<p>Molecular recognition via noncovalent interactions plays a key role in many biological processes such as antigen-antibody interactions, protein folding, the bonding and catalytic transformation of substrates by enzymes, etc. Amongst these noncovalent interactions, electrostatic interactions, hydrogen bonding, π-π interactions, and metal-to-ligand bonding are the most prominent. Exploring noncovalent interactions in host-guest systems that range from small hydrocarbon systems to more complex systems is the main motivation of this thesis. The present study involves the design, synthesis and characterization of clip-shaped molecules as host structures, and an examination of their binding properties with a variety of guests using NMR spectroscopy. </p><p>Several clips with a hydrocarbon or glycoluril backbone were synthesized. The binding of cations to small, hydrocarbon-based clips suggests that binding is enhanced by the rigidity and cooperativity between the two sidewalls of the clip. Binding is also very much dependant on the solvent properties. </p><p>Glycoluril-based clips built with aromatic sidewalls provide a deep cavity for binding guest molecules. The binding properties of these hosts were studied with several guests such as cations, Lewis acids and Lewis bases. Lewis basic binding sites in the acenaphthene-terminated clip were dominating in guest binding. Complexation-induced conformational changes in the wall-to-wall distance were observed for this clip.</p><p>In contrast, for a porphyrin-terminated clip with metal centers, very strong binding to a series of Lewis basic guests of various sizes into the clip cavity was observed. Conformational locking of guests with long alkyl chains was achieved, suggesting that, this clip could be useful as a potential molecular tool for the structural characterization of acyclic molecules with several stereogenic centers. This porphyrin clip was also shown to bind substituted fullerenes in the cavity.</p>

Molecular recognition via noncovalent interactions plays a key role in many biological processes such as antigen-antibody interactions, protein folding, the bonding and catalytic transformation of substrates by enzymes, etc. Amongst these noncovalent interactions, electrostatic interactions, hydrogen bonding, π-π interactions, and metal-to-ligand bonding are the most prominent. Exploring noncovalent interactions in host-guest systems that range from small hydrocarbon systems to more complex systems is the main motivation of this thesis. The present study involves the design, synthesis and characterization of clip-shaped molecules as host structures, and an examination of their binding properties with a variety of guests using NMR spectroscopy. Several clips with a hydrocarbon or glycoluril backbone were synthesized. The binding of cations to small, hydrocarbon-based clips suggests that binding is enhanced by the rigidity and cooperativity between the two sidewalls of the clip. Binding is also very much dependant on the solvent properties. Glycoluril-based clips built with aromatic sidewalls provide a deep cavity for binding guest molecules. The binding properties of these hosts were studied with several guests such as cations, Lewis acids and Lewis bases. Lewis basic binding sites in the acenaphthene-terminated clip were dominating in guest binding. Complexation-induced conformational changes in the wall-to-wall distance were observed for this clip. In contrast, for a porphyrin-terminated clip with metal centers, very strong binding to a series of Lewis basic guests of various sizes into the clip cavity was observed. Conformational locking of guests with long alkyl chains was achieved, suggesting that, this clip could be useful as a potential molecular tool for the structural characterization of acyclic molecules with several stereogenic centers. This porphyrin clip was also shown to bind substituted fullerenes in the cavity.

Les azacycles tels que les morpholines ou les pyrrolidines, sont très répandus dans le domaine de l’organocatalyse et de la chimie médicinale. Cette thèse traitera d’analogues contraints de ces azacycles, qui peuvent moduler de par leurs structures, les propriétés de certains médicaments ou la sélectivité de certaines réactions. Le cas de l’halopéridol, qui est connu pour son activité sur les récepteurs dopaminergiques D2 et D4, est au centre de la première partie de cette thèse, dans laquelle de nouveaux analogues contraints de type 2-oxa-5-azabicyclo[2.2.2]octane ont été développés pour pallier ses problèmes de stabilité métabolique. Dans une seconde partie, la synthèse de deux nouvelles chimères morpholine-proline pontées est rapportée. Leurs structures rigides et conformationnellement verrouillées permettent aux doublets d’électrons non liants sur les atomes d'azote et d'oxygène d’être respectivement orientés dans des directions « Est-Ouest » et « Nord-Est » spatialement différentes. En combinaison avec la présence d'un acide carboxylique, les propriétés électroniques de ces composés peuvent être utiles dans le contexte de la conception peptidomimétique de composés biologiquement pertinents. Des estimations quantitatives de la basicité des atomes d'azote ont été obtenues en utilisant une analyse DFT conceptuelle. Dans la troisième partie de cette thèse, la synthèse de nouvelles pyrrolidines oxabicycliques sera développée. Les cyclopentan[c]pyrroles sont très répandus dans la littérature, et connus pour leurs propriétés analgésiques. Des dérivés fonctionnalisés en positions 4 et 5, synthétisés par Servier, ont notamment présenté de bonnes activités en tant que ligands nicotiniques 7, mais aussi des problèmes d’inhibition de hERG. Afin d’obtenir des composés moins lipophiles et donc de pallier les problèmes d’inhibition hERG, de nouveaux analogues oxygénés de type furo[2,3-c]pyrroles ont été développés par différentes voies de synthèse. Ces nouveaux composés pourront notamment être obtenus sous formes énantiomériquement enrichies, grâce à une étape clé de résolution enzymatique. La proline a été largement utilisée ces dernières années comme organocatalyseur au sein d’importantes transformations asymétriques comme les aldolisations ou les additions de Michael. Cependant, malgré le succès de ce motif, plusieurs de ses dérivés ont été rapportés dans la littérature. C’est notamment le cas des 4,5-méthanoprolines qui furent rapportées pour la première fois par Hanessian en 1997, dont l’efficacité en tant qu’organocatalyseur pour la réaction de Hajos-Parrish ainsi que plusieurs autres types de réaction fut par la suite établie. Les dernières parties de cette thèse viennent compléter ces études. La synthèse de nouvelles 4,5-ethanoprolines a été développée, ainsi que leurs utilisations comme catalyseur lors de réactions de Hajos-Parrish et d’addition catalytique asymétrique de nitroalcanes sur des énones cycliques. Une étude DFT a été effectuée afin d’expliquer l’inversion de sélectivité observée pour ces nouveaux catalyseurs lors des réactions de Hajos-Parrish, le mécanisme de formation des énamines réactives a aussi été investigué. / Azacycles such as morpholines and pyrrolidines, are very widespread in chemistry, especially in the fields of organocatalysis and medicinal chemistry. This thesis will deal with constrained analogues of those azacycles, which, depending on their structures, can modulate the properties of certain drugs or the selectivity of certain reactions. The case of haloperidol, which is known for its activity on the dopamine D2 and D4 receptors, is at the center of the first part of this thesis, in which new constrained analogs of the 2-oxa-5-azabicyclo type [2.2.2] octane have been developed to overcome its metabolic stability problems. In a second part, the synthesis of two new bridged morpholine-proline chimeras are reported. Their rigid structures allow the lone pairs on the nitrogen and oxygen atoms to be oriented in spatially different "East-West" and "North-East" directions, respectively. In combination with the presence of a carboxylic acid, the electronic properties of these compounds could be useful in the context of the design of biologically relevant peptidomimetics. Quantitative estimations of the basicity of the nitrogen atoms were obtained using DFT analysis. In the third part of this thesis, the synthesis of new oxabicyclic pyrrolidines is described. Cyclopentan[c]pyrroles are widely encountered and known for their analgesic properties. The Servier laboratories have synthesized derivatives with substituents at positions 4 and 5, exhibiting good activities as 7 nicotinic ligands, but problems of hERG inhibition. In order to obtain less lipophilic compounds and therefore overcome the problems of hERG inhibition, new oxygenated analogs of the furo[2,3-c]pyrrole type have been developed by different synthetic routes. These new compounds were obtained in enantiomerically enriched forms, using enzymatic resolution. Proline has been widely used in recent years as an organocatalyst in asymmetric transformations such as aldolizations or Michael additions The success of this motif, has inspired synthesis of derivatives, such as 4,5-methanoprolines, which were first reported by Hanessian in 1997, and shown to be effective as organocatalysts in the Hajos-Parrish and other reactions. The last parts of this thesis develop further these studies by the synthesis of new 4,5-ethanoprolines which act as a catalysts in the Hajos-Parrish reaction and the asymmetric catalytic addition of nitroalkanes to cyclic enones. A DFT study was carried out to explain the reversal of selectivity observed for the new catalysts in Hajos-Parrish reaction and to investigate formation of a reactive enamine in the mechanism.

No description available.