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Masters Degrees (Chemistry)

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    One-pot, multicomponent oxidative synthesis of 2,4,5-trisubstituted imidazoles from internal alkenes using an I2/DMSO system.
    (2023) Majola, Nonhlelo.; Jeena, Vineet.
    Imidazoles are vital heterocyclic compounds usually incorporated in natural products such as biotin, vitamin B12, histamine, and histidine. 2,4,5-trisubstituted imidazoles, in particular, possess versatile biological and pharmaceutical activities such as antidiabetic, antimalarial, and analgesic properties. A traditional procedure for the synthesis of these elegant compounds involves the cyclocondensation reaction between a 1,2-diketone, an aldehyde, and ammonia in the presence of an acid or metal catalyst. However, this methodology suffers from various shortcomings such as the use of acid or metal catalysts, tedious work-up procedures, use of toxic reagents, and substrate scope limitations. Hence, the development of new methods to synthesize 2,4,5-trisubstituted imidazoles is of vital importance. This study describes the preparation of 2,4,5-trisubstituted imidazoles from alkenes using an environmentally benign iodine/DMSO system. This novel methodology was applied to a broad substrate scope such as substituted benzaldehydes, heterocyclic aldehydes, bulkier aldehydes, and substituted stilbenes, and afforded the target compounds in moderate to high yields under mild reaction conditions. Preliminary mechanistic studies revealed that 1,2-diketone is a key intermediate and that the mechanism is not radical-mediated. It also revealed that the oxygen source is DMSO and that the coupling step is catalyzed by iodine coordination and hydrogen bonding from the solvent. Based on the results obtained from the preliminary mechanistic investigations, a reasonable mechanism is proposed.
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    Synthesis of non-natural amino acids as covalent inhibitors for protein-protein interactions.
    (2023) Dladla, Siphamandla Austen.; Sithebe, Siphamandla.; Veale, Clinton Gareth Lancaster.
    There is still a need to develop new cancer therapies for troubling cancers. Hence, a resurging interest in compounds that engage their target through covalent interactions. Lysine’s amine can be engaged covalently with a weak electrophile (SO2F) extending the potential of covalent inhibitors. Herein, we were prompted to investigate the synthesis of non-natural amino acids, modified to include weakly electrophilic warheads, which could potentially target specific lysine residues. Three new non-natural amino acids were successfully synthesized, methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-((fluorosulfonyl)oxy)phenyl)propanoate, 3.5, methyl (S)-2-((tert-butoxycarbonyl)amino)-2-(4-((fluorosulfonyl)oxy)phenyl)acetate, 3.9, and methyl (S)-2-((tert-butoxycarbonyl)phenyl)propanoate, 3.35, in 85%, 89%, and 63.7% yield, respectively. Our study explored the synthetic pathway of a three-step procedure toward the target compounds, with the initial esterification of the carboxylic acid group, followed by the N-Boc protection of the amine group. Finally, the key sulfonation of the N-Boc protected amino methyl ester, where for 3.5 and 3.9, was performed through ex-situ generation of sulfuryl fluoride, which was installed following the substitution of the hydrogen on the hydroxyl group by SO2F. For 3.35, it was achieved through a palladium-catalyzed system and an in-situ fluorine introduction, where para iodine was substituted by the SO2 generated from DABSO. Under physiological conditions, compound 3.5 was assessed for possible interaction through its electrophilic warhead, with nucleophilic N-Boc-lysine side chain. The LCMS and NMR buffered assays were conducted, and in both these studies, the characteristics of a possible binding happening can be observed, hence an adduct N2-(tert-butoxycarbonyl)-N6-((4-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)phenoxy)sulfonyl)-L-lysine 3.5a formation.