LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re-distribution from target expressing cells resulted in a long terminal half-life and a long-lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well-tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose-limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil-driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.

The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor LYS006 is described. In a biochemical assay, their optical antipodes showed similar potencies, which could be rationalized by the cocrystal structures of these compounds bound to LTA4H. Despite comparable stabilities in liver microsomes, they showed distinct in vivo PK properties. Selective O-phosphorylation of the (R)-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the (S)-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo. Introduction of two pyrazole rings led to compound (S)-2 with a more balanced distribution of polarity across the molecule, exhibiting high selectivity and excellent potency in vitro and in vivo. Furthermore, compound (S)-2 showed favorable profiles in 16-week IND-enabling toxicology studies in dogs and rats. Based on allometric scaling and potency in whole blood, compound (S)-2 has the potential for a low oral efficacious dose administered once daily.

The cytosolic metalloenzyme leukotriene A(4) hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B-4 (LTB4). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB 4 generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.

Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential. Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant.

The enantioselectivity of a chiral catalyst can be determined from its racemic form by mass spectrometric screening of a nonequal mixture of two mass-labeled quasienantiomeric substrates. The presented method opens up new possibilities for evaluating catalyst structures that are not readily available in enantiomerically pure form.

X-ray absorption near the iron K edge (XANES) was used to investigate the characteristics of temperature-induced low-spin-to-high-spin change (SC) in metallo-supramolecular polyelectrolyte amphiphile complexes (PAC) containing FeN6 octahedra attached to two or six amphiphilic molecules. Compared to the typical spin-crossover material Fe(phen)(2)(NCS)(2) XANES spectra of PAC show fingerprint features restricted to the near-edge region which mainly measures multiple scattering (MS) events. The changes of the XANES profiles during SC are thus attributed to the structure changes due to different MS path lengths. Our results can be interpreted by a uniaxial deformation of FeN6 octahedra in PAC. This is in agreement with the prediction that SC is originated by a structural phase transition in the amphiphilic matrix of PAC, but in contrast to Fe(phen)(2)(NCS)(2), showing the typical spin crossover being associated with shortening of all the metal-ligand distances.

Thin gold films were deposited on float glass substrates held at cryogenic temperatures down to 77 K and investigated in-situ using X-ray reflectometry and surface sensitive reflection mode X-ray absorption spectroscopy (XAFS). The combination of these in-situ X-ray methods with simultaneous electrical resistivity measurements yields information about the surface and volume microstructure of the deposited films as a function of the deposition temperature and their changes induced by a subsequent annealing treatment. The surface sensitive XAFS experiments clearly proved that the films exhibit a polycrystalline structure throughout the temperature range studied here. The data were fitted using a correlated Debye-model. The results show that for film deposition at low substrate temperatures < 130 K, a significantly decreasing Debye-temperature was found, reaching values of about 100 K in comparison to 165 K for the polycrystalline bulk material. This decrease was interpreted to be predominantly related to defective film regions with an increased static disorder. (C) 2008 Elsevier B.V. All rights reserved.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The use of quasi-enantiomeric substrates and ESI-MS as an analytical tool has made it possible to determine the intrinsic enantioselectivity of chiral catalysts by monitoring catalytic intermediates. In this way, potential problems of methods based on product analysis, which may be caused by catalytically active impurities, partial dissociation of a chiral ligand-metal complex, or a non-catalytic background reaction can be avoided. ESI-MS-based screening is fast, reliable, and operationally simple, as it does not require work-up or purification steps. Moreover, mixtures of catalysts with different molecular masses can be screened simultaneously, which is not possible with methods relying on product analysis. In this way catalyst libraries prepared in one batch by combinatorial methods can be screened without the need to synthesize and purify the catalysts individually. This screening method was successfully applied to Pd-catalyzed allylic substitutions and metal-catalyzed and organocatalytic Diels-Alder reactions.

Mixtures of chiral ligands were prepared from simple precursors and evaluated in the asymmetric Pd-catalyzed allylation by simultaneous screening using ESI-MS and quasienantiomeric substrates.

ESI-MS monitoring of the title reaction has led to the discovery that dinuclear allyl-bridged PdI complexes are formed reversibly in substantial amounts during catalysis (see scheme; Bz=benzoyl). The structure of one such complex was determined by X-ray analysis (see picture; P yellow, N blue, O red, Pd dark gray). Upon consumption of the starting materials a new dinuclear complex resulting from reductive C[BOND]Cl bond cleavage of CH2Cl2 was observed.

The combination of in situ electrical resistivity measurements and ex situ tapping-mode atomic force microscopy (AFM) in air was used to study the surface topography and the electrical properties of thin d.c. magnetron-sputtered gold films on float glass substrates. In particular, the influence of the deposition temperature and a subsequent isochronous annealing process on the electrical resistivity and the surface structure of the polycrystalline gold films were analysed. The results show that a minimum surface roughness of about 0.4 nm was achieved for a deposition temperature of about 350 K. After the annealing process, an increase of the surface roughness and the lateral crystallite size was observed in general, suggesting that the measured decrease in resistivity during annealing is not related to a smoothing of the surface, but to the decrease of the grain-boundary scattering of the conduction electrons. Assuming that the annealing processes are diffusion-limited reactions, we calculated the corresponding activation energies from the irreversible branch of the annealing curves, yielding values of about 0.6-1.0 eV, which also correspond to grain-boundary diffusion. Copyright (C) 2006 John Wiley & Sons, Ltd.

Angewandte Chemie International EditionVolume 44, Issue 15 p. 2183-2184 Book Review High-Throughput Screening in Chemical Catalysis. Technologies, Strategies and Applications. Edited by Alfred Hagemeyer, Peter Strasser and Anthony F. Volpe, Jr.. Christian Markert, Christian Markert Department of Chemistry, University of Basel, SwitzerlandSearch for more papers by this author Christian Markert, Christian Markert Department of Chemistry, University of Basel, SwitzerlandSearch for more papers by this author First published: 06 April 2005 https://doi.org/10.1002/anie.200385264Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume44, Issue15April 8, 2005Pages 2183-2184 RelatedInformation

Angewandte Chemie International EditionVolume 43, Issue 19 p. 2498-2500 CommunicationFree Access Screening of Chiral Catalysts and Catalyst Mixtures by Mass Spectrometric Monitoring of Catalytic Intermediates† Christian Markert Dipl.-Chem., Christian Markert Dipl.-Chem. Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland, Fax: (+41) 61-267-1103Search for more papers by this authorAndreas Pfaltz Prof. Dr., Andreas Pfaltz Prof. Dr. [email protected] Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland, Fax: (+41) 61-267-1103Search for more papers by this author Christian Markert Dipl.-Chem., Christian Markert Dipl.-Chem. Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland, Fax: (+41) 61-267-1103Search for more papers by this authorAndreas Pfaltz Prof. Dr., Andreas Pfaltz Prof. Dr. [email protected] Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland, Fax: (+41) 61-267-1103Search for more papers by this author First published: 28 April 2004 https://doi.org/10.1002/anie.200453844Citations: 140 † We thank Solvias AG, Basel, for a free sample of their ligand kit. Financial support by the Swiss National Science Foundation is gratefully acknowledged. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract The enantioselectivity of chiral palladium catalysts in the kinetic resolution of allylic esters can be determined by mass spectrometric monitoring of allyl–Pd intermediates A and B, which are derived from pseudoenantiomeric substrates 1 a and 1 b. In contrast to conventional screening methods, which are based on product analysis, simultaneous screening of catalyst mixtures in homogeneous solution is possible. Combinatorial methods have become an important focus of research in asymmetric catalysis.1, 2 During the last few years efficient techniques have been developed for the high-throughput parallel screening of chiral catalysts.3 However, parallel screening based on product analysis has potential pitfalls, since the enantioselectivity of a reaction is often lower than the inherent selectivity of the catalyst because of an unselective background reaction, catalytically active impurities, or partial dissociation of a chiral ligand from a metal catalyst. Problems of this kind would be avoided if the catalyst's ability for enantiodiscrimination could be determined directly from examining catalyst–reactant complexes rather than from product analysis. Here we report the realization of this concept for a palladium-catalyzed kinetic resolution of allylic esters by using electrospray mass spectrometry (ESI-MS) as an analytical tool. Our work was inspired by an ingenious screening method for homogeneous polymerization catalysts developed by Chen:4 by using ESI-MS, which is selective for ionic species, he could detect reaction intermediates derived from cationic metal catalysts. In this method the growing polymer chain remains bound to the catalyst during polymerization and so the most effective catalysts carry the longest chains. Thus, the chain length, which can be determined by ESI-MS, is a measure of the activity of a catalyst. Since the signals of the various catalyst intermediates all appear at different m/z values, the screening of catalyst mixtures of different molecular mass is possible. We thought that it should be possible to develop a method of this kind for measuring the inherent enantioselectivity of chiral catalysts directly. The kinetic resolution of allylic esters by palladium-catalyzed allylic substitution5 seemed an ideal candidate for this endeavor (Scheme 1). Scheme 1Open in figure viewerPowerPoint Kinetic resolution of allylic esters 1 a and 1 b. The first step of the catalytic cycle, formation of Pd–allyl complexes A and B is fast, while the second step, nucleophilic addition to the allyl system, to give products 2 a and 2 b as well as the corresponding regioisomers (nucleophilic attack at the position next to the Ph substituent), is slower and turnover-limiting. The cationic intermediates A and B correspond to the resting state of the catalytic cycle and, therefore, should exist in sufficient concentration to be observable by ESI-MS. The ratio A:B reflects the catalyst's ability to discriminate between the two enantiomeric substrates 1 a and 1 b. Clearly, the two intermediates A and B, which are derived from the two enantiomers of the substrate, have the same molecular mass and, therefore, can not be distinguished by mass spectrometry. However, if we label 1 a and 1 b with two different alkyl groups at the para position of the aryl group (for example, Ar=4-methylphenyl in 1 a and 4-ethylphenyl in 1 b), then the signals of A and B would appear at different positions in the mass spectrum and their ratio could be determined by integration. Since the para-alkyl substituents are too remote from the reactive part of the molecule to have a notable influence on the reaction, we expected the same selectivity as for the reaction of the parent enantiomers 1 a and 1 b with Ar=phenyl. Mass-labeled enantiomers (or pseudoenantiomers as they are often called) have been used before for determining the enantiomeric purity of chiral products.6 As a first test we treated an equimolar mixture of two pseudoenantiomers with an achiral Pd catalyst and used the anion of diethyl ethylmalonate as the nucleophile. The ESI mass spectrum indeed showed the expected signals corresponding to the allyl intermediates A and B with the characteristic isotope distribution for palladium (Figure 1). The two signal groups had the same intensity, as anticipated for an achiral catalyst. The reaction with a chiral, enantiomerically pure catalyst derived from ligand 3 showed a strong bias toward one of the two pseudoenantiomers (A:B=9:91). The control experiment performed using the same catalyst but inversely labeled pseudoenantiomers (methyl and ethyl groups interchanged) gave a reversed ratio of 91:9. Figure 1Open in figure viewerPowerPoint ESI-MS screening of Pd catalysts for the kinetic resolution of 1 a and 1 b. In the initial phase of the reaction, when the two pseudoenantiomeric substrates are present in equal concentrations, the ratio A:B is equivalent to the stereoselectivity factor s, which is defined as the ratio of rate constants kA:kB of the faster- and slower-reacting substrate enantiomer, respectively. Screening by ESI-MS is extremely fast and requires minimal amounts of substrate compared to conventional screening, which necessitates taking samples at regular time intervals and analyzing them by HPLC on columns with chiral stationary phases. By using our ESI-MS screening technique we were able to test up to ten chiral catalysts per hour, which would have taken several days by conventional methods. We identified several ligands with s factors of >20 from a library of 60 ligands comprising mainly P,N ligands previously developed in our group7 and commercially available diphosphanes.8 An s factor of 100 was observed under optimized conditions using the most selective ligand 4;0 9 this value is significantly higher than the best selectivities previously reported for this reaction.10 In several cases we compared the data from ESI-MS screening with results obtained from kinetic analyses of preparative reactions. Pleasingly, the s factors calculated from the curve obtained by plotting the enantiomeric excess of the remaining substrate against conversion closely matched the s factors determined by ESI-MS (deviation <10 % for s factors in the range of 1–20). The transition states of the first step in the catalytic cycle (1 a→A, 1 b→B; Scheme 1) and the second step (A→2 a, B→2 b) have essentially the same geometry. Accordingly, ligands identified by our screening protocol for efficient kinetic resolution should also induce high selectivities in the second step and, therefore, produce high ee values in the nucleophilic addition to symmetrically substituted allyl systems (for example, A; Ar=Ph). This postulate has been verified in preparative reactions of the racemate 1 a/1 b (Ar=Ph). After establishing a reliable protocol for the screening of single catalysts, we wanted to test if our method could be used for screening mixtures of several Pd catalysts in one reaction. Preliminary experiments gave disappointing results, because rapid exchange of chiral ligands between the different Pd–allyl intermediates took place under the reaction conditions. This strongly affected the relative intensities of the signals corresponding to the two pseudoenantiomers, thus making the results unreliable. However, at lower temperatures (−78 °C instead of 23 °C) ligand exchange was suppressed while the catalytic reaction was still sufficiently fast. Figure 2 shows the results of a typical experiment carried out under these conditions. Figure 2Open in figure viewerPowerPoint Simultaneous screening of a mixture of five Pd catalysts. Five different catalyst precursors were combined with the pseudoracemate 1 a/1 b (50-fold excess based on the total Pd concentration) at −78 °C in toluene. The control spectrum before addition of the nucleophile showed the expected signals corresponding to the five Pd–allyl complexes (Figure 2 a). The reaction was initiated by addition of malonate (2 equiv per equiv of Pd). Allyl transfer from Pd to malonate generated the active Pd0 catalysts, which reacted with the two pseudoenantiomers to give the corresponding allyl intermediates (Figure 2 b). The five catalyst precursors and the ten catalyst complexes derived from the two pseudoenantiomeric substrates all have different molecular masses and, therefore, could all be readily observed and identified in the ESI mass spectrum taken after a reaction time of two minutes. In addition to the selectivity factors, a qualitative reactivity order could be established from the spectrum. Complex 5 shows the lowest reactivity, as evident from the intense signal of the allyl precursor. Complexes 6 and 8 react significantly faster, as demonstrated by the complete consumption of the catalyst precursors. A selectivity order 8>7>6∼5∼9 is derived from the signal ratios, with complex 8 clearly being the most selective catalyst. The results show that it is indeed possible to obtain reliable selectivity data from catalyst mixtures in homogeneous solution. In principle, there is no restriction on the number of catalysts that can be screened simultaneously, as long as the signals do not overlap. However, the reactivity of the individual catalysts should be on the same order, otherwise the signals corresponding to the least-reactive catalysts become too small. In addition to speed, the fact that the results reflect the inherent enantioselectivity of the catalyst is a big advantage of this method. The same methodology should also be applicable to allylic substitutions starting from meso substrates bearing two enantiotopic leaving groups.5 There are also other reactions that proceed through ionic catalyst–reactant complexes and, therefore, could be amenable to this screening method. Experimental Section Substrates 1 a and 1 b were prepared according to reference [11]. In a typical reaction, a precatalyst solution (100 μL, 2.5 mM in toluene, prepared from equimolar amounts of ligand and [Pd(C3H5)(MeCN)2]OTf) (Tf=triflate) was mixed with a solution of 1 a and 1 b (100 μL, 125 mM in toluene, 2×25 equiv per equiv of Pd). The reaction was started by addition of two equivalents of a nucleophile solution (50 μL, 10 mM in toluene; prepared from NaH, diethyl ethylmalonate, and [15]crown-5 in THF with subsequent evaporation to dryness). The screening of single catalysts was performed at room temperature, whereas mixtures of complexes were tested at −78 °C. After stirring the reaction mixture for 2 min, a sample was taken, diluted to 10−5 M (dichloromethane) and analyzed by ESI-MS (MAT Finnigan LCQ). Reactions in Figure 1 were repeated several times with consistent results (relative ESI-MS integrations could be reproduced with deviations of less than ±3 %). References 1 Comprehensive Asymmetric Catalysis, Vol. I–III (Eds.: ), Springer, Berlin, 1999. 2 Catalytic Asymmetric Synthesis, 2 ed. (Ed.: I. Ojima), Wiley-VCH, New York, 2000. 3 3aM. T. Reetz, Angew. Chem. 2001, 113, 292– 320; Angew. Chem. Int. Ed. 2001, 40, 284– 310; 3bM. T. Reetz, Angew. Chem. 2002, 114, 1391– 1394; Angew. Chem. Int. Ed. 2002, 41, 1335– 1338; 3cJ. F. Traverse, M.-L. Snapper, Drug Discovery Today 2002, 7, 1002– 1012; 3dB. Archibald, O. Brümmer, M. Devenney, S. Gorer, B. Jandeleit, T. Uno, W. H. Weinberg, T. Weskamp in Handbook of Combinatorial Chemistry (Eds.: ), Wiley-VCH, Weinheim, 2002, pp. 885– 990; 3eA. H. Hoveyda in Handbook of Combinatorial Chemistry (Eds.: ), Wiley-VCH, Weinheim, 2002, pp. 991– 1016; 3fJ. P. Stambuli, J. F. Hartwig, Curr. Opin. Chem. Biol. 2003, 7, 420– 426. 4P. Chen, Angew. Chem. 2003, 115, 2938– 2954; Angew. Chem. Int. Ed. 2003, 42, 2832– 2847. 5 5aB. M. Trost, C. Lee in reference [2], pp. 593–649; 5bM. Lautens, A. Pfaltz in reference [1], pp. 833–886. 6 6aA. Horeau, A. Nouaille, Tetrahedron Lett. 1990, 31, 2707– 2710; 6bM. T. Reetz, M. H. Becker, H.-W. Klein, D. Stöckigt, Angew. Chem. 1999, 111, 1872– 1875; Angew. Chem. Int. Ed. 1999, 38, 1758– 1761; 6cS. Yao, J.-C. Meng, G. Siuzdak, M. G. Finn, J. Org. Chem. 2003, 68, 2540– 2546. 7G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336– 345. 8Solvias ligand kit: Solvias AG, P.O. Box, 4002 Basel, Switzerland; www.solvias.com. 9F. Glorius, PhD thesis, University of Basel (Switzerland), 2000. 10S. R. Gilbertson, P. Lan, Org. Lett. 2001, 3, 2237– 2240. 11P. von Matt, G. C. Lloyd-Jones, A. B. E. Minidis, A. Pfaltz, Helv. Chim. Acta 1995, 78, 265– 284. Citing Literature Volume43, Issue19May 3, 2004Pages 2498-2500 FiguresReferencesRelatedInformation

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.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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.

Sonogashira C,C couplings in a fluorous biphasic system by application of three differently perfluoro-tagged Pd complexes are reported. All three complexes were probed in the coupling of four bromoarenes to three alkynes. The parallel workup procedure allowed for straightforward product isolation and catalyst recovery by simple extraction steps. In particular, the coupling of electron-deficient bromoarenes proceeded with good yields and allowed for the catalyst to be used up to three times.

Es geht auch ohne: Auf fluorigem Umkehrphasen-Kieselgel immobilisierte perfluormarkierte Katalysatoren können in Suzuki- und Sonogashira-C-C-Kupplungen auch ohne perfluorierte Lösungsmittel eingesetzt werden (siehe Schema; R1=Phenyl, 4-MeO-C6H4 u. a.; R2=4-NO2-C6H4, 4-MeCO-C6H4 u. a.; X=Br, I). Die Produkte lassen sich im Anschluss an die Reaktion durch einfaches Dekantieren abtrennen, und die eingesetzten Pd-Katalysatoren können zurückgewonnen und wieder verwendet werden.