The aim of this project was to develop a synthetic strategy for the production of uncommon sugars thevetose (6-deoxy-3-O-methylglucose) and cymarose (2,6-dideoxy-3-O-methylallose or 2,6-dideoxy-3-O-methylaltrose) derivatives, present in the trisaccharide moiety of a pregnane glycoside with appetite-suppressant activity. A D-thevetose glycosyl donor was prepared from methyl D-glucopyranoside. The first step of the synthesis was the formation of a 4,6-O-benzylidene derivative that was selectively methylated on the 3-hydroxy group by using a copper mediated alkylation process. Treatment with NBS and reductive removal of the resultant bromide produced the required protected thevetose glycoside. This success is a vast improvement compared to the published results of the patent reporting this synthesis. Attempts to prepare the 2α-iodo derivative by direct nucleophilic substitution of a 2-O-triflate manno-derivative resulted in a most unusual rearrangement reaction. Allal derivatives as starting materials in the preparation of 2α-iodo sugars were also unsuccessful due to steric hindrance provided by the axial 3-methoxy group. Preparation of a cymaroside precursor was achieved by using glucal as a starting material and by the inversion of C-3 in a consecutive oxidation/reduction sequence of the iodo acetate. Lastly, the preparation of the β-oleandroside derivative of cholesterol was achieved in a model reaction. The sugar oleandrose is a C-3 epimer to cymarose and it can be found in pregnane and cardenolide glycosides. / Professor F.R. van Heerden

M.Sc. / The main objective of this project was to synthesize carbohydrates that contain a thiol functional group, commonly known as thiocarbohydrates and subsequently employ them as stabilizing agents in the synthesis of gold nanoparticles and as ligands in the synthesis of phosphine thiocarbohydrate gold(I) complexes. In achieving our objective, thiocarbohydrate compounds 62, 64, 69 and 71 were successfully synthesized from acetylated 60 or benzylated glucal 66 using a Ferrier rearrangement reaction. NaHSO4-SiO2 was used as a catalyst for Ferrier rearrangement reaction in the presence of dithiol type nucleophiles (i.e. 1,2-dithiol ethane or 1,5-dithiol pentane) to afford the desired thiocarbohydrate compounds. The S-acetate derivatives 63, 65, 70 and 72 of the corresponding thiocarbohydrates were prepared as a confirmatory test for the presence of the terminal thiol (SH) in the thiocarbohydrate compounds. C-2 modified thiocarbohydrate compounds 78 and 80 were synthesized from C-2 iodomethyl glycoside 77 following a literature reported procedure in the presence of 1,2-dithiol ethane or 1,5-dithiol pentane as nucleophiles. S-acetate derivatives 79 and 81 of the corresponding thiocarbohydrate compounds were synthesized again to confirm the presence of the terminal thiol (SH). All the thiocarbohydrate compounds and their corresponding S-acetate derivatives were characterized with NMR spectroscopy and HRMS. Ethyl thiocarbohydrate compounds 62, 69 and 78 were successfully employed as stabilizing agents in the preparation of gold nanoparticles GNP1-GNP9 following a Brust-Schiffrin procedure. UV-Vis spectroscopy and transmission electron microscopy (TEM) were used to characterize these gold nanoparticles. Phosphine thiocarbohydrate gold(I) complexes 84-94 were synthesized from selected thiocarbohydrate compounds. NMR spectroscopy and HRMS were used to characterize these gold(I) complexes. Having synthesized the target thiocarbohydrate compounds, gold nanoparticles and gold(I) complexes, our aim was to investigate their biological activity against cancer and HIV. However, the biological testing process took considerably longer and as a result this dissertation was submitted without the biological tests results.

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Several camphor and pinane derivatives have been synthesised and evaluated for use as chiral auxiliaries in asymmetric synthesis. Various blocking groups have been attached to the camphor skeleton in attempts to improve stereofacial selectivity; these include α-methoxybenzyl and xylyl groups, and novel stereoisomeric ketal moieties derived from meso- and (R,R)-(-)-2,3-butanediol. Benzylation reactions carried out on the lithium enolates of ester derivatives of the camphor-derived chiral auxiliaries afforded α-benzylated products in 5-60% diastereomeric excess. Stereochemical aspects have been explored using high resolution NMR, X-ray crystallographic and computer modelling techniques, and hydrolysis of selected α-benzylated products has permitted the diasteroselective bias to be confirmed. Opposite configurations at the new stereogenic centre are clearly favoured by the xylyl and ketal blocking groups - an observation rationalised in terms of the presence or absence of chelating potential in the blocking group. Baylis-Hillman reactions carried out on a series of specially prepared camphor-derived acrylic esters containing the ketal blocking group exhibited both low diastereoselectivities (0-30% d.e.) and very long reaction times. Chiral silyl enol ethers, synthesised using both pinane and camphor derivatives as chiral auxiliaries, showed up to 20% diastereomeric excess in MCPBA oxidation, alkylation and Mukaiyama reactions. Attempts to bring the prochiral centre in the silyl enol ether substrates closer to the chiral auxiliary, and thus improve the stereofacial selectivity, proved unsuccessful. The silyl enol ether derivatives, however, display interesting fragmentation patterns in their electron impact mass spectra, which were investigated using a combination of high resolution MS, comparative low resolution MS and metastable peak analysis.

The investigation has been concerned with the application of the Baylis-Hillman methodology to the synthesis of quinoline derivatives. An extensive range of novel Baylis-Hillman products has been prepared, typically in moderate to excellent yields, by condensing 2-nitrobenzaldehyde derivatives with various vinyl ketones and acrylic esters in the presence of diazabicyclo[2.2.2]octane (DABCO). Reduction of the nitro group in the Baylis-Hillman products was effected by catalytic hydrogenation in ethanol using a 10% palladium-on-carbon catalyst to afford quinoline, quinoline-N-oxide and quinolone derivatives. In all cases, it is apparent that cyclisation involves exclusive attack of nucleophilic nitrogen at the carbonyl centre, with acrylic ester derivatives affording quinolones and vinyl ketone derivatives affording quinolines and the corresponding quinoline-N-oxides. No products arising from a conjugate addition pathway were observed. The use of stannous chloride as an alternative reagent to effect reductive cyclisation of the Baylis-Hillman products has been explored, and found to favour the formation of 1,2- dihydroquinoline derivatives, with cyclisation occurring via a conjugate addition pathway. Isolation of the products, following work-up of the stannous chloride reactions, however, presented some difficulty. All compounds were characterised by spectroscopic (NMR and IR) and, where appropriate, elemental (high-resolution MS) analysis. Interconversion of the quinoline and quinoline-N-oxide derivatives has been explored and finally achieved in quantitative yields. Reduction of 2,3-dimethylquinoline-N-oxide to the corresponding quinoline was effected using phosphorus tribromide in DMF, and the reverse transformation with meta-chloroperbenzoic acid (MCPBA) in CHCl₃. Application of these methods to mixtures of 2,3-dimethylquinoline and its N-oxide has afforded, selectively, either the quinoline derivative or the corresponding N-oxide. / KMBT_363 / Adobe Acrobat 9.53 Paper Capture Plug-in

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For years now, opium alkaloids and morphinans have been attractive synthetic targets for numerous organic chemists due to their important biological activity and interesting molecular architecture. Morphine is one of the most potent analgesic drugs used to alleviate severe pain. Our research group maintains a longstanding interest in tandem pericyclic reactions such as the oxy-Cope/Claisen/ene reaction cascade and their application to the total synthesis of complex natural products. Herein we report the ventures towards the formal synthesis of (+/-)-morphine based on the novel tandem oxy- Cope/Claisen/ene reaction developed in our laboratory. These three highly stereoselective pericyclic reactions occurring in a domino fashion generate the morphinan core structure after only 7 steps from commercially available material. The formal synthesis culminated in the production of a formal intermediate after a total of 18 linear steps, with an overall yield of 1.0%, successfully intersecting two previous syntheses of the alkaloids, namely the ones of Taber (2002) and Magnus (2009).

The affinity of hemoglobin for CO relative to O₂ is decreased compared to simple iron-porphyrin systems mainly due to electronic effects. Hydrogen-bond formation with the His E7 residue of hemoglobin has been revealed to stabilize the bound dioxygen. This thesis describes the development of a series porphyrin models, benzene-4/4 (49a), benzene-5/5 (49b), amidobenzene-4/4 (49c) and amidobenzene-5/5 (49d) capped porphyrins, which serve as simple models to imitate the hydrogen bonding in hemoglobin. The chain linked bis pyrroles 38 were synthesized by Friedel-Crafts acylation of the benzene and nitrobenzene diacid chain derivatives with two equivalents of the β-unsubstituted pyrrole 36, followed by diborane reduction of the ketonic groups. After the nitro functions were transformed to the acetamides, modification of the ethyl ester functions of 38a, 38b and 39 via the benzylesters 40, the carboxypyrroles 41 and the α-unsubstituted pyrroles 42 afforded the important bis formyl pyrroles 43. The cyanoacrylate protected formyl pyrrole derivatives 44 were subjected to monochlorination at the α-methyl groups followed by condensation with two equivalents of the α-unsubstituted pyrrole 46 to give dipyrromethane dimers 47. Strong aqueous alkali caused saponification of the two ester groups and deprotection of the formyl functions to give 48. The α formyl-α′-unsubstituted dipyrromethane dimer, resulting from the thermal decarboxylation of 48, was cyclized to produce the porphyrin 49 in acidic medium. The interactions of CO and O₂ with the heme derivatives, Fe[superscript]Ⅱ(porphyrin)(DcIm), have been studied. The CO binding constant of the amide substituted heme is two foldlarger than that of the non-amide substituted heme. In contrast, the low temperature (-45°C) O₂ binding constants of the hemes have shown a 6-8 fold increase from nonamide to amide substituted hemes, probably because of a hydrogen bonding between the amide function and bound dioxygen similar to the hydrogen bonding in hemoglobin. [formula omitted] / Science, Faculty of / Chemistry, Department of / Graduate

This dissertation concerns the stereoselective synthesis of optically pure compound 196, the C₁₆-C₃₂ fragment of the polyether antibiotic ionomycin (1). Fragment 196 was synthesized by preparing and joining the two subunits 172 (C₁₆-C₂₂) and 122 (C₁₆-C₃₂). Compound 172 was synthesized by repetitive asymmetric aldol condensations of optically pure crotonyl imide 69 with aldehydes 129 and 139. The use of 69 allowed for the enantioselective construction of the two propionate units of fragment 172 having the "anti" configuration. Compound 122 was synthesized using the highly stereospecific oxidative permanganate cyclization of the 1,5-diene 93 to give racemic tetrahydrofuran 94, having the correct relative stereochemistry at the four asymmetric centres. The diene 93 was in turn prepared via the β-keto ester dianion methodology which allows for the stereospecific introduction of the isoprenoid unit. Diol 103, derived from 94 was resolved as its mono (+)- ̲O̲-acetylmandelate and was transformed into optically active fragment 122. Finally, to complete the synthesis of optically active fragment C₁₆-C₃₂ of ionomycin, compounds 172 and 122 were coupled via a Wittig reaction to afford the cis olefin 194 and the second tetrahydrofuran ring of 196 was introduced stereoselectively via an internal oxymercuration reaction. / Science, Faculty of / Chemistry, Department of / Graduate