Submitted by Ronildo Prado (ri.bco@ufscar.br) on 2018-09-17T13:47:42Z No. of bitstreams: 1 TeseKSF.pdf: 23261470 bytes, checksum: 5b1d96df4f120f2aa4446a1eda8ba6c0 (MD5) / Approved for entry into archive by Ronildo Prado (ri.bco@ufscar.br) on 2018-09-17T13:47:54Z (GMT) No. of bitstreams: 1 TeseKSF.pdf: 23261470 bytes, checksum: 5b1d96df4f120f2aa4446a1eda8ba6c0 (MD5) / Approved for entry into archive by Ronildo Prado (ri.bco@ufscar.br) on 2018-09-17T13:48:07Z (GMT) No. of bitstreams: 1 TeseKSF.pdf: 23261470 bytes, checksum: 5b1d96df4f120f2aa4446a1eda8ba6c0 (MD5) / Made available in DSpace on 2018-09-17T13:49:31Z (GMT). No. of bitstreams: 1 TeseKSF.pdf: 23261470 bytes, checksum: 5b1d96df4f120f2aa4446a1eda8ba6c0 (MD5) Previous issue date: 2016-04-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / This thesis consists in a collection of projects wherein the focus is the application of organocatalysts to accelerate the reactions, its primary function, as to induce asymmetry to the synthetic targets, within a perspective of sustainable chemistry. Thus, this thesis was arranged in four sections, the first two being about conjugate additions reactions; the third one related to 1,6-Friedel-Crafts/ 1,4-oxa-Michael cascade, and finally the fourth related to a formal [3 + 3] cycloaddition reaction. The first chapter describes the application of ionic liquids as basic catalysts in the conjugate addition of diketones to nitroolefins irradiated by ultrasound. Thus, the Michael adducts, which are important synthetic building blocks were synthesized efficiently under solvent free conditions. In the second chapter is presented the formal synthesis of Pregabalin Phenibut and Bacoflen. The synthetic intermediate of theses are obtained via a conjugate addition of aldehydes to nitroolefins, using an organocatalyst developed by our group in PEG-400, as recyclable solvent. In this regard, a collection of Michael adducts was synthesized within the principles of green chemistry in good yields and selectivities. The third section describes the first organocatalytic asymmetric cascate 1,6- Friedel-Crafts / 1,4- Oxa-Michael of hydroxyarenes to 2,4-dienal for the construction of chiral chromans, which are important bioactive compounds. A collection of chiral chromans was synthesized with high yields and selectivities (94-99% ee). Furthermore, several manipulations were made including the formation of a macrocyclic lactam. Finally, the fourth section dedicated to the formal [3 + 3] cycloaddition of azomethine imine with methyl isocyanoacetates leading to 1,2,4 triazines derivatives, which are relevant biological activity heterocyclic. We used either organocatalytic approach as cooperative catalysis (organocatalysis and metal catalysis). This work is still in the primary stages, however the product has been obtained with up to (42% ee, 69% yield), as just one diastereomer. / Essa tese consiste em uma coleção de projetos cujo foco central foi a aplicação de organocatalisadores tanto para acelerar as reações, sua função primária, quanto para induzir assimetria aos alvos sintéticos, dentro de uma ótica da química sustentável. Assim, a presente tese foi organizada em quatro capítulos, sendo os dois primeiros envolvendo reações de adições conjugadas, o terceiro referente a uma reação cascata tipo Friedel-Crafts seguida de oxa-Michael e por fim o quarto referente a uma reação de cicloadição formal [3+3]. O primeiro capítulo refere-se a aplicação de uma classe de líquidos iônicos de tarefa específica, como catalisadores básicos em reações de adição conjugada de dicetonas à nitroolefinas irradiadas por ultrassom. Desta forma, em uma condição livre de solventes, foram sintetizados de forma eficiente, uma coleção de adutos de Michael, os quais são importantes blocos de construção sintéticos. No segundo capítulo apresenta-se a síntese formal dos fármacos Pregabalina, Phenibut e Bacofleno. O intermediário sintético dos medicamentos citados são produtos de adição conjugada de aldeídos à nitroolefinas, os quais foram facilmente sintetizados utilizando um organocatalisador desenvolvido pelo próprio grupo em PEG-400, como solvente reciclável. Assim foi sintetizado uma coleção de adutos de Michael em bons rendimentos e seletividades, dentro dos príncipios da química verde. O terceiro capítulo descreve o primeiro exemplo de adição-1,6 tipo Friedel-Crafts seguida de adição- 1,4 Oxa-Michael organocatalítica assimétrica de hidroxiarenos a 2,4-dienais para a construção de cromanos enantioenriquecidos. Foram sintetizados uma coleção de cromanos quirais com altos rendimentos e seletividades (94-99% ee), os quais, posteriormente sofreram uma série de manipulações, incluindo uma macrolactamização.Por fim, o quarto capítulo dedica-se a cicloadição formal [3+3] de azometina imina com isocianoacetato de metila, levando a produtos derivados do 1,2,4 triazenos, heterocíclicos de relevante atividade biológica. Utilizou-se tanto a organocatálise, quanto a catálise cooperativa (organocatálise e catálise metálica) como ferramentas sintéticas. Este trabalho está ainda nas etapas iniciais, sendo os resultados preliminares, entretanto o produto já foi obtido com até (42% de ee e 69%) de rendimento, sendo a síntese diastereoseletiva.

No description available.

De nouvelles méthodologies en catalyse asymétrique au cuivre ont été développées. D’une part, une réaction d’addition conjuguée asymétrique 1,4 du diméthylzinc sur des acylimidazoles a,b-insaturés catalysée par un complexe cuivre-NHC a été mise au point, avec une excellente énantiosélectivité. Cette réaction a été étendue à des acylimidazoles a,b,g,d-insaturés : les produits d’addition 1,4 ont été obtenus de manière hautement régio- et énantio-sélective. Cette sélectivité originale (1,4 vs 1,6) a pu être rationnalisée par des calculs DFT. La transformation de la fonction acylimidazole a ensuite ouvert l’accès à un processus itératif d’additions conjuguées. Cette stratégie a conduit à la synthèse de motifs polydéoxypropionates : la versatilité de cette méthodologie a été illustrée grâce à la synthèse de motifs syn,syn et anti,anti avec une excellente diastéréosélectivité. Différentes applications en synthèse de produits naturels et bioactifs ont permis d’illustrer le potentiel de cette méthodologie. / New methodologies in asymmetric copper catalysis have been developed. First, a reaction of 1,4-asymmetric conjugate addition of dimethylzinc on a,b-unsaturated acylimidazoles catalysed by a copper-NHC complex has been developed, with an excellent enantioselectivity. This reaction has been extended to a,b,g,d-unsaturated acylimidazoles: 1,4-addition products have been obtained with high regio- and enantio-selectivity. This original selectivity (1,4 vs 1,6) has rationalized by DFT calculations. The transformation of the acylimidazole moiety led us to an iterative process of conjugate additions. This strategy has guided us towards the synthesis of polydeoxypropionate motifs: the versatility of the methodology has been illustrated via the synthesis of syn,syn and anti,anti motifs with high diastereoselectivities. Different applications in natural and bioactive product synthesis allowed us to illustrate the potential of this methodology.

Les nanoparticules métalliques (MNPs) ont un grand succès dans les dernières décennies dû à la variété d'applications dans différents domaines (microélectronique, matériaux, catalyse). Mis à part les solvants organiques, les liquides ioniques, l'eau, le CO2 supercritique et les polyols, en particulier le glycérol, ont démontré leur capacité à stabiliser et immobiliser les nanoparticules métalliques. Ces milieux évitent l'agglomération des MNPs et facilitent leur recyclage. Des nanoparticules de Pd(0) et Ni(0) dans le glycérol, sphériques, petites en taille et bien dispersées, ont été synthétisées avec succès à partir d'une méthodologie simple sous pression d'hydrogène, en présence de différents stabilisants (alkaloïdes, phosphine, polymer). La caractérisation complète de ces matériaux en solution et à l'état solide, ainsi que la possibilité de faire des synthèses à grande échelle et de stocker les solutions catalytiques longtemps, montrent la grande stabilité de ces solutions colloïdales. Les nanoparticules dans le glycérol ont été impliquées dans une large variété de transformations : hydrogénations, hydrodéhalogénations, couplages de Hiyama, additions conjuguées et hydrosilylations. De plus, nous avons étudié l'effet du stabilisant sur la réactivité catalytique, nous permettant de contrôler l'état de surface des nanoparticules et moduler ainsi leur réactivité. Nous avons montré, de même, la capacité du glycérol pour immobiliser les catalyseurs, ce qui s'est traduit par la possibilité de recycler la phase catalytique entre 4 et 10 fois sans perte de metal. En parallèle, nous avons évalué le comportement du Ni(OAc)2 libre de ligands dans le glycérol, en tant que catalyseur alternatif pour des couplages C-C et C-hétéroélément. Nous présentons aussi une étude en flux continu, en collaboration avec la Maison Européenne des Procédés Innovants (MEPI), pour l'hydrogénation de différents groupes fonctionnels, en utilisant les PdNPs dans le glycérol synthétisées préalablement. / Metal nanoparticles (MNPs) have been largely studied in the last decades due to their interesting properties which found applications in several fields (microelectronics, materials and catalysis, among others). In contrast to common organic solvents, ionic liquids, water, supercritical CO2, polyols such as glycerol, represent innovative solvents for the immobilization of MNPs, avoiding their agglomeration and facilitating their recycling. Small, spherical, and well-dispersed Pd(0) and Ni(0) nanoparticles were synthesized under hydrogen pressure in glycerol, in the presence of different kinds of stabilizers (cinchona-based alkaloids, phosphine, polymer). The high stability of these colloidal solutions permitted the full characterization both in solution and at solid state, large-scale synthesis, and stocking the solutions for months. These colloidal catalysts were applied in a large variety of transformations including hydrogenations, hydrodehalogenations, Hiyama C-C couplings, hydrosilylation reactions, and Michael conjugate additions. Furthermore, we conducted a comparative study exhibiting the differences in catalytic reactivity by effect of the stabilizer, allowing us tuning the surface-state of the nanoparticles. Moreover, we showed the ability of glycerol to immobilize metal nanoparticles permitting the recycle of the catalytic phase between 4 and 10 times, without metal leaching. Additionally, we studied the behavior of ligand-free Ni(OAc)2 in glycerol as an alternative catalyst for C-C and C-heteroatom couplings. Also, we developped a continuous flow study, in collaboration with the Maison Européenne des Procédés Innovants (MEPI), for the hydrogenation of different functional groups, using PdNPs in glycerol