Multicomponent Reactions - Superior Chemistry Technology For The New Millennium
Multicomponent Reactions (MCRs) are convergent 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 (A. Dömling, I. Ugi, Angew. Chem. Intl. Ed. 2000, 39, 3168. ). In an MCR, a product is assembled according to a cascade of elementary chemical reactions. Thus, there is a network of reaction equilibria, which all finally flow into an irreversible step yielding the product. The challenge is to conduct an MCR in such a way that the network of pre-equilibrated reactions channel into the main product and do not yield side products. The result is clearly dependent on the reaction conditions: solvent, temperature, catalyst, concentration, the kind of starting materials and functional groups. Such considerations are of particular importance in connection with the design and discovery of novel MCRs (A. Dömling in: Multicomponent Reactions (J. Zhu, H. Bienayme) Wiley-VCH, Weinheim 2005, p. 76.).
Figure 1 A divergent 1-component reaction, and convergent 2- and 6-component reactions.
Applications of MCRs in all areas of applied chemistry are very popular because they offer a wealth of products, while requiring only a minimum of effort. As opposed to the classical way to synthesize complex molecules by sequential synthesis, MCRs allow the assembly of complex molecules in one pot. A simple mathematical analysis highlights another important aspect of MCR chemistry. The number of potential products increases with Xth power of the number of starting materials N of each of the classes X used in the particular reaction. For example, using N = 1,000 starting materials of each class in the Ugi-4CR (X = 4; RCOOH, R’NH2, R”CHO, R”’NC) yields an incredibly large product space of NX = 1,000 x 1,000 x 1,000 x 1,000 = 1012 structures from one-pot reactions; thus, 1012 product molecules are potentially accessible from only 4,000 starting molecules (I. Ugi, C. Steinbrückner, Chem. Ber. 1961, 94, 734.). With tremendous foresight, Ivar Ugi recognized already in 1961 that MCR is ideally suited to probe structure-activity relationships via the synthesis of “large collections of compounds”, which nowadays are referred to as libraries. The labor efficiency and the access to such an enormous chemical structure space is a major driving force behind the recent flurry of activity in MCR research and patent applications.
Figure 2 A portion of the very large MCR chemical space represented by 12 exemplary scaffolds. More than 500 MCR scaffolds have been described in literature so far.*
In the more specific applications to the drug discovery process, MCR offers many advantages over traditional approaches. Thus the chemistry development time, typically up to 6 months for a linear 6 step synthesis, is considerably shortened. With only a limited number of chemists and technicians, more scaffold synthesis programs can be achieved within a shorter time. With one-pot reactions, each synthesis procedure (weighing of reagents, addition of reagents, reaction/time control) and work-up procedure (quenching, extraction, distillation, chromatography, weighing, analysis) needs to be performed only once, in contrast to multi-step syntheses. MCRs are mostly compatible with a solution phase approach, thus enabling a simple monitoring, and they are easily amenable to automation with inexpensive 96 well liquid dispensers. Moreover, each scaffold is expandable from a low number of compounds (scouting library) to a larger library. Thus, “hit-to-lead” transitions are normally accomplished easily and promptly. Certain physicochemical properties can be built into a library, e.g. lipophilicity and aqueous solubility, molecular weight, numbers of hydrogen donors and acceptors, and the number of rotatable bonds, as well as the polar surface area. Finally, scale-up is often possible from a preclinical lab-scale (mg, gram) to clinical exploratory amounts (kg) using the same type of chemistry. (C. Hulme, V. Gore, Curr. Med. Chem. 2003, 10, 51. Link)
Figure 3 MCR chemistry in drug discovery. Recent applications include inhibitors of protein-protein interactions, novel GPCR ligands, protease inhibitors, tubulin polymerization inhibitors and kinase inhibitors, but are by no means restricted to any target class.
The usefulness of a reaction is correlated to several factors: the number of bonds which are formed in one sequence, which Tietze (Chem. Rev. 1996, 96, 115. ) has referred to as the bond-forming efficiency (BFE, or bond-forming economy); moreover, to the increase in structural complexity (structure economy); and finally, to its suitability for general application. Multicomponent reactions have attracted considerable interest owing to their exceptional synthetic efficiency. The BFE is an important measure to determine the quality of a multicomponent reaction. Unlike the usual stepwise formation of individual bonds in the target molecule, the defining attribute of MCRs is the inherent formation of several bonds in one operation without isolating the intermediates, changing the reaction conditions, or adding further reagents. It is obvious that adopting such strategies would allow the minimization of both waste production and the expenditure of human labor. The products are formed simply by mixing the corresponding set of starting materials. Since the structures of the products carry portions of all the reactants employed, MCRs that have a high attendant BFE assure a marked increase in molecular complexity and diversity. A wide variation among these starting materials opens up versatile opportunities for the synthesis of compound libraries. The generalization to as many available starting materials as possible is an indispensable characteristic for the most general application. Multicomponent reactions thus address the requirements for efficient high-throughput synthesis of compounds in a cost- and time-effective manner. Reactions that build up carbon-carbon, carbon-nitrogen and other carbon-heteroatom bonds and at the same time introduce heteroatom-containing functionality into the structural framework are especially attractive for the rapid construction of organic molecules.
Figure 4 Two example of IMCRs with high bound forming efficacy (BFE). The 3-CR of shown above of a β-aminothiocarboxylic acid, an aldehyde and a 2,2-dimethylamino-1-isocyano alkene affords a complex molecule under mild conditions, with two heterocycles in the product that are not present in the starting materials: a β-lactam and a thiazole. During this one-pot transformation 1 C-C (blue), 2 C-S (green) and 2 N-C (red) bonds are formed. (J. Kolb, B. Beck, A. Dömling, Tetrahedron Lett. 2002, 43, 6897. ) Below: In the second IMCR, the isocyanoacetamide reacts four times in a highly ordered manner creating three heterocyclic rings with the concomitant formation of five chemical bonds (3 C-C bonds, 2 C-N bonds) and a minimal loss of molecular weight. (A. Fayol, J. Zhu Org. Lett. 2005, 7, 239. )
There are many different types of MCR reactions, according to different classifications, but among the most useful are isocyanide-based MCRs (IMCR). IMCRs allow for the synthesis of the largest number of different scaffolds. Moreover many of these scaffolds are assembled from commercially available starting materials, thus potentially large libraries of compounds are accessible through one type of reaction.
What distinguishes between IMCRs and other types of MCRs? The principal differences between MCRs and IMCRs arise from the particular reactivity and topologically unique nature of isocyanides. As opposed to most functional groups in Organic Chemistry, isocyanides react with both nucleophiles and electrophiles at the same atom (!), the isocyanide carbon, to form a reactive α-adduct intermediate. This α-adduct forms the basis for all of the subsequent rearrangements and product forming steps. Isocyanides share this unique feature in common with carbon monoxide and carbenes. During the α-addition, the formally divalent carbon is oxidized to a tetravalent carbon (CII => CIV).
Figure 5 Differential reactivity of isocyanides vs. other functional groups. The Michael addition of a nucleophile with a α,β-unsaturated carbonyl is shown at top. The intermediate enolate anion is then the substrate for a reaction with an electrophile. Overall the electrophile adds to the O-atom while the nucleophile adds to the C-atom. Isocyanides behave differently: nucleophiles and electrophiles react at the C-atom to form a α-adduct.
New reactions must show their usefulness in the efficient synthesis of complex products, and a particularly advantageous application of IMCRs is in natural product synthesis. Many groups have leveraged their projects in natural product total synthesis with the power of MCR, e.g. Ugi, Jouillé, Fukuyama, Hofheinz, Banfi, Semple, Armstrong, Hatanaka, Schmidt and our group (Figure 6).
Figure 6 IMCR in the total synthesis of the natural product (-)-lemonomycin. Fukuyama et al. used a U-4CR to assemble the natural product in a highly convergent manner. (Chem. Commun. 2005, 394. )
The potential advantage of very large libraries spanned by the huge chemical space of MCR can also turn into a disadvantage. For example, consider the above mentioned U-4CR leading to 1012 possible products, assuming a 50 μmol scale for each reaction; moreover, let’s assume a median product molecular weight of 400g/mol; and finally, let’s assume that 100,000 compounds can be produced per day. The number of compounds produced per year is then 36 million. In this case it will take a total of 27,000 years to produce the library. Assuming 100% yield per reaction, one would obtain 20 mg per compound. The full library would weight 240,000 tons. It is immediately obvious that a library of 1012 compounds is virtual and can never be produced in reality.
Moreover this also points to the need to limit the search and synthesis to a practicable and relatively small subspace. This begs the question of how to search and discover molecules in a reasonable small space and with a feasible effort, without compromising the quality of the results. The answer lies in computational screening and suitable algorithms to leverage the potential of the full chemical space with the chosen subset (Figure 7).
Figure 7 Computational methods help to investigate very large areas of chemical structure space. Left: a genetic algorithm-based, feedback-driven drug discovery cycle was implemented by us in order to screen very large chemical MCR spaces for useful biological activity. Recently, an application of this methodology for the discovery of potent diabetes type-2 target glucose-6-phosphate translocase inhibitors has been published. (S. Bräuer, M. Almstetter, W. Antuch, D. Behnke, R. Taube, P. Furer, S. Hess J. Comb. Chem. 2005, 218. ). Right: Similarity and pharmacophore screening of a large library of compounds against two known growth hormone secretagogue agonists. An initial μM hit from the corresponding corporate library was also a Ugi product, which could be converted to a low nM lead by preparing a small library of only ~40 U-4CR products. (M. Shoda, T. Harada, Y. Kogami, R. Tsujita, H. Akashi, H. Kouji, F. L. Stahura, L. Xue, J. Bajorath J. Med. Chem. 2004, 47, 4286. )
By their nature, MCRs are by no means restricted to a particular application, but rather they can be used advantageously in any area of modern chemistry-based technology. Recent applications of MCRs unrelated to drugs include EPR-spin labeling, biocompatible materials, e.g. for artificial eye lenses, polymers with novel properties, chiral phases for HPLC, natural product synthesis, peptide-nucleic acids and agrochemicals.
It is an exciting time for science and one of unprecedented opportunity for chemistry. This arises from the fact that “chemists can create new matter" (Sir Jack Baldwin) and new matter forms the basis of technological, scientific and health advancements of our global community. A detailed molecular understanding of our world is crucial, therefore, to shaping the direction, development, and destiny of scientific research. Chemical biology, molecular medicine, and nanotechnology are but a few of the significant scientific fusions that have resulted from neighborhood disciplines.
MCR chemistry with its tremendous advantages in terms of accessible chemical structure space, diversity and efficiency can help to achieve more rapidly technological and scientific advancements. It seems a safe prediction that the use of MCRs for the fast, efficient discovery and development of novel materials will dramatically increase in the near future.
Thus the following series of small and monthly review articles are intended as an introduction to the world of MCR chemistry, and will hopefully stimulate potential applications in the research areas of the readers.*
*The author has collected MCR scaffolds into a database of reactions that to date total more than 500 MCR backbones. These will form the basis for the upcoming series of small reviews.