducts, but were unsuccessful. A number of alternative routes were attempted for the synthesis of amide adducts and conjugate addition products resulting from these adducts. From all the alternative routes, the best route was the originally proposed route.
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    The synthesis of aryl benzamides as potential HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs)
    (University of the Witwatersrand, Johannesburg, 2023-07) Mohasoa, Likhopotso Cecilia; Zimuwandeyi, Memory; Bode, Moira L.
    Dihydro-alkoxybenzyloxopyrimidines are heteroaryl-containing compounds that have previously been shown to exhibit excellent activity against HIV-1 reverse transcriptase (RT) enzyme. In our own laboratory, 2-chloro-N-(6-(piperidin-1-yl)pyridin-2-yl)benzamide was identified as a compound with activity against wild-type HIV-1. Using these two structural types as a guide, as part of our ongoing studies to search for anti-HIV therapeutic agents that target the RT enzyme, a library of arylbenzamide compounds bearing a pyrimidine ring as a central core was synthesized. These compounds contained an oxygen linker to allow flexible rotation of the molecule in the RT active site, with the aim of achieving activity against wild-type and mutant HIV-1. As a starting point, in order to first identify a suitable synthetic method and then apply it for our target novel compounds, four different carboxylic acids and two classes of amines were tested. Amidation reactions were carried out on unsubstituted benzoic acid, 3-methoxybenzoic acid, 3-hydroxybenzoic acid, and 3-((2,6-dichloropyrimidin-4-yl)oxy)benzoic acid. In this last case, the 3-hydroxybenzoic acid moiety had already been linked to the pyrimidinyl core in order to test which order of reaction worked best: linking followed by amidation, or the reverse. Reaction of these benzoic acid derivatives with anilines and aminopyridines gave the resulting benzamides in 22-99% yields after optimization. When triethylamine was used as a base in amidation reactions involving 2-amino-3-bromopyridine, 2-amino 5-bromopyridine and 2-amino-5-methylpyridine, diacylation was favoured, while when pyridine was used, monoacylation predominated. The reactions to link benzoic acid derivatives to the pyrimidinyl core were carried out by displacement of chlorine on 2,4,5-trichloropyrimidine. The displacement of the first chloride was tested using three types of nucleophiles. The first nucleophile was methyl 3-hydroxybenzoate, effectively a protected benzoic acid, which afforded methyl 3-((2,6-dichloropyrimidin-4-yl)oxy)benzoate in 81% yield. Problems with subsequent hydrolysis of the ester made this route impractical. The second nucleophile was 3-hydroxybenzoic acid which provided 3-((2,6-dichloropyrimidin-4-yl)oxy)benzoic acid in 81% yield. The third nucleophile was N-(5-bromopyridin-2-yl)-3-hydroxybenzamide, where amidation had already been performed, which transformed into the desired compound N-(5-bromopyridin-2-yl)-3- ((2,6-dichloropyrimidin-4-yl)oxy)benzamide in 28%. The low yield obtained from reaction of the amidated nucleophile identified the most promising route to be linking of 3-hydroxybenzoic acid to 2,4,5-trichloropyrimidine first, followed by amidation. After the successful displacement of the first chlorine atom, two of the resulting analogues 3-((2,6-dichloropyrimidin-4-yl)oxy)-N-(p-tolyl)benzamide and N-(4-bromophenyl)-3-((2,6-dichloropyrimidin 4-yl)oxy)benzamide were functionalized with sulfur and nitrogen nucleophiles by displacement of a second chlorine atom. Ethanethiol proved to be highly nucleophilic, leading to pyrimidine C-O bond cleavage and sulfur disubstitution, while the nitrogen ucleophiles propylamine and piperidine afforded their corresponding derivatives in good yields without breaking the carbon-oxygen bond. The newly coupled propyl compound was further derivatized by means of hydrolysis with sodium hydroxide to yield the desired novel 3-((6-hydroxy-2-(propylamino)pyrimidin-4-yl)oxy)-N-(p tolyl)benzamide or 3-((6-oxo-2-(propylamino)-1,6-dihydropyrimidin-4-yl)oxy)-N-(p-tolyl)benzamide compound.