Electrospray ionization tandem mass spectrometry in high-throughput screening of homogeneous catalysts

The frontispiece shows an illustration by John Tenniel and an excerpt from the 1865 edition of Lewis Carroll's "Alice in Wonderland". Because everything in Wonderland runs counter to logic, the Queen of Hearts declares in Alice's trial "Sentence first-verdict afterwards". High-throughput screening of catalysts, as it is conventionally practiced, does "Synthesis first-screening afterwards" which, as is argued in this review, also backwards. Given the particular constraints present in organometallic complexes, it is more efficient to develop a selective synthesis only when it has already been determined that a structure is likely to be better. The consequence is that screening methods must be able to handle ill-defined mixtures. Electrospray ionization tandem mass spectrometry is presented as a technical solution to this problem.     

A practical high-throughput screening system for enantioselectivity by using FTIR spectroscopy

For the first time FTIR spectroscopy has been applied to the measurement of enantiomeric purity. The underlying concept is based on the use of pseudo-enantiomers that are (13)C-labeled at appropriate positions. Upon applying Lambert-Beer's law in the determination of the concentrations of both enantiomers, the ee values are accessible, accuracy to within +/-5 % of the true values being possible. The application of a commercially available high-throughput FTIR system results in a slightly decreased accuracy (+/-7% for the ee values), but this allows a throughput of up to 10000 samples per day. The method is of interest in the area of combinatorial symmetric catalysis and directed evolution of enantioselective enzymes.     

High-throughput heterogeneous catalytic science

High-throughput experimentation in heterogeneous catalysis has recently experienced nearly exponential growth. Initial qualitative screening has evolved into quantitative high-throughput experimentation, characterization, and analysis. This allows high-throughput catalysis now to rise above simple screening to the level of fundamental understanding of reaction mechanisms, which will lead on a faster path to the Holy Grail of catalysis: rational catalyst design.     

Combinatorial chemistry approach to chiral catalyst engineering and screening: rational design and serendipity

An efficient asymmetric catalyst relies on the successful combination of a large number of interrelated variables, including rational design, intuition, persistence, and good fortune-not all of which are necessarily well-understood; this renders such practice largely empirical. As a result, the possibility of using combinatorial chemistry methods in asymmetric catalysis research has been widely recognized to be highly desirable. In this account, we attempt to show the principle and application of combinatorial approach in the discovery of chiral catalysts for enantioselective reactions. The concept focuses on the strategy for the creation of a modular chiral catalyst library by two-component ligand modification of metal ions on the basis of molecular recognition and assembly. The self-assembled chiral catalyst with two different ligands indeed exhibited synergistic effects in terms of both enantioselectivity and activity in comparison with its corresponding homocombinations in many reactions. The examples described in this paper demonstrated the powerfulness of combinatorial approach for the discovery of novel chiral catalyst systems, particularly for the development of highly efficient, enantioselective, and practical catalysts for enantioselective reactions. We hope this concept will stimulate further work on the discovery of more highly efficient and enantioselective catalysts, as well as unexpected classes of catalysts or catalytic enantioselective reactions in the future with the help of a combinatorial chemistry approach.     

High-throughput characterisation of materials by photoluminescence spectroscopy

An automatic system for high-throughput (HT) characterisation of large libraries of solid materials by photoluminescence spectroscopy is described. The system provides time-resolved transient emission spectra in the microsecond scale and can be employed for characterisation of materials of interest in the fields of catalysis and electroluminescence, amongst others. Here, we present its application to the optimisation of the ship-in-a-bottle synthesis of a novel electroluminescent polymer (PPV) and a photocatalyst (TP+), both encapsulated in large-pore zeolites.     

Solution-phase combinatorial libraries: modulating cellular signaling by targeting protein-protein or protein-DNA interactions

The high-throughput synthesis and screening of compound libraries hold tremendous promise for drug discovery and powerful methods for both solid-phase and solution-phase library preparation have been introduced. The question of which approach (solution-phase versus solid-phase) is best for the preparation of chemical libraries has been replaced by which approach is most appropriate for a particular target or screen. Herein we highlight distinctions in the two approaches that might serve as useful considerations at the onset of new programs. This is followed by a more personal account of our own focus on solution-phase techniques for the preparation of libraries designed to modulate cellular signaling by targeting protein-protein or protein-DNA interactions. The screening of our libraries against a prototypical set of extracellular and intracellular targets, using a wide range of assay formats, provided the first small-molecule modulators of the protein-protein interactions studied, and a generalized approach for conducting such studies.     

A library of chiral imidazoline-aminophenol ligands: discovery of an efficient reaction sphere

A library of imidazoline-aminophenol ligands was synthesized on solid supports. After immobilization of chiral chloromethylimidazolines 1 and 2 onto the polystyrylsulfonyl chloride, nucleophilic substitution with (R)- or (S)-phenylethylamine (3 and 4) provided four combinations of polymer-supported imidazoline-amine ligands. Further reductive alkylation using salicylaldehydes 7-10 provided a series of imidazoline-aminophenol ligands (L9-L24). Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95 % ee. The combination of stereogenic centers was crucial in promoting the highly stereoselective reactions. The unique reaction sphere of L25 was also examined in a Friedel-Crafts alkylation of indole and nitroalkene to give the adduct in up to 83 % ee.