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.     

Chemically modified nylons as supports for enzyme immobilization. Polyisonitrile-nylon

Four-component condensations between amine, carboxyl, isocyanide and aldehyde lead to the formation of N-substituted amides (Ugi, 1962). The present paper describes the use of such condensations for the introduction of chemically reactive groups on to the polyamide backbone of nylon. Polyisonitrile-nylon was synthesized by partial hydrolysis of nylon-6 powder, followed by resealing of the newly formed -CO(2)... NH(2) (-) pairs via a four-component condensation, by using acetaldehyde and 1,6-di-isocyanohexane. Polyisonitrile-nylon could also be converted into a diazotizable arylamino derivative, polyaminoaryl-nylon, by a four-component condensation by using a bifunctional amine, pp'-diaminodiphenylmethane, in the presence of an aldehyde and a carboxylate compound. The versatility of four-component condensations involving the isocyanide functional group of polyisonitrile-nylon allowed coupling of proteins, in an aqueous medium at neutral pH, through either their amino or carboxyl groups. Trypsin and papain were bound to polyisonitrile-nylon through their amino groups by a four-component condensation by using acetaldehyde and acetate; conversely, succinyl-(3-carboxypropionyl-)trypsin, pepsin and papain were coupled through their carboxyl groups in the presence of acetaldehyde and an amine (Tris). Diazotized polyaminoaryl-nylon could be utilized for the immobilization of papain, via the tyrosine residues of the enzyme.     

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

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.     

Synthesis of Nh-acyl-α-aminoamides on rink resin: Inhibitors of the hematopoietic protein tyrosine phosphatase (HePTP)

Cinnamic acid derivatives were prepared on Rink resin using tert-butyl-4-carboxycinnamate in a four-component Ugi condensation. Inhibition of the hematopoietic protein tyrosine phosphatase (HePTP) by these small molecules is reported. An IC₅₀ value of 3.9 μM was determined for the most potent inhibitor discovered.     

Practical and convenient synthesis of coumarins from phenols and propiolic acid esters

This protocol describes the synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2 catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in trifluoroacetic acid at room temperature (15-20 degrees C) under atmospheric conditions. This protocol can be completed in 3 d.     

Synthesis of peptide macrocycles using unprotected amino aldehydes

This protocol describes a method for synthesizing peptide macrocycles from linear peptide precursors, isocyanides and aziridine aldehydes. The effects of the reaction components on the efficiency of the process are discussed. Macrocyclization is exemplified by the preparation of a nine-membered ring peptide macrocycle. The product is further functionalized by nucleophilic opening of the aziridine ring with a fluorescent thiol. This transformation constitutes a useful late-stage functionalization of a macrocyclic peptide molecule. The experimental section describes the selection of the required starting materials, and the preparation of a representative aziridine-2-carboxaldehyde dimer. The synthesis and isolation of the peptide macrocycle can be accomplished in 6 h, and the ring-opening requires approximately 6-8 h. The aziridine-2-carboxaldehyde reagent is commercially available or can be synthesized from readily available starting materials in approximately 4 d. The strategy described is not limited to the specific peptide, isocyanide, aziridine aldehyde or nucleophile used in the representative synthesis.     

Application of the four-component Ugi condensation for the preparation of sulfated glycoconjugate libraries

A focused library of novel, sulfated glycoconjugates was synthesized by utilizing carbohydrate-derived blocks in the four-component Ugi condensation. Library members comprise a sulfated monosaccharide linked by various spacers to either an aromatic or monosulfated moiety, or a second sulfated monosaccharide. The affinities of these heparan sulfate (HS) mimetics for the HS-binding fibroblast growth factors FGF-1 and FGF-2 were measured via a surface plasmon resonance solution affinity assay.     

An efficient one-pot synthesis of polyphenolic amino acids and evaluation of their radical-scavenging activity

A simple and efficient procedure for the synthesis of N-acyl 4-hydroxy, 4-hydroxy-3-methoxy and 3,4-dihydroxy phenylglycine amides by a strategy based on the multicomponent Ugi reaction is proposed. Hydroxybenzaldehyde derivatives were reacted with 4-methoxybenzylamine, cyclohexyl isocyanide and benzoic acid or 2-naphthylacetic acid to give Ugi adducts that were treated with trifluoroacetic acid yielding N-acyl hydroxyphenylglycine amides in good yields. The same procedure using as acid component protocatechuic acid or hydrocaffeic acid gave N-catechoyl 3,4-dihydroxyphenylglycine amides. The use of N-benzyloxycarbonylglycine as acid component allowed the preparation of a 3,4-dihydroxyphenylglycyl dipeptide derivative. Radical-scavenging activity studies of the polyphenolic amino acid derivatives showed a sharp increase in activity with the increase in number of hydroxyl or catechol groups present. Cyclic voltammetry experiments established a correlation between oxidation peak potentials and the radical-scavenging activity.     

Synthesis and biological evaluation of (2S)- and (2R)-2-(3'-phosphonobicyclo[1.1.1]pentyl)glycines as novel group III selective metabotropic glutamate receptor ligands

The synthesis of (2S)- and (2R)-2-(3'-phosphonobicyclo[1.1.1]pentyl)glycine isomers (10 and 11), characterized by the bioisosteric replacement of the distal carboxylic group of 2-(3'-carboxybicyclo[1.1.1]pent-1-yl)glycine by the phosphonate moiety, was accomplished by a stereoselective Ugi condensation. The two isomers were tested for their activity against an array of metabotropic glutamate receptors, and the S-isomer (10) turned out to be a moderately potent and selective mGluR4 agonist.     

Synthesis of lactones using substituted benzoic anhydride as a coupling reagent

This protocol describes a procedure for the synthesis of a 29-membered macrolactone. The facile mixed-anhydride method is very effective for the preparation of carboxylic esters and lactones using substituted benzoic anhydrides by the promotion of Lewis acid or basic catalysts under mild reaction conditions. Owing to the reaction rapidly proceeding to produce the monomeric compounds with high chemoselectivity, the protocol is quite powerful for the synthesis of not only the giant-sized lactones but also the highly strained cyclic compounds such as medium-sized lactones. The remarkable efficiency of the lactonizations promoted by the substituted benzoic anhydrides has been already shown in the synthesis of many natural complex molecules. It takes approximately 19 h to complete the protocol: 0.5 h to set up the reaction, 13.5 h for the reaction and 5 h for isolation and purification.     

Generation of an Ugi library of phosphate mimic-containing compounds and identification of novel dual specific phosphatase inhibitors.

The four-component Ugi reaction was utilized to prepare a library of dipeptidic compounds in order to explore the binding requirements of the key cell cycle phosphatase, Cdc25. Several phosphate surrogates were incorporated into the Ugi product to mimic either the mono- or bis-phosphorylated substrate.     

Synthesis of cluster mannosides via a Ugi four-component reaction and their inhibition against the binding of yeast mannan to concanavalin A

The Ugi four-component reaction (U-4CR) was utilized to prepare divalent and trivalent cluster mannosides with different scaffolds. The glycoclusters obtained were tested for their relative inhibitory potency against the binding of yeast mannan to concanavalin A by solid-phase enzyme-linked lectin assays (ELLA) using methyl alpha-D-mannopyranoside as a standard. Among them, a divalent mannoside containing aromatic groups showed the strongest binding affinity to concanavalin A.     

A focused sulfated glycoconjugate Ugi library for probing heparan sulfate-binding angiogenic growth factors

A library of small molecule heparan sulfate (HS) mimetics was synthesized by employing the Ugi four-component condensation of d-mannopyranoside-derived isocyanides with formaldehyde as the carbonyl component and a selection of carboxylic acids and amines, followed by sulfonation. The library was used to probe the subtle differences surrounding the ionic binding sites of three HS-binding angiogenic growth factors (FGF-1, FGF-2 and VEGF). Each compound features 3 or 4 sulfo groups which serve to anchor the ligand to the HS-binding site of the protein, with a diverse array of functionality in place extending from C-1 or C-6 to probe for adjacent favorable binding interactions. Selectivity of binding to these proteins was clearly observed and supported by molecular docking calculations.     

A new strategy for the synthesis of cyclopeptides containing diaminoglutaric acid.

A new synthesis of orthogonally protected diaminoglutaric acid containing peptides using the Ugi four component condensation is presented. To demonstrate that this method is useful to replace cystine by diaminoglutaric acid in biologically interesting peptides, we built up two cyclic somatostatin analogues deriving from Sandostatin and from TT-232. A photolytically cleavable amine derivative of the nitroveratryl type is used for the Ugi four component condensation. Because of a racemic build up of the new stereocentre of the diaminoglutaric acid, and racemization of the isonitrile component, four diastereomeric peptides resulted that were separated by HPLC. The stereochemistry of the cyclopeptides could be easily and unambiguously assigned by chiral gas chromatography and a reference sample of enantiomerically pure (2S,4S)-diaminoglutaric acid.     

Multicomponent synthesis of novel amino acid-nucleobase chimeras: a versatile approach to PNA-monomers

This paper describes a multicomponent approach to novel totally protected precursors of PNA-monomers via Ugi 4CC. The obtained bisamides are converted into several partially protected PNA-monomers or derivatives thereof using three different procedures. Methods for hydrolysis are shown to be dependent on the nature of the isocyano component required for Ugi 4CC. Several novel monomers suitable for oligomer synthesis are prepared demonstrating the high versatility of the reaction sequence.     

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-l-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.     

Preparation of arylzinc reagents and their use in the rhodium-catalyzed asymmetric 1,4-addition for the synthesis of 2-aryl-4-piperidones

A protocol for the catalytic asymmetric synthesis of 2-aryl-4-piperidones with high enantiomeric excess (ee) (typically > or = 99% ee) has been described here. The preparation of arylzinc reagents, which are used as nucleophiles in catalysis, is also included. The whole protocol can be completed in 10-20 h, starting from the preparation of the arylzinc reagents, depending on the reaction time of the rhodium-catalyzed process. A detailed protocol is described using the preparation of 4-fluorophenylzinc chloride and its addition to benzyl 3,4-dihydro-4-oxo-1(2H)-pyridinecarboxylate in the presence of [RhCl((R)-binap)]2 as an example.     

Facile synthesis of Ag nanocubes and Au nanocages

This protocol describes a method for the synthesis of Ag nanocubes and their subsequent conversion into Au nanocages via the galvanic replacement reaction. The Ag nanocubes are prepared by a rapid (reaction time < 15 min), sulfide-mediated polyol method in which Ag(I) is reduced to Ag(0) by ethylene glycol in the presence of poly(vinyl pyrrolidone) (PVP) and a trace amount of Na(2)S. When the concentration of Ag atoms reaches supersaturation, they agglomerate to form seeds that then grow into Ag nanostructures. The presence of both PVP and Na(2)S facilitate the formation of nanocubes. With this method, Ag nanocubes can be prepared and isolated for use within approximately 3 h. The Ag nanocubes can then serve as sacrificial templates for the preparation of Au nanocages, with a method for their preparation also described herein. The procedure for Au nanocage preparation and isolation requires approximately 5 h.     

The role of nickel in acetyl-CoA synthesis by the bifunctional enzyme CO dehydrogenase/acetyl-CoA synthase: enzymology and model chemistry

 CO dehydrogenase/acetyl-CoA synthase (CODH/ACS) is one of the four known nickel enzymes. It is a bifunctional protein that catalyzes the oxidation of CO to CO₂ at a nickel iron-sulfur cluster (Cluster C) and a remarkable condensation reaction between a methyl group (donated from a methylated corrinoid iron-sulfur protein), carbon monoxide, and coenzyme A to form acetyl-CoA at a separate nickel iron-sulfur cluster (Cluster A). This review focuses on the current understanding of the structure and function of Cluster A and on related model chemistry. It describes studies that uncovered the first example of a biological organometallic reaction sequence. The mechanism of acetyl-CoA synthesis includes enzymebound methylnickel, iron-carbonyl, and acylmetal intermediates. Discovery of the methylnickel species constituted the first example of an alkylnickel species in biology and unveiled a new biological role for nickel. Received: 10 April 1996 / Accepted: 4 July 1996     

Selective synthesis of 3-hydroxy acids from Meldrum's acids using SmI2-H2O

The single-step synthesis of 3-hydroxy carboxylic acids from readily available Meldrum's acids involves a selective monoreduction using a SmI(2)-H(2)O complex to give products in high crude purity, and it represents a considerable advancement over other methods for the synthesis of 3-hydroxy acids. The protocol includes a detailed guide to the preparation of a single electron-reducing SmI(2)-H(2)O complex and describes two representative examples of the methodology: monoreduction of a fully saturated Meldrum's acid (5-(4-bromobenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione) and tandem conjugate reduction-selective monoreduction of α,β-unsaturated Meldrum's acid (5-(4-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione). The protocol for selective monoreduction of Meldrum's acids takes ～6 h to complete.