Dresden, Techn. Univ., Diss., 2001. / Computerdatei im Fernzugriff.

Dresden, Techn. Univ., Diss., 2001. / Computerdatei im Fernzugriff.

No description available.

Activated cyclopropanes have been extensively used in synthetic chemistry as precursors for cycloaddition reactions. The rationale behind this is their ability to undergo ring-opening when activated by a Lewis acid, this can be enhanced further by the presence of a carbocation stabilising group like electron-rich aromatics. The stabilised dipole formed after ring opening can be trapped with suitable electrophiles such as imines and aldehydes via a [3+2] cycloaddition reaction. This results in the synthesis of pyrrolidines and tetrahydrofurans in excellent yields but moderate diastereoselectivity. Similarly, 6-membered heterocycles can be formed via a [3+3] cycloaddition reaction of activated cyclopropanes with nitrones. Now to extend the scope of the methodology, a [3+3] dipolar cycloaddition has been developed using activated 2,3 disubstituted cyclopropane diesters to access a range of highly functionalised oxazines in moderate to good yields (50-75%) and with reasonable diastereoselectivity. The use of activated symmetrical disubstituted cyclopropanes afforded the desired oxazines in a regio- and diastereocontrolled manner, while the use of unsymmetrical cyclopropanes significantly reduced the diastereoselectivity of the reaction. The stereochemistry outcome of the reaction developed was determined by nOe analyses and X-ray diffraction structures could be recorded in some examples. A new methodology has also been developed to gain access to novel N-heterocyclic- and phenol- substituted cyclopropanes in one step from the corresponding cyclopropene via a conjugated addition.

Techn. Universiẗat, Diss., 2007--Darmstadt.

Techn. Universiẗat, Diss., 2001--Dresden.

La nature contient un grand nombre de molécules naturelles à visée thérapeutique. Depuis plusieurs années, la chimie médicinale ne cesse de s’en inspirer afin de développer de nouvelles thérapies pour améliorer le quotidien des personnes atteintes de certaines pathologies. Cette thèse traitera de la conception de molécules hétérocycliques comme inhibiteurs d’enzymes et médiateurs d’interactions protéine-protéine. Les molécules bioactives sont la pierre angulaire de la chimie thérapeutique. Depuis la découverte de l’Aspirine en 1899, elles n’ont cessé d’impacter la société à plusieurs niveaux et ont contribué à l’amélioration de la qualité de vie des patients. Il y a cependant, plusieurs pathologies pour lesquelles il n’existe à ce jour aucun remède, ce qui met en exergue les limitations de la chimie médicinale et implique le développement de nouvelles stratégies thérapeutiques. La stéato-hépatite non-alcoolique ou NASH (Non-Alcoholic Steatohepatitis) est une maladie caractérisée par une accumulation de graisses dans le foie, menant à la formation de tissus cicatriciels sur le foie. Ces derniers altèrent les fonctions hépatiques du foie et peuvent mener à la cirrhose si aucun traitement n’est administré. A ce jour, il existe aucun médicament pour guérir de NASH. La serine-thréonine kinase 25 (STK25) est une sérine-thréonine kinase, qui serait impliquée dans le développement de la maladie de NASH. Ainsi, le premier chapitre de cette thèse rapporte la synthèse de triazolo-oxazines comme inhibiteurs potentiels de STK25. Il s’agit de la première approche inhibitrice rapportée dans la littérature. Des tests biologiques ont été effectués et la modélisation moléculaire des triazolo-oxazines a été réalisée. Face au problème de pharmacorésistance et l’absence de remèdes pour certaines maladies, il y a un besoin urgent pour de nouvelles stratégies thérapeutiques est présent. Depuis quelques années, les dégradeurs ciblés de protéines suscitent un engouement. En effet, ces derniers induisent la dégradation de protéines défectueuses en recrutant les complexes de ligase E3. Cette stratégie vient pallier l’absence de sites de liaison, caractéristique de plusieurs protéines impliquées dans le développement de cancers. Parmi les dégradeurs de protéines, il y a les agrafes moléculaires et les PROTACs. Dans le second chapitre de cette thèse, la synthèse de molécules hétérocycliques comme ligand de la ligase E3 DCAF15 pour le développement éventuel de nouveaux PROTACS sera rapportée. L’outil de modélisation moléculaire a permis la sélection de molécules indoliques comportant le motif -lactame et pyrrolidine . Bien qu’ils aient été synthétisés comme un mélange racémique, des tests pour la synthèse asymétrique de ces derniers seront également discuter. Les maladies infectieuses ravagent les pays de l’Amérique latine et l’Afrique subsaharienne. Les ressources insuffisantes, les conditions sanitaires et l’instabilité des régimes politiques rendent difficile l’administration et l’acheminement de traitements. Parmi ces maladies infectieuses, il y a la leishmaniose, la trypanosomiase humaine africaine et la trypanosomiase humaine américaine lesquelles sont toutes causés par des protozoaires. Dans le troisième chapitre, des molécules hétérocycliques, comportant le motif imidazolo-oxazine seront synthétisés comme candidats potentiels pour le traitement de ces maladies infectieuses. / Nature has provided an infinite number of bioactive small molecules for therapeutic benefits. For many years, it has inspired medicinal chemistry to develop new therapies to improve the well-being of humankind. This thesis will be about the conception of heterocyclic small molecules as enzyme inhibitors and protein-protein interaction mediators. Small molecules are the cornerstone of therapeutic chemistry. Since the discovery of Aspirin in 1899, small molecules have had a significant impact on several levels and have contributed to the improvement of quality of life. Nonetheless, many diseases still have no remedy; hence there exists a need for new therapeutic strategies. Non-alcoholic steatohepatitis, (NASH) is a disease characterized by a buildup of fat in the liver, leading to the formation of scars on the liver. These scars will affect the different functions of the liver and can even lead to cirrhosis if not treated. Up until now, there is no drug for NASH. STK25 is a serine-threonine kinase, suspected to be involved in the mechanism of action of NASH. The first chapter in this thesis involves the synthesis of triazolo-oxazines as potential STK25 inhibitors for NASH treatment. It is the first example of an enzymatic approach for NASH treatment. The synthesis of potential inhibitors was designed based of molecular modeling of other inhibitors targeting CDK. In a second chapter, a new approach of small molecules degraders that recruits E3 ligases complexes for the degradation of protein is described. Among the small molecule degraders, there are molecular glues and PROTACs. This chapter will describe the design and the synthesis of heterocyclic molecules as DCAF15 ligands for the eventual development of new PROTACs. Molecular docking has been useful for the selection of the - lactams et pyrrolidines small molecules. Infectious diseases have tremendous consequences in Latin America and Africa. The lack of means, health hazards and the political instability of governments make difficult the supply and administration of treatments. Among the infectious diseases, there are Leishmaniasis, human African trypanosomiasis, human American trypanosomiasis, which are caused by bacteria. In the third chapter, imidazolo-oxazine small molecules will be synthesized as potential candidates for the treatment of these parasitic infections.

Synthesis of a polymer with benzoxazine units in the main chain backbone by a trifunctional phenol, a difunctional amine, and paraformaldehyde was achieved. Thermal, mechanical and spectroscopic characterization and the viscosity properties of the synthesized polymer were studied. In the first step of this study, a fast and feasible method for the synthesis of the benzoxazine precursors was developed since some methods mentioned in the literature about the synthesis of the benzoxazine derivatives last long time. The second step was to polymerize the benzoxazine precursors thermally. The curing of benzoxazine precursors was done via ring opening polymerization at 150 oC and a final polymerization was observed at about 250 oC. 1H NMR, 13C NMR and FT-IR spectroscopies revealed the characteristic peaks for the formation of benzoxazine ring. Among them, 13C NMR gave important clue on the formation of the benzoxazine. The thermal characterization of the benzoxazine precursors and the polymers indicated that the ring opening polymerization of these precursors started at around 110 oC and a final polymerization was about at 230 oC. Differential Scanning Calorimetry thermograms of the polybenzoxazine indicated a secondary transition at around 270 oC. An onset decomposition of the benzoxazine oligomers started around 100 oC in Thermal Gravimetric Analysis thermograms performed under N2 atmosphere and two major maximum weight losses were observed at 273 oC and 439 oC. However, polybenzoxazine showed a starting degradation at about 260 oC and the maximum weight loss temperatures were seen at 296 oC and 465 oC. Viscosity variation of the reaction mixture was studied by Ubbelohde Viscometer at 30 oC. Viscosity results indicated that the increase in the intrinsic viscosity of the reaction mixture till 50th minute and followed by a decrease due to possible branching and the intra-crosslinking of the benzoxazine oligomers. Mechanical properties of the polymer films, prepared by compression molding at 180 0C, were investigated. Test results showed that low tensile strength whereas comparatively high elongation.

6H-1,2-Oxazines were functionalised at the C-C double bond by 1,3-dipolar cycloadditions and halogenation reactions. The reactions were carried out with 6-ethoxy-3-phenyl-6H-1,2-oxazine, 6-ethoxy-3-ethoxycarbonyl-6H-1,2-oxazine and 6-ethoxy-3-trifluoromethyl-6H-1,2-oxazine. The cycloadditions of 6H-1,2-oxazines were performed with nitrile oxides, nitrile imines, nitrile ylides, diazoalkanes, azomethine ylides and a nitrone. High diastereoselectivity was observed, induced by the steric hindrance of the ethoxy group at the 6H-1,2-oxazines. The cycloadditions occur with high regioselectivity. In addition, the constitutions of the bicycles were predicted by the frontier-orbital model using the semi-empirical PM3-method, and subsequently compared with those of the isolated products. The low strength of the N-O bond of 1,2-oxazines can often be used for mild hydrogenolysis reactions, but the reductions of the biheterocycles obtained here were not selective and led in most cases to decomposition. For the derivatives of 3-ethoxycarbonyl-3a,7a-dihydro-4H-isoxazolo[5,4-d]-1,2-oxazine the conversion of the five-membered ring into cis-configurated α-hydroxynitriles (saponification and decarboxylation) was demonstrated. Finally, the 4-chloro- and 4-bromo-6H-1,2-oxazines were prepared in good yields. Investigations with palladium catalysed coupling reactions were initiated. The halogen of 4-bromo-6H-1,2-oxazines was substituted by the phenyl group of benzolboronic acid using the Suzuki method. / Im Verlauf dieser Arbeit wurden 6H-1,2-Oxazine an der C-C-Doppelbindung durch 1,3-dipolare Cycloadditionen und Halogenierungen funktionalisiert. Als Modellsubstrate für die 6H-1,2-Oxazine wurden 6-Ethoxy-3-phenyl-6H-1,2-oxazin, 6-Ethoxy-3-ethoxycarbonyl-6H-1,2-oxazin und 6-Ethoxy-3-trifluormethyl-6H-1,2-oxazin eingesetzt. Die 6H-1,2-Oxazine konnten bei den Cycloadditionen erfolgreich mit Nitriloxiden, Nitriliminen, Nitrilyliden, Diazoverbindungen, Azomethinyliden und einem Nitron umgesetzt werden, wobei die Ausbeuten stark variieren. Die Reaktionen verliefen mit hoher Regioselektivität. Durch die sterische Abschirmung der Ethoxygruppe an den 6H-1,2-Oxazinen (Briefumschlagskonformation der 6H-1,2-Oxazine und pseudoaxiale Ausrichtung der Ethoxygruppe) wurde ebenfalls eine hohe Diastereoselektivität beobachtet. Ergänzend wurden die Konstitutionen der Cycloaddukte mit der semiempirischen PM3-Methode auf Basis des Grenzorbitalmodells vorhergesagt und mit denen der isolierten Biheterocyclen verglichen. Die dargestellten Cycloaddukte sollten unter Ausnutzung der geringen Bindungsenergie der N-O-Bindung hydrogenolysiert werden. Die Reduktionen waren jedoch im allgemeinen nicht selektiv, so daß die Umsetzungen zu komplexen Produktgemischen führten. Für die 3-Ethoxycarbonyl-3a,7a-dihydro-4H-isoxazolo[5,4-d]-1,2-oxazinderivate wurde ferner der Abbau des Fünfringes (Verseifung und Decarboxylierung) in cis-konfigurierte α-Hydroxynitrile beschrieben. Die 4-Chlor- und 4-Brom-6H-1,2-oxazine konnten in guten Ausbeuten unter milden Reaktionsbedingungen dargestellt werden. Anschließend wurden mit den bromierten Verbindungen verschiedene palladiumkatalysierte Kupplungsreaktionen getestet. Durch die Methode von Suzuki konnte das Halogen der 4-Brom-6H-1,2-oxazine durch den Phenylrest der Benzolboronsäure substituiert werden.

6H-1,2-Oxazines were functionalised at the C-C double bond by 1,3-dipolar cycloadditions and halogenation reactions. The reactions were carried out with 6-ethoxy-3-phenyl-6H-1,2-oxazine, 6-ethoxy-3-ethoxycarbonyl-6H-1,2-oxazine and 6-ethoxy-3-trifluoromethyl-6H-1,2-oxazine. The cycloadditions of 6H-1,2-oxazines were performed with nitrile oxides, nitrile imines, nitrile ylides, diazoalkanes, azomethine ylides and a nitrone. High diastereoselectivity was observed, induced by the steric hindrance of the ethoxy group at the 6H-1,2-oxazines. The cycloadditions occur with high regioselectivity. In addition, the constitutions of the bicycles were predicted by the frontier-orbital model using the semi-empirical PM3-method, and subsequently compared with those of the isolated products. The low strength of the N-O bond of 1,2-oxazines can often be used for mild hydrogenolysis reactions, but the reductions of the biheterocycles obtained here were not selective and led in most cases to decomposition. For the derivatives of 3-ethoxycarbonyl-3a,7a-dihydro-4H-isoxazolo[5,4-d]-1,2-oxazine the conversion of the five-membered ring into cis-configurated α-hydroxynitriles (saponification and decarboxylation) was demonstrated. Finally, the 4-chloro- and 4-bromo-6H-1,2-oxazines were prepared in good yields. Investigations with palladium catalysed coupling reactions were initiated. The halogen of 4-bromo-6H-1,2-oxazines was substituted by the phenyl group of benzolboronic acid using the Suzuki method. / Im Verlauf dieser Arbeit wurden 6H-1,2-Oxazine an der C-C-Doppelbindung durch 1,3-dipolare Cycloadditionen und Halogenierungen funktionalisiert. Als Modellsubstrate für die 6H-1,2-Oxazine wurden 6-Ethoxy-3-phenyl-6H-1,2-oxazin, 6-Ethoxy-3-ethoxycarbonyl-6H-1,2-oxazin und 6-Ethoxy-3-trifluormethyl-6H-1,2-oxazin eingesetzt. Die 6H-1,2-Oxazine konnten bei den Cycloadditionen erfolgreich mit Nitriloxiden, Nitriliminen, Nitrilyliden, Diazoverbindungen, Azomethinyliden und einem Nitron umgesetzt werden, wobei die Ausbeuten stark variieren. Die Reaktionen verliefen mit hoher Regioselektivität. Durch die sterische Abschirmung der Ethoxygruppe an den 6H-1,2-Oxazinen (Briefumschlagskonformation der 6H-1,2-Oxazine und pseudoaxiale Ausrichtung der Ethoxygruppe) wurde ebenfalls eine hohe Diastereoselektivität beobachtet. Ergänzend wurden die Konstitutionen der Cycloaddukte mit der semiempirischen PM3-Methode auf Basis des Grenzorbitalmodells vorhergesagt und mit denen der isolierten Biheterocyclen verglichen. Die dargestellten Cycloaddukte sollten unter Ausnutzung der geringen Bindungsenergie der N-O-Bindung hydrogenolysiert werden. Die Reduktionen waren jedoch im allgemeinen nicht selektiv, so daß die Umsetzungen zu komplexen Produktgemischen führten. Für die 3-Ethoxycarbonyl-3a,7a-dihydro-4H-isoxazolo[5,4-d]-1,2-oxazinderivate wurde ferner der Abbau des Fünfringes (Verseifung und Decarboxylierung) in cis-konfigurierte α-Hydroxynitrile beschrieben. Die 4-Chlor- und 4-Brom-6H-1,2-oxazine konnten in guten Ausbeuten unter milden Reaktionsbedingungen dargestellt werden. Anschließend wurden mit den bromierten Verbindungen verschiedene palladiumkatalysierte Kupplungsreaktionen getestet. Durch die Methode von Suzuki konnte das Halogen der 4-Brom-6H-1,2-oxazine durch den Phenylrest der Benzolboronsäure substituiert werden.