Ein neues Konzept der kombinatorischen Chemie in Lösung mit den Vorteilen der Festphasensynthese: Bildung von N-Betainen durch Mehrkomponenten-Domino-Reaktionen
Abstract:Professor Ivar Ugi zum 70. Geburtstag gewidmet Die kombinatorische Chemie ist eine wichtige Methode sowohl für die Suche als auch die Optimierung von Leitstrukturen pharmakologisch wirksamer Verbindungen [1] und findet darüber hinaus Anwendung in der supramolekularen Chemie, [2] in der Katalysatorentwicklung [3] und in den Materialwissenschaften. [4] Hierbei hat die kombinatorische Festphasensynthese [5] den Vorteil der einfachen Automatisierung, da Reagentien im Überschuss eingesetzt und Verunreinigungen un… Show more
“…Phase-switchable tags can be used to precipitate a product from organic solutions either through salt formation [376,377] or by configurational change (for example, cis/trans isomerization). [378,379] Perrier and Labelle described a simple solutionphase/solid-phase work-up protocol in which a phase-switchable tag was employed.…”
Section: Phase Switchmentioning
confidence: 99%
“…[376] In this case, the formation of a zwitterionic compound induces precipitation after a multicomponent domino reaction (Scheme 66). [376] In this case, the formation of a zwitterionic compound induces precipitation after a multicomponent domino reaction (Scheme 66).…”
The shift of paradigm in combinatorial chemistry, from large compound libraries (of mixtures) on a small scale towards defined compound libraries where each compound is prepared in an individual well, has stimulated the search for alternative separation approaches. The key to a rapid and efficient synthesis is not only the parallel arrangement of reactions, but simple work-up procedures so as to circumvent time-consuming and laborious purification steps. During the initial development stages of combinatorial synthesis it was believed that rational synthesis of individual compounds could only be achieved by solid-phase strategies. However, there are a number of problems in solid-phase chemistry: most notably there is the need for a suitable linker unit, the limitation of the reaction conditions to certain solvents and reagents, and the heterogeneous reaction conditions. Further disadvantages are: the moderate loading capacities of the polymeric support and the limited stability of the solid support. In the last few years several new separation techniques have been developed. Depending on the chemical problem or the class of compounds to be prepared, one can choose from a whole array of different approaches. Most of these modern separation approaches rely on solution-phase chemistry, even though some of them use solid-phase resins as tools (for example, as scavengers). Several of these separation techniques are based on liquid-liquid phase separation, including ionic liquids, fluorous phases, and supercritical solvents. Besides being benign with respect to their environmental aspects, they also show a number of advantages with respect to the work-up procedures of organic reactions as well as simplicity in the isolation of products. Another set of separation strategies involves polymeric supports (for example, as scavengers or for cyclative cleavage), either as solid phases or as soluble polymeric supports. In contrast to solid-phase resins, soluble polymeric supports allow reactions to be performed under homogeneous conditions, which can be an important factor in catalysis. At the same time, a whole set of techniques has been developed for the separation of these soluble polymeric supports from small target molecules. Finally, miscellaneous separation techniques, such as phase-switchable tags for precipitation by chemical modification or magnetic beads, can accelerate the separation of compounds in a parallel format.
“…Phase-switchable tags can be used to precipitate a product from organic solutions either through salt formation [376,377] or by configurational change (for example, cis/trans isomerization). [378,379] Perrier and Labelle described a simple solutionphase/solid-phase work-up protocol in which a phase-switchable tag was employed.…”
Section: Phase Switchmentioning
confidence: 99%
“…[376] In this case, the formation of a zwitterionic compound induces precipitation after a multicomponent domino reaction (Scheme 66). [376] In this case, the formation of a zwitterionic compound induces precipitation after a multicomponent domino reaction (Scheme 66).…”
The shift of paradigm in combinatorial chemistry, from large compound libraries (of mixtures) on a small scale towards defined compound libraries where each compound is prepared in an individual well, has stimulated the search for alternative separation approaches. The key to a rapid and efficient synthesis is not only the parallel arrangement of reactions, but simple work-up procedures so as to circumvent time-consuming and laborious purification steps. During the initial development stages of combinatorial synthesis it was believed that rational synthesis of individual compounds could only be achieved by solid-phase strategies. However, there are a number of problems in solid-phase chemistry: most notably there is the need for a suitable linker unit, the limitation of the reaction conditions to certain solvents and reagents, and the heterogeneous reaction conditions. Further disadvantages are: the moderate loading capacities of the polymeric support and the limited stability of the solid support. In the last few years several new separation techniques have been developed. Depending on the chemical problem or the class of compounds to be prepared, one can choose from a whole array of different approaches. Most of these modern separation approaches rely on solution-phase chemistry, even though some of them use solid-phase resins as tools (for example, as scavengers). Several of these separation techniques are based on liquid-liquid phase separation, including ionic liquids, fluorous phases, and supercritical solvents. Besides being benign with respect to their environmental aspects, they also show a number of advantages with respect to the work-up procedures of organic reactions as well as simplicity in the isolation of products. Another set of separation strategies involves polymeric supports (for example, as scavengers or for cyclative cleavage), either as solid phases or as soluble polymeric supports. In contrast to solid-phase resins, soluble polymeric supports allow reactions to be performed under homogeneous conditions, which can be an important factor in catalysis. At the same time, a whole set of techniques has been developed for the separation of these soluble polymeric supports from small target molecules. Finally, miscellaneous separation techniques, such as phase-switchable tags for precipitation by chemical modification or magnetic beads, can accelerate the separation of compounds in a parallel format.
“…Any cyclic 1,3-dicarbonyl compounds such as 1,3-cyclohexanediones, Meldrum’s acid or N,N -dimethylbarbituric acid, as well as reactive acyclic 1,3-dicarbonyl compounds, can be employed. Tietze et al examined the multicomponent domino Knoevenagel HDA reactions of 1,3-dicarbonyl compounds 34 with amino aldehydes 32 and enol ethers 33 , followed by a reductive amination with the formation of betaines 37 which can be precipitated from the solution in high purity (Scheme 6 ) [ 79 , 80 ]. Scheme 6 Domino sequence comprising Knoevenagel, inverse-electron-demand HDA reaction and hydrogenation starting from amino aldehydes 32 , 1,3-dicarbonyl compounds 34 , and enol ethers 33 …”
Section: Inverse-electron-demand Hetero-diels–alder Reactions Of 1-oxmentioning
This review is an endeavor to highlight the progress in the inverse-electron-demand hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes in recent years. The huge number of examples of 1-oxadienes cycloadditions found in the literature clearly demonstrates the incessant importance of this transformation in pyran ring synthesis. This type of reaction is today one of the most important methods for the synthesis of dihydropyrans which are the key building blocks in structuring of carbohydrate and other natural products. Two different modes, inter- and intramolecular, of inverse-electron-demand hetero-Diels–Alder reactions of 1-oxadienes are discussed. The domino Knoevenagel hetero-Diels–Alder reactions are also described. In recent years the use of chiral Lewis acids, chiral organocatalysts, new optically active heterodienes or dienophiles have provided enormous progress in asymmetric synthesis. Solvent-free and aqueous hetero-Diels–Alder reactions of 1-oxabutadienes were also investigated. The reactivity of reactants, selectivity of cycloadditions, and chemical stability in aqueous solutions and under physiological conditions were taken into account to show the potential application of the described reactions in bioorthogonal chemistry. New bioorthogonal ligation by click inverse-electron-demand hetero-Diels–Alder cycloaddition of in situ-generated 1-oxa-1,3-butadienes and vinyl ethers was developed. It seems that some of the hetero-Diels–Alder reactions described in this review can be applied in bioorthogonal chemistry because they are selective, non-toxic, and can function in biological conditions taking into account pH, an aqueous environment, and temperature.
“…Die Verwendung von phasenschaltbaren Markierungsgruppen zur Abtrennung von Produkten aus organischen Lösungen beruht entweder auf einer Salzbildung376, 377 oder einer Konfigurationsänderung (z. B. cis‐trans ‐Isomerisierung) 378, 379.…”
Section: Sonstige Trenntechnikenunclassified
“…Tietze et al beschrieben kürzlich einen ausgeklügelten Phasenwechsel für die Herstellung von Pyrrolidin‐, Piperidin‐ und Azepanderivaten 376. Dabei führt die Bildung eines Betains im Anschluss an eine Mehrkomponenten‐Dominoreaktion zur Ausfällung (Schema ).…”
Die kombinatorische Synthese [1,2] wird als eine der Schl¸s-seldisziplinen f¸r den konstanten Nachschub an chemischen Verbindungen angesehen, die auf biologische Aktivit‰t gegen¸ber der immens wachsenden Zahl biologischer Zielmolek¸le getestet werden kˆnnen. Zusammen mit dem Hochdurchsatz-Screening und einem effizienten Datenmanagement wird ihre Anwendung den Prozess der Wirkstoffentdeckung zweifelsohne beschleunigen. Urspr¸nglich konzentrierte sich die Kombinatorische Chemie auf die schnelle Synthese von hochkomplexen Gemischen mit winzigen An-
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