This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol. The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain. The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity. / QC 20101222

Au cours des trois dernières décennies, les programmes d'observation des GES se sont orientés vers des échelles de plus en plus fines. Il est devenu indispensable de développer les réseaux d'observation pour s'adapter aux échelles visées. On s'oriente également vers une augmentation des espèces observables afin de disposer d'une palette de traceurs atmosphériques. Dans le cadre de l'infrastructure de recherche européenne ICOS, le Laboratoire des Sciences du Climat et de l’Environnement (LSCE) est en charge de la veille technologique en matière d’instruments de mesure des GES. Dans le cadre de ma thèse, j’ai évalué en premier lieu les performances d’un spectromètre infrarouge à transformée de Fourier (FTIR) ciblant cinq composés: N2O, CH4, CO, CO2 et son isotope 13CO2.Hormis le FTIR, d’autres nouvelles techniques sont apparues sur le marché, en particulier concernant la mesure du N2O. Contrairement au CO2 et CH4 les stations ICOS n'ont pas encore l'obligation de mesurer le N2O car aucun instrument n'a été reconnu comme suffisamment performant. Dans le cadre de ma thèse j'ai eu la responsabilité de faire l'évaluation de sept analyseurs de N2O provenant de cinq constructeurs différents. Grâce à cette étude, j’ai pu regrouper les analyseurs en deux catégories : les instruments performants pour de hautes fréquences de mesures (<1 min) et les instruments stables sur le long terme. La première catégorie est plus adaptée aux mesures des échanges avec les écosystèmes par la méthode des flux turbulents, alors que la deuxième permet le suivi à haute précision dans l'atmosphère. La plupart des instruments présentent une sensibilité aux variations de température ambiante ainsi qu’une correction de la vapeur d’eau insuffisante (Lebegue et al., 2016).Par la suite, j’ai utilisé les données de N2O obtenues avec le FTIR afin de déterminer les émissions de ce gaz à l’aide de la méthode Radon qui repose sur la corrélation entre l’accumulation nocturne du 222Rn et celle de N2O. L’instrument FTIR proposant une meilleure justesse de mesure que le GC utilisé par le passé, j’ai pu obtenir un plus grand nombre d’évènements exploitables (+45%). Par la suite, j'ai installé le FTIR sur le site de Trainou, une tour radio près d'Orléans, début 2014 afin de caractériser les gradients verticaux de N2O et 13CO2.Le LSCE a acquis en mars 2015 un spectromètre laser de marque Aerodyne Research dédié à l’étude des échanges atmosphère-biosphère du carbone. Les trois composés cibles sont CO2, H2O et l’oxysulfure de carbone (COS). Dans la mesure où les plantes assimilent COS et CO2 et qu’il n’existe pas de mécanisme équivalent à la respiration du CO2 pour le COS, l’absorption du COS par les plantes serait directement proportionnelle à leur activité photosynthétique. Dans ce contexte, j’ai évalué les performances de l’instrument Aerodyne puis comparé ces dernières à celles du GC qui évalue depuis août 2014 les variations diurne et saisonnière du rapport de mélange à l’Orme des Merisiers. Enfin, j’ai installé l’instrument Aerodyne à la tour ICOS de Saclay afin d’y documenter les variations diurnes du gradient vertical de COS.Mes études montrent (1) que l'Aerodyne et le GC présentent des performances similaires mais que l'Aerodyne a l’avantage de nécessiter une maintenance nettement moins importante, et (2) que l’instrument Aerodyne est capable de détecter un gradient vertical de quelques ppt en période de stratification nocturne. Dans cette partie de mon travail de thèse, j’évalue aussi les variations saisonnières du COS dans la basse troposphère, déterminées à partir des données GC, que je compare à d’autres sites à travers le monde. J’ai également pu estimer sur cette période, par la méthode Radon, les vitesses de dépôt de COS sur le Plateau de Saclay. Cette méthode m’a permis de mettre en évidence l’existence d’un puits nocturne de COS dans la région du plateau de Saclay qui demeure actif quasiment tout au long de l’année. / During the last three decades, GHG observations programs went towards ever smaller scales, and it is becoming necessary to develop observation networks and adapt them to the different scales studied. Besides denser networks, we are going toward an increase of the species monitored in order to have a wide range of atmospheric tracers available to identify processes. As a member of the European research program ICOS (Integrated Carbon Observing System), the LSCE (Laboratoire des Sciences du Climat et de l’Environnement) is in charge of technological watch for GHG measuring analyzers. In the scope of my thesis, I first tested a Fourier Transform Infra-Red Spectrometer (FTIR) commercialized by Ecotech which can analyze five species: N2O, CH4, CO, CO2 and its isotope 13CO2.Apart of the FTIR, other new technologies appeared on the market, particularly relating to N2O measurements. Unlike CO2 and CH4, ICOS stations don’t require measuring N2O, as no instrument has been found to be performant enough concerning measurement precision and reliability for the ICOS network. During my thesis, I had the responsibility to make an exhaustive evaluation of seven analyzers of N2O from five different manufacturers. I’ve been able to gather the analyzers in two categories: those with good high frequency measurements (< 1 min) and those which are stable over long periods. The first category is particularly adapted to measurement of exchange rates between different ecosystems, whereas the second allows for high precision monitoring of the atmosphere. Most instruments show dependence to ambient temperature variations as well as a water vapor correction either useless or lacking (Lebegue et al., AMT, 2016).Then, I used N2O measurements from the FTIR in order to determine night emissions of this gas by using the Radon method which calculates the correlation between the nocturnal accumulation of 222Rn and N2O. Thanks to the better repeatability of the FTIR over the gas chromatograph one, I have been able to obtain more workable events than with the GC (+45%). Start of 2014, I installed the FTIR at the Trainou station, a radio tower near Orléans, in order to document the vertical gradients of N2O and 13CO2.The LSCE received in March 2015 a laser spectrometer from Aerodyne Research dedicated to the study of atmosphere/biosphere carbon fluxes. Three species are analyzed, CO2, H2O and carbonyl sulfide (COS) for which the mixing ratio in the troposphere is a million times smaller than CO2’s. Considering that vegetation assimilate COS and CO2 in similar proportions and that there is no mechanism similar to respiration for COS, the absorption of COS by the vegetation should be directly proportional to the photosynthetic activity. In this respect, I have characterized the performances of the new instrument Aerodyne. I then compared measurements of COS from this instrument to those obtained with a GC which document, since August 2014, the diurnal and seasonal variations of COS mixing ratios and fluxes at the LSCE. Finally, I installed the Aerodyne analyzer at the ICOS tower of Saclay in order to document the diurnal variations of the vertical gradient of COS during the winter period.My studies showed (1) that the Aerodyne and the GC show similar performances although the Aerodyne analyzer has the advantage of needing less maintenance, and (2) that the Aerodyne analyzer is able to detect a vertical gradient of a few ppt during a nocturnal stratification. Here, I also study the seasonal variations of COS in the low troposphere, from GC data, which I compare to other stations across the world. I’ve also been able to estimate over this period, with the Radon method, the deposition velocity of COS over the Saclay plateau. Thanks to this method, I was able to document a nocturnal sink active for almost the full year over the Saclay Plateau.

Die vorliegende Dissertation beschreibt die Synthese und Charakterisierung von neuartigen perferrocenylierten, cyclischen Komplexen unter Anwendung der Cobalt-vermittelten Cyclomerisierung in Kombination mit einer C-H-Bindungsaktivierung als auch die Bildung von ferrocenylierten Phosphinoalkinid-Komplexen mit Eisen- und Cobaltcarbonylen. Die elektrochemischen Eigenschaften und die Elektronentransfer-prozesse zwischen den terminalen Ferrocenyleinheiten in den unterschiedlichen cyclischen Verbindungen wurden unter Einbeziehung der Struktur/chemischen Zusammensetzung der Brückenbausteine ermittelt. Elf perferrocenylierte, cyclische Komplexe wurden mittels [2+2] bzw. [2+2+2] Cyclomerisierung von 1,4-Diferrocenylbutadiin FcC≡C–C≡CFc (Fc = Fe(η5-C5H4)(η5-C5H5)) unter Verwendung von Dicarbonylcyclopentadienylcobalt Co(η5-C5H5)(CO)2 erhalten. Diese können in drei Gruppen unterteilt werden: (i) Produkte der Cyclodimerisierung mit zusätzlicher Kettenverlängerung, welche Cyclobutadienyl-einheiten als zentrale Brückenbausteine besitzen (3a,b und 4a,b), (ii) Produkte der Cyclodimerisierung mit gleichzeitiger CO-Insertion (6a,b,c und 7), und (iii) Produkte der Cyclotrimerisierung gefolgt von einem Ringschluss durch eine C-H-Bindungsaktivierung (5a,b,c). Die Optimierung der Reaktionsbedingungen wurde zur Ausbeutemaximierung der jeweiligen Verbindungsfamilien durchgeführt. Ein weiterer Teil dieser Forschungsarbeit bezieht sich auf die verschiedenen Reaktionsmuster von (Ferrocenylethinyl)diphenylphosphan- mit zweikernigen Eisen- bzw. Cobaltcarbonylverbindungen in Form von Dieisennonacarbonyl und Dicobaltoctacarbonyl als Reagenzien. Dabei konnten sechs gemischte Carbonyl- und Ferrocenyl-funktionalisierte Phosphinoacetylid-Komplexe mit Eisen(0) und Cobalt(0) erhalten und charakterisiert werden. / The present PhD study focuses on the synthesis and characterization of novel perferrocenylated cyclic complexes utilizing cobalt - mediated cyclomerization in combination with C–H bond activation as well as formation of ferrocenylated phosphino-alkyne compounds with iron and cobalt carbonyls. Electrochemical properties and electron-transfer processes between terminal ferrocenyl units in the diverse cyclic compounds are explored in relation to the chemical composition of the building blocks connecting them. Eleven perferrocenylated cyclic compounds were obtained via [2 + 2] and [2 + 2 + 2] cyclomerization of 1,4-diferrocenylbutadiyne FcC≡C–C≡CFc (Fc = Fe(η5-C5H4)(η5-C5H5)) by the reaction with dicarbonylcyclopentadienylcobalt Co(η5-C5H5)(CO)2. They are subdivided into three groups: (i) products of cyclodimerization with additional chain extension, possessing cyclobutadienyl moieties as a central linkage unit (3a,b and 4a,b), (ii) products of cyclodimerization with consecutive CO insertion (6a,b,c and 7), and (iii) products of cyclotrimerization followed by cycle formation via C–H bond activation (5a,b,c). Optimization of the reaction conditions was made in order to maximize the amount of each group of compounds. Furthermore, another part of this research work focuses on diverse reaction patterns of (ferrocenylethynyl)diphenylphosphane with diironnonacarbonyl and dicobaltocta-carbonyl. Six mixed carbonyl and ferrocenyl-functionalized phospinoalkynyl compounds of iron(0) and cobalt(0) were obtained and characterized.

Die vorliegende Dissertation beschreibt die Synthese und Charakterisierung von neuartigen perferrocenylierten, cyclischen Komplexen unter Anwendung der Cobalt-vermittelten Cyclomerisierung in Kombination mit einer C-H-Bindungsaktivierung als auch die Bildung von ferrocenylierten Phosphinoalkinid-Komplexen mit Eisen- und Cobaltcarbonylen. Die elektrochemischen Eigenschaften und die Elektronentransfer-prozesse zwischen den terminalen Ferrocenyleinheiten in den unterschiedlichen cyclischen Verbindungen wurden unter Einbeziehung der Struktur/chemischen Zusammensetzung der Brückenbausteine ermittelt. Elf perferrocenylierte, cyclische Komplexe wurden mittels [2+2] bzw. [2+2+2] Cyclomerisierung von 1,4-Diferrocenylbutadiin FcC≡C–C≡CFc (Fc = Fe(η5-C5H4)(η5-C5H5)) unter Verwendung von Dicarbonylcyclopentadienylcobalt Co(η5-C5H5)(CO)2 erhalten. Diese können in drei Gruppen unterteilt werden: (i) Produkte der Cyclodimerisierung mit zusätzlicher Kettenverlängerung, welche Cyclobutadienyl-einheiten als zentrale Brückenbausteine besitzen (3a,b und 4a,b), (ii) Produkte der Cyclodimerisierung mit gleichzeitiger CO-Insertion (6a,b,c und 7), und (iii) Produkte der Cyclotrimerisierung gefolgt von einem Ringschluss durch eine C-H-Bindungsaktivierung (5a,b,c). Die Optimierung der Reaktionsbedingungen wurde zur Ausbeutemaximierung der jeweiligen Verbindungsfamilien durchgeführt. Ein weiterer Teil dieser Forschungsarbeit bezieht sich auf die verschiedenen Reaktionsmuster von (Ferrocenylethinyl)diphenylphosphan- mit zweikernigen Eisen- bzw. Cobaltcarbonylverbindungen in Form von Dieisennonacarbonyl und Dicobaltoctacarbonyl als Reagenzien. Dabei konnten sechs gemischte Carbonyl- und Ferrocenyl-funktionalisierte Phosphinoacetylid-Komplexe mit Eisen(0) und Cobalt(0) erhalten und charakterisiert werden.:Table of contents Bibliografische Beschreibung und Referat iii Abstract iv Ort und Zeitraum der Durchführung v Widmung vi Präambel vii List of Abbreviations xii CHAPTER A Introduction 15 References 16 CHAPTER B State of Knowledge 19 1 (Spectro)electrochemical studies of mixed-valent transition metal complexes. Theoretical background 19 1.1 Mixed-valent compounds – classification 20 1.2 Spectroelectrochemistry 21 1.3 Electrochemistry 25 2 (Di)ferrocenylalkynes – synthesis and reactions 28 2.1 1,4-Diferrocenylbutadiyne 29 2.2 Other (poly)ferrocenyl substituted alkyne derivatives 35 3 Dicarbonylcyclopentadienylcobalt – [2+2] and [2+2+2] cyclo-addition reactions 37 3.1 [2+2] and [2+2+2] cycloaddition – cyclobutadiene, cyclopentadienone, benzene and pyridine based systems 38 3.2 Mechanism of [2+2] and [2+2+2] cycloaddition/cyclization and [2+2] cycloaddition/cyclization with CO insertion mediated by CoCp(CO)2 40 4 Chelation-assisted C–H bond activation mediated by cobalt species 42 5 Phosphinoalkynes and their reaction with iron and cobalt carbonyls 44 5.1 Mechanism of the P–C(sp) bond cleavage in phosphinoalkynes 48 6 Complexes setup by (ferrocenylethynyl)diphenylphosphane 50 References 56 CHAPTER C Multiferrocenyl Cobalt-Based Sandwich Compounds 64 1 Introduction 64 2 Results and Discussion 65 2.1 Synthesis and Characterization 65 2.2 Solid-State Structures 71 2.3 Electrochemistry 73 2.4 Spectroelectrochemistry 76 3 Experimental Section 79 3.1 Instrumentation 79 3.2 General Conditions 81 3.3 Reagents 81 3.4 General Procedure - Reaction of 1 with 2 81 3.4.1 Compound 3a 82 3.4.2 Compound 3b 82 3.4.3 Compound 4b 83 3.4.4 Compound 5c 83 3.4.5 Compound 6a 84 3.4.6 Compound 6b 84 3.4.7 Compound 6c 85 3.4.8 Compound 7 85 4 Supporting information 86 5 References 86 CHAPTER D Combining Cobalt-Assisted Alkyne Cyclotrimerization and Ring Formation through C–H Bond Activation: A “One-Pot” Approach to Complex Multimetallic Structures 91 1 Introduction 91 2 Results and Discussion 92 3 Experimental Section (Supporting information) 98 3.1 General Information 98 3.2 Starting Materials 98 3.3 Synthesis of 3a and 3b from 2 99 3.3.1 Complex 3a: 99 3.3.2 Complex 3b: 100 3.4 Synthesis of 9a and 9b from 1-Ferrocenylethynyl-2-Ferrocenyl Benzene (8) 101 3.4.1 Synthesis of 1-Bromo-2-Ferrocenylethynyl Benzene (7) 101 3.4.2 Synthesis of 1-Ferrocenylethynyl-2-Ferrocenyl Benzene (8) 102 3.4.3 Synthesis of 9a and 9b from 8 103 3.5 Synthesis of 3a and 3b from 1,3,5-Triethynylferrocenyl-2,4,6-Triferrocenyl Benzene (4) 105 3.5.1 Synthesis of 1,3,5-Trichloro-2,4,6-Triethynylferrocenyl Benzene (12) 105 3.5.2 Synthesis of 1,3,5-Triethynylferrocenyl-2,4,6-Triferrocenyl Benzene (4) 105 3.5.3 Synthesis of 3a and 3b from 4 106 4 Supporting information 107 4.1 Spectroelectrochemistry of 3a,b 107 4.2 Conversion of Isomer 9a to 9b – Electrochemical and Chemical oxidation 109 4.3 Chemical oxidation experiment 110 5 References 111 CHAPTER E Coordination Behavior of (Ferrocenylethynyl)diphenyl-phosphane Towards Binuclear Iron and Cobalt Carbonyls 114 1 Introduction 114 2 Results and Discussion 115 3 Experimental Section 126 3.1 Instrumentation 126 3.2 General 128 3.3 Reagents 128 3.4 Synthesis of 4 128 3.5 Synthesis of 4, 5 and 6 129 3.6 Synthesis of 6 by reacting 4 with 2 131 3.7 Synthesis of 7 and 8 131 3.8 Synthesis of 8 from 1 with 3 132 3.9 Synthesis of 9 in the reaction of 7 with 2 133 3.10 Synthesis of 9 in the reaction of 4 with 3 133 4 Electronic Supplementary Material (Supporting information) 134 5 References 134 CHAPTER F Summary 139 1 Conclusions of Chapter C (Appendix A) 139 2 Conclusions of Chapter D (Appendix B) 141 3 Conclusions of Chapter E (Appendix C) 142 Appendix 145 1 Appendix D (Chapter C) 145 2 Appendix E (Chapter D) 146 3 Appendix F (Chapter E) 147 Curriculum Vitae 150 Publications 152 Acknowledgements 154 Selbstständigkeitserklärung 155 / The present PhD study focuses on the synthesis and characterization of novel perferrocenylated cyclic complexes utilizing cobalt - mediated cyclomerization in combination with C–H bond activation as well as formation of ferrocenylated phosphino-alkyne compounds with iron and cobalt carbonyls. Electrochemical properties and electron-transfer processes between terminal ferrocenyl units in the diverse cyclic compounds are explored in relation to the chemical composition of the building blocks connecting them. Eleven perferrocenylated cyclic compounds were obtained via [2 + 2] and [2 + 2 + 2] cyclomerization of 1,4-diferrocenylbutadiyne FcC≡C–C≡CFc (Fc = Fe(η5-C5H4)(η5-C5H5)) by the reaction with dicarbonylcyclopentadienylcobalt Co(η5-C5H5)(CO)2. They are subdivided into three groups: (i) products of cyclodimerization with additional chain extension, possessing cyclobutadienyl moieties as a central linkage unit (3a,b and 4a,b), (ii) products of cyclodimerization with consecutive CO insertion (6a,b,c and 7), and (iii) products of cyclotrimerization followed by cycle formation via C–H bond activation (5a,b,c). Optimization of the reaction conditions was made in order to maximize the amount of each group of compounds. Furthermore, another part of this research work focuses on diverse reaction patterns of (ferrocenylethynyl)diphenylphosphane with diironnonacarbonyl and dicobaltocta-carbonyl. Six mixed carbonyl and ferrocenyl-functionalized phospinoalkynyl compounds of iron(0) and cobalt(0) were obtained and characterized.:Table of contents Bibliografische Beschreibung und Referat iii Abstract iv Ort und Zeitraum der Durchführung v Widmung vi Präambel vii List of Abbreviations xii CHAPTER A Introduction 15 References 16 CHAPTER B State of Knowledge 19 1 (Spectro)electrochemical studies of mixed-valent transition metal complexes. Theoretical background 19 1.1 Mixed-valent compounds – classification 20 1.2 Spectroelectrochemistry 21 1.3 Electrochemistry 25 2 (Di)ferrocenylalkynes – synthesis and reactions 28 2.1 1,4-Diferrocenylbutadiyne 29 2.2 Other (poly)ferrocenyl substituted alkyne derivatives 35 3 Dicarbonylcyclopentadienylcobalt – [2+2] and [2+2+2] cyclo-addition reactions 37 3.1 [2+2] and [2+2+2] cycloaddition – cyclobutadiene, cyclopentadienone, benzene and pyridine based systems 38 3.2 Mechanism of [2+2] and [2+2+2] cycloaddition/cyclization and [2+2] cycloaddition/cyclization with CO insertion mediated by CoCp(CO)2 40 4 Chelation-assisted C–H bond activation mediated by cobalt species 42 5 Phosphinoalkynes and their reaction with iron and cobalt carbonyls 44 5.1 Mechanism of the P–C(sp) bond cleavage in phosphinoalkynes 48 6 Complexes setup by (ferrocenylethynyl)diphenylphosphane 50 References 56 CHAPTER C Multiferrocenyl Cobalt-Based Sandwich Compounds 64 1 Introduction 64 2 Results and Discussion 65 2.1 Synthesis and Characterization 65 2.2 Solid-State Structures 71 2.3 Electrochemistry 73 2.4 Spectroelectrochemistry 76 3 Experimental Section 79 3.1 Instrumentation 79 3.2 General Conditions 81 3.3 Reagents 81 3.4 General Procedure - Reaction of 1 with 2 81 3.4.1 Compound 3a 82 3.4.2 Compound 3b 82 3.4.3 Compound 4b 83 3.4.4 Compound 5c 83 3.4.5 Compound 6a 84 3.4.6 Compound 6b 84 3.4.7 Compound 6c 85 3.4.8 Compound 7 85 4 Supporting information 86 5 References 86 CHAPTER D Combining Cobalt-Assisted Alkyne Cyclotrimerization and Ring Formation through C–H Bond Activation: A “One-Pot” Approach to Complex Multimetallic Structures 91 1 Introduction 91 2 Results and Discussion 92 3 Experimental Section (Supporting information) 98 3.1 General Information 98 3.2 Starting Materials 98 3.3 Synthesis of 3a and 3b from 2 99 3.3.1 Complex 3a: 99 3.3.2 Complex 3b: 100 3.4 Synthesis of 9a and 9b from 1-Ferrocenylethynyl-2-Ferrocenyl Benzene (8) 101 3.4.1 Synthesis of 1-Bromo-2-Ferrocenylethynyl Benzene (7) 101 3.4.2 Synthesis of 1-Ferrocenylethynyl-2-Ferrocenyl Benzene (8) 102 3.4.3 Synthesis of 9a and 9b from 8 103 3.5 Synthesis of 3a and 3b from 1,3,5-Triethynylferrocenyl-2,4,6-Triferrocenyl Benzene (4) 105 3.5.1 Synthesis of 1,3,5-Trichloro-2,4,6-Triethynylferrocenyl Benzene (12) 105 3.5.2 Synthesis of 1,3,5-Triethynylferrocenyl-2,4,6-Triferrocenyl Benzene (4) 105 3.5.3 Synthesis of 3a and 3b from 4 106 4 Supporting information 107 4.1 Spectroelectrochemistry of 3a,b 107 4.2 Conversion of Isomer 9a to 9b – Electrochemical and Chemical oxidation 109 4.3 Chemical oxidation experiment 110 5 References 111 CHAPTER E Coordination Behavior of (Ferrocenylethynyl)diphenyl-phosphane Towards Binuclear Iron and Cobalt Carbonyls 114 1 Introduction 114 2 Results and Discussion 115 3 Experimental Section 126 3.1 Instrumentation 126 3.2 General 128 3.3 Reagents 128 3.4 Synthesis of 4 128 3.5 Synthesis of 4, 5 and 6 129 3.6 Synthesis of 6 by reacting 4 with 2 131 3.7 Synthesis of 7 and 8 131 3.8 Synthesis of 8 from 1 with 3 132 3.9 Synthesis of 9 in the reaction of 7 with 2 133 3.10 Synthesis of 9 in the reaction of 4 with 3 133 4 Electronic Supplementary Material (Supporting information) 134 5 References 134 CHAPTER F Summary 139 1 Conclusions of Chapter C (Appendix A) 139 2 Conclusions of Chapter D (Appendix B) 141 3 Conclusions of Chapter E (Appendix C) 142 Appendix 145 1 Appendix D (Chapter C) 145 2 Appendix E (Chapter D) 146 3 Appendix F (Chapter E) 147 Curriculum Vitae 150 Publications 152 Acknowledgements 154 Selbstständigkeitserklärung 155

O processo de isquemia-reperfusão é responsável pela geração de um dano agudo em uma série de órgãos do corpo humano, e, no coração, é o principal causador da doença crônica conhecida por insuficiências cardíaca. Atualmente não existe nenhuma opção terapêutica disponível na prática clínica contra esta injúria. Com o objetivo de desenvolver uma nova estratégia de combate a este dano, no presente trabalho investigamos a promessa da aplicação da recém-descoberta via UPRam num modelo de hipóxia reoxigenação in-vitro, sem obter sucesso. Contudo, os resultados gerados nestes experimentos forneceram pistas de que o uso do desacoplador CCCP é capaz de reduzir o dano deste insulto, porém o mecanismo celular responsável por esta proteção permanece desconhecido. Tentativas de desvendar este mecanismo utilizando a via lisossomal-autofágica ou a clivagem de OPA-1 falharam, mas produziram importantes insights a respeito do papel da protease mitocondrial OMA-1 no processo de hipóxia-reoxigenação, abrindo caminho para novos estudos subsequentes. / Ischemia-reperfusion injury is a process that occurs in many human organs including the heart, where it is the main trigger to heart failure, a chronic disease that kills over 40% patients only five years following the first diagnosis. Despite the bulky research on the subject, there is no available therapy on clinical practice against this insult. Attempting to develop a novel strategy to mitigate this damage, we investigated if the pro-survival effect of the recently discovered UPRam pathway could be protective in an in-vitro model of ischemia reperfusion. Despite the negative results regarding its conservation on mammalian cells, treatment with the mitochondrial uncoupler CCCP was proven to reduce cell death under this process, but the cellular mechanism responsible for this protection remained elusive. Aspiring to unravel this cellular response, we tested whether autophagy or OPA-1 cleavage was capable of abrogating the verified protection, but the results came back negative. Regardless of that, the behavior of OMA-/- cells over H/R stress has given new insights on novel strategies comprising I/R injury abrogation.

A presente tese relata o estudo conformacional e das interações eletrônicas de algumas: a) &#945;-etilsulfinil- (Ia), &#945;-etilsulfonil- (Ib) acetofenonas-para-substituídas Y-&#934;-C(O)CH2SOnEt [I, n=1 (a) e n=2 (b)]; b) &#945;-metiltio-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIa) e suas formas mono- (IIb) e di- (IIc) oxigenadas Y-&#934;-C(O)CH[SOnMe][P(O)(OEt)2] [II, n=0 (a), n=1 (b)] e n=2 (c)]; c) &#945;-bromo-&#945;-etilsulfonilacetofenonas-para-substituídas Y-&#934;-C(O)CH[Br][SO2Et] (III). Este estudo foi realizado através das espectroscopias no Infravermelho, Ressonância Magnética Nuclear, Ultravioleta e cálculos ab initio HF/6-31G**. Nas &#945;-etilsulfinilacetofenonas-para-substituídas (Ia) a conformação cis é a preferencial para toda série, enquanto nas &#945;-etilsulfonilacetofenonas-para-substituídas (Ib) a conformação gauche é a predominante. Nas &#945;-metiltio-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIa) existe uma única conformação estável que apresenta o grupo (SMe) na geometria gauche e o grupo [P(O)(OEt)2] na geometria quasi-cis em relação à carbonila. As &#945;-metilsulfinil-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIb) apresentam duas conformações estáveis, sendo cada uma delas referente a um diastereômero, tanto em solução de solventes de polaridade crescente quanto no estado gasoso. A conformação mais estável (CSSS) apresenta o grupo (MeSO) numa geometria quasi-periplanar (quasi-cis) e o grupo [(P(O)(OEt)2] numa geometria anti-clinal (gauche). A segunda conformação CRSS apresenta os dois substituintes, (MeSO) e [(P(O)(OEt)2], numa geometria sin-clinal (gauche). Nas &#945;-metilsulfonil-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIc) a conformação preferencial apresenta os grupos (MeSO2) e [(P(O)(OEt)2] na geometria sin-clinal em relação à carbonila. As &#945;-bromo-&#945;-etilsulfonilacetofenonas-para-substituídas (III) apresentam-se numa única conformação estável, contendo o grupo (SO)2Et) na geometria sin-periplanar (quasi-cis) e o átomo de (Br) na geometria sin-clinal (gauche). / This thesis reports the conformational and electronic interaction studies of some: a) &#945;-ethylsulfinyl- (Ia) and &#945;-ethylsulfonyl- (Ib) para-substituted acetophenones Y-PhC(O)CH2SOnEt [I, n=1 (a) and n=2 (b)]; b) &#945;-methylthio-&#945;-diethoxyphosphoryl-para-substituted acetophenones (IIa) and their corresponding mono- (IIb) and di- (IIc) oxygenated derivatives Y-PhC(O)CH[SOnMe][P(O)(OEt2)] [II, n=0 (a), n=1 (b)] and n=2 (c)]; c) &#945;-bromo, &#945;- ethylsulfonyl-para-substituted acetophenones Y-PhC(O)[Br][SO2Et] (III). This study was performed by means of Infrared, Nuclear Magnetic Resonance, Ultraviolet spectroscopies, ab initio computations and X-ray diffraction analysis. For the &#945;-ethylsulfinylacetophenones (Ia) the cis conformer predominates over the gauche one while in the case of the &#945;-ethylsulfonylacetophenones (Ib) the gauche conformer is the more stable relative to the quasi-cis one. The &#945;-methylthio-&#945;-diethoxyphosphoryl acetophenones (IIa) present only a single stable conformer which bears the (SMe) group in a syn-clinal (gauche) geometry and the [P(O)(OEt2)] group in the quasi-periplanar (quasi-cis) geometry with respect to the carbonyl group. The &#945;-methylsulfinyl-&#945;-diethoxyphosphoryl acetophenones (IIb) display two stable conformations corresponding each one to a different diastereomer. The most stable conformer CSSS presents the methylsulfinyl group [MeS(O)] in a quasi-periplanar (quasi-cis) geometry and the diethoxyphosphoryl group [P(O)(OEt2)] in a anti-clinal (gauche) geometry relative to the carbonyl group. The second less stable conformer corresponds to the CRSS diastereomer and displays both the [MeS(O)] and the [P(O)(OEt2)] groups in a syn-clinal (gauche) geometry. The &#945;-methylsulfonyl-&#945;-diethoxyphosphoryl acetophenones (IIc) presents only a single stable conformer bearing both the [MeSO2] and [P(O)(OEt)2] groups in a sin-clinal geometry with respect to the carbonyl group. The &#945;-bromo-&#945;-ethylsulfonylacetophenones III present a single stable conformation bearing the the [SO2Et] group in a syn-periplanar (quasi-cis) geometry and the [Br] atom in a syn-clinal (gauche) geometry relative to the carbonyl group.

Pour notre travail de thèse, nous avons établi une méthodologie, basée sur la DFT et sa variante dépendante du temps, qui permet l'évaluation efficace et la prédiction rapide des couleurs de différentes familles de colorants carbonylés dans différents environnements. Ainsi, nous sommes capables de fournir des valeurs théoriques très précises pour les énergies de transition des dérivés de l'anthraquinone, de la coumarine et de l'indigo ainsi que du thioindigo. Notre stratégie prend en compte aussi bien les effets de solvatation, dans le cadre d'une modélisation en continuum, que les effets du pH, sur la position de la bande d'absorption maximale du spectre UV/VIS. / The project of the Ph. D. work consists in the elaboration of a theoretical methodology able to evaluate and predict the color of organic dyes (see the List of recent publications for more details). Our methodology takes into account the solvent effects as well as the pH impact on the color of the dyes. The theoretical tools used are the Density Functional Theory (DFT, for ground-state optimization) and the Time Dependent TDDFT for excitation spectra calculations. The solvent effects are taken into account via the PCM (Polarizable continuum Model).

The homoaldol reaction is one of the most powerful methods for the construction of C–C bonds as well as 1,4-oxygenated compounds yet this reaction remains in challenging tasks due to the instability of homoenolates which spontaneously cyclize to the cyclopropanolate. A regioselective catalytic homoaldol equivalent reaction of 3-bromo vinyl acetate with aldehydes under Cr(III)-Mn(0) redox condition was developed. This homoaldol equivalent reaction allows access to the 1,4-oxygenated compounds that are not possible by a conventional aldol process. Mild hydrolysis of the vinyl acetate and reduction of the homoaldol adducts generated diols and lactols in high yield (99%). Further manipulation including stereoselective epoxidation and cyclopropanation was achieved in an efficient manner. Furans, found in many natural products and utilized in drug discovery, have been well studied but current synthetic methods toward furans have some limitations in functional group tolerance, substrate scope, and low product yield in many cases. A highly efficient and catalytic cycloisomerization reaction that transforms acetylenic α,β-epoxides to 2,3,5-tri-substituted furans under InCl3 catalysis was developed. This reaction sequence allows access to rapid construction of highly valuable, tri-substituted furan derivatives. Cross-coupling reactions utilizing transition metals and Lewis acids are important synthetic tools for the formation of C–C and C–N bonds and a number of cross-coupling reactions between α-bromo carbonyl compounds and metal reagents such as aryl metals, alkenyl metals, and alkyl metals have been reported. Transition metal-catalyzed cross-coupling reaction for the construction of α-alkynyl carbonyl compounds has reported in a limited case. The first approach to secondary α-alkynyl carbonyl compounds from secondary α-bromo esters and amides with tributyl(phenylethynyl)stannane under palladium-catalyzed cross-coupling reaction conditions was developed. This synthetic method allows access to secondary α-alkynyl carbonyl compounds which are valuable precursors in pharmaceuticals and agricultural applications.

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No. of bitstreams: 1 Tese Albertinho.pdf: 2368551 bytes, checksum: 417090fff955b8696ce1e600d35af5e0 (MD5) / CNPq, à CAPES e à FINE / Este trabalho foi realizado com os seguintes objetivos: apresentar uma metodologia analítica aplicável à determinação de compostos carbonílicos (CC) em fase vapor, em amostras estacionárias e pessoais coletadas em ambientes de trabalho de carvoarias; determinar o perfil dos CC presentes no ar inalado pelos trabalhadores e; quantificar os CC no ar, na fase vapor, em locais de trabalho e na zona respiratória de trabalhadores carvoeiros. Os trabalhos de campo foram realizados em quatro carvoarias que produziam o carvão a partir da queima de pinho e de eucalipto, todas localizadas a cerca de 150 km, a nordeste de Salvador. Cartuchos Sep-Pak® C18 impregnados com solução ácida a 0,2% de 2,4 dinitrofenilhidrazina coletaram eficientemente os CC atmosféricos, em vazões em torno de 0,1 L/min e quando a duração da coleta foi de, no máximo, 240 minutos, para as amostras pessoais e 120 minutos, para as estacionárias. Foram desenvolvidos dois protocolos analíticos (Método “1” e Método “2”), ambos por cromatografia líquida de alta eficiência utilizando bomba com gradiente de eluição de solventes e sistema de detecção por UV/Visível (365 nm), para a separação e quantificação das 2,4-dinitrofenilhidrazonas de vários CC. O Método “1” permitiu separar e quantificar, em menos de 16 minutos, acetaldeído, acroleína, benzaldeído, ciclohexanona, ciclopentanona, 2- etil hexanal, formaldeído, furfural, hexanal, 2-hexenal, octanal, 2-pentenal, propanal, e propanona, com destaque para a separação dos pares acroleína-furfural e propanona-propanal. Além disso, permitiu estimar a soma das concentrações dos isômeros C4, butanal-isobutanal- butanona. O Método “2” permitiu separar e quantificar, em menos de 30 minutos, 13 dos 17 CC citados para o Método “1”. Por este método foi possível separar a butanona da mistura de butanal e isobutanal. O mesmo não ocorreu com a acroleína e o furfural, que co-eluíram. Os limites de detecção e de quantificação para o formaldeído, o acetaldeído e a propanona foram bastante afetados pelos níveis desses compostos encontrados nos brancos de amostra. Acetaldeído, formaldeído, furfural, isômeros C4 e propanona foram os CC confirmados em todas as amostras coletadas, nas quatro carvoarias. Vários outros CC desconhecidos foram detectados nas amostras. Ciclopentanona, 2-pentenal e CC acima de C8 não foram detectados nas amostras pelos dois métodos cromatográficos. Em amostras válidas foram determinadas concentrações de formaldeído entre 15,0 e 139,1 µg m-3, de acetaldeído entre 37,9 e 164,8 µg m-3, de propanona entre 9,6 e 483,0 µg m-3, de furfural entre 38,9 e 113,7 µg m-3 e de isômeros C4 (butanal+isobutanal+butanona) entre 9,8 e 132,4 µg m-3, em amostras pessoais. Em amostras estacionárias, as faixas de concentrações desses mesmos compostos foram respectivamente, 20,4 a 160,2 µg m-3, 118,6 a 283,6 µg m-3, 327,5 a 643,6 µg m-3, 69,9 a 162,9 µg m-3 e 100,0 a 176,1 µg m-3. Os resultados indicam que os trabalhadores das carvoarias se expõem a concentrações de formaldeído, acetaldeído e furfural acima dos limites estabelecidos por alguns organismos internacionais, como o National Institute for Occupational Safety and Health - NIOSH e o Health Based Exposure Levels Committee - HBELC, ambos dos Estados Unidos. Estes são os primeiros resultados de concentrações de CC no ar obtidos em ambientes de trabalho e na zona respiratória de trabalhadores de carvoarias, que se tem conhecimento até o momento. / The goals of the present work were to present an analytical methodology applicable to the determination of carbonyl compounds (CC) in vapor phase, in area and personal samples collected in charcoal company workplaces; to determine the CC profile in air inhaled by charcoal workers; and to quantify the CC in vapor phase in air of workplaces and breathing zone of workers in charcoal companies. The measurements were obtained in air samples collected in four companies located about 150 km north of Salvador, Bahia, Brazil, which burn eucalyptus and pinus to produce charcoal. The results showed that CC were efficiently collected on Sep-Pak® C18 cartridges coated with 0.2% acidic solution of 2,4- dinitrophenylhydrazine when the sampling flow rates were around 100 mL/min and the sampling time was 240 minutes for the personal samples and 120 minutes for area samples. Two chromatographic methods (Method 1 and Method 2) for separation and quantification of several 2,4-dinitrophenylhydrazones (2,4-DNPHO) were developed using a high performance liquid chromatography system with a gradient pump for the solvent elution and a UV detector (365 nm). Method 1 was able to separate and quantify, in less than 16 minutes, the 2,4- DNPHO of acetaldehyde, acrolein, benzaldehyde, cyclohexanone, cyclopentanone, 2-ethyl hexanal, formaldehyde, furfural, hexanal, 2-hexenal, octanal, 2-pentenal, propanal, and propanone, and estimated the sum of C4 isomers, butanal-isobutanal-butanone. This method separated well acrolein from furfural and propanal from propanone hydrazones. Method “2” allowed separation and quantification, in less than 30 minutes, of 13 of the 17 CC listed for Method 1. This method separated butanone from other components of the C4 mixture and enables the separation of acrolein from furfural. In both methods, the detection and the quantification limits of acetaldehyde, formaldehyde, and propanone were affected by the amount of these compounds found in the blank samples. Acetaldehyde, formaldehyde, furfural, C4 isomers, and propanone were the CC confirmed in all samples collected in all charcoal companies. Several unknown CC were also found. Cyclopentanone, 2-pentenal, and carbonyl compounds with more than 8 carbon atoms were not detected in any of the samples by these methods. Concentrations of formaldehyde, acetaldehyde, propanone, furfural, and C4 isomers (butanal+isobutanal+butanone) found in personal samples ranged between 15.0 and 139.1 µg m-3, 37.9 and 164.8 µg m-3, 9.6 and 483.0 µg m-3, 38.9 and 113.7 µg m-3, and 9.8 and 132.4 µg m-3, respectively. In area samples, the concentrations of the same CC were between 20.4 and 160.2 µg m-3, 118.6 and 283.6 µg m-3, 327.5 and 643.6 µg m-3, 69.9 and 162.9 µg m-3, and 100.0 and 176.1 µg m-3. These results indicated that charcoal workers were exposed to formaldehyde, acetaldehyde, and furfural concentrations that exceed the limit values suggested by the National Institute for Occupational Safety and Health - NIOSH and the Health Based Exposure Levels Committee - HBELC. These were the first results of CC concentrations in workplace air and in breathing zone of charcoal workers reported in the scientific literature up to this mome

A presente tese relata o estudo conformacional e das interações eletrônicas de algumas: a) &#945;-etilsulfinil- (Ia), &#945;-etilsulfonil- (Ib) acetofenonas-para-substituídas Y-&#934;-C(O)CH2SOnEt [I, n=1 (a) e n=2 (b)]; b) &#945;-metiltio-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIa) e suas formas mono- (IIb) e di- (IIc) oxigenadas Y-&#934;-C(O)CH[SOnMe][P(O)(OEt)2] [II, n=0 (a), n=1 (b)] e n=2 (c)]; c) &#945;-bromo-&#945;-etilsulfonilacetofenonas-para-substituídas Y-&#934;-C(O)CH[Br][SO2Et] (III). Este estudo foi realizado através das espectroscopias no Infravermelho, Ressonância Magnética Nuclear, Ultravioleta e cálculos ab initio HF/6-31G**. Nas &#945;-etilsulfinilacetofenonas-para-substituídas (Ia) a conformação cis é a preferencial para toda série, enquanto nas &#945;-etilsulfonilacetofenonas-para-substituídas (Ib) a conformação gauche é a predominante. Nas &#945;-metiltio-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIa) existe uma única conformação estável que apresenta o grupo (SMe) na geometria gauche e o grupo [P(O)(OEt)2] na geometria quasi-cis em relação à carbonila. As &#945;-metilsulfinil-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIb) apresentam duas conformações estáveis, sendo cada uma delas referente a um diastereômero, tanto em solução de solventes de polaridade crescente quanto no estado gasoso. A conformação mais estável (CSSS) apresenta o grupo (MeSO) numa geometria quasi-periplanar (quasi-cis) e o grupo [(P(O)(OEt)2] numa geometria anti-clinal (gauche). A segunda conformação CRSS apresenta os dois substituintes, (MeSO) e [(P(O)(OEt)2], numa geometria sin-clinal (gauche). Nas &#945;-metilsulfonil-&#945;-dietoxifosforilacetofenonas-para-substituídas (IIc) a conformação preferencial apresenta os grupos (MeSO2) e [(P(O)(OEt)2] na geometria sin-clinal em relação à carbonila. As &#945;-bromo-&#945;-etilsulfonilacetofenonas-para-substituídas (III) apresentam-se numa única conformação estável, contendo o grupo (SO)2Et) na geometria sin-periplanar (quasi-cis) e o átomo de (Br) na geometria sin-clinal (gauche). / This thesis reports the conformational and electronic interaction studies of some: a) &#945;-ethylsulfinyl- (Ia) and &#945;-ethylsulfonyl- (Ib) para-substituted acetophenones Y-PhC(O)CH2SOnEt [I, n=1 (a) and n=2 (b)]; b) &#945;-methylthio-&#945;-diethoxyphosphoryl-para-substituted acetophenones (IIa) and their corresponding mono- (IIb) and di- (IIc) oxygenated derivatives Y-PhC(O)CH[SOnMe][P(O)(OEt2)] [II, n=0 (a), n=1 (b)] and n=2 (c)]; c) &#945;-bromo, &#945;- ethylsulfonyl-para-substituted acetophenones Y-PhC(O)[Br][SO2Et] (III). This study was performed by means of Infrared, Nuclear Magnetic Resonance, Ultraviolet spectroscopies, ab initio computations and X-ray diffraction analysis. For the &#945;-ethylsulfinylacetophenones (Ia) the cis conformer predominates over the gauche one while in the case of the &#945;-ethylsulfonylacetophenones (Ib) the gauche conformer is the more stable relative to the quasi-cis one. The &#945;-methylthio-&#945;-diethoxyphosphoryl acetophenones (IIa) present only a single stable conformer which bears the (SMe) group in a syn-clinal (gauche) geometry and the [P(O)(OEt2)] group in the quasi-periplanar (quasi-cis) geometry with respect to the carbonyl group. The &#945;-methylsulfinyl-&#945;-diethoxyphosphoryl acetophenones (IIb) display two stable conformations corresponding each one to a different diastereomer. The most stable conformer CSSS presents the methylsulfinyl group [MeS(O)] in a quasi-periplanar (quasi-cis) geometry and the diethoxyphosphoryl group [P(O)(OEt2)] in a anti-clinal (gauche) geometry relative to the carbonyl group. The second less stable conformer corresponds to the CRSS diastereomer and displays both the [MeS(O)] and the [P(O)(OEt2)] groups in a syn-clinal (gauche) geometry. The &#945;-methylsulfonyl-&#945;-diethoxyphosphoryl acetophenones (IIc) presents only a single stable conformer bearing both the [MeSO2] and [P(O)(OEt)2] groups in a sin-clinal geometry with respect to the carbonyl group. The &#945;-bromo-&#945;-ethylsulfonylacetophenones III present a single stable conformation bearing the the [SO2Et] group in a syn-periplanar (quasi-cis) geometry and the [Br] atom in a syn-clinal (gauche) geometry relative to the carbonyl group.