Nitrogen-Containing Six-Membered Heterocycles: Solid-Phase Synthesis

Solid-phase organic synthesis is a rapidly expanding area of synthetic chemistry that is being widely exploited in the search for new medicinally important compounds using combinatorial techniques. In recent decades, a large number of reports related to solid-phase synthesis of heterocycles have appeared because of the wide variety of their biological activity. In this review, we report the important role of solid-phase synthesis in the synthesis of nitrogen containing six-membered ring heterocycles.     

聚乙二醇支载的杂环化合物库的液相合成

随着组合化学的迅速发展, 兼容固相合成和溶液相合成优点的液相合成方法已成为实现组合化学的一条重要途径. 综述了近年来聚乙二醇为可溶性聚合物载体支载的杂环化合物库的研究, 并展望了其今后的发展方向.     

液相组合化学

综述了液相组合化学的研究进展，重点介绍了液相组合合成中的分离纯化方法和合成方法策略，基本分离纯化方法包括利用固相载体协助分离纯化法，相萃取分离纯化法和色谱法，主要合成方法策略有平行合成策略和索引合成策略。     

Combinatorial library synthesis of antioxidant compounds

Since oxidative cellular damage contributes to the development of cancers, heart disease and ageing, the synthesis of antioxidative agents which are able to either prevent or mitigate oxidative stress to cells is an important area of investigation. Combinatorial chemistry has had a profound impact on the discovery and optimisation of potential lead compounds, especially in the medicinal field. This review details recent examples of combinatorial chemistry dealing with the synthesis of novel antioxidants with an emphasis on solid phase compound synthesis and parallel library synthesis.     

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.     

Solid-Phase Synthetic Approach Toward the Synthesis of Oxygen-Containing Heterocycles

Solid-phase organic synthesis is a rapidly expanding area of synthetic chemistry which is being widely exploited in the search for new medicinally important compounds using combinatorial techniques. In recent decades, a large number of reports related to solid-phase synthesis of heterocycles have appeared because of the wide variety in their biological activity. In this review, we report the important role of solid-phase synthesis in the synthesis of oxygen-bearing heterocycles.     

High resolution magic angle spinning NMR in combinatorial chemistry

Solid phase organic chemistry coupled with combinatorial methods promises to increase dramatically the diversity and number of small molecules available for medical and biological applications. However, optimizing the reaction conditions can be a time consuming step, especially since analytical tools to monitor reaction progress and detect impurities for solid phase chemistry are less developed than for solution chemistry. The use of high resolution magic angle spinning (HRMAS) NMR is described here as such an analytical tool. Whereas initial applications of molecular identification using deuterated organic solvents to swell the resins presented a significant gain in time over the cleave-and-analysis methods, the introduction of a differential diffusion filter has made immediate recording of spectra possible without any sample treatment. The applications of HRMAS NMR to different solid supports that are used in combinatorial chemistry will be described in terms of rapidity, robustness and sensitivity.     

固相有机合成研究进展

组合化学技术给固相有机合成带来了新的发展契机,同时也提出了新的发展要求。目前这一研究领域发展迅速,应用范围不断扩大,技术日臻完善。本文综述了近期固相有机合成研究方面的最新进展。     

The combinatorial synthesis of organophosphorus compounds

The primary literature concerning the combinatorial synthesis of organophosphorus compounds is reviewed and discussed. The subject matter is divided into three main sections describing the solid phase, solution phase and solvent-free synthesis of phosphorus containing organic molecules. The review covers the synthesis of compounds in which the final products contain phosphorus-carbon bonds, primarily phosphonates, phosphinates, phosphine oxides and phosphines.     

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.     

Preparation of new polyfunctional magnesiated heterocycles using a chlorine-, bromine-, or iodine-magnesium exchange

The reaction of heteroaryl iodides with i-PrMgBr (ca. 1.0 equiv) in THF provides the corresponding magnesiated heterocycles. Functional groups such as an ester, cyano, or chloride functions are tolerated in these new Grignard reagents if the exchange can be performed below -20 degrees C. This is the case for all heterocycles bearing electron-withdrawing groups or chelating functions facilitating the iodine-magnesium exchange. In many cases, the exchange can be extended to heteroaryl bromides, and a case of a chlorine-magnesium exchange is described with tetrachlorothiophene. This new preparation of functionalized heteroarylmagnesium compounds provides after reaction with various electrophiles a new entry to a broad range of polyfunctional pyridines, imidazoles, furanes, thiophenes, pyrroles, antipyrines, and uracil derivatives. The application of the halogen-magnesium exchange in the solid phase allows the performance of solid-phase synthesis, with potential applications for combinatorial chemistry.     

过渡金属催化合成含氮杂环化合物的研究进展

含氮杂环化合物是一类非常重要的有机杂环化合物,也是有机合成化学的研究热点之一。本文首先简要介绍了含氮杂环化合物在天然产物、合成药物和功能材料中的分布及其广泛应用;然后以不同过渡金属催化剂为线索,按照时间由远至近的顺序分别概述了Pd、Ag、Fe、Ni、Zn、Cu等六类过渡金属催化剂在合成五、六元含氮杂环化合物方面的研究进展,对反应条件、反应特征进行了概括;最后对含氮杂环化合物合成领域的过渡金属催化剂的整体发展趋势进行了归纳总结。     

卤素盐参与下有机电合成含氮杂环化合物的研究进展

含氮杂环化合物广泛存在于医药、农药及天然产物中,是许多具有生理活性的化合物和药物的基本骨架.开发高效、绿色的含氮杂环化合物的构建方法具有重要意义.近年来,卤素盐参与下有机电合成含氮杂环化合物取得了诸多进展.该类反应具有操作简单、绿色环保等特点.综述了有机电化学合成反应中,卤素盐作媒介,含氮杂环化合物的合成研究新进展.     

利用离子液体负载反应底物的有机合成

综述了固相、液相组合化学中以可溶性离子液体为载体的有机合成新概念及最新研究进展,并主要介绍了离子液体作为载体负载反应底物在有机合成中的一些应用,如有关的重要有机反应、组合化学、小分子库合成等。该方法具有上载率高、适用反应范围宽、分离纯化简便、结构检测容易和可回收重复使用等诸多优越性,这对于传统的固相、液相合成方法是一个重大的进步。     

Organic azides: an exploding diversity of a unique class of compounds

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aubé rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.     

Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives

The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed heterocycles belong to biologically active and industrially demanded compounds. Newly developed synthesis methods can be divided into conventional multistep processes and one-pot, atom economy procedures, realized using green chemistry principles and simple reagents. The easy functionalization of the 2-NH₂ and 2-SH groups and the benzene ring of the benzothiazole moiety allows considering them as highly reactive building blocks for organic and organoelement synthesis, including the synthesis of pharmacologically active heterocycles. The review provides a summary of findings, which may be useful for developing new drugs and materials and new synthetic approaches and patterns of reactivity.     

Mass spectrometry and combinatorial chemistry: new approaches for direct support-bound compound identification

Mass spectrometry is a powerful analytical tool allowing rapid and sensitive structural elucidation of a wide range of molecules issued from solution-, solid- and liquid-phase syntheses. Therefore, mass spectrometry has become the most widely used tool to probe combinatorial libraries. A significant portion of the reported combinatorial data are being produced using solid phase organic synthesis. In contrast to indirect strategies where the tethered structures were released from the support into solution to undergo standard mass spectrometric analyses, static - secondary ion mass spectrometry (S-SIMS) has enabled the identification of support-bound molecules without any chemical treatment of the resin bead. Such non-destructive characterization was applied at the bead level and facilitated the step-by-step monitoring of solid-phase peptide syntheses. Side-reactions were also detected. The relevance of S-SIMS in the rehearsal phase of combinatorial chemistry is demonstrated by comparison with infrared and nuclear magnetic resonance (NMR) spectroscopies, the two other techniques investigated in that field. An alternative to solid-phase synthesis consists of assembling molecules on a soluble polymer. This methodology is termed liquid-phase synthesis. Compound characterization is facilitated since the derivatized support is soluble in spectroscopic solvents used in NMR or in electrospray ionization mass spectrometry. The advantages and drawbacks of this approach will be discussed in terms of the direct monitoring of supported reactions during chemistry optimization and rehearsal library validation.     

Ketenes in polymer-assisted synthesis

Since its inception, ketene chemistry has developed into a unique and well-established source of useful transformations for conventional synthetic organic chemistry. It is, therefore, not surprising that soon after their movement from the realm of peptide and peptoid libraries to that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability of these versatile molecules to undergo reactions with nucleophiles, and to participate in cycloadditions and cyclocondensations, has been utilized for the preparation of diverse heterocyclic compounds, and has added to the advantages of polymer-assisted synthesis for rapid purification. Different types of ketenes and different methods for their generation have been involved, which illustrates the potential diversity of the chemistry. There is now a better grasp of the effect of the fragility of these sometimes transient molecules on the reactions involving solid supports, and this augurs well for the application of some of the more recent developments in ketene chemistry to the generation of small-molecule libraries.     

固相载体上的环加成反应及其应用

固相有机合成和组合化学是近年来发展起来的快速合成数种有机化合物的新方法。本文介绍了在固相载体上进行的环加成反应, 及其在有机合成及反应机理研究中的应用。     

Multicomponent reactions and combinatorial chemistry

Multi-component reactions (MCRs) constitute a methodology to shorter syntheses of natural products or complex molecules for drug discovery. Due to the large number of accessible compounds, this type of chemistry has become very popular between scientists who are working in the area of combinatorial chemistry. Over the last decade combinatorial chemistry has evolved from the synthesis of great quantity of simple compounds to the parallel synthesis of complex molecules with a widely varied structure. MCRs are ideally suited for this trend, being free of limitations of a traditional multistep synthesis. The close connection and interference of multicomponent reactions and combinatorial chemistry are discussed in this review.