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This study was designed to develop some predictive models for the dielectric properties of the chemicals and chemical reactions and make use of dielectric properties and microwave irradiation in the chemical reactions. Specifically, the dielectric properties of the following systems were investigated at microwave frequencies of 2450 and 915 MHz: (1) C1--C5 alcohols, (2) glucose aqueous solutions, (3) lysine aqueous solutions, (4) mimicked esterification reaction model systems of parahydroxybenzoic acid with methanol, 1-propanol and 1-butanol in the presence of para-toluene sulfonic acid as a catalyst, (5) Maillard reaction model system consisting of glucose, lysine and water. / The dielectric properties of the model systems showed that they depended on the frequency applied, concentration of the material, and temperature. Most of the predictive models showed that there exists a linear or quadratic relationship between dielectric constant and concentration or temperature. However, the quadratic equation is better than the linear one to describe the variation of the loss factor with temperature or concentration. / Esterification showed great advantages for the use of microwave irradiation in chemical reaction. It included reduction in reaction time, and provided distinct temperature profiles due to microwave environment during chemical reactions. The reason for rate enhancement of this type of reaction was also demonstrated from the temperature profile. / Microwave-assisted solvent free Maillard reaction model system, consisting of glucose and lysine, demonstrated that the heating method applied was not one of the crucial factors, but the temperature level was important during the chemical reaction. / The relationship of loss factor with yield of reaction showed that it is possible to use dielectric data to analyze, and monitor the chemical reaction. It provided a new methodology to analyze the reaction. / The relationship between the loss factor, loss tangent and the reaction time, and concentration of the material showed that it is also possible to use dielectric data at microwave frequencies of 2450 and 915 MHz to study chemical reactions, especially the kinetics.

The "modified triester" and phosphodichloridite procedures for oligoribonucleotide synthesis, using 2'- silylated nucleosides, were compared. Phosphodichloridite reagents were faster and more efficient than the arylsulphonyl reagents for both dinucleotide and mononucleotide phosphotriester synthesis. / The trichloroethyl group was better than tribromoethyl, p-nitrophenethyl or methyl protecting groups for solution-phase synthesis. Trichloroethyl dichlorophosphite was used in block condensations to prepare CCCGA and UCAUAA. / An automated RNA synthesizer was developed. Nucleoside methyl chlorophosphites were used with silica gel supports. Polystyrene, polyacryloylmorpholide and controlled pore glass supports were also used but were not as satisfactory. Oligoribonucleotides, up to 17 units long, were rapidly prepared in high overall yield. The sequences were purified by TLC and gel electrophoresis. Enzymatic degradations and HPLC confirmed the composition of the products.

The emergence of multi-drug resistance (MDR) to antimalarial and anticancer drugs has stimulated a search for novel MDR inhibitors/reversers. Bisbenzylisoquinoline alkaloids (BBIQ) are potential agents for reversing MDR, especially when used as synergistic enhancers of anticancer and antimalarial drugs with improved therapeutic efficacy. Despite numerous useful biological activities reported for BBIQ’s, the various syntheses of individual members remained cumbersome and the overall yields are low. In addition, published methods are nonstereospecific and produced racemates. The aim of this project was to develop a synthetic pathway for the preparation of cycleanine, a natural BBIQ with a symmetrical structure. The protocols developed for the synthesis of cycleanine will serve as a template for the synthesis of other BBIQ’s with more complex structures. The only published total synthesis of cycleanine did not address regioselectivity and stereoselectivity, furthermore, key steps suffered from extremely low yields of the products. Our synthetic pathway is a chiral auxiliary-based asymmetric synthesis that generates enantioselectively a 1,2,3,4-tetrahydroisoquinolines (THIQ) monomers. Cheap, commerciallyavailable starting materials were used to prepare monomers in a regioselective as well as stereoselective manner in good yields. The key feature of this method entails coupling of a chiral β-phenethylamine and halophenylacetaldehyde using the Pictet-Spengler reaction. Due to the difficulties encountered during the course of the preparation of monomers, different methods were tried and formation of unanticipated products rationalised. Dimeric BBIQ’s are constituted of monomeric THIQ’s which are reported to have array of biological properties including MDR reversing activities, therefore, the total synthesis of cycleanine will serve two purposes. In this investigation, the THIQ monomers were synthesised by a pathway that avoid harsh reaction conditions. Major reactions employed include nucleophilic aromatic substitutiton, Wittig reaction, hydroboration and IBX oxidation. Some of the steps were attempted on model compounds to optimise the conditions prior to attempting the reaction on cycleanine precursors. Two major contributions toward the synthesis of BBIQ’s were made in this study. The reaction conditions to control the regioselectivity and enantioselectivity of the Pictet- Spengler reaction for the preparation of THIQ moiety were developed. A major drawback of the published syntheses of BBIQ’s is the harsh conditions and low yields associated with the Ullmann reaction, which is used in the formation of the diaryl ether bonds. We have shown that the microwave-assisted nucleophilic aromatic substitution of aryl fluorides provide a much superior method for the formation of the key diaryl ether bond. Although we failed to form the final diaryl ether bond, the pitfalls encountered in the synthetic pathway are discussed and potential solutions are presented. The developed synthetic pathways are of general applicability and therefore can also be employed in the synthesis of other macrocyclic natural products containing diaryl ethers. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.

The biosynthesis of Aflatoxin B1 (AFB1) has been the subject of conflicting speculation and numerous reviews. The currently accepted scheme for the aflatoxin pathway is based on data obtained from feeding studies using isotopically labelled precursors. In these studies the conversion of possible intermediate metabolites to AFBl by mutants of Aspergillus parasiticus illustrated their role as biogenetic precursors. Currently there is now agreement on the identity of most of the intermediate Illetabolites involved in the biosynthesis of AFB1. However, there is a lack of clarity on the details of AFB1 biosynthesis including the conversion of sterigmatocystin (ST) to AFB1 via the metabolite O-methylsterigmatocystin (OMST). There is no clear cut evidence of the metabolic role of OMST, i.e., either it is a compulsory intermediate or a shunt metabolite and hence part of a metabolic grid. In order to investigate this step in AFBl biosynthesis, ST was isolated from surface cultures of A. versicolor (M1101) and purified by silica gel column chromatography and repeated recrystallisation. Sterigmatocystin was characterised by thin layer chromatography (t.1.c.), low resolution mass spectrometry (M.S) and nuclear magnetic resonance spectroscopy (N.M.R). A series of seven derivatives of the free hydroxyl group of ST were synthesised by known chemical reactions, purified by silica gel column chromatography and characterised by high resolution mass spectrometry and proton nuclear magnetic resonance spectroscopy. A high pressure liquid chromatography (HPLC) method was developed using a fluorescence detector. The optimum parameters for the separation of the four major aflatoxins, namely AFBl, AFB2, AFGl and AFG2, using trifluoroacetic acid as the derivatising reagent, were obtained for a reversed phase Prodigy C18 column with a mobile phase of water: acetonitrile: isopropanol: acetic acid (8: 1: 0.5: 0.5, v/v). Feeding studies, using whole cells of A. parasiticus (WhI-11-105), showed that ST and the ST derivatives were converted to AFB1. A time courser study for the conversion of ST and selected ST derivatives to AFB1 indicated a decrease in the rate of conversion in the order: a-propyl sterigmatocystin (OPROST) > a-ethyl sterigmatocystin > a-methylsterigmatocystin > Sterigmatocystin> a-benzoyl sterigmatocystin (OBzST). It was apparent that the "enzyme" responsible for the conversion of the derivatives to AFB1 did not display a high degree of substrate specificity, since it was unable to recognize the difference between the various alkyl groups, either as ether or ester functional groups. An HPLC method was developed using a diode array detector. The optimum parameters for the separation of aflatoxin metabolites and the synthesised derivatives were obtained for a reversed phase Lichrosphere RP-I8 column with a 30 minute gradient elution program with water and acetonitrile as the mobile phase. Crude cell-free extracts were prepared by lyophilisation of the mycelia of A. parasiticus (Whl-11l-105) with phosphate buffer. The temperature and pH for the conversion of ST to AFB1, were found to be optimum at 28°C and 7.2, respectively. The addition of SAM (1.5 mM) and NADPH (1.5 mM) increased the conversion of ST to AFBl from 11.21 % to 27.10 %. A time course study with ST, OMST and OPROST showed that the rate of conversion to AFBl was close to linear for an incubation time of up to 60 minutes. Approximation of the reaction rate indicated a decrease in the order: OMST > ST > OPROST. This indicated that the time course reaction using whole cells was in part a measure of membrane permeability rather than substrate specificity. Molecular exclusion chromatography was used to separate enzymatic protein from primary and secondary metabolites, small biomolecules and indigenous co-factors (MW < 10 000) and the partially purified "enzyme" was concentrated by dialysis against solid sucrose. The "enzyme" was subjected to non-denaturing polyacrylamide gel electrophoresis and was found to be made of sub-units ranging from 58 kDa to over 200 kDa. Enzymatic investigations with ST, as substrate, indicated that OMST is a compulsory intermediate in the biosynthesis of AFBl. Also, enzymatic investigations of selected ST derivatives showed that the partially purified "enzyme" displayed relative specificity for these substrates, viz., OMST, OPROST and OBzST. Three xanthones, namely, 1-hydroxy-,6-dimethylxanthone, I-methoxy-3,6-dimethylxanthone and l-acetyl-3,6-dimethylxanthone were synthesised, purified and characterised spectroscopically. Whole cell studies of A. parasiticus (CMI 91019b) and A. parasiticus (Wh1-11-105) showed that these xanthones inhibited AFBl production to varying extents. Kinetic studies of cell-free extracts revealed that the 1-methoxy-3,6-dimethylxanthone derivative was a non-competitive inhibitor. The Michaelis Menten constant (Km) of approximately 5.60 uM (for OMST) was determined for a cell-free reaction at pH 7.2 and 28 QC. A Clark oxygen electrode was used to carry out oxygen consumption studies in a partially purified "enzyme" preparation. A calibration system was designed and the enzymatic conversion of OMST to AFB1 and NADPH consumption were monitored by HPLC and UV spectroscopy, respectively. From the results of these enzymatic reactions, the following stoichiometric relationship was determined: 2 mole oxygen consumed = 1 mole NADPH consumed = 1 mole AFB1 produced A tentative mechanism is discussed for the conversion of OMST to AFB1 which utilizes a monooxygenase and a dioxygenase. / Thesis (Ph.D.)-University of Natal, Durban, 1996.

This thesis explores three rare synthetic routes: the synthesis of hydrazines via the aza-Lossen rearrangement, the synthesis of carbamoyl azides from amines, and deprotection reactions using water at elevated temperatures. The aza-Lossen reaction was found to be ideal at “infinite dilution” conditions and could be performed with both aryl and alkyl example. Carbamoyl azides could be synthesized in high yields from both aryl and alkyl amines. The carbamoyl azide reaction was found to be much more efficient with Cs (+1) present. Lastly, water at elevated temperatures conditions was efficient at removing various amine and hydroxyl protecting groups.

The work described in the two parts of this thesis is concerned with the development of two methods for the synthesis of substituted olefins. Both methods involve elimination reactions of (beta)-hydroxysilanes to form the double bond, therefore in the general introduction these reactions are discussed together with the methods available for the preparation of (beta)-hydroxysilanes ... [see pdf file for full abstract].