Browsing by Author "Mkhize, Zimbili."

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Structure and synthesis of bioactive natural products.
(2015) Mkhize, Zimbili.; Van Heerden, Fanie Retief.
Selected South African medicinal plants were screened in vitro for the anti‐HIV activity using the HIV‐RT colorimetric assay and XTT cell viability assay. In the cell‐based assay the plant extracts screened exhibited no anti‐HIV activity and most plant extracts were not highly toxic, with a few exceptions. In the HIV‐RT assay extracts of Harpephyllum caffrum, Combretum kraussii, Plumbago spp., Berkheya speciosa, Polygala fruticosa, Vernonia glabra, Lippia javanica, Smilax anceps, and Vernonia spp showed inhibition greater than 50% at a concentration of 500 μg/mL. Combretum kraussii stem extract inhibited 70% of the HIV‐RT and the leaf extract inhibited 67%. Because of these results obtained for Combretum kraussii, the leaf extract was investigated further resulting in the isolation of three compounds, combretastatin B‐1, combretastatin B‐5, and combretastatin B‐1 2‐β‐D‐glucoside. These compounds were not investigated further because of the non‐activity observed on the cell‐based assay. The plant metabolites arzanol and lepidissipyrone were chosen for synthesis. Arzanol, a prenylated α‐pyrone‐phloroglucinol, isolated from Helichrysum italicum ssp. microphyllum, exhibits antioxidant, anti‐inflammatory and anti‐HIV activities. Despite failure to complete its total synthesis, its two precursors, 2‐(2‐ethyl‐1,3‐dioxolan‐2‐yl)propanal and ethyl 3‐ (3‐acetyl‐2,4,6‐tribenzoxyphenyl)propanoate were successfully synthesised. Lepidissipyrone, the α‐pyrone flavanone structurally similar to arzanol, was isolated from Helichrysum lepidissimum and from Helichrysum excisum. Both species are endemic to South Africa. The first total synthesis of lepidissipyrone was successfully achieved by a multicomponent Carba‐Betti strategy to couple 6‐ethyl‐4‐hydroxy‐5‐methyl‐α‐pyrone and 7‐tert‐butyldimethylsilyloxy‐5‐hydroxyflavanone. During the last step of the total synthesis of lepidissipyrone, helipyrone was also synthesised. Various structural analogues of α‐pyrone, i.e. 4‐hydroxy‐5,6‐dimethyl‐α‐pyrone and 4‐hydroxy‐5‐ methyl‐6‐propyl‐α‐pyrone and acylphloroglucinols, i.e. 2,4‐bis(tertbutyldimethylsilyl) phloroacetophenone, 2,4‐bis(tert‐butyldimethylsilyl)‐3‐ prenylphloroacetophenone, and 2,4‐bis(tert‐butyldimethylsilyl)‐ 3‐prenylisobutyrophenone, were synthesised. These analogues could be used to synthesise arzanol derivatives
Studies towards the synthesis of perhydropyrrolo[2,1-j]quinoline and perhydropyrido[2,1-j]quinoline ascidian alkaloids.
(2002) Mkhize, Zimbili.; Gravestock, David.; Robinson, Ross Stuart.
Cylindricines A-K [1-11], lepadifonnine [12] and fasicularin [13] are tricyclic ascidian alkaloids exhibiting the perhydropyrrolo[2,1 :j]quinoline and perhydropyrido[2,1-j]quinoline ring systems. The structural features and biological activity of these alkaloids make them ideal targets for total synthesis. The first aim of this project was to construct the azabicycles [111] and [112] that resemble the spirocyclic core of these alkaloids. The synthesis began with the C ring intact and the attempted construction of the B ring using Diels-Alder methodology. A key step was the Eschenmoser coupling reaction between thiolactams [105] and [106] to give the vinylogous amides [107] and [108]. All attempts to convert the vinylogous amides to the corresponding dienes proved to be unsuccessful, due to the fact that the preferred site for deprotonation was ~ to nitrogen and not a to the carbonyl group. Due to time constraints we moved to our second aim, the enantioselective synthesis of the B and C rings offasicularin [13]. Significant progress was made towards our second goal. (5S)-5-Hydroxytetrahydro2(lH)pyridinone [127], which represents the C ring of fasicularin, was successfully synthesized in 5 steps from L-glutamic acid [113]. This lactam was O-protected with tertbutyldiphenylsilyl group to afford (5S)-5-tert-butyldiphenylsilyloxy-2-piperidinone [114]. Thionation of lactam [114] gave the thiolactam [160]. Conjugate addition of this thiolactam to methyl acrylate gave methyl 3-[(5S)-5- {[tert-butyl(diphenyl)silyl]oxy}-2-thioxotetrahydro1(2H)-pyridinyl ]propanoate [163], which underwent a Eschenmoser coupling reaction with bromoacetone to gIve methyl 3-[(5S)-5-{ [tert-butyl(diphenyl)-silyl]oxy} 2-[(£)-2oxopropylidine] tetrahydro-2(1H)-pyridinyl]propanoate [164]. Unfortunately conversion of [164] into the corresponding diene using KHMDS and TBSCI was unsuccessful. The reaction conditions caused the cleavage of the methyl acrylate protecting group on nitrogen, affording the secondary E-vinylogous amide [167]. This constituted an important serendipitous discovery - methyl acrylate can be used to protect the nitrogen atom of enaminones and can be removed by KHMDS to access secondary E-enaminones that are otherwise difficult to synthesise. Another route pursued was to introduce the hexyl chain in the A ring of fasicularin by means of an SN2 reaction between lactam [114] and mesylate [116]. The stereodefined (lR)1-(2-{[tert-butyl-(dimethyl)sily]oxy}ethyl)heptyl methanesulfonate [116] was successfully x synthesized in 5 steps from l-octyne [115]. Unfortunately the subsequent SN2 reaction with lactam [114] failed when we using t-BuOK and THF and time constraints prevented us from attempting this coupling reaction using alternative conditions.