Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity
TL;DR: An overview of general strategies that allow the design of novel multicomponent reactions is presented and the challenges and opportunities for the future are discussed.
Abstract: Multicomponent reactions have become increasingly popular as tools for the rapid generation of small-molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed.
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TL;DR: In this article, the utility of multicomponent reactions as methods for green synthesis is highlighted and the practical value of these type of reactions for meeting many of the criteria set by the green chemistry philosophy.
873 citations
TL;DR: The present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions.
Abstract: Heterocycles constitute the largest and the most diverse family of organic compounds Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis 2
Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools
Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc Reviews devoted to an application of a particular type of starting materials have also been published Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed
The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed
811 citations
TL;DR: 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 of asymmetric multicomponent reactions.
Abstract: 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.
686 citations
TL;DR: In this review, recent progress in isocyanide insertion chemistry is presented and two catalytic systems have been developed, that is, Lewis (Brønsted) acid-catalyzed isOCyanide insertions and transition-metal-enabled isocianide insertion, respectively.
Abstract: As valuable C1 building blocks, isocyanides represent an important class of reactive species and synthons. During the past decades, exhaustive efforts have been devoted to the discovery of highly efficient reactions involving isocyanide on the basis of the development of the Passerini and Ugi reactions. Several types of reactions involving isocyanides have been reported, such as nucleophilic attack, electrophilic addition, imidoylation reactions, and oxidation etc. In this review, recent progress in isocyanide insertion chemistry is presented. Among all isocyanide insertions, two catalytic systems have been developed, that is, Lewis (Bronsted) acid-catalyzed isocyanide insertions and transition-metal-enabled isocyanide insertions, respectively. This review is hence written in the sequence of Lewis (Bronsted) acid-catalyzed isocyanide insertion and transitional metal-enabled isocyanide insertion, where isocyanide insertion into heteroatom–hydrogen bonds, carbon–halogen bonds, carbon–hydrogen bonds, and metal carbenes are summarized.
468 citations
TL;DR: This tutorial review aims to critically describe the developments achieved in recent years inMulticomponent reactions, charting the ideas, challenges, and milestone reactions that were essential for the progress of this field.
Abstract: Multicomponent reactions (MCRs) are by far the most successful class of reactions leading to high structural diversity and molecular complexity through a single transformation. As part of the ongoing search for pharmacologically active lead structures, the obtained structural diversity allows for the fast exploration of a large chemical space. Not surprisingly, the development of MCRs, leading to new structural frameworks or serving as key transformations in the total synthesis of natural products, has expanded rapidly over the last few decades. To date a multitude of new three- and four-component reactions have already been described; however, examples of “higher-order” MCRs where five or even more components are combined in a single reaction vessel are remarkably scarce. This tutorial review aims to critically describe the developments achieved in recent years, charting the ideas, challenges, and milestone reactions that were essential for the progress of this field.
446 citations
References
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TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
14,026 citations
3,685 citations
TL;DR: 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 M CRs, something that this review wishes to stimulate.
Abstract: 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.
3,619 citations
TL;DR: Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.
Abstract: Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.
2,229 citations
TL;DR: Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously and has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects.
Abstract: Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.
1,479 citations