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.     

High‐Throughput Reaction Optimisation and Activity Screening of Ferrocene‐Based Lewis Acid–Catalyst Complexes by Using Continuous‐Flow Reaction Detection Mass Spectrometry

Optimising synthetic conversions and assessing catalyst performance is a tedious and laborious endeavour. Herein, we present an automated alternative to the commonly applied sequential approaches that are used to increase catalyst discovery process efficiencies by increasing the number of entities that can be tested. This new approach combines conversion of the reactants and determination of product formation into a single comprehensive reaction detection system that can be operated with minimal catalyst and reactant consumption. With this approach, rudimentary reaction conditions can be quickly optimised and the same system can then be used to screen for the optimal homogenous catalyst in a selected solution‐phase synthetic conversion. The system, which is composed of standard HPLC components, can be used to screen catalyst libraries at a repetition rate of five minutes and can be run unsupervised. The sensitive mass spectrometric detection that is implemented in the reaction detection methodology can be used for the simultaneous monitoring of reactants, catalysts and product ions. In the experiments, the three‐component reaction that gives a substituted 2‐imidazoline was optimised. Afterwards, the same method was used to assess a library of ferrocene‐based Lewis acid catalysts for performance in the aforementioned conversion in six different solvents. We demonstrate the feasibility of using this methodology to directly compare the performance results obtained in different solvents by calibrating the solvent‐specific MS responses.     

The even-handed approach: strategies for the deployment of racemic chiral catalysts

Asymmetric catalysis is predominantly associated with the use of enantiomerically pure chiral ligands and catalysts. Although racemic chiral catalysts have been employed quite extensively in polymerization, their utility in mainstream organic synthesis and catalyst development has arguably been rather overlooked. This Minireview collates various themes for the strategic application of racemic ligands and catalysts, ranging from the estimation of selectivity and determination of enantiomeric excess, through to control of regio- and stereochemical outcomes, and mechanistic studies. What emerges is a clear picture that, in isolation or in concert with enantiopure catalysts, the "even-handed" approach has much to offer.     

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 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.     

High-throughput glycosylation analysis of intact monoclonal antibodies by mass spectrometry coupled with capillary electrophoresis and liquid chromatography

The analysis of monoclonal antibodies glycosylation is a crucial quality control attribute of biopharmaceutical drugs. High throughput screening approaches for antibody glycoform analysis are required in various stages of process optimization. Here, we present high throughput screening suitable mass spectrometry-based workflows for the analysis of intact antibody glycosylation out of cell supernatants. Capillary electrophoresis and liquid chromatography were coupled with quadrupole time-of-flight mass spectrometry or Orbitrap mass spectrometry. Both separation methods offer fast separation (10–15 min) and the capability to prevent the separated cell supernatant matrix to enter the mass spectrometry by post-separation valving. Both mass spectrometry instruments provide comparable results and both are sufficient to determine the glycosylation pattern of the five major glycoforms of the measured antibodies. However, the Orbitrap yields higher sensitivity of 25 μg/mL (CE-nanoCEasy-Orbitrap mass spectrometry) and 5 μg/mL (liquid chromatography-Orbitrap mass spectrometry). Data processing was optimized for a faster processing and easier detection of low abundant glycoforms based on averaged charge-deconvoluted mass spectra. This approach combines a non-target glycoform analysis while yielding the same glycosylation pattern as the traditional approach based on extracted ion traces. The presented methods enable the high throughput screening of the glycosylation pattern of antibodies down to low μg/mL-range out of cell supernatant without any sample preparation.     

液相色谱-高分辨质谱快速筛查海水中磺胺类药物

建立了海水中15种磺胺类药物的液相色谱-静电场轨道阱高分辨质谱方法.采用C18固相萃取膜提取海水中磺胺类药物,使用Hypersil GOLD Cl8色谱柱分离,乙腈和5 mmol/L乙酸铵(含0.1％甲酸)为流动相梯度洗脱.正离子模式全扫描/数据依赖二级扫描(Full MS/dd-MS2),提取一级质谱图中准分子离子的...     

Screening for pharmaco‐toxicologically relevant compounds in biosamples using high‐resolution mass spectrometry: a ‘metabolomic’ approach to the discrimination between isomers

High‐resolution mass spectrometry (HRMS) enables the identification of a chemical formula of small molecules through the accurate measurement of mass and isotopic pattern. However, the identification of an unknown compound starting from the chemical formula requires additional tools: (1) a database associating chemical formulas to compound names and (2) a way to discriminate between isomers. The aim of this present study is to evaluate the ability of a novel ‘metabolomic’ approach to reduce the list of candidates with identical chemical formula. Urine/blood/hair samples collected from real positive cases were submitted to a screening procedure using ESI‐MS‐TOF (positive‐ion mode) combined with either capillary electrophoresis or reversed phase liquid chromatography (LC). Detected peaks were searched against a Pharmaco/Toxicologically Relevant Compounds database (ca 50 500 compounds and phase I and phase II metabolites) consisting of a subset of PubChem compounds and a list of candidates was retrieved. Then, starting from the mass of unknown, mass shifts corresponding to pre‐defined biotransformations (e.g. demethylation, glucuronidation, etc.) were calculated and corresponding mass chromatograms were extracted from the total ion current (TIC) in order to search for metabolite peaks. For each candidate, the number of different functional groups in the molecule was automatically calculated using E‐Dragon software (Talete srl, Milan, Italy). Then, the presence of metabolites in the TIC was matched with functional groups data in order to exclude candidates with structures not compatible with observed biotransformations (e.g. loss of methyl from a structure not bearing methyls). The procedure was tested on 108 pharmaco‐toxicologically relevant compounds (PTRC) and their phase I metabolites were detected in real positive samples. The mean list length (MLL) of candidates retrieved from the database was 7.01 ± 4.77 (median, 7; range, 1–28) before the application of the ‘metabolomic’ approach, and after the application it was reduced to 4.08 ± 3.11 (median 3, range 1–17). HRMS allows a much broader screening for PTRC than other screening approaches (e.g. library search on mass spectra databases). The ‘metabolomic’ approach enables the reduction of the list of candidate isomers. Copyright © 2009 John Wiley & Sons, Ltd.     

高分辨质谱技术在农药残留检测中的应用

农药残留检测是农产品中有害物质控制的重要组成部分,随着农药残留限量标准体系的发展完善,农药残留检测方法也在不断进步。近年来质谱技术发展迅速,已被广泛应用于农药残留检测领域,高分辨质谱由于具有较高的分辨率和质量精确度,在复杂基质的农药多残留高通量检测中发挥着越来越重要的作用。本文从高分辨质谱与液相色谱、气相色谱及其他分离模式联用等方面出发,简述了近5年来高分辨质谱在农药残留检测中的应用,对目前高分辨质谱在农药残留检测应用中发现的问题进行了讨论,并对其未来发展趋势进行展望。     

Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors

A microscale chemistry improvement engine: a pre-dosed microscale high-throughput experimentation additives platform enables rapid, serendipitous reaction improvement. This platform allowed one chemist to set up 475 experiments and analyze the results using MISER chromatography in a single day, thus resulting in two high-quality catalytic systems for the construction of the title compound 1. Support for a single-electron transfer mechanism was obtained.