Browsing by Author "Sithebe, Siphamandla."

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Base-Free Suzuki acylation reactions of sodium (aryl trihydroxyborate) salts: a novel synthesis of substituted aryl ketones.
(2018) Molefe, Patience Snenhlanhla Sthembile.; Sithebe, Siphamandla.
Asymmetric biaryl ketones are important building block in organic chemistry since they occur in large number of biological active compounds, natural product, cosmetics as well as in organic synthesis. The aim of this project was to develop a novel base-free Suzuki-Miyaura cross-coupling of biaryl ketones from sodium (aryl trihydroxyborate) salts coupled with acyl chlorides catalysed by palladium precursor and investigate the electron effect of substituents attached to acyl chloride and sodium (aryl trihydroxyborate) salts on the yields of ketones produced. A novel synthesis of biaryl ketones was successfully developed in coupling of commercially available substituted acyl chlorides with easily accessible substituted sodium (aryl trihydroxyborate) salts catalysed by Pd(PPh3)4 in aqueous toluene. A wide range of functional groups were accommodated including CF3, OMe, SMe, Br, F, NO2, OH, NH2 yielding up to 96% in 24 hours. Encouraged by successful cross-coupling reaction between sodium (aryl trihydroxyborate) salts and acyl chlorides under the Suzuki-Miyaura cross-coupling acylation reaction conditions, we thought it would be logical to extend the scope of the developed reaction condition to include carboxylic anhydrides as electrophiles. As a result, substituted benzoic anhydrides were first synthesised following previously published procedures giving the desired products in excellent yields (87-99%). The synthesised carboxylic anhydrides were subsequently cross-coupled with boronate salts under base-free and ligandless palladium catalysed cross-coupling reaction conditions to synthesise biaryl ketones in aqueous acetone. The developed method appears sensitive to electronic effects both on the electrophile and on the nucleophile and on the nucleophile furnishing the desired ketones in moderate yields. Two novel methods have been developed to synthesise ketones from stable, easy to prepare and free flowing pure sodium (aryl trihydroxyborate) salts.
Exploring the structure activity relationship of antiplasmodial compounds identified from the MMV Pathogen Box.
(2024) Mafuleka, Sean Manqoba.; Sithebe, Siphamandla.; Veale, Clinton Gareth Lancaster.
Over 200 million new infections are caused by malaria-causing plasmodium species. This results in over 500 000 annual deaths. These deaths are mostly young children under the age of five years. As there is an emergence of resistance to primitive first-line treatments, there is an increasing need for the development of new targets with novel scaffolds. For such advancements, we have to consider the structure-activity of antiplasmodial compounds. The Pathogen Box is a concept modelled on the Malaria Box, except the 400 drug-like compounds it contains are a diverse range of compounds which are active against numerous neglected diseases of interest, and is readily accessible. It unpacks 125 compounds of antiplasmodial activity, a lot of which have been identified from phenotypic screening of the GSK Tres Cantos Anti-Malarial Set (TCAMS). Upon request, select researchers around the globe receive a set of compounds from the Pathogen Box to help in the advancements towards neglected disease drug discovery. In turn, the researchers are requested to present, in the public domain, any data they will have generated in their work within two years. This presents an opportunity for a collaborative space for neglected disease drug research. In this project, compound MMV023227 was found to have promising antiplasmodial activity. We have therefore designed and synthesized some analogues of the hit compound with the purpose of identifying an SAR. We initiated the synthesis of the designed analogues of compound MMV023227 by successfully synthesising the three imidazole compounds that are 2-(3-bromophenyl)-4,5-dimethyl-1H-imidazole (3.1), 2-(3-bromophenyl)-4-methyl-1H-imidazole (3.2), and 2-(3-bromophenyl)-1H-imidazole (3.3) in yields between 33 – 42 %. We moved these compounds towards the desired final compounds through several stages, but we could only go as far as producing compounds N-(2-chlorobenzyl)-3-(1-(ethoxymethyl)-1H-imidazol-2-yl)aniline (3.9), N-(2 chlorobenzyl)-3-(1-(ethoxymethyl)-4-methyl-1H-imidazol-2-yl)aniline (3.10) and N-(2-chlorobenzyl)-3-(1-(ethoxymethyl)-5-methyl-1H-imidazol-2-yl)aniline (3.11) in yields between 7 – 41 %.
Kumada and liebeskind-srogl coupling of aryl thiosulfonates as electrophilic coupling partners in the synthesis of biaryls.
(2021) Madlala, Nokuphiwa Prudence.; Sithebe, Siphamandla.
The need and desire for versatility and diversity in cross-coupling reactions was the drive for the studies conducted in this thesis. Traditionally, transition-metal catalyzed crosscoupling reactions have heavily relied on organohalides and pseudo-halides as electrophilic-coupling partners. As a result, alternative compounds such as organosulfur compounds, which are potential electrophilic-coupling partners, have often been overlooked and subsequently understudied. Hence, this study was aimed at exploring the reactivity of S-phenylarylthiosulfonates as electrophilic-coupling partners in the transition metal-catalyzed cross-coupling such as Liebeskind-Srogl and Kumada-Corriu crosscoupling reactions towards the synthesis of biaryls. In this study, disulfides were synthesized from the economical, time-efficient and catalystfree oxidation of thiols in good to excellent yields (70-83%). The disulfides were in-turn reacted with sodium arylthiosulfonates to produce the desired symmetrical and unsymmetrical S-arylthiosulfonates in 69-73% yields. With different S-arylthiosulfonates in hand, we investigated their reactivity as electrophilic coupling partners in transition metal catalyzed C-C bond forming cross-coupling reactions, namely: Kumada-Corriu and Liebeskind-Srogl in an attempt to expand the scope of electrophilic coupling partners in organic synthesis portal.
Synthesis elaboration of fragments that potentially inhibit the HOP-HSP90 protein-protein interaction.
(2024) Molefe, Patience Snenhlanhla Sthembile.; Sithebe, Siphamandla.; Veale, Clinton Gareth Lancaster.
Heat Shock Protein 90 (HSP90) is a molecular chaperone that mediates the stability and maturation of many important proteins for oncogenesis. There is an overexpression of the Heat Shock Protein 70/Heat Shock Protein 90 Organising Protein- HSP90 (HOP-HSP90) protein-protein interaction (PPI) complex in tumour tissues unlike in healthy cells. This PPI complex of HSP90 displayed a potential druggable target because of the crucial role it plays in cancer development. However, the challenge is the development of HOP-HSP90 PPI inhibitors. The literature showed the activity of valsartan (27) for the inhibition of HOP-HSP90 PPI as it entails the features of ortho-biphenyl tetrazole fragments that were obtained from the Structural-Binding Relationship (SBR) of the active fragments using fragment-based drug discovery (FBDD). These fragments bound to the tetratricopeptide repeat 2A (TPR2A) domain of HOP and inhibited the PPI of HOP-HSP90. As a result, this study aimed to synthesise and assay ortho-biphenyl tetrazole fragments as inhibitors of HOP-HSP90 for novel anticancer inhibitors, triple-negative breast cancer (TNBC). Valsartan (27) and its analogues were synthesised following reported procedures and modified methods. A series of 13 ortho-biphenyl tetrazole desired fragments were successfully synthesised using a Suzuki-Miyaura cross-coupling reaction and [3 + 2] cycloaddition of nitrile with sodium azide. The cross coupling of 2-iodobenzonitrile or 2-(2-bromophenyl) acetonitrile with para-substituted phenylboronic acid was conducted using different substrates including Cl, Br, F, CH3, CF3, H, and OCH3. Cycloaddition was done after the cross-coupling to skip the protection step of the tetrazole. With the desired ortho-biphenyl tetrazole fragments in hand, the PPI inhibition activity was evaluated at different concentrations from 0 mM to 2.0 mM. It is interesting to observe that some of these fragments showed PPI activity at different concentrations including compounds 76, 80, 82, 83 and 84. No activity was observed following the incorporation of the benzylic carbon. The data presents the successful lead optimisation for the development of HOP-HSP90 novel PPI inhibitors for the treatment of TNBC.
Synthesis of ketones through aerobic transition metal-catalyzed cross-coupling of thioesters.
(2021) Mthombothi, Zabenguni Zakithi.; Sithebe, Siphamandla.
Asymmetric diaryl ketones are an important class of compounds in organic chemistry due to their presence in natural products, synthesis, cosmetics as well as in biological active compounds. The aim of this project was to expand the scope of thiophilic metal carboxylates catalysts that can be applied to the aerobic Liebeskind-Srogl cross coupling reaction between various thioesters and phenylboronic acids. Thioesters bearing electron neutral, withdrawing and donating groups were successfully synthesized in yields ranging from 35 to 54%Xcv. The electron neutral thioester was used in the optimization of the aerobic Liebeskind-Srogl reaction and CuMeSal proved to be the most effective catalyst in this protocol. CuMeSal was applied in the aerobic synthesis of the asymmetric diaryl ketones bearing a wide range of functional groups including CF3, SMe, OMe and F yielding up to 65% in 24hrs. Aerobic Liebeskind-Srogl cross-coupling reaction was applied in the successful synthesis of chalcones, through the coupling of commercially available phenylboronic acids with previously synthesised thioesters catalysed by CuMeSal in DMF for 24hrs,furnishing desired products in poor to excellent yields 26-89%.
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.
Synthesis, characterization and substitution reaction studies of pyridyl N,N’-bidentate palladium(II) complexes. A kinetic and mechanistic study.
(2023) Mjwara, Pinky Ncomela.; Sithebe, Siphamandla.; Papo, Tshephiso Rose.
The influence of structural as well as electronic properties of bidentate N,N chelates with different substituents on the mononuclear Pd(II) complexes were investigated. The complexes were synthesized and characterized by various spectroscopic methods such as 1H & 13C NMR, FT-IR, LC-MS, CHN and single x-ray crystallography. For the first set of complexes (Chapter 3), we studied the unexplored kinetics and mechanistic behaviour of N,N’-pyridyl Pd(II) complexes, viz. dichloro-(N-((pyridin-2-yl)methyl)aniline)palladium(II) (PdL1), dichloro-(4-fluoro-N-((pyridin-2-yl)methyl)aniline)-palladium(II) (PdL2), dichloro-(4-bromo-N-((pyridin-2-yl)methyl)aniline)-palladium(II) (PdL3), dichloro-(4-methoxy-N-((pyridin-2-yl)methyl)aniline)-palladium(II) (PdL4) and dichloro-(4-ethyl-N-((pyridin-2-yl)methyl)aniline)-palladium(II) (PdL5). The substitution behaviour of coordinated chloride atoms by three bio-relevant thiourea nucleophiles, viz. thiourea (TU), N,N’-dimethylthiourea (DMTU) and N,N,N’,N’-tetramethylthiourea (TMTU), of different steric demands was studied in a 0.1 M solution of ultra-pure water under pseudo-first order conditions. The reactions were studied as a function of concentration and temperature using standard Stopped-Flow and UV-Vis spectrophotometric technique. The substitution of the chloride atoms from the Pd metal by thiourea nucleophiles was a two-step reaction where the chloride trans to the pyridine ligand was substituted first, since the pyridine has a stronger trans effect compared to the amine group. The reactivity of mononuclear Pd(II) complexes containing bidentate N,N’-donor ligands with different substituents depends on the electronic effects of the complexes. The reactivity of the complexes increased with the presence of electron withdrawing substituents and decreased when an electron donating group was attached on the para position of the aniline moiety. The electron withdrawing groups influence the pull of electrons from the electron deficient amine that is coordinated to the metal center which results in the loss of electron density from the ligand moiety and increases the electrophilicity of the metal center and thus the substitution reaction. The reactivity of the nucleophiles depends on steric effects, with the bulky TMTU being the least reactive. The negative entropies and second order kinetics for all the substitution reactions support an associative mode of substitution mechanism. DFT calculations were performed to account for the observed reactivity of all the complexes studied. For the second set of novel Pd(II) complexes (Chapter 4), viz. bis[N-(4-bromophenyl)pyridine-2-carboxamidato] Palladium (Pd1) and Palladium(II) [N-(4-bromophenyl)-2-pyridinecarboxamide), pyridine chloride (Pd2), crystals were obtained and the structures were studied. Pd1 crystallizes in the monoclinic crystal system and in the P21/c space group, and Pd2 crystallizes in the orthorhombic system, with the space group Pbca.
Synthesis, structural characterization, and subsequent applications of salicyldiminato Pd (II) complexes as efficient catalysts for C-C bond-forming reactions.
(2024) Khoza, Khethukuthula Petronella Mallecia.; Sithebe, Siphamandla.
Palladium-catalysed cross-coupling reactions (i.e., Heck, Stille, Liebeskind Strogl, and Suzuki-Miyaura) are perceived as one of the most prominent, successful, and widely used strategies for the construction of complex organic compounds such as biaryls from simple precursors. Amongst the known carbon-carbon bond-forming reactions, the Suzuki-Miyaura (SM) cross-coupling reaction has emerged as one of the most efficient and powerful methodologies due to its high versatility, use of non-toxic reagents, mild reaction conditions, broad substrate scope, and functional group tolerance. The SM cross-coupling has not only greatly changed the landscape of the field of organic chemistry, but also profoundly impacted pharmaceuticals, agrochemicals, natural products, material science, and various related industries. Stable supporting ligands are key in the catalytic activities of Pd complexes. The design and development of supporting ligands that will result in stable Pd complexes while maintaining high catalytic activity and catalytic turnover through stereo-electronic effect alteration are highly desirable. With the aim of developing stable highly catalytic Pd complexes, our research focus is directed towards the synthesis, characterisation, and application of novel N, O-bis Schiff base chelated Pd (II) complexes (PdC1 - PdC7) from Schiff base ligands (L1 - L7). The synthesis of (E)-2-((phenylimino)methyl) phenol (L1), (E)-2-((4 tolylimino)methyl) phenol (L2), (E)-2-(((4-ethylphenyl)imino)methyl) phenol (L3), (E)-2-(((4-methoxyphenyl) imino)methyl) phenol (L4), (E)-2-(((4-fluorophenyl)imino)methyl) phenol (L5), (E)-2-(((4-bromophenyl)imino)methyl) phenol (L6), and (E)-4-((2-hydroxybenzylidene)amino) benzonitrile (L7) was achieved in excellent yields (80% - 94%) through a condensation reaction of salicyldehyde with various electron-withdrawing and donating para-substituted anilines. The reaction between L1 - L7 and Palladium acetate Pd (OAc)2) afforded PdC1 - PdC7 with yields ranging from 78% - 95%. The successful synthesis of L1 - L7 was verified by NMR, FTIR, and MS analyses, while all complexes (PdC1 - PdC7) were characterised using NMR, FTIR, MS, and Single X-ray crystallography. However, a comprehensive X-ray data report was only obtained for PdC2, as the X-ray crystallographic structures of PdC3 - PdC7 proved difficult to solve. The crystallographic analysis of PdC2 revealed that L2 is coordinated to the Pd metal center in a bidentate mode via the N-donor of the imine bond and the O-donor of the phenolic group. The complex displayed a distorted square planar geometry and crystallised in a monoclinic crystal system with a P21/c space group. All the complexes were tested for catalytic activity in the SM cross-coupling reaction between sodium (trihydroxy)phenylborate salt and 4-bromotoluene. The reactions were catalysed with a catalyst loading of 2 mol% for 24 hours in ethanol, yielding 18% - 32% of the desired biaryl product. Motivated by the successful cross-coupling reaction between sodium (trihydroxy)phenylborate salt and 4-bromotoluene, we opted to broaden the application scope of the complexes using the established reaction conditions in SM cross-coupling acylation reaction. We used the most active catalysts, PdC2 and PdC6 for constructing biaryl ketones through the reaction of benzoyl chloride with sodium (trihydroxy)phenylborate salt in toluene for 24 hours. The reactions yielded 15% and 30% of the desired products, respectively.
Synthetic, photophysical studies of 2-alkenyl/arylbenzo-1,3,2- diazaborole compounds and their palladium-catalysed cross-coupling reactions.
(2013) Sithebe, Siphamandla.; Robinson, Ross Stuart.
This study was aimed at investigating the suitability of 2-alkyl/alkenylbenzo-1,3,2-diazaborolane compounds as potential nucleophilic coupling partners in the Suzuki-Miyaura cross-coupling reaction. A range of aryl bromides and iodides bearing electron-donating as well as electron-withdrawing substituents were reacted with 2-alkyl/alkenylbenzo-1,3,2-diazaborolane compounds under the influence of Pd(OAc)2/PCy3 combination. The cross coupling reaction afforded the desired products in yields ranging from 35% to 89% in less than 20 minutes. The catalytic system was found to be versatile and general tolerating a variety of functional groups including OMe, NO2, OH, COOMe and COMe2, thus demonstrating the suitability of 2-alkyl/alkenylbenzo-1,3,2-diazaborolane as coupling partners in the Suzuki-Miyaura cross-coupling methodology. The results from this study have been accepted for publication, full reference: (Sithebe, S., Hadebe, S. W., Robinson, R. S. Tetrahedron, 2011, 67, 4277.) Encouraged by the successful application of 2-alkyl/alkenylbenzo-1,3,2-diazaborolanes as coupling partners in the Suzuki-Miyaura (SM) cross-coupling reaction, we then extended our studies to investigate the synthesis and subsequent application of 2-arylbenzo-1,3,2-diazaborole analogues as potential coupling partners under the Suzuki-Miyaura cross-coupling reactions. The cyclocondensation of arylboronic acids with the corresponding 1,2-phenylenediamine afforded 2-arylbenzo-1,3,2-diazaboroles in yields ranging from 43% to 93%. The cross-coupling reaction of 2-arylbenzo-1,3,2-diazaboroles with the range of aryl bromides afforded the desired biaryl products in moderate to excellent yields ranging from 62% to 96%. Substrates bearing electron-withdrawing substituents were shown to be more reactive under these reaction conditions affording biphenyls in excellent isolated yields ranging from 83% to 96%. While our yields are comparable with the yields reported in literature, our reactions take only 10 minutes (!) compared to many hours of reflux as reported in the literature. This project was also aimed at investigating the spectroscopic characteristics of 2-arylbenzo-1,3,2-diazaborole compounds by acquiring and studying their absorption and emission spectra. The data obtained revealed the lack of significant v solvatochromism for all the compounds in the ground state which is indicative of the presence of low dipole moments. These values were confirmed computationally which showed low calculated dipole in a range 0.1379-2.2773 D. In the excited state, all chromophores are influenced by the polarity of the solvent used pointing to the presence of solvatochromism. The introduction of a donor group such as thioether (MeS) and the introduction of bromine atom, on the π-system, have proven beneficial for the emission maxima of the species investigated. The extension of π-conjugation length at the 2-position of these species and the methylation at the backbone of 1,3,2-benzodiazaborolyl group leads to bathochromic shifts of the emission maxima, which in turn lead to large Stokes shifts of up to 11000 cm-1. Alternatively, the formal insertion of the phenyl spacer between the naphthyl ring and the 1,3,2-benzodiazaborolyl group does not have any influence on the photophysical properties of these compounds. The HOMOs solvatochromism for all the compounds in the ground state which is indicative of the presence of low dipole moments. These values were confirmed computationally which showed low calculated dipole in a range 0.1379-2.2773 D. In the excited state, all chromophores are influenced by the polarity of the solvent used pointing to the presence of solvatochromism. The introduction of a donor group such as thioether (MeS) and the introduction of bromine atom, on the π-system, have proven beneficial for the emission maxima of the species investigated. The extension of π-conjugation length at the 2-position of these species and the methylation at the backbone of 1,3,2-benzodiazaborolyl group leads to bathochromic shifts of the emission maxima, which in turn lead to large Stokes shifts of up to 11000 cm-1. Alternatively, the formal insertion of the phenyl spacer between the naphthyl ring and the 1,3,2-benzodiazaborolyl group does not have any influence on the photophysical properties of these compounds. The HOMOs of all the chromophore are purely represented by the 1,3,2-benzodiazaborolyl group except for anthracenyl-functionalised benzo-1,3,2-diazaborolane compounds in which the HOMO are located on the π-system with no contribution of the vacant 2pz-orbital of the boron atom. The large Stokes shifts and significant solvatochromism displayed by these compounds are suggestive of the potential application in organic light emitting diodes (OLED) as emitters. The results from this study have been drafted for publication in Dalton Transition.