Multicomponent Reactions, Union of MCRs and Beyond.

Multicomponent reactions (MCRs), which are located between one- and two-component and polymerization reactions, provide a number of valuable conceptual and synthetic advantages over stepwise sequential approaches towards complex and valuable molecules. To address current limitations in the number of MCRs and the resulting scaffolds, the concept of union of MCRs was introduced two decades ago by Dömling and Ugi and is rapidly advancing, as is apparent by several recently published works. MCR technology is now widely recognized for its impact on drug discovery projects and is strongly endorsed by industry in addition to academia. Clearly, novel scaffolds accessible in few steps including MCRs will further enhance the field of applications. Additionally, broad expansion of MCR applications in fields such as imaging, materials science, medical devices, agriculture, or futuristic applications in stem cell therapy and theragnostics or solar energy and superconductivity are predicted.

[1]  K. Khoury,et al.  Concise Synthesis of Tetrazole-keto-piperazines by Two Consecutive Ugi Reactions. , 2015, European journal of organic chemistry.

[2]  A. Basso,et al.  Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir. , 2015, The Journal of organic chemistry.

[3]  L. Grimaud,et al.  The Ugi–Smiles and Passerini–Smiles Couplings: A Story About Phenols in Isocyanide‐Based Multicomponent Reactions , 2014 .

[4]  A. Dömling,et al.  Modern Multicomponent Reactions for better Drug Syntheses** , 2014, Organic chemistry frontiers : an international journal of organic chemistry.

[5]  Michael A R Meier,et al.  Sequence control in polymer chemistry through the Passerini three-component reaction. , 2014, Angewandte Chemie.

[6]  T. Holak,et al.  Discovery of Highly Potent p53-MDM2 Antagonists and Structural Basis for Anti-Acute Myeloid Leukemia Activities , 2014, ACS chemical biology.

[7]  R. Kakuchi.  Multicomponent reactions in polymer synthesis. , 2014, Angewandte Chemie.

[8]  Alexander Dömling,et al.  Transient protein states in designing inhibitors of the MDM2-p53 interaction. , 2013, Structure.

[9]  M. Vendrell,et al.  Multicomponent reactions for de novo synthesis of BODIPY probes: in vivo imaging of phagocytic macrophages. , 2013, Journal of the American Chemical Society.

[10]  K. Khoury,et al.  Various cyclization scaffolds by a truly Ugi 4-CR. , 2013, Organic & biomolecular chemistry.

[11]  K. Khoury,et al.  Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot. , 2013, Chemistry.

[12]  K. Khoury,et al.  Efficient assembly of iminodicarboxamides by a "truly" four-component reaction. , 2012, Angewandte Chemie.

[13]  Wei Wang,et al.  Chemistry and biology of multicomponent reactions. , 2012, Chemical reviews.

[14]  T. Holak,et al.  Exhaustive Fluorine Scanning toward Potent p53–Mdm2 Antagonists , 2012, ChemMedChem.

[15]  B. Day,et al.  Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs. , 2011, Journal of the American Chemical Society.

[16]  Eelco Ruijter,et al.  Multicomponent reaction design in the quest for molecular complexity and diversity. , 2011, Angewandte Chemie.

[17]  Laurent Mugherli,et al.  Combinatorial discovery of fluorescent pharmacophores by multicomponent reactions in droplet arrays. , 2011, Journal of the American Chemical Society.

[18]  A. Wheeler,et al.  Synchronized synthesis of peptide-based macrocycles by digital microfluidics. , 2010, Angewandte Chemie.

[19]  A. Dömling,et al.  Efficient multicomponent reaction synthesis of the schistosomiasis drug praziquantel. , 2010, Chemistry.

[20]  N. Turner,et al.  A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions. , 2010, Chemical communications.

[21]  Raed A. Al‐Qawasmeh,et al.  Rapid Assembly of Polyfunctional Structures Using a One‐Pot Five‐ and Six‐Component Sequential Groebke–Blackburn/Ugi/Passerini Process , 2010 .

[22]  Alexander Dömling,et al.  Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists. , 2010, Angewandte Chemie.

[23]  Vishal Rai,et al.  Macrocyclization of linear peptides enabled by amphoteric molecules. , 2010, Journal of the American Chemical Society.

[24]  Wei Wang,et al.  (-)-Bacillamide C: the convergent approach. , 2010, Organic & biomolecular chemistry.

[25]  T. Kawasaki,et al.  Total syntheses of (-)-fructigenine A and (-)-5-N-acetylardeemin. , 2010, The Journal of organic chemistry.

[26]  R. Orru,et al.  The efficient one-pot reaction of up to eight components by the union of multicomponent reactions. , 2009, Angewandte Chemie.

[27]  A. Riera,et al.  Synthesis of prostaglandin and phytoprostane B1 via regioselective intermolecular Pauson-Khand reactions. , 2009, Organic letters.

[28]  A. Spek,et al.  A multicomponent reaction towards N-(cyanomethyl)amides. , 2009, Chemistry.

[29]  Dennis G Hall,et al.  Natural product synthesis using multicomponent reaction strategies. , 2009, Chemical reviews.

[30]  Christopher R Lowe,et al.  Affinity ligands for immunoglobulins based on the multicomponent Ugi reaction. , 2009, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[31]  W. Erb,et al.  Ugi-post functionalization, from a single set of ugi-adducts to two distinct heterocycles by microwave-assisted palladium-catalyzed cyclizations: tuning the reaction pathways by ligand switch. , 2009, The Journal of organic chemistry.

[32]  M. Kozlowski,et al.  Design of a bisamidinium claisen rearrangement catalyst for monodentate substrates. , 2009, Organic letters.

[33]  R. Orru,et al.  Selective formation of 2-imidazolines and 2-substituted oxazoles by using a three-component reaction. , 2008, Chemistry.

[34]  Xuechen Li,et al.  New chemistry with old functional groups: on the reaction of isonitriles with carboxylic acids--a route to various amide types. , 2008, Journal of the American Chemical Society.

[35]  A. De Mesmaeker,et al.  Multicomponent reactions in fungicide research: the discovery of mandipropamid. , 2008, Bioorganic & medicinal chemistry.

[36]  G. Beutner,et al.  A Concise Synthesis of (S)-N-Ethoxycarbonyl-α-methylvaline , 2007 .

[37]  Yoshihisa Kobayashi,et al.  New entry to convertible isocyanides for the Ugi reaction and its application to the stereocontrolled formal total synthesis of the proteasome inhibitor omuralide. , 2007, Organic letters.

[38]  Yoshihisa Kobayashi,et al.  Expeditious access to unprotected racemic pyroglutamic acids. , 2007, The Journal of organic chemistry.

[39]  I. E. Smith,et al.  Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency. , 2006, Journal of medicinal chemistry.

[40]  S. Roberts,et al.  A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands. , 2006, Journal of the American Chemical Society.

[41]  P. Woollard,et al.  2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics. , 2005, Journal of medicinal chemistry.

[42]  Ryszard Ostaszewski,et al.  Solid-phase synthesis of five-dimensional libraries via a tandem Petasis–Ugi multi-component condensation reaction , 2003 .

[43]  D. E. Portlock,et al.  A tandem Petasis–Ugi multi component condensation reaction: solution phase synthesis of six dimensional libraries , 2003 .

[44]  A. Dömling,et al.  One-pot synthesis and biological evaluation of aspergillamides and analogues. , 2000, Bioorganic & medicinal chemistry letters.

[45]  A. Dömling,et al.  The discovery of new isocyanide-based multi-component reactions. , 2000, Current opinion in chemical biology.

[46]  J. Aizpurua,et al.  Asymmetric Synthesis of β‐Lactams by Staudinger Ketene‐Imine Cycloaddition Reaction , 1999 .

[47]  A. Dömling,et al.  A novel method to highly versatile monomeric PNA building blocks by multi component reactions. , 1999, Bioorganic & medicinal chemistry letters.

[48]  H. Bienaymé.  “Reagent explosion”: an efficient method to increase library size and diversity , 1998 .

[49]  J. Sisko.  A One-Pot Synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4- (4-fluorophenyl)-5-(2-amino-4-pyrimidinyl)- imidazole: A Potent Inhibitor of P38 MAP Kinase , 1998 .

[50]  L. Weber,et al.  Synthesis of Imidazo[1,2-a] annulated Pyridines, Pyrazines and Pyrimidines by a Novel Three-Component Condensation , 1998 .

[51]  C. Blackburn,et al.  Parallel synthesis of 3-aminoimidazo[1,2-a]pyridines and pyrazines by a new three-component condensation , 1998 .

[52]  J. Clader,et al.  Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption. , 1998, Journal of medicinal chemistry.

[53]  I. Zavialov,et al.  A New and Practical Synthesis of α-Amino Acids from Alkenyl Boronic Acids , 1997 .

[54]  I. Ugi,et al.  The Seven‐Component Reaction** , 1993 .

[55]  I. Ugi.  From Isocyanides via Four-Component Condensations to Antibiotic Syntheses†‡ , 1982 .

[56]  F. Bossert,et al.  4‐Aryldihydropyridines, a New Class of Highly Active Calcium Antagonists , 1981 .

[57]  M. Joullié,et al.  Total synthesis of (+)-furanomycin and stereoisomers , 1980 .

[58]  H. Immer,et al.  The synthesis of cyclic peptides by the four component condensation (4 CC) , 1979 .

[59]  P. Pauson,et al.  USES OF COBALT‐CARBONYL ACETYLENE COMPLEXES IN ORGANIC SYNTHESIS * † , 1977 .

[60]  G. Gokel,et al.  Absolute Configuration of a 1,2-Disubstituted Ferrocene Derivative with Two Different Chiral Substituents† , 1972 .

[61]  F. Bossert,et al.  [Dihydropyridines, a new group of strongly effective coronary therapeutic agents]. , 1971, Die Naturwissenschaften.

[62]  G. Gokel,et al.  The Retentive Nucleophilic Substitution of (R)α-Ferrocenylethyl Acetate , 1971 .

[63]  G. Gokel,et al.  Stereoselective syntheses. VI. Correlation of central and planar chirality in ferrocene derivatives , 1970 .

[64]  Ivar Ugi,et al.  The α‐Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions , 1962 .

[65]  I. Ugi,et al.  Über ein neues Kondensations‐Prinzip , 1960 .

[66]  F. Asinger,et al.  Einfache Synthesen und chemisches Verhalten neuer heterocyclischer Ringsysteme , 1958 .

[67]  L. Claisen.  Über Umlagerung von Phenol-allyläthern in C-Allyl-phenole , 1912 .

[68]  Kan Wang,et al.  Cyanoacetamide MCR (III): three-component Gewald reactions revisited. , 2010, Journal of combinatorial chemistry.

[69]  C. Hulme,et al.  "Multi-component reactions : emerging chemistry in drug discovery" 'from xylocain to crixivan'. , 2003, Current medicinal chemistry.

[70]  I. Ugi,et al.  Multicomponent reactions in organic chemistry , 1994 .

[71]  R. Sachleben,et al.  Synthetic approach to bicyclomycim: Synthesis of the bicyclic system of bicyclomycin , 1981 .

[72]  G. Gokel,et al.  Stereoselective synthesis. VIII. Absolute configuration of a 1,2-disubstituted ferrocene derivative with planar and central elements of chirality and the mechanism of the optically active .alpha.-ferrocenyl tertiary amines , 1973 .

[73]  E. Ruch,et al.  Die Stereochemie des α - Ferrocenyl - äthyl - Kations† , 1970 .

[74]  K. Gewald,et al.  Heterocyclen aus CH‐aciden Nitrilen, VIII. 2‐Amino‐thiophene aus methylenaktiven Nitrilen, Carbonylverbindungen und Schwefel , 1966 .

[75]  C. Mannich,et al.  Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin , 1912 .

[76]  H. Staudinger.  Zur Kenntniss der Ketene. Diphenylketen , 1907 .

[77]  A. Strecker.  Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper; , 1850 .