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Cette thèse décrit le développement de nouvelles méthodes de catalyse à l’or et au cuivre pour la synthèse de composés hétérocycliques et de produits trifluorométhylés.Dans un premier temps, une synthèse d’allènes trifluorométhylés par catalyse à l’or a été développée, dont l’étape clé est un transfert d’hydrure 1,5. Cette méthode donne accès de manière efficace et sélective à une large gamme d’allène perfluoroalkylés dont le potentiel synthétique a également été démontré.Le pouvoir catalytique de l’or a alors été utilisé dans une synthèse de 2H-1,3-oxazines reposant sur une cyclisation de type 6-endo d’azido alcynes. Cette méthode donne accès dans des conditions très douces à une gamme sans précédent d’oxazines polysubstituées avec d’excellents rendements.Dans un dernier temps, une méthode d’hydrofonctionnalisation radicalaire d’alcènols catalysée au cuivre. La stratégie impliquée repose sur une abstraction d’hydrogène 1,5, dans laquelle un groupement benzyloxy joue le rôle de donneur d’hydrogène. / This manuscript presents the development of gold- and copper-catalyzed methods for the synthesis of heterocyclic compounds and trifluoromethylated products.Firstly, a gold-catalyzed synthesis of trifluoromethyl allenes was developed, relying on a 1,5 hydride shift. This method allows to access, in a very efficient and selective way, a large range of perfluoroalkylated allenes, of which the synthetic potential was also demonstrated.Afterwards, the catalytic power of gold was then used in a synthesis of 2H-1,3-oxazines, relying on a 6-endo type cyclization of azide-yne substrates. This methods allows to access, in very mild condition, an unprecedently large range of polysubstituted oxazines in excellent yields.Finally, a method for the copper-catalyzed radical hydrofunctionalization of alkenols was developed. The strategy involved relies on a 1,5 hydrogen abstraction, in which a benzyloxy moiety plays the role of the hydrogen donor.

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Thesis (Ph. D.)--University of Wisconsin--Madison, 1975. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 135-144).

L’objectif de nos travaux consiste en la préparation de C-glycosides et d’aminoacides glycosylés trifluorométhylés dans le but d'obtenir des structures biologiquement actives stabilisées. L'intérêt des C-glycosides est lié à leur stabilité autorisant une pharmacocinétique plus appropriée pour un usage thérapeutique. La 1ière partie de mon travail a été de créer une liaison C-C en position anomérique d'un sucre par différentes méthodes d’alkylation, d’alcynylation à l’indium et par la réaction de Réformatsky. Ensuite après avoir fonctionnalisé les C-glycosides synthétisés, une étude tournée vers la synthèse d’aminoacides C-glycosylés par le biais d’alkylations énantiosélectives a été réalisée. Ensuite nous avons étudié la synthèse d’aminoacides glycosylés stabilisés par l’introduction d’un groupement trifluorométhylé en une position stratégique. D’abord nous avons étudié la synthèse d’aminoacides N-glycosylés obtenus par la réaction entre un aminoacide trifluorométhylé et un sucre. Le groupe fluoré, en  de l’azote, diminue la basicité de l’amine et empêche sa protonation. Ainsi, l’hydrolyse du lien anomérique est très défavorisée. Plusieurs conditions réactionnelles ont été étudiées. Le milieu acide protonique a montré des résultats encourageant notamment entre le 2-déoxy-glucose et un dipeptide trifluorométhylé. Ensuite nous avons travaillé sur la synthèse de O-glycosides. 2 stratégies ont été développé à partir d’un sucre trifluorométhylé. D’abord l’éthérification de Williamson a été étudié entre un sucre trifluorométhylé et différents dérivés halogénés. Cette voie a donné des résultats satisfaisant avec des dérivés halogénés linéaires uniquements. Puis la réaction de Mitsunobu a été étudié entre un sucre trifluorométhylé et différents alcools. La réaction donne des résultats variés dépendant de l’alcool. Cette voie nous a aussi permis de synthétiser des aminoacides O-glycosylés trifluorométhylé en utilisant la sérine comme alcool. / The aim of our work consists in the preparation of C-glycosides and trifluorinated glycosylated aminoacids in order to obtain biogically active structures. The interest of such C-glycosides, is due to its stability. It allows a better pharmacokinetics to a therapeutic use. The first part of my work was to create a C-C bond at the anomeric position of a carbohydrate by different methods such as alkylation, alcynylation and Reformatsky reaction. Then, after functionalized these C-glycosides, a study on C-glycosylated aminoacids synthetized by an enantioselectiv alkylation way was made. The second part of my work was to synthesized stabilized glycoaminoacidsby the introduction of a trifluoromethylated group at a strategic position: at the anomeric position of the carbohydtare or at  position of the anomeric position of the carbohydtare. We first studied the synthesis of N-glycosides with a trifluoromethylated group at  position of the anomeric position of the carbohydtare. This strategy is based on the reaction of a protected sugar with a trifluoromethylated amine catalysed by an acid. Then we studied the synthesis of O-glycoaminoacids with a trifluoromethylated group at the anomeric position of the carbohydtare. Two strategies have been developed. The first one is the alkylation of Williamson. The second one is the reaction of Mitsunobu.

The studies described herein relate to the co-ordination chemistry of l,3,5-tris(trifluoromethyl)benzene, Ar(^F)H. The unique combination of steric bulk and a highly electron-withdrawing nature found in the a- bound Ar(^F) ligand has already been exploited to stabilise a variety of unusual main group compounds including the surprisingly air- and moisture-stable diphosphene Ar(^F)P=Par(^F). Other examples are discussed in the introductory chapter, as is the increasingly active area of diphosphene research. Chapter 2 describes the synthesis and structural characterisation of six early σ-Ar(^F) transition metal complexes, Mo(N(^t)Bu)(_2)(Ar(^F))2, Cr(NAd)(_2)(Ar(^F))(_2), [Mo(NAr)(_2)(Ar(^F))Cl-LiCl(dme)](_2), V(Ar(^F))(_2)Cl(thf), V(Ar(^F))(_3)-O -Li(thf)(_3) and Cr(Ar(^F))(_2)(PMe(_3))(_2). The first five of these compounds exhibit the rare phenomenon of weak metal-fluorine interactions, which is discussed in terms of several structural factors such as tilting of the aryl ring towards the direction of the M-F interaction The co-ordination chemistry of the diphosphenes Ar(^F)p=PArF, Ar*P=PAr* and Ar*P=PArF (Ar* = 2,4,6-(^t)BuC6H3) is reported in chapter 3. Ar(^F)p=Par(^F) is shown to displace olefins from a bis(imido)molybdenum centre to generate complexes such as Mo(NR)(_2)(PMe)(_3)(Ti2-ArFp=PArF) (R = tBu, 2,6-iPr2C6H3). The crystal structure of Mo(NtBu)2(PMe)3(Ti2- ArFp=PArF) has been elucidated. Related investigations have focused on the co-ordination mode of the diphosphenes Ar*P=PAr* and Ar*P=PArFwith [Pt(PEt3)Cl2]2/ and a variety of Til-complexes has been spectroscopically observed. The development of phosphorus based analogue of the industrially important olefin metathesis reaction is detailed in chapter 4. The reaction of ArPCl2, [Ar = Ar(^F), Ar* and 2,6-(CF3)2-C6H3 (Ar(^f1)] with the halide abstractor W(PMe3)6 leads to the generation of ArP=PAr via a postulated [W]=PAr phosphinidene intermediate. The unsymmetrical diphosphene ArFp=PAr* has been synthesised analogously from a mixture of ArFPCl2 and Ar*PCl2 with W(PMe3)6- When Ar is small (2,4,6-iPr3C6H2, 2,4,6- Me3C6H2), ArPCl2 reacts with W(PMe3)6 to give three-membered tricyclophosphanes, [ArP](_3) π-bound complexes of the Ar(^F)H ligand have been synthesised via metal vapour synthesis experiments, carried out in collaboration with Prof. F.G.N. Cloke at Sussex University. Chapter 5 describes the preparation of the bis-arene complexes M(T|6-ArFH)2 (M=Cr, V, Nb) and Ru(Ti6-ArFH)(Ti4-ArFH).Full experimental details and characterising data for chapters 2-5 are collected in chapter 6.

Chapter 1 provides a general introduction on the role of bioisosterism of fluorine aiming to improve the pharmacokinetics properties of lead compounds. GABAA receptors specifically, synaptic GABAA receptors, extrasynaptic GABAA receptors and GABAA rho receptors are then presented. Compounds that exhibit agonist and partial agonist effects at these receptors are also discussed. The applications of some compounds as GABAA receptor PET radiotracers are also described. Chapter 2 details the synthesis of two fluorinated analogues of muscimol, fluoromuscimol and trifluoromethylmuscimol. Fluoromuscimol was obtained from the lithiation of a Boc-protected isoxazole followed by in-situ fluorination using NFSI, whereas trilfuoromethylmuscimol was obtained from the coupling of a heteroaryl iodide with trifluoromethylcopper species, which was generated in-situ from MFSDA in the presence of CuI. Fluoromuscimol and trifluoromethylmuscimol were assessed on human synaptic, (α₁β₂γ₂), extrasynaptic, (α₄β₂δ) and ρ₁ subunits of the GABAA receptor. The biological results show that fluoromuscimol exhibits greater maximum response in comparison to GABA at the extrasynaptic GABAA receptors (α₄β₂δ), but lower overall potency, whereas trifluoromethylmuscimol was inactive at all the tested GABAA receptors. Chapter 3 discusses the synthesis and late stage fluorination of diaryliodonium salts as precursors to fluoromuscimol. Application of iodonium salts as precursors for nucleophilic fluorination in PET studies are also highlighted. The last part of this chapter focuses on the synthesis of iodomuscimol as a potential alternative SPECT radiotracer to fluoromuscimols in probing GABA binding sites on GABAA receptors.

Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides.  With the goal of developing new human-safe, resistance-breaking insecticides we have explored several classes of acetylcholinesterase inhibitors.  In vitro assay studies have shown that trifluoromethyl ketones (TFK's) are potent inhibitors of An. gambiae AChE (AgAChE), that inhibit the enzyme by making a covalent adduct with the catalytic serine of the enzyme.  However research in the Carlier group has shown that trifluoromethyl ketones bearing benzene and pyrazole cores have shown very little toxicity to An. gambiae, perhaps due to hydration and rapid clearance. Focus was directed towards synthesis of oximes, oxime ethers, and hydrazones as potential prodrugs to prevent immediate hydration and reach the central nervous system.  The synthesis of various oximes, oxime ethers, and hydrazones has been shown to give cimpounds toxic to Anopheles gambiae within 3- to 4-fold of the toxicity of propoxur. However, thus far we have not been able to link the toxicity of these compounds to a cholinergic mechanism.  Pre-incubation studies suggest that significant hydrolysis of these compounds to TFKs does not occur or 22 h at pH 7.7 or 5.5.   Future work will be directed towards TFKs that have better pharmacokinetic properties.  Work will also be directed at synthesis of oxime and hydrazone TFK isosteres to determine the mechanism of action of these compounds. / Master of Science

L'introduction d'atomes de fluor sur des composés organiques peut avoir une forte influence sur les propriétés physico-chimiques, ainsi que sur l'activité biologique de ces composés. Par ailleurs, des amines possédant un groupement trifluorométhyle en peuvent présenter un réel intérêt en chimie médicinale, de par la grande présence des amines dans les composés bioactifs. Dans un tel contexte, nous avons développé deux nouvelles voies de synthèses permettant la formation de 2 (trifluorométhyl)pipéridines et 2-(trifluorométhyl)azépanes par agrandissement de cycle de pyrrolidines trifluorométhylées obtenues à partir de la L-proline. Les 2 (trifluorométhyl)pipéridines énantio-enrichies substituées en C3 ont été formées via un aziridinium intermédiaire, et les 2 (trifluorométhyl)azépanes substitués en C4 ont été obtenues via un azétidinium intermédiaire. La régiosélectivité de l'attaque nucléophile sur l'aziridinium ou l'azétidinium intermédiaire est induite par la position du groupement trifluorométhyle (CF3). Les pipéridines et les azépanes ainsi synthétisés, ont été obtenus avec une très bonne diastéréosélectivité. / The incorporation of fluorine atom in organic compounds can have a profound impact on the physico-chemical properties and, therefore, on the biological activity of the molecules. Thus, amines possessing an α-trifluoromethyl substituent are of great importance in medicinal chemistry, as amines are present in a variety of bioactive compounds. In this context, we have developed a new access to 3 substituted 2-(trifluoromethyl)piperidines and 4 substituted 2 (trifluoromethyl)azepanes by stereospecific ring expansion of trifluoromethylated pyrrolidines synthesized from L-proline. 3 Substituted 2 (trifluoromethyl)piperidines were obtained from trifluoromethylated prolinol via an aziridinium intermediate, and 4-substituted 2 (trifluoromethyl)azepanes were formed from pyrrolidines via an azetidinium intermediate. The regioselective attack of the nucleophile on the aziridinium or azetidinium intermediate, is induced by the position of the trifluoromethyl group (CF3). The resulting piperidines and azepanes are produced with good diastereoselectivity.