Romano V. A. Orru

Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity

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.

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.

Isocyanoacetate Derivatives: Synthesis, Reactivity, and Application

The sphingolipid bases, D-erythro- and D-threo-sphingosines, are the target molecules that have been synthesized to demonstrate the efficiency of a new methodology to control both absolute and relative configurations in acyclic systems. Tubulysins are compounds of extraordinary potency, rapidly degrading the tubulin cytoskeleton, with tubulysin D being the most active tubulin-modifier known so far. Among other isonitriles, isocyanoacetate derivatives occupy an important place in the field of synthetic application and reaction diversity, which makes them strongly attractive objects for investigation. The unique multifunctional nature of isocyanoacetic acid derivatives opens up a range of exciting reactions, especially tandem/cascade processes for the synthesis of complex cyclic and macrocyclic systems. Multicomponent chemistry of isocyanoacetates is also a powerful instrument to access different classes of biochemically relevant compounds such as peptides, peptide molecules, and nitrogen heterocycles.

Palladium-catalyzed migratory insertion of isocyanides: an emerging platform in cross-coupling chemistry.

Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-containing fine chemicals. This Minireview discusses all the achievements in this emerging field.

Recent applications of multicomponent reactions in medicinal chemistry

Multicomponent reactions are flexible reactions for the rapid generation of complex molecules with often biologically relevant scaffold structures. Combined with the ease of parallelization and the exploratory power with regard to chemical space, multicomponent reactions have attracted significant attention from the medicinal chemistry community. In this Review, we present an overview of recent literature concerning this topic to provide insight into the applications of multicomponent reactions in this field.

1-Azadienes in cycloaddition and multicomponent reactions towards N-heterocycles

1-Azadienes are versatile building blocks for the efficient construction of various N-heterocycles. Depending on the substitution pattern and reaction partner, they may participate in a range of different reactions. An overview of recent methods for the generation of 1-azadienes is presented, as well as their application in cycloaddition, electrocyclization, and multicomponent reactions. Considering the broad range of reactivities and resulting heterocyclic scaffold structures, 1-azadienes are very useful reactive intermediates for the development of modular reaction sequences in diversity-oriented synthesis.

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

Summary In the recent past, the design and synthesis of peptide mimics (peptidomimetics) has received much attention. This because they have shown in many cases enhanced pharmacological properties over their natural peptide analogues. In particular, the incorporation of cyclic constructs into peptides is of high interest as they reduce the flexibility of the peptide enhancing often affinity for a certain receptor. Moreover, these cyclic mimics force the molecule into a well-defined secondary structure. Constraint structural and conformational features are often found in biological active peptides. For the synthesis of cyclic constrained peptidomimetics usually a sequence of multiple reactions has been applied, which makes it difficult to easily introduce structural diversity necessary for fine tuning the biological activity. A promising approach to tackle this problem is the use of multicomponent reactions (MCRs), because they can introduce both structural diversity and molecular complexity in only one step. Among the MCRs, the isocyanide-based multicomponent reactions (IMCRs) are most relevant for the synthesis of peptidomimetics because they provide peptide-like products. However, these IMCRs usually give linear products and in order to obtain cyclic constrained peptidomimetics, the acyclic products have to be cyclized via additional cyclization strategies. This is possible via incorporation of bifunctional substrates into the initial IMCR. Examples of such bifunctional groups are N-protected amino acids, convertible isocyanides or MCR-components that bear an additional alkene, alkyne or azide moiety and can be cyclized via either a deprotection–cyclization strategy, a ring-closing metathesis, a 1,3-dipolar cycloaddition or even via a sequence of multiple multicomponent reactions. The sequential IMCR-cyclization reactions can afford small cyclic peptide mimics (ranging from four- to seven-membered rings), medium-sized cyclic constructs or peptidic macrocycles (>12 membered rings). This review describes the developments since 2002 of IMCRs-cyclization strategies towards a wide variety of small cyclic mimics, medium sized cyclic constructs and macrocyclic peptidomimetics.

Sustainable Synthesis of Diverse Privileged Heterocycles by Palladium‐Catalyzed Aerobic Oxidative Isocyanide Insertion

O(2) in, H(2)O out: Various diamines and related bisnucleophiles readily undergo oxidative isocyanide insertion with Pd(OAc)(2) (1 mol %) as the catalyst and O(2) as the terminal oxidant to give a diverse array of medicinally relevant N heterocycles. The utility of this highly sustainable method is demonstrated by a formal synthesis of the antihistamines astemizole and norastemizole.

Palladium-catalyzed synthesis of 4-aminophthalazin-1(2H)-ones by isocyanide insertion.

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.

The Efficient One‐Pot Reaction of up to Eight Components by the Union of Multicomponent Reactions

The development of synthetic methods has advanced enormously in the past decades. At present, chemists can design and prepare almost any type of molecule. The typical approach for the synthesis of (complex) molecules with predefined properties is, however, still characterized by rather inefficient step-by-step reaction sequences. The greatest challenge for synthetic chemists is therefore the improvement of overall efficiency by using atom-, step-, and energyeconomic procedures that proceed with high yield and selectivity. 2] This goal can be achieved by focusing on bond construction and functional-group compatibility in the development of new reaction types. Multicomponent reactions (MCRs) are important tools for the accomplishment of this goal as they inherently involve the formation of several bonds in one operation. As such, MCRs are convergent stepefficient procedures that can take place with remarkably high atom economy and E factors, by reducing the number of functional-group manipulations and thus avoiding the use of protecting groups. Synthetic efficiency can be further improved by combining more than one MCR. Central to this concept of the union of MCRs is the orthogonal reactivity of functional groups, which can be combined in one molecule to allow the union of different reactions if their reactivity is fully independent (orthogonal). Such strategies avoid the use of protective groups and increase efficiency in organic synthesis. The most straightforward approach to such combinations is the incorporation of a functional group in one of the inputs of the primary MCR that does not participate in the reaction, but does react as one of the components in a secondary MCR (Figure 1). In an ideal case, both reactions are combined in one pot to create a higher-order MCR. Although there are several reports of combinations of MCRs in the literature, the true one-pot combination (union of MCRs first introduced by the research group of Ugi) is generally not possible because: 1) the experimental procedure limits the scope in substrate inputs, 2) additional (de)protection steps are required, and 3) solvent incompatibilities mean that the solvent must be changed between subsequent reaction steps. Consequently, one-pot sequences of MCRs have remained limited to isolated examples by Ugi and co-workers, Portlock and co-workers, and our research group. We report herein a novel approach that combines two or more MCRs in one pot to achieve higher-order MCRs with unprecedented possibilities for complexity generation and diversification. Our strategy is based on two recently reported MCRs that display extraordinary functional-group and solvent compatibilities and lead to 2H-2-imidazolines and N(cyanomethyl)amides, respectively. In an initial approach, we focused on the introduction of a carboxylic acid function in the 2H-2-imidazoline produced by the primary MCR using an amino acid as one of the starting materials. Thus, reaction of isocyanide 1, acetone, and sodium glycinate (2) led to a clean conversion to form intermediate A (Scheme 1). After protonation of the intermediate carboxylate A (methanolic HCl, one equivalent), a one-pot combination with iPrCHO, n-propylamine, and tBuNC in an Ugi 4CR led to the isolation of 3a in 38% yield. The yield could be improved to 62% by using benzylamine instead of npropylamine, which is excellent when considering the number Figure 1. Combination (or union) of MCRs.