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This thesis describes the use of 2H-azirines, three-membered unsaturatednitrogen-containing heterocycles, as reactive intermediates ina number of Lewis acid promoted alkylations and Diels-Alderreactions providing synthetically useful aziridines. In order to carry out this investigation a new generalprocedure for the ring closure of vinyl azides, forming theresultant 3-substituted-2H-azirines, was developed applying low boiling solventsin closed reaction vessels at elevated temperatures. The addition of organolithium reagents in the presence ofcommercially available chiral ligands, to the 3-(2-naphthyl)-2H-azirine was studied, which gave the correspondingaziridines. Several Lewis acids were shown to catalyze the normalelectron-demand Diels-Alder reaction between 3-alkyl-,3-aromatic-, and 3-ester-substituted 2H-azirines and various dienes. These reactions gave theexpected cycloadducts in moderate yields. Using a chiral auxiliary high diastereoselectivity wasobtained in the addition of alkyl radicals to a8-phenylmenthyl-substituted 2H-azirine-3-carboxylate. The alkyl radicals weregenerated from the corresponding trialkyl borane and molecularoxygen. Hydroborations and transmetallations were used toprepare these trialkylboranes. Catalytic amounts of CuClincreased the diastereoselectivity in the radical additionreactions. Attempts were made to explain how the coordination of aLewis acid to the azirine nitrogen atom affects thereactivity/stability of the azirine. DFT calculations and NMRexperiments involving Lewis acid-azirine complexes wereperformed. Keywords:Enantioselective, diastereoselective, vinylazide, 2H-azirines, aziridines, Lewis acid, chiral ligand,chiral auxiliary, organolithiums, Diels-Alder reaction, alkylradicals, triethylborane.

<p>This thesis describes the use of 2<i>H</i>-azirines, three-membered unsaturatednitrogen-containing heterocycles, as reactive intermediates ina number of Lewis acid promoted alkylations and Diels-Alderreactions providing synthetically useful aziridines.</p><p>In order to carry out this investigation a new generalprocedure for the ring closure of vinyl azides, forming theresultant 3-substituted-2<i>H</i>-azirines, was developed applying low boiling solventsin closed reaction vessels at elevated temperatures.</p><p>The addition of organolithium reagents in the presence ofcommercially available chiral ligands, to the 3-(2-naphthyl)-2<i>H</i>-azirine was studied, which gave the correspondingaziridines.</p><p>Several Lewis acids were shown to catalyze the normalelectron-demand Diels-Alder reaction between 3-alkyl-,3-aromatic-, and 3-ester-substituted 2<i>H</i>-azirines and various dienes. These reactions gave theexpected cycloadducts in moderate yields.</p><p>Using a chiral auxiliary high diastereoselectivity wasobtained in the addition of alkyl radicals to a8-phenylmenthyl-substituted 2<i>H</i>-azirine-3-carboxylate. The alkyl radicals weregenerated from the corresponding trialkyl borane and molecularoxygen. Hydroborations and transmetallations were used toprepare these trialkylboranes. Catalytic amounts of CuClincreased the diastereoselectivity in the radical additionreactions.</p><p>Attempts were made to explain how the coordination of aLewis acid to the azirine nitrogen atom affects thereactivity/stability of the azirine. DFT calculations and NMRexperiments involving Lewis acid-azirine complexes wereperformed.</p><p><b>Keywords:</b>Enantioselective, diastereoselective, vinylazide, 2<i>H</i>-azirines, aziridines, Lewis acid, chiral ligand,chiral auxiliary, organolithiums, Diels-Alder reaction, alkylradicals, triethylborane.</p>

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La trypanosomiase humaine africaine, la maladie de Chagas et les leishmanioses sont des maladies parasitaires qui représentent un problème majeur de santé publique dans de nombreux pays et notamment ceux en voie de développement. Afin de trouver de nouveaux candidat-médicaments contre ces parasites, deux séries chimiques ont été étudiées : les diarylidèneacétones et les 2,6-diaryl-4H-tetrahydrothiopyranones.Précédemment initiée au laboratoire, l'étude approfondie de la série diarylidèneacétone a nécessité la mise au point et l'optimisation de protocoles. Une nouvelle méthodologie de synthèse des (hétéro)diarylidèneacétones dissymétriques par palladocatalyse a ainsi été développée en collaboration avec le Pr. T. J. Müller (Université de Düsseldorf). En dépit d'excellentes activités antiparasitaires, la plupart des diarylidèneacétones synthétisées se sont révélées trop toxiques sur les cellules humaines.Les 2,6-diaryl-4H-tétrahydrothiopyranones et leurs S-oxydes ont été conçues pour résoudre ce problème de toxicité. Agissant comme prodrogues, ces molécules sont susceptibles de régénérer les diarylidèneacétones parentes par β-élimination du groupement soufré intracyclique. Peu décrite dans la littérature, la synthèse diastéréosélective de ces structures a été intégralement mise au point et généralisée à de nombreuses substitutions. Les résultats obtenus prouvent que la toxicité des produits a été grandement diminuée tout en maintenant une activité antiparasitaire importante, ce qui valide l'approche de la stratégie prodrogue. / Human African trypanosomiasis, Chagas disease and leishmaniasis are parasitic diseases that significantly affect the populations and thus the economy of many developing countries. With the aim of developing new therapeutic agents to cure these diseases, we focused our research on two series: the diarylideneacetone and the 2,6-diaryl-4H-tetrahydrothiopyranone series.To complete and expend preliminary results that had been previously obtained in our laboratory, a generalization and an optimization of the protocols was intended. Thus, a novel Palladium-catalyzed synthesis of (hetero)dissymmetric diarylideneacetones was developed and optimized in collaboration with Prof. T. J. Müller (University of Düsseldorf). In spite of excellent antiparasitic activities, most of the diarylideneacetones were toxic toward human cells.2,6-Diaryl 4H-tetrahydrothiopyranones and their related S-oxides were designed to cope with major toxicity issues. Acting as prodrugs, these molecules are prone to undergo β-elimination of the sulfurated intracyclic group, regenerating the parent diarylideneacetone. The diastereoselective synthesis of this scaffold is not extensively described in the literature. Consequently, novel diastereoselective methodologies have been developed and generalized to a wide panel of substitution patterns. Results of the biological assays demonstrated that sulfide and S-oxide prodrugs displayed a lowered toxicity while the potency was maintained, thus confirming the validity of the prodrug strategy.

Made available in DSpace on 2015-05-14T13:21:52Z (GMT). No. of bitstreams: 1 parte1.pdf: 1989190 bytes, checksum: 883070176caa740fdfb17ea349bcf0ca (MD5) Previous issue date: 2010-12-20 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / We developed in this study the total synthesis of new potential ligands and / or chiral organocatalysts to be initially used in the Morita- Baylis-Hillman reaction and / or in other enantioselective reactions. The preparation of four new chiral unpublished compounds (31, 32, 33, 34) derivatives of pyridine and of R-(+)-camphor (21a) were performed. The chiral aldol adducts (31 and 32) were obtained by the reaction between 21a and aldehyde 35 or 36 in god chemical yields (80%-85%).The synthesis of 31 was done in 86% of diastereoisomeric excess. The new diois 33 and 34 were prepared from diastereoselective reduction of the corresponding aldol of 31 and 32 in high yield (88-90%) and 33 was prepared in de=77%. Determination of were performed from hydrogen NMR studies. We also present here, a toughly studies from spectroscopic techniques of 1H and 13C NMR, including COSY H,H; HETCOR and NOESY. The preliminary evaluation of 31 as organocatalysts was investigated from the Morita-Baylis-Hillman reaction between the methyl acrylate or acrylonitrile and p-nitrobenzaldehyde. This theory opens borders, for our group of researches, in the area of synthesis enantiosselective. / Desenvolvemos neste trabalho a síntese de novos ligantes e / ou organocatalisadores quirais em potenciais para serem inicialmente utilizados na reação de Morita-Baylis-Hillman e / ou em outras reações enantiosseletivas. As preparações dos quatro compostos quirais inéditos (31, 32, 33, 34) foram realizadas a partir dos aldeídos piridinicos comerciais derivados e da R-(+)-cânfora (21a). Os adutos quirais (31 e 32) foram obtidos pela reação entre 21a e o aldeído 35 ou 36 em bons rendimentos químicos (80%-85%). A síntese de 31 foi feita em 86% de excesso de diastereoisomérico. Os novos Dióis 33 e 34 foram preparados a partir da redução diastereosseletiva dos correspondentes aldóis 31 e 32, em altos rendimentos (88-90%) e 33 foi preparado em d.e. = 77%. A determinação dos excessos diastereoisoméricos foi feita a partir de estudos de RMN de hidrogênio. Apresentamos também aqui, estudos espectroscópicos de forma rigorosa, a partir de técnicas de espectroscopia de 1H e 13C, incluindo COSY H,H; HETCOR e NOESY. A avaliação preliminar de 31 como organocatalisador foi investigado através da reação de Morita-Baylis-Hillman entre o acrilato de metila ou acrilonitrila e o pnitrobenzaldeído. Esta tese abre fonteiras , para o nosso grupo de pesquisas, na área de síntese enantiosseletiva.

Les tétrahydropyranes et les pipéridines sont des motifs que l'on retrouve dans de nombreuses molécules naturelles bioactives. L'intérêt pour ces familles de composés ne cesse de croître. En effet le noyau pipéridine est le troisième motif cyclique le plus retrouvé dans les molécules thérapeutiques après les noyaux phényle et pyridine alors que le tétrahydropyrane prend lui la 6ème place. Il apparaît donc opportun de développer des voies d'accès simples et efficaces afin d'obtenir de façon stéréosélective (diastéréo et/ou énantiosélective) ces motifs structuraux. Les travaux de recherche présentés dans ce manuscrit concernent le développement de deux nouvelles méthodologies de la cyclisation d'aza-Prins. La cyclisation d'aza-Prins permet par la réaction entre une amine homoallylique et un aldéhyde en présence d'un acide (Lewis ou Brønsted) la formation de pipéridine. La première a été développée pour pallier à l'absence dans la littérature de méthodologie applicable à tous types d'amines homoallyliques. Cette nouvelle méthodologie repose sur la promotion de la réaction par un effet synergétique entre un acide de Lewis (TiCl4 1 éq.) et un acide de Brønsted (p-TSA 0.1 éq.). Cette méthodologie a permis l'obtention de pipéridine avec de bons rendements et une excellente diastéréosélectivité a été obtenue selon la nature de l'amine homoallylique utilisé. La deuxième méthodologie qui a été développée permet l'aminolyse de pipéridine-lactone. Ces pipéridine-lactones, obtenues par une réaction d'aza-Prins, sont ainsi aminolysées par un acide aminé en présence d'un promoteur puissant LiNTf2. Ces deux méthodologies combinées nous ont permis d'obtenir divers motifs pipéridines. Un certain nombre de ces pipéridines synthétisées seront testées afin de mettre en évidence une éventuelle activité biologique. / Tetrahydropyrans and piperidines are cyclic motifs found in numerous bioactive natural products. Interest in these families of compounds is continuously growing. Indeed, piperidine is the 3rd most common cyclic motif found in therapeutic molecules after phenyl and pyridine structures, while the tetrahydropyran takes the 6th place. Thus the development of simple and effective methodologies to obtain these structures stereoselectively (diastereo and/or enantioselectively) is of great interest. The research presented in this manuscript concerns the development of two new methodologies for aza-Prins cyclization. These reactions involve condensation of homoallylic amines with aldehydes in the presence of a Lewis or Brønsted acid to give piperidine compounds. The first method was promoted by a synergistic combination of a Lewis acid and a Brønsted acid and employs N-alkyl, N-aryl, and unprotected homoallylamines to efficiently form piperidines with good yields and excellent diastereoselectivity, which was controlled by the nature homoallylamine. The second method allows piperidine-lactone aminolysis in presence of aminoacids with the help of a powerful promoter LiNTf2. These two combined methodologies allowed us to obtain a library of piperidine structures, some of which will be tested in order to assess their possible biological activity.

This thesis is concerned with the development of methodology for the asymmetric synthesis of a range of amino polyol containing compounds. Chapter 1 highlights the abundance of the amino polyol motif in nature, the wide range of biological activities displayed by amino polyol containing compounds, and their occurrence in drug molecules. A variety of different methods for the synthesis of stereodefined amino polyols is then discussed. Chapter 2 details a full investigation into the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to enantiopurealpha,beta-unsaturated esters which contain a dioxolane unit. The “matched” conjugate addition reactions were further coupled with a highly diastereoselective in situ enolate oxidation using camphorsulfonyloxaziridine for the synthesis of keyalpha-hydroxy-beta-amino ester intermediates. Subsequent cyclisation and further elaboration allowed access to a range of amino polyol containing compounds including imino sugars, amino sugars, and amino acids. Chapter 3 extends the investigation into the doubly diastereoselective lithium amide conjugate addition reaction to enantiopure alpha,beta-unsaturated esters which contain two dioxolane units. A full assessment into the conjugate addition of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a series of D-pentose derived alpha,beta-unsaturated esters is reported. Subsequent elaboration of thebeta-amino ester products of these conjugate addition reactions resulted in the synthesis of (2'S,3'S,4'R)-dihydroxyhomoproline and (2'S,3'R,4'S)-dihydroxyhomoproline. Chapter 4 describes the asymmetric syntheses of protected forms of APTO and AETD, the 2,4,5-trihydroxy substitutedbeta-amino acid residues found within the hexapeptide marine natural products microsclerodermins C, D and E. The optimised synthetic routes to APTO and AETD involved three key steps: a diastereoselective aminohydroxylation [via conjugate addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to an achiralalpha,beta-unsaturated ester followed by in situ enolate oxidation with camphorsulfonyloxaziridine], a diastereoselective dihydroxylation, and an olefination. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.

This thesis deals with the preparation of enantiomerically and diastereomerically pure spirocompounds using asymmetric organocatalysis. The first part is focused on the enantioselective synthesis of spirocompounds by organocatalytic reaction of α,β-unsaturated aldehydes with sulfur heterocyclic compounds catalysed with secondary amines. It is a domino Michael/Michael/aldol reaction using iminium and enamine activation. The second part is focused on the subsequent transformation of the prepared spirocompounds.

L'objet de ce travail de thèse concerne la synthèse par réaction cascade pallado-catalysé d'une nouvelle famille de chromophores pentacycliques azotés dont les propriétés de fluorescence peuvent être modulées en fonction des groupements fonctionnels présents dans la molécule. Ces chromophores sont obtenus par réaction one-pot entre des acides 2-formyl boroniques et des 2,5-dihalopyridines. Le processus cascade est initié par un couplage de Suzuki suivi par deux cyclisations successives. La première se fait sur l'azote de la pyridine et la seconde se produit de façon régio-sélective sur le carbone adjacent à l'azote. Les structures cristallines et le calcul théorique DFT ont montré la régio et la stéréo-sélectivité de la réaction. De plus, des études préliminaires ont montré que ces composés polycycliques possèdent d'excellentes propriétés de fluorescence ainsi qu'une activité biologique qui devraient nous permettre d'étendre le champ d'application de ces nouveaux chromophores vers le domaine médical et l'électronique moléculaire / The aim of this work concerns the synthesis of a new family of aza-pentacyclic chromophore whose fluorescence properties can be modulated according to the functional groups present in the molecule. These chromophores were obtained through a cascade process between 2-formylbenzene boronic acid and 2,5-dihalopyridines. The cascade process is initiated by a palladium-catalyzed cross-coupling reaction and is followed by two successive nucleophilic cyclizations; the first cyclization performed on the pyridine nitrogen and the second occurred regioselectively on the adjacent carbon atom. This new cascade reaction allowed the formation of a pentacycle as a single regioisomer with four new bonds and two contiguous stereocenters with trans relationships. In addition, preliminary studies have shown that these polycyclic compounds have excellent fluorescence properties as well as biological properties that should enable us to extend the scope of these new chromophores to the medical field and molecular electronics