Thèse (M.Sc.)--Université Laval, 2008. / Bibliogr.: f. 106-116. Publié aussi en version électronique dans la Collection Mémoires et thèses électroniques.

Proefschrift Universiteit van Amsterdam. / Met bibliogr., lit. opg. - Met samenvatting in het Nederlands.

Reproduction de : Thèse de doctorat : Structure et dynamique des systèmes réactifs : Lille 1 : 2005. / N° d'ordre (Lille 1) : 3724. Résumé en français et en anglais. Titre provenant de la page de titre du document numérisé. Bibliogr. p. 227-250.

Cyclic peroxides are abundant in Nature and synthetic manipulation of the peroxide linkage and alkene portion of 1,2-dioxines has established 1,2-dioxines as important compounds as both chemical building blocks and bioactive compounds. Much of the chemistry performed thus far utilizing 1,2-dioxines involves the initial rearrangement of 1,2-dioxines to γ-hydroxyenones allowing for the generation of structural motifs such as cyclopropanes, THF’s, THP’s, 1,4-diketones and natural sugars. Herein describes the synthesis of novel 1,2-dioxines with a variety of tethered functionalities and their transformations to afford novel cyclic compounds whilst maintaining the peroxide linkage intact. Chapter two outlines the intramolecular cyclisations of tethered hydroxyl and carboxylic acid moieties onto the olefin of 1,2- dioxines to generate both tetrahydrofurans and dihydrofuran-2(3H)-ones, whilst maintaining the peroxide linkage. This work presents the first examples of syn fused cyclic peroxide furans through intramolecular cyclisation of tethered hydroxyl groups. Improved methods for the oxidation of hydroxyl tethered 1,2-dioxines to carboxylic acid moieties are also reported. In addition, improved methods for intramolecular cyclisation of carboxylic acid moieties where developed to afford syn fused cyclic peroxide lactones. Furthermore, reduction of the peroxide bond enabled generation of functionalized tetrahydrofurans and dihydrofuran-2(3H)-ones which have previously been utilized as synthetic building blocks for several natural products. Chapter three reports the first examples of carbenoid insertion into the peroxide linkage of 1,2-dioxines allowing for the generation of novel bicyclic hemiacetals. Alternatively novel tricyclic cyclopropyl peroxides where generated through insertion into the olefin whilst maintaining the peroxide linage intact. Additionally, the attempted intramolecular cyclisation of diazoketone tethered bicyclic 1,2-dioxines was also probed. Furthermore, the attempted intermolecular insertion of diazoketones onto 1,2-dioxines are presented within this chapter. Finally, Chapter four outlines the intramolecular cyclisations of bromo-alkyl tethered 1,2-dioxines to furnish novel cyclic cyclopentyl peroxides whilst maintaining the peroxide linkage intact. The work presented in this chapter represents the first examples of the synthesis of syn fused cyclic cyclopentyl peroxides. In summary, this thesis outlines methodology towards the synthesis of novel cyclic peroxides from 1,2-dioxines containing tethered functional groups. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2009

L’endométriose est une maladie gynécologique pour laquelle l’exposition à certains contaminants chimiques environnementaux est évoquée parmi les facteurs de risque associés. Les conclusions des études épidémiologiques existantes restent toutefois non convergentes. Leur hétérogénéité en termes de lésions décrites, de méthodologie et d’effectifs contribuent à ce constat, de même que l’étendue limitée des marqueurs d’exposition considérés dans ces études. Nous avons réalisé une étude cas-témoins appariés à partir d’une bio-collection de 113 patientes réunissant68 cas de patientes opérées d’endométriose profonde et 45 patientes témoins. Un ensemble unique de 78 polluants organiques persistants a été recherché, incluant dioxines, polychlorobiphényles, retardateurs de flamme polybromés, et pesticides organochlorés. Les niveaux d’exposition interne des sujets ont été mesurés à la fois dans les tissus adipeux pariétal et épiploïque ainsi que dans le sérum. La distribution de ces différents polluants au sein de ces trois compartiments a tout d’abord été caractérisée. Celle-ci a permis la prise en compte encore très rare de l’équilibre entre compartiments de stockage et compartiment circulant, ce rapport de concentration apparaissant comme un potentiel indicateur additionnel permettant d’affiner d’éventuels liens de causalité entre exposition chronique à des dangers chimiques et pathologie chez l’homme. Certains des contaminants ciblés sont ensuite apparus significativement associés à l’endométriose profonde, la stratification plus fine de notre population de cas indiquant un lien d’autant plus significatif en présence d’endométriome. Les mécanismes sous-jacents de cette association restent toutefois à élucider. / Endometriosis is a gynecological disease for whichexposure to some environmental chemicals is evocatedamong the associated risk factors. Epidemiological studies are however globally non convergent and finally fairly conclusive. Their heterogeneity in terms of lesion localization and sub-phenotype, methodology, size and nature of the populations studied, as well as the limited number of monitored markers of exposure contribute to this situation. We realized a matched case-control study based on a biocollection of 113 patients including 68 patients suffering of deep endometriosis and 45 controls. We characterized the internal exposure levels of an extended range of around 78 persistent organic pollutants (including dioxins, polychlorobiphenyls, brominated flame retardants and organochlorine pesticides). Internal level exposures were measured in three biological compartments (omental fat, subcutaneous fat and serum). First, the distribution of these chemicals was characterized within these compartments. These extended exposure data from deep infiltrating endometriosis patients are the first ones available for France and give a new insight about the equilibrium of chemicals between storage and circulating compartments that should be further considered as a potential indicator permitting to establish a possible association between a chronic exposure to chemical hazards and human pathology. Afterwards, some of the targeted chemicals appeared significantly associated with deep endometriosis. A sub-stratification of our case population indicated a more significant relationship with the presence of endometrioma. Underlying mechanisms remain to be determined.

Le lait peut être utilisé comme indicateur de pollutions environementales car en général on est assuré de la bonne tracabilité de sa collecte. De nombreux solvants ont été utilisés pour séparer les principales phases du lait (protéines, lipides, sérum). Le mélange de solvants utilisés pour cette étude est le suivant: 1 vol de lait, 1 vol de solution NaCL à 0.9%, 2 vol d'éthanaol et 4 vol de dichlorométhane......

A series of new cobalt(II) beta-keto iminato complexes and cobalt(II) salens have been made and the effect of chirality in the northern, southern and peripheral quadrants of these catalysts, with respect to induced enantiomeric excess, during the ring-opening of 1,2-dioxines has been determined. Synthesis of a series of cobalt beta-keto iminato complexes was achieved after modification of literature procedures used for the synthesis of manganese beta-keto iminato complexes and this procedure was applied to generate ligands with ethyl, t-butyl, (-)-bornyl, (+)-menthyl and (-)-menthyl esters and a methyl side chain. Synthesis of the cobalt salens was also achieved using a modified literature procedure, in respect to the more complex aldehydes made. It was ascertained that chirality in the northern quadrant of these catalysts, obtained by the use of optically pure diamines, was of greatest importance in introducing enantiomeric excess into the products of ring-opening of 1,2-dioxines; namely gamma-hydroxy enones, and chirality in the southern and peripheral quadrants was of lesser, although still significant, importance. The reaction conditions were optimised and the conditions under which the highest enantiomeric excess was introduced were determined. The ideal solvent for the ring-opening was found to be THF with a catalyst concentration between 5 and 10 mol% at a temperature of -15oC. These conditions were found to be applicable to all catalysts and 1,2-dioxines tested. Enantiomeric excess as high as 76 % could be introduced when the optimised reaction conditions were used in large scale syntheses of cyclopropane (61). LC-MS studies indicate the presence of a solvent chelated species present in the reaction mixture when the solvent used is THF, however, the use of non-chelating solvents, such as dichloromethane, did not exhibit this same solvent chelated species. Catalyst dimers were also present in the mixture when analysed by LC-MS. The presence of oxygen in the reaction mixture was found to inhibit rearrangement of the dioxine with catalyst oxygen dimers (two molecules of catalyst bound to a single molecule of oxygen) present when analysed by LC-MS, however, the catalyst could be 're-activated' by de-aeration of the solution and was able to introduce the same enantiomeric excess, as prior to the addition of oxygen was unaffected. It was found that not only cobalt(II) tetradentate complexes were useful in the ring-opening of meso 1,2-dioxines. Achiral iron(II) salen and ruthenium(II) salen were also made and shown to be capable of ring-opening the dioxine. A purchased chiral manganese(III) salen was also shown to be capable of ring-opening the 1,2-dioxine, however, the time taken for the rearrangement to occur led to ring closure of the gamma-hydroxy enone and dehydration of the cyclic hemiacetal. The catalysts were also applied to the enantioselective ring-opening of epoxy-1,2-dioxines for the first time with a high level of success with enantiomeric excesses of between 60 and 90 % introduced with most of the catalysts. To show that these catalysts have the potential for use in the synthesis of potentially bioactive cyclopropyl amino acids, amines, acids and alcohols a small number were prepared, including both racemic and optically enriched or optically pure cyclopropanes. / Thesis (Ph.D.)--School of Chemistry and Physics, 2003.

1,2-Dioxines are a specific class of cyclic peroxide that are both prevalent in nature and important synthetic building blocks. To date, much of the chemistry involving 1,2-dioxines is concerned with cleavage of the weak peroxide bond, providing a convenient method for the incorporation of 1,4-oxygen functionality into molecules. Comparatively little attention has been directed towards transformations of the alkene unit contained within 1,2-dioxines, which is the focus of this thesis. The synthesis of a broad range of diversely functionalised 1,2-dioxines from commonly available starting materials is presented. Subsequently, the osmium catalysed dihydroxylation of 3,6-disubstituted 1,2-dioxines was investigated, furnishing novel peroxy diols in high yield and with excellent diastereoselectivity. The peroxy diols were then reduced, affording stereospecific tetraols and higher polyols, including the rare sugar allitol. In addition, homolytic ring-opening of the 1,2-dioxanes was examined, providing a new route to polyhydroxylated furanoses, highlighted by the synthesis of the natural keto-sugar psicose. Several 4-substituted 1,2-dioxines were also dihydroxylated, followed by reduction of the peroxide bond, providing a convenient route to branched erythritol derivatives, including the important plant sugar 2-C-methyl-erythritol. The cobalt catalysed ring-opening of the peroxy diols produced novel erythrose derivatives in high yield. In addition, the triphenylphosphine induced ring contraction of the peroxy diols is presented, which allowed for the synthesis of novel dihydroxylated tetrahydrofurans in excellent yield. Asymmetric dihydroxylation of the achiral 4-substituted 1,2-dioxines was explored, furnishing optically enriched peroxy diols with varying enantioselectivity depending on the substrate. The synthesis of novel alkyl and aryl branched erythrono-γ-lactones via oxidation of lactols derived from the acetonide protected peroxy diols is also documented. The utility of this sequence is illustrated by the preparation of potassium 2,3,4-trihydroxy-2-methylbutanoate, a leaf-closing substance of Leucaena leucocephalam. Additionally, γ-lactones were prepared from epoxy hydroxy ketones derived from epoxy-1,2-dioxanes, facilitated by a Baeyer-Villiger lactonisation protocol. The requirements and limitations of this procedure are discussed. The proposed and attempted synthesis of other lactones from 1,2-dioxines was also examined. Finally, several other general alkene transformations were investigated on 1,2- dioxines including: halo-hydrin formation, phenylselenyl chloride addition, aminohydroxylation, cyclopropanation, and aziridination, allowing for the preparation of several new classes of functionalised 1,2-dioxines. In summary, the work presented in this thesis establishes clear and efficient methodology towards several interesting and useful sugar-type core structures from modified 1,2-dioxines. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1313493 / Thesis (Ph.D) -- University of Adelaide, School of Chemistry and Physics, 2008

A series of new cobalt(II) beta-keto iminato complexes and cobalt(II) salens have been made and the effect of chirality in the northern, southern and peripheral quadrants of these catalysts, with respect to induced enantiomeric excess, during the ring-opening of 1,2-dioxines has been determined. Synthesis of a series of cobalt beta-keto iminato complexes was achieved after modification of literature procedures used for the synthesis of manganese beta-keto iminato complexes and this procedure was applied to generate ligands with ethyl, t-butyl, (-)-bornyl, (+)-menthyl and (-)-menthyl esters and a methyl side chain. Synthesis of the cobalt salens was also achieved using a modified literature procedure, in respect to the more complex aldehydes made. It was ascertained that chirality in the northern quadrant of these catalysts, obtained by the use of optically pure diamines, was of greatest importance in introducing enantiomeric excess into the products of ring-opening of 1,2-dioxines; namely gamma-hydroxy enones, and chirality in the southern and peripheral quadrants was of lesser, although still significant, importance. The reaction conditions were optimised and the conditions under which the highest enantiomeric excess was introduced were determined. The ideal solvent for the ring-opening was found to be THF with a catalyst concentration between 5 and 10 mol% at a temperature of -15oC. These conditions were found to be applicable to all catalysts and 1,2-dioxines tested. Enantiomeric excess as high as 76 % could be introduced when the optimised reaction conditions were used in large scale syntheses of cyclopropane (61). LC-MS studies indicate the presence of a solvent chelated species present in the reaction mixture when the solvent used is THF, however, the use of non-chelating solvents, such as dichloromethane, did not exhibit this same solvent chelated species. Catalyst dimers were also present in the mixture when analysed by LC-MS. The presence of oxygen in the reaction mixture was found to inhibit rearrangement of the dioxine with catalyst oxygen dimers (two molecules of catalyst bound to a single molecule of oxygen) present when analysed by LC-MS, however, the catalyst could be 're-activated' by de-aeration of the solution and was able to introduce the same enantiomeric excess, as prior to the addition of oxygen was unaffected. It was found that not only cobalt(II) tetradentate complexes were useful in the ring-opening of meso 1,2-dioxines. Achiral iron(II) salen and ruthenium(II) salen were also made and shown to be capable of ring-opening the dioxine. A purchased chiral manganese(III) salen was also shown to be capable of ring-opening the 1,2-dioxine, however, the time taken for the rearrangement to occur led to ring closure of the gamma-hydroxy enone and dehydration of the cyclic hemiacetal. The catalysts were also applied to the enantioselective ring-opening of epoxy-1,2-dioxines for the first time with a high level of success with enantiomeric excesses of between 60 and 90 % introduced with most of the catalysts. To show that these catalysts have the potential for use in the synthesis of potentially bioactive cyclopropyl amino acids, amines, acids and alcohols a small number were prepared, including both racemic and optically enriched or optically pure cyclopropanes. / Thesis (Ph.D.)--School of Chemistry and Physics, 2003.

L'objectif principal de cette étude était de mesurer les concentrations plasmatiques des composés de type dioxine (DLCs) dans un échantillon représentatif de la population inuite du Nunavik et d'étudier les divers facteurs pouvant les moduler. Des échantillons plasmatiques de 874 sujets ont été analysés à l'aide d'un bioessai sensible aux dioxines. La moyenne arithmétique chez les participants était de 13,3 pg TEQ (équivalents toxique de dioxine)/g de lipides avec des valeurs comprises entre < 5 à 144 pg TEQ/g de lipides. Une analyse multivariée a montré que l'âge et la teneur en acide gras oméga-3 dans les membranes de globules rouges étaient positivement, et les graisses corporelles négativement, associés aux concentrations plasmatiques de DLCs (r2 total ajusté = 0,24; p<0,001). Les concentrations plasmatiques des congénères de BPCs no. 105, 118, 153, 156, 157, 167 et 189, déterminées par chromatographie gazeuse couplée à la spectrométrie de masse sont intercorrélées (r = 0,626-0,973; p < 0,001) et corrélées aux concentrations de DLCs (r = 0,521-0,562; p < 0,001). Cette étude dont les données sont analysées de façon transversale permettra d'examiner dans le futur les associations entre l'exposition à ces substances chimiques et le risque de maladies chroniques au sein de cette population.