In this report we demonstrate the suitability of hyperbranched polyglycerol as high-loading support for asymmetric catalysis. A polyglycerol-supported unsymmetrical salen ligand was prepared and purified by means of ultrafiltration. The polymeric ligand was metalated with cobalt acetate to afford the corresponding supported Co-salen complex which was further utilized in the hydrolytic kinetic resolution (HKR) of terminal epoxides. Kinetic studies for HKR of 1,2-epoxyhexane using polyglycerol-supported Co-salen showed improved catalytic performance compared to the respective non-immobilized catalyst. This observation points to the presence of a positive dendrimeric effect assuming a cooperative bimetallic mechanism. Furthermore, a polymer-supported Mn-salen catalyst was prepared and successfully applied in the asymmetric epoxidation of olefins. The respective dendritic catalyst was recycled by precipitation up to three times in the epoxidation of 6-cyano-2,2-dimethylchromene (ee up to 95 %). Experiments with repetitive batches revealed enhanced stability of the catalyst as a result of immobilization whereby the total turnover number increased from 23 in a single batch to around 80 for four repetitive batches. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

In this paper we demonstrate the application of hyperbranched polyglycerol (PG) 3 as a polymeric support for asymmetric catalysis. A new polyglycerol-supported unsymmetrical salen ligand 4 is described, which was successfully purified by gel permeation chromatography (GPC) or by ultrafiltration. After the insertion of the metal, e.g., chromium, the corresponding polymeric chromium complex was used as catalyst for asymmetric Diels-Alder reactions between Danishefsky's diene and benzaldehyde. The catalytic activities (up to 98 % conversion) and enantioselectivities (up to 78 % ee) were comparable to the original catalyst reported by Jacobsen. The soluble polyglycerol-supported catalysts were recovered by dialysis after the catalytic reactions and were recycled two times to afford identical reactivities as in the first run, with slightly reduced enantioselectivities. Moreover, this polymeric support catalyst showed a high retention (99.02 %) in a continuously operated membrane reactor.

An efficient and general route to soluble polymer-assisted synthesis of N-substituted pyrroles using dendritic polyglycerol was achieved. Thus, 3-(2,5-dihydro-2,5-dimethoxy­furan-2-yl)pyropanoic acid polyglycerol ester (2) was prepared according to reported procedures (Angew. Chem. Int. Ed. 2004, 43, 2297-2299). The transformation of 2,5-dihydrofuran 2 to tetra­hydrofuran 3 was performed via catalytic hydro­genation with Pt/C. Paal-Knorr-type condensation of 3 with primary amines followed by the cleavage of the polyglycerol with LiOH gave the corresponding pyrroles 5 in 50-65% yields.

An efficient and general route to the soluble polymer-assisted synthesis of a set of 14 different N-substituted pyrroles using dendritic polyglycerol as a high-loading support is presented. The transformation of furan to the key intermediate 2,5-dialkoxytetrahydrofuran was performed by electrochemical oxidation followed by catalytic hydrogenation with Pt/C in high yield. Both reactions required heterogeneous reagents which can be conveniently used with polyglycerol as a soluble support.

The preparation of a dendritic graft polymer by a very efficient synthesis of polyglycerol directly on a polystyrene resin is presented. This one-step process can be performed on a multigram scale to provide a chemically stable polymeric support. The resulting hybrid polymers were fully characterized by diverse analytical methods (NMR, IR, ESEM, UV detection of cleaved protecting groups, and mass-spectrometric methods). They combine a high loading capacity (up to 4.3 mmol g(-1)) with good swelling properties in a wide range of solvents (including water), which is the major drawback for many existing solid phase supports. In comparison to the widely employed PEGylated resins, these hybrid materials offer a 10-fold higher loading capacity. Their suitability as supports for organic synthesis and for the immobilization of reagents has been demonstrated. These materials also swell in water, and consequently, it should be possible to use these new hybrid materials for synthesis in protic solvents.

In this paper we present soluble dendritic polyglycerol (PG) supported reagents PG-DEAD, PG-PPh3, and PG-DCC as well as scavengers PG-carbonate, PG-carbazate, and PG-amine, which all have been synthesized in high overall conversions and yields using simple purification techniques. The supported reagents have been used simultaneously in Mitsunobu and acylation reactions. All polymeric reagents and scavengers can be removed by simple precipitation/filtration protocols to give chromatography-free products of high purity. In the course of the syntheses of the polymeric reagents three intermediates turned out to be precious polyglycerol derivatives: a mixed carbonate as an electrophilic derivative, polyglyceryl carbazate as a scavenger for carbonyl compounds, as well as polyglycerylamines as amino analogues of polyglycerol.

A general route to 4-substituted azolidin-2-ones (GABA lactam analogues) on a soluble high-loading polyglycerol support has been developed and optimized. These biologically interesting compounds (anticonvulsive drugs) can be synthesized in three steps commencing from a polyglycerol supported (diethylphosphono)acetic acid and a carbonyl compound. The key features of this parallel approach are the cyclative cleavage and simple separation techniques (i.e., dialysis).

This chapter summarises the most frequently used polymeric supports for catalysis and highlights some recent developments in the field. Two classes of polymers, crosslinked solid phase supports and non-crosslinked soluble polymeric supports, are discussed with the focus on covalently attached catalysts. In addition, for soluble polymeric supports the different separation techniques are critically compared and evaluated for their application in catalysis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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.

Die Entwicklung in der Kombinatorischen Chemie, weg von großen Verbindungsbibliotheken (aus Gemischen) hin zu Bibliotheken aus definierten Einzelverbindungen, die jeweils in eigenen Reaktionseinheiten synthetisiert werden, hat eine intensive Suche nach alternativen Trennverfahren ausgelöst. Den Schlüssel zu einer schnellen und effizienten Synthese liefert zum einen die parallele Reaktionsführung, zum andern die Anwendung einfacher Aufarbeitungsverfahren, mit denen sich zeitaufwändige und mühsame Reinigungsschritte vermeiden lassen. In der anfänglichen Entwicklungsphase der Kombinatorischen Chemie war man der Auffassung, für die rationale Synthese einzelner Verbindungen kämen ausschließlich Festphasenstrategien infrage. Allerdings bringen Festphasen-Ansätze eine Reihe von Nachteilen mit sich. Beispielsweise benötigt man passende Linker-Einheiten, und die Reaktionsbedingungen sind hinsichtlich bestimmter Lösungsmittel und Reagentien beschränkt. Hinzu kommen die mäßige Beladungskapazität von polymeren Trägern und die geringe Stabilität von Festphasen. In den vergangenen Jahren wurden alternative Trennverfahren entwickelt, und je nach chemischer Aufgabenstellung oder Produktklasse kann man heute aus einem Sortiment unterschiedlicher Methoden auswählen. Die meisten dieser modernen Trennstrategien beruhen auf Flüssigphasen-Ansätzen, wenn auch in einigen Fällen Festphasenharze genutzt werden (z. B. als Abfangreagentien). Mehrere der Techniken basieren auf einer Flüssig-flüssig-Phasentrennung, darunter Verfahren auf Basis von ionischen Flüssigkeiten, fluorigen Phasen und überkritischen Lösungsmitteln. Sie sind umweltverträglich und bringen eine ganze Reihe von Vorteilen etwa bei der Aufarbeitung und der Produktisolierung mit sich. Andere Trennstrategien nutzen polymere Träger (z. B. Abfangreagentien oder cyclisierende Abspaltung), die fest oder gelöst vorliegen können. Mit löslichen polymeren Trägern lassen sich – anders als mit Festphasenharzen – Reaktionen unter homogenen Bedingungen ausführen, ein Vorteil, der sich bei Katalysen als wichtig erweisen kann. Zugleich wurden viele Techniken für die Abtrennung der löslichen polymeren Träger von den Zielmolekülen entwickelt. Schließlich existieren etliche maßgeschneiderte Verfahren, die die Aufarbeitung von Verbindungen bei der Parallelsynthese beschleunigen, darunter die Anwendung von magnetischen Harzkügelchen oder „phasenschaltbaren Einheiten“ zur Fällung durch chemische Modifizierung.

Das Titelbild zeigt den Fortschritt der Trennmethoden in der Chemie im Laufe der Jahrhunderte. Retorte und Destillationsapparatur versinnbildlichen das Repertoire an Reinigungsmethoden, das seit den Anfängen der Chemie bis in die 1980er Jahre kaum weiterentwickelt wurde. Die verstärkte Automatisierung multiparalleler Reaktionen, die einfachere Aufarbeitungstechniken erfordern, symbolisiert der Syntheseautomat. Eine Vielzahl spezieller Trennstrategien wurde entwickelt, deren Auswahl heute von der klassischen wässrigen Aufarbeitung über den Einsatz ionischer, perfluorierter oder überkritischer Flüssigkeiten bis hin zur Anwendung Polymer- und Dendrimer-gestützter Methoden reicht. Eine aktuelle Übersicht über die Entwicklungen und Anwendungen moderner Trennverfahren finden Sie in dem Aufsatz von W. Bannwarth und R. Haag et al. auf S. 4136 ff.

This paper describes the use of dendritic polyglycerol as a new high-loading polymeric support. The soluble polyether skeleton allows the parallel synthesis of small libraries on a large scale (1-5 mmol). Purification of polymer-bound products is easily achieved by a parallel dialysis apparatus, which was developed to separate up to 12 reaction mixtures simultaneously. The terminal 1,2-diol groups of polyglycerol (loading capacity: 4.1 mmol diol/g) can be directly coupled with carbonyl compounds without additional linker groups. At the same time the polyglycerol support acts as a polymeric ketal protecting group. The coupling of the carbonyl compounds occurs in high yields, and effective loading capacities of up to 3.5 mmol of ketone/g can be reached. The obtained polymeric acetals can easily be characterized by standard analytical techniques, such as NMR, IR, UV, and SEC. The versatility of this new polymeric support for solution-phase organic synthesis is demonstrated by two efficient polymer-supported syntheses: nucleophilic substitutions of gamma-chloroketones with amines and Suzuki-coupling on p-bromobenzaldehyde. The acid-catalyzed acetal cleavage with a solid-phase acidic ion-exchange resin in methanol demonstrates the orthogonal use of these soluble polymeric supports with conventional solid-phase reagents. Cleavage of products occurs in high yields, and almost complete recovery (>95%) of the polyglycerol support has been demonstrated after phase separation or ultrafiltration.

The cover picture shows the progress made in the development of separation techniques over the centuries. The retort and the distillation apparatus symbolize the repertoire of purification methods, which expanded only slightly from the foundations of chemistry to the 1980s. The automated synthesizer symbolizes the increasing demand for the automation of multiparallel techniques, which require simple work-up protocols. Thus, a large variety of specialized separation techniques has been developed. Today the spectrum contains, in addition to classical aqueous work-up, the use of ionic, perfluorinated, or supercritical liquids as well as the application of polymer- and dendrimer-supported separation strategies. An overview of the recent developments and applications of modern separation methods can be found in the Review by W. Bannwarth, R. Haag, et al. on p. 3964 ff.