No description available.

The vinylepoxide-diliydrofuran rearrangement offers a route to substituted 2,3- dihydrofurans with a high degree of diastereoselectivity. The rearrangement proceeds via an ylide-type intermediate arising from the thermolysis of a carbon-carbon epoxide bond. This thesis discusses work aimed at developing the rearrangement, introducing asymmetric control, and application of the dihydrofuran products in target molecule synthesis. Synthesis of the vinylepoxide rearrangement precursors is described, and development of the rearrangement to achieve a moderate scale rearrangement process is discussed. Alternative rearrangement technologies are also explored. Asymmetric induction into the rearrangement was approached by the use of chiral auxiliaries and in particular C2 symmetric amines. A novel synthesis of (S,S)-2,5-diphenylpyrrolidine and (S,S)-2,6-diphenylpiperidine is reported. High degrees of enantiomeric purity were achieved through the application of an effective oxazaborolidine catalyst in the reduction of dibenzoylethane and dibenzoylpropane. Use of this chiral reduction catalyst on further diketones is described. Application of the dihydrofuran products in the synthesis of several 2,6-disubstituted- 3,7-dioxabicyclo[3.3.0]octanes. These compounds, commonly termed furofuran lignans exhibit a wide range of biological properties. The dihydrofuran products were combined with a range of dimethylacetals, in a one pot synthesis, with high degrees of stereocontrol, by a Noyori type transacetalisation. Further derivatisation of these bicyclic compounds was accomplished and is discussed.Finally, with the vinylepoxide - dihydrofuran rearrangement established a preliminary exploration of the related vinylaziridine - 2-pyrroline rearrangement is reported.

Effet de la salinité pendant la croissance de plants de riz sur la biosynthèse de la 2-acétyl-1-pyrroline (2AP), composé aromatique clé des variétés de riz aromatique,le rôle de la 1-pyrroline dans la biosynthèse de la 2AP ainsi que l'origine du groupe acétyle ont été étudiés. La variété aromatique de Camargue (France), Aychade, a été cultivée soit dans un milieu liquide soit dans des pots en serre. Dans le milieu de culture liquide, une augmentation significative de la teneur en 2AP dans les feuilles a été observée quelle que soit la concentration en NaCl (de 1,7 à 170 mM). Une corrélation positive a été mise en évidence entre la teneur en sel et en 2AP. A de plus fortes concentrations en NaCl, il a également pu être montré qu'il y avait une relation entre la concentration en proline, un précurseur aminé majeur de la 2AP, et la teneur en 2AP. Inversement, les changements en acide -aminobutyrique (GABA), un des métabolites compétitif de la biosynthèse de la 2AP, n'ont pas été corrélés avec ceux de la 2AP. Dans les expérimentations menées en serre, la variété Aychade a été cultivée dans une solution saline à 30 mM, correspondant à une conductivité électrique de 3800 ± 400 S.cm-1, valeur considérée comme suffisante pour induire un stress salin sur le plant de riz. Cette solution saline a été appliquée à des dates et pour des durées différentes en fonction du cycle de développement de la plante. A la phase végétative, une relation positive a été observée dans les feuilles entre le traitement salin et la teneur en 2AP ainsi qu'en proline. Il est intéressant de noter que tous les grains provenant des plants traités avec la solution saline contenaient des teneurs nettement plus élevées en 2AP par rapport au contrôle. La synthèse de la 2AP la plus importante s'est produite lorsque les plants ont été soumis à un traitement salin pendant l'ensemble des phases végétative et reproductive. Cependant, dans le dernier cas, le rendement en grain était beaucoup plus faible. En supplémentant des cals de riz avec de la 1-pyrroline, il a été démontré que cette imine cyclique était un facteur limitant pour la biosynthèse de la 2AP non seulement dans la variété aromatique, mais également dans la non aromatique. Les essais conduits avec le glucose et les acides gras marqués 13C ont montré que ces molécules pourraient être précurseurs du groupe acétyle de la molécule de 2AP. / The effect of salinity during rice plant growth on the biosynthesis of 2-acetyl-1-pyrroline (2AP), characteristic flavour compound of fragrant rice cultivars was studied. Additionally role of 1-pyrroline in 2AP biosynthesis together with source of acetyl group were investigated. Aychade, a fragrant rice was cultivated either in a liquid medium adapted for seedlings or in pots in a greenhouse. A significant increase in 2AP levels in the leaves was observed whatever the concentration of NaCl (1.7 to 170 mM NaCl) in the culture medium. A positive correlation was found between the level of salt and that of 2AP. There was a relationship between the concentration of proline, a major amino precursor of 2AP and 2AP level at highest concentrations of NaCl. Conversely the changes in -aminobutyric acid (GABA), a competitive metabolite in 2AP biosynthesis were not correlated with those of 2AP. In greenhouse experiments, Aychade cultivar was grown under one level of salt solution, 30 mM that corresponds to EC of 3800 ±400 S.cm-1, value considered sufficient to induce salt stress in rice. Timing and duration of application of salt solution varied according to the growth stages. At vegetative phase a positive relation was observed between salt treatment and 2AP as well as proline levels in the leaves. Interestingly grains from all salt treated plants contained significantly higher levels of 2AP than those from control. The highest synthesis occurred when plants were subjected to salt treatment during whole vegetative and reproductive phases. However in the latter case crop yield decreased significantly. Through supplementation of rice callus with 1-pyrroline it was demonstrated that this cyclic imine was limiting factor for the 2AP biosynthesis not only in a fragrant variety but also in a non fragrant variety. Experiments with 13C labelled glucose and fatty acids showed that glucose and fatty acids could be precursors of acetyl group of 2AP.

A l'aide de la spectroscopie par Résonance Paramagnétique Électronique (RPE), la détection des certaines espèces radicalaires à très faible durée de vie se fait par la méthode du spin-trapping. Cette technique permet de caractériser ces radicaux “libres” en les piégeant à l'aide d'une molécule diamagnétique (nitrone) pour donner naissance à une espèce paramagnétique persistante (adduit de spin), ayant un spectre RPE caractéristique du radical piégé. Le temps de demi-vie d'un adduit du spin est fortement corrélé à la nature de la nitrone et du radical piégé (alkyle, alcoxyle, alkylperoxyle, ...). Cependant, le lien entre la structure de l'adduit et sa durée de vie n'est toujours pas clairement établi. De ce fait, nous avons entrepris une étude théorique des réactions mises en jeu dans la disparition de l'adduit de spin résultant du piégeage de radicaux alkylperoxyle par des nitrones de type N-oxy-pyrroline. Plus précisément nous avons postulé un mécanisme de dégradation unimoléculaire en deux étapes. Étant donné la complexité des états de spin dans les composés considérés dans le profil réactionnel, nous avons effectué cette étude par l'approche ab initio multidéterminantale (CASSCF). Les calculs ab initio CASSCF en phase gazeuse sur une série d'adduits de spin nous ont permis de valider ce mécanisme de décomposition dans les solvants organiques et de mieux comprendre le lien entre la structure de l'adduit et sa durée de vie. / In the field of electron paramagnetic resonance (EPR) spectroscopy, the detection of some radical species with a very short half-life time is possible using the spin-trapping method. This technique allows us to characterize transient radicals by trapping them with a diamagnetic molecule (nitrone for example) to give rise to a persistent paramagnetic species (spin-adduct), whose EPR spectrum is characteristic of the trapped radical. Half-life times are strongly correlated to the nature of the nitrone and the trapped radical (alkyl, alkoxyl, alkylperoxyl, ...). However, the link between the structure of the adduct and its half-life time is still not clear. Therefore, we carried out a theoretical study of the reactions involved in the decay of spin-adducts resulting from the trapping of alkylperoxyl radicals by pyrroline-N-oxide nitrones. More precisely, we were interested in the mechanism of the two-step unimolecular degradation. Given the difficulty to discribe the spin states in the considered compounds, we chose to rationalize this study by means of ab initio multireference approach (CASSCF). The ab initio CASSCF calculations of a series of nitroxides allowed to validate this mechanism in organic solvents and to better understand the relationship between the structure of the spin-adduct and its half-life time.

<p>Five-membered rings are readily prepared by <i>5-exo-trig</i> radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of <i>5-exo-dig</i> cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly <i>cis</i>-selective manner. When cyclizations were performed at 17 ^oC, <i>cis</i>/<i>trans</i>-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the <i>trans</i>-diastereomer as the major product (<i>cis</i>/<i>trans </i>= 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 ^oC produced 2,4-disubstituted pyrrolidines substantially enriched in the <i>trans</i>-isomer (<i>cis</i>/<i>trans</i> = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried.</p><p>The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.</p>

Five-membered rings are readily prepared by 5-exo-trig radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of 5-exo-dig cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly cis-selective manner. When cyclizations were performed at 17 oC, cis/trans-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the trans-diastereomer as the major product (cis/trans = 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 oC produced 2,4-disubstituted pyrrolidines substantially enriched in the trans-isomer (cis/trans = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried. The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.

No description available.

The flavour or fragrance of Basmati rice is associated with the presence of 2-acetyl-1- pyrroline. This work shows that a gene with homology to betaine aldehyde dehydrogenase (BAD) has significant polymorphisms in the coding region of fragrant genotypes relative to non fragrant genotypes. Accumulation of 2-acetyl-1-pyrroline in fragrant rice genotypes may be explained by the presence of mutations resulting in loss of function of the fgr gene product. The fgr gene corresponds to the gene encoding BAD2 in rice while BAD1 is encoded by a gene on chromosome 4. Development of an allele specific amplification (ASA) based around the deletion in the gene encoding BAD2 allows, perfect, simple and low cost discrimination between fragrant and non-fragrant rice varieties and identifies homozygous fragrant, homozygous non-fragrant and heterozygous non-fragrant individuals in a population segregating for fragrance. The cDNAs transcribed from rice chromosomes 4 and 8, each encoding an enzyme with homology to betaine aldehyde dehydrogenase were cloned and expressed in E. coli. The enzyme responsible for fragrance, encoded from chromosome 8, had optimum activity at pH 10, showed low affinity towards betaine aldehyde (bet-ald) with Km value of approximately 63ìM but a higher affinity towards -aminobutyraldehyde (GABald) with a Km value of approximately 9ìM. The enzyme encoded from chromosome 4 had optimum activity at pH 9.5 and showed generally lower affinity towards most substrates compared to the enzyme encoded from chromosome 8, substrate specificities suggest that the enzymes have higher specificity to aminoaldehydes and as such both should be renamed as an aminoaldehyde dehydrogenase (AAD). The inactivation of AAD2 (BAD2) in fragrant rice varieties likely leads to accumulation of its main substrate GABald which then cyclises to 1-pyrroline the immediate precursor of 2AP.

Very little is known about why and how the Parkinson's disease (PD) neurodegenerative process begins and progresses. In the course of developments for treatment of PD, the discovery of the inhibition of monoamine oxidase (MAO B) was a conceptual breakthrough, and has now been firmly established. MAO B has also been implicated in the neurodegenerative processes resulting from exposure to xenobiotic amines. For example, MAO B catalyzes the first step of the bioactivation of the parkinsonian inducing pro-neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Additional insight into the mechanism of catalysis of MAO B and the mechanism of neurotoxicity by MPTP is therefore very valuable in the pursuit of the treatment of PD. / Thesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2008.

Very little is known about why and how the Parkinson's disease (PD) neurodegenerative process begins and progresses. In the course of developments for treatment of PD, the discovery of the inhibition of monoamine oxidase (MAO B) was a conceptual breakthrough, and has now been firmly established. MAO B has also been implicated in the neurodegenerative processes resulting from exposure to xenobiotic amines. For example, MAO B catalyzes the first step of the bioactivation of the parkinsonian inducing pro-neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Additional insight into the mechanism of catalysis of MAO B and the mechanism of neurotoxicity by MPTP is therefore very valuable in the pursuit of the treatment of PD. / Thesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2008.