M.Sc. (Chemistry) / The objective of the project was the synthesis of thiosemicarbazone-triazole hybrid compounds and evaluation of their biological activities against malaria and obesity. In achieving our objective, compound 63 was synthesized from the reaction of benzaldehyde 62 with propargyl bromide. Click chemistry reaction of compound 63 with benzyl azide provided triazole 68. Schiff’s base condensation of triazole 68 with methyl hydrazine carbodithioate 67 furnished compound 69 which then underwent nucleophilic substitution reaction and afforded thiosemicarbazone-triazole hybrids 61a-j. The structures of the compounds were characterized using NMR spectroscopy and elemental analysis. Hybrids 61a-h were then investigated for their biological activities against malaria and obesity. The antimalarial activities of the hybrids against the 3D7 strain of the malaria parasite plasmodium falciparum showed that only hybrid 61f exhibited less than 50% parasite viability (46% compared to 37% of chloroquine). The dose response of the hybrids was not carried out due to their poor activities. Hybrids 70a-h that incorporated electron donating group in their aromatic linker were synthesized similarly as hybrids 61a-h were synthesized. Their antimalarial activities showed that all except 70c and 70g exhibited less than 50% parasite viability. The test results indicated that the addition of methoxy group to the hybrids 61b, 61e and 61f decreased their percentage parasite viability which were exhibited by their corresponding hybrids 70b, 70e and 70f, respectively. Hybrid 70f was found to be marginally active with a dose response of 7.09 μM. The anti-obesity and anti-diabetic effects of hybrids 61a-h were investigated against the mitochondrial genes (Acc-1, Cpt-1 and Pgc-1) and glucose transport genes (Glut-4, Mef2a and Nrf-1), respectively. The test results against the mitochondrial genes showed that hybrids 61e and 61h consistently exhibited on the 3 genes which indicated that the presence of a non-polar short branched chain of the amine moiety might be important in the up-regulation of oxidative (Cpt-1 and Pgc-1) and down regulation of lipid accumulation (Acc-1) genes. The test results on the glucose transport genes showed that 61e followed by 61f consistently exhibited on the 3 genes which indicated that the presence of a non-polar short branched chain of the amine moiety might be important in the up-regulation of Glut-4, Mef2a and Nrf-1.Hybrids 70a-h were also tested against obesity and type 2 diabetes mellitus. Their investigation on the mitochondrial genes showed that the addition of methoxy group to the hybrids 61a-h that have a non-polar long branched chain of the amine moiety could be a reason for the expression and suppression of Cpt-1, Pgc-1 and Acc-1, respectively. The test results of hybrids 70a-h on glucose transport genes showed that the addition of methoxy group to the hybrids 61a-h that have a non-polar short (straight and branched) alkyl chain of the amine moiety might be a reason for the up-regulation of Glut-4, Mef2a and Nrf-1. Carbohydrate incorporated thiosemicarbazone-triazole hybrid compound 75 was successfully synthesized. However, the synthesis of more libraries of compound 75 and investigation of their biological activities against malaria and obesity were not carried out due to time constraints.

M.Sc. / Carbon nanotubes are among the most exciting new materials being investigated and synthesized, owing to their outstanding mechanical, electronic and optical properties. For more than a decade, the translation of these properties into realistic applications has been hindered by solubility and processing difficulties. Recently the development of efficient methodologies for covalent chemical modification has raised hope for the use of these materials in various fields of application such as biosensors, vaccine and drug delivery systems, medical imaging, biomaterials, water purification, etc... Phosphorylation of functionalized and unfunctionalized multiwalled carbon nanotubes (MWCNTs) is reported in this dissertation. This was achieved by the incorporation of phosphorus moieties on the end and side walls of the MWCNTs. Pristine MWCNTs were functionalized through oxidation by sodium hypochlorite and with a mixture of sulphuric and nitric acids, a diazonium coupling method and by reduction of amide functions on the surface of MWCNTs. Then condensation reactions with alkyl or aryl chlorophosphates were undertaken to obtain compounds 7 to 12. Phosphorylation of pristine MWCNTs was achieved by a 1, 3 dipolar cyclo addition of diphenyl phosphoryl azide. Characterization of the phosphorylated multiwalled carbon nanotubes has been performed by Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Energy X-Ray Dispersive Spectroscopy (EXDS), Thermal Gravimetric Analysis (TGA), Fourier Transform Infrared (FTIR) and Raman Spectroscopy. These techniques together gave evidence for surface, structure and chemical modifications of the synthesized material.

The enzyme polyphenolase, which catalyses the oxidation of phenols to catechols and subsequently dehydrogenates these to o-quinones, is widely distributed in nature. The multicopy plasmid vector pIJ702 contains a mel gene from Streptomyces antibioticus, that codes for the production of a polyphenol oxidase. The plasmid was isolated from Streptomyces lividans 66pIJ702 and subjected to a variety of mutagenic treatments in order to establish a structurefunction relationship for the polyphenolase enzymes. An attempt was made to engineer the polyphenolase enzyme by localized random mutagenesis in vitro of the mel gene on pIJ702, in order to alter properties like productivity, activity and substrate specificity. It was hoped to alter the amino acid sequence of the active site of the enzyme in order to facilitate catalysis in an organic environment. The plasmid was subsequently transformed into a plasmid-free Streptomyces strain, and enzyme production was carried out in batch culture systems, in order to determine the effect of the height treatment, and to isolate and propagate functional polyphenolase mutants for organic synthesis.

The stereoselectivity of TiCI₄-catalysed Mukaiyama reactions of a camphor acetal-derived chiral silyl enol ether with a range of substituted aromatic aldehydes has been examined. The enantiomeric excess in each of the resulting ß-hydroxy ketones, determined by ¹H NMR spectroscopy using the lanthanide chiral shift reagent Pr(Etcf₃), ranged between 9 and 13%. The stereo-directing potential of the camphor acetal as a chiral auxiliary in the α-benzylation of carboxylate esters has been studied; the acids were chosen to illustrate substituent effects on asymmetric induction. The observed diastereoselectivity increased with increasing steric bulk of the ester group and α-benzylation of the tert-butylacetate derivative proceeded with 48% diastereoselectivity. It is proposed that the enolate adopts an endo-s-trans conformation in the transition state and preferential attack by the electrophile at the somewhat less hindered Si-face is supported by both the optical rotation data and computer modelling studies. Reductive cleavage and hydrolysis of one of the benzylated esters furnished known products from whose optical rotation the configuration of the major diastereomer was established. In order to improve the steric advantage of Si-facial attack, methods of increasing the steric bulk of the blocking group were explored. A novel 2,2-propylenedioxy hydroxycamphor acetal and its 3,3-propylenedioxy analogue were prepared. Selected carboxylate esters of these propylenedioxy acetals were subjected to α-benzylation and the 2,2-(propylenedioxy)-3-exo-tert-butylacetate derivative showed a diastereoselectivity of 57% during a-benzylation. Hydrolysis of the abenzylated phenylacetate analogue offered the known 2,3-diphenylpropanoic acid whose optical rotation indicated the preferred configuration at the new chiral centre to be (R), a result which is consistent with the proposed approach of the electrophile to the less hindered Re-face of theendo-s-trans enolate moiety and reflects an inversion of the configurational bias observed with 2-v exo-carboxylate analogues. Attempts to prepare the monocatechol acetal of the hydroxy camphor derivative although unsuccessful, led to the isolation of two novel dibornyl ethers whose structures were established by 1- and 2-D NMR spectroscopy. A study of novel applications of camphor-derived auxiliaries in the asymmetric synthesis of α-amino acids has been initiated. The several approaches tried led to the preparation of three novel dural glycine derivatives in good yield

Herein an alternative approach to the conventional batch synthesis of L-menthyl glyoxylate hydrate (MGH), an important intermediate in the synthesis of drugs of importance is reported, through flow chemistry technology. MGH was initially synthesized in batch and various reaction parameters optimized. It was found to proceed to completion after 6 hours of esterifying glyoxylic acid with excess alcohol (L-menthol) in the presence of a catalyst, ideally amberlyst-15 (an ion exchange resin) at 105 °C giving a yield of 72 %. The batch reaction conditions were adopted in a continuous flow synthesis setup, using the Labtrix Start system, in which reaction conditions were optimized. The optimization of glyoxylic acid conversion (92 %) in the Labtrix Start system gave reaction conditions that resulted in low MGH selectivity (25 %) whereas the optimization for MGH selectivity (100 %) gave a conversion a poor glyoxylic acid conversion (15 %). The FlowSyn system fitted with a column reactor gave the best results, in which the optimum conditions were an excess of L-menthol (1.5 M, 6.0 equiv.), temperature (80 °C) and a residence time of 2.5 minutes with a high selectivity (77 %) and average conversion (50 %). The optimized reaction conditions for conversion and selectivity on the different flow systems did not vary significantly and similar trends were observed for the systems. It was shown that an increase in temperature, mole equivalents and residence time led to an increase in MGH conversion in all flow systems. The scale up of the esterification reaction from the Labtrix Start system (19 μL microreactor) to the FlowSyn system fitted with a 2 mL reactor chip, showed that the reaction proceeds with a slight drop in selectivity from 100 % to 92 % while conversion dropped from 15 to 12 %. On the contrary, a significant drop in conversion and selectivity were observed when the FlowSyn column reactor was up-scaled to the Elite-tubular furnace, owing to the poor mixing in the larger channel size reactor.

Nitrate esters of aromatic alcohols were synthesized by esterification which involved competition between 0-nitration and aromatic C-nitration. TLC analysis gave a pattern of adsorption affinities for the nitroxy group and other substituents consistent with the molecular conformations. The NMR frequency of the α-protons showed a linear correlation with the accepted group electronegativities of the substituents in molecules with rigid carbon skeletons and gave a value of 4.18 kcal/mole for the nitroxy group. The symmetric and asymmetric IR stretching frequencies of nitroxy groups in dilute cyclohexane solution were shifted to higher values by steric interaction between contiguous groups when the C-ONO₂ bonds were constrained to coplanarity. The UV spectra showed benzenoid, π→π*, and n→π* bands and a solvent perturbation effect assigned to a solvent → solute charge-transfer interaction. The nitrate esters reacted with the solvent when irradiated in solution in the wavelength range of the n→π* excitation. Product analysis indicated that C-C bond cleavage occurred via intermediate alkoxyl radicals. Rate studies showed the following order of reactivity: benzyl nitrate < dl-hydrobenzoin dinitrate < meso-hydrobenzoin dinitrate, < trans-1, 2-acenaphthenediol nitrate < cis-1, 2-acenaphthenediol dinitrate. The rate measurements and ESR spectra gave evidence of intramolecular energy transfer from the naphthalene moiety to the nitroxy groups in the 1, 2-acenaphthenediol dinitrates assigned as a singlet→singlet transfer. Calculations from the apparent first-order rate constants and spectra showed that benzyl nitrate, and meso- and dl-hydrobenzoin dinitrates photolysed with a quantum yield of about 2 in benzene solution. A solvent effect caused k[subscript Et₂O] > k[subscript EtOH] >k[subscript PhH]. On the basis of product analysis, rate measurements, estimated quantum yields and ESR spectra a mechanism for the nitrate ester photolysis was proposed. / Science, Faculty of / Chemistry, Department of / Graduate

Tetra-p-nitrophenyl pyrophosphate, generated in situ by the reaction of di-p-nitrophenyl phosphate with di-p-tolyl carbodiimide in anhydrous dioxane, has been shown to be a new and powerful phosphorylating agent, it has been used for the phosphorylation of various aliphatic alcohols and carbohydrate derivatives, particularly nucleosides, as well as of aliphatic amines and mercaptans. The removal of the protecting groups from the initially formed di-p-nitrophenyl alkyl phosphates has been accomplished by both alkaline hydrolysis and catalytic hydrogenolysis. Various other chemical reactions of the intermediate neutral esters, as typified by di-p-nitrophenyl methyl phosphate, have been studied in considerable detail. Included in these are: mild alkaline hydrolysis, partial hydrogenolysis, the action of anhydrous amines, acidic hydrolysis, base catalysed transesterification, and reductive cleavage with sodium in liquid ammonia. The method has been specifically applied, to the phosphorylation of 2',3'-0-isopropylidine guanosine and has led to the first efficient synthesis of the biologically interesting guanosine-5'-phosphate. Also the enzymatic-ally useful guanosine-5’-mono-p-nitrophenyl phosphate and uridine-5’-mono-p-nitrophenyl phosphate have been prepared and the formation of 3,5’-cyclo-guanosine quaternary salts observed. Several synthetic routes have been developed for the synthesis of 1,2-0-isopropylidine-D-xylofuranose-3,5-cyclic phosphate and of D-xylofuranose-3,5-cyclic phosphate. Hot alkaline hydrolysis of the former followed by acidic removal of the isopropylidine group has led to a mixture of D-xylofuranose-5-phosphate and D-xylopyranose-3-phosphate which were separated by ion exchange chromatography. Both products have been fully characterized and the method constitutes the first successful synthesis of D-xylose-3-phosphate. A previously reported isolation of the latter compound has been reexamined and shown to be in error. Reinterpretation of the data has shown the reported compound to be in fact D-xylulose-5-phosphate. / Science, Faculty of / Chemistry, Department of / Graduate

This thesis describes the synthesis and chemistry of alkyl 2,3-bis(trimethylstannyl)-2-alkenoates ((78) and (83)). It was shown that these compounds could be readily transformed into useful intermediates for the synthesis of functionalized, stereochemically defined tetrasub-stituted alkenes (87) and tricyclic dienes of general structure (322A). The synthesis and chemistry of compounds (277) and (278) is also described. The palladium(O)-catalyzed addition of hexamethylditin to a variety of α,β-acetylenic esters (90), afforded in a stereoselective manner, the corresponding alkyl (Z)-2,3-bis(trimethylstannyl)-2-alkenoates (83). Subsequent thermolysis of these compounds afforded the corresponding alkyl (E)-2 , 3-bis(trimethylstannyl)-2-alkenoates (78). It was found that treatment of alkyl (E)- and (Z)-2,3-bis(tri-methylstannyl)-2-alkenoates with methyllithium at low temperature, followed by reaction of the resultant nucleophilic intermediate with a variety of alkylating agents, afforded the trisubstituted vinylstannanes (80). On the other hand, successive treatment of methyl w-halo-2,3-bis-(trimethylstannyl)-2-alkenoates (202) with methyllithium and HMPA provided a facile route to cyclic β-trimethylstannyl α,β-unsaturated esters (203). Compounds (80) were readily converted into vinyl iodides of general structure (219) in which W is a functionalized group derived from the CO₂R moiety. These latter compounds served as useful intermediates for the synthesis of functionalized, stereochemically defined tetrasubstituted alkenes (87). For example, treatment of compounds (219) with 1.1 or 2.2 equiv of n-butyllithium at -78°C afforded the corresponding vinyllithium species (86) , which could either be alkylated directly or further transposed into the organocopper(I) reagent (263A) and then alkylated, to afford in each case, the tetrasubstituted alkenes (87). The Pd(0)-catalyzed addition of tri-n-butylstannyltrimethylgermane (276) to a variety of α,β-acetylenic esters (90) afforded the corresponding compounds (277) and (278) in a ratio of approximately 3:1, respectively. Treatment of the (E) isomers (277) with n-butyllithium at -98°C, followed by alkylation of the resultant nucleophilic intermediate afforded the corresponding trisubstituted vinylgermanes (293). One of these latter compounds was readily converted into the iodo bromide (308), which is potentially synthetically equivalent to the d,a synthon (310). When the enolate anion of compounds (203) was successively treated with HMPA and compound (308) the esters (311) were obtained. The Pd(0) catalyzed intramolecular coupling of the vinylstannane-vinyl iodide moieties of (311) provided a facile route to the bicyclic triene esters (312). Similarly, alkylation of the enolate anion of compounds (203) with (325) (which was readily obtained from (203), in which n - 1), followed by the Pd(0)-catalyzed coupling of the resulting alkylated material afforded the tricyclic diene esters (322A). [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

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