La thèse porte sur de nouvelles préparations et utilisations en synthèse du 4,4,6-trimethyl- 1,3,2-dioxaborinane (MPBH) comme agent d'hydroboration d'alcynes et de borylation d'halogénures d'aryle. La préparation de MPBH à partir de diverses sources de borane a été mise au point et la stabilité du réactif confirmée. L'hydroboration d'alcyne terminaux par MPBH, catalysée par le réactif de Schwartz, donne accès à des esters vinylboroniques hautement fonctionnalisés dans des conditions douces. Les produits obtenus sont stables, isolables, stockables. Ces esters vinylboroniques, par transmétallation avec le diméthylzinc et piégeage par une nitrone, conduisent efficacement à des E-allyl-hydroxylamines. Les conditions sont compatibles avec de nombreux groupes fonctionnels. Deux réactions de borylation d'halogénures d'aryle par MPBH ont été ensuite développées. Elles conduisent à d'excellents rendements en esters arylboroniques, stables et faciles à purifier, à partir d'iodures et de bromures. L'efficacité de ces esters boroniques dans des couplages de Suzuki-Miyaura a été vérifiée. Donc, l'utilisation de MPBH donne accès à des esters vinyl- et aryl-boroniques stables, faciles à purifier et à stocker ; ces esters sont des intermédiaires de synthèse très efficaces.

Zugl.: Stuttgart, Univ., Diss., 2009

Techn. Universiẗat, Diss., 2004--Berlin.

β-lactam antibiotics have been the most widely used drug of choice to combat infectious disease caused by bacteria. Unfortunately, the effectiveness of these antibiotics is drastically threatened by bacterial β-lactamases. β-lactamases are currently responsible for the resistance to most β-lactam antibiotic drugs. For decades, β-lactam β-lactamases inhibitors have been used to reduce bacterial resistance, however, in this study, we will employ the use of 1,2,4-oxadiazolidinone derivatives as a non-β-lactam β-lactamases inhibitor against TEM-1 and P99 β-lactamases. The significance of oxadiazolidinone is the prominent five-membered ring in its structure, which is configurationally stable and present in other biologically active compounds such as linezolid and avibactam. Oxadiazolidinones were synthesized in two steps procedure using nitroalkanes and benzaldehyde as starting materials to produce nitrones, which in turn undergo 1,3- dipolar cycloaddition with substituted isocyanates to give the desired 1,2,4-oxadiazolidin analogs (2a, 2b, 2c and 3). Each product was purified and characterized using 1H NMR and 13C NMR, GC-MS, IR, and UV/Vis analysis. Following their successful synthesis and structural elucidation, they were tested with TEM-1 and P99 serine β-lactamase using Nitrocefin as the substrate to ascertain their effectiveness against β-lactamase. 2a, 2b, 2c and 3 showed inhibition ranging from 12-38 %.

Le stress oxydant se définit comme un déséquilibre entre la production d’espèces oxygénées et azotés réactives et les défenses antioxydants. Ce phénomène est associé à de nombreuses pathologies telles que des maladies neurodégénératives et cardiovasculaires ou des cancers. Pour contrecarrer les dégâts causés par le stress oxydant, l’utilisation d’antioxydants synthétiques s’est avérée intéressante car il devient alors possible de modifier les propriétés physico-chimiques des antioxydants et de leur assurer un meilleur ciblage cellulaire et tissulaire. Nos travaux de recherche se positionnent dans la recherche de nouveaux agents antioxydants synthétiques. Au cours de cette thèse nous nous sommes focalisés sur l’utilisation de l’alpha-phényl-N-tert-butylnitrone (PBN), qui présente une bonne activité pharmacologique contre les dégâts liés aux radicaux libres, et qui est également largement utilisée en tant que sonde analytique pour l’identification d’espèces radicalaires par la technique de piégeage de spin couplée à la résonance paramagnétique électronique (RPE). Dans la première partie de ces travaux de thèse, nous avons tenté d’améliorer les propriétés intrinsèques de la PBN en greffant divers substituants soit sur le cycle aromatique, soit sur le groupement N-tert-butyl de la fonction nitrone. L’analyse des propriétés physico-chimiques et biologiques de ces composés nous a permis de mesurer l’impact de la nature et de la position des substituants sur les propriétés antioxydantes de la PBN. La seconde partie de ces travaux a consisté à greffer le motif PBN sur des structures moléculaires amphiphiles dérivées d’un acide-aminé. Cette deuxième partie a pour but d’améliorer l’activité biologique et la biodisponibilité des dérivés PBN. / Oxidative stress is defined as an unbalance between the production of free radicals and the antioxidant defenses. The oxidative stress state has been associated with several pathologies such as neurodegenerative and cardiovascular diseases or cancers. To prevent oxidative stress-mediated damage, the use of synthetic antioxidants is attractive as it allows to tune their physico-chemical properties as well as their cellular targeting specificity. Of particular interest is the linear alpha-phenyl-N-tert-butylnitrone (PBN) which exhibits pharmacological activity against radical-mediated pathophysiological conditions and has been widely used as analytical reagent for the identification of radical species by the spin-trapping method coupled to electron paramagnetic resonance (EPR) spectroscopy. In this thesis report, we first tried to improve the intrinsic antioxidant properties of PBN by grafting various substituents either onto the aromatic ring or the N-tert-butyl-group of the nitronyl function. The physico-chemical and biological properties of the compounds were then determined. With optimized nitrone derivatives in hand, the second part of this project consisted in improving the bioactivity and bioavailability of our nitrone agents using amphiphilic carriers or specific targeting ligands.

Le travail présenté dans ce manuscrit concerne la synthèse et une évaluation biologique de 10 nouveaux iminosucres. Les iminosucres sont une classe importante d'inhibiteurs de glycosidases (enzymes catalysant l'hydrolyse d'oligosaccharides), et l'activité inhibitrice de nos produits a été évaluée vis-à-vis d'un panel de 7 glycosidases différentes.Notre laboratoire a récemment décrit la préparation de cétonitrones cycliques polyalcoxylées à partir de cétoses tels que le D-fructose ou le L-sorbose (des sucres naturels abondants). Nous avons imaginé utiliser ces cétonitrones comme intermédiaires clés pour la synthèse de nouveaux iminosucres de structure originale, comportant un centre quaternaire en alpha de leur atome d'azote. Une partie de ce travail de thèse a consisté à améliorer la synthèse de ces cétonitrones, puis à trouver des conditions de C-vinylation diastéréosélective afin d'accéder sélectivement et efficacement à quatre pipéridines diastéréoisomères après réduction de la fonction N-hydroxylamine formée. La N-allylation de ces dernières a permis l'accès à des bis-alcénylpipéridines qui ont pu être aisément transformées en N-propylpipéridines,alpha-gem-disubstituées tétrahydroxylées après hydrogénation (des deux chaînes insaturées) et débenzylation.Les bis-alcénylpipéridines ont également été employées pour une réaction de métathèse cyclisante qui conduit au squelette indolizidine avec une double liaison en C1-C2. L'hydrogénation ou la dihydroxylation de cette double liaison, suivie par une étape de débenzylation a permis la synthèse d'indolizidines polyhydroxylées (tétra- et hexahydroxylées) inédites, substituées en jonction de cycle (position 8a). Un des composés synthétisés (une indolizidine) s'est révélé être un inhibiteur puissant et sélectif d'-glucosidases avec une concentration inhibitrice médiane de 52 nM (sur alpha-glucosidase de riz) et un mode d'inhibition peu répandu dans cette famille de molécules (inhibition non compétitive mixte). / This manuscript describes the synthesis and bioevaluation of 10 new iminosugars. Iminosugars are an important class of compounds, which can inhibit the activity of glycosidases (enzymes which catalyze oligosaccharide hydrolysis). The inhibitory activity of our products was assessed towards a panel of 7 glycosidases.Our laboratory has recently succeeded in the preparation of polyalkoxylated cyclic ketonitrones from ketoses such as D-fructose or L-sorbose (abundant natural sugars). Herein, we envisaged their utilization as precursors of new, structurally original iminosugars, bearing a quaternary center in of their nitrogen atom. We firstly improved the synthesis of these ketonitrones, and then we optimized conditions for their diastereoselective C-vinylation, in order to access selectively and efficiently four diastereoisomeric piperidines after reduction of the formed N-hydroxylamine function. The N-allylation of these piperidines gave access to the corresponding bis-alkenylpiperidines, which were readily transformed into ,alpha-gem-disubstituted tetrahydroxylated N-propylpiperidines after hydrogenation (of both unsaturated chains) and debenzylation.The bis-alkenylpiperidines were also engaged in a ring closing metathesis reaction, providing the indolizidine skeleton with a double bond in C1-C2. Hydrogenation or dihydroxylation of the latter, followed by a debenzylation step, produced original polyhydroxylated indolizidines (tetra- and hexahydroxylated), which are substituted at their ring junction (8a position). One of the synthesized compounds (an indolizidine) was found to be a highly potent and selective inhibitor of -glucosidases with a median inhibitory concentration of 52 nM (rice alpha-glucosidase) and an uncommon mode of inhibition for this class of molecules (mixed non-competitive inhibition).

The research in this thesis describes an asymmetric pericyclic cascade approach to the synthesis of a range of enantioenriched oxindoles using enantiopure oxazolidine derived nitrones and disubstituted ketenes. Chapter 1 aims to place this work in the context of the literature, describing other commonly employed or state-of-the-art asymmetric approaches to oxindoles and related compounds. Examples of where these approaches have been used successfully in the total synthesis of related indole alkaloids are also presented. The conception of this project within the group is also described alongside initial attempts to develop the first enantioselective variant of the same reaction using nitrone chiral auxiliaries. Chapter 2 details the optimisation of this asymmetric oxindole forming reaction by structural variation of the nitrone component, culminating in the preparation of an N-TIPBS nitrone based on an oxazolidine framework, which proved to be optimal for this process. Also detailed are attempts to gain insight towards the mechanism of this transformation and to understand the mode of chirality transfer. Chapter 3 details the use of the N-TIPBS nitrone scaffold as a transmitter of chiral information in the synthesis of 3-alkyl-3-aryloxindoles and spirocyclic oxindoles. Chapter 4 delineates the mechanism of this transformation as a pericyclic cascade process. The key stereo-determining features are discussed including the conformational preferences of such chiral oxazolidine derived nitrones and the influence of the N-protecting group on the stereochemical outcome. Synthetic endeavours to provide evidence as to the validity of this computational mechanistic rationale are also presented. Chapter 5 describes regioselectivity studies, and tolerance of both the racemic and asymmetric reactions to varying substitution on the nitrone N-aryl ring. Initial studies were undertaken using achiral nitrones before the interplay between regio- and stereoselectivity was explored, initially with enantiopure N-Boc Garner's aldehyde derived nitrones, and further with N-TIPBS nitrones. Chapter 6 initially describes attempts to transform this chiral auxiliary methodology into a catalytic asymmetric protocol, by investigating in situ ketene formation via various strategies including activation of carboxylic acids. Also described are investigations into related nitrone-ketenimine cycloadditions, and related [3+2] nitrone cycloadditions. Chapter 7 describes the application of this methodology toward the synthesis of compounds with biological relevance. The concise asymmetric synthesis of a Roche anti-cancer agent is outlined, as is the extension of this methodology to the synthesis of indole alkaloid-like species. Finally, the attempted application of this methodology toward the asymmetric synthesis of (+)-gliocladin C is outlined.

Zugl.: Stuttgart, Univ., Diss., 2008

Techn. Universiẗat, Diss., 2004--Berlin.

Nitrones are alternatives to azides in rapid strain-promoted 1,3-dipolar cycloadditions with cyclooctynes. To evaluate the differences between nitrones and azides we have performed kinetic studies of strain-promoted alkyne-nitrone cycloaddition (SPANC) reactions of biarylazacyclooctynone (BARAC) with various acyclic and cyclic nitrones. The reactions were conducted under pseudo first-order reaction conditions using UV-visible spectroscopy. The reactivity of the acyclic nitrones was evaluated by varying the stereoelectronic and steric character of substituents at both the α-aryl and nitrogen positions. Cyclic nitrone reactivity was assessed according to the size of the ring and additional steric and strain effects. The obtained second-order rate constants for reactions of BARAC with cyclic nitrones were found to be greater than those for acyclic nitrones. However, all nitrones employed in the kinetic studies herein displayed significantly greater reactivity than azides in the analogous cycloadditions with BARAC. It is of particular note that the five-membered cyclic nitrones showed exceptional reactivity and, if used as rapid alternatives to azides in reactions with BARAC, can increase the reaction rates by up to 50 fold. An attempt to synthesize an allylated BARAC analogue is also described; the rearrangement reaction leading to the unexpected products is reported. The reaction rate for the novel rearrangement under both neutral and acidic conditions was obtained and plausible mechanisms for formation of products are proposed. Based on the results reported herein we anticipate that development of a labelling probe based on BARAC and a five-membered cyclic nitrone would allow for significant decrease of the concentrations of labelling reagents, thereby minimizing reaction time and reagent usage in life sciences applications. Nevertheless, a possible labelling decrease due to side reactions should be given consideration for prolonged labelling.