催化不对称反应最新进展(Ⅱ)－组合化学方法之 应用

组合化学技术已经成为药物、新型固体材料和催化剂合成、评价和筛选的一种有力工具,最近它在催化不对称反应的手性催化剂高效率合成与筛选方面的应用也受到了重视,本文将综述组合化学技术在发展不对称合成新型催化剂方面的应用。第一部分主要介绍手性催化剂(或配体)库的固相平行合成;第二部分重点总结了所建立的手性催化剂库的高效率评价技术及其应用。     

The Application of Combinatorial Chemistry in Catalysis

In recent few years combinatorial methodology has been extensively used in material science research. Based on the desired properties of materials, various high throughput synthesizing and screening technologies were developed. These high throughput technologies can increase our speed to more than hundred folds for finding and optimizing materials. One of the most active areas is catalysis. Scientists are developing novel high throughput technologies to screen catalyst libraries to find and optimize new catalysts for chemical industry. In this area die key is combinatorial catalytic reactor design, catalyst library synthesis, and product detection. Systematic technologies for catalyst library synthesis and characterization were developed in our laboratory. In this work, catalyst in situ synthesis, parallel reactor design, and detection methods will be introduced. Combining with the powerful combinatorial methodology, good chemistry design will make our work even more efficient. Hence, as an example of combining combinatorial technologies with chemistry design, a successful catalyst design is also introduced.     

Combinatorial Chemistry—Challenge and Chance for the Development of New Catalysts and Materials

One should not underestimate the capability of the combinatorial method in solid-state chemistry; this is the opinion of the author. Combinatorial chemistry can provide a large number of new compounds, but once the components that are interesting for a certain application have been successfully selected, the techniques of conventional catalysis and materials research are required. The strengths of conventional chemistry lie in the optimization, systematic modification, and improvement of new lead structures. In contrast, discovery is the potential strength of combinatorial chemistry. Careful design is most important for the synthesis of useful libraries, since the diversity of the periodic table is much too large to be accessed comprehensively or systematically by such large libraries.     

Discovery of new heterogeneous catalysts for the selective oxidation of propane to acrolein

Combinatorial synthesis and screening technique have been applied to investigate the catalytic activity and selectivity of ternary and quaternary mixed-metal oxide catalysts for the selective oxidation of propane. The catalyst libraries were prepared via a modified sol-gel method using a synthesis robot and library design software, and examined for the catalytic activities in a simple high-throughput reactor system connected to a mass spectrometer for product analysis. Ternary Mo-Cr-Te, V-Cr-Sb, and Mo-V-Cr catalysts have been selected for potential candidate by composition spread approach. In a next generation composition spread library, the composition space of these three ternary compositions was sampled. Screening of this 198-member library provided substantial evidence that each ternary system has its own optimum composition where acrolein formation is highest. In addition, the composition space of the quaternary reference system Mo-V-Te-Nb mixed-oxides has also been prepared and sampled.     

Integrating virtual screening and combinatorial chemistry for accelerated drug discovery

Virtual screening is increasingly being used in drug discovery programs with a growing number of successful applications. Experimental methodologies developed to speed up the drug discovery processes include high-throughput screening and combinatorial chemistry. The complementarities between computational and experimental screenings have been recognized and reviewed in the literature. Computational methods have also been used in the combinatorial chemistry field, in particular in library design. However, the integration of computational and combinatorial chemistry screenings has been attempted only recently. Combinatorial libraries (experimental or virtual) represent a notable source of chemically related compounds. Advances in combinatorial chemistry and deconvolution strategies, have enabled the rapid exploration of novel and dense regions in the chemical space. The present review is focused on the integration of virtual and experimental screening of combinatorial libraries. Applications of virtual screening to discover novel anticancer agents and our ongoing efforts towards the integration of virtual screening and combinatorial chemistry are also discussed.     

固态组合化学及其在材料科学中的应用

概述了固态组合化学的概念及其在新材料开发中的应用 ,着重阐述了材料化合物薄膜库的组合制备方法和筛选技术的特点 ,简述了固态组合化学技术在超导、巨磁阻、磷光、催化剂、沸石等新材料开发中的应用以及固态组合化学现有技术中的困难和今后的发展方向     

Quantitative electrospray mass spectrometry for the rapid assay of enzyme inhibitors

Background: Combinatorial chemistry has become an important method for identifying effective ligand-receptor binding, new catalysts and enzyme inhibitors. In order to distinguish the most active component of a library or to obtain structure-activity relationships of compounds in a library, an efficient quantitative assay is crucial. Electrospray mass spectrometry has become an indispensable tool for qualitatively screening combinatorial libraries and its use for quantitative analysis has recently been demonstrated.Results: This paper describes the use of quantitative electrospray mass spectrometry for screening libraries of inhibitors of enzymatic reactions, specifically the enzymatic glycosylation by β-1,4-galactosyltransferase, which catalyzes the transfer of galactose from uridine-5′-diphosphogalactose to the 4-position of N-acetylglucosamine βOBn (Bn: benzene) to form N-acetyllactosamine βOBn. Our mass spectrometric screening approach showed that both nucleoside diphosphates and triphosphates inhibited galactosyltransferase while none of the nucleoside monophosphates, including uridine-5′-monophosp hate, showed any inhibition. Additional libraries were generated in which the concentrations of the inhibitors were varied and, using mass spectrometry, uridine-5′-diphosphate-2-deoxy-2-fluorogalactose was identified as the best inhibitor.Conclusions: This report introduces quantitative electrospray mass spectrometry as a rapid, sensitive and accurate quantitative assaying tool for inhibitor libraries that does not require a chromophore or radiolabeling. A viable alternative to existing analytical techniques is thus provided. The new technique will greatly facilitate the discovery of novel inhibitors against galactosyltransferase, an enzyme for which there are few potent inhibitors.     

Synthesis and mass spectrometry studies of branched oxime ether libraries. Mapping the substitution motif via linker stability and fragmentation pattern.

The oxime ether chemistry has recently been used as a convenient approach to preparing potentially highly diverse combinatorial libraries. The synthetically easiest way to form the libraries is convergent, i.e., via reaction of a branched scaffold containing two or more aminooxy linker groups, with a variety of carbonyl substituents. We show here that such reactions between aldehydes and ketones of different structure with the scaffolds containing different types of aminooxy groups can lead to the formation of virtually all expected components in the model mixtures 1-3 formed from three scaffolds (7-9) and eight substituents (R(1)-R(8)). One important problem with the branched libraries is that the libraries formed from the more complex scaffolds, such as 11, contain multiple regioisomers. The results of extensive analysis of a variety of library components by mass spectrometry presented here show that the differences in the MS-MS fragmentation energies for different linkers yield regiochemical information essential for identification of individual library components.     

Eine neuartige Methode zur Analyse kombinatorischer Substanzbibliotheken mittels paramagnetischer Reporter

A Novel Method to Identify Chemical Compounds of Combinatorial Libraries by the Use of Paramagnetic Tags An EPR method to identify non‐destructively chemical compounds bound to a single solid‐phase‐synthesis bead for combinatorial chemistry applications is discribed. During synthesis chemical inert paramagnetic substances can be attached in small amounts to a solid‐phase‐synthesis resin for tagging of organic compounds or even reaction steps. The identification of single members of a combinatorial library in short time and high sensitivity can be carried out by using an EPR‐spectrometer.     

High Speed Development and Synthesis of Novel Small Molecule Libraries

Combinatorial chemistry has produced libraries of millions of compounds in the last decade. Screening of those compounds, unfortunately, has not yet yielded as many new drug candidates as initially expected. Among a number of possible reasons, one is that many libraries combinatorial chemistry produced in the early periods are of the nature of linear, flat, and flexible molecules such as peptides and oligonucleotides, which do not have the desired properties to selectively interact with their targets to yield high quality hits and leads. In order to increase the number of quality hits and leads, rigid, structural featurerich and drug-like compound libraries are highly desirable. Design and development of structural features-rich and natural product-like combinatorial libraries, as well as high speed library production using modern solution and solid phase synthesis techniques such as IRORI's Directed Sorting technology, will be discussed.     

Combinatorial Heterogeneous Catalysis-A New Path in an Old Field

Combinatorial catalysis is the systematic preparation, processing, and testing of large diversities of chemically and physically different materials libraries in a high-throughput fashion. It also embodies microfabrication, robotics, automation, instrumentation, computational chemistry, and large-scale information management (informatics), and as such carries the promise of a renaissance in catalytic reaction engineering. Significant progress has already been made in demonstrating the speed and economic advantage of combinatorial approaches by the discovery of superior catalytic materials in a matter of hours and days, as opposed to the months and years required using traditional methods. Combinatorial methods can also significantly contribute to our understanding of catalytic function by increasing our chances of discovering totally new and unexpected catalytic materials, and by expediting the recognition of trends and patterns of structure-activity relations, from which new catalytic materials can be designed more efficiently. Combinatorial catalysis undoubtedly will be the new paradigm of catalysis research as the industry faces increasing global competition and pressure for the development of environmentally friendly processes at a time when resources for research are diminishing.     

A novel approach to high-throughput quality control of parallel synthesis libraries

Combinatorial chemistry is a powerful tool to enhance drug discovery efforts in the pharmaceutical industry. One type of combinatorial chemistry, parallel synthesis, is now widely used to prepare numerous compounds of structural diversity. A novel high-throughput method for quality control of parallel synthesis libraries has been developed. The method uses flow injection MS, for proof of structure and estimation of purity, and a novel direct injection CLND technique for quantitation of amount. Following the synthesis of a small molecule library, compounds analyzed using this technique were characterized by mass spectrometry, and an accurate concentration of the compound was assessed by CLND. Characterization of one compound is completed in 60 s, allowing for up to 1000 compounds to be analyzed in a single day. The data is summarized using pass/fail criteria using internally developed software.     

Molecular libraries in liquid phase via UGI-MCR

Standard chemistry prescribes the conversion of one or two compounds into their products. In contrast, Eintopf (one-pot) multicomponent reactions (MCRs) involve at least three different compounds. One-pot MCRs are a useful tool in combinatorial chemistry: From a mixture of educts a large number of products can be simultaneously formed in liquid phase, called a soluble molecular library. The member compounds of such libraries are investigated simultaneously for desired properties, e.g. antibiotic activity. The main constraint is, that the underlying chemistry must not produce unknown side reactions and must lead to a broad spectrum of stable products with high yields. Isocyanide multicomponent chemistry allows the generation of soluble libraries of very different sizes, which are easy to screen for biological or pharmaceutical efficacy using the algorithms presented. Products can easily be enumerated and the kinetics of the isocyanide chemistry is simple to investigate. Combinatorial chemistry is capable of generating and optimizing leads faster and with fewer resources than by conventional means. Combinatorial chemistry based on isocyanide chemistry is by far the most important and most impressive technique in use today to reducing time and costs associated with lead generation and optimization during the drug discovery process. The simplicity of the reaction conditions involved means that the generation and screening of libraries can be automated.     

Nucleic acids for recognition and catalysis: landmarks, limitations, and looking to the future

Combinatorial selection of nucleic acids has led to the discovery of novel ligands and catalysts that have implications for both chemistry and medicine. In the context of combinatorial chemistry, degenerate syntheses of nucleic acid libraries readily generate as many as 10(15) different molecules in which a small percentage exhibit interesting binding and/or catalytic properties. The primary advantage of nucleic acids is that library coding is an intrinsic property; sequential composition directly determines the activity. At low temperatures, the sequential composition of single stranded nucleic acids governs folding into irregular tertiary structures resulting in interesting activities. At higher temperatures, the same structures are unfolded and decoded by polymerases to reveal sequential information. The use of PCR (polymerase chain reaction) permits amplification and thus enrichment of the selected activity which is then regenerated chemi-enzymatically. Iterative selection and amplification result in one of the highest throughput screens conceivable whereby each molecule encodes its own activity permitting the ultimate in parallel sampling. Finally, sequence information, and by extension the chemical composition, is obtained by simple sequencing techniques obviating the need for mass spectrometric deconvolution, parallel tagging, and/or large volumes needed for viral and cell culture. This review begins with an introduction of general concepts and considerations. The potential for nucleic acids to generate tight-binding ligands is of interest to structural biologists and medicinal chemists. The therapeutic implications to medicine are also touched upon. Since combinatorially selected nucleic acids and antibodies share many conceptual similarities, their respective advantages and limitations are compared. Theoretical and practical limitations for catalyst discovery are discussed along with the use of other chemical and physical approaches to address some current catalytic shortcomings. Finally some future directions are suggested.     

Discovery of Novel Catalysts for Alkene Epoxidation from Metal-Binding Combinatorial Libraries

New lead structures for olefin oxidation catalysts have been obtained from a combinatorial library of 5760 metal–ligand complexes (see the microscopy picture). Iron complexes led to clean epoxide product formation using H₂O₂ as the terminal oxidant. Parallel libraries were used to determine ligand features important for high catalytic activity and to identify enantioselective catalyst structures (see the Equation).     

化合物库的组合技巧和组合合成

从化合物库的组合技巧和组合合成方法两个方面探讨了组合化学及其在药物开发中的应用。     

Streamlined approach to high-quality purification and identification of compound series using high-resolution MS and NMR

Automated medicinal chemistry (parallel chemistry) has become an integral part of the drug-discovery process in almost every large pharmaceutical company. Parallel array synthesis of individual organic compounds has been used extensively to generate diverse structural libraries to support different phases of the drug-discovery process, such as hit-to-lead, lead finding, or lead optimization. In order to guarantee effective project support, efficiency in the production of compound libraries has been maximized. As a consequence, also throughput in chromatographic purification and analysis has been adapted. As a recent trend, more laboratories are preparing smaller, yet more focused libraries with even increasing demands towards quality, i.e. optimal purity and unambiguous confirmation of identity. This paper presents an automated approach how to combine effective purification and structural conformation of a lead optimization library created by microwave-assisted organic synthesis. The results of complementary analytical techniques such as UHPLC-HRMS and NMR are not only regarded but even merged for fast and easy decision making, providing optimal quality of compound stock. In comparison with the previous procedures, throughput times are at least four times faster, while compound consumption could be decreased more than threefold.     

组合化学在功能材料合成方面的应用

组合化学方法是当今材料科学和化学领域的研究热点。组合化学方法首先在新药的合成领域得到应用, 很快就以其合成周期短、合成的样品数量大、节约经费等诸多优点而拓展到功能材料的合成等其它领域。组合化学的方法有许多种, 按照反应相的不同可以分为液相中的组合合成法和固相中的组合合成法, 固相组合合成又可以根据所选用的掩模方式的不同而分为二分阴影掩模法、四分阴影掩模法、可移动百叶窗式掩模法等几种, 可以根据材料合成的实际需求加以选择。