In recent years, two mechanisms have been proposed for the enzymatic formation of acetoacetate by liver extracts. One of these, the "HMG-CoA cycle", involves the condensation of acetyl-CoA and acetoacetyl-CoA to form β-hydroxy- β-methylglutaryl-CoA (HMG-CoA) via the action of the HMG-CoA condensing enzyme, with the release of free coenzyme A (CoASH) (reaction 1). Acetyl-CoA + acetoacetyI-CoA + H₂O⇆ HMG-CoA + CoASH (1) followed by cleavage of the HMG-CoA to acetyl-CoA and free acetoacetate, via the action of the HMG-CoA cleavage enzyme (reaction 2). HMG-CoA⇆ acetoacetate + acetyl-CoA (2) The second mechanism which has been proposed involves a direct deacylation of acetoacetyl CoA through the action of a specific acetoacetyl-CoA thioesterase (reaction). Acetoacetyl-CoA + H₂O→ acetoacetate + CoASH (3) Evidence is presented which indicates acetoacetate formation by a soluble enzyme system from bicarbonate extracts of whole beef liver proceeds largely, if not exclusively, via HMG-CoA (reactions 1 and 2). Both the HMG-CoA condensing and cleavage enzymes have been partially purified from beef liver bicarbonate extracts, each free of contamination by the other, in good yields. The level of activity of these two enzymes is sufficiently high to account for all the acetoacetate formed by liver tissue. The possibility that the specific acetoacetyl-CoA thioesterase may play a minor role in the enzymatic synthesis of acetoacetate is also discussed. The intracellular and tissue localization of the enzymes of acetoacetate formation is also discussed. In liver homogenates, most, if not all, of the acetoacetate-synthesizing activity appears to be associated with the mitochondrion. Evidence is also presented that the primary reason for the inability of extrahepatic tissue preparations to catalyze the accumulation of acetoacetate may be the lack of one of the enzymes involved, i.e., the HMG-CoA condensing enzyme, and not merely further metabolic degradation of acetoacetate, as has generally been assumed. An enzyme fraction in chicken liver extracts which inhibits the in vitro formation of acetoacetate by chicken liver homogenates has also been studied. Evidence is presented that this enzyme fraction exerts its effect through the inactivation of coenzyme A. Preliminary observations indicate that this enzyme may be a 3’-nucleotidase, removing the 3’- phosphate of coenzyme A, forming dephosphocoenzyme A. The occurrence of a highly active β-hydroxybutyryl dehydrogenase in extracts of dry culture of C. kluyveri has been noted. This enzyme differs from the similar enzyme reported in mammalian tissues, in that it is very specific for triphosphopyridine nucleotide, and is virtually inactive with diphosphopyridine nucleotide (DPN) (reaction). Acetoacetyl-CoA + TPNH + H⁺⇆β - hydroxybutyryl-CoA (4) + TPN⁺ / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The products arising from the liquid-phase pyrolyses of 3,5-dimethyl-3-carbomethoxy-1-pyrazoline and 4,5-dimethyl-3-carbomethoxy-2- pyrazoline have been isolated and identified. The pyrolysis of 3,5-dimethyl-3-carbomethoxy-1-pyrazoline has been found to yield a mixture of 5 isomers consisting of 15% methyl trans-2-methyl-2-pentenoate, 10% methyl cis-2-methyl-2-pentenoate, 3% methyl trans-2-methyl-3-pentenoate. 45% methyl cis-1,2-dimethylcyclopropane-1-carboxylate and 27% methyl trans-1,2-dimethylcyclopropane-1-carboxylate. The pyrolysis of 4,5-dimethyl-3-carbomethoxy-2-pyrazoline yielded a mixture of 7 isomers consisting of 25.5% methyl trans-3-methy1-2-pentenoate, 26% methyl cis-3-methyl-2-pentenoate, 3% methyl trans-3-methyl-3-pentenoate, 2% methyl cis-3-methyl-3-pentenoate, 26% methyl trans-1,2-dimethylcyclo-propane-3-carboxylate, 16% methyl cis-1,2-dimethylcyclopropane-3-trans-carboxylate and 0.8% methyl 3-ethyl-3-butenoate. Pyrolysis of both pyrazolines has also been obtained in the vapour-phase and under these conditions a higher proportion of cyclopropanecarboxylic esters was formed than that obtained in the liquid-phase pyrolysis: 3,5-dimethyl-3-carbo-methoxy-1-pyrazoline yielded a mixture containing 94.5% cyclopropane carboxylic esters and 4,5-dimethyl-3-carbomethoxy-2-pyrazoline yields a mixture containing 67% of cyclopropane carboxylic esters. The vapour-phase pyrolysis of the 1-pyrazoline occurred readily at 200° whereas the vapour-phase pyrolysis of the 2-pyrazoline was found to require a catalyst. This catalyst is believed to facilitate the transformation of the 2-pyrazoline to the readily pyrolisable 1-pyrazoline form. Studies have been made of the equilibration of the unsaturated, esters arising from the pyrolysis of the pyrazolines and have shown that the composition of the olefin portion of the pyrolysis mixture in general is not an equilibrium mixture. A mechanism for the pyrolysis is suggested. The unsaturated esters arising from the pyrolysis of 4,5-dimethyl-3-carbomethoxy-2-pyrazoline have been synthesised and identified and structural assignments have been made. / Science, Faculty of / Chemistry, Department of / Graduate

The research presented in this study combines natural product chemistry with organic / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

The olefin metathesis reaction is a well established and powerful method for the synthesis of alkenes. This reaction can be further classified into the intermolecular process known as cross-metathesis and the intramolecular process known as ring-closing metathesis. The aim of these studies is the use of the two variants of the metathesis reaction for the development of new methods for the synthesis of heteroaromatic structures, in particular the synthesis of polysubstituted pyridines.

No description available.

The research programme involved the exploitation of ultrasound with a view to applications within commercial and processing industries. This was accomplished by employing dosimetry and calorimetry to study the efficiency of several sonochemical reactors. The effect of factors such as reaction vessel geometry and volume was investigated and the general trends obtained for all three dosimeters were comparable. The effects of various parameters e.g. power, solvent, volume etc etc on the sonochemical 0-allcylation of 2,6-dimethylphenol was examined. Decreases in temperature and volume, and increases in concentration and power, led to increases in the sonochemical effect. A study of the allcylation products from a reaction between 5-hydroxychromone-2-carboxylic acid ethyl ester with less reactive alkyl halides such as 1- and 2-bromobutane resulted in comparisons with phase transfer catalysis and conventional thermal methods. An investigation of the dehydrogenation of tetrahydronaphthalene under the influence of sonication was also attempted. Dehydrogenation was enhanced by sonication with sonochemical dehydrogenation occurring 20-40°C below the corresponding thermal reaction. Sonication as a processing aid was studied using examples taken from the food industry. The applications of particle size reduction, emulsification and crystallisation of various foodstuffs such as rice, sugar and cocoa grains were examined. The effect of sonication on the viscosity of gelled starch was also monitored with a view to achieving either a permanent or temporary reduction in viscosity.

The research presented in this study demonstrates the critical role that organic synthesis plays in natural product chemistry. The biological activity demonstrated by 2-methyl-6-(3-methyl-2- butenyl)benzo-1,4-quinone prompted an investigation into the synthesis of this compound. This natural product showed significant activity against Staphylococcus epidermidis. Therefore the aim of this study was to synthesise 2-methyl-6-(3-methyl-2-butenyl)benzo-1,4- quinone and structural analogues. The regioselective synthetic route formulated for the synthesis of 2-methyl-6-(3-methyl-2- butenyl)benzo-1,4-quinone involved five steps. Different strategies towards the synthesis of this compound were investigated. The regioselective C-alkylation step was proving to be the most challenging. The synthetic strategies investigated included carbon alkylation of a phenoxide, directed-o-metallation, metal-halogen exchange and copper(II) Grignard-type metal halogen exchange. Problems were encountered with regioselectivity when carbon alkylation of a phenoxide was employed for the o-prenylation of o-cresol. The C-prenylated isomer was formed along with the O-prenylated isomer. When the reaction temperature was lowered, the yield of the desired C-prenylated isomer improved, whereas the yield of O-prenylated isomer declined. Although the reaction was performed under different conditions, the formation of the O-prenylated isomer could not be prevented. Therefore, another synthetic strategy was considered. The directed-o-metallation reaction was subsequently employed because of the associated regioselectivity. Unfortunately the desired product was not obtained when this method was employed. The reaction was attempted using different conditions, but the product could not be isolated. Since the directed-o-metallation protocol did not yield the desired results, another method was considered. Therefore, a metal-halogen exchange reaction was employed. The metal-halogen exchange transformation was preceded by the preparation of the o-brominated precursor. Regioselectivity-related problems were initially encountered during the synthesis of the obrominated precursor. The o-brominated isomer was formed in a 1:1 ratio with the pbrominated isomer. Further investigation led to a synthetic protocol that afforded the desired o-brominated isomer in a better yield. The metal-halogen exchange transformation was subsequently attempted, but the product was obtained in an unsatisfactory yield. Therefore, another method was employed in an effort to achieve regioselective C-alkylation with a better yield. Copper(II) Grignard-type metal-halogen exchange was successfully employed to achieve regioselective C-alkylation in good yield. The subsequent step was the deprotection, although problems were encountered, it was eventually achieved. The final step was the oxidation to obtain the desired compound, 2-methyl-6-(3-methyl-2-butenyl)benzo-1,4- quinone. The same procedure was successfully applied in the synthesis of structural analogues 2-isopentyl-6-methylbenzo-1,4-quinone, 2-(3,7-dimethylocta-2,6-dienyl)-6-methyl-1,4- benzoquinone and 2-(3,7-dimethyl-octyl)-6-methyl-1,4-benzoquinone. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

The main electrophilic source used in radiolabelling is [18F]F2, which is highly reactive, toxic and requires specialist equipment for safe handling. The Gouverneur group has initiated a research programme focused on the preparation of new stable and easy-to-handle N-18F reagents. In the development of [18F]radiolabelling reactions it would be extremely valuable to develop a library of selective N-18F reagents possessing reactivity tailored to the desired chemical transformation. The aim of this thesis is to further assess the scope of electrophilic N- 18F reagents in new transformations for the construction of C-18F bonds.

In this thesis, firstly, a Pd-catalysed diastereoselective carbocyclisation of allenes with aryl halides or vinyl iodides was designed and developed to form arylative or vinylative spirolactam compounds. High yields and diastereoselectivities were obtained in the presence of Pd₂(dba)₃/dppe and K₂CO₃ in DMSO at 70 &deg;C, particularly when spiropiperidin-2-ones were formed. The method is simple to perform and broad in scope. Having established the diastereoselective methodology for the arylative or vinylative allene carbocyclisation, a Pd-catalysed enantioselective version was developed by using bisoxazolines as chiral ligands. Aryl halides and vinyl iodides were investigated in this carbocyclisation. High yields and enantioselectivities were obtained in the presence of Pd(OAc)₂, a bisoxazoline ligand <strong>L7d</strong> derived from L-isoleucine and Ag₃PO₄ in 1,2-dichloroethane at 70 &deg;C. No olefin isomerisation was observed when cis-vinyl iodides were used. The method is mild, efficient and broad in scope. A palladium catalysed diastereoselective allene carbocyclisation reaction was developed via enamine catalysis and palladium catalysis, which allows for the efficient carbocyclisation of formyl or ketone allenes. Good yields and high diastereoselectivities were obtained in the presence of Pd(OAc)₂ and pyrrolidine in toluene at 60 °C when formyl allenes were investigated. The cyclisation is diastereoselective and can also performed as a catalytic asymmetric reaction by using prolinol derivatives as chiral catalysts. Good yields and high diastereo- and enantioselectivities were obtained in the presence of catalyst <strong>(S)-L19</strong>. Additionally, a boronic acid catalysed ene carbocyclisation of acetylenic dicarbonyl compounds was developed. An attempted transesterification of a &beta;-ketoester substrate bearing a pendent terminal alkyne substituent at the &beta;-position led to the discovery of an efficient 3-nitrobenzeneboronic acid catalysed ene carbocyclisation of acetylenic dicarbonyl compounds. The reaction is easy to perform, efficient, broad in scope and provides a convenient transition metal-free alternative to existing catalytic protocols.

trans-2,5-Disubstituted tetrahydrofurans (THFs) are a common structural motif in a multitude of biologically active natural products. This thesis explores new synthetic routes for their synthesis and subsequent application towards the C_31-40 fragment of pectenotoxin-4. <b>Chapter 1: Introduction</b> This chapter reviews methods for the synthesis of trans-2,5-disubstituted tetrahydrofurans with a special emphasis on those that have been applied towards the synthesis of natural products. <b>Chapter 2: Results and Discussion</b> The Acyloin Coupling Reaction towards trans-THFs A brief overview of the acyloin coupling reaction is followed by description of the aim for this part of the project, using this process as a key step towards trans-THFs. Work directed towards the stereoselective protonation of the bis-enolate intermediate formed during the acyloin coupling is discussed. The exploitation of A^1,3 strain was the most effective strategy found to control the diastereoselectivity in the protonation of the bis-enolate intermediate. Desymmetrisation Using Sharpless Asymmetric Epoxidation towards trans-THFs Strategy developed towards the synthesis of a 2,5-disubstituted 3-hydroxy trans-THF is studied. The optimisation of the synthesis of meso-hepta-1,6-diene-3,5-diol was examined and subsequent desymmetrisation using the Sharpless asymmetric epoxidation was explored. Approaches towards the FG Fragment of Pectenotoxin-4 The previous synthesis of the FG fragment was reviewed. Details of the retrosynthesis to be employed for the preparation of the southern hemisphere of pectenotoxin-4 are discussed. The desymmetrisation strategy previously explored was applied towards forming the F ring of pectenotoxin-4. The C_31-40 carbon skeleton was successfully formed in 12 steps using a convergent synthesis. The elucidation of an X-ray crystal structure requires further exploration to confirm the relative and absolute configuration of the THF formed. <b>Chapter 3: Experimental</b> Full experimental procedures and characterisation of compounds are reported.