Since 1995 the new chemistry of multicomponent reactions and their libraries,including their heterocyclic chemistry

A growing number of products, including many heterocycles, can be prepared by the one‐pot MultiComponent Reactions (MCRs) just by mixing three or more educts, and in many cases practically quantitative yields of pure products can be obtained. The 3CR by α‐aminoalkylations of nucleophiles began in the middle of the last century, and the syntheses of heterocycles by MCRs of three and four components were introduced by Hantzsch in the 1880s. The MCRs of the isocyanides with four and more educts began in 1959, and their compound libraries were mentioned since 1961. However, only since 1995 the often automated one‐pot chemistry of the MCR of the isocyanides is used extensively. If a chemical compound can be prepared by a sequence of two component reactions or a suitable MCR, the latter is always a superior procedure. The U‐4CR can be combined with other chemical reactions and MCRs as one‐pot reactions of n > 4 components, and such unions even have a much greater variety of structurally and stereochemically different products. The educts and products of Ugi‐type MCRs are more variable than those of all previous chemical reactions and other MCRs. Due to the progress in screening and automation processes in the last few years, many new compounds have been formed and investigated more rapidly than ever before. The search for new desirable products can be accomplished more than 10,000 times faster than by the older conventional methods. The now popular chemistry of the MCRs of the isocyanides fills the since long empty part of organic chemistry.     

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.     

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 multicomponent reactions and their libraries for natural and preparative chemistry

It was recently recognized that three different types of multi-component reactions (MCRs) exist. In preparative chemistry, the MCRs of type II form their products particularly efficiently. These reactions correspond to equilibria of educts and intermediate products, whose final products are formed practically irreversibly. In recent years, the four component reaction of the isocyanides (U-4CR) of type II and their unions with various reactions and MCRs have become an important industrial process for preparing products and their libraries. It has been demonstrated that all conceivable collections of U-4CR educts can be converted into the corresponding products. In the usual chemical reactions, only the substituents of the products can be varied, whereas the U-4CR and related reactions can also produce skeletally different types of products with diverse substituents. The preparative advantages of forming products by the one-pot MCRs and the great variety of the possible products are illustrated in this review.     

Recent developments in asymmetric multicomponent reactions

Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs.     

Trityl Isocyanide as a Mechanistic Probe in Multicomponent Chemistry: Walking the Line between Ugi‐ and Strecker‐type Reactions

Herein, we describe the versatile application of triphenylmethyl (trityl) isocyanide in multicomponent chemistry. This reagent can be employed as a cyanide source in the Strecker reaction and as convertible isocyanide in the preparation of N‐acyl amino acids by Ugi 4CR/detritylation and free imidazo[1,2‐a]pyridin‐3‐amines by a Groebke–Blackburn–Bienaymé 3CR condensation/deprotection protocol. The mechanisms of these three classical MCRs intersect at the common N‐trityl nitrilium ion intermediate, whose predictable reactivity can be exploited towards chemoselective transformations.     

组合化学、分子库与新药研究

组合化学是进入90 年代以来寻找及优化新药先导化合物的主要研究方法, 其特点是改变了传统的逐一合成、逐一纯化、逐一筛选的模式, 而是以合成和筛选化学库的形式完成寻找及优化药物先导化合物, 极大地加快了药物先导化合物出现的速度。本文就目前有关组合化学研究的基本理论、基本方法、发展趋势、研究成果以及我国应当采取的措施进行了综述。     

A "single-sample concept" (SSC): a new approach to the combinatorial chemistry of inorganic materials

Combinatorial estimations show that, within an unreacted ceramic sample prepared by mixing N different starting materials MxOy with average particle size approximately 1 microm, there are about 10(12) grains per cubic centimeter, sufficient for local reactions to occur that may produce a larger number of product oxides than presently accessible by 2D plate techniques. The "single-sample concept" (SSC) is proposed for performing property-directed syntheses for the preparation of ferri-/ferromagnetic or superconducting compounds. Because of the magnetic properties of the products, libraries of product grains can be sorted by means of magnetic separation techniques. For materials with a large magnetization, the separation efficiency is so high that traces of products can be isolated. The SSC concept was tested experimentally to prepare Fe-based oxides (N=17, 24, 30). The large yields (<75 wt %, N=17) of product grains agree with the literature data, which indicate that 3d metal magnetic oxide phases (Tc>300 K) are most probably Fe oxides. In combination with magnetic separation techniques, SSC seems particularly adapted for exploring the solid-state chemistry of metallic lead elements that form ferri-/ferromagnetic or superconducting oxide phases difficult to detect systematically within the large phase space of theoretically existing compounds.     

用组合化学建立天然产物类似物库

天然产物是药物先导化合物的重要来源.组合化学技术在天然产物的研究中起着越来越重要的作用.目前已构建并合成了许多以天然产物为模板的化合物库,为基于天然产物的药物研究开辟了广阔的空间.     

Base Metal Catalyzed Isocyanide Insertions

Isocyanides are diverse C₁ building blocks considering their potential to react with nucleophiles, electrophiles, and radicals. Therefore, perhaps not surprisingly, isocyanides are highly valuable as inputs for multicomponent reactions (MCRs) and other one‐pot cascade processes. In the field of organometallic chemistry, isocyanides typically serve as ligands for transition metals. The coordination of isocyanides to metal centers alters the electronic distribution of the isocyano moiety, and reaction pathways can therefore be accessed that are not possible in the absence of the metal. The tunable reactivity of the isocyanide functional group by transition metals has evolved into numerous useful applications. Especially palladium‐catalyzed isocyanide insertion processes have emerged as powerful reactions in the past decade. However, reports on the use of earth‐abundant and cheap base metals in these types of transformations are scarce and have received far less attention. In this Minireview, we focus on these emerging base metal catalyzed reactions and highlight their potential in synthetic organic chemistry. Although mechanistic studies are still scarce, we discuss distinct proposed catalytic cycles and categorize the literature according to 1) the (hetero)atom bound to and 2) the type of bonding with the transition metal in which the (formal) insertion occurs.     

Copper-Catalyzed Borylative Couplings with C−N Electrophiles

Copper-catalyzed borylative multicomponent reactions (MCRs) involving olefins and C−N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper-catalyzed MCRs are particularly attractive because they use a relatively abundant and non-toxic catalyst to selectively deliver high-value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C−N electrophiles.     

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.     

Sequential one-pot combination of multi-component and multi-catalysis cascade reactions: an emerging technology in organic synthesis

Creating sequential one-pot combinations of multi-component reactions (MCRs) and multi-catalysis cascade (MCC) reactions is a challenging task that has already emerged as a new technology in synthetic organic chemistry. Through one-pot sequential combination of MCRs/MCC reactions, the chemical products (fine chemicals, agrochemicals and pharmaceuticals) that add value to our lives can be produced with less waste and greater economic benefits. Within this Emerging Area, we describe our recent developments and designs for sequential one-pot MCRs/MCC reactions to facilitate their realization as biomimetics in organic chemistry.     

点击化学及其应用

点击化学反应选用易得原料，通过可靠、高效化学反应快速合成大量新化合物，且反应条件温和、产物收率高和不需要专门的分离提纯。本文介绍了点击化学（click chemistry）的一些基本概念，综述了点击化学作为一种新的合成方法在药物中的先导化合物库、糖类化合物、天然化合物、生物大分子和高分子中聚合物上的应用，并对其发展前景进行了展望。     

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.     

The multiple multicomponent approach to natural product mimics: tubugis, N-substituted anticancer peptides with picomolar activity

The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide-N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four-component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs.     

A gradient descent algorithm for minimizing amino acid coupling reactions when synthesizing cyclic-peptide libraries

Combinatorial chemistry has become an invaluable tool in medicinal chemistry for the identification of new drug leads. For example, libraries of predetermined sequences and head-to-tail cyclized peptides are routinely synthesized in our laboratory using the IRORI approach. Such libraries are used as molecular toolkits that enable the development of pharmacophores that define activity and specificity at receptor targets. These libraries can be quite large and difficult to handle, due to physical and chemical constraints imposed by their size. Therefore, smaller sub-libraries are often targeted for synthesis. The number of coupling reactions required can be greatly reduced if the peptides having common amino acids are grouped into the same sub-library (batching). This paper describes a schedule optimizer to minimize the number of coupling reactions by rotating and aligning sequences while simultaneously batching. The gradient descent method thereby reduces the number of coupling reactions required for synthesizing cyclic peptide libraries. We show that the algorithm results in a 75% reduction in the number of coupling reactions for a typical cyclic peptide library.     

Applications of Multicomponent Reactions to the Synthesis of Diverse Heterocyclic Scaffolds

The sequencing of multicomponent reactions (MCRs) and subsequent cyclization reactions is a powerful stratagem for the rapid synthesis of diverse heterocyclic scaffolds. The optimal MCR is sufficiently flexible that it can be employed to generate adducts bearing a variety of functional groups that may then be selectively paired to enable different cyclization manifolds, thereby leading to a diverse collection of products. The growing interest in diversity‐oriented synthesis has led to increased attention to this paradigm for library synthesis, which has inspired many advances in the design and implementation of MCRs for the construction of diverse heterocyclic scaffolds.     

Glycoconjugate libraries accessed by multicomponent reactions

Glycobiology opens a wide field for new therapeutic approaches. However, the complexity and unavailability of various carbohydrate test compounds has excluded this class of natural products from modern screening systems. Alternatively, glycomimetics are considered to be more drug-like candidates for development. By means of multicomponent condensations (MCCs) utilizing suitable carbohydrate synthons, rapid and effective access to glycoconjugate libraries can be obtained. The flexibility of MCCs allows the assembly of diverse carbohydrate containing libraries. It may be assumed that MCCs containing carbohydrate moieties will play an important role in glycomimetic chemistry and biology.