Recent developments in the combinatorial synthesis of nitrogen heterocycles using solid phase technology

Recognizing the potential of combinatorial chemistry to accelerate drug discovery and development, most pharmaceutical and related industries are seriously looking toward combinatorial synthesis of compounds in order to facilitate the identification of 'lead' molecules. In particular, solid phase synthesis is the core technology for combinatorial chemistry and is widely used for generating libraries of structurally related compounds. Since many drugs contain the nitrogen heterocyclic component and since heterocycles possess a high order of structural diversity, a precise overview of recent progress in the combinatorial synthesis of nitrogen heterocycles using solid phase methodology would be useful. Since the progress in solid phase synthesis of organic molecules has been reviewed regularly from 1992 to 1998, only the development of solid phase combinatorial synthetic approaches of small nitrogen heterocycles since 1999 will be reviewed here. This review describes the solid phase synthesis of azepanes, benzodiazepines, benzimidazoles, benzothiazepines, cinnolines, indolizines, beta lactams, oxazepins, oxazoles including benzisooxazoles, hydantoins, piperidines, pyrimidines, pyrazolones, quinolones, trizolopyridazines and thiazoles.     

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.     

PEG based resins for protease drug discovery synthesis, screening and analysis of combinatorial on-bead libraries

This review will cover the entire hit identification process performed with biocompatible, aqueous solvated, poly[ethylene glycol] (PEG) based resins - from synthesis, through screening, to analysis. The different types of resins (including their preparation) will be discussed and compared individually. Examples of one-bead-one-compound substrate libraries will be presented, as will one-bead-two-compounds libraries used for the discovery of enzyme inhibitors. The review includes a section covering organic and bio-organic reactions performed on all-PEG resins and discusses on-bead screening of the libraries with biomolecules. Finally, analysis of compounds on single beads, either via investigation by on-bead NMR or by ladder-coding of the combinatorial compound is covered. In general, the review will focus on chemistry, libraries, synthesis, screening, and analysis, using all-PEG based resins.     

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.     

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.     

Modern separation techniques for the efficient workup in organic synthesis

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.     

From polymer to small organic molecules: a tight relationship between radical chemistry and solid-phase organic synthesis

Since Gomberg's discovery of radicals as chemical entities, the interest around them has increased through the years. Nowadays, radical chemistry is used in the synthesis of 75% of all polymers, inevitably establishing a close relationship with Solid-Phase Organic Synthesis. More recently, the interest of organic chemists has shifted towards the application of usual "in-solution" radical chemistry to the solid-phase, ranging from the use of supported reagents for radical reactions, to the development of methodologies for the synthesis of small molecules or potential libraries. The aim of this review is to put in perspective radical chemistry, moving it away from its origin as a synthetic means for solid supports, to becoming a useful tool for the synthesis of small molecules.     

Diversified strategy for the synthesis of DNA-encoded oxindole libraries

DNA-encoded library technology (DELT) employs DNA as a barcode to track the sequence of chemical reactions and enables the design and synthesis of libraries with billions of small molecules through combinatorial expansion. This powerful technology platform has been successfully demonstrated for hit identification and target validation for many types of diseases. As a highly integrated technology platform, DEL is capable of accelerating the translation of synthetic chemistry by using on-DNA compatible reactions or off-DNA scaffold synthesis. Herein, we report the development of a series of novel on-DNA transformations based on oxindole scaffolds for the design and synthesis of diversity-oriented DNA-encoded libraries for screening. Specifically, we have developed 1,3-dipolar cyclizations, cyclopropanations, ring-opening of reactions of aziridines and Claisen–Schmidt condensations to construct diverse oxindole derivatives. The majority of these transformations enable a diversity-oriented synthesis of DNA-encoded oxindole libraries which have been used in the successful hit identification for three protein targets. We have demonstrated that a diversified strategy for DEL synthesis could accelerate the application of synthetic chemistry for drug discovery.

Constructing DNA-encoded oxindole libraries by a diversified strategy.     

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.     

生物催化在药物合成中的应用

生物转化是生产单一对映体产品的有效方法。水解酶是最常用的一种酶，特别 是脂肪酶广泛使用于水解，酯化和氨解反应中。在有机合成中很少被使用的裂合酶 也开始引起人们的关注，例如，用（R）-醇腈酶可以合成具有光学活性的氰醇，它 是一种重要的医药中间体。主要介绍了用于医药化学领域的四种生物催化反应：酶 法醇的转化、酶法胺的区域选择性乙酰化、天然产物的烷氧羰基化和以（R）-醇腈 酶为催化剂，化学-酶法合成高附加值的产品的反应。     

Probing the bioactivity-relevant chemical space of robust reactions and common molecular building blocks

In the search for new bioactive compounds, there is a trend toward increasingly complex compound libraries aiming to target the demanding targets of the future. In contrast, medicinal chemistry and traditional library design rely mainly on a small set of highly established and robust reactions. Here, we probe a set of 58 such reactions for their ability to sample the chemical space of known bioactive molecules, and the potential to create new scaffolds. Combined with ~26,000 common available building blocks, the reactions retrieve around 9% of a scaffold-diverse set of compounds active on human target proteins covering all major pharmaceutical target classes. Almost 80% of generated scaffolds from virtual one-step synthesis products are not present in a large set of known bioactive molecules for human targets, indicating potential for new discoveries. The results suggest that established synthesis resources are well suited to cover the known bioactivity-relevant chemical space and that there are plenty of unexplored regions accessible by these reactions, possibly providing valuable "low-hanging fruit" for hit discovery.     

Multicomponent Reactions with Isocyanides

Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the "language" of MCRs, something that this review wishes to stimulate.     

The Inner Phase of Molecular Container Compounds as a Novel Reaction Environment

The conceptual idea of molecular container compoundsand their synthesis has opened an entirely new andvery interesting research field: the chemistry of andwithin molecular container compounds and theircomplexes. Molecular containers have inner phases justlarge enough to accommodate a single guest molecule.Beginning with Donald J. Cram's first synthesis of acarcerand, which permanently entrapped a single guestmolecule, many other containers such ashemicarcerands, molecular lantern, self-assembledcapsules and fullerenes have been synthesized andstudied. Not only is the design and development of newcontainer compounds an ongoing challenge for organicchemists, but also the systematic investigation ofchemical reactions within their inner phases. Theresults of a large variety of inner phase reactionsspanning acid-base, reduction, oxidation, nucleophilicsubstitution, addition, thermal, photochemical andpericyclic reactions have provided us with moreinsight into the relationship between bulk phase andinner phase reactants and the mechanism of thetransfer of electrons and photons through theinsulating shell of a container molecule. They havealso led to very spectacular applications of molecularcontainer compounds such as the stabilization ofreactive intermediates by incarceration. Thesehighlights of inner phase chemistry and the currentefforts and successes towards using molecularcontainers as catalytic reaction vessels are presentedand discussed.     

Microwave-assisted reactions in heterocyclic compounds with applications in medicinal and supramolecular chemistry

Microwave irradiation has been successfully applied in organic chemistry. Spectacular accelerations, higher yields under milder reaction conditions and higher product purities have all been reported. Indeed, a number of authors have described success in reactions that do not occur under conventional heating and modifications in selectivity (chemo-, regio- and stereoselectivity) have even been reported. Recent advances in microwave-assisted combinatorial chemistry include high-speed solid-phase and polymer-supported organic synthesis, rapid parallel synthesis of compound libraries, and library generation by automated sequential microwave irradiation. In addition, new instrumentation for high-throughput microwave-assisted synthesis continues to be developed at a steady pace. The impressive speed combined with the unmatched control over reaction parameters justifies the growing interest in this application of microwave heating. In this review we highlight our recent advances in this area, with a particular emphasis on cycloaddition reactions of heterocyclic compounds both with and without supports, applications in supramolecular chemistry and the reproducibility and scalability of organic reactions involving the use of microwave irradiation techniques.     

From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries

In the continuing effort to find small molecules that alter protein function and ultimately might lead to new drugs, combinatorial chemistry has emerged as a very powerful tool. Contrary to original expectations that large libraries would result in the discovery of many hit and lead structures, it has been recognized that the biological relevance, design, and diversity of the library are more important. As the universe of conceivable compounds is almost infinite, the question arises: where is a biologically validated starting point from which to build a combinatorial library? Nature itself might provide an answer: natural products have been evolved to bind to proteins. Recent results in structural biology and bioinformatics indicate that the number of distinct protein families and folds is fairly limited. Often the same structural domain is used by many proteins in a more or less modified form created by divergent evolution. Recent progress in solid-phase organic synthesis has enabled the synthesis of combinatorial libraries based on the structure of complex natural products. It can be envisioned that natural-product-based combinatorial synthesis may permit hit or lead compounds to be found with enhanced probability and quality.     

Organic Chemistry on Solid Supports

Until recently, repetitive solid-phase synthesis procedures were used predominantly for the preparation of oligomers such as peptides, oligosaccharides, peptoids, oligocarbamates, peptide vinylogues, oligomers of pyrrolin-4-one, peptide phosphates, and peptide nucleic acids. However, the oligomers thus produced have a limited range of possible backbone structures due to the restricted number of building blocks and synthetic techniques available. Biologically active compounds of this type are generally not suitable as therapeutic agents but can serve as lead structures for optimization. “Combinatorial organic synthesis” has been developed with the aim of obtaining low molecular weight compounds by pathways other than those of oligomer synthesis. This concept was first described in 1971 by Ugi.^[56f,g,59c] Combinatorial synthesis offers new strategies for preparing diverse molecules, which can then be screened to provide lead structures. Combinatorial chemistry is compatible with both solution-phase and solid-phase synthesis. Moreover, this approach is conducive to automation, as proven by recent successes in the synthesis of peptide libraries. These developments have led to a renaissance in solid-phase organic synthesis (SPOS), which has been in use since the 1970s. Fully automated combinatorial chemistry relies not only on the testing and optimization of known chemical reactions on solid supports, but also on the development of highly efficient techniques for simultaneous multiple syntheses. Almost all of the standard reactions in organic chemistry can be carried out using suitable supports, anchors, and protecting groups with all the advantages of solid-phase synthesis, which until now have been exploited only sporadically by synthetic organic chemists. Among the reported organic reactions developed on solid supports are Diels–Alder reactions, 1,3-dipolar cycloadditions, Wittig and Wittig–Horner reactions, Michael additions, oxidations, reductions, and Pd-catalyzed C? C bond formation. In this article we present a comprehensive review of the previously published solid-phase syntheses of nonpeptidic organic compounds.     

Combining coordination and supramolecular chemistry for the formation of uranyl-organic hybrid materials

Three hybrid compounds have been synthesized through hydrothermal reactions of UO(2)(NO(3))(2)·6H(2)O with 4-halobenzoic acid (X = Cl, Br, I). The formation of these compounds utilizes a composite synthesis methodology that explicitly employs aspects of both coordination chemistry and supramolecular chemistry (namely halogen···halogen interactions).     

Microwave Assisting Solid Phase Organic Reactions-Approach to the Efficient Solid Phase Organic Synthesis

Solid phase organic synthesis provides a rapid mean for the preparation of compounds libraries, and has been successfully used for the construction of both oligometric compounds and small molecule compounds libraries^[1]. That leads the resurgence of interest in solid phase organic synthesis, which encourages organic chemists to develop new reliable reactions, linkers and analytical techniques.     

Two-vial, LC-MS identification of ephedrine receptors from a solution-phase dynamic combinatorial library of over 9000 components

Reports on dynamic combinatorial chemistry have almost exclusively involved small libraries of 10-100 compounds. We now show how more than 9000 compounds can be screened in a single LC-MS analysis to reveal a series of new receptors that bind ephedrine in water. These results demonstrate the feasibility of screening DCLs that are substantially larger than the solution-phase libraries reported thus far.