Modeling-based Approach Towards Quality by Design for a Telescoped Process

A telescoped, two-step synthesis was investigated by applying Quality by Design principles. A kinetic model consisting of 12 individual reactions was successfully established to describe the synthesis and side reactions. The resulting model predicts the effects of changes in process parameters on total yield and quality. Contour plots were created by varying process parameters and displaying the model predicted process response. The areas in which the process response fulfils predetermined quality requirements are called design spaces. New ranges for process parameters were explored within these design spaces. New conditions were found that increased the robustness of the process and allowed for a considerable reduction of the used amounts of a reagent. Further optimizations, based on the newly generated knowledge, are expected. Improvements can either be direct process improvements or enhancements to control strategies. The developed strategies can also be applied to other processes, enhancing upcoming and preexisting research and development efforts

Synthesis of oligovalent amino-C-glycosides using transition metal-catalyzed reactions of enantiopure 1,2-oxazines

Das Ziel der Doktorarbeit war die Entwicklung neuer Methoden für die Synthese von unnatürlichen mono- und oligovalenten Amino-C-glycosiden. Die oligovalenten Derivate wurden über substituierte enantiomerenreine bicyclische 1,2-Oxazine, welche durch geeignete Linker verknüpft waren, unter Verwendung von verschiedenen Übergangsmetall-katalysierte Reaktionen dargestellt. Anschließende Reduktionen (z.B. durch Zink/Säure, Palladium katalysierte Hydrogenolyse oder Samariumdiiodid) überführen die verknüpften Produkte in oligovalente Amino-C-glycoside mit D-Talose Konfiguration. Die erhaltenen Produkte wurden abschließend polysulfatiert. Die oligovalenten C-Glycoside unterscheiden sich in Anzahl und Abstand der Aminopyraneinheiten zueinander und sind potente L-, P- und E-Selektininhibitoren. Die Schlüsselverbindungen, substituierte 1,2-Oxazine, wurden in einer stereoselektiven [3+3]-Cyclisierung von Aldonitronen und lithiierten (2-Trimethylsilyl)ethoxyallen oder durch die Einführung von neuen funktionellen Gruppen in den 1,3-Dioxolanylsubstituenten eines 1,2-Oxazins dargestellt. Eine Lewis-Säure induzierte Umlagerung der Heterocyclen führte zu den entsprechenden bicyclischen Derivaten. Nach Reduktion der Carbonylgruppe wurden die bicyclischen Verbindungen als Bausteine für Übergangsmetall-katalysierte Reaktionen verwendet. Ein p-bromphenylsubstituiertes bicyclisches 1,2-Oxazin konnte dargestellt werden und wurde in Suzuki-Reaktionen eingesetzt, um ein Biphenylaminopyran oder p-terphenylverknüpftes Dimer zu erhalten. Für die Spaltung der N-O-Bindung wurde Zink und Säure oder Samariumdiiodid verwendet, um starre p-terphenylverknüpfte Amino-C-glycoside zu erhalten. Außerdem wurde der Baustein benutzt um funktionalisierte mono- sowie di-, tri- und tetravalente bicylische 1,2-Oxazine durch Sonogashira-Reaktionen in exzellenten Ausbeuten zu erhalten. Weiterhin wurden zwei divalente Amino-C-glycoside, ein starres und ein flexibles, unter Verwendung von Glaser-Kreuzkupplung dargestellt. Durch Hydrogenolyse wurde die Alkineinheiten reduziert und die N-Benzylgruppen der oligovalenten Produkte entfernt. Samariumdiiodid wurde hingegen verwendet um die N-O-Bindung der erhaltenen oligovalenten Kohlenhydratmimetika selektiv zu spalten, wodurch man C-Glycoside mit D-Talose Konfiguration erhält. Einige der Verbindungen konnten mit einem Schwefeltrioxid-N,N-dimethylformamid- Komplex polysulfatiert werden und werden zukünftig auf ihre inhibitorischen Eigenschaften bezüglich L-, P- und E-Selektin untersucht. Ein vinyl- und homoallylsubstituiertes bicyclisches 1,2-Oxazin konnte synthetisiert und durch Olefinmetathese dimerisert werden. Im Fall des vinylsubstituieren bicyclischen 1,2-Oxazins konnte das „Dimer“ in exzellenten Ausbeute erhalten werden. Durch Hydrogenolyse konnte die Verbindung in einer guten Gesamtausbeute in ein divalentes C-Aminoglycosid mit D-Talose Konfiguration überführt werden.Aim of the dissertation was the development of a new approach to the synthesis of unusual mono- and oligovalent amino-C-glycosides. The oligovalent derivates were synthesized by substituted enantiopure bicyclic 1,2-oxazines which were connected by suitable linkers employing with different transition metal- catalyzed reactions. Subsequent reductions (like zinc in presence of acid, palladium catalyzed hydrogenolyses and samarium diiodide) convert the connected products into oligovalent amino-C-glycosides with D-talose configuration. Finally, these C-glycosides were polysulfated. The oligovalent C-glycosides differ in number and distance of their aminopyran units and are potential L-, P- and E-selectin inhibitors. The key compounds, substituted 1,2-oxazines, were prepared by a stereoselective [3+3]-cyclization of aldonitrones and lithiated (2-trimethylsilyl)ethoxyallene or the introduction of new groups into the 1,3-dioxolanyl substituent of a 1,2-oxazine. The Lewis acid-induced rearrangement of these heterocycles provided the corresponding bicyclic 1,2-oxazine derivatives. After subsequent reduction of the carbonyl group, the resulting bicyclic compounds were used as building blocks for transition metal-catalyzed reactions. A parabromphenyl- substituted bicyclic 1,2-oxazine could be obtained and used in Suzuki-reactions to form biphenyl aminopyran or rigid p-terphenyl-linked dimers. For the N-O bond cleavage zinc in the presence of acid or samarium diiodide were applied to obtain rigid p-terphenyllinked amino-C-glycosides. Moreover this building block was used in Sonogashira reactions to synthesize functionalized mono as well as di-, tri- and tetravalent bicyclic 1,2-oxazines in excellent yields. Besides, by Glaser cross-coupling two divalent amino-C-glycosides could be prepared, one with a rigid and one with a flexible linker unit. Hydrogenation was used to reduce the alkyne moiety and to remove the N-benzyl groups, whereas samarium diiodide was employed to selectively cleave the N-O bond to obtain oligovalent carbohydrate mimetics with D-talose configuration. Some of these compounds could be polysulfated by a sulfur trioxide-N,N-dimethylformamide complex and are ready for studies of inhibitory properties towards L-, P- and E-selectin. A vinyl- and homoallyl-substituted bicyclic 1,2-oxazine could be synthesized and “dimerized” by olefin metatheses. In case of the vinyl-substituted bicyclic 1,2-oxazine the “dimer” could be obtained in excellent yields. Its hydrogenolysis furnished the divalent C-aminoglycoside with D-talose configuration in good overall yield

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is described. Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki cross-couplings. The key compound, a p-bromophenyl-substituted 1,2-oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE-allene. The Lewis acid-induced rearrangement of this heterocycle provided the corresponding bicyclic 1,2-oxazine derivative that may be regarded as internally protected amino sugar analogue. After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross-couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers

Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

New compounds with carbohydrate-similar structure (carbohydrate mimetics) are presented in this article. Starting from enantiopure nitrones and lithiated TMSE-allene we prepared three 1,2-oxazine derivatives which underwent a highly stereoselective Lewis acid-induced rearrangement to give bicyclic products in good yield. Subsequent reductive transformations delivered a library of new poly(hydroxy)aminooxepane derivatives. The crucial final palladium-catalyzed hydrogenolysis of the 1,2-oxazine moiety was optimized resulting in a reasonably efficient approach to a series of new seven-membered carbohydrate mimetics