Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-04-27T10:56:43Z No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-04-27T11:18:27Z (GMT) No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) / Made available in DSpace on 2018-04-27T11:18:27Z (GMT). No. of bitstreams: 1 isabellafloresdesouzamarra.pdf: 6949720 bytes, checksum: 3ef266443c230cb7ef58f9760b630a2f (MD5) Previous issue date: 2018-02-20 / A obtenção de aminoácidos halogenados é de grande importância para síntese orgânica e para a área biológica, uma vez que estes são valiosos intermediários sintéticos e se apresentam como produtos biologicamente funcionais. Neste contexto, as azalactonas são precursores interessantes, uma vez que podem atuar como aminoácidos protegidos e serem utilizadas na síntese de derivados de aminoácidos e heterociclos complexos. Neste trabalho são descritas a abertura e halogenação das azalactonas de Erlenmeyer-Plöchl sob uma abordagem organocatalítica, utilizando ácido canforsulfônico (ACS) e N-bromosuccinimida (NBS) como agente halogenante. A condição otimizada para obtenção do produto halogenado consistiu na utilização de 30 mol% de ACS, 1.2 equivalente de NBS e 4 mL de metanol, a 65°C por 7 horas, obtendo-se uma imina halogenada com 83% de rendimento. Devido as dificuldades encontradas durante a avaliação do escopo de substratos, investigou-se a redução one-pot da imina halogenada, entretanto não foi possível obter um aumento da razão diastereoisomérica no produto desejado. Diante dos contratempos encontrados na metodologia proposta, investigou-se o uso da catálise foto redox irradiada por luz visível na tentativa de halogenação do heterociclo azalactônico. Entretanto, ao utilizar esta abordagem, observou-se a homodimerização das azalactonas de Erlenmeyer-Plöchl ao invés da halogenação da mesma, levando a um produto de cicloadição [2+2]. Em diclorometano, a utilização do fotocatalisador de rutênio favoreceu a formação de um sistema tricíclico do tipo espiro. Já em meio metanólico, o fotocatalisador metálico favoreceu a formação do produto de abertura dos dois anéis azalactônicos com 59% de rendimento, enquanto que o uso do corante orgânico Eosina Y levou à formação de um cicloaduto assimétrico, com a abertura de apenas um dos anéis azalactônicos (40% de rendimento). Avaliou-se o escopo de substratos utilizando Eosina Y como fotocatalisador e os rendimentos obtidos foram de moderados a bons (12 a 78%). Todos os produtos foram caracterizados por RMN de 1H, 13C, e IV. / Halogenated amino acids are of great importance for both organic synthesis and biological areas, once these are valuable synthetic intermediates and presented as biologically functional products. In this context, azlactones are interesting precursors that can act as protected amino acids and have been used in the synthesis of amino acid derivatives and complex heterocycles as well. This work describes Erlenmeyer-Plöchl’s azlactone ring opening following by halogenation under an organocatalytic approach, using camphorsulfonic acid (CSA) and N-bromosuccinimide (NBS) as halogenating agent. The optimized reaction conditions for the halogenated product consisted on the use of 30 mol% CSA, 1.2 equivalent of NBS and 4 mL of methanol, at 65°C for 7 hours, to afford a halogenated imine with 83% of yield. Due to the difficulties in the substrate scope (purification process), a one-pot reduction of the halogenated imine was investigated, however, it was not possible to obtain a good diastereoisomeric ratio of the desired product. In view of setbacks encountered in the proposed methodology, the use of visible light photoredox catalysis in attempt to halogenate the azlactone heterocycle was investigated. However, using this approach, homodimerization of Erlenmeyer-Plöchl’s azlactones was observed instead of halogenation, leading to a cycloaddition [2+2] derived product. In dichloromethane, the use of ruthenium photocatalyst favored the formation of a tricyclic spiro type system. Switching to methanol as solvent, the metallic photocatalyst led the formation of the opening product with two azlactone rings, in 59% yield, whereas the organic dye Eosin Y conducted the formation of an asymmetric cycloadduct, with the ring opening of only one of the azlactone (40% yield). The substrate scope was evaluated using Eosin Y as photocatalyst and the products were isolated in yields ranging from 12 to 78%. All products were characterized by 1H NMR, 13C and IR.

L'objectif du projet est de synthétiser et de tester de nouveaux catalyseurs organiques supportés qui servont à la préparation d'amines chirales par la réaction de réduction de ketimines et à la préparation d'acides aminés phosphoniques par la réaction de Pudovik. La présence d'un support facilite la récupération et le recyclage du catalyseur. Le projet est basé sur le développement de nouveaux types de catalyseurs organiques, comme les acides de Bronsted chiraux, sur support polymérique – polyéthylène glycol, possédant une activité catalytique et de stéréodifférentiation élevée, facilement récupérables d'un mélange réactionnel pour une utilisation dans plusieurs cycles catalytiques. Les diesters de l'acide phosphorique, dérivés de bisphenols, ont étés utilisés comme catalyseurs acides. Une série de dérivés polymériques basés sur des PEG monofonctionnalisés de différentes tailles ont été préparée. Ces catalyseurs ont testés dans plusieurs réactions énantiosélectives d'addition de différents nucléophiles sur liaisons C = N permettant l'accès à des précurseurs importants, que sont les amines chirales et les acides α-aminés phosphorés. / Asymmetric organocatalysis has emerged recently as a powerful tool for the preparation of chiral molecules. The aim of the project was to design, synthesize and test new supported organocatalysts for the preparation of molecules by transfer hydrogenation reaction of ketimines and by Pudovik reaction for the amino phosphonic acid. The presence of a soluble support provided homogeneous conditions for catalysis and facilitated recovery and recycling of the catalyst. A series of derivatized polymers based on monofunctional PEG's with different sizes were prepared. These catalysts were tested in several enantioselective addition reactions of various nucleophiles to multiple C=N-bond leading to precursors of practically important compounds such as chiral amines, amino phosphonic acids.

Ces travaux de thèse ont porté sur le développement d’une méthodologie de conversion de chiralité centrale vers axiale pour la formation de 4-arylpyridines atropoisomères, et de son application en synthèse totale. En premier lieu, une méthodologie de synthèse organocatalysée a été optimisée pour la préparation de 1,4-dihydropyridines énantioenrichies et hautement encombrées. Le défi a été, ici, de réussir à trouver le bon compromis entre sélectivité et réactivité afin de générer suffisamment d’encombrement sur la position C4 de la 1,4-dihydropyridine énantioenrichie, et de pouvoir accéder, après conversion du centre stéréogène (C4) en axe de chiralité, à un atropoisomère 4-arylpyridine stable. Une optimisation des conditions opératoires pour l’oxydation de ces 1,4-dihydropyridines énantioenrichies en 4-arylpyridines correspondantes a ensuite été menée et a permis d’atteindre des conversions de chiralité modérées à totales. Sur la base de cette stratégie, la synthèse énantiosélective de la (+)-streptonigrine, produit naturel présentant un motif 4-arylpyridine, a été envisagée selon deux stratégies principales s’appuyant sur des processus organocatalysés. / This work focused on the development of central-to-axial chirality conversion methodology for the synthesis of 4-arylpyridine atropisomers, and its application in total synthesis. In the first place, synthetic methodology was optimised for the synthesis of enantioenriched and hindered 1,4-dihydropyridines. At this point, the challenge was to find the right compromise between selectivity and reactivity to get enantioenriched dihydropyridines with sufficient bulkiness around the C4 position, for formation of stable 4-arylpyridine atropisomers after conversion of the chiral center (C4) to a chiral axis. A detailed screen was performed to find the optimal oxidation conditions leading to moderate to full chirality conversion. Based on this strategy, the total synthesis of (+)-streptonigrin, a natural product containing a 4-arylpyridine framework, was planned following two main pathways using organocatalytic transformations as key steps.

The biological activity of the pharmaceutical drugs often depends on how it fits with a receptor making stereochemistry a key component. Selective reactions can limit or avoid the mixture of enantiomers obtained. One such reaction is the selective reduction of a carbon-carbon double bond in the presence of a carbonyl. Although efficient, current asymmetric synthesis methods have limitations such as harsh reaction conditions, the high costs of chiral catalysts and the toxicity of the metal-based catalysts. Catalysts derived from small organic molecules have become an attractive alternative which have been explored more rigorously in recent years. Using a BINOL-derived boro-phosphate catalyst, we have developed a methodology that selectively reduces the carbon-carbon double bond of linear α, β-unsaturated ketones, exclusively giving the corresponding saturated ketone. To the best of our knowledge, this reaction is the first of its kind to accomplish this transformation and results give high yields of >93% and enantioselectivities >90% at room temperature. Furthermore, the products of this novel reaction can be subjected to a choice electrophile, in example benzaldehyde, to afford diastereoselective tertiary alcohol products with enantioselectivities of >88% and diastereoselectivities of up to 99:1.

Le développement de procédés catalytiques pour la valorisation chimique du dioxyde de carbone (CO2), suscite un intérêt grandissant en termes de chimie du carbone et de développement durable. Les travaux de cette thèse portent sur l’étude de la synthèse de carbonates cycliques à partir du couplage du CO2 avec des époxydes. De nombreux catalyseurs ont été développés dont les sels d’ammoniums fournissant le nucléophile nécessaire pour initier la réaction par ouverture de l’époxyde. Notre projet propose une nouvelle approche qui consiste à augmenter la nucléophilicité du catalyseur via une chimie hôte-invité dans laquelle des récepteurs moléculaires de type cavitands viennent sélectivement encapsuler les cations ammoniums, libérant ainsi l’anion nucléophile pour une meilleure réactivité. Notre système catalytique, testé à 1 bar de CO2, a notamment démontré tout son potentiel par l’activation accrue de sels de tétraméthylammonium initialement inactifs. Des expériences effectuées sous une pression de CO2 de 10 bar, ont permis d'étudier l’influence de la structure des cavitands et de montrer qu’une double activation était possible grâce à la conception de cavitands comportant des fonctions acides de Brönsted et des propriétés d’encapsulation optimales. Une application à la catalyse hétérogène a finalement été initiée par l’immobilisation des ammoniums ou des cavitands sur des supports à base de silice pour profiter des avantages de tels procédés. / The utilization of carbon dioxide (CO2) as a key component in organic transformations has recently drawn much attention as a greener alternative to fossil fuel based resources. The objectives of this work aim at studying the synthesis of cyclic carbonates from the coupling of CO2 with epoxide. Numerous catalysts have been proposed for this reaction among which the ammonium halides providing the nucleophile to initiate the reaction by opening the epoxide. Herein, we propose a new approach based on host-guest chemistry, to improve catalytic reactivity by increasing the nucleophilicity of the halide anion. For this purpose, cavitand molecular receptors able to bind quaternary ammonium ions are used, releasing the anionic nucleophile for the initial epoxide ring-opening reaction. At CO2 atmospheric pressure, our catalytic systems demonstrated a great potential by the dramatic activation of tetramethylammonium halides, whereas when used alone, these catalysts had never shown any activity. The influence of the cavitand structure was investigated through experiments run under 10 bar of CO2 pressure, and revealed that a double activation was possible with cavitand bearing Brönsted acidic hydroxyl functions and optimal recognition properties. The heterogeneization of such catalytic systems was finally studied with the grafting of either ammoniums or cavitands on silica based materials.

Les 1,3-diols acycliques sont des motifs ubiquitaires, essentiels dans la structure de nombreux produits naturels. Le développement d’approches permettant leur obtention de manière énantiosélective se révèle donc d’un grand intérêt synthétique. Dans ce contexte, notre équipe a envisagé une stratégie reposant sur des transferts d’acyle énantiosélectifs organocatalysés multiples. Cette approche a abouti à la mise en oeuvre d’une méthodologie de désymétrisation énantiosélective organocatalysée de 1,3-diols méso acycliques. Les composés ainsi obtenus constituent des briques moléculaires aisément valorisables en synthèse totale. Une approche similaire a permis de décrire, dans un second temps, une méthode inédite de double dédoublement cinétique de 1,3-diols anti. Générale et pratique, ce procédé fournit des diols énantiopurs de structures variées. La particularité de ces méthodologies réside dans l’exploitation du principe de Horeau se traduisant par une amplification de l’énantiosélectivité déployée par le catalyseur chiral. Les isothiourées employés dans ces réactions constituent une famille de bases de Lewis azotées dont la capacité à promouvoir les réactions d’acylation énantiosélectives n’a été découverte que récemment. Bien que leur utilisation en catalyse énantiosélective se soit rapidement démocratisée, les éléments structuraux responsables de leur sélectivité n’ont pas été totalement identifiés. Avec le nouvel objectif d’établir une relation entre structure, réactivité et sélectivité de ces molécules, des isothiourées originales ont été synthétisées et leur potentiel catalytique étudié en détail. / Acyclic 1,3-diols are ubiquitous scaffolds, essential in the structure of numerous natural products. The developpment of innovative pathways allowing their enantioselective obtention is of first interst in organic synthesis. In this context, our team envisaged a strategy of multiple organocatalyzed enantioselective acyl transfers. This approach led to the implement of a methodology based on the organocatalyzed desymmetrization of meso 1,3-diols. The desymmetrized compounds were obtained with high level of enantioselectivity and were used as useful building blocks easily valorizable in total synthesis. In a second time, we developed an organocatalyzed method of double kinetic resolution (DoCKR) of anti 1,3-diols. Very general, practicable and useful, this process allows the preparation of enantiopur diols with a large structural diversity. The particularity of these methods reside in the exploitation of the Horeau principle leading to the amplification of the enantioselectivity. These phenomons of kinetic amplification, often anecdotic, were used in this study as a powerful tool.The employed isothioureas belong to the nitrogenated Lewis bases family which were discovered only very recently to promote enantioselective acyl transfer. Although their uses in enantioselective catalysis were rapidly democratized, the structural feature responsible of their selectivity are not all clearly identified. To establish a relationship between structure, reactivity and selectivity of theses molecules, new isothioureas were synthesized and evaluated in enantioselective catalysis.

Devant l’intérêt grandissant pour le développement de stratégies innovantes applicables à la synthèse de molécules complexes, notre groupe s’est orienté vers la construction de motifs présents dans un grand nombre de produits biologiquement actifs : les tétrahydropyranes (THP) et les polypropionates. Notre stratégie, basée sur la formation diastéréosélective de diols méso primaires, fait intervenir une étape inédite de désymétrisation organocatalysée par transfert d’acyle asymétrique. Cette approche permet la synthèse énantiosélective de THP pentasubstitués qui par la suite peuvent être valorisés par l’obtention de polypropionates fonctionnalisés, possédant quatre centres stéréogènes contigus. Par ailleurs, cette nouvelle méthodologie de désymétrisation donne accès à des motifs cycliques et acycliques comportant plusieurs centres stéréogènes quaternaires. Elle constitue, de plus, l’unique exemple de désymétrisation énantiosélective de diols méso primaires catalysée par une dialkylaminopyridine chirale. Bien que le transfert d’acyle asymétrique organocatalysé ait été très largement étudié depuis la fin des années 90, de nombreuses études sont en cours pour accéder à des catalyseurs plus sélectifs et plus nucléophiles. Inspiré des récents travaux de Steglich et Vedejs, notre deuxième objectif s’est porté sur la synthèse énantiosélective et modulaire d’une nouvelle famille d’organocatalyseurs chiraux plus polyvalents dérivés de la 1,6-naphtyridine. Leur application, en catalyse nucléophile, a pu être évaluée dans des réactions de dédoublement cinétique d’alcools et dans les réarrangements de Steglich. / Alongside metallocatalysis and biocatalysis, organocatalysis has emerged as a complementary and powerful tool that can circumvent limitations associated to the use of metals or enzymes. Because of the growing interest for new innovative methodologies useful for complex molecules synthesis, we get interested in the preparation of versatile building blocks present in many bioactive molecules: tetrahydropyrans (THP) and polypropionates. Based on the diastereoselective formation of primary meso diols, our strategy involves an original organocatalyzed desymmetrization of these compounds by asymmetric acyl transfer. This approach allows the enantioselective synthesis of pentasubstituted THP which were valorized through the synthesis of polypropionates bearing four consecutive stereogenic centers. In addition, this new methodology provides cyclic and acyclic scaffolds with several all carbon quaternary stereogenic centers. It represents the first example in organocatalyzed asymmetric desymmetrization by acyl transfer using a chiral dialkylaminopyridine. Although asymmetric organocatalyzed acyl transfer has been widely studied since the late 90s, several investigations are currently underway to access to new chiral nucleophilic catalysts. Following the recent work of Steglich and Vedejs, we were interested in the development of new chiral organocatalysts derived from 1,6-naphthyridine. Their applications in nucleophilic catalysis have then been evaluated in kinetic resolutions of alcohols and in asymmetric Steglich rearrangements.

La catalyse hétérogène est en plein développement pour des raisons économiques, de santé et de protection environnementale. Les travaux de cette thèse s'intéressent à la préparation des silices fonctionnalisées par des sous-structures ioniques pour leur application en catalyse hétérogène. D'abord, des matériaux mésoporeux fonctionnalisés par des entités di-aryl imidazoliums ont été préparés par des réactions de post-greffage. En plus, films de type PMO contenant des entités di-aryl imidazoliums ont été synthétisés en présence d'un surfactant anionique. Ensuite, complexes carbéniques N-hétérocycliques du cuivre et du palladium supportés ont été préparés et appliqués en tant que catalyseurs organométalliques dans des réactions A3 (Cu-NHC) et de couplage de Suzuki (Pd-NHC). Les silices fonctionnalisées avec des entités imidazoliums ont également été utilisées en tant qu'organocatalyseurs des réactions de Henry et dans de cycloaddition du dioxyde de carbone aux époxydes. Des matériaux de type ‘PMO' contenant des entités amines/ammoniums ainsi que des sous-structures zwitterioniques ont été utilisés en réactions organocatalysées de Henry et Biginelli. / Heterogenous catalysis is an area in continuous development due to economical, health and environmental issues. This thesis deals with the preparation of i-silica materials for the posterior application in heterogeneous catalysis. First, di-aryl imidazolium containing silica materials were synthesized by post-grafting reactions on mesoporous SBA-15. Moreover, di-alkyl imidazolium containing PMO films were prepared in presence of an anionic surfactant. Then, supported copper and palladium N-heterocyclic carbenes were synthesized from di-aryl imidazolium silica and applied to A3 reactions (Cu-NHC) and Suzuki cross-coupling reactions (Pd-NHC). Imidazolium functionalized silicas were also utilized as heterogeneous organocatalysts in Henry reactions and in reactions of cycloaddition of carbon dioxide to epoxides. Finally, PMO type materials containing amine/ammonium and zwitterionic substructures were applied to Henry and Biginelli organocatalysed reactions, respectively.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-04T13:24:36Z No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T15:55:49Z (GMT) No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) / Made available in DSpace on 2016-01-25T15:55:49Z (GMT). No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) Previous issue date: 2015-03-31 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Carboidratos têm sido utilizados como organocatalisadores em síntese orgânica devido a sua quiralidade intrínseca. Neste trabalho foi sintetizado um novo organocatalisador aproveitando a estrutura da D-galactose como indutor de quiralidade. A síntese ocorreu em cinco etapas, a saber: proteção seletiva das hidroxilas das posições 1, 2, 3 e 4, seguida pela iodação da posição 6, substituição nucleofílica pelo grupo azido, redução à amina e por fim uma reação com anidrido ftálico. O rendimento global foi de 60 %. O organocatalisador foi testado na reação de adição de Michael entre o dibenzilideno acetona e a azalactona derivada da alanina. 20 mol% do catalisador conduziu ao produto com 57 % de rendimento e com total controle da régio- e diasteroseletividade. No escopo, vários produtos com funcionalização no esqueleto de dbas foram preparados e devidamente caracterizados pelas técnicas convencionais de análise. A determinação da estereoquímica relativa foi realizada através do uso de HPLC com fase estacionária quiral e foi atribuída como 1,2-anti após a comparação do tempo de retenção com um padrão já descrito na literatura. De maneira geral, é reportada, pela primeira vez, uma metodologia mais geral para a dessimetrização diasterosseletiva entre dbas e azalactonas catalisadas por ácido de Brønsted. / Carbohydrates have been used as organocatalysts in organic synthesis due to its inherent chirality. In this work, D-galactose was choose as a chiral pool in the catalyst design and it was prepared in five steps: selective ketalyzation of hydroxyl groups, following by an iodination and nucleophilic substitution in the presence of azide. To complete, reduction of the azide to amine and a coupling reaction with phthalic anhydride leading to the catalyst. Overall yield was 60 % for five steps. Then, the catalyst was adopted in the Michael addition reaction between dibenzylidene acetone and azalactone derivative of alanine. The product was obtained in 57% yield and with fully control of both regio- and diastereoselectivity. Next, various funcionalizated dbas were evaluated under the optimized reaction condition and the corresponding final products were fully characterized through conventional elemental analysis. The relative stereochemistry was assigned as being 1,2-anti by using chiral HPLC method. To this end, an authentic sample already described in the literature was prepared in order the retention time. In general, for the first time, a method more general to perform a diastereoselective dessymetrization of dbas in presence of azlactones by using a Brønsted acid as catalyst was described.

L’organocatalyse est reconnue comme une approche attractive dans la synthèse énantiosélective, offrant de nombreux avantages par rapport à la métallo-catalyse et biocatalyse. Dans la première partie de cette thèse, nous nous sommes intéressés dans le développement de nouveaux catalyseurs tropos de transfert de phase, basée sur les dérivés de dibenzazepinium et leurs applications en synthèse asymétrique. Nous avons mis en évidence la possibilité d’utiliser le principe de transfert de chiralité centrale-axiale. La deuxième partie de cette thèse a été consacrée à l'élaboration de méthodologies organocatalytiques en utilisant la catalyse par transfert de phase ou de base de Brønsted. Notre nouvelle approche, basée des réactions organocatalytiques de cycloaddition formelles [3 + 2], ouvre l'accès aux différents cycles chiraux comme des cyclopentènes, pyrrolidines ou isoxazolidinones. Toutes ces molécules sont potentiellement intéressantes pour leur évaluation comme des ligands bioactif. / Organocatalysis is recognized as a versatile and attractive tool in enantioselective synthesis, offering a number of advantages over metal-based and bioorganic methods. During the first part of this thesis, we were interested in development of novel tropos Phase-Transfer catalysts, based on the dibenzazepinium derivatives and their applications in asymmetric synthesis. Their design was tackled by anoriginal central-axial chirality transfer principal. The second part of this thesis was devoted to the elaboration of novel organocatalytic methodologies under chiral PTC or Brønsted base organocatalysis. Based on formal organocatalytic [3+2]cycloaddition reactions our novel approach opens the access to various chiral cycles like cyclopentenes, pyrrolidines or isoxazolidinones. All these molecules are potentially interesting for their evaluation as bio-ligands.