Julian A Cooper This work describes the functionalisation of carbon-hydrogen bonds in saturated hydrocarbons via free radical addition to fluorinated alkenes. For example, hexafluoropropene can be added to produce a mono-adduct:- A range of fluoroalkenes have been used. These adducts can be functionalised by elimination of hydrogen fluoride to give new fluoroalkenes whose chemistry has been investigated. This has resulted in new fluorinated building blocks.

The work presented investigates various aspects of glutathione-dependent electrophile metabolism in bacteria. First, we studied the response of <I>Staphyloccocus aureus</I> to the electrophile methylglyoxal. We found that under our experimental conditions, this organism is incapable of methylglyoxal metabolism by either glutatione-dependent or independent mechanisms. Glutatione was found to sensitise <I>S. aureus</I> to methylglyoxal. Furthermore, the sulphydryl group of glutathione is essential in this process. This implies that a glutathione conjugate may be involved in the increased sensitivity. Methylglyoxal does not activate K⁺ efflux from <I>S. aureus</I> cells, suggesting that the KefB K⁺ efflux system is absent from this organism. NEM activates a slow release of K⁺ indicating that the KefC system may be present. We investigated the response of <I>E. coli</I> and <I>Pseudomonas</I> sp. to the electrophilic herbicide alachlor. This compound activates a release of K⁺ from <I>E.coli</I> but not from any Pseudomona tested. K⁺ efflux is not mediated by KefB, KefC or the major mechanosensitive channels. In addition to the K⁺ efflux, alachlor stimulated an increase in the absorbance at 265 nm of media containing <I>E. coli</I>. It is not fully understood what this absorbance increase represents but it may reflect an increase in the solubility of alachlor over time. Despite its potential toxicity, alachlor did not affect the growth of either <I>E. coli</I> or <I>P. fragi</I>. However, when <I>E. coli</I> were treated with EDTA they became sensitive to alachlor. This result and data obtained using ¹⁴C-labelled alachlor indicated that alachlor does not normally enter <I>E. coli</I> cells. Finally, we investigated the response of <I>E. coli</I> expressing <I>dcm</I>A from <I>Methylophilus</I> sp. DM11 to DCM. Addition of DCM resulted in immediate cessation of growth, which was not due to formaldehyde accumulation. Cells washed free of DCM after a short incubation resume growth at the pre-addition rate, indicating DCM dehalogenation causes no permanent damage to the cell.

No description available.

The work presented in this thesis focuses on the total synthesis of (-)-6,7- Dideoxysqualestatin H5. Particular emphasis was the development of a cross- coupling strategy for direct delivery of the side chain towards the end of the synthesis. Various methods investigated to perform the key Csp3-Csp2 coupling initially led to the Fu variant of the Negishi coupling at elevated temperatures and subsequent cross- electrophile coupling at rt. Key features of the asymmetric synthesis of (-)-6,7- dideoxysqualestatin H5, include: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a Î2-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalysed cyclic carbonyl ylide formation-cycloaddition by cogeneration of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalysed Csp³-Csp² cross-electrophile coupling between tricarboxylate core and unsaturated side-chain to complete the natural product. Following completion of the natural product, further work was carried out on the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyls. The scope and limitations of reacting unsaturated tosylhydrazones with O₃ followed by Et₃N for the generation of 1,4- and 1,5-diazocarbonyl systems were explored. Tosylhydrazones, from tosylhydrazide condensation with readily available Î ́- and Îμ- unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-Îμ-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Tosylhydrazones from cyclic enones also allowed access to 1,4- and 1,5-diazocarbonyl systems using the ozonolysis-Et₃N strategy.

No description available.

Constructing C-C and C-heteroatom bonds is of the utmost importance in organic chemistry. Cross-coupling is a reaction where a transition metal catalyst facilitates the formation of a C-C or C-heteroatom bond between two coupling partners. Cross-coupling reactions are often very robust and reliable and thus have established themselves as one of the most powerful and versatile tools for the modern synthetic organic chemist. A great area of modern cross-coupling research has been the expansion of electrophiles that can participate in cross-coupling reactions. By expanding the scope of available electrophiles, one can access a greater variety of products from simpler starting materials. Esters are relatively robust scaffolds and are difficult to engage in cross-coupling reactions due to the substantial double-bond character of the C(acyl)-O bond. Developing methods to functionalize esters via cross-coupling reactions would be highly beneficial as esters are ubiquitous and readily available. The cross-coupling of phenyl esters has been relatively well established throughout the past decade. The cross-coupling of simple methyl esters largely remains elusive in the primary literature. Chapter 1 of this thesis provides a detailed literature background on the field of carboxylic acid derivative cross-coupling, with a primary focus on esters. Chapter 2 describes our efforts in discovering new methodologies for methyl ester cross-coupling reactions. We invoked the use of high throughput experimentation (HTE) studies to facilitate our search for novel methyl ester cross-coupling reactivity. Chapter 3 describes our efforts in developing an additive free, Ni-catalyzed transesterification reaction of methyl esters. The use of alcohols as nucleophilic coupling partners for methyl esters has yet to be reported. We obtained a scope of 20 isolated examples and were able to identify scaffolds that could not be tolerated under our reaction conditions. Lastly, we began preliminary reaction kinetics studies in order to gain useful mechanistic insights for methyl ester cross-coupling reactions.

La liaison halogène est une interaction intermoléculaire très directionnelle. Elle est observée dans les systèmes C-Hal•••X, où l'atome d'halogène (Hal), qui est lié à un atome de carbone, interagit avec un autre halogène (X = Hal) ou avec une base de Lewis (X = base de Lewis). L'objectif principal de cette thèse est de mieux comprendre ces interactions. Le travail présenté est consacré principalement à l'étude de la densité électronique et du potentiel électrostatique des composés halogénés par diffraction X haute résolution. Dans ce travail quatre composés chlorés, contenant des interactions Hal•••X (Hal = Cl, X = Cl, O, H, C?), ont été analysés dans leur phase cristalline pour étudier la liaison halogène. Parmi les résultats les plus importants issus de cette étude, il faut signaler la détermination expérimentale de la distribution électronique anisotrope de l'atome d'halogène. Cette anisotropie génère des régions électrophiles et nucléophiles autour du noyau de l'halogène qui sont à l'origine de l'interaction très particulière que cet atome réalise avec l'environnement moléculaire. / Halogen bonding is a highly directional intermolecular interaction. It is observed in systems C-Hal•••X, where the halogen atom (Hal) is bound to a carbon atom and interacts with another halogen (X = Hal) or a Lewis base (X = Lewis base). The main objective of this thesis is to better understand these interactions. The thesis is mainly devoted to the study of the electron density and the electrostatic potential of halogenated compounds by high resolution X-ray diffraction. In this work, four chlorinated compounds, containing interactions Hal•••X (Hal = Cl, X = Cl, O, H, C?) were analyzed in their crystalline phase to study the halogen bond. Among the most important results from this work, we report the experimental determination of the anisotropic electronic distribution of the halogen atom. This anisotropy generates electrophilic and nucleophilic regions around the halogen nucleus that are responsible for the interaction that this kind of atom establishes with the environment.

Au cours de nos différents travaux sur les réactions de cyclisations électrophiles diastéréosélectives 5-endo d’hydroxamates insaturés par l’hexafluorophosphate de bromo biscollidine (HBB). Nous avons constaté la formation d’imidates cycliques et nous avons mis en évidence un réarrangement lactames-imidates. Une fragmentation de type Beckman aboutissant à la formation d’une famille de cyano énones, anisi qu’une nouvelle formation d’imidates a été étudiée.Dans l’introduction générale, nous avons rapporté différents exemples d’halolactonisations électrophiles 5-endo et 5-exo, énantio et diastériosélectives rapportés dans la littérature, ainsi que les facteurs influençant la régio et la diastereoselectivité de ces cyclisations.Dans le premier chapitre, après un rappel bibliographique sur les différentes synthèses de lactames à partir de différents substrats par cyclisation électrophile, nous avons présenté nos propres travaux.Le traitement d’hydroxamates β, γ−éthyléniques γ-disubstitués avec de l’hexafluorophosphate de bromo bis(sym-collidine) dans du dichlorométhane aboutit à la formation de lactames et d’imidates cycliques. On a pu confirmer par des études RMN, l’existence d’un réarrangement lactame-imidate cyclique.Dans une deuxième partie, nous avons étudié la diastereosélectivité de la cyclisation. A cet effet, des hydroxamates optiquement actifs ont été synthétisés via la méthodologie développée par Evans. Dans tous les cas, un seul produit, un bromo-imidate cyclique optiquement actif est obtenu.Dans le deuxième chapitre, l’étude de la réaction de cyclisation des hydroxamates β, γ−éthyléniques γ-monosubstitués avec HBB, nous a permis de mettre en évidence une fragmentation de type Beckmann. Cette dernière est améliorée par réaction des produits de cyclisation avec de la triethylamine. On a généralisé cette fragmentation en l’appliquant à différents substrats.Enfin, dans le troisième chapitre, après une étude bibliographique sur la synthèse d’imidates et leurs utilités en synthèse organique, on a synthétisé des imidates β, γéthyléniques, afin de les utiliser comme substrats dans la réaction de cyclisation éléctrophile utilisant HBB. Dans ce cas aussi, la formation d’imines cycliques est constatée. / This work deals with the 5-endo halogeno electrophilic cyclization reactions of β,γ-ethylenic hydroxamates to give halolactames and halo cyclic iminolactones.In the first chapter, the reaction of γ-disubstituted β,γ-unsaturated hydroxamates with bis(collidine)bromine(I) hexafluorophosphate is studied. This type of reaction led mainly to the formation of bromo cyclic imidates, which were the thermodynamic products. Unsaturated cyclic imidates were then obtained by reaction with triethylamine. A lactame-iminolactone rearrangement was obtained during those reactions. In a next step we decided to study the diastereoselectivity of the reaction, using optically actif hydroxamates. In the second chapter, we decided to study the reaction of bis(collidine)bromine(I) hexafluorophosphate with γ-aryl β,γ-unsaturated hydroxamates, the corresponding bromo cyclic imidates were also obtained. However, by reaction with triethylamine, these compounds led with good yields, to the formation of 3-cyano-2-propen-1-ones by a Beckmann type fragmentation reaction. In the third chapter, the reaction of γ-mono and disubstituted β,γ-unsaturated imidates with bis(collidine)bromine(I) hexafluorophosphate is studied. The results that we obtained were not sufficient enough to understand the electrophilic cyclization mechanism of these types of substrates.

Partie 1 : De plus en plus de molécules fluorées sont utilisées dans bon nombre de domaines variés, allant des matériaux aux sciences de la vie. Ces dernières années, un intérêt croissant a émergé avec l'association du groupement CF3 avec un hétéroatome, comme OCF3 ou SCF3. Le groupement SCF3 est très intéressant à cause de son paramètre d'hydrophobie (π=1.44). Par conséquent, les composés portant ce groupement sont des cibles importantes pour de nombreuses applications, en particulier en chimie médicinale. Cependant, la majorité des précédentes méthodes décrites dans la littérature utilisent des réactifs toxiques dans des conditions drastiques. Les trifluorométhanesulfénamides (1ère et 2nde génération) ont démontré leur potentiel dans la trifluorométhylthiolation électrophile. En raison de leur réactivité intéressante, ces deux générations de réactifs stables sont maintenant dans la boîte à outils de la chimie organique pour la trifluorométhylthiolation de molécules. Partie 2 : Des aggrégats d'α-synucléine sont une caractéristique neuropathologique de nombreuses maladies neurodégénératives, notamment la maladie de Parkinson (MP) et la démence à corps de Lewy (DLB), collectivement appelés synucléinopathies. L'imagerie TEP pourrait révéler la quantité et la distribution des agrégats d'α-synucléine dans le cerveau et serait plus avantageuse à utiliser pour le diagnostic spécifique de synucléinopathies présymptomatiques à différents stades de lamaladie. Nous avons concentré nos efforts sur des dérivés de benzimidazole comme composés de petites tailles, plans et π-délocalisés pour concevoir des traceurs radioactifs des agrégats de la synucléine. Ainsi des structures assemblant des benzimidazoles, un espaceur rigide (alcyne et triazole) et enfin une autre partie aromatique ont été envisagées. Le radiomarquage pourra être effectué par une substitution nucléophile avec K18F au cours de la dernière étape. Avec cette stratégie convergente, nous pourrions avoir accès à une grande série de molécules à évaluer / Part 1 : More and more applications for fluorinated molecules are being found in various fields, from materials to life sciences. In recent years, a growing interest has emerged in the association of the trifluoromethyl group with heteroatoms such as CF3O or CF3S. The CF3S moiety is of particular interest, because of its high hydrophobicity parameter (π=1.44). Consequently compounds bearing this group are important targets for various applications, in particular in medicinal chemistry and agrochemistry. However, the majority of previous methods described in the literature use toxic reagents under harsh conditions. Trifluoromethanesulfenamides (1st and 2nd generation) have demonstrated their potential in the electrophilic trifluoromethylthiolations. Because of their interesting reactivity, these two generations of shelf-stable reagents are now in the toolbox of organic chemists for the trifluoromethylthiolation of molecules, providing a convenient method to pursue less toxic pathways. Part 2 : α-synuclein aggregation is a neuropathological hallmark of many neurodegenerative diseases including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), collectively termed synucleinopathies. PET imaging can reflect the amount and distribution of alpha-synuclein aggregates in the brain and would be advantageous to use for specific diagnosis of synucleinopathies in presymptomatic stages of disease. We focused our interest onto benzimidazole derivatives as small, planar and -delocalized compounds to design radiotracers of synuclein aggregates. Compounds based on the association of benzimidazole moiety, rigid linker (alkyne and triazole) and another aromatic part have been designed. The radiolabeling could be performed by nucleophilic substitution with K18F during the last step. With this convergent strategy, we could have acces to a large series of molecules to be evaluated

No description available.