Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

ABSTRACT STEREOSELECTIVE SYNTHESIS OF OPTICALLY ACTIVE CYCLITOL PRECURSORS VIA CHEMOENZYMATIC METHOD AND SYNTHESIS OF A NUCLEOSIDE PRECURSOR Oguzkaya, Funda M.S., Department of Chemistry Supervisor: Prof. Dr. Cihangir Tanyeli June 2006, 99 pages &amp / #945 / &#039 / -acetoxylation of &amp / #945 / ,&szlig / -unsaturated cyclic ketones was adjusted via Mn(OAc)3 in regioselective manner. Then, PLE hydrolysis was carried out so as to afford enantiomerically enriched &amp / #945 / &#039 / -acetoxylated and &amp / #945 / &#039 / -hydroxylated cyclic compounds. From our knowledge about the literature and previous works dealing with &amp / #945 / &#039 / -hydroxylated products which are easily racemized, protection was directly adjusted via acetylation so as to prevent this possibility. Resulting enantiomerically enriched products were subjected to Upjohn Dihydroxylation to obtain cyclitol precursors and following Luche Reduction of ketone was adjusted so as to obtain corresponding cyclitols. In addition with such synthetic design, firstly dimethyl cyclopent-3-ene-1,1-dicarboxylate was obtained so as to reach in former manner 3-cyclopentene-1,1-dicarboxylic acid, and in latter manner cyclopent-3-enecarboxylic acid. Resulting compound was converted to 6-iodo-2-oxa-bicyclo[2.2.1]heptan-3-one and followingly to the target nucleoside precursor which is 2-oxa-bicyclo[2.2.1]hept-5-en-3-one.

Chiral polyfunctionalized 1,5-dicarbonyl compounds are important synthetic intermediates and starting materials for many biologically active compounds so their synthesis has a great importance in the literature. In the first step, 1,3-cyclohexandione and other b-diketone derivatives are protected under acid catalyzation and their corresponding b-keto enol ether derivatives are obtained. These b-keto enol ethers are then converted to a-acetoxy enones in racemic form by Mn(OAc)3 mediated oxidation. Enzymatic kinetic resolution is applied to the racemic acetoxy enones by using different lipases and enantiomerically pure a-acetoxy and hydroxy enones are obtained. Then, dicarbonyl derivatives are obtained by hydrolizing racemic a-acetoxy enones. Oxidative cleavage of racemic a-acetoxy diketones in the presence of oxone gives corresponding racemic 1,5-dimethyl ester derivatives. By using this reaction as a reference, same reactions are applied to the chiral a-acetoxy and hydroxy diketones in order to synthesize chiral a-acetoxy and hydroxy 1,5-diester derivatives.

Small-molecule DNA interactive compounds are critical as both carcinogens and therapeutic agents. In this research, a synthetic precursor to a known carcinogen, (±)-N’-nitrosonicotine-5’-acetate was synthesized, and its interactions with DNA were evaluated by polyacrylamide gel electrophoresis and electrospray-ionization mass spectrometry. A library of skipped benzimidazolium aza-enediynes which selectively target unmethylated cytosines in presence of unmethylated cytosines were synthesized, and their biological properties were evaluated in a nicking assay and cytotoxicity study. Finally, a series of structural analogs to a antineoplastic agent, UK-1, were synthesized via a biaryl coupling at C2 on the benzoxazole. / text

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Although this project refers to theory and literature about giftedness and independent learning, it is based primarily on narratives of classroom experience. The key belief is that the best way to build on the strengths and meet the needs of adolescent gifted learners is for the teachers involved to create a classroom learning climate and curriculum which coaches those students towards independent learning. Such a climate and curriculum provide opportunities for gifted adolescents to reach their potential. An adaptable and practical three-stage model for designing such a curriculum is provided. By integrating self-and teacher assessment and evaluation throughout three stages of curriculum, the model provides opportunities for students to develop the skills necessary for independent learning. Three narratives of my own experiences in using the three-stage model outlined above are provided. The three situations include the role of classroom teacher of OAC English, co-author of a literature anthology and teacher resource for grade nine destreamed English classes, and facilitator of an Interdisciplinary Autonomous Learner programme for gifted/highly able adolescent learners. Thus, the three-stage curriculum model has been used and shown to be effective. My own, and my students' experiences in using the model, and the common ground discovered in all three roles, form the basis of the recommendations being made in the final chapter. Practical recommendations are made to teachers who are interested in implementing a curriculum which promotes independent learning for gifted adolescents. / Thesis / Master of Arts (MA)

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Ce travail est consacré à la recherche et au développement de nouvelles molécules à viséepharmacologique en série naphtoquinonique en utilisant des réactions par transfert monoélectroniquede type SRN1 et des cyclisations radicalaires oxydatives induites par l'acétate de manganèse(III). Lapremière partie décrit l’étude de la réactivité SRN1 de la 2-(chlorométhyl)-3-méthoxynaphtoquinoneavec divers anions nitronates conduisant à la formation de produits de C-alkylation avec de bonsrendements. Ces derniers ont fait l’objet d’une réaction de réduction-cyclisation permettant la synthèsede nouveaux dérivés benzo[g]indol-5(3H)-ones. Dans la seconde partie, une nouvelle réactiond’oxydation initiée par l’acétate de manganèse(III) a été développée sur la 2-hydroxy-3-méthylnaphtoquinone dans des conditions opératoires douces. En effet, la réactivité originale de la 2-hydroxy-3-méthylnaphtoquinone avec divers alcènes aromatiques en présence de Mn(OAc)3 et dedioxygène, a permis pour la première fois en série naphtoquinonique, l’obtention de nouveaux dérivésoriginaux dihydronaphto[2,3-c][1,2]dioxine-5,10(3H,10aH)-diones sous forme d’un mélange dediastéréoisomères à potentialités antipaludiques. Un mécanisme réactionnel original a été proposé pourla formation de ces produits. / This work is focused on the research and development of new pharmacologicalmolecules in naphthoquinonic series, synthesized by single electron transfer reaction SRN1 ormanganese(III) acetate catalyzed oxidative radical cyclization. The first part describes the SRN1reactivity of 2-(chloromethyl)-3-methoxynaphthoquinone with various nitronate anions leading to theC-alkylation products. The reduction-cyclization reaction of the latter derivatives allowed us to obtainnew benzo[g]indol-5(3H)-one derivatives. In the second part, a new reaction initiated by Mn(OAc)3 on2-hydroxy-3-methylnaphthoquinone was developed under mild conditions. Indeed, the original reaction of2-hydroxy-3-methylnaphthoquinone with various aromatic alkenes in presence of dioxygen led to newdihydronaphtho[2,3-c][1,2]dioxine-5,10(3H,10aH)-dione derivatives as a mixture of diastereoisomerswith antimalarial potential. An original mechanism was proposed in order to explain the formation ofthese products.

Chiral cyclic polyoxo-ketones are important structural units in many natural products, biologically active compouds, such as prostaglandins, didemnenones, sarkomycin, punaglandin, clavulone, etc. In this work, a chemoenzymatic synthesis of both enantiomers of the &amp / #945 / &rsquo / -acetoxy-&amp / #945 / -methyl and &amp / #947 / -hydroxy-&amp / #945 / -methyl cyclic enones starting from &amp / #945 / -methyl-&amp / #946 / -methoxy cyclic enone is described. Manganese (III) acetate-mediated acetoxylation followed by the enzyme-mediated hydrolysis of &amp / #945 / &rsquo / -acetoxy enone provides acetoxy enones. The reduction of the hydroxy enone, obtained from hydrolysis, furnished both enantiomers of 4-hydroxy enone or &amp / #947 / -hydroxy enone by using LiAlH4. This study is a model for the synthesis of these type compounds

Ce travail s'inscrit dans la recherche et le développement de nouvelles molécules à visée thérapeutique via la mise au point de cyclisations radicalaires oxydatives médiées par l'acétate de manganèse(III). Deux problématiques ont dirigé nos recherches. Tout d'abord, nous avons développé une stratégie de synthèse de prodrogues analogues de la pafuramidine, molécule antileishmanienne. Ainsi, une 1ère série d'amidoximes a été obtenue à partir de β-cétosulfones par une synthèse multi-étapes faisant appel aux réactions i) de cyclisations radicalaires oxydatives médiées par Mn(OAc)3 et ii) de couplages pallado-catalysées de Buchwald-Hartwig et de Heck. Suite à l'évaluation biologique in vitro sur Leishmania donovani et sur des cellules humaines, une 2ème série d'amidoximes et en particulier des monoamidoximes a été réalisée, ce qui a révélé une molécule présentant un index de sélectivité 40 fois plus élevé que celui de la pentamidine, médicament utilisé comme référence. Nous avons également mis au point un double couplage "one-pot" de Buchwald-Hartwig dans le but d'obtenir des produits dicouplés dissymétriques, précurseurs éventuels de futures diamidoximes. Dans une deuxième partie, nous nous sommes focalisés sur la synthèse de composés spirocycliques pouvant constituer un pharmacophore original. De ce fait, une stratégie de synthèse conduisant à divers noyaux tels des tétralines spirocycliques, des spirolactones, des spirobenzophénanthrédin-6(5H)-ones a été mise au point. Ce travail nous a également menés vers la synthèse de dérivés thiobarbiturates, analogues de composés anesthésiques ou anticonvulsivants. / This work focuses on the research and development of new therapeutic molecules through optimized radical cyclizations mediated by manganese(III) acetate. Two problematics directed our research. First, we developed analogous prodrugs of pafuramidine, an antileishmanial molecule. Thus, a 1rst series of amidoximes was obtained from β-ketosulfones by a multi-step synthesis involving i) radical oxidative cyclizations mediated by Mn(OAc)3 and ii) pallado-catalyzed Buchwald-Hartwig and Heck coupling reactions. The 1rst series being biologically evaluated in vitro, both on Leishmania donovani and human cells, a 2nd series and particularly monoamidoximes was prepared and revealed a molecule presenting a selectivity index 40 times higher than the one of pentamidine, used as reference drug compound. We also developed a one-pot double Buchwald-Hartwig coupling reaction in the aim to obtain dissymmetric dicoupled products, potential precursors of future diamidoximes. In a second time, we focused on the synthesis of spirocyclic compounds which could constitute an original pharmacophore. Therefore, we performed a synthesis allowing access to a wide variety of scaffolds such as spirocyclic tetralins, spirolactones, spirobenzophenanthridin-6(5H)-ones. This work allowed the synthesis of thiobarbiturates, analogous of anesthetic or anticonvulsive compounds.