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De par les propriétés uniques de l'atome de fluor, les molécules fluorées sont très appréciées dans la conception de nouvelles molécules biologiquement actives en chimie pharmaceutique et en agrochimie. Ainsi, de nombreuses études ont porté sur le développement de réactions de fluoro-fonctionnalisation performantes de Csp2 et plus particulièrement sur l'introduction directe du groupement CF3. Etonnamment, peu d'attention a été accordée à la fonctionnalisation directe de Csp2 par le groupement CF2CO2Et alors que ce motif est très attractif du fait de son fort potentiel de post-fonctionnalisation. Aussi, nous décrivons dans ce manuscrit le développement d'une méthodologie originale pour l'introduction directe et sélective du groupement CF2CO2Et sur des dérivés vinyliques et aromatiques enrichis en électrons. Notre méthode, basée sur l'utilisation de catalyseurs au cuivre et de BrCF2CO2Et, qui est un réactif commercial, a été appliquée avec succès à un large panel de dérivés dihydropyraniques, glycosidiques, énamidiques, benzofuraniques et furaniques. De plus, les résultats préliminaires sur les dérivés de l'anisole et de l'aniline sont prometteurs. Cette méthodologie représente le premier exemple de réaction d'éthoxycarbonyldifluorométhylation directe et non radicalaire de Csp2 et permettrait d'accéder aisément à des molécules originales à fort potentiel biologique. En outre, les études mécanistiques supportent un probable cycle catalytique de type Cu(D/Cu(III) pour cette réaction. / Due to the unique properties of the fluorine atom, fluorinated molecules are of great interest in the design of new biological active compounds in pharmaceutical and agrochemical fields. As a result, much synthetic efforts have been devoted to the development of efficient fluoro-functionalization reactions of Csp2 and particularly to the direct introduction of the CF3 group. Quite surprisingly, less attention has been paid to the direct introduction of the CF2CO2Et moiety on a Csp2 whereas this scaffold is extremely appealing due to the huge possibility of post-functionalization. Thus, we report in this manuscript the development of an original methodology for the direct and selective introduction of the CF2CO2Et group onto electron-rich vinylic and aromatic compounds. Our process, based on the use of copper catalysts and the commercially available BrCF2CO2Et, was successfully applied to a broad range of dihydropyran, glycal, enamide, benzofuran and furan derivatives. In addition, preliminary results on anisole and aniline derivatives are quite promising. This methodology represents the first example of a radical free direct ethoxycarbonyldifluoromethylation of Csp2 and affords an easy access to original fluorinated compounds with potent biological interest. Moreover, mechanistic studies support a plausible Cu(I)/Cu(III) catalytic cycle involved in this process.

Th.--Sci.--Bordeaux 1, 1981. N°: 707.

No description available.

Masters Research - Master of Philosophy (Physics) / Fluoro-deoxyglucose (FDG) labeled with fluorine-18 is commonly used in positron emission tomography (PET) imaging. PET imaging is a powerful tool used primarily in the diagnosis and management of cancer. The growth of PET has been limited partly by the difficulties associated in producing fluorine-18. This project involves a theoretical investigation of a novel method of producing fluorine-18 utilising proton generation via the 3He(d,p)4He nuclear reaction. Currently the most common method of producing fluorine-18 for PET is with a medical cyclotron that accelerates protons to mega-voltage energies. These protons are then directed onto a target rich in oxygen-18. This initiates the 18O(p,n)18F reaction to produce fluorine-18. The 3He(d,p)4He reaction, utilized for the present study, has a Q-value of 18.35 MeV and this results in protons being produced at energies similar to that produced in a medical cyclotron. This reaction was investigated as an alternative proton source for the 18O(p,n)18F reaction. The expected advantage of this method over the cyclotron is that particles need only be accelerated to keV energies rather than the tens of MeV that a medical cyclotron accelerates protons to. This is expected to significantly reduce the cost and associated size of the system. Two systems based on the 3He(d,p)4He reaction were designed and calculations were performed to determine the respective yields of fluorine-18. The first system involved separate targets for the 3He(d,p)4He and 18O(p,n)18F reactions. Helium-3 ions are initially fired onto a deuterated plastic target. A heavy-water (H2O18) target is placed immediately behind this plastic target to absorb mega-voltage protons produced by the reaction 3He(d,p)4He in the plastic. The second system involved a single, super heavy water (D2O18) target onto which helium-3 is fired so that both the 3He(d,p)4He and 18O(p,n)18F reactions can occur concurrently in the one target. The input parameters of energy and beam current for the helium-3 beam required for the 3He(d,p)4He reaction were selected on the basis of the performance of currently available ion sources and in particular the saddle-field ion source. Practical considerations such as radiation safety, target degradation and lifetime and ultra high vacuum (UHV) issues were also investigated to further determine the feasibility of the two systems. With the beam current and energy at the extreme limits of the saddle-field ion source it was calculated that insufficient fluorine-18 could be produced daily to supply a PET facility with FDG. It was also found that the high helium-3 beam currents and energy required to produce significant amounts of fluorine-18 resulted in prohibitive temperature rises in the targets that would likely result in target vaporization.

Masters Research - Master of Philosophy (Physics) / Fluoro-deoxyglucose (FDG) labeled with fluorine-18 is commonly used in positron emission tomography (PET) imaging. PET imaging is a powerful tool used primarily in the diagnosis and management of cancer. The growth of PET has been limited partly by the difficulties associated in producing fluorine-18. This project involves a theoretical investigation of a novel method of producing fluorine-18 utilising proton generation via the 3He(d,p)4He nuclear reaction. Currently the most common method of producing fluorine-18 for PET is with a medical cyclotron that accelerates protons to mega-voltage energies. These protons are then directed onto a target rich in oxygen-18. This initiates the 18O(p,n)18F reaction to produce fluorine-18. The 3He(d,p)4He reaction, utilized for the present study, has a Q-value of 18.35 MeV and this results in protons being produced at energies similar to that produced in a medical cyclotron. This reaction was investigated as an alternative proton source for the 18O(p,n)18F reaction. The expected advantage of this method over the cyclotron is that particles need only be accelerated to keV energies rather than the tens of MeV that a medical cyclotron accelerates protons to. This is expected to significantly reduce the cost and associated size of the system. Two systems based on the 3He(d,p)4He reaction were designed and calculations were performed to determine the respective yields of fluorine-18. The first system involved separate targets for the 3He(d,p)4He and 18O(p,n)18F reactions. Helium-3 ions are initially fired onto a deuterated plastic target. A heavy-water (H2O18) target is placed immediately behind this plastic target to absorb mega-voltage protons produced by the reaction 3He(d,p)4He in the plastic. The second system involved a single, super heavy water (D2O18) target onto which helium-3 is fired so that both the 3He(d,p)4He and 18O(p,n)18F reactions can occur concurrently in the one target. The input parameters of energy and beam current for the helium-3 beam required for the 3He(d,p)4He reaction were selected on the basis of the performance of currently available ion sources and in particular the saddle-field ion source. Practical considerations such as radiation safety, target degradation and lifetime and ultra high vacuum (UHV) issues were also investigated to further determine the feasibility of the two systems. With the beam current and energy at the extreme limits of the saddle-field ion source it was calculated that insufficient fluorine-18 could be produced daily to supply a PET facility with FDG. It was also found that the high helium-3 beam currents and energy required to produce significant amounts of fluorine-18 resulted in prohibitive temperature rises in the targets that would likely result in target vaporization.

Le Réacteur Nucléaire à sel fondu à spectre rapide (Molten Salt Fast Reactor, MSFR) est un concept innovant de quatrième génération développé par le CNRS depuis 2004 et actuellement étudié dans le cadre du projet européen SAMOFAR de H2020. Le MSFR fonctionne avec un combustible nucléaire liquide constitué d’un mélange de sels fluorures LiF-ThF₄-(UF₄/UF₃) (77,5-20-2,5) mol% fondus à haute température (700-900°C). Ce réacteur est particulièrement intéressant pour le cycle de combustible du thorium (²³²Th-²³³U). Ce concept propose un retraitement intégré du combustible nucléaire basé sur des méthodes pyrochimiques afin d’extraire la matière fissile et de séparer les actinides des produits de fission.Un schéma de traitement du sel combustible, proposé lors d’un précédent projet européen (EVOL, FP7), est basé sur les propriétés redox et acido-basiques des éléments produits par les réactions de fission et de capture ayant lieu dans le cœur du réacteur. La base d’évaluation de ce schéma a été dans un premier temps thermodynamique. Une validation expérimentale est actuellement en cours qui consiste à étudier le comportement chimique et électrochimique du sel fondu et des éléments qui y sont solubilisés. Les études précédentes sur les réacteurs sels fondus ne peuvent être utilisées que partiellement pour ce concept car la composition du sel du MSFR définie par le projet européen EVOL est différente en nature et composition des sels proposés jusqu’à présent pour ce type de réacteurs. Or, les coefficients de diffusion et d’activité dépendent des propriétés physico-chimiques du sel fondu (en particulier de la solvatation) et nous avons, lors d’études précédentes, montré que les propriétés de solvatation des sels fondus dépendent fortement de leur nature et de leur composition.Les objectifs de ce travail de thèse sont l’étude du mélange fondu LiF-ThF₄ et du comportement électrochimique de l’uranium et de l’iode dans ce mélange.L’étude électrochimique du comportement de l’uranium a montré la stabilité de deux espèces solubles (UF₄ et UF₃) de cet élément dans le milieu fondu et la possibilité de le réduire à l’état métallique. Ce point est d’importance car la co-existence de ces deux composés permettra de contrôler le potentiel du sel combustible dans le cœur du réacteur et de limiter les réactions de corrosion avec les matériaux de structure. Les coefficients d’activité de U(IV) et de U(III) ont été déterminés. Les valeurs obtenues montrent que la solvatation de l’uranium au degré d’oxydation (IV) par les ions fluorure est beaucoup plus importante que celle de l’uranium au degré (III), ce qui est en accord avec des observations ultérieures dans d’autres sels fluorures. Notre choix pour l’étude des produits de fission dans le sel combustible s’est porté sur l’iode. Dans le cœur du réacteur, la forme stable de l’iode est la forme halogénure soluble I- et dans le schéma général de traitement du sel combustible, il est prévu d’extraire l’iode par une étape de fluoration qui permet de produire le gaz I₂. Cette étude a montré la contribution d’une réaction chimique à l’oxydation des ions iodures en iode gazeux. Cette réaction chimique d’oxydo-réduction correspond à l’oxydation des ions iodures par l’oxygène. Cette réaction n’est expliquée que par l’existence d’un oxyfluorure de thorium soluble ThOF₂. Une efficacité d’extraction de I₂ (g) supérieure à 95 % a été obtenue par électrolyse à potentiel contrôlé. Ces électrolyses, qui simulent la fluoration, permettent de valider l’étape d’extraction de l’iode dans le schéma de traitement.Ce travail de recherche a permis d’acquérir une meilleure connaissance de la stabilité du sel et du comportement chimique et électrochimique de différents composés (U et I) dans le sel. / The Molten Salt Fast Reactor (MSFR) is an innovative concept of GEN IV developed by the CNRS since 2004. It is currently studied in the framework of the European project SAMOFAR of H2020. The MSFR operates with a liquid nuclear fuel consisting of a mixture of fluoride salts LiF-ThF₄- (UF₄ / UF₃) (77.5-20-2.5) mol% melted at high temperature (700-900° C). This reactor is particularly advantageous for the thorium fuel cycle (²³²Th-²³³U). This concept proposes an integrated reprocessing of the nuclear fuel based on pyrochemical methods in order to extract the fissile material and to separate the actinides from the fission products.A scheme for the treatment of the fuel salt, proposed in a previous European project (EVOL, FP7), is based on the redox and acido-basic properties of the elements produced by the fission and capture reactions occurring in the reactor core. The baseline for this scheme was initially thermodynamic. Experimental validation is currently under way to study the chemical and electrochemical behavior of the molten salt and the elements solubilized therein. Previous studies on molten salt reactors can only be partially used for this concept because the composition of the MSFR salt defined by the European EVOL project is different from the composition of the salts proposed up to now for this type of reactor. However, the diffusion and activity coefficients depend on the physicochemical properties of the molten salt (in particular solvation) and in previous studies we have shown that the solvation properties of molten salts are strongly dependent on their nature and their composition.The objectives of this thesis are the electrochemical characterization of the molten mixture LiF-ThF₄ and the study of the electrochemical behavior of uranium and iodine.The electrochemical study of the behavior of uranium shows the stability of two soluble species (UF₄ and UF₃) of this element in the molten medium and the possibility of its reduction to the metallic state. This point is important because the co-existence of these two compounds will make possible to control the potential of the fuel salt in the core of the reactor in order to limit the corrosion reactions with the structural materials. The activity coefficients of U (IV) and U (III) were determined. The values obtained show that the solvation of uranium to the degree of oxidation (IV) by fluoride ions is much greater than that of uranium to degree (III), which is in agreement with subsequent observations in other fluoride salts.Our choice for the study of fission products in the fuel salt has focused on iodine. In the core of the reactor, the stable form of the iodine is the soluble halide form I- and in the general scheme of treatment of the fuel salt, it is planned to extract iodine by a fluorination step in order to produce the gaseous compound I₂. The electrochemical study shows the contribution of a chemical reaction to the electrochemical oxidation of iodide ions in gaseous iodine. This redox chemical reaction corresponds to the oxidation of the iodide ions by oxygen. This reaction is explained for the existence of a soluble thorium oxifluoride ThOF₂. Extraction efficiencies of I₂ (g) greater than 95% were obtained by electrolysis at controlled potential. These electrolysis, which simulate fluorination process, make it possible to validate the method for the extraction of the iodine in the reprocessing scheme.This research has led to a better understanding of salt stability and of the chemical and electrochemical behavior of several compounds (U and I) in the molten salt.

New psychoactive substances are becoming increasingly common in many parts of the world, and some of them are marketed as “legal highs” and are produced to circumvent the drug legislation, and they come in many unregulated forms. The aim of this research was to characterize the metabolites of a new psychoactive substance and hence provide the fundamental data needed for further research of toxicity and future drug testing. The synthetic cannabinoid 4-fluoro-CUMYL-5-fluoro-PICA was incubated in cryopreserved hepatocytes for 1, 3 and 5 hour and then the formed metabolites was analyzed with an LC-QTOF-MS method, data analysis was performed by using the software MassHunter Qualitative Analysis. For 4-fluoro-CUMYL-5-fluoro-PICA a total of ten metabolites were identified, with three hydroxylations, two oxidative defluorinations to carboxylation, three oxidative defluorination and two fluoropentyl dealkylation. The metabolite with the highest intensity was oxidative defluorination.

inositol Triphosphate is a second messenger that releases calcium stored in the endoplasmatic reticulum, providing several cell responses depending on the cell where the process is done. Adenophostin A and B are two potent glyconucleotides triphosphate that were isolated from a penicillium brevicompactum culture in 1993. They are the powerful agonist described up to now for the IP3 receptor, with affinities 10-100 higher than IP3.The replacement of a phosphate group by an isoster methylencarboxilate group in biological active molecules doesn't altered the recognition of their specific receptors, being more stable to the phosphatases hydrolisis. On the other hand, the introduction of a fluorine atom in a biological active molecule involves a significant change in their activity, enhancing the stability of the nearby positions of the molecule at the same time.This thesis is the beginning of a wide investigation project where the target is synthesize different analogues of Adenophostin A. In these analogues phosphate groups have been replaced systematically by isoster methylencarboxilate groups. On the other hand, another analogue with a fluorine atom in the 2" position would be synthesized in order to determine the function of the replaced essential hydroxil group and, at the same time, enhance the neighbour glycosidic bond. First of all, we have done three different synthesis towards the glucose 3,4-dialquilated derivative. We obtain the adenosine 2'-allyl derivative in six synthetic stages. After doing a study of the glycosidic reaction with three different glycosil donors (glucose fluoride, phosphite and tricloroacethimidate derivatives), we found that the best result was with the glycosil tricloroacethimidate with tert-buthyldimethylsilil as activator. The yield of this reaction weren't brilliant, so we decide to investigate a second synthetic way, where the functionalities of the target molecule were included in the glycosil donor and acceptor before the glycosilation reaction. Firstly, the glucopyranoside with two phosphate groups in the positions 3 and 4 was synthesized, being this a new interesting way to obtain adenophostin derivatives. But it was not possible to obtain the 2'-methylencarboxilate derivative of adenosine because of an unexpected lactonization. The Selectfluor treatment of different protected glycals lead to four glycosil 2-deoxy-2-fluoro-glucopyranoside donors with estereoselectivity and yields good. The glycosilation reaction was performed with a protected adenosine derivative as glycosil acceptor, which had been synthesized before. The best result was obtained with glycosil bromide and silver triflate and silver carbonate activation system. Subsequent deprotection steps led us to a very close synthetic precursor of the target molecule. This work has opened the synthetic route to the different target molecules and, nowadays, there is another doctoral thesis which is developing this project in the laboratory. / El inostilo trifosfato (IP3) es un mensajero secundario, responsable de la liberación del calcio almacenado en el retículo endoplasmático, dando lugar a diferentes respuestas celulares en función de la célula en la cual se dé el proceso. En 1993 se aislaron de un cultivo de penicillium brevicompactum dos potentes gliconucleósidos trifosfatados, la Adenofostina A y B. Éstos son los agonistas más potentes descritos hasta el momento para el receptor específico del IP3, con afinidades 10-100 veces superiores al mismo IP3.Se ha descrito que la substitución de un grupo fosfato por un grupo metilencarboxilato isóstero en moléculas con actividad biológica no modifica el reconocimiento por parte de sus receptores específicos, siendo más estables frente la hidrólisis por parte de las fosfatasas. Por otro lado, la introducción de un átomo de flúor en una molécula con actividad biológica supone un importante cambio en su actividad, reforzando al mismo tiempo la estabilidad de las posiciones vecinas, y con ello toda la molécula.La presente tesis se encuadra dentro de un proyecto de investigación más amplio, constituyendo el punto de partida del mismo. En este proyecto se pretende, en primer lugar, sintetizar diferentes análogos de la Adenofostina A en los que se ha substituido sistemáticamente los grupos fosfatos de la molécula original por grupos metilencarboxilatos isósteros, y por otro lado introducir un átomo de flúor en la posición 2" para estudiar el grupo hidroxilo esencial que substituye y al mismo tiempo reforzar el enlace glicosídico vecinal.En primer lugar se han realizado tres aproximaciones sintéticas diferentes para obtener el derivado 3,4-dialquilado de la glucosa.Se obtenió el 2'-alil derivado de la adenosina en seis etapas sintéticas, realizándose un estudio de la reacción de glicosilación con tres diferentes dadores de glicosilo (fluoruro, fosfito y tricloroacetimidato de glicosilo derivado de glucosa). El mejor resultado fue con el tricloroacetimidato de glicosilo y triflato de terc-butildimetilsililo cómo activador.Sin embargo, el rendimiento de esta reacción no era muy bueno, así que se decidió estudiar una segunda aproximación sintética, donde la funcionalización de la molécula final estuviera incluida en el dador y aceptor de glicosilo antes de la reacción de glicosilación. Por un lado se obtuvo el glucopiranósido con los dos grupos fosfato en las posiciones 3 y 4, abriendo así una nueva vía de obtención de derivados de la adenofostina que puede resultar muy interesante. Pero no fue viable la síntesis del derivado 2'-metilencarboxilato de la adenosina porque se daba una inesperada lactonización.El tratamiento con selectflúor de un glical protegido condujo a quatro diferentes dadores de glicosilo 2-desoxi-2-flúoro-glucopiranósidos con muy buena estereoselectividad y buenos rendimientos. Se ensayo la reacción de glicosilación con un derivado de la adenosina protegido como aceptor de glicosilo, sintetizado previamente, obteniéndose un muy buen resultado con bromuro de glicosilo y triflato de plata-carbonato de plata como sistema activador. La síntesis continuó con el tratamiento de grupos protectores llevando a la obtención del precursor sintético más inmediato de la molécula objetivo.El trabajo ha abierto las rutas sintéticas para obtener las diferentes moléculas objetivo y actualmente se está continuando la síntesis en el laboratorio dentro de otra tesis doctoral.

S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to produce both adenosine and L-homocysteine and is a feedback inhibitor of S-adenosyl-L-methionine (SAM). Nucleoside analogues bearing an alkenyl or fluoroalkenyl chain between sulfur and C5′ utilizing Negishi coupling reactions were synthesized. Palladium-catalyzed cross-coupling between the 5′-deoxy-5′-(iodomethylene) nucleosides and alkylzinc bromides gives analogues with the alkenyl unit. Palladium-catalyzed selective monoalkylation of 5′-(bromofluoromethylene)-5′-deoxy-adenosine with alkylzinc bromide afford adenosylhomocysteine analogues with a 6′-(fluoro)vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases. Stannydesulfonylation reaction is a critical step in the synthesis of E-fluorovinyl cytidine (Tezacitabine) a ribonucleoside reductase inhibitor with a potent anticancer activity. The synthesis involves the removal of the sulfonyl group by a radical-mediated stannyldesulfonylation reaction using tributyltin hydride. In order to eliminate the toxicity of tin, I developed a radical-mediated germyldesulonylation utilizing less toxic germane hydrides. Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)-methylene]uridine and adenosine derivatives with tributyl- or triphenylgermane hydride effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxynucleoside derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'-[(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)-methylene-5'-deoxy nucleosides with NIS or NBS provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively. Radical-mediated thiodesulfonylation of the readily available vinyl and (α-fluoro) vinyl sulfones with aryl thiols in organic or aqueous medium to provide a bench and environmentally friendly protocol to access (α-fluoro)vinyl sulfides were developed. Methylation of the vinyl or (α-fluoro)vinyl phenyl sulfide gave access to the corresponding vinyl or (α-fluoro)vinyl sulfonium salts. These sulfonium ions were tested as possible methyl group donors during reactions with thiols, phenols or amino groups which are commonly present in natural amino acids.