Les travaux de recherche réalisés, dans le cadre de la préparation de cette thèse ont pour objectif l’élaboration de nouveaux réseaux thermoréversibles biodégradables à base de polyglycolide (PGA) et d’hydrogels à base de polylactide (PLA) modifiés chimiquement au moyen du noyau furanique et du cycle maléimide. La réticulation du PGA, en suivant deux stratégies, en vue d’élaborer des réseaux thermoréversibles et biodégradables via la réaction de Diels-Alder a fait l’objet de la première partie de ce travail. Le but était entre autres de valoriser le PGA en conduisant à des structures réticulées avec des propriétés mécaniques requises tout en améliorant ses propriétés de stabilité. Des réseaux hybrides de PLA/PEG et PLA/PHEMA ont été ensuite synthétisés en phase fondu en adoptant la réaction de Diels-Alder comme mécanisme de réticulation. Une fois obtenus, leur mise au contact de l’eau conduit à la formation d’hydrogels. Les analyses structurales menées par RMN ont permis de confirmer la formation des structures attendues. La thermoréversibilité des réseaux obtenus a été montrée par des analyses rhéologiques. La morphologie des gels avant et après gonflement a été analysée par Microscopie Electronique à balayage. La dégradabilité des réseaux préparés a été examinée selon deux modes : hydrolytique et par les microorganismes en milieu aérobie. / The research conducted for the preparation of this thesis aims to develop new thermoreversible and biodegradable polyglycolic-acid (PGA) based networks and polylactic-acid (PLA) based hydrogels, from polymers chemically modified by means of furanic, and maleimide cycle. The cross-linking of PGA to develop thermoreversible and biodegradable networks via the Diels-Alder reaction has been done by following two strategies and was the first part of this work. The aim was, among other things, to enhance the PGA by leading to reticulated structures with required mechanical properties while improving its stability properties. Hybrid networks of PLA / PEG and PLA / PHEMA were then synthesized in the melt by adopting the Diels-Alder reaction as a crosslinking mechanism. Once obtained, their contact with water leads to the formation of hydrogels. NMR structural analyzes confirmed the formation of expected structures. The thermoreversibility of the obtained networks has been shown by rheological analyzes. The morphology of the gels before and after swelling was analyzed by Scanning Electron Microscopy. The degradability of prepared networks was examined in two modes: hydrolytic and aerobic by microorganisms.

O objetivo deste trabalho foi desenvolver métodos para sintetizar o esqueleto carbônico básico de furanoeliangolidos. Goiazensolido é um típico exemplo destes produtos naturais, cujo núcleo estrutural podemos considerar como sendo de um biciclo[6.2.1]undecano. Imaginamos que este tipo de estrutura poderia ser preparado através da reação de Diels-Alder seguida da ruptura de uma ligação interna de um sistema policíclico. Na nossa primeira tentativa, fomos capazes de preparar o dimesilato 75, mas a clivagem da ligação C2-C7 não pôde ser efetivada, nem sob condições solvolíticas, nem por tratamento com base, somente misturas complexas foram obtidas em todas as tentativas. Nossa próxima abordagem foi baseada no possível rearranjo térmico de um sistema contendo dois anéis de ciclobutanos fundidos entre si (um sistema tetraciclo[6.2.1.02,7.03,6]undecano). Entretanto, embora tenhamos conseguido preparar os compostos 87 e 101 com bons rendimentos, o produto de fotocicloadição [2 + 2] não pôde ser obtido. Finalmente, em nossa terceira abordagem, baseada em uma reação de retro-aldol, conseguimos obter o sistema biciclo[6.2.1]undecano 117, pelo tratamento de 116 com NaH em tolueno aquecido até refluxo. O composto foi preparado por dois caminhos diferentes, ambos envolvendo reações de Diels-Alder. / The aim of this work was to develop methods to synthesize the main carbon skeleton of the furanoheliangolides. Goyazensolide is a typical example of these natural products, whose core structure is a bicyclo[6.2.1]undecane. We envisioned that this framework could be prepared through the Diels-Alder reaction followed by a cleavage of an internal bond of the polycyclic ring system. In our first attempt, we were able to prepare the dimesilate 75, but the desired cleavage of the C2-C7 bond could not be effected, neither under solvolytic conditions, nor by base treatment, complex mixtures being the result in all attempts. Our next approach was based in the possible thermal rearrangement of the system consisting of two fused cyclobutane rings (a tetracyclo[6.2.1.02,7.03,6]undecane ring system). However, although compounds 87 and 101 could be prepared in good yields, no photochemical [2 + 2] cycloaddition product could be obtained from them. Finally, in our third approach, based in a retro aldol reaction, we succeeded in preparing the desired bicyclo[6.2.1]undecane system 117 by treatment of 116 with NaH in refluxing toluene. Compound 116 was prepared by two different ways, both involving Diels-Alder reactions.

Die Aufgabe des synthetischen Chemikers besteht darin neue Moleküle, Bauelemente oder Medikamente aus einfachen Edukten herzustellen. Die wachsende Komplexität dieser synthetischen Produkte bedingt jedoch, dass die Entwicklung der dazu benötigten Werkzeuge ebenso schritthalten muss. Licht ist mit seiner herausragenden räumlichen, zeitlichen und energetischen Auflösung sowie seinem nicht-invasiven Charakter den traditionell verwendeten Stimuli überlegen. In dieser Arbeit wurde durch die Kombination eines molekularen Photoschalters mit der Diels-Alder-Reaktion die Photokontrolle über eine dynamisch-kovalente Reaktion erlangt. Das Ergebnis der Reaktion eines furyl-substituierten Diarylethens mit Maleinimid konnte ausschließlich durch die Bestrahlung mit Licht unterschiedlicher Farbe bestimmt werden. Dieses prototypische System wurde dann unter Erhalt seiner photochemischen Eigenschaften für die Anwendung unter physiologischen Bedingungen weiterentwickelt. Es konnte die photoreversible Freisetzung therapeutisch wirksamer Konzentrationen verschiedener Anti-Tumor-Medikamente in gepufferter, wässriger Lösung bei Körpertemperatur durch bioorthogonales sichtbares Licht ausgelöst werden. Weiterhin wurden die Feinabstimmung der Freisetzung dieser photoschaltbaren Diels-Alder-Addukte und eine ausführliche Untersuchung der Freisetzungs-Dynamiken gezeigt. Hierdurch wurde das System auf eine Stufe gehoben, an der in vivo Anwendungen erwägt werden können. Des Weiteren wurden die Grundlagen zur Implementierung der photokontrollierbaren Diels-Alder-Reaktion in der reversiblen kovalenten Funktionalisierung von Kohlenstoffnanoröhren gelegt. Trotzdem noch keine erfolgreiche Funktionalisierung nachgewiesen werden konnte, wurde durch die Untersuchung der zugrundeliegenden Prinzipien der Weg für die Anwendung fortgeschrittener Techniken zur Modulation physikochemischer Eigenschaften von sp2-Kohlenstoff Allotropen geebnet. / The synthetic chemist’s profession is devoted to the formation of chemical bonds to create new molecules, building blocks, or drugs from basic starting materials. However, the growing complexity of these synthetic products necessitates that the development of the tools to fulfill this task must also keep pace. Light as a stimulus with its superior spatial, temporal, as well as energetic resolution in combination with its non-invasive character outperforms the traditional means to control a chemical reaction, such as heat, pressure, or pH, clearly. In this work, the unprecedented reversible photocontrol over a dynamic covalent reaction was established by the combination of a molecular photoswitch and the well-known Diels-Alder reaction. The outcome of the reaction of a furyl-substituted diarylethene and maleimide could be determined exclusively by illumination with differently colored light. This prototypical system was then advanced for the application under physiological conditions while retaining its superior photochemical properties. The release of therapeutically effective concentrations of different antitumor agents could be photoreversibly triggered in buffered, aqueous solution at body temperature employing bioorthogonal visible light. It is shown how the release properties of these photoswitchable prodrugs can be fine-tuned and a thorough investigation of the release dynamics is presented promoting this system to a level where in vivo application can be considered. Furthermore, the foundations for the implementation of the photocontrollable Diels-Alder reaction in the reversible covalent functionalization of carbon nanotubes have been laid. Despite the fact that a successful functionalization has not yet been achieved, the basic principles were investigated and have paved the way for the application of more advanced techniques to effectively modulate the physicochemical properties of sp2-carbon allotropes.

Nos travaux ont débuté par la synthèse diastéréo/énantiosélective de 14 béta-hydroxyandrostanes en faisant appel à une réaction de Diels-Alder visant la formation du cycle B. Nous avons ainsi préparé une large palette de 14 béta-hydroxyandrostanes naturels, non naturels, racémiques ou énantiopurs. Par exemple au départ de la 2-méthyl-cyclopentane-1,3-dione divers 14 béta-hydroxyandrostanes polyfonctionnalisés possédant 5 à 7 centres stéréogéniques ont été synthétisés. D’autre part, avec la (R) ou (S)-carvone comme diénophile, nous avons mis en évidence diverses réactions de Diels-Alder sous contrôle d’une résolution cinétique parallèle chemodivergente ce qui a donné accès à des 14 béta-hydroxyandrostanes et à leurs énantiomères optiquement purs. Par la suite, nous avons développé la synthèse diastéréospécifique de 1,3-oxazines racémiques ou énantiomériquement pures en traitant des alpha-alkyloxyamides polyfonctionnalisés par des acides de Lewis ou de Brønsted. Au départ de ces mêmes composés, nous avons également synthétisé des pyrrolizidinones et des indolizidinones polyfonctionnalisées en faisant varier la nature des acides de Brønsted. Une synthèse formelle de la (+/-)-tashiromine a ainsi été réalisée. Finalement, la dernière partie de nos travaux a été consacrée à l’obtention des systèmes tricycliques caractéristiques de la famille des cédranoides et de la famille des quadranes/subérosanes. Ces deux systèmes tricycliques ont été obtenus au départ de la cyclopentane-1,3-dione en utilisant comme étape clé une réaction de Morita-Baylis-Hillman intramoléculaire initiée par de la tri-n-butylphosphine. / In the first part of our work, we have developed highly diastereo/enantioselective Diels-Alder reactions to promote the synthesis of 14 beta-hydroxyandrostanes. Thus, numerous non-natural or natural racemic and optically pure 14 beta-hydroxyandrostanes were obtained. For example, starting from the 2-methyl-cyclopentane-1,3-dione, the synthesis of 14 beta-hydroxyandrostane derivatives bearing 5 to 7 stereogenic centers was readily achieved. Moreover, by using (R) or (S)-carvone as dienophile, the Diels-Alder reaction proved to be under a chemodivergent parallel kinetic resolution control leading to optically pure (ent)-14 beta-hydroxyandrostanes. The second part of our work was dealing with the synthesis of heterocyclic compounds like pyrrolizidinones, indolizidinones and 1,3-oxazines. For that purpose, we have shown that the latter were readily available by Lewis or Brønsted acids treatment of polyfunctionalized alpha-alkyloxyamides. Furthermore, by changing the nature of the Brønsted acid, pyrrolizidinones and indolizidinones derivatives were obtained allowing a formal synthesis of (+/-)-tashiromine. Finally, the synthesis of the tricyclic cores found in cedranoids and quadranes/subersonanes sesquiterpenes was achieved, the key step being a tri-n-butylphosphine promoted intramolecular Morita-Baylis-Hillman reaction.

<p>The synthesis of 2-aza-norborane derivatives is presented. The use of these compounds in preparation of Ir catalysts for asymmetric hydrogenations is described. The evaluation and optimization of the catalysts as well as the mechanistic aspects of the catalytic process are discussed.</p><p>The use of non-activated iminodieniphiles in stereoselective aza-Diels-Alder reaction has expanded the scope of the reaction and provided a convenient root for preparation of 2-aza-norboranes, analogues of which were developed into novel bicyclic 2-aza-norbornyl-oxazoline ligands for Ir-catalyzed asymmetric transfer hydrogenations. Using ths Ir complexes acetophenone was hydrogenated in 79% ee.</p><p>2-Aza-norbornyl-oxazolines were also developed into novel N,P-ligands. Resulting phosphine-oxazolines were evaluated in Ir-catalyzed asymmetric hydrogenation of structurally diverse imines and olefins.</p><p>Optimization of ligands was performed through: 1) Alteration of the stereoconfiguration at the 5’-position as well as variation of the size and geometry of the substituents at this position; 2) Screening through various phosphine substituents of the ligand. Both directions of optimization reflect on the influence of the ligands’ sterik bulk on stereoselectivity of catalytic process. High performance catalysts were developed for both transformations allowing asymmetric hydrogenation of imines with 92% ee and asymmetric hydrogenation of olefins with 99% ee.</p><p>Possible mechanisms for these transformations were suggested based on computational studies. Selectivity model for rationalization of results of Ir-catalyzed olefin hydrogenation also was designed.</p>

The synthesis of 2-aza-norborane derivatives is presented. The use of these compounds in preparation of Ir catalysts for asymmetric hydrogenations is described. The evaluation and optimization of the catalysts as well as the mechanistic aspects of the catalytic process are discussed. The use of non-activated iminodieniphiles in stereoselective aza-Diels-Alder reaction has expanded the scope of the reaction and provided a convenient root for preparation of 2-aza-norboranes, analogues of which were developed into novel bicyclic 2-aza-norbornyl-oxazoline ligands for Ir-catalyzed asymmetric transfer hydrogenations. Using ths Ir complexes acetophenone was hydrogenated in 79% ee. 2-Aza-norbornyl-oxazolines were also developed into novel N,P-ligands. Resulting phosphine-oxazolines were evaluated in Ir-catalyzed asymmetric hydrogenation of structurally diverse imines and olefins. Optimization of ligands was performed through: 1) Alteration of the stereoconfiguration at the 5’-position as well as variation of the size and geometry of the substituents at this position; 2) Screening through various phosphine substituents of the ligand. Both directions of optimization reflect on the influence of the ligands’ sterik bulk on stereoselectivity of catalytic process. High performance catalysts were developed for both transformations allowing asymmetric hydrogenation of imines with 92% ee and asymmetric hydrogenation of olefins with 99% ee. Possible mechanisms for these transformations were suggested based on computational studies. Selectivity model for rationalization of results of Ir-catalyzed olefin hydrogenation also was designed.

No description available.

Orientadora: Profa. Dra. Mirela Inês de Sairre / Tese (doutorado) - Universidade Federal do ABC. Programa de Pós-Graduação em Ciência e Tecnologia/Química, 2017. / Cerca de 98% do total de nióbio encontra-se no Brasil, sendo este o maior produtor de mundial com aproximadamente 90%. Neste trabalho serão apresentadas duas reações a Reação Multicomponente de Hanzsch (RMC) e a Reação de Diels-Alder, nas quais foram utilizados compostos de nióbio (pentóxido de nióbio (NBO), oxalato amoniacal de nióbio (ANO), fosfato de nióbio (NBP) e pentacloreto de nióbio) como catalisadores. A primeira reação estudada foi a RMC de Hanzsch para a produção de 1,4-dihiropiridinas (DHP). Uma nova metodologia foi desenvolvida para a produção de 1,4-DHP simétricas utilizando os catalisadores NBO, NPB e ANO, foram obtidos rendimentos moderados a bons (23%-63%). Após a obtenção destes resultados, foi decidido produzir DHP diferentemente substituídas, para isso foi sintetizada a 3-aminocrotonitrila via reação de Thorpe, o produto foi obtido como mistura de isómeros E e Z (rendimento de 46%). Utilizando a mesma metodologia sintetizouse então as ciano-l,4-di-hidropiridinas que foram obtidas em baixo rendimento (3% - 25%),pois também foi formada a DHP simétrica. Tentando utilizar o pentacloreto de nióbio como catalisador criar uma nova metodologia, que foi desenvolvida na ausência de solvente, oproduto obtido não foi a 1,4-DHP diferentemente substituída, mas sim uma diciano-1,4-DHP. Essas moléculas apresentam grande importância, pois estudo computacionais feitos previamente mostram que as 1,4-DHP são moléculas precursoras para o desenvolvimento de possíveis inibidores da enzima dipeptidil peptidase IV (DPP IV), que podem ser utilizadas no tratamento de Diabetes Melito do Tipo 2. A segunda reação estudada foi a reação de Diels- Alder, para esta reação utilizou o N-Boc-pirrol e o furano como dienos, e o acrilato de etila e de metila como dienófilos. As reações realizadas com o N-Boc-pirrol não produziram o biciclo resultante da reação de Diels-Alder. As reações entre o furano e o acrilato de etila só apresentaram resultados positivos quando se utilizou pentacloreto de nióbio, no entanto o produto foi obtido em baixo rendimento (7%). Quando o dienófilo foi alterado para acrilato de metila o rendimento aumentou para 75%. Os biciclos produzidos apresentam grande importância, pois eles são precursores de um intermediário para a síntese de duas moléculas bastante importantes como a Gabaculina, que pode ser utilizada como fármaco no tratamento de epilepsia, esquizofrenia e mal de Parkinson, e o Oseltamivir Fosfato, um fármaco utilizado no tratamento do vírus influenza. / About 98% of the total niobium is found in Brazil, the country is the largest producer with approximately 90%. In this work, we will present two reactions: the Hanzsch Multicomponent Reaction (MCR) and the Diels-Alder Reaction, these reactions were promoted by niobium compounds (nobium pentoxide (NBO), ammoniacal niobium oxalate (ANO), niobium phosphate (NBP) and niobium pentachloride). The first reaction studied was Hanzsch MCR for the production of 1,4-dihiropyridines (DHP). A new methodology was developed to produce 1,4-DHP symmetrical using the NBO, NPB and ANO catalysts, moderate to good yields were obtained (23% - 63%). After obtaining these results, it was decided to produce DHP differently substituted, however it was necessary to synthesize the 3-aminocrotonitrile via Thorpe reaction, the product was obtained as a mixture of E and Z isomers (yield 46%). Using the same methodology, the cyano-1,4-dihydropyridines were synthesized which were obtained in low yield (3% - 25%), because the DHP symmetrical was also formed. In attempting to produce a novel methodology promoted by niobium pentachloride, using no solvent, the product obtained was not 1,4-DHP differently substituted, but a dicyano-1,4- DHP. A previously molecular modeling computational study has shown that these molecules are of great importance for the development of possible enzyme dipeptidyl peptidase IV (DPP IV) inhibitors, and they can be used in the treatment of type 2 diabetes mellitus. The second reaction studied was the Diels-Alder reaction; the reactions were performed using N-Bocpyrrole and furan as dienes, and ethyl acrylate and methyl acrylate as dienophiles. Reactions performed using N-Boc-pyrrole did not produce the aduct resulting from Diels-Alder reaction. Reactions performed using furan and ethyl acrylate only showed positive results promoted by niobium pentachloride; however the product was obtained in low yield (7%). When the dienophile was changed to methyl acrylate the yield increased to 75%. The aducts produced are of great importance because they are precursors of an intermediate for the synthesis of two very important molecules such as Gabaculin, it can be used as a medicine in the treatment of epilepsy, schizophrenia and Parkinson's disease, and Oseltamivir Phosphate, a medicine used in the treatment of influenza virus.

O objetivo deste trabalho foi desenvolver métodos para sintetizar o esqueleto carbônico básico de furanoeliangolidos. Goiazensolido é um típico exemplo destes produtos naturais, cujo núcleo estrutural podemos considerar como sendo de um biciclo[6.2.1]undecano. Imaginamos que este tipo de estrutura poderia ser preparado através da reação de Diels-Alder seguida da ruptura de uma ligação interna de um sistema policíclico. Na nossa primeira tentativa, fomos capazes de preparar o dimesilato 75, mas a clivagem da ligação C2-C7 não pôde ser efetivada, nem sob condições solvolíticas, nem por tratamento com base, somente misturas complexas foram obtidas em todas as tentativas. Nossa próxima abordagem foi baseada no possível rearranjo térmico de um sistema contendo dois anéis de ciclobutanos fundidos entre si (um sistema tetraciclo[6.2.1.02,7.03,6]undecano). Entretanto, embora tenhamos conseguido preparar os compostos 87 e 101 com bons rendimentos, o produto de fotocicloadição [2 + 2] não pôde ser obtido. Finalmente, em nossa terceira abordagem, baseada em uma reação de retro-aldol, conseguimos obter o sistema biciclo[6.2.1]undecano 117, pelo tratamento de 116 com NaH em tolueno aquecido até refluxo. O composto foi preparado por dois caminhos diferentes, ambos envolvendo reações de Diels-Alder. / The aim of this work was to develop methods to synthesize the main carbon skeleton of the furanoheliangolides. Goyazensolide is a typical example of these natural products, whose core structure is a bicyclo[6.2.1]undecane. We envisioned that this framework could be prepared through the Diels-Alder reaction followed by a cleavage of an internal bond of the polycyclic ring system. In our first attempt, we were able to prepare the dimesilate 75, but the desired cleavage of the C2-C7 bond could not be effected, neither under solvolytic conditions, nor by base treatment, complex mixtures being the result in all attempts. Our next approach was based in the possible thermal rearrangement of the system consisting of two fused cyclobutane rings (a tetracyclo[6.2.1.02,7.03,6]undecane ring system). However, although compounds 87 and 101 could be prepared in good yields, no photochemical [2 + 2] cycloaddition product could be obtained from them. Finally, in our third approach, based in a retro aldol reaction, we succeeded in preparing the desired bicyclo[6.2.1]undecane system 117 by treatment of 116 with NaH in refluxing toluene. Compound 116 was prepared by two different ways, both involving Diels-Alder reactions.

La Gymnodimine et le 13-desméthyle Spirolide C sont des neurotoxines macrocycliques à imine cyclique. Elles ont été isolées dans des organismes filtreurs tels que les moules et les huitres et sont produites par des algues unicellulaires de type dinoflagellé. Lors d’efflorescences algales, la forte concentration de ces molécules est à l’origine de problèmes de santé publique car les micro-algues sont absorbées puis concentrées par les organismes filtreurs. Elles se retrouvent ensuite transmises aux animaux marins et à l’Homme via la chaîne alimentaire. Dans ce contexte, leur synthèse s’avère indispensable pour disposer de quantités suffisantes à leur étude pharmacologique. Cette thèse a porté sur la synthèse des fragments spiromines du 13-desméthyle Spirolide C et de la Gymnodimine. Plusieurs stratégies unifiées ont été testées au cours de ces travaux. Dans un premier temps, des cyclisations cationiques et radicalaires d’époxy-allylsilanes obtenus par une réaction clé de substitution allylique sont présentées. Dans un second temps, une approche diastéréosélective à la synthèse d’allylsilanes et des cyclisations par ouverture radicalaire d’époxydes ont été testés. Finalement, une stratégie de synthèse basée sur la réaction de Diels-Alder a permis la synthèse d’une imine cyclique modèle et d’un intermédiaire avancé pour la synthèse totale de la Gymnodimine. / The Gymnodimine and the 13-desméthyle Spirolide C are two macrocyclic neurotoxins bearing a cyclic imine. They were isolated in filter organisms such as mussel and oysters and are produced by marine unicellular organisms called dinoflagellates. In the occurrence of algal blooms, a massive production of these molecules creates public health issues. The absorption and concentration by filter organisms, allow this molecules to be delivered to marine wild life and human trough the food chain. To date, the mode of action of spirolides is not fully elucidated and the toxicity toward humans still needs studies. Considering their low bioavailability, their synthesis proves to be crucial to have enough material for pharmacological studies. This manuscript present the synthesis of the spiroimine fragment of the 13-desméthyle Spirolide C and the Gymnodimine. Various unified strategies were tested in this work. In the first part, cationic and radical cyclisations of epoxy-allylsilanes obtained by a key allylic substitution are presented. In the second part, a diastereoselective approach for the synthesis of allylsilanes and cyclisation attempts by radical opening of epoxides are presented. Finally, a Diels-Alder based strategy allowed the synthesis of a model cyclic imine and a highly substituted fragment for the total synthesis of the Gymnodimine.