Le couplage de Stille modifié développé par l’équipe du Pr Fouquet a été appliqué à la méthylation de nucléosides, dinucléotides et oligonucléotides dans le but de mettre au point une méthodologie de marquage d’aptamères au carbone 11 pour le diagnostic précoce de cancer par TEP. Ce couplage pallado-catalysé est basé sur l’utilisation de monoorganoétain activé par une source de fluorure permettant d’accélérer la réaction. Dans un premier temps, les essais méthodologiques ont permis de mettre au point le transfert de groupement méthyle sur différents nucléosides et un dinucléotide modifiés dans des conditions compatibles avec la durée de demi-vie du carbone 11 (20,4 min) et la nature particulière des oligonucléotides. Puis, cette méthodologie a été appliquée à des oligonucléotides modèles obtenus après incorporation des nucléosides les plus prometteurs. / The modified Stille cross-coupling developed by Pr. Fouquet’s group was applied to the methylation of nucleosides, dinucleotides and oligonucleotides in order to develop a methodology for labelling aptamers with carbon 11 for the early diagnosis of cancer by PET. This pallado-catalyzed cross-coupling is based on the use of monoorganotin activated by a source of fluoride accelerating the reaction. Initial methodology tests helped to finalize the transfer of methyl group on various nucleosides and a dinucleotide, with reaction conditions compatible with the short half-life of carbon 11 (20.4 min) and the special nature of oligonucleotides. Then, this methodology was applied to oligonucleotide models obtained after incorporation of the most promising nucleosides.

Le paludisme et la leishmaniose sont les deux plus importantes infections parasitaires au monde, en termes de mortalité. La recherche de nouvelles molécules actives contre les protozoaires responsables de ces « maladies tropicales négligées », Plasmodium sp et Leishmania sp, est un enjeu majeur de santé publique. Après une première partie dressant un état des lieux des connaissances disponibles en matière de chimiothérapie antiplasmodiale, une seconde partie s’est intéressée à l’étude des propriétés anti-infectieuses du noyau 2-trichlorométhyl-quinazoline, en introduisant en position 4 des motifs alcynyles par couplage de Sonogashira, optimisés par LC/MS. Une troisième partie a porté sur la pharmacomodulation en positions 2 et 4 du même noyau, notamment par réactions de SNAr. Une quatrième partie a consisté à rechercher le mécanisme d'action des meilleures quinazolines antiplasmodiales, via une approche de chromatographie d'affinité sur inhibiteur immobilisé. La fonctionnalisation multi-étapes des molécules les plus puissantes, par un bras espaceur, a été suivie de leur ancrage sur divers supports solides, pour constituer des matrices biocompatibles spécifiques. L’une d’entre-elles a permis la mise en évidence de 2 cibles plasmodiales protéiques originales : la GTPase Pfrab6 et la pyruvate-kinase PfpyrK1. Enfin, une cinquième partie relate la pharmacomodulation antileishmanienne du noyau 8-nitroquinoléin-2(1H)-one. Les travaux se sont intéressés à l'étude de la substitution de la position 4 de ce noyau par des réactions de SNAr, ainsi que des réactions de couplages pallado-catalysés optimisées à l’aide de la technologie micro-ondes. / Malaria and leishmaniasis are the two most important parasitic infections worldwide, in terms of mortality. Thus, the research for new molecules targeting the protozoa parasites responsible for these “neglected tropical diseases”, Plasmodium sp and Leishmania sp, constitute a major challenge in public health. Our work focused first on a current state of knowledge about antiplasmodial chemotherapy. In a view to develop the study of the anti-infective properties of the 2-trichloromethylquinazoline scaffold, a second part presented antiplasmodial pharmacomodulation at position 4 using Sonogashira cross-coupling reaction, optimized with the LC/MS technology. A third part concerned other pharmacomodulation reactions, especially at positions 2 and 4, using especially SNAR reactions. A fourth part consisted in the research of the mechanism of action of the best antiplasmodial quinazolines by using the affinity chromatography on immobilized inhibitor approach. The multi-step functionalization of the most potent derivatives by a spacer side chain was followed by their anchoring onto various solid supports, so as to generate different biocompatible specific matrices. One of them, put in contact with a parasitic lysate, allowed the identification of two original plasmodial targets: the GTPase Pfrab6 and the pyruvate-kinase PfpyrK1. Finally, a fifth part presented the antileishmanial pharmacomodulation of the 8-nitroquinolin-2(1H)-one scaffold, especially at position 4 of the quinoline ring, involving SNAr reactions (with amines, phenols or thiophenols) or pallado-catalyzed coupling reactions (in particular Suzuki-Miyaura), some of them being optimized under microwave irradiation.

Ce travail de thèse est consacré à la synthèse et l’évaluation biologique de nouveaux nitromidazoles à potentialités anti-infectieuses. Dans les trois premiers chapitres, nous avons abordé les propriétés biologiques des 5-nitroimidazoles, et la synthèse de nouveaux composés fonctionnalisés en positions 2 et 4 dans le but d'améliorer l'activité sur les souches résistantes au métronidazole, le 5-nitroimidazole de référence, tout en contrôlant au mieux la mutagénicité. Nous avons développé une méthode de couplage régiosélectif de Suzuki-Miyaura en position 4 du 2,4-dibromo-1-méthyl-5-nitro-1H-imidazole, suivi d’un deuxième couplage de Suzuki-Miyaura ou de Sonogashira par méthodologie « one-pot » séquentielle en position 2. Cette méthodologie nous a permis d’obtenir 30 nouveaux composés qui ont été testés pour leur propriétés antibactériennes et antiparasitaires. Une dizaine de composés ont été synthétisés par méthodologie TDAE sur le 4-[4-(chlorométhyl)phényl]-1,2-diméthyl-5-nitro-1H-imidazole. Dans le dernier chapitre, nous avons initié un travail de pharmacomodulation en série imidazooxazole, motif bien connu pour ses propriétés antituberculeuses et antileishmaniennes. Nous avons présenté la synthèse et l’évaluation biologique de dérivés 5-nitroimidazooxazoles et 7-nitro-2,3-dihydroimidazo[5,1-b]oxazoles. La synthèse de dérivés 6-nitroimidazooxazoles fonctionnalisés en position 5 est en cours de développement et nous avons présenté quelques essais de CH-arylation sur le 2-méthyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole. / We have developed in this work the synthesis and the biological evaluation of novel nitromidazoles with anti-infectious potentialities. In the first three parts, we discussed the biological properties of 5-nitroimidazole scaffold, and the synthesis of new compounds functionalized at 2- and 4-position in order to improve the activity on metronidazole-resistant strains, while controlling mutagenicity. We developed a regioselective Suzuki-Miyaura cross- coupling reaction at 4-position of 2,4-dibromo-1-methyl-5-nitro-1H-imidazole, followed by a second Suzuki-Miyaura or Sonogashira cross-coupling reaction at 2-position by a "one-pot" sequential process. This methodology has enabled us to obtain 30 new products which were tested for their antibacterial and antiparasitic properties. Twelve compounds were synthesized by TDAE methodology on {4- [4- (chloromethyl) phenyl]} -1,2-dimethyl-5-nitro-1H-imidazole. In the last part, we initiated a work of pharmacomodulation in imidazooxazole series, scaffold well-known for its antituberculous and antileishmanial properties. We have described the synthesis and the biological evaluation of 6-functionalized 5-nitroimidazooxazole and 7-nitro-2,3-dihydroimidazo [5,1-b]oxazole derivatives. We have presented some CH-arylation assays on 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole to obtain 5-functionalized 6-nitroimidazooxazole derivatives.

Ces travaux de thèse traitent de la synthèse et de la fonctionnalisation d’hétérocycles azotés catalysées par les métaux de transition. La première partie de ce projet a été consacrée à la mise en place d’une méthode simple et efficace pour la N-cyclopropylation de différents composés azotés. A partir de l’acide cyclopropylboronique, en présence de sels de cuivre et dans des conditions de couplage oxydant, une grande variété de composés azotés ont pu être N-cyclopropylés. Cette méthode permet une nouvelle voie d’accès aux substrats N-cyclopropylés.La deuxième partie de ces travaux de thèse porte sur l’étude de la synthèse de benzimidazole. Ces hétérocycles azotés ont pu être obtenus à partir d’amidines grâce à une séquence réactionnelle faisant intervenir une réaction de N-arylation suivi d’une cyclisation via la fonctionnalisation d’une liaison C-H.La troisième partie de ce manuscrit se focalise sur la synthèse de pyrroles. Cette famille de composés est réputée pour son abondance dans les molécules biologiquement actives. Nous avons développé une réaction séquentielle monotope, permettant la synthèse de N-H pyrroles poly-fonctionnalisés via la formation d’un énaminone, catalysée par de l’indium (III), suivi d’une étape d’hétéroannulation catalysée par du palladium.Enfin, la dernière partie de ce projet scientifique décrit notre approche vers la synthèse totale d’un alcaloïde : la (-)-norsuavéoline. L’originalité de notre approche est basée sur la synthèse, dans un premier temps, du noyau pyridinique de la molécule à partir de l’acide L-(-)-glutamique, pour finir par la formation tardive du noyau indolique. Jusqu’à maintenant, nous avons développé et optimisé la synthèse de la pyridine. Des études sont toujours en cours au laboratoire afin de former la partie indolique et de terminer cette synthèse. / These scientific project deals with synthesis and functionalization of nitrogen heterocycles catalyzed by transition metals. The first part of this project was devoted to the development of a simple and efficient reaction for the N-cyclopropylation of various nitrogen compounds. From cyclopropylboronic acid under copper oxidative coupling conditions, a wide variety of nitrogen compounds have been N-cyclopropylated. This method allows a new access to N-cyclopropylated substrates.The second part of this work deals with benzimidazoles synthesis. These nitrogen heterocycles have been obtained from amidines through a sequence involving a N-arylation reaction followed by cyclization via a C-H bond functionalization.The third part of this manuscript focuses on pyrroles synthesis. Pyrroles are known for their abundance in biologically active molecules. We have developed a new sequential one-pot procedure for poly-functionalized N-H pyrroles synthesis. Through a enaminone formation catalyzed by indium (III), followed by a palladium catalyzed heteroannulation, various N-H pyrroles have been synthesizedThe final part of this scientific project describes our approach to total synthesis of an alkaloid: the (-)-norsuavéoline. The specificity of our approach was based on the formation of pyridine ring in the beginning of the synthesis and a late formation of indole ring. To date, we have developed and optimized the pyridine synthesis from L-(-)-glutamic acid. Studies are ongoing in the laboratory to obtain the indole part and complete the synthesis of this natural product.

Im ersten Teil der Arbeit wird die Synthese neopentyl- und neosilylsubstituierter Phosphane zur Verwendung als Liganden in katalytisch aktiven Palladiumkomplexen beschrieben. Die Aktivität wurde in der Suzuki-Miyaura Kreuzkupplungsreaktion getestet. Während die neosilylsubstituierten Phosphane 2:1 Addukte (5b und 5d) mit geeigneten Palladiumsalzen bilden, welche moderate Katalyseaktivität zeigen, untergehen die neopentylsubstituierten Komplexe schnelle Cyclometalierungsreaktionen in Gegenwart von Basen und bilden die katalytisch wenig aktiven Palladacyclen (6a, 6e, and 6g). Die deaktivierende Cylometallierung konnte durch Darstellung der Palladiumcomplexe ausgehend von Pd(cod)Cl2 in Abwesenheit von Basen vermieden werden. Die erhaltenen 2:1 Phosphaneaddukte zeigten deutlich verbesserte Aktivität. Daraus wurde geschlossen, dass die Cyclomettalierung als Nebenreaktion eine wichtige Deaktiverungsmöglichkeit darstellt, diese Überlegung veranlasste uns Trialkylphosphane mittlerer Größe, mit Substituenten die nur schwer eine Cyclometallierungen eingehen können zu testen. Die Verwendung der Phosphoniumsalze 4h (R = Cy, R‘ = neopentyl) und 4m (R = iPr, R‘ = CH2Cy) führt zu höheren Aktivitäten in der Suzuki-Miyaura Kreuzkupplung, als bestes Katalysatorsystem hat sich die Kombination aus Pd2(dba)3 oder Pd(OAc)2 und entsprechendem Phosphoniumsalz ergeben. Im zweiten Teil dieser Arbeit werden Synthesen zu neuen biphenylbasierten Diphosphanen (70, 71, 76, and 77) vorgestellt. Die Palladiumkomplexe wurden ebenfalls auf ihre Eignung als Katalysatoren in palladiumkatalysierten Suzuki-Miyaura Kreuzkupplungen getestet und zeigen für diese Klasse von Komplexen gute Aktivität. Das Tetraphosphan 82 wurde für die Synthese des zweikernigen Palladium(II)-komplex 83 eingesetzt. Durch die Koordination des D2h-symmetrischen Tetraphosphanes an die Palladiumatome wird die Symmetrie des Moleküls erniedrigt und folglich erhält man den formal D2-symmetrischen Komplex 83. / In the first part of this thesis, the synthesis and catalytic activity of neopentyl and neosilyl substituted phosphine palladium complexes is described. The complexes have been tested in the Suzuki-Miyaura cross-coupling reaction. Whereas the neosilyl substituted phosphines form 2:1 adducts (5b and 5d) with Palladium salts which showed moderate activity, the neopentyl complexes quickly undergo cyclometallation in presence of bases to form Palladacycles (6a, 6e, and 6g) which showed only moderate catalytic activity. Cyclometallation could be avoided by the preparation starting from Pd(cod)Cl2 in the absence of bases. The obtained 2:1 phosphine adducts showed superior activity. We concluded that cyclometallation process is an important deactivation pathway, this prompted us to test trialkyl phosphine ligands with medium size but substituents not reliable to cyclometallation. We have been pleased to find that 4h (R = Cy, R‘ = neopentyl) and 4m (R = iPr, R‘ = CH2Cy) showed good activity in the Suzuki-Miyaura cross-coupling reaction. The best results have been obtained by in situ preparation of active catalyst from Pd2(dba)3 or Pd(OAc)2 and the appropriate phosphonium salt. In the second part of this thesis, the first synthesis of a new family of biphenyl based bisphosphine ligands (70, 71, 76, and 77) has been reported. Their palladium complexes were successfully tested as catalyst in the Suzuki cross-coupling reaction. Within the class of bisphosphine based palladium complexes they show good activity in Suzuki-Miyaura cross-coupling reaction. Systematically, was expanded our synthesis strategy and we were able to introduce the first synthesis of a highly symmetric 2,2',6,6'-tetraphosphinobiphenyl. Tetraphosphine 82 was used as ligand in a dinuclear palladium(II) complex 83. Upon complexation the D2h symmetric 2,2’,6,6’-tetraphosphine lead to a chiral D2 symmetric complex 83.

We describe the regioselective prenylation of 3-bromocarbazole by palladium(0)-catalysed cross coupling with a prenylstannane or a prenylboronate. The procedure is applied to the synthesis of precursors for biologically active carbazole alkaloids.

The advent and proliferation of planar technologies for power converters are driven in part by the overall trends in analog and digital electronics. These trends coupled with the demands for increasingly higher power quality and tighter regulations raise various design challenges. Because inductors and transformers constitute a rather large part of the overall converter volume, size and performance improvement of these structures can subsequently enhance the capability of power converters to meet these application-driven demands. Increasing the switching frequency has been the traditional approach in reducing converter size and improving performance. However, the increase in switching frequency leads to increased power loss density in windings and core, with subsequent increase in device temperature, parasitics and electromagnetic radiation. An accurate set of reduced-order modeling methodologies is presented in this work in order to predict the high-frequency behavior of inductors and transformers. Analytical frequency-dependent expressions to predict losses in planar, foil windings and cores are given. The losses in the core and windings raise the temperature of the structure. In order to ensure temperature limitation of the structure is not exceeded, 1-D thermal modeling is undertaken. Based on the losses and temperature limitation, a methodology to optimize performance of magnetics is outlined. Both numerical and analytical means are employed in the extraction of transformer parasitics and cross-coupling. The results are compared against experimental measurements and are found to be in good accord. A simple near-field electromagnetic shield design is presented in order to mitigate the amount of radiation. Due to inadequacy of existing winding technology in forming suitable planar windings for PCB application, an alternate winding scheme is proposed which relies on depositing windings directly onto the core. / Master of Science

No description available.

3,5-Dibromo-2-aminobenzamide was reacted with 1,3-cyclohexanedione derivatives in the presence of iodine as catalyst in toluene under reflux to afford novel 6,8-dibromo-2-[3-(2´-alkyl-1´,2´,3´,4´-tetrahydro-6´,8´-dibromo-4´-oxoquinazoline-2yl)propyl]quinazolin-4(3H)-ones in high yields. Suzuki-Miyaura cross-coupling of the latter with arylboronic acids in the presence of Pd(PPh3)2Cl2–Xphos catalyst complex and K2CO3 as a base in dioxane-water mixture (3:1, v/v) afforded the corresponding polyaryl-substituted bis-heterocycles in a single step operation. The resultant compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques, as well as mass spectrometry. The electronic absorption and emission properties of these polyaryl-substituted bis-heterocycles comprising 2,3-dihydroquinazolin-4(1H)-one and quinazolin-4(3H)-one moieties linked by a flexible carbon chain were measured in dimethylsulfoxide (DMSO) and acetic acid by means of UV-Vis and fluorescence spectroscopic techniques. The absorption spectra of the resultant polyaryl-substituted bis-heterocycles showed blue-shift in acetic acid and red-shift in DMSO, while their emission spectra are blue-shifted in DMSO and red-shifted in acetic acid. The 4-methoxy groups on aryl-substituents caused red shift on π‒π* transition of the aryl-substituents. Moreover, it was also observed that as the propyl linkage becomes more substituted, the absorption and emission intensities decrease. / Chemistry / M. Sc. (Chemistry)

Chemical modification of proteins is critical for many areas of biochemistry and medicine. Several methods for site-selective protein modification are reported in this Thesis that are useful in accessing both natural and artificial protein architectures. Multiple, complementary methods for the conversion of cysteine to dehydroalanine are described. Dehydroalanine is used as a general precursor to several post-translational modifications and glycosylation, polyprenylation, phosphorylation, and lysine methylation and acetylation are all accessible. These modifications and their mimics were explored on multiple proteins, including histone proteins. Unnatural modifications were also explored. The first examples of olefin metathesis and Suzuki-Miyaura cross-coupling on protein substrates are reported. Allyl sulfides were discovered to be remarkably reactive substrates in olefin metathesis, allowing use of this reaction in water and on proteins. For Suzuki-Miyaura cross-coupling, a new catalyst is described that is fully compatible with proteins. Both olefin metathesis and cross-coupling allow the formation of carbon-carbon bonds on proteins. The prospects of these transformations in chemical biology are discussed. Finally, a novel strategy is reported for the installation of natural, unnatural, and post-translationally modified amino acid residues on proteins. This technology relies on addition of carbon radicals to dehydroalanine. This method of "chemical mutagenesis" is anticipated to complement standard genetic manipulation of protein structure.