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.

Multicomponent Reactions with Isocyanides.

Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis.






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Figure 1


Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.

Chemistry and Biology Of Multicomponent Reactions

The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of organic synthesis and biochemical screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compounds in the thousands. With automated synthesis, the number of compounds to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chemical libraries are made wisely. The objective of this work is to provide both quantitative and qualitative characterization of known drugs which will help to generate “drug-like” libraries. In this work we analyzed the Comprehensive Medicinal Chemistry (CMC) database and seven different subsets belonging to different classes of drug molecules. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quantitative characterization ...

A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases.

The applications of copper (Cu) and Cu-based nanoparticles, which are based on the earth-abundant and inexpensive copper metal, have generated a great deal of interest in recent years, especially in the field of catalysis. The possible modification of the chemical and physical properties of these nanoparticles using different synthetic strategies and conditions and/or via postsynthetic chemical treatments has been largely responsible for the rapid growth of interest in these nanomaterials and their applications in catalysis. In addition, the design and development of novel support and/or multimetallic systems (e.g., alloys, etc.) has also made significant contributions to the field. In this comprehensive review, we report different synthetic approaches to Cu and Cu-based nanoparticles (metallic copper, copper oxides, and hybrid copper nanostructures) and copper nanoparticles immobilized into or supported on various support materials (SiO2, magnetic support materials, etc.), along with their applications i...

http://pubs.acs.org/doi/pdfplus/10.1021/acs.chemrev.5b00482

Cu and Cu-Based Nanoparticles: Synthesis and Applications in Catalysis.

Historically, the paradigm of drug development has followed an iterative cycle of screening and synthesis, involving the manipulation of individual structures. The feedstock of molecules for this process has traditionally incorporated both natural products and proprietary and commercial compound collections. The latter usually represent a collectively monumental effort of synthesis over a period of many years. The introduction of high-throughput biological screening and the accelerated discovery of new biological targets has increased the demand on synthetic chemists to produce new compounds for testing. One response to this demand has been the development of techniques to greatly increase the speed and efficiency of compound synthesis. In the case of peptides1-4 and oligonucleotides,5,6 combinatorial libraries containing large numbers of individual components have afforded high-affinity ligands and potent inhibitors to a variety of targets. However, synthetic methods for these biopolymers are well-established, and it is only recently that chemists have applied some of these strategies to the currently more difficult task of generating libraries of small-molecule therapeutics. In this Account, we will focus on multiple-component condensations (MCCs) as one subset of strategies for the generation of compound libraries. While most libraries have been generated using a linear, multistep process, MCCs provide a complementary approach to a number of structures and should find applications in library generation. Multiple-component condensations are those reactions in which three or more reactants come together in a single reaction vessel to form a new product which contains portions of all the components. These reactions may be carried out in solution or on a solid support. A catalyst or other additive which might facilitate the coupling of two other components in a reaction but which does not structurally contribute to the product is not considered a component in an MCC reaction. It is not necessary that all components condense in a mechanistically concerted fashion; however, the MCC reactions considered herein do not require extensive manipulations: they are one-pot reactions. In this and the succeeding section, it is instructive to contrast this approach with linear synthesis to highlight the differences in methods, potential library size, and output format. For example, an MCC reaction with four components provides, in a single step, a molecular scaffold characterized by a core set of atoms common to the condensation reaction and displaying aspects of the four components. In contrast, to achieve the same structure in a linear fashion, multiple steps with attendant workup cycles may be required. It is our belief that the methods used to synthesize a particular library are dictated by (1) the need for a specific core structure and (2) the commercial availability or ease of access to inputs which give the structural variability to the core. Approaches to desired core structures vary greatly, and the chosen route may be a linear synthesis, an MCC, or a combination of the two. The term linear synthesis as used in this Account refers to a multistep process requiring the isolation of intermediates or washing of the solid support resin and re-exposure to new reagents for each step of the synthesis. While synthetic chemists may be more familiar with the distinction between “linear” and “convergent” when applied to synthetic strategies, in this Account we refer to as linear any library strategy that builds up the target molecule one step at a time. By this definition, both a solid-phase peptide synthesis and, for example, Ellman’s 1,4-benzodiazepine synthesis7 (Figure 1) constitute linear syntheses, because each constructs the target skeleton in a stepwise manner. We define “linear” in this manner as a means of distinguishing the MCC strategy, which we feel is an underutilized tool for library synthesis.8 This Account will focus on two related core struc-

Multiple-Component Condensation Strategies for Combinatorial Library Synthesis

The concept of a “universal isocyanide” that enables postcondensation modification of Ugi four-component condensation products is introduced. This strategy is suited for the synthesis of libraries. By using 1-isocyanocyclohexene as the isocyanide input in the Ugi reaction, the product cyclohexenamides can be converted to a variety of products. From the original α-(acylamino) amides, new carboxylic acids, esters, and thioesters are produced from acid-activated conversion of the cyclohexenamide moiety. It has been determined that the intermediate in conversion of this type is an oxazolinium-5-one (munchnone) that reacts with many nucleophiles to yield the products above. The munchnone can also undergo cycloaddition with acetylenic dipolarophiles to form pyrroles. Through internal nucleophilic attack, Ugi products are shown to convert to a protected monosaccharide derivative and to 1,4-benzodiazepine-2,5-diones. All of the conversions described consist of a single step. Resin capture of Ugi products is demon...

Postcondensation Modifications of Ugi Four-Component Condensation Products: 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture

Molecular Diversity via a Convertible Isocyanide in the Ugi Four-Component Condensation

A two-step, general synthesis of 1,4-benzodiazepine-2,5-diones (BZDs) is presented. This synthesis employs an Ugi four-component condensation using a convertible isocyanide (1-isocyanocyclohexene), followed by an acid-activated cyclization reaction. This synthesis represents a dramatically improved route to BZDs over those currently in the literature. In addition, since amino acids are not used as inputs, the potential for molecular diversity is much greater than that with existing syntheses. It was also found that BZDs substituted with methylenes at the C-3 and N-4 positions display conformational isomerism in the NMR spectra at room temperature. Variable-temperature NMR experiments support this observation and offer the interesting conclusion that the BZD core structure, in certain examples, might not be as rigid as previously supposed.

Thomas A. Keating

Papers

Multiple-Component Condensation Strategies for Combinatorial Library Synthesis

Postcondensation Modifications of Ugi Four-Component Condensation Products: 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture

Molecular Diversity via a Convertible Isocyanide in the Ugi Four-Component Condensation

A Remarkable Two-Step Synthesis of Diverse 1,4-Benzodiazepine-2,5-diones Using the Ugi Four-Component Condensation.

Use of a convertible isocyanide for generation of Ugi reaction derivatives on solid support: Synthesis of α-acylaminoesters and pyrroles