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General Introduction to MCRs: Past, Present, and Future

Alexander Dömling and AlAnod D. AlQahtani

1.1 Introduction

Multicomponent reactions (MCRs) are generally defined as reactions in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product [1]. Their usefulness can be rationalized by multiple advantages of MCRs over traditional multistep sequential assembly of target compounds. In MCRs, a molecule is assembled in one convergent chemical step in one pot by simply mixing the corresponding starting materials as opposed to traditional ways of synthesizing a target molecule over multiple sequential steps. At the same time, considerably complex molecules can be assembled by MCRs. This has considerable advantages as it saves precious time and drastically reduces effort.

MCRs are mostly experimentally simple to perform, often without the need of dry conditions and inert atmosphere. Molecules are assembled in a convergent way and not in a linear approach using MCRs. Therefore, structure-activity relationships (SARs) can be rapidly generated using MCRs, since all property-determining moieties are introduced in one step instead of sequentially [2]. Last but not least, MCRs provide a huge chemical diversity and currently more than 300 different scaffolds have been described in the chemical literature. For example, more than 40 different ways to access differentially substituted piperazine scaffolds using MCRs have been recently reviewed [3].

Although MCR chemistry is almost as old as organic chemistry and was first described as early as 1851, it should be noted that early chemists did not recognize the enormous engineering potential of MCRs. However, it took another >100 years until Ivar Ugi in a strike of a genius discovered his four-component condensation and also recognized the enormous potential of MCRs in applied chemistry (Figure 1.1) [4].

Figure 1.1 A three-component reaction toward the local anesthetic xylocaine and the first combinatorial library of small molecules proposed by Ivar Ugi in the 1960.

1.2 Advances in Chemistry

Many MCRs have been described in the past one and a half century and recently not many fundamental advances in finding new MCRs have been made [5-7]. A strategy to enhance the size and diversity of current MCR chemical space is the concept of combining a MCR and a subsequent secondary reaction, also known as postcondensation or Ugi-deprotection-cyclization (UDC) [2]. Herein, bifunctional orthogonally protected starting materials are used and ring cyclizations can take place in a secondary step upon deprotection of the secondary functional groups. Many different scaffolds have been recently described using this strategy. One example is shown in Figure 1.2. It is based on a recently discovered variation of the Ugi reaction of a-amino acids, oxo components, and isocyanides, now including primary and secondary amines [8-10].

Figure 1.2 Discovery of the Ugi-5C-4CR variation employing unprotected a-amino acids, oxo components, primary or secondary amines, and isocyanides, and the synthesis of several heterocyclic scaffolds using orthogonally protected bifunctional starting materials. Generalized scaffolds are shown in color, and synthesized examples in black and white.

1.3 Total Syntheses

While the Bucherer-Bergs and the related Strecker synthesis are well-established methods for the one-pot synthesis of natural and unnatural amino acids, the complex antibiotic penicillin was synthesized 50 years ago in a highly convergent approach by Ivar Ugi by using two MCRs, the Asinger reaction and his own reaction (Figure 1.3) [11]. Other recent natural product targets using MCR as a key step in their synthesis are also shown in Figure 1.3. Although early example of the advantageous use of MCR in the conscious total synthesis of complex natural products leads the way, its use has been neglected for decades and only recently realized by a few organic chemists [12-17].

Figure 1.3 (a) The union of the Asinger-4CR and the Ugi-4CR allows for the convergent and fast assembly of 6-aminopenicillanic acid natural product. (b) Recent synthetic targets of MCR natural product chemistry.

1.4 Applications in Pharmaceutical and Agrochemical Industry

Two decades ago, MCR chemistry was almost generally neglected in pharmaceutical and agro industry. The knowledge of these reactions was often low and it was generally believed that MCR scaffolds are associated with useless drug-like properties (absorption, distribution, metabolism, excretion, and toxicity (ADMET)). Now MCR technology is widely recognized for its impact on drug discovery projects and is strongly endorsed by industry as well as academia [18]. An increasing number of clinical and marketed drugs were discovered and assembled by MCR since then (Figure 1.4). Examples include nifedipine (Hantzsch-3CR), praziquantel, or ZetiaT. Two oxytocin receptor antagonists for the treatment of preterm birth and premature ejaculation, epelsiban and atosiban, are currently undergoing human clinical trials. They are both assembled by the classical Ugi MCR [19-21]. Interestingly, they show superior activity for the oxytocin receptor and selectivity toward the related vasopressin receptors than the peptide-based compounds currently used clinically. Perhaps against the intuition of many medicinal chemists, the Ugi diketopiperazines are orally bioavailable, while the currently used peptide derivatives are i.v. only and must be stabilized by the introduction of terminal protecting groups and unnatural amino acids. An example of a MCR-based plant protecting antifungal includes mandipropamide [22]. These examples show that pharmaceutical and agrochemical compounds with preferred ADMET properties and superior activities can be engineered based on MCR chemistry.

Figure 1.4 Examples of marketed drugs or drugs under (pre)clinical development and incorporating MCR chemistry.

The very high compound numbers per scaffold based on MCR may be regarded as friend or foe. On the one hand, it can be fortunate to have a MCR product as a medicinal chemistry starting point, since a fast and efficient SAR elaboration can be accomplished; on the other hand, the known chemical space based on MCRs is incredibly large and can neither be screened nor exhaustively synthesized with reasonable efforts. The currently preferred path to medicinal chemistry starting points in industry, the high-throughput screening (HTS), however, is an expensive process with rather low efficiency yielding hits often only in low double-digit or single-digit percentage. Modern postgenomic targets often yield zero hits. The initial hits are often ineffective to elaborate due to their complex multistep synthesis. Thus, neither the screening even of a very small fraction of the chemical space accessible by the classical Ugi-4CR and other scaffolds, nor the synthesis is possible. Recent advances in computational chemical space enumeration and screening, however, allow for an alternative process to efficiently foster a very large chemical space. The free web-, anchor-, and pharmacophore-based server AnchorQueryT (anchorquery.ccbb.pitt.edu/), for example, allows for the screening of a very large virtual MCR library with over a billion members (Figure 1.5) [23]. AnchorQuery builds on the role deeply buried amino acid side chains or other anchors play in protein-protein interactions. Proposed virtual screening hits can be instantaneously synthesized and tested using convergent MCR chemistry. The software was instrumental to the discovery of multiple potent and selective MCR-based antagonists of the protein-protein interaction between p53 and MDM2 [24-26]. Thus, computational approaches to screen MCR libraries will likely play a more and more important role in the early drug discovery process in the future.

Figure 1.5 MCR-based computational methods can help to effectively query the very large chemical MCR space. Clockwise: generation of a pharmacophore model based on a 3D structure, screening of the pharmacophore model against a very large MCR 3D compound database (AnchorQuery), synthesis, and refinement of hits.

More and more high-resolution structural information on MCR molecules bound to biological receptors is available (Figure 1.6) [18]. With the advent of structure-based design and fragment-based approaches in drug discovery, access to binding information of MCR molecules to their receptors is becoming crucial. Once the binding mode of a MCR molecule is defined, hit-to-lead transitions become more facile and time to market can be shortened and attrition rate in later clinical trials can be potentially reduced.

Figure 1.6 Examples of cocrystal structures of MCR molecules bound to biological receptors. Clockwise left: Povarov-3CR molecule bound to kinesin-5 (PDB ID 3L9H) [27], Ugi-3CR molecule bound to FVIIa (PDB ID 2BZ6) [28], Ugi-4CR molecule bound to MDM2 (PDB ID 4MDN) [26], and Gewald-3CR molecule targeting motor protein KSP (PDB ID 2UYM) [29].

Other worthwhile applications of MCRs in medicinal chemistry are in route scouting for shorter, convergent, and cheaper syntheses. An excellent showcase is the synthesis of the recently approved HCV protease inhibitor...