Les dérivés cyclopropaniques di-accepteurs représentent des intermédiaires synthétiques précieux dans l’élaboration de structures moléculaires complexes, ayant des applications dans plusieurs domaines de la chimie. Au cours de cet ouvrage, nous nous sommes intéressés à la synthèse de ces unités sous forme énantioenrichie en utilisant la cyclopropanation d’alcènes par catalyse avec des complexes de Rh(II) utilisant des composés diazoïques di-accepteurs comme substrats. Suite au développement initial d’une méthode de cyclopropanation d’alcènes catalytique asymétrique utilisant des nitro diazocétones, de multiples études expérimentales quant au mécanisme de stéréoinduction dans ce type de réaction ont été effectuées. Nous avons alors pu identifier le groupement p-méthoxyphénylcétone du substrat et le catalyseur Rh2(S-TCPTTL)4 comme étant une combinaison clé pour l’atteinte de diastéréosélectivités et d’excès énantiomères élevés. Ceci a mené au développement de deux autres méthodes de cyclopropanation stéréosélectives distinctes, utilisant soit une cyano diazocétone ou un céto diazoester. Nous avons démontré l’utilité des dérivés cyclopropaniques énantioenrichis obtenus par ces trois méthodes dans une panoplie de manipulations synthétiques, dont l’addition nucléophile d’amines et de cuprates, la cycloaddition formelle avec un aldéhyde, et la synthèse de dérivés cyclopropaniques importants en chimie médicinale. Une étude structurelle approfondie des complexes de Rh(II) chiraux nous a permis de déterminer les facteurs responsables de leur pouvoir d’énantioinduction dans notre système réactionnel, ce qui a d’énormes implications dans d’autres méthodologies utilisant ces mêmes catalyseurs. Le dévoilement d’une conformation inattendue dite ‘All-up’, ainsi que de la présence d’interactions stabilisantes régissant la rigidité de cet arrangement se sont avérés cruciaux dans notre compréhension du mécanisme. Dans le cadre de cette investigation, nous avons développé une méthode générale pour la synthèse de complexes de Rh(II) hétéroleptiques, multipliant ainsi le nombre de catalyseurs accessibles dans l’élaboration éventuelle de nouvelles réactions stéréosélectives, et nous permettant d’effectuer une étude structurelle plus détaillée. De plus, nous avons développé une méthode particulièrement efficace pour la synthèse d’un autre type de dérivé cyclopropanique di-accepteur par catalyse avec des complexes de Rh(II), les cyano-cyclopropylphosphonates. Les produits de cette transformation sont obtenus avec des énantiosélectivités élevées, et sont des substrats intéressants pour des réactions tandem d’ouverture de cycle par addition nucléophile / oléfination de composés carbonylés. De plus, ces composés sont des précurseurs de molécules utiles en chimie médicinale tels que les acides aminocyclopropylphosphoniques. / Di-acceptor cyclopropane derivatives are valuable synthetic intermediates in the preparation of complex molecular structures, with applications in several fields of chemistry. During this work, we investigated the synthesis of these units in enantioenriched form via the Rh(II)-catalyzed cyclopropanation of alkenes using di-acceptor diazo compounds as substrates. Following the initial development of a method for the catalytic asymmetric cyclopropanation of alkenes using nitro diazoketones, many experimental studies on the mechanism of stereoinduction in this reaction were performed. We were able to identify the p-methoxyphenylketone group of the substrate and catalyst Rh2(S-TCPTTL)4 as a key combination for the obtention of high diastereoselectivities and enantiomeric excesses. This led to the development of two distinct stereoselective cyclopropanation methods, using either an cyano diazoketone or a keto diazoester. We demonstrated the utility of the enantioenriched cyclopropane derivatives obtained by these three methods in a variety of synthetic manipulations, including the nucleophilic addition of amines and cuprates, the formal cycloaddition with an aldehyde, and the synthesis of biologically relevant cyclopropane derivatives. A thorough structural study of chiral Rh(II) complexes allowed us to determine the factors responsible for their enantioinduction ability in our reaction system, which has enormous implications in other metal-carbene reactions using these catalysts. The unveiling of an unexpected conformation called 'All-up', and the presence of stabilizing interactions controlling the rigidity of this arrangement have been crucial in our understanding of the mechanism. As part of this investigation, we developed a general method for the synthesis of heteroleptic Rh(II) complexes, thus multiplying the number of catalysts available in the development of new stereoselective reactions, and allowing us to conduct a more detailed structural study. Moreover, we have developed a particularly efficient method for the synthesis of another type of di-acceptor cyclopropane derivative via Rh(II) catalysis, cyanocyclopropylphosphonates. The highly enantioenriched products obtained in this transformation are interesting substrates for tandem reactions of nucleophilic addition / olefination of carbonyl compounds, and are precursors of useful molecules in medicinal chemistry, such as aminocyclopropylphosphonic acids.

Les sulfilimines et les sulfoximines sont des motifs structuraux dont l’intérêt synthétique est grandissant, notamment du fait de leurs applications en chimie médicinale et en agrochimie. Les travaux rapportés dans cet ouvrage décrivent le développement de nouvelles méthodes de synthèse efficaces pour la production de ces unités atypiques. Ces méthodes sont basées sur la réactivité d’une source d’azote électrophile, vis-à-vis de thioéthers et de sulfoxydes. L’utilisation d’un complexe métallique introduit en quantité catalytique a permis de favoriser le processus réactionnel. En tirant bénéfice de l’expertise de notre groupe de recherche sur le développement de réactions d’amination stéréosélectives de liaisons C-H et d’aziridination de styrènes, nous avons d’abord étudié la réactivité des N-mésyloxycarbamates comme source d’azote électrophile. Après avoir optimisé sa synthèse sur grande échelle, ce réactif chiral a été utilisé dans des réactions d’amination de thioéthers et de sulfoxydes, catalysées par un dimère de rhodium (II) chiral. Un processus diastéréosélectif efficace a été mis au point, permettant de produire des sulfilimines et des sulfoximines chirales avec d’excellents rendements et sélectivités. Au cours de l’optimisation de cette méthode de synthèse, nous avons pu constater l’effet déterminant de certains additifs sur la réactivité et la sélectivité de la réaction. Une étude mécanistique a été entreprise afin de comprendre leur mode d’action. Il a été observé qu’une base de Lewis telle que le 4-diméthylaminopyridine (DMAP) pouvait se coordiner au dimère de rhodium(II) et modifier ses propriétés structurales et redox. Les résultats que nous avons obtenus suggèrent que l’espèce catalytique active est un dimère de rhodium de valence mixte Rh(II)/Rh(III). Nous avons également découvert que l’incorporation de sels de bispyridinium avait une influence cruciale sur la diastéréosélectivité de la réaction. D’autres expériences sur la nature du groupe partant du réactif N-sulfonyloxycarbamate nous ont permis de postuler qu’une espèce nitrénoïde de rhodium était l’intermédiaire clé du processus d’amination. De plus, l’exploitation des techniques de chimie en débit continu nous a permis de développer une méthode d’amination de thioéthers et de sulfoxydes très performante, en utilisant les azotures comme source d’azote électrophile. Basée sur la décompositon photochimique d’azotures en présence d’un complexe de fer (III) simple et commercialement disponible, nous avons été en mesure de produire des sulfilimines et des sulfoximines avec d’excellents rendements. Le temps de résidence du procédé d’amination a pu être sensiblement réduit par la conception d’un nouveau type de réacteur photochimique capillaire. Ces améliorations techniques ont permis de rendre la synthèse plus productive, ce qui constitue un élément important d’un point de vue industriel. / Sulfilimines and sulfoximines are interesting building blocks that have found many applications both in medicinal chemistry and agrochemistry. During our work, we have developed new efficient methods for the synthesis of these moieties. A catalytic amount of metal complex is used to enhance the reactivity of an electrophilic nitrogen source towards thioethers and sulfoxides. Our group has developed an expertise in the development of stereoselective C-H bond amination and aziridination reactions using chiral N-mesyloxycarbamate as electrophilic amination reagents. The large scale synthesis of the chiral reagent was first investigated. It was then tested in a diastereoselective dirhodium(II)-catalyzed amination of thioethers and sulfoxides, to produce respectively chiral sulfilimines and sulfoximines in excellent yields and selectivities. During the optimization process, we have found that some additives proved instrumental to enhance both the reactivity and the selectivity of the reaction. Mechanistic studies has been carried out to elucidate the exact role of the additives. We have observed that Lewis bases, namely 4-dimethylaminopyridine (DMAP), can coordinate to a rhodium(II) dimer catalyst, modifying its structural and redox properties. These studies suggest that a mixed-valent dirhodium Rh(II)/Rh(III) complex is the catalytically active species in the thioether amination process. Moreover, we have discovered that the use of bispyridinium salts is crucial to enhance the selectivity of the amination reaction. Diastereoselectivities were also influenced by the nature of the leaving group of the N-sulfonyloxycarbamate. Based on the results, we hypothetized a rhodium nitrenoïd species as key intermediate in the amination process. Continuous flow techniques were employed in the development of a very efficient amination process of thioethers and sulfoxides, using azides as electrophilic amination reagents. Based on the photochemical decomposition of azide derivatives with a simple and commercially available iron(III) complex, we were able to produce sulfilimines and sulfoximines in excellent yields. We investigated the design of a new type of capillary photoreactor to further reduce the residence time of the amination process. The technical improvements were pivotal to enhance the efficiency and productivity of the reaction process.

A hemólise decorrente da doença aloimune desencadeia mecanismos adaptativos hematológicos e hemodinâmicos fetais, com intuito de garantir o suprimento adequado de oxigênio para todos os tecidos e órgãos. Na anemia grave, a sobrecarga imposta ao coração fetal, devido ao fluxo hiperdinâmico, tem sido considerada responsável pela insuficiencia cardiaca, e posterior desenvolvimento de hidropisia fetal. No entanto, a literatura médica ainda apresenta controvérsias acerca da integridade da função cardiaca nesta doença. O índice de performance miocárdico (IPM) é uma ferramenta propedêutica não invasiva, derivada do Doppler pulsátil, que permite avaliar a função cardíaca global (sistólica e diastólica). Objetivo: Estudar a função cardíaca fetal, na doença aloimune, utilizando o índice de performance miocárdica. Métodos: Foram seguidos, prospectivamente, fetos únicos, de gestantes sensibilizadas pelo antígeno eritrocitário D, sem malformações estruturais, na Clinica Obstétrica, Hospital das Clinicas da Faculdade de Medicina de São Paulo. A cada avaliação ultrassonográfica, o IPM foi investigado por meio de Doppler pulsátil, com janela de 2-4mm, filtro>190Hz e velocidade de varredura que permitisse observar de 3 a 4 ciclos cardíacos simultâneos no ecrã. O IPM corresponde à soma dos tempos isovolumétricos (contração e relaxamento) dividido pelo tempo de ejeção do ciclo cardíaco. O IPM do ventrículo equerdo (IPM VE) foi realizado em ciclo único, sendo possível obter seus componentes: tempo de contração isovolumétrico (TCI), tempo de relaxamento isovolumétrico (TRI) e tempo de ejeção (TE). O IPM do ventrículo direito (IPM VD) foi obtido em dois tempos. Os valores obtidos de IPM VE, seus componentes foram convertidos em escore zeta para a idade gestacional. Frente à suspeita de anemia fetal, realizou-se cordocentese com determinação dos níveis de hemoglobina fetal antes e após a transfusão intra-uterina. Os respectivos valores foram convertidos em escore-zeta (Hb zeta). Na análise estatística, foram incluidas avaliações do IPM realizadas com menos de 72 horas antes, e até 24 horas após cada transfusão. Para cada transfusão foi calculada a variação no IPM (delta IPM = IPM antes - IPM após). O nível de significância estatísca adotado foi de 0,05. Análises por regressão linear simples e logística foram utilizadas para examinar a associação entre os valores de IPM e delta IPM e as seguintes variáveis: idade gestacional no procedimento, múltiplos da mediana (MoM) da Vmax ACM, Hb zeta pré e após TIU, volume de sangue transfundido e porcentagem da expansão do volume feto-placentário (EVFP). Resultados: Foram incluidas 14 gestações submetidas a 31 procedimentos de cordocentese para transfusão intra-uterina. A idade gestacional média na 1ª transfusão foi de 28,2 ± 4,1 semanas Em 6 procedimentos, a avaliação do IPM pós transfusional foi incompleta, e esses dados não foram incluídos na análise. Quanto à análise dos dados obtidos nas cordocenteses, observou-se correlação significativa entre os valores de escore zeta de IPM VE (r= 0,59, p <0,001), TRI (r= 0,45, p =0,01) e o TE (r= 0,42, p=0,2) e o escore zeta da hemoglobina fetal. Não foi observada correlação significativa com o escore zeta do TCI (r= 0,35, p=0,054) e do IPM VD (r=0,12, p= 0,53). Quando comparados aos valores observados antes das transfuões intra-uterinas, observou-se aumento significativo do escore zeta de IPM VE após os procedimentos (Delta MPI = 1,10 ± 2,47, p = 0,036). Não foi observada correlação entre os valores de escore zeta de IPM antes e após TIU. Delta MPI do VE se correlacionou inversamente, e de forma significativa, com a idade gestacional no procedimento (r= 0,47, p=0,018), escore zeta IPM VE pré-TIU (r= 0,50, p=0,012) e EVFP (r= 0,41, p=0,044). Conclusões: O desempenho miocárdico do ventriculo esquerdo fetal permanece preservado frente a anemia, e nos casos de anemia moderada e grave encontra-se ainda mais eficiente. Após a realização da transfusão intrauterina, observou-se aumento significativo do índice de performance miocárdica, e este aumento esteve relacionado com idade gestacional no procedimento, valores de IPM pré-transfusionais e a expansão do volume feto-placentário / Fetal anemia is associated with several adaptative mechanisms in order to maintain adequate tissue oxygenation. Circulatory changes play a key role in such circumstances. In severe anemia, the overload imposed on the fetal heart, due to the hyperdynamic flow, has been considered to be responsible for cardiac failure and finally hydrops fetalis. However, cardiac failure in this pathology remains controversy. Myocardial performance index (MPI) is a novel technique, Doppler derived and non-invasive that allows assesses global cardiac function (systolic and diatolic). Objective: Evaluate global cardiac function in alloimune disease through myocardial performance index. Methods: This prospective study was carried out at a tertiary referral center for fetal medicine (Clínica Obstetrica do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo). Women with singleton pregnancies and Rh D alloimmune disease were invited to take part in the study and gave informed consent. Fetal examinations did not show structural abnormalities. At every ultrasonography evaluation, MPI was examined with Doppler sample gate set between 2-4mm, wall motion filter >190Hz and high sweep-speed to allow simultaneous identification of 3-4 cardiac cycles on the screen. MPI is the sum of isovolumetric times (contraction and relaxation) divided by ejection time. Left ventricle MPI (LV MPI) was obtained in a single cycle and the MPI components were obtained: isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET). Right ventricle MPI (RV MPI) was obtained in two cycles. The values obtained for LV MPI and its components were converted in zeta score for gestacional age. Cordocentesis was perfomed if fetal anemia was suspicion and fetal hemoglobin levels were determined: before and after intrauterine transfusion. Hemoglobin values were converted into the zeta score (Hb zeta). Statistical analysis included MPI evaluations performed within less than 72 hours before and until 24 hours after every transfusion. Variation in the MPI was calculated for every transfusion (delta MPI = MPI before - MPI after). Significance level was set at 0,05. Linear and regression analyses were made in order to examine association between MPI values and delta MPI gestational age at procedure, fetal ACM multiples of median (MoM), Hb zeta before and after the IUT, volume of blood transfused and percentage of the feto-placental expansion volume (FPEV). Results: 14 pregnancies were included. Overall 31 cordocentesis for intrauterine transfusion were performed at mean gestational age of 28,2 ± 4,1 weeks. In 6 procedures, post transfusion MPI evaluation was incomplete and these data were not included in the analysis. Zeta-score values LV MPI (r= 0,59, p < 0,001), IRT (r= 0,45, p =0,01) and ET (r= 0,42, p=0,02) correlated significantly with fetal hemoglobin zeta score. Left ventricle ICT zeta-score (r= 0,35, p=0,054) and RV MPI (r=0,12, p= 0,53). did not show significant correlation. After intrauterine transfusion, LV MPI z-score ]increases and it was statistical significant (Delta MPI = 1,10 ± 2,47, p = 0,036). No correlation was observed between MPI zeta score values before and after the IUT. Delta LV MPI had inverse and significant correlation with pregnancy age in the proceedings (r= 0,47, p=0,018), LV MPI zeta score before IUT (r= 0,50, p=0,012) and FPEV (r= 0,41, p=0,044). Conclusions: Left ventricle myocardial performance not only remains preserved but is actually enhanced in cases of moderate/severe fetal anemia. After intrauterine transfusion procedure, left ventricle myocardial performance index increases significantly and greater changes are associated with procedures at earlier gestational age, lower pre transfusion MPI z-scores and smaller feto-placental volume expansion

Les composés aminés représentent une grande part des substances actives en chimie médicinale. Les travaux rapportés dans cette thèse décrivent les efforts consacrés au développement d’une nouvelle méthode d’amination de liens C-H propargyliques. Notre groupe de recherche a développé depuis quelques années un nouveau précurseur de nitrène métallique, les N-mésyloxycarbamates, permettant d’effectuer des réactions d’amination de liaisons C-H diversement activées. Au cours du développement de notre méthodologie, la synthèse du N-mésyloxycarbamate a fait l’objet de nombreuses optimisations, notamment en améliorant l’échelle globale de la synthèse ainsi que son efficacité. De même, des efforts ont été consacrés pour diminuer le nombre d’étapes nécessaires à la synthèse du réactif en développant la synthèse d’un des intermédiaires de manière énantiosélective. Enfin, la synthèse de ce réactif a également été envisagée à l’aide de la chimie en flux continu. Au cours du développement de la méthode de synthèse d’amines propargyliques, nous avons constaté que l’acide acétique jouait un rôle déterminant dans la conservation de bonnes sélectivités et réactivités de la réaction. Ces différentes observations ont permis de mettre au point un procédé diastéréosélectif efficace permettant d’obtenir des amines propargyliques avec des rendements allant de moyens à bons et avec d’excellentes diastéréosélectivités. A la suite de l’étude de l’étendue de notre procédé, nous avons tenté de déterminer les mécanismes réactionnels qui régissaient la réactivité et la sélectivité de celui-ci. Nous avons ainsi montré que l’espèce réactive du système catalytique était bel et bien un nitrène métallique, et que l’étape cinétiquement déterminante était celle d’insertion. Des expériences faites en oxydant l’espèce catalytique de rhodium ont suggéré que plusieurs états d’oxydation de cette espèce peuvent être présents et actifs dans le système catalytique. / The nitrogen containing compounds represent a large portion of the active substances in medicinal chemistry. The work reported in this manuscript describe the efforts devoted to the development of a new method of amination of propargylic C-H bonds. Our research group has developed recently a new metal nitrene precursor, N-mesyloxycarbamates, to perform amination reactions on various C-H bonds. During the development of our methodology, the synthesis of N-mesyloxycarbamate has undergone many improvements, including improved global scale synthesis and effectiveness. Similarly, efforts were devoted to reduce the number of steps required for the synthesis of the reagent by developing the synthesis of an intermediate enantioselectively. Finally, the synthesis of this reagent was also considered using continuous flow chemistry. During development of the method of synthesis of propargylic amines, we have found that acetic acid plays a key role in the conservation of good selectivity and reactivity of the reaction. These observations allowed to develop an efficient diastereoselective process in order to obtain propargylic amines with moderate to good yields and with excellent diastereoselectivities. Following the study of the scope of our process, we tried to determine the reaction mechanisms governing the reactivity and selectivity. We have shown that the reactive species of the catalyst system was indeed a metal nitrene, and that the rate-determining step was the insertion. Experiments made by oxidizing the rhodium catalytic species suggested that several oxidation states of this species may be present and active in the catalytic system.

A hemólise decorrente da doença aloimune desencadeia mecanismos adaptativos hematológicos e hemodinâmicos fetais, com intuito de garantir o suprimento adequado de oxigênio para todos os tecidos e órgãos. Na anemia grave, a sobrecarga imposta ao coração fetal, devido ao fluxo hiperdinâmico, tem sido considerada responsável pela insuficiencia cardiaca, e posterior desenvolvimento de hidropisia fetal. No entanto, a literatura médica ainda apresenta controvérsias acerca da integridade da função cardiaca nesta doença. O índice de performance miocárdico (IPM) é uma ferramenta propedêutica não invasiva, derivada do Doppler pulsátil, que permite avaliar a função cardíaca global (sistólica e diastólica). Objetivo: Estudar a função cardíaca fetal, na doença aloimune, utilizando o índice de performance miocárdica. Métodos: Foram seguidos, prospectivamente, fetos únicos, de gestantes sensibilizadas pelo antígeno eritrocitário D, sem malformações estruturais, na Clinica Obstétrica, Hospital das Clinicas da Faculdade de Medicina de São Paulo. A cada avaliação ultrassonográfica, o IPM foi investigado por meio de Doppler pulsátil, com janela de 2-4mm, filtro>190Hz e velocidade de varredura que permitisse observar de 3 a 4 ciclos cardíacos simultâneos no ecrã. O IPM corresponde à soma dos tempos isovolumétricos (contração e relaxamento) dividido pelo tempo de ejeção do ciclo cardíaco. O IPM do ventrículo equerdo (IPM VE) foi realizado em ciclo único, sendo possível obter seus componentes: tempo de contração isovolumétrico (TCI), tempo de relaxamento isovolumétrico (TRI) e tempo de ejeção (TE). O IPM do ventrículo direito (IPM VD) foi obtido em dois tempos. Os valores obtidos de IPM VE, seus componentes foram convertidos em escore zeta para a idade gestacional. Frente à suspeita de anemia fetal, realizou-se cordocentese com determinação dos níveis de hemoglobina fetal antes e após a transfusão intra-uterina. Os respectivos valores foram convertidos em escore-zeta (Hb zeta). Na análise estatística, foram incluidas avaliações do IPM realizadas com menos de 72 horas antes, e até 24 horas após cada transfusão. Para cada transfusão foi calculada a variação no IPM (delta IPM = IPM antes - IPM após). O nível de significância estatísca adotado foi de 0,05. Análises por regressão linear simples e logística foram utilizadas para examinar a associação entre os valores de IPM e delta IPM e as seguintes variáveis: idade gestacional no procedimento, múltiplos da mediana (MoM) da Vmax ACM, Hb zeta pré e após TIU, volume de sangue transfundido e porcentagem da expansão do volume feto-placentário (EVFP). Resultados: Foram incluidas 14 gestações submetidas a 31 procedimentos de cordocentese para transfusão intra-uterina. A idade gestacional média na 1ª transfusão foi de 28,2 ± 4,1 semanas Em 6 procedimentos, a avaliação do IPM pós transfusional foi incompleta, e esses dados não foram incluídos na análise. Quanto à análise dos dados obtidos nas cordocenteses, observou-se correlação significativa entre os valores de escore zeta de IPM VE (r= 0,59, p <0,001), TRI (r= 0,45, p =0,01) e o TE (r= 0,42, p=0,2) e o escore zeta da hemoglobina fetal. Não foi observada correlação significativa com o escore zeta do TCI (r= 0,35, p=0,054) e do IPM VD (r=0,12, p= 0,53). Quando comparados aos valores observados antes das transfuões intra-uterinas, observou-se aumento significativo do escore zeta de IPM VE após os procedimentos (Delta MPI = 1,10 ± 2,47, p = 0,036). Não foi observada correlação entre os valores de escore zeta de IPM antes e após TIU. Delta MPI do VE se correlacionou inversamente, e de forma significativa, com a idade gestacional no procedimento (r= 0,47, p=0,018), escore zeta IPM VE pré-TIU (r= 0,50, p=0,012) e EVFP (r= 0,41, p=0,044). Conclusões: O desempenho miocárdico do ventriculo esquerdo fetal permanece preservado frente a anemia, e nos casos de anemia moderada e grave encontra-se ainda mais eficiente. Após a realização da transfusão intrauterina, observou-se aumento significativo do índice de performance miocárdica, e este aumento esteve relacionado com idade gestacional no procedimento, valores de IPM pré-transfusionais e a expansão do volume feto-placentário / Fetal anemia is associated with several adaptative mechanisms in order to maintain adequate tissue oxygenation. Circulatory changes play a key role in such circumstances. In severe anemia, the overload imposed on the fetal heart, due to the hyperdynamic flow, has been considered to be responsible for cardiac failure and finally hydrops fetalis. However, cardiac failure in this pathology remains controversy. Myocardial performance index (MPI) is a novel technique, Doppler derived and non-invasive that allows assesses global cardiac function (systolic and diatolic). Objective: Evaluate global cardiac function in alloimune disease through myocardial performance index. Methods: This prospective study was carried out at a tertiary referral center for fetal medicine (Clínica Obstetrica do Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo). Women with singleton pregnancies and Rh D alloimmune disease were invited to take part in the study and gave informed consent. Fetal examinations did not show structural abnormalities. At every ultrasonography evaluation, MPI was examined with Doppler sample gate set between 2-4mm, wall motion filter >190Hz and high sweep-speed to allow simultaneous identification of 3-4 cardiac cycles on the screen. MPI is the sum of isovolumetric times (contraction and relaxation) divided by ejection time. Left ventricle MPI (LV MPI) was obtained in a single cycle and the MPI components were obtained: isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT) and ejection time (ET). Right ventricle MPI (RV MPI) was obtained in two cycles. The values obtained for LV MPI and its components were converted in zeta score for gestacional age. Cordocentesis was perfomed if fetal anemia was suspicion and fetal hemoglobin levels were determined: before and after intrauterine transfusion. Hemoglobin values were converted into the zeta score (Hb zeta). Statistical analysis included MPI evaluations performed within less than 72 hours before and until 24 hours after every transfusion. Variation in the MPI was calculated for every transfusion (delta MPI = MPI before - MPI after). Significance level was set at 0,05. Linear and regression analyses were made in order to examine association between MPI values and delta MPI gestational age at procedure, fetal ACM multiples of median (MoM), Hb zeta before and after the IUT, volume of blood transfused and percentage of the feto-placental expansion volume (FPEV). Results: 14 pregnancies were included. Overall 31 cordocentesis for intrauterine transfusion were performed at mean gestational age of 28,2 ± 4,1 weeks. In 6 procedures, post transfusion MPI evaluation was incomplete and these data were not included in the analysis. Zeta-score values LV MPI (r= 0,59, p < 0,001), IRT (r= 0,45, p =0,01) and ET (r= 0,42, p=0,02) correlated significantly with fetal hemoglobin zeta score. Left ventricle ICT zeta-score (r= 0,35, p=0,054) and RV MPI (r=0,12, p= 0,53). did not show significant correlation. After intrauterine transfusion, LV MPI z-score ]increases and it was statistical significant (Delta MPI = 1,10 ± 2,47, p = 0,036). No correlation was observed between MPI zeta score values before and after the IUT. Delta LV MPI had inverse and significant correlation with pregnancy age in the proceedings (r= 0,47, p=0,018), LV MPI zeta score before IUT (r= 0,50, p=0,012) and FPEV (r= 0,41, p=0,044). Conclusions: Left ventricle myocardial performance not only remains preserved but is actually enhanced in cases of moderate/severe fetal anemia. After intrauterine transfusion procedure, left ventricle myocardial performance index increases significantly and greater changes are associated with procedures at earlier gestational age, lower pre transfusion MPI z-scores and smaller feto-placental volume expansion

Η ηλεκτροχημική ενίσχυση της κατάλυσης (EPOC ή αλλιώς μη-φαρανταϊκή τροποποίηση της καταλυτικής ενεργότητας, φαινόμενο NEMCA) είναι ένα φαινόμενο όπου εφαρμογή μικρών ρευμάτων ή δυναμικών (±2V) σε ένα καταλύτη που είναι υποστηριγμένος σε ένα ηλεκτρολύτη, ιοντικό ή μικτό ιοντικό-ηλεκτρονικό αγωγό, μπορεί να επιφέρει τροποποιήσεις στην καταλυτική ενεργότητα αλλά και εκλεκτικότητα, με τρόπο ελεγχόμενο, αντιστρεπτό και έως ένα βαθμό προβλέψιμο. Η ηλεκτροχημική ενίσχυση έχει βρεθεί, με χρήση διαφόρων τεχνικών, ότι πηγάζει από την ηλεκτροχημικά ελεγχόμενη παροχή ενισχυτικών ιοντικών ειδών από το φορέα-ηλεκτρολύτη στα καταλυτικά σωματίδια. Στο πρώτο κεφάλαιο της παρούσας διατριβής γίνεται μια εκτεταμένη αναφορά στους στερεούς ηλεκτρολύτες, στις ιδιότητες τους και τους τομείς στους οποίους χρησιμοποιούνται με ιδιαίτερη σημασία στη σταθεροποιημένη με οξείδιο του υττρίου ζιρκονία (YSZ), που αποτελεί ένα πολύ συχνά χρησιμοποιούμενο αγωγό ιόντων οξυγόνου. Επίσης, εισάγονται οι έννοιες της μετανάστευσης (spillover) και της αντίστροφης μετανάστευσης (backspillover), οι οποίες χρησιμοποιούνται στην ερμηνεία και την κατανόηση του φαινομένου της ηλεκτροχημικής ενίσχυσης και των αλληλεπιδράσεων μετάλλου-φορέα (MSI). Στο δεύτερο κεφάλαιο γίνεται εισαγωγή στις γενικές αρχές του φαινομένου της ηλεκτροχημικής ενίσχυσης όπου παρουσιάζονται μερικά παραδείγματα εφαρμογής του και γίνεται ανασκόπηση όλων των εργασιών που έχουν εμφανιστεί στη βιβλιογραφία και αφορούν στο συγκεκριμένο φαινόμενο. Συζητείται, επίσης, η μελέτη του φαινομένου με χρήση διαφόρων πειραματικών τεχνικών, όπως ηλεκτροκινητικών πειραμάτων δυναμικής απόκρισης, μετρήσεων έργου εξόδου, κυκλικής βολταμμετρίας, XPS, TPD και STM, καθώς και θεωρητικών μελετών, με σκοπό την κατανόηση της αρχής του φαινομένου σε ατομικό επίπεδο καθώς και την επίλυση σημαντικών προβλημάτων που αφορούν στην ετερογενή κατάλυση. Με βάση τα αποτελέσματα από τις ανωτέρω μελέτες, παρουσιάζεται το μαθηματικό μοντέλο που έχει αναπτυχθεί και εξηγεί τα παρατηρούμενα φαινόμενα σε μοριακό επίπεδο καθώς και οι πρόσφατα εδραιωμένοι κανόνες που το διέπουν. Στο τρίτο κεφάλαιο παρουσιάζεται η αξιοποίηση του φαινομένου της ηλεκτροχημικής ενίσχυσης στην αντιμετώπιση ενός εκ των δυσκολότερων και προκλητικότερων προβλημάτων της ετερογενούς κατάλυσης που είναι η αναγωγή του μονοξειδίου του αζώτου (ΝΟ) από αιθυλένιο παρουσία υψηλής περίσσειας (10%) οξυγόνου. Στην μελέτη χρησιμοποιήθηκε ένας πρόσφατα ανεπτυγμένος και βελτιωμένος για την παρούσα διατριβή, μονολιθικός ηλεκτροχημικά ενισχυόμενος αντιδραστήρας (monolithic electrochemically promoted reactor, MEPR) εξοπλισμένος με 22 ηλεκτροχημικά καταλυτικά στοιχεία του τύπου Rh/YSZ/Pt με μικρό πάχος ηλεκτροδίων (~40 nm). Βρέθηκε, δε, ότι η βέλτιστη λειτουργία επιτυγχάνεται σε χαμηλές θερμοκρασίες (220-240οC) με σημαντική ηλεκτροχημική ενίσχυση ακόμα και κάτω από τις ανωτέρω ισχυρά οξειδωτικές συνθήκες (λόγος αέρα-καυσίμου=16.7, περίσσεια οξυγόνου=9.43). Σε αυτό το στενό θερμοκρασιακό εύρος η εκλεκτικότητα προς Ν2 που επετεύχθη από τα Rh/YSZ/Pt ηλεκτροκαταλυτικά στοιχεία, είναι περίπου 100% ενώ η παραγωγή των ανεπιθύμητων CO, ΝΟ2, Ν2Ο ήταν σχεδόν μη-ανιχνεύσιμη. Στο τέταρτο κεφάλαιο μελετάται η χρήση λεπτών καταλυτικών ηλεκτροδίων Pt σκελετικής δομής (Pt-skeletal/YSZ/Au) στην έκταση του φαινομένου της ηλεκτροχημικής ενίσχυσης, χρησιμοποιώντας την πρότυπη αντίδραση οξείδωσης αιθυλενίου, στον μονολιθικό ηλεκτροχημικά ενισχυόμενο αντιδραστήρα. Βρέθηκε ότι και τέτοιου τύπου ηλεκτρόδια – καταλυτικά υμένια είναι ιδιαίτερα καταλυτικά ενεργά και είναι δυνατό να ενισχυθούν ηλεκτροχημικά σε μεγάλο βαθμό. Επίσης, ο αντιδραστήρας λειτούργησε επιτυχώς και παρατηρήθηκε ηλεκτροχημική ενίσχυση, υπό υψηλές ογκομετρικές παροχές (25 l/min), με ταχύτητες χώρου αντιδραστήρα που είναι κοντά σε αυτές που λειτουργούν οι βιομηχανικοί αντιδραστήρες (12000 h-1). Στο πέμπτο κεφάλαιο παρουσιάζεται η ηλεκτροχημική ενίσχυση της αντίδρασης υδρογόνωσης του CO2 με στόχο την παραγωγή μεθανίου χρησιμοποιώντας ηλεκτροχημικά στοιχεία του τύπου Rh/YSZ/Pt. Βρέθηκε ότι η αντίδραση μπορεί να ενισχυθεί σε μεγάλο βαθμό και επιπλέον να τροποποιηθεί και η εκλεκτικότητά της σε CΗ4 που είναι και το επιθυμητό προϊόν. Στο έκτο κεφάλαιο παρουσιάζεται η μελέτη της αντίδραση οξείδωσης του SO2 προς SO3, μιας πολύ σημαντικής αντίδρασης από βιομηχανική (παραγωγή H2SO4) αλλά περιβαλλοντική άποψη, με χρήση του φαινομένου της ηλεκτροχημικής ενίσχυσης, σε λεπτά (~40 nm) ηλεκτροχημικά στοιχεία του τύπου Pt/YSZ/Au. Βρέθηκε πως ηλεκτροχημική ενίσχυση μπορεί να επιτευχθεί ακόμα και σε πολύ υψηλές ογκομετρικές παροχές (30 l/min), όπου αντιστοιχούν σε ταχύτητες χώρου αντιδραστήρα (14000 h-1) πολύ κοντά σε αυτές που λειτουργούν οι βιομηχανικοί αντιδραστήρες και να επιτευχθούν σχετικά υψηλές μετατροπές SO2. / Electrochemical Promotion of Catalysis (EPOC or Non-Faradaic Electrochemical Modification of Catalytic Activity, NEMCA effect) is a phenomenon where the application of small currents or potentials (±2V) alters the activity and selectivity of catalysts supported on ionic or mixed ionic-electronic conductors and modifies the catalytic activity and selectivity, in a controllable, reversible and to some extend predictable manner. As shown by numerous surface science techniques, including STM, electrochemical promotion is due to electrochemically controlled migration (backspillover) of promoting or poisoning ionic species (Oδ- in the case of YSZ) between the ionic or mixed ionic-electronic conductor and the gas exposed catalytic surface. The utilization of electrochemical promotion of catalysis, in order to tackle one of the most difficult and challenging problems of heterogeneous catalysis, which is the NO reduction under high excess oxygen (10%), has been performed. This gas mixture is a typical mixture in a lean-burn engine (or Diesel engine) exhaust. In this study, a recently developed and improved monolithic electrochemically promoted reactor (MEPR) has been used, equipped with 22 thin (~40 nm catalyst-electrode thickness) electrochemical catalytic elements Rh/YSZ/Pt type. It was found that there is an optimum operation temperature of the reactor, in the range from 220oC to 240oC, where the maximum electropromotion effect occurs, even under these extremely oxidizing conditions (air/fuel ratio = 16.7 and oxygen excess = 9.43%). In this narrow temperature window the selectivity to N2 was almost 100% since the production of the undesired N2O and NO2 was almost undetectable. Also, the use of thin catalytic Pt electrodes with skeletal structure (Ptskeletal/ YSZ/Au) was examined in the MEPR for the model reaction of C2H4 oxidation. It was found that such skeletal structure electrodes are catalytically active and can be electropromoted even under high gas flow rates (25 l/min) or high space velocity (HSV~12000 h-1), close to those that the industrial reactors operate. The electrochemical promotion of the CO2 hydrogenation reaction was also examined, towards methane production using Rh/YSZ/Pt type electrochemical catalytic elements. It was found that the reaction rates can be enhanced and similarly the selectivity to CH4 which found to increase upon polarization. Finally, the effect of electrochemical promotion was examined in the study of the SO2 oxidation to SO3 reaction, which is a very important reaction by industrial (H2SO4 production) and environmental point of interest. The monolithic reactor was equipped with 5 or 22 thin (~40 nm) Pt/YSZ/Au type electrocatalytic elements. It was found that electrochemical promotion can be obtained by positive polarization even under high hourly space velocities (14000 h-1), close to those that the industrial reactors operate, with relatively high SO2 conversions.

Les dérivés cyclopropaniques di-accepteurs représentent des intermédiaires synthétiques précieux dans l’élaboration de structures moléculaires complexes, ayant des applications dans plusieurs domaines de la chimie. Au cours de cet ouvrage, nous nous sommes intéressés à la synthèse de ces unités sous forme énantioenrichie en utilisant la cyclopropanation d’alcènes par catalyse avec des complexes de Rh(II) utilisant des composés diazoïques di-accepteurs comme substrats. Suite au développement initial d’une méthode de cyclopropanation d’alcènes catalytique asymétrique utilisant des nitro diazocétones, de multiples études expérimentales quant au mécanisme de stéréoinduction dans ce type de réaction ont été effectuées. Nous avons alors pu identifier le groupement p-méthoxyphénylcétone du substrat et le catalyseur Rh2(S-TCPTTL)4 comme étant une combinaison clé pour l’atteinte de diastéréosélectivités et d’excès énantiomères élevés. Ceci a mené au développement de deux autres méthodes de cyclopropanation stéréosélectives distinctes, utilisant soit une cyano diazocétone ou un céto diazoester. Nous avons démontré l’utilité des dérivés cyclopropaniques énantioenrichis obtenus par ces trois méthodes dans une panoplie de manipulations synthétiques, dont l’addition nucléophile d’amines et de cuprates, la cycloaddition formelle avec un aldéhyde, et la synthèse de dérivés cyclopropaniques importants en chimie médicinale. Une étude structurelle approfondie des complexes de Rh(II) chiraux nous a permis de déterminer les facteurs responsables de leur pouvoir d’énantioinduction dans notre système réactionnel, ce qui a d’énormes implications dans d’autres méthodologies utilisant ces mêmes catalyseurs. Le dévoilement d’une conformation inattendue dite ‘All-up’, ainsi que de la présence d’interactions stabilisantes régissant la rigidité de cet arrangement se sont avérés cruciaux dans notre compréhension du mécanisme. Dans le cadre de cette investigation, nous avons développé une méthode générale pour la synthèse de complexes de Rh(II) hétéroleptiques, multipliant ainsi le nombre de catalyseurs accessibles dans l’élaboration éventuelle de nouvelles réactions stéréosélectives, et nous permettant d’effectuer une étude structurelle plus détaillée. De plus, nous avons développé une méthode particulièrement efficace pour la synthèse d’un autre type de dérivé cyclopropanique di-accepteur par catalyse avec des complexes de Rh(II), les cyano-cyclopropylphosphonates. Les produits de cette transformation sont obtenus avec des énantiosélectivités élevées, et sont des substrats intéressants pour des réactions tandem d’ouverture de cycle par addition nucléophile / oléfination de composés carbonylés. De plus, ces composés sont des précurseurs de molécules utiles en chimie médicinale tels que les acides aminocyclopropylphosphoniques. / Di-acceptor cyclopropane derivatives are valuable synthetic intermediates in the preparation of complex molecular structures, with applications in several fields of chemistry. During this work, we investigated the synthesis of these units in enantioenriched form via the Rh(II)-catalyzed cyclopropanation of alkenes using di-acceptor diazo compounds as substrates. Following the initial development of a method for the catalytic asymmetric cyclopropanation of alkenes using nitro diazoketones, many experimental studies on the mechanism of stereoinduction in this reaction were performed. We were able to identify the p-methoxyphenylketone group of the substrate and catalyst Rh2(S-TCPTTL)4 as a key combination for the obtention of high diastereoselectivities and enantiomeric excesses. This led to the development of two distinct stereoselective cyclopropanation methods, using either an cyano diazoketone or a keto diazoester. We demonstrated the utility of the enantioenriched cyclopropane derivatives obtained by these three methods in a variety of synthetic manipulations, including the nucleophilic addition of amines and cuprates, the formal cycloaddition with an aldehyde, and the synthesis of biologically relevant cyclopropane derivatives. A thorough structural study of chiral Rh(II) complexes allowed us to determine the factors responsible for their enantioinduction ability in our reaction system, which has enormous implications in other metal-carbene reactions using these catalysts. The unveiling of an unexpected conformation called 'All-up', and the presence of stabilizing interactions controlling the rigidity of this arrangement have been crucial in our understanding of the mechanism. As part of this investigation, we developed a general method for the synthesis of heteroleptic Rh(II) complexes, thus multiplying the number of catalysts available in the development of new stereoselective reactions, and allowing us to conduct a more detailed structural study. Moreover, we have developed a particularly efficient method for the synthesis of another type of di-acceptor cyclopropane derivative via Rh(II) catalysis, cyanocyclopropylphosphonates. The highly enantioenriched products obtained in this transformation are interesting substrates for tandem reactions of nucleophilic addition / olefination of carbonyl compounds, and are precursors of useful molecules in medicinal chemistry, such as aminocyclopropylphosphonic acids.

This paper deals with the determination of the capillary pore-size distribution (CPSD) and equilibrium moisture content (EMC) of untreated and thermally modified (TM) Norway spruce [Picea abies (L.) Karst.] by means of the pressure plate technique (PPT). Desorption experiments were conducted at very high values of relative humidity (RH) in the range between 99.2% and 100%. The thermal modification of spruce results in an alteration of the CPSD, owing to the formation of intercellular cracks in the middle lamella, as a result of cell-wall compression. The desorption curves for both untreated and TM spruce show an extremely upward bend at 99.97% RH. This step reflects an EMC of 38.1% for untreated spruce and 33.8% for TM spruce. None of the samples shrunk during the PPT measurements. Following desorption experiments at 97.4% RH, all samples shrunk. This step reflects an EMC of 27.9% for untreated spruce and 21.7% for TM spruce.

Städte sind Hotspots des Globalen Wandels. Sie zählen über ihren Konsum und Ressourcenverbrauch zu den Haupttreibern des Klimawandels, der Biodiversitätskrise und sozio-ökonomischer Prozesse wie Urbanisierung und Demographischer Wandel. Gleichzeitig stellen diese Prozesse insbesondere für Städte eine große Herausforderung dar. Für die Anpassung an den Globalen Wandel spielen städtische Grünflächen als Werkzeug der Stadtplanung eine zentrale Rolle. Parks, Friedhöfe, Gärten, bis hin zu einzelnen Straßenbäumen stellen Ökosystemleistungen bereit, die einerseits, z.B. durch Abmilderung von hohen Temperaturen, die Umweltqualität verbessern und andererseits, z.B. durch die Bereitstellung von Erholungsräumen, einen direkten Einfluss auf das Wohlbefinden und die Aktivitäten der Stadtbevölkerung haben. Jedoch sind auch Grünflächen und deren Ökosystemleistungen, wie die gesamte Stadt an sich, hohen Belastungen durch die Folgen des Globalen Wandels ausgesetzt, z.B. durch Hitze, Trockenheit und Verdichtungsprozesse. Diese kumulative Dissertation zeigt, dass sich Form, Ausstattung und Lage einer Grünfläche unterschiedlich auf die Bereitstellung von verschiedenen Ökosystemleistungen auswirken. Während für die Kühlungsfunktion ein dichter Bestand von ausgewachsenen Bäumen entscheidend ist, spielt für die Erholungsfunktion einer Grünfläche eine ausgewogene Vegetationsstruktur, vielfältige (gebaute) Infrastruktur und eine gute Einbettung in die Umgebung eine zentrale Rolle. Die Arbeit formuliert schließlich Empfehlungen an die Stadtplanung für eine qualitative Aufwertung der Grünflächen im Hinblick auf eine bessere und gerechte Versorgung der Bevölkerung und eine größere Widerstandsfähigkeit gegenüber extremen Wetterereignissen. Eine im Rahmen dieser Arbeit entwickelte und frei zugängliche Online-Kartenanwendung kann dabei als ein unterstützendes Entscheidungsinstrument dienen und zukünftig auf andere Städte übertragen werden. / Cities are hotspots of global change. Through their consumption and resource use, cities are among the main drivers of climate change, the biodiversity crisis and socio-economic processes such as urbanisation and demographic change. At the same time, these processes represent a major challenge for cities. Extreme weather events caused by climate change, such as heat and heavy rain, often occur with greater intensity in densely populated areas and can potentially cause more damage to people and infrastructure there. For adaptation to global change, urban green spaces play a central role as a tool in urban planning. Green spaces or individual street trees provide ecosystem services that can improve, on the one hand, environmental quality, e.g. by mitigating high air temperatures, and, on the other hand, the health and well-being of the urban population, e.g. through the provision of recreational opportunities. However, green spaces and their ecosystem services are also exposed to high pressures from the impacts of global change such as extreme heat, drought and densification processes. This cumulative thesis shows that the form, equipment and location of a green space have different effects on the provision of different ecosystem services. While a dense stand of mature trees is crucial for the cooling function, a balanced vegetation structure, diverse (built) infrastructure and a good embedding in the surroundings play a central role for the recreational function of a green space. Finally, the thesis formulates recommendations for urban planning for a qualitative upgrading of green spaces with regard to a better and equitable provision for the population and a greater resilience to extreme weather events. An open access online map application developed as part of this thesis is intended to serve as a decision support tool and may be transferred to other case studies in the future.

Made available in DSpace on 2016-04-25T16:45:03Z (GMT). No. of bitstreams: 1 Mestrado_PUC_SP_Decio_Forni_2005.pdf: 2631852 bytes, checksum: a3771d261c48405ed26df7aae4e6979b (MD5) Previous issue date: 2005-05-16 / The research explores the Innovation opportunity that Human and Organizational Development areas HOD ( that brings the space of traditional Human Resources HR with the emergence of Corporative Universities, among other Organizational Development politics) becomes to having with de demand of information of non-financial assets from the several external and internal clients of the organizations. The Corporative Governance practices start to demanding more internal information also. Meanwhile, the research brings evidences that the People Management areas have been having difficulties to obtain fastly relevant information from the non-financial capital, enabling to evaluate that an innovative phocus to develop platforms with flexible technologies would turn easyer these tasks. Exploratory researches contribute with the theorycal revision in Governance and Strategic Management and a Case Study of the area of Software shows, from the perspective of a large Brazilian corporation client, that the search for innovation for HOD strengthen its role among the leaders, growing its chances to competing in the future for positions in the top management. Human and competitive management that can bring good consequences also to society in Brazil. / A pesquisa explora a oportunidade de Inovação que as áreas de Desenvolvimento Humano e Organizacional DHO - (que tomam espaço do RH, dentro de políticas de Universidades Corporativas, entre outras de Desenvolvimento) passam a ter com a demanda de informações sobre ativos intangíveis pelos diversos clientes externos e internos. As práticas de Governança Corporativa passam a exigir mais informações. Entretanto, a pesquisa traz evidências de que as áreas de Gestão de Pessoas têm dificuldade em ter com rapidez informações relevantes dos capitais intangíveis, possibilitando avaliar que um enfoque inovador para desenvolver plataformas com tecnologias flexíveis facilitariam estas tarefas. Pesquisas Exploratórias corroboram a revisão teórica sobre Governança e Gestão Estratégica e um Estudo de Caso da área de software mostra, a partir de uma corporação brasileira que a busca de Inovação por parte do DHO fortalece mais a sua atuação junto aos líderes, aumentando as chances de concorrer futuramente ao alto comando. Gestão competitiva e humana que podem trazer melhores reflexos para a sociedade no Brasil.