Neste trabalho, avaliou-se o potencial do uso de oxidantes quirais em oxidações enantiosseletivas de compostos orgânicos de boro. É de conhecimento geral que compostos orgânicos de boro, especialmente ésteres e ácidos borônicos são facilmente oxidados por hidroperóxidos em meio básico. No entanto, são escassos na literatura exemplos destas reações de modo enantiosseletivo. A fim de realizar as reações mencionadas, sintetizou-se os hidroperóxidos quirais TADOOH ({(4R,5R)-5-[(hidroperoxidifenil)metil]-2,2-dimetil-1,3-dioxolan-4il}difenilmetanol) e o hidroperóxido quiral derivado de carboidrato, 2,3-dideoxi1-O-oxidanil-4,6-di-O-pivaloil-α-D-eritro-hex-2-enopiranose (di-O-PivOOH). Estes compostos apresentaram resultados interessantes na literatura em oxidações enantiosseletiva de sulfetos orgânicos, em epoxidações de alcenos e em oxidações de Baeyer-Villiger. Inicialmente o potencial oxidativo de ambos hidroperóxidos, bem como a seletividade destes, foi avaliado frente a diversos ésteres borônicos, sendo que somente o TADOOH apresentou resultados promissores. (Ver esquema no PDF) Observou-se uma melhor seletividade do TADOOH frente a ésteres borônicos que possuíam grupos carbonílicos em sua estrutura. Ao submeter o β-boronil-éster, 3-fenil-3-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)propanoato de etila, à oxidação com o TADOOH em THF utilizando NaOH como base, a -30°C por 1 hora, obteve-se o respectivo álcool com 40% de e.e. Cálculos de DFT para o estado de transição na oxidação dos ésteres borônicos com o TADOOH foram realizados em colaboração com o grupo do Prof. Dr. Ataualpa Albert Carmo Braga. Estes cálculos demonstraram que o estado de transição é estabilizado por uma ligação de hidrogênio não clássica entre o oxigênio da carbonila e umas das ligações C-H dos grupos fenila do TADOOH. Além dos estudos relatados, a reconhecida metodologia de Sharpless na epoxidação assimétrica de alcoóis alílicos foi adaptada para a oxidação enantiosseletiva de ésteres borônicos. Ao trocar o ligante derivado de éster tártarico, normalmente utilizado nas epoxidações de Sharpless, por (-)-efedrina observou-se uma moderada seletividade deste sistema frente ao pinacol l-fenietilboronato. Investigações mais detalhadas demonstraram que a presença do Ti(IV) não era necessária, sendo que a (-)efedrina era a responsável pela ativação e indução quiral nesta reação. / In this work, it was investigated the potential use of chiral oxidants in organic boron compound oxidation. It is known in the literature, that organic boron compounds can be easily oxidized by hydroperoxides. However, an enantioselective approach in literature is scarce. In order to perform these reactions, hydroperoxide TADOOH ({(4R,5R)-5[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-l,3-dioxolan-4-yl}diphenylmethanol) and carbohydrate derived hydroperoxide, 2,3-dideoxy-1-O-oxidanyl-4,6-di-O-pivaloyl-α-D-erythro-hex-2-enopyranose (di-O-PivOOH), have been synthesized. These compounds showed interesting results in several enantioselective oxidations, as like, organic sulfides oxidation, alkenes epoxidation and Baeyer-Villiger oxidations. The oxidative potential of both hydroperoxides, as well as their selectivity, were evaluated against several boronic esters. Only TADOOH has shown promissing results for further studies. (See Scheme on PDF). Boronic esters containing a carbonyl moiety showed better selectivities with TADOOH, for example, the reaction of β-boronyl-ester, ethyl 3-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanoate, gave the correponding alcohol with 40% e.e. DFT calculations for the transition state in the oxidation of the boronic esters with TADOOH were carried out in collaboration with the group of Prof. Dr. Ataualpa Albert Carmo Braga. These calculations have shown that the transition state is stabilized by a non-classical hydrogen bond between the carbonyl oxygen and one of the C-H bonds of the TADOOH phenyl groups. In addition to the studies, the well-known Sharpless protocol for asymmetric epoxidation of allylic alcohols was adapted in the enantioselective oxidation of boronic esters. By replacing the tartaric ester-derived, commonly used in the Sharpless experiments, for (-)-ephedrine moderate selectivity was observed with pinacol 1-phenylethyl boronate. Further investigations showed that the presence of Ti (IV) was not necessary, and (-)-ephedrine was responsible for the activation and chiral induction in this reaction.

Neste trabalho, avaliou-se o potencial do uso de oxidantes quirais em oxidações enantiosseletivas de compostos orgânicos de boro. É de conhecimento geral que compostos orgânicos de boro, especialmente ésteres e ácidos borônicos são facilmente oxidados por hidroperóxidos em meio básico. No entanto, são escassos na literatura exemplos destas reações de modo enantiosseletivo. A fim de realizar as reações mencionadas, sintetizou-se os hidroperóxidos quirais TADOOH ({(4R,5R)-5-[(hidroperoxidifenil)metil]-2,2-dimetil-1,3-dioxolan-4il}difenilmetanol) e o hidroperóxido quiral derivado de carboidrato, 2,3-dideoxi1-O-oxidanil-4,6-di-O-pivaloil-α-D-eritro-hex-2-enopiranose (di-O-PivOOH). Estes compostos apresentaram resultados interessantes na literatura em oxidações enantiosseletiva de sulfetos orgânicos, em epoxidações de alcenos e em oxidações de Baeyer-Villiger. Inicialmente o potencial oxidativo de ambos hidroperóxidos, bem como a seletividade destes, foi avaliado frente a diversos ésteres borônicos, sendo que somente o TADOOH apresentou resultados promissores. (Ver esquema no PDF) Observou-se uma melhor seletividade do TADOOH frente a ésteres borônicos que possuíam grupos carbonílicos em sua estrutura. Ao submeter o β-boronil-éster, 3-fenil-3-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)propanoato de etila, à oxidação com o TADOOH em THF utilizando NaOH como base, a -30°C por 1 hora, obteve-se o respectivo álcool com 40% de e.e. Cálculos de DFT para o estado de transição na oxidação dos ésteres borônicos com o TADOOH foram realizados em colaboração com o grupo do Prof. Dr. Ataualpa Albert Carmo Braga. Estes cálculos demonstraram que o estado de transição é estabilizado por uma ligação de hidrogênio não clássica entre o oxigênio da carbonila e umas das ligações C-H dos grupos fenila do TADOOH. Além dos estudos relatados, a reconhecida metodologia de Sharpless na epoxidação assimétrica de alcoóis alílicos foi adaptada para a oxidação enantiosseletiva de ésteres borônicos. Ao trocar o ligante derivado de éster tártarico, normalmente utilizado nas epoxidações de Sharpless, por (-)-efedrina observou-se uma moderada seletividade deste sistema frente ao pinacol l-fenietilboronato. Investigações mais detalhadas demonstraram que a presença do Ti(IV) não era necessária, sendo que a (-)efedrina era a responsável pela ativação e indução quiral nesta reação. / In this work, it was investigated the potential use of chiral oxidants in organic boron compound oxidation. It is known in the literature, that organic boron compounds can be easily oxidized by hydroperoxides. However, an enantioselective approach in literature is scarce. In order to perform these reactions, hydroperoxide TADOOH ({(4R,5R)-5[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-l,3-dioxolan-4-yl}diphenylmethanol) and carbohydrate derived hydroperoxide, 2,3-dideoxy-1-O-oxidanyl-4,6-di-O-pivaloyl-α-D-erythro-hex-2-enopyranose (di-O-PivOOH), have been synthesized. These compounds showed interesting results in several enantioselective oxidations, as like, organic sulfides oxidation, alkenes epoxidation and Baeyer-Villiger oxidations. The oxidative potential of both hydroperoxides, as well as their selectivity, were evaluated against several boronic esters. Only TADOOH has shown promissing results for further studies. (See Scheme on PDF). Boronic esters containing a carbonyl moiety showed better selectivities with TADOOH, for example, the reaction of β-boronyl-ester, ethyl 3-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanoate, gave the correponding alcohol with 40% e.e. DFT calculations for the transition state in the oxidation of the boronic esters with TADOOH were carried out in collaboration with the group of Prof. Dr. Ataualpa Albert Carmo Braga. These calculations have shown that the transition state is stabilized by a non-classical hydrogen bond between the carbonyl oxygen and one of the C-H bonds of the TADOOH phenyl groups. In addition to the studies, the well-known Sharpless protocol for asymmetric epoxidation of allylic alcohols was adapted in the enantioselective oxidation of boronic esters. By replacing the tartaric ester-derived, commonly used in the Sharpless experiments, for (-)-ephedrine moderate selectivity was observed with pinacol 1-phenylethyl boronate. Further investigations showed that the presence of Ti (IV) was not necessary, and (-)-ephedrine was responsible for the activation and chiral induction in this reaction.

L'objectif de cette thèse était d'évaluer des nitroxydes chiraux à squelette imidazolidin-4-one comme catalyseurs d'oxydation énantiosélective d'alcools par le dioxygène. Pour cela, plusieurs nitroxydes avec différents substituants en position α ont été synthétisés afin de voir les effets possibles de chacun des groupements. Différents co-catalyseurs décrits dans la bibliographie ont été testés afin de faire ces réactions qui ont lieu à température ambiante et pression atmosphérique. Ces systèmes catalytiques peuvent se différencier selon s'ils utilisent ou pas de métal comme additif.La stratégie utilisée pour la synthèse des catalyseurs a été développée au laboratoire à partir de travaux sur des nitrones réalisés précédemment. Grâce à cette stratégie et à l'utilisation de différentes nitrones de départ, des analogues différemment substitués en position α peuvent être synthétisés rapidement en seulement deux étapes. En particulier, l'utilisation d'une nitrone chirale nous permettra l'obtention de catalyseurs énantiopurs qui pourront être utilisés pour les réactions d'oxydation énantiosélectives.Dans la première partie de notre étude, différents systèmes catalytiques ont été testés avec nos catalyseurs sur un substrat modèle : l'alcool benzylique. Les résultats obtenus nous ont aidé à déterminer : (1) la capacité des nitroxydes de type imidazolidin-4-one à agir en tant que catalyseurs pour les réactions d'oxydation aérobie ; (2) la différence de réactivité selon la substitution en position α ; (3) les systèmes catalytiques les plus efficaces avec nos catalyseurs ; (4) le type de substrats qui pourront être envisagés lors de l'oxydation énantiosélective.C'est ainsi la désymétrisation de diols conduisant à la formation d'atropoisomères qui a été envisagée. L'oxydation par le dioxygène de trois substrats a ainsi été testée avec plusieurs catalyseurs énantiopurs et un système catalytique à base de cuivre. Les résultats d'énantiosélectivité obtenus ont été variables selon le substrat et le catalyseur utilisés. Des résultats très encourageants ont été obtenus pour l'un des substrats, avec des excès enantiomériques d'environ 60 %.En parallèle avec les différentes réactions d'oxydation, des études de voltammétrie cyclique et de résonance paramagnétique électronique (RPE) ont aussi été réalisées. La voltammétrie cyclique nous a servi surtout pour expliquer la différence de réactivité de différents analogues selon leur substitution en position α. Avec la RPE, nous avons essayé de comprendre un peu plus l'organisation autour du cuivre des différents éléments qui font partie du système catalytique à base de cuivre utilisé pour les oxydations énantiosélectives.Grâce à tous ces travaux, nous avons démontré que les nitroxydes à squelette imidazolidin-4-one peuvent être utilisés en tant que catalyseurs pour l'oxydation aérobie d'alcools. Nous avons noté l'importance des substituants en position α qui jouent un rôle important sur la stabilité de l'espèce active, ce qui pourra faire varier l'efficacité de chaque composé. Les nitroxydes contenant le squelette imidazolidin-4-one ont aussi donné des bons résultats dans des réactions d'oxydation énantioséletive de diols benzyliques. / The aim of this thesis was to evaluate the use of chiral nitroxides containing an imidazolidin-4-one squeletton as enantioselective catalysts for the aerobic oxidation of alcohols. In this view, several nitroxides with different α substituents have been synthesized to investigate the influence of these groups. Several co-catalysts reported in the literature have been tested for the oxidation reactions that take place at room temperature and atmospheric pressure. These catalytic systems can be classified relatively to the presence or the absence of metal as additive.The strategy used for the catalyst synthesis has been developped in the laboratory from previous studies about nitrones. Using this strategy and different starting nitrones, several α-substituted analogues can be rapidly synthesized in only two steps. Particularly, the use of a chiral nitrone will permit the obtention of enantiopur catalysts that will be able used for the enantioselective oxidations.In the first part of our study, several catalytic systems have been tested with our catalysts with a reference substrate: benzylic alcohol. According to the results, we have been able to determine: (1) the capacity of imidazolidin-4-one nitroxides to behave as catalysts for the aerobic oxidations; (2) the difference of reactivity depending on the α substituents; (3) the more effective catalytic systems for our catalysts; (4) the scope of the reaction in order to determine the suitable substrates for enantioselective reactions.With all these results in hand, diol desymmetrization for the synthesis of atropoisomers has been considered. Dioxygen oxidation of three diols has been tested using different enantiopur catalysts with a copper-based catalytic system. The enantioselectivity obtained proved variable depending on the substrate and the catalyst used. Very encouraging results have been obtained for one of the substrate, with enantiomeric excess of about 60 %.At the same time as the oxidation reactions, cyclic voltammetry and electron paramagnetic resonance (EPR) studies have been carried out. Cyclic voltammetry has been useful to explain the difference of reactivity of the catalysts according the α substituents. Using the EPR, we have tried to understand the organisation around copper for the different species from the catalytic system used for the enantioselective oxidations.By means of this study, we have demonstrated that imidazolidin-4-one nitroxides can be used as catalysts for the aerobic oxidation of alcohols. The α substituents play an important role in the stability of the active species that can change the efficacity of each compound. Imidazolidin-4-one nitroxides have also given encouraging results in the enantioselective oxidation of benzylic diols.

Les molécules chirales représentent environ 60% des médicaments présents sur le marché pharmaceutique et plus de 80% des médicaments en développement avec plus de 150 milliards de dollars de chiffre d’affaire pour l’année 2002. Les intermédiaires chiraux sont fortement demandés dans l’industrie pharmaceutique atteignant 15 milliards de dollars de chiffre d’affaire en 2009. D’autres domaines en sont demandeurs avec une répartition d’environ 15% dans l’agrochimie et 5% pour la parfumerie. L’obtention de composés d’intérêt pharmaceutique de façon asymétrique est un réel défi et une réelle nécessité. Ces molécules possèdent une architecture spatiale qui entraîne des interactions spécifiques et des affinités particulières avec les enzymes ou des récepteurs biologiques chiraux. L’utilisation de catalyseurs pour accéder à des composés organiques chiraux et plus précisément l’oxydation d’alcanes prochiraux ou d’oléfines constitue un domaine en essor ces dernières décennies. Pour parvenir à synthétiser des molécules chirales, l’industrie pharmaceutique s’est tournée vers l’utilisation de biocatalyseurs en partie pour réaliser différentes réactions stéréo-contrôlées avec la nécessité de séparer les mélanges racémiques par résolution enzymatique. Cependant, les biocatalyseurs présentent un inconvénient majeur qui est généralement le faible rendement en composé chiral recherché et nécessite un savoir faire pour la manipulation de ces enzymes. Les métalloporphyrines sont des catalyseurs comportant un macrocycle tétrapyrrolique et différentes fonctionnalisations en positions méso. Ces molécules ont fait l’objet de nombreuses études qui ont conduit à la synthèse de métalloporphyrines chirales très complexes. Malheureusement, leur synthèse est souvent longue avec de faibles rendements et leur application à un nombre limité de substrats ne permet pas leur généralisation. Ce travail de thèse, développé pour la première fois au laboratoire, s’inscrit dans le cadre d'un contrat CIFRE, dans le but de parvenir à la synthèse de porphyrines chirales facilement accessibles, applicables dans des réactions d’oxydation énantiosélectives efficacement (stabilité). Le premier objectif visé est la synthèse de porphyrines chirales dont la structure ciblée comporte des groupements hétérocycliques azotés chiraux en position méso, reliés par une liaison carbone-hétéroatome (C-N). Nous avons pu atteindre 4 séries de porphyrines qui ont été évaluées dans des réactions d’oxydation énantiosélectives (époxydation, hydroxylation). Le deuxième objectif visé est d’exploiter les propriétés électroniques particulières des porphyrines permettant l’application des porphyrines en tant que photosensibilisant après photoactivation en thérapie anticancéreuse. L’étude des paramètres physiques est primordiale pour déterminer la longueur d’onde d’activation et le rendement quantique. Nous avons souhaité utiliser nos porphyrines et leurs précurseurs en tant qu’agents antiparasitaires, sans photoactivation dans un premier temps, conduisant à la découverte d’activités très intéressantes sur certaines espèce de leishmanies. Enfin, leur application sur P. falciparum nous a permis d’isoler une molécule avec une activité très intéressante. Dans les deux cas, des manipulations avec photoactivation sont en cours. / Chiral molecules represent about 60% of drugs in pharmaceutical market and over 80% of drugs in development with more than 150 billion dollars in 2002. Chiral intermediates are in high demand in the pharmaceutical industry producing a turnover of 15 billion dollars in 2009. Other areas are seekers of chiral molecules with a distribution of about 15% in agrochemicals and 5% for the perfume. Asymmetrically production of compounds of pharmaceutical interest is a real challenge. These molecules have a spatial architecture that results in specific interactions and affinity with the enzymes or biological chiral receptors. The use of catalysts to synthesis chiral organic compounds, and more specifically to oxidize alkenes and alkanes having prochiral positions, is a very important area extensively studied in recent decades with few positive results. To achieve the synthesis of chiral molecules, the pharmaceutical industry has turned to the use of biocatalysts, in part, to perform various stereo-controlled reactions with systematically followed by separation of the different isomers by different methodes. However, biocatalysts have a major disadvantage relative to low yields of chiral compound and requires expertise for handling these enzymes. Metalloporphyrins are tetrapyrrolic macrocyle substituted in meso position with various functional groups and incorporating metals (Fe, Mn, Co, Ru). These molecules have been extensively studied and led to the synthesis of many complex chiral metalloporphyrins. Unfortunately, their synthesis is often long with low yields and their application to a limited number of substrates is a major drawback. The first objective of this work is the synthesis of original chiral porphyrins. The targeted structure contains chiral heterocyclic nitrogen groups in two meso positions, connected by a carbon-heteoatom bond (C-N). We were able to reach 4 porphyrins-series that have been evaluated as catalyst in oxidation reactions (epoxidation, hydroxylation). The second objective is to take advantage of specific electronic properties of porphyrins for applications as photosensitizer after photoactivation for cancer by photodynamic therapy. The use of this therapy increased during last decades but poor specificity and solubility of the different porphyrins used in clinic against many cancers prompt us to investigate this area. The study of the physical parameters is essential to determine wavelength activation and quantum yield of a photosensitizer. We wanted to use our porphyrins and their precursors as antiparasitic agents, with and without photoactivation against L. donovani, L. major, T. brucei brucei. Malaria is caused by a protist of the genus of Plasmodium. This parasite has an iron deficiency on one hand and cannot biosynthesize certain amino acids. Strucure analogy of porphyrins with heme led us to evaluate antimalarial activity of several porphyrins against P. falciparum.