Ugi Four-component Condensation Research Articles

Studies of Isocyanides and Related Compounds; Synthesis of 1,4‐Benzodiazepine‐2,5‐diones via Ugi Four‐Component Condensation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Thiomorpholines by an Intramolecular Ugi Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Studies on Isocyanides and RelatedCompounds: A Facile Synthesis of 1,6-Dihydro-6-oxopyrazine-2-carboxylicAcid Derivatives via Ugi Four-Component Condensation

The Ugi four-component condensation (U-4CC) between arylglyoxals 7, amines 6, benzoylformic acid (4) and isocyanides 5 afforded the expected products 8 which were cyclized in a 5+1 fashion with ammonium acetate to give I,N-disubstituted 4-aryl-1,6-dihydro-6-oxo-5-phenylpyrazine-2-carboxamides 9 in good yields. Evidence for the assigned structures 9 was provided by 1 3 C NMR spectra and X-ray analysis of 9a.

Studies on Isocyanides and Related Compounds; A Facile Synthesis of Functionalized 3(2H)-Pyridazinones via Ugi Four-Component Condensation

The reaction between diarylglyoxal monohydrazones 1, isocyanides 2, aldehydes 3a-c, and methylene active acids 4 afforded a series of 3(2H)-pyridazinones 5 in a very simple manner. The intermediate Ugi four-component condensation products were never observed because of their tendency to cyclize. When the less reactive cyclopentanone (3d) is used instead of aldehydes 3a-c, satisfactory yields of 3(2H)-pyridazinones 7 were obtained by employing the pre-formed azine 8.

Synthesis of PNA Monomers andDimers by Ugi Four-Component Reaction

Peptide nucleic acids (PNA) have received great attention as tools in molecular biology and biotechnology, diagnostic agents, and potential antisense drugs. Many derivatives and analogues of PNA were designed and preparedto improve their physico-chemical and biological properties. In most cases, PNA oligomers were synthesized by peptide synthesis from N-protected monomers. In this work, a new method to obtain PNA monomers and PNA chain prolongation by Ugi four-component condensation reaction was tested by synthesizing PNA monomers and dimers. This method differs from classical peptide chemistry in that no prior preparation of PNA monomers is needed as they are built up along with the extension of chain. The synthesis of the key component isocyanide is also presented.

A Convenient Solution and Solid‐Phase Synthesis of Δ5‐2‐Oxopiperazines via N‐Acyliminium Ions Cyclization.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of thiomorpholines by an intramolecular Ugi reaction

The Ugi four-component condensation between 5-oxo-3-thiacarboxylic acids, benzylamines and cyclohexyl isocyanide gave 5-oxothiomorpholine-3-carboxamides. The configuration of bicyclic thiomorpholine derivatives was established by NOESY experiments.

A convenient solution and solid-phase synthesis of Δ 5-2-oxopiperazines via N-acyliminium ions cyclization

An extremely efficient synthesis of Δ 5-2-oxopiperazines in solution phase and on solid support has been established via a Ugi four-component condensation reaction (U-4CC) followed by N-acyliminium ion cyclization between the aldehyde (acetal) functionality and the newly formed amide bond. The desired Δ 5-2-oxopiperazines are obtained in excellent yields and purity.

Studies on Isocyanides and Related Compounds; Synthesis of 1,4-Benzodiazepine-2,5-diones via Ugi Four-Component Condensation

A convenient two-step synthesis of the title compounds based on the isocyanide chemistry is reported. The Ugi four-component condensation between 4-chloro-2-nitrobenzoie acid (1). aldehydes 2, cyclohexyl isocyanide (3) and α-amino esters as the amino components afforded the expected nitro compounds 5 which were reductively cyclized to the desired 1,4-benzodiazepine-2,5-di-ones 7 via the intermediate amino derivatives 6.

Design and synthesis of N-nonpolar nucleobase dipeptides: application of the Ugi reaction for the preparation of dipeptides having fluoroarylalkyl groups appended to the nitrogen atom

A single-step one-pot synthesis based on the Ugi four-component condensation of previously unknown dipeptides, 2, 3, 4 and 5, having a fluoroaromatic group appended to the nitrogen atom, is described. The series of dipeptides produced here can be viewed as nonpolar nucleobase dipeptides since the difluorotoluene nucleoside 1 is a well known nonpolar analogue of natural thymidine. A mixture of N-protected amino acids 7, fluorophenethylamines 6, isocyanides 8, and acetone or paraformaldehyde are stirred in methanol in the presence of 3 A molecular sieves to furnish the N-fluoroarylethyl-Aib- or -Gly-containing dipeptides 2 or 3, in moderate yields. The dipeptides 2d and 3b, having a cyclohex-1-enamide moiety, are deprotected readily with 3 M HCl in THF to afford the free dipeptides in high yields. The N-fluoroarylmethyl-Aib- or -Gly-containing β-alanyl dipeptides 4 or 5, designed based on the structure of 2′,5′-linked isoDNA, are also synthesized in a similar fashion to the preparation of 2, in moderate to good yields as both protected and free dipeptides.

A facile synthesis of 2,5-diketopiperazines based on isocyanide chemistry

The Ugi four-component condensation (4-CC) between amines 4 , aromatic aldehydes 5 , chloroacetic acid 6 and isocyanides 7 afforded the expected 4-CC adducts 8 which were cyclised to the title compounds 9 upon treatment with ethanolic KOH under ultrasonication.

Maximizing synthetic efficiency: multi-component transformations lead the way

With the emergence of high-throughput screening in the pharmaceutical industry in the early 1990's, organic chemists were faced with a new challenge: how to prepare large collections of molecules (the libraries) to "feed" the high-throughput screen? The unique exploratory power of some reactions (such as the 40 year-old Ugi four-component condensation) was soon recognized to be extremely valuable to produce libraries in a time- and cost-effective manner. Over the last five years, industrial and academic researchers have made these powerful transformations into one of the most efficient and cost-effective tools for combinatorial and parallel synthesis.

Synthesis and preliminary characterisation of charged derivatives and hydrogels from scleroglucan

The synthesis of negatively and positively charged polyelectrolytes from scleroglucan is described. Polycarboxylates were synthesised through nucleophilic substitution with chloroacetic acid or through a selective 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)-mediated oxidation of the primary alcohol groups. Amine groups were introduced through nucleophilic substitution with 2-chloroethylamine or 3-chloropropylamine. Reaction conditions were varied to obtain insight into the influence of variables on the degree of substitution. The conformational behaviour of the obtained polyelectrolytes was studied as a function of pH, temperature and solvent. For the products with a low degree of modification, evidence of an ordered conformation was found, whereas the polymers with a higher degree of modification behaved as random coils in solution. The negatively charged polymers were reticulated using the Ugi four-component condensation, obtaining negatively charged hydrogels. The positively charged polymers were reticulated using diethyl squarate (3,4-diethoxy-3-cyclobutene-1,2-dion, DES) to obtain positively charged hydrogels.

Application of the Ugi four-component condensation reaction for the synthesis of α,α- and α,β-dipeptides substituted with fluoroarylalkyl pendent groups†

We report a single step synthesis based on the Ugi four-component condensation of previously unknown α,α- and α,β-dipeptides, 2 and 8, having fluoroaromatic groups appended to the nitrogen atom.

Chemoenzymatic construction of a four-component Ugi combinatorial library

The chemoenzymatic preparation of a nine-member Ugi condensation library is described. The carboxylic acid and amine precursors are based on 3-hydroxybutyrate and 4-amino-1-butanol, respectively, and have been acylated selectively using a variety of acyl donors catalyzed by porcine pancreatic lipase. The enzyme is selective for the hydroxyl functionalities on both precursors, thereby yielding 3-acyl-butyric acid and 4-amino-1-acyl compounds. These enzymatically generated derivatives were then subjected to a four-component Ugi condensation reaction in the presence of acetaldehyde and methyl isocyanoacetate. Isolated yields of the alpha-(acylamino)amide Ugi products ranged from 72-95%. The inherent chemoselectivity of enzymatic catalysis may play an increasingly important role in expanding the structural diversity that can be achieved by chemical multicomponent condensation reactions.

Total Synthesis of Motuporin (Nodularin-V)

The serine/threonine phosphatase (protein phosphatase 1 and 2A) inhibitors constitute a biologically and structurally interesting class of natural products. Among this class of inhibitors are cyclic pentapeptides (nodularins) and cyclic heptapeptides (microcystins), both of which inhibit at the nanomolar level and are the only peptide inhibitors of these enzymes. Described herein is the total synthesis of motuporin, which utilizes an Ugi four-component condensation (4CC) reaction to synthesize the 2-(N)-methylaminobutenyl residue, Matteson's dihalomethyllithium insertion methodology for the construction of a key fragment, and an overall synthetic strategy amenable to the synthesis of analogues.

Solid-phase synthesis of potential protein tyrosine phosphatase inhibitors via the Ugi four-component condensation

A library of 108 α,α-difluoromethylenephosphonic acids was prepared by Ugi four-component condensation using Rink-NH 2 resin, 4-[(diethoxyphosphinyl)difluoromethyl]benzoic acid, and a set of 18 aldehydes and 6 isonitriles. Following resin cleavage, the diethylphosphonate esters were hydrolyzed with trimethylsilyl bromide to yield the free acids which were assayed for inhibition of PTPα, PTPβ and PTPε.

Synthesis of sialyl Lewis X mimetics using the Ugi four-component reaction

Application of the Ugi four-component condensation to rapidly synthesize a library of glycopeptide mimics of the tetrasaccharide SLe x as inhibitors of E- and P-selectin, and to study the effect of varied functionality in mimics on the inhibition is described.

Solution-phase synthesis of a combinatorial monocyclic β-lactam library: Potential protease inhibitors

Abstract A 126-member library of monocyclic β-lactams was generated in parallel fashion by solution-phase Ugi four-component condensation reaction between β-amino acids, aldehydes, and isocyanides. The library was designed to identify potential human leukocyte elastase inhibitors. The approach is also capable of optimizing the lead compounds generated in the original library.

(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors.

Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu6 (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the "Ugi four-component condensation", 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on 1H NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM).