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.

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.

, B 8 , and B 9 has not been clarified, but the proposed mechanism would require only a minimal rearrangement of the bonds (one DSD rearrangement and the closing of the cluster after the loss of B 1 ). The loss of B 1 , which is not part of the open face, is surprising. Quantum-mechanical computations might give indications about the feasibility of the proposed pathway, the relative stability of the proposed intermediates, the origin of the H atoms which leave together with B 1 , and the rearrangement of the other H atoms. Experimental Section1, 8±12: Isopropylamine (0.1 g, 1.74 mmol) was added to a solution of (Me 2 S)B 9 H 13 in dry benzene (10 mL, 0.1 g) at room temperature. The mixture was heated to reflux for 3 h. All volatile components were removed under vacuum and the resulting substance was recrystallized from ethanol:water (1:1). Compounds 8 and 9 were purified by TLC by using CH 2 Cl 2 as eluent (R f ¼ 0.31). For further purification the substance was dissolved in CHCl 3 :hexane (1:3) at À20 8C. The solution was filtered and the resulting filtrate was evaporated to dryness to yield the purified product. 1 (DCI): m/z (%) 214 (95)

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 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.