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Review
. 2012 Jun 13;112(6):3083-135.
doi: 10.1021/cr100233r. Epub 2012 Mar 22.

Chemistry and biology of multicomponent reactions

Alexander Dömling  1 , Wei Wang, Kan Wang
Affiliations
Review

Chemistry and biology of multicomponent reactions

Alexander Dömling et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.
Figure 2
Figure 2
The immense scaffold diversity based on MCR is derived from primary (often “classical”) MCRs and secondary reactions made possible by the great functional group compatibility of MCRs (Reprinted with permission from Reference 44. Copyright 2009 ACS.).
Figure 3
Figure 3
Distributions of MoI-derived shapes for Ro5 compliant libraries deriving from the corresponding color-coded scaffolds (Reprinted with permission from Dr. Akritopoulou-Zanze, Abbott Laboratories).
Figure 4
Figure 4
Two examples (9 and 10) of the 3D structure of unususal pyramidalized nitrogen in bicyclic bridgeheaded amides accessible by a 3-step sequence Ugi/RCM/Heck. The pyramidalization χ of planar formamide is 0° and 60° for a fully pyramidalized sp atom and is calculated from the X-ray structures.
Figure 5
Figure 5
An Ugi MCR involving orthogonal coumarine 13 and allyl moieties 12 followed by a [2+2] photocyclisation leads to unusual densely functionalized scaffolds and libraries thereof.
Figure 6
Figure 6
Complex indole natural product-like polycyclic compounds 19 made in two steps from simple commercial starting materials, involving a U-4CR and a subsequent Pictet-Spengler cyclization (CCDC ID: 749252).
Figure 7
Figure 7
Unusual bicyclic aminol scaffold 23 and 3D structure as determined by X-ray structure analysis (CCDC ID: 675996).
Figure 8
Figure 8
Compounds 28 with three cyclopropyl groups can be easily assembled using a mild and convergent U-MCR (CCDC ID: 604792).
Figure 9
Figure 9
Spiroheterocycles of great diversity, e.g. 32 can be accessed by different MCRs (CCDC ID: 643526).
Figure 10
Figure 10
Macrocyclic compounds 38 featuring natural product-like properties can be assembled by an efficient and short three-step sequence involving a Passerini-3CR (CCDC ID: 200226).
Figure 11
Figure 11
A flat heteroaromatic bicyclic chemotype (42) by the Groebke-Blackburne-Bienaymé-MCR (GBB-MCR) (CCDC ID: 614188).
Figure 12
Figure 12
Sector of the piperazine scaffold space offered by IMCR. Above the relationship of 15 different piperazine scaffolds based on different heterocyclic systems and hydrogen-bond donor-acceptor features is depicted. Below several piperazine scaffolds are shown with their imminent 2D hydrogen bond donor acceptor propensity (blue and red arrows, H-bond acceptors and donors, respectively).
Figure 13
Figure 13
Cyclotheonamide C in complex with human thrombin (PDB ID: 1TYN). Thrombin receptor is shown as grey sticks (several amino acids have been omitted for clarity). Highlighted in pink cyclotheoamide C and in yellow the active side Ser195 forming a covalent hemi acetale bond with the α-ketoamide moiety of cyclotheonamide C. Additionally, the structure is stabilized by a hydrogen bond network of the hydroxyl group of the hemi acetale and backbone amide Gly, Asp and Ser, the so called oxy anion hole.
Figure 14
Figure 14
Atomic details of a macrocyclic (64, above) and linear (Boceprevir, below) α-ketoamide HCV NS3 protease inhibitors (PDB-IDs: 2A4Q and 2OC8). The active Ser is marked by a cyan surface, the inhibitor by yellow sticks and the binding surface of the protease is shown as grey surface and sticks.
Figure 14
Figure 14
Atomic details of a macrocyclic (64, above) and linear (Boceprevir, below) α-ketoamide HCV NS3 protease inhibitors (PDB-IDs: 2A4Q and 2OC8). The active Ser is marked by a cyan surface, the inhibitor by yellow sticks and the binding surface of the protease is shown as grey surface and sticks.
Figure 15
Figure 15
U-4CR and U-3CR based generation of potent and selective thrombin inhibitors (73) using genetic algorithm techniques. In the graph the evolution of active compounds (EC50) over the number of generations is shown.
Figure 16
Figure 16
Phenylglycine derivative 78 co-crystallized with FVIIa (PDB ID: 2BZ6).
Figure 17
Figure 17
Inhibitor 85 (green sticks) (PDB ID: 1PR8) and a docked piperazine imidazole inhibitor 87 (yellow sticks) bound into a very deep cleft in renin. The piperazine-N is sandwiched between the two active side Asp38 and Asp226 (pink sticks) and replacing the active water.
Figure 18
Figure 18
TOSMIC is a densely functionalized reagent, which accounts for its versatility in different reaction pathways.
Figure 19
Figure 19
A new MCR derived scaffold showing promising BACE-1 activity. Above: synthesis of the general scaffold involving a key Ugi-4CR and representative inhibitors (90) with enzyme and cellular activity. Below: Binding mode of compound 90 (PDB ID: 3E3W) and schematic representation of the major short contacts to the BACE-1 receptor and to water molecules. Noteworthy there is no direct contact of the ligand to the two catalytic asp, it is however mediated by two crystal water molecules. Also noteworthy is a short contact between the fluorine of the ligand and a backbone carbonyl-O with the aromatic plane almost perpendicular to the amide group (α (CF-OC) = 177°). The distance of 3.49 Å, however is more than the sum of the atom radii (r (F) 1.47 Å + r (O) 1.52 Å = 2.99 Å). The two central Asp residues are marked pink.
Figure 20
Figure 20
Cocrystal of a tetronic acid MCR-derivative (97) bound into HIV protease. The enol group is sandwiched between the two active site aspartates.
Figure 21
Figure 21
vL-3CR compound SB220025 is a potent p38 inhibitor. Above: Binding of SB220025 into p38 active site (PDB ID: 1BL7). The 2-amino portion forms hydrogen bonds, the kinase hinge region and the fluorine of the ligand is involved in a short contact to the backbone carbonyl-C (3.1 Å). Below: reaction scheme of the vL-3CR.
Figure 22
Figure 22
MCR derived 2-aminofuranes are potential kinase scaffolds displaying kinase inhibitor specific pharmacophores: they are flat heteroaromatic and display a vicinal H-bond donor/acceptor moiety (shown in comparison to the ATP bond to the hinge region of kinases).
Figure 23
Figure 23
MCR kinase inhibitors. Above: 2-Step synthesis of kinase inhibitors (139) using the GBB-3CR. Middle: Selectivity profile of some representative compounds (140-143) against a panel of kinases. Below: Docking of compound 142 (yellow sticks) into the active site of CDK2 together with the cocrystallized anilino-purine compound 144 (pink lines) (PDB ID: 1OI9). Compound 142 forms a strong hydrogen bond network with the hinge region of CDK2 (grey sticks, red dotted lines), a prerequisite for a potent kinase inhibitor.
Figure 24
Figure 24
Kinase inhibitory natural product meridianin in a short and efficient MCR synthesis and its natural origin, an Aplidium sp. sponge. Below: The cocrystal structure of the 7-aza meridianin in complex with CDK2 (PDB ID: 3BHT). Shown with red dotted lines is the extensive H-bond network of the natural products with the hinge region and other amino acid side chains of the receptor. A tight water network on top of meridianin is shown as turquoise balls and blue dotted lines.
Figure 25
Figure 25
Above: Structure of different MCR derived phosphatase inhibitors. Below: Glycogen phosphatase (PDB ID: 2AMV) in complex with a Hantzsch MCR derived dihydropyrimidine 155. Note the typical boat conformation of the central heterocycl
Figure 26
Figure 26
Above: The DHODH inhibitor brequinar synthesized by Doebner-3CR. Below: The Doebner-MCR product is located in a deep and hydrophobic protein binding site (PDB ID: 1UUO). The key interaction is the salt bridge between the carboxylic acid and the guanidine unite of Arg136. Noteworthy the tight interaction of the two fluorine atoms located at the isoquinoline and the external biphenyl ring with the hydrophobic protein environment.
Figure 27
Figure 27
Scaffold hopping via virtual screening towards discovery of novel COX inhibitors. Compound 171 served as a template to screen a 1323 compound library using a screening cascade. Amongst the hits several scaffolds based on MCR were discovered. The most potent hit, compound 172 showed nM activity in a cell based assay.
Figure 28
Figure 28
Gewald-3CR product 174 (turquoise sticks) as subtype specific 3′,5′-nucleotide phosphodiesterase enzyme inhibitor bound to PDE4B (PDB ID: 3HMV). The inhibitor pocket is shown in a cut-off view. Several amino acid side chains are removed for clarity. The primary amide of the inhibitor makes a hydrogen bonding contact to Asn395 and an adjacent water molecule. A π-π interaction can be observed between the thiophene ring and Phe446. Additionally there are hydrophobic contacts to Phe506 and Met431.
Figure 29
Figure 29
Above: Retrosynthesis of the oxytocin antagonist (compound 175 and GSK221149A). Below: X-ray structure of oxytocin (grey sticks, PDB ID: 1XY2) and an energy minimized model of GSK221149A (yellow sticks). It is hypothesized that the indane part of GSK221149A mimics Tyr2 and the Ile fragment Ile3 of oxytocin. The oxazole fragment imparts a conformational lock and the morpholine water solubility, respectively.
Figure 30
Figure 30
Potent NPY antagonist 193 made by an old and experimentally simple MCR.
Figure 31
Figure 31
Various GPCR MCR-receptor binders. Below: Overlap of the CB1 receptor antagonist rimonabant with an imidazole isostere 211 synthesized by vL-3CR.
Figure 32
Figure 32
Left: Structure and X-ray structure of glycosylated dihydropyridine 215 in its typical bioactive boat conformation (CCDC ID: 182892); right: Patch-clamp recording for individual Ca2+ channels in the absence (left) and in the presence (right) of a dihydropyridine calcium antagonist.
Figure 33
Figure 33
Synthesis and cocrystal structure of potent small molecular weight p53-mdm2 antagonists 238. The synthesis involves a U-4CR of N-protected anthranilic acid, a primary amine, and aldehyde and the convertible isocyanide cyclohexenylisocyanide, followed by acid deprotection and cyclisation via a Münchone intermediate. A highly affine benzodiazepindione derivative 238 bound to mdm2 is shown below (PDB ID: 1T4F). The 4-chlorophenyl glycine, the 4-chlorophenyl and the 7-iodophenyl moieties occupy the Leu26, Trp23 and Phe19 binding pockets in mdm2, respectively.
Figure 34
Figure 34
Schematic process of discovery of PPI antagonists, based on structural information, hot spot anchors and rapid MCR chemistry.
Figure 35
Figure 35
Interaction of vL-indoloimidazole 253 with the p53 binding islet of the mdm2 receptor (PDB ID: 3LBK). The anchor residue chloro-indole occupies the Trp23 binding site, whereas the 4-chlorobenzyl mimics the Leu26 and the phenyl moiety the Phe19 site. Notably, the indole forms a nice hydrogen bridge to Leu54 backbone carbonyl of the mdm2 receptor similar to the Trp23p53 mdm2 interaction.
Figure 36
Figure 36
Interaction of vL-indoloimidazole 254 with the p53 binding site of the mdm4 receptor (PDB ID: 3LBJ). The anchor residue chloro-indole occupies the Trp23 binding site, whereas the 4-chlorobenzyl mimics the Leu26 and the phenyl moiety the Phe19 site. Notable, the indole forms a nice hydrogen bridge to Leu54 backbone carbonyl of the mdm2 receptor similar to the Trp23p53 mdm2 interaction.
Figure 37
Figure 37
Sepharose solid-support Ugi products (272) for the affinity purification of therapeutic Fab fragments. Docking of the best Ugi ligand (blue sticks) into human Fab fragment (PDB ID: 1AQK).
Figure 38
Figure 38
Alignment of the cocrystal structures of S-276 (yellow sticks) and optimized S-278 (marine sticks) to hFXR (PDB ID: 3OKI, 3OMM). The FXR binding site of 3OKI is shown as grey surface and selected amino acids as sticks. The inhibitors are encapsulated almost fully into the receptor. The highly conserved Tyr373 is making a hydrogen bridge to the scaffold benzimidazole-3N and is key to the efficient ligand binding (red dotted line). π-Stacking can be seen between Phe333 and the carboxylic acid derived p-chlorophenol. Ser336 (not shown) is engaged into hydrogen binding to the amide-NH resulting from the isocyano component. Additionally, in the hydrophilicity-optimized structure 277 a p-carboxyphenyl moiety at the mouth of the binding site mimics two tight waters (grey balls), forming an extensive hydrogen bond network with Arg335 and Gln267. The o-fluoro substituent of the isocyanide derived phenyl of 277 is accommodated in a hydrophobic bulb formed by the two Met332 and 294 (not shown) forming short hydrophobic contacts.
Figure 39
Figure 39
Synthesis of Biginelli product monastrol and a Gewald thiophene 291.
Figure 40
Figure 40
Cocrystal structure of 295 with kinesin-5. The dilemma of target-required hydrophobicity and inherent bad water solubility, poor PK properties and metabolic instability was solved by adding the solubilizing dimethylaminoethylamine urea moiety onto the tetrahydropyrane ring which points into the solvent space. The tetrahydroquinoline NH is involved into a hydrogen bond to backbone carbonyl Glu116 as is the urea carbonyl forming a hydrogen bond to a water molecule and backbone carbonyl Arg119.
Figure 41
Figure 41
Marketed mandipropamide as an agrochemical application of MCRs. It is used to protect wine grapes from fungal infections. Below: Infected and healthy grapes (Phytophthora infestans)
Scheme 1
Scheme 1
The UDC-strategy allows for the great scaffold diversification of an initial Ugi reaction by using orthogonal protected bifunctional starting materials.
Scheme 2
Scheme 2
Above: The generalized scheme as an archetypical example to illustrate the synthetic power of MCR chemistry. Middle: In a sequence of only 2-3 steps molecular diversity of high relevance for protease inhibitors (47) is assembled. Below: the complex natural product thrombin inhibitor cyclotheonamide C has been synthesized using this strategy as a key transformation in an unprecedented efficient and convergent approach.
Scheme 3
Scheme 3
2-Hydroxy-3-amino-ethyltetrazoles (51-53) as targeted Asp-protease library accessible in high number and diversity by the 3-step sequence Passerini reaction, deprotection and acylation.
Scheme 4
Scheme 4
Heterocyclic norstatine 56 accessible by an intramolecular Passerini variation of isocyanoacetamides 55 and α-amino acid derived aldehydes 54.
Scheme 5
Scheme 5
Various heterocyclic motifs combined with a secondary alcohol amenable by different (intramolecular) isocyanide chemistry variations.
Scheme 6
Scheme 6
Ugi and Passerini reaction can be performed under retention of stereochemistry using chiral α-amino acid derived isocyanides.
Scheme 7
Scheme 7
Use of Passerini reactions to convergently synthesize the α-ketoamide fragment, which is essential in many classes of serine protease inhibitors.
Scheme 8
Scheme 8
Convergent FXa inhibitor (72) synthesis by U-4CR.
Scheme 9
Scheme 9
Synthesis of an oral bioavailable, highly potent and selective FVIIa inhibitors 78 involves a U-3CR variation.
Scheme 10
Scheme 10
Synthesis of proteasome inhibitor and natural product omuralide by an elegant short sequence involving an intermolecular and highly stereoselective U-4CR using a new cleavable isocyanide.
Scheme 11
Scheme 11
The marketed DPP-IV inhibitor vildagliptin and two complementary MCR approaches towards the pharmacophore α-amino nitrile.
Scheme 12
Scheme 12
Approved renin inhibitor aliskiren, an early piperidine inhibitor (85) and general one-pot synthesis of 1,4,5-trisubstituted imidazole using van Leusen's 3CR of TOSMICs, aldehydes and unprotected 4-aminopiperidine (86).
Scheme 13
Scheme 13
Synthesis of spiropiperidine-hydantoine-4-imides (88-90) by Ugi-MCR and representative BACE inhibitors with their bioactivity.
Scheme 14
Scheme 14
Introduction of MCR chemistry into the total synthesis of complex pharma products can potentially lead to a considerable shortage of steps and thus to lower cost-of-goods as exemplified here with the HIV protease inhibitor crixivan (indinavir).
Scheme 15
Scheme 15
The sequence P-3CR – Dieckmann condensation leads into a tetronic acid backbone with HIV protease inhibitor activity.
Scheme 16
Scheme 16
Top: the recently approved metalloproteinase inhibitor SAHA; bottom: a U-3CR product with a novel type of metal binding war head, mono-acyl-o-phenylendiamine (98) and hydroxamic acids (99).
Scheme 17
Scheme 17
Selected reported cysteine protease inhibitors.
Scheme 18
Scheme 18
MCR scaffold diversity of malonodinitrile derivatives.
Scheme 19
Scheme 19
MCR chemistry of acetylenedicarboxylicacid diesters (DMAD) leads to multiple scaffolds (108-123) with hydrogen donor acceptor fragments thus potentially providing a kinase inhibitor pharmacophore.
Scheme 20
Scheme 20
Kinase inhibitors by Gewald MCR.
Scheme 21
Scheme 21
A diversity of products based on secondary reaction of the initial G-3CR.,
Scheme 22
Scheme 22
Synthesis of the potent Rho kinase inhibitors 148 by a 3-CR.
Scheme 23
Scheme 23
MCR library synthesis of phosphatase inhibitors involving hetero Diels Alder of α,β-unsaturated Schiff bases and allylboration.
Scheme 24
Scheme 24
Structure of almorexant, a first in class orexin I antagonists currently in advanced clinical trials for sleeping disorders.
Scheme 25
Scheme 25
Synthesis of the (RRR)-180 and (RRS)-181 stereoisomers of oxytocin antagonist derivatives.
Scheme 26
Scheme 26
Alternative MCR synthesis of the RRR and SSS stereoisomers of oxytocin antagonist derivatives.
Scheme 27
Scheme 27
CRF receptor antagonist (R)-185 optimisation by Petasis or Ugi-3CR.
Scheme 28
Scheme 28
The Orru-3CR and a biologically active m-opioid receptor antagonist (194) thereof.
Scheme 29
Scheme 29
Two scale-up asymmetric routes towards a preclinical MCH inhibitor SNAP-7941.
Scheme 30
Scheme 30
Ugi-ligation of Gn-RH analogues.
Scheme 31
Scheme 31
Examples of chloride channel interacting MCR products.
Scheme 32
Scheme 32
Channel blockers derived from the classical Hantzsch-4CR.
Scheme 33
Scheme 33
U-3CR scheme and the structure of xylocaine which can be advantageously synthesized by it.
Scheme 34
Scheme 34
Different MCR derived channel modulators and the natural product philanthotoxin-433.
Scheme 35
Scheme 35
Intramolecular Ugi-MCR leading into activators of P2x7 receptor (225).
Scheme 36
Scheme 36
Natural product GABA antagonist alantrypinone MCR synthesis. In 227 the Ala and Gly fragments are shown in red and blue, respectively.
Scheme 37
Scheme 37
Potent protein-protein interaction antagonists 231 of the entrance of HIV into cells have been assembled using Ugi-4CR.
Scheme 38
Scheme 38
MCR compounds 243 and 245 antagonizing p53-mdm2.
Scheme 39
Scheme 39
P53-mdm2 antagonists (246-254) accessible by MCR and predicted by a new approach, ANCHOR-QUERY.
Scheme 40
Scheme 40
Above: the pharmacophore of XIAP antagonists. The N-terminus is very important in forming a tight charge charge interaction with Glu314. In addition to the tight network of hydrogen bonds addressing the hydrophobic pockets, the central heterocycle with cis-geometry is of importance for inhibitor design. Below: several MCR scaffolds with μM XIAP activity and accessible by a rather short synthesis sequence.
Scheme 41
Scheme 41
Antagonists of antiapoptotic Bcl2.
Scheme 42
Scheme 42
HSP-70 inhibitors by MCR.
Scheme 43
Scheme 43
A new MCR lead to a new class of VEGF receptor antagonists.
Scheme 44
Scheme 44
Peptide-like RGD mimetics 269 and 270 and a viral capsid assembly inhibitor 271 by MCRs.
Scheme 45
Scheme 45
FXR nuclear hormone receptor modulators by UDC.
Scheme 46
Scheme 46
The Schistosomiasis drug PZQ can be convergently assembled using a key U-4CR and PS-2CR.
Scheme 47
Scheme 47
MCR compounds for different NTDs.
Scheme 48
Scheme 48
Enantioselective and short oseltamivir synthesis.
Scheme 49
Scheme 49
(Homo) glutathione derivatives by U-4CR and the structure of Acetyl CoA.
Scheme 50
Scheme 50
Immunosuppressive and anti-MS drug FTY720 synthesized by Petasis-3CR.
Scheme 51
Scheme 51
Staudinger-3CR product Zetia ™ and a bioactive aza-steroid.
Scheme 52
Scheme 52
Antiviral quinazolinone N-nucleoside (302).
Scheme 53
Scheme 53
Classical synthesis of a progesterone receptor agonist and a corresponding MCR synthesis.
Scheme 54
Scheme 54
MCRs leading into natural product-like furopyrans.
Scheme 55
Scheme 55
Napthyridinomycin, lemonomycin and ecteinascidin's piperazine moiety all has been assembled using one-pot U-4CR.
Scheme 56
Scheme 56
Versatile assembly of 5-aminothiazoles (315 and 316) based on the U-4CR leading to antiprion-active compounds.
Scheme 57
Scheme 57
Who can solve the jigsaw? One pot 8-CR to compound 323 based on three sequential MCRs with an 85% yield per bond formation.
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References

    1. Ugi I, Dömling A, Horl W. Endeavour. 1994;18:115.
    1. Tietze LF. Chem Rev. 1996;96:115. - PubMed
    1. Ugi I, Meyr R, Fetzer U, Steinbrückner C. Angew Chem. 1959;71:386.
    1. Passerini M. Gazz Chim Ital. 1921;51:126.
    1. van Leusen D, van Leusen AM. Org React (NY) 2003;57:419.

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