La fonctionnalisation par voie catalytique de substrats naturels a été menée dans le but d’accroître l’activité biologique reconnue de la molécule naturelle de départ ou de découvrir de nouvelles activités. Des réactions catalytiques telles que l’hydroformylation et l’alcoxycarbonylation mettant en jeu le monoxyde de carbone et catalysées par des complexes du rhodium et du palladium ou encore la réaction de cycloisomérisation catalysée par des complexes d’or ou du platine ont déjà permis d’accéder sélectivement à de nouvelles molécules intéressantes. Dans une première partie nous nous sommes intéressés à l’huile essentielle du cèdre de l’atlas (cedrus atlantica) qui est constituée d’une partie hydrocarbure et d’une partie oxygénée. Notre étude s’est focalisée sur la partie oxygénée de l’huile essentielle du cèdre de l’atlas qui est composée de deux cétones isomères, les Z- et E-α- atlantones. La réaction de cyclocarbonylation des alcools allyliques dérivés des α-atlantones a été étudiée. Cette réaction catalysée par des complexes du palladium permet d’obtenir des lactones à 5 et à 6 chainons. Plusieurs systèmes catalytiques de type [PdCl2L2]/SnCl2.2H2O ont été testés, lors de cette étude et nous avons montré que la regiosélectivité de la réaction peut être contrôlée par la nature du ligand utilisé. Ainsi, les ligands monophosphines favorisent la formation des lactones à 6 chainons obtenues sous forme de deux diastéréoisomères et les ligands diphosphines favorisent la formation de celles à 5 chainons obtenues sous forme de quatre diastéréoisomères. Ces lactones sont complètement caractérisées par RMN 1D et 2D et la spectrométrie de masse. Des monocristaux ont été obtenus et analysés par diffraction des rayons X. Dans une deuxième partie, la synthèse d’aldéhydes par réaction d’hydroformylation à partir de l’estragol, un allylbenzène extrait de l’huile essentielle de l’estragon, a été étudiée en présence du système catalytique [Rh(cod)(OMe)]2/ligand phosphole. Ainsi, nous avons évalué l’activité de plusieurs ligands phospholes dans cette réaction d’hydroformylation. Tous les ligands phospholes testés se sont révélés actifs et chimiosélectifs dans la réaction d’hydroformylation d’estragol pour donner majoritairement l’aldéhyde linéaire correspondant. Dans une étude préliminaire, nous avons étudié la réaction de cycloisomérisation d’énynes oxygénés dérivés d’α-atlantones catalysée par des complexes d’or ou du platine. / The catalytic functionnalisation of the natural substrates have been developped to increase their own biological activity or to give them new biological properties. The reactions such as hydroformylation, alkoxycarbonylation and cyclocarbonylation in presence of carbon monoxide catalyzed by rhodium or palladium complexes or cycloisomerisation catalyzed by gold or platinium complexes give an access to new interesting molecules with high selectivity. In first part we have been interested in study of the essential oil of the Atlas Cedar (Cedrus Atlantica). We focused in this study on the oxygenated fraction, which contains the two sesquiterpenic ketone,isomers Z- and E-α-atlantone. Starting from allylic alcohols derived from α-atlantone, the cyclocarbonylation reaction catalyzed by palladium complexes have been investigated. This reaction provide a mixture of five and six membered ring lactones with excellent conversion and excellent chemioselectivity. Different catalytic systems [PdCl2L2]/SnCl2.2H2O or [Pd(OAc)2]/L have been studied. The regiochemical control depends on the nature of the ligand L. The monophosphine ligands favor the formation of the six-membered ring lactones obtained as two diastereomers, while the diphosphine ligands allow the formation of the five- membered ring lactone obtained as four diastereomers. These new lactones were fully characterized by 1D and 2D NMR and mass spectrometry. Monocrystals of the six- and five-membered ring lactones suitable for X-ray diffraction analysis have been obtained. In a second part the hydroformylation reaction of estragol, a natural allylbenzene extracted from the essential oil of estragon, have been studied with the catalytic system [Rh(cod)(OMe)]2/phospholes. All the phosphole ligands show good activities and chemoselectivities in the hydroformylation of estragol and affords the linear aldehyde corresponding as a major product. In a preliminary study, we have investigated the cycloisomerisation reaction of o-tethered enynes derived from α-atlantones catalyzed by gold or platinum complexes.

Hormis la préparation de l’acide salicylique et de l’urée, peu de tentatives ont été réalisées jusqu’à présent pour promouvoir la formation de liaisons C–C et C–N à partir du CO₂. Cette thèse présente de nouveaux procédés catalytiques permettant la formation de molécules organiques azotées grâce à la création de liaisons C–N et C–C par transformation catalytique du CO et du CO₂. Les cibles retenues sont les amides ainsi que les alkylamines qui sont essentiels en chimie organique fine et sont souvent d’origine pétrosourcés. Dans un premier temps, la synthèse d’amide par carbonylation formelle de la liaison C–N d'amine sera étudiée grâce à des catalyseurs à base de métaux carbonyles. Dans un second temps, des procédés d’homologation des amines seront décrits grâce à l’utilisation de catalyseurs métalliques. La première stratégie impliquera l’utilisation de catalyseur de cobalt, en présence de CO et de silanes et permettra l’homologation sélective des liaisons N-méthyle en N-éthyle sous de faible pression de CO (P = 8 bar) et jusqu’au N-pentyle sous de fortes pressions. Dans un second temps, l’utilisation d’un catalyseur de ruthénium en présence d’un gaz de synthèse (CO/H₂) nous permettra de démontrer la possibilité de l’homologation de la diphénylamine. Enfin, la compréhension de ce système nous permettra de transposer cette réaction à l’utilisation du CO₂ comme substitut du CO. / Apart from the preparation of salicylic acid and urea, few attempts have been made so far to promote the formation of C-C and C-N bonds from CO₂. This thesis describes new catalytic processes allowing the formation of nitrogen compounds through the creation of C-N and C-C bonds by catalytic transformations of CO and CO₂. The chosen targets are the amides and the alkylamines which are essential in fine organic chemistry and yet prepared from petrochemicals. In a first part, the amide synthesis by formal carbonylation of the C-N bond HAS been studied using catalysts based on first row transition metal carbonyl complexes. In a second part, methods enabling homologation of amines are described through the use of metal catalysts. The first strategy involved the use of cobalt catalysts in presence of CO and hydrosilanes which allow the selective homologation of N-methyl into N-ethyl derivatives under a low CO pressure (P= 8 bar). Also, the alkyl chain can be homologated under elevated CO pressures to reach N-pentyl derivatives. Finally, the use of a ruthenium catalyst in presence of a synthesis gas (CO / H₂) allowed us to demonstrate the possibility of the homologation of the diphenylamine. Understanding this system led to translate the amine homologation with syngas to the use of CO₂ as a substitute for CO.

Le présent projet de maîtrise s’intitule Conversion du méthanol en éther di-méthylique (DME) et de ce dernier en acétate de méthyle. Échelonné sur 24 mois, le travail a été scindé en deux parties importantes : la synthèse du DME par déshydratation du méthanol; la carbonylation du DME en acétate de méthyle. La caractérisation de ces deux systèmes catalytiques a pour but d’être une alternative à la synthèse industrielle des acétyles passant par la carbonylation du méthanol sous l’action de l’iodure de méthyle comme co-catalyseur avec le rhodium. L’impact de l’iodure de méthyle sur le plan économique fait l’objet du plusieurs efforts de développement dont une des avenues est celle passant par le DME. L’optimisation de la première réaction s’est conduite autour du choix de catalyseur, de la température, de la pression et des conditions hydrodynamiques. Ceci a permis de caractériser les performances de la réaction dont les trois principaux indicateurs choisis sont la conversion, la sélectivité et le taux de production. L’alumine-[gamma] comme catalyseur dans un réacteur à lit fixe permet d’atteindre une conversion du méthanol totalement sélective au DME de 80% à une LHSV (liquid hour space velocity) de 11h[indice supérieur -1] et ce à 330 °C et 2514 kPa. Le taux de production maximal calculé a été de 7.35 {gDME / gcat. [indice supérieur Xh]}. La carbonylation du DME s’est faite sous l’action de la zéolithe Mordénite et également dans un réacteur à lit fixe. Le ratio molaire des réactifs CO:DME, la température et la pression et ont été l’objet de l’étude paramétrique. À une GHSV[indice inférieur CO] de 1062 h[indice supérier -1], un ratio CO:DME de 10:1, une température de 230 °C et une pression de 3204 kPa (450 psig), il a été possible d’atteindre une conversion du DME en acétate de méthyle de 9%. Les résultats expérimentaux de chacune de ces deux réactions ont été analysés par rapport aux modèles théoriques d’équilibre thermodynamique ainsi qu’aux valeurs expérimentales répertoriées dans la littérature scientifique.

In the first part of the thesis, the aim was to devise a new simple catalytic system based on palladium to allow insertion of carbon monoxide in the presence of an alcohol into unsaturated systems with retention of the double bond to give an unsaturated ester. The process is known as oxidative carbonylation. To allow the process to become catalytic, the palladium needs to be reoxidised in situ. Optimal conditions for the catalytic system were developed and a wide range of substrates have been examined. Simple terminal alkenes and alkenes bearing functional group have been successfully carbonylated (yield 16%-87%). The method was applied to the synthesis of a known pharmaceutical intermediate. The aim of the second part was to develop an efficient system for the intramolecular oxidative amination of unsaturated hydrazine carboxylates to form novel vinyl oxazolidines. After optimisation of the reaction conditions, the scope and limitations of the reaction were established. Attempts were also carried out to develop an enantioselective version of the cyclisation. The method was applied to the synthesis of a known intermediate in a sequence towards (-)-kainic acid thus accomplishing a formal total synthesis of this compound.

Oxidative stress can result in changes to many biomolecules and also affect their activities. We are interested in protein carbonylation, a type of unnatural oxidation which has been associated with numerous degenerative disease states and is also a consequence of the natural aging process. Protein carbonyls are stable species, but countless analytical barriers exist in terms of their identification. Thus, the main goal of this work was to develop and optimize analytical methods that could be used to help us better understand which, where, and how proteins are being carbonylated. Initial studies involved method validation for carbonylating, tagging, and enriching the model protein human serum albumin (HSA). We have developed a reproducible method of producing carbonylated protein in vitro in which HSA is treated with acrolein to carbonylate cysteines, histidines, and lysines. Protein carbonyls are compatible with various affinity labels and enrichment techniques. We strived to learn more about the efficiencies of various biotin affinity labels and avidin enrichment techniques using quantitative assays and mass spectrometry. Results showed a preference for different affinity labels based on their chemical properties and suggested that monomeric columns are selective for particular peptides. Most recently, method development and validation work was done involving a cleavable biotin tag that enables both enrichment and identification of protein carbonylation modification sites. This affinity tag offered the highest labeling efficiency of all tags tested in the past and greater coverage of modification sites than biotin hydrazide reagents. We applied our analytical methods to two sets of human blood samples. The first sample set was plasma taken from chronic kidney disease (CKD) patients. No carbonylation patterns were elucidated, but this project marked the beginning of blood analyses in which existing protocols were adapted to blood samples. The second sample set was serum/plasma taken from patients with traumatic injuries. We effectively applied our analytical methods to these sample sets and were able to visualize and quantitate temporal protein carbonylation patterns via Western blotting and iTRAQ-based mass spectrometry experiments. ProteoMiner experiments proved successful in that we were able to identify a larger and more diverse amount of carbonylated proteins via mass spectrometry.

Accumulated evidence indicates oxidative stress plays important roles in disease and aging. Under oxidative stress, lipid peroxidation (LPO) leads to reactive carbonyl species (RCS) that can modify a wide range of biomolecules including protein, DNA and carbohydrate. In this dissertation, we investigate the modification of two model proteins, human serum albumin (HSA) and aconitase (ACO), by the LPO-relevant a, b-unsaturated aldehydes, acrolein (ACR) and 4-hydroxy-2-nonenal (HNE). The investigation is focused on the characterization and quantification ACR and HNE addition to the model proteins. A correlation between HNE modification and ACO activity is also determined. These results provide insights into the impact of oxidative stress at the molecular level and are relevant to aging and disease states. We finally investigate protein carbonylation in ischemic mouse heart mitochondria, and develop a quantitative method for detecting carbonylated protein in this system. The research is based on liquid chromatography/mass spectrometry (LC/MS), Western Blots, and enzymatic assay.

It is well established that free radical mediated oxidative stress plays a critical role in aging and age-related diseases. Among the post-translational protein modifications, carbonylation has attracted a great deal of attention due to its irreversible and irreparable nature. Despite the fact that protein carbonylation is associated with a series of physiological and pathological processes, there are still issues to be clarified such as why certain proteins are more vulnerable to modification, what are the locations of the protein modifications, and how does the nature of the oxidant affect the preferred site of modification. In this study, we will seek an answer to these questions and examine the global effect of oxidative stress on protein abundance. The study embraces three distinct specific aims. In the first, methods are developed for identifying sites of protein carbonylation. In the second specific aim, these methods are used to identify carbonylaytion sites in model proteins subjected to chemical oxidants. In the third aim, the focus is on a model organism, C. elegans, subjected to paraquat-induced oxidative stress. This is exploratory work and mass spectrometry is used to assess the impact of oxidative stress on the mitochondrial proteome.

This thesis comprises three projects on the theme of catalytic C(sp3)–H carbonylation of secondary aliphatic amines. Chapter 2 describes the development of a general methyl C–H carbonylation of secondary aliphatic amines to form synthetically useful β-lactam building blocks. Amines exhibiting a range of substitution patterns around the nitrogen functionality, and bearing a wide variety of functional groups, could be tolerated in the reaction. The desired β-lactam products were delivered in high yields, with excellent selectivity observed for the β-C–H position. Computational studies suggested that the reaction proceeds through a novel carbamoyl cyclopalladation pathway, which is distinct from classical cyclopalladation. The subsequent discovery of a selective methylene C–H carbonylation of α-tertiary amines (ATAs) is discussed in chapter 3. By employing the ATA motif, remarkable levels of selectivity for β-methlyene C–H bonds were achieved, even in the presence of traditionally more reactive methyl C–H and C(sp2)–H bonds. Once more, the reaction was found to exhibit excellent functional group tolerance, delivering highly functionalised β-lactam building blocks in high yields and selectivity. Chapter 4 presents work towards the total synthesis of the marine natural product (±)cylindricine C. The key step of this synthesis was demonstrated to proceed in good yield and excellent selectivity.

Thèse de doctorat : Chimie organique et macromoléculaire : Lille 1 : 2001. / Bibliogr. p. 195-205.

Esta tesis se ha centrado en el estudio de las reacciones de carbonilación de norborneno catalizada por metales. Este sustrato puede ser funcionalizado a través de este proceso, empleando sistemas catalíticos y condiciones de reacción adecuadas, en productos intermedios con aplicación en la industria de perfumes y química fina. En este trabajo se han llevado a cabo estudios en la reacción de metoxicarbonilación de norborneno catalizada por paladio empleando ligandos monofosfina y difosfina logrando un importante control de la selectividad hacia la formación del producto deseado. Algunos aspectos mecanísticos de esta reacción han sido desarrollados empleando métodos de resonancia magnética nuclear que incluyen experimentos de alta presión. Finalmente, se ha estudiado la reacción de hidroformilación asimétrica de norborneno catalizada por complejos de rodio usando ligandos difosfito derivados de carbohidrato. Estos sistemas catalíticos han mostrado alta actividad y selectividad con excesos enantioméricos moderados. / This thesis focuses on the study of the metal-catalyzed carbonylation of norbornene. The transformation of this substrate in esters and aldehydes offers potential applications for the production of valuable compounds in fine chemistry and perfumery industry. In this work we have performed studies on the palladium-catalyzed methoxycarbonylation of norbornene bearing monodentate and bidentate phosphine ligands achieving an important control of the selectivity towards the formation of the desired product. Mechanistic aspects of this reaction have been developed using nuclear magnetic resonance methods, including High-Pressure techniques. Finally, we have studied the asymmetric rhodium-catalyzed hydroformylation of norbornene using chiral 1,3-diphosphites ligands derived from carbohydrates. These catalytic systems have shown high activities with excellent stereoselectivities and moderate enantioselectivities.