Ugi Three-component Reaction Research Articles

Modular Divergent Synthesis of Indole Alkaloid Derivatives by an Atypical Ugi Multicomponent Reaction.

We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma-type monoterpene indole alkaloids. By variation of the isocyanide and carboxylic acid inputs we demonstrate the rapid generation of molecular diversity and the possibility to introduce handles for further modification. The key Ugi three-component reaction showed full diastereoselectivity towards the cis-fused ring system, which can be rationalized by DFT calculations that moreover indicate that the reaction proceeds via a Passerini-type hydrogen bonding mechanism. Several post-Ugi modifications were also performed, including Pictet-Spengler cyclization to highly complex nonacyclic natural product hybrid scaffolds.

Protein-Templated Ugi Reactions versus In-Situ Ligation Screening: Two Roads to the Identification of SARS-CoV-2 Main Protease Inhibitors.

Protein-templated fragment ligation was established as a method for the rapid identification of high affinity ligands, and multicomponent reactions (MCR) such as the Ugi four-component reaction (Ugi 4CR) have been efficient in the synthesis of drug candidates. Thus, the combination of both strategies should provide a powerful approach to drug discovery. Here, we investigate protein-templated Ugi 4CR quantitatively using a fluorescence-based enzyme assay, HPLC-QTOF mass spectrometry (MS), and native protein MS with SARS-CoV-2 main protease as template. Ugi reactions were analyzed in aqueous buffer at varying pH and fragment concentration. Potent inhibitors of the protease were formed in presence of the protein via Ugi 4CR together with Ugi three-component reaction (Ugi 3CR) products. Binding of inhibitors to the protease was confirmed by native MS and resulted in the dimerization of the protein target. Formation of Ugi products was, however, more efficient in the non-templated reaction, apparently due to interactions of the protein with the isocyanide and imine fragments. Consequently, in-situ ligation screening of Ugi 4CR products was identified as a superior approach to the discovery of SARS-CoV-2 protease inhibitors.

Local Anesthetics via Multicomponent Reactions.

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage-gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)-based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single-crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three-component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.

Use of convertible isocyanides for the synthesis of benazepril hydrochloride

Herein, we have described a novel and concise synthesis of the potent angiotensin-converting enzyme (ACE) inhibitor, benazepril hydrochloride (7) in trifluoroethanol via an Ugi three-component reaction in shorter reaction times. The key step is the trifluoroacetic acid-mediated hydrolysis of secondary amides (4a and 4b) followed by esterification as a domino process to form corresponding ethyl ester (6). Mainly two universal convertible isocyanides (1a and 1b) were used for the synthesis of benazepril hydrochloride. Synopsis: An efficient synthesis of benazepril hydrochloride using Ugi three-component reaction.

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents.

An Ugi three-component reaction using preformed α-phosphorated N-tosyl ketimines with different isocyanides in the presence of a carboxylic acid affords tetrasubstituted α-aminophosphonates. Due to the high steric hindrance, the expected acylated amines undergo a spontaneous elimination of the acyl group. The reaction is applicable to α-aryl ketimines bearing a number of substituents and several isocyanides. In addition, the densely substituted α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell line A549 (carcinomic human alveolar basal epithelial cell).

The Ugi three-component reaction and its variants

A broad variety of α-aminoamide-based compounds have been synthesized via the three-component version of the Ugi reaction (U-3CR) or by any of its variants (Ugi-Zhu-3CR, Orru-3CR, Ugi-4C-3CR, Ugi-Joullié-3CR, GBB-3CR, Ugi-Reissert-3CR, and so on).

5-Endo Trig Oxidative Radical Cyclizations of Ugi-3CR Products toward 1,4-Imidazolidinones.

A 5-endo trig oxidative radical cyclization of benzylamine-derived Ugi three-component reaction products rapidly affords imidazolidinones with three diversity elements. This adaptation of our previously described multicomponent reaction-oxidation methodology further showcases manipulation of the diversity elements in multicomponent reaction products via oxidative radical cyclizations, which generates highly decorated privileged heterocycles.

Enantioselective three-component Ugi reaction catalyzed by chiral phosphoric acid

A catalytic enantioselective three-component Ugi reaction was developed. SPINOL-derived phosphoric acid with bulky 2,4,6-tricyclohexylphenyl groups at the 6,6′ positions was found to be the best catalyst to afford α-amino amide derivatives in good to excellent yields (62% to 99%) and enantiocontrol (81% to >99% enantiomeric excess). This asymmetric reaction was applicable well to an array of aliphatic aldehydes. The gram-scale synthesis, modification of dapsone, and enantioselective synthesis of ( R )-Lacosamide underline the general utility of this methodology. Influence of dihedral angles and substituents of the chiral phosphoric acids on the enantioselectivity was also discussed in this article.

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides.

The synthesis of a novel category of pseudo-peptides via intramolecular Ugi reaction of levulinic acid (4-oxopentanoic acid), aromatic and aliphatic amines, and amino acid-based isocyanides is reported. Levulinic acid was applied as a bifunctional substrate containing both carbonyl and acid moieties suitable for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields.

DFT Studies on the Stereoselective Three-Component Ugi Reaction

Mechanism and stereochemistry of three component Ugi reaction (3C-Ugi) were studied theoretically based on DFT calculations. Structures of reagents, products, intermediates, and transition states were optimized at M062X/6-31+g(d,p) level of theory in gas phase and in methanol as a common solvent for this reaction. The reaction takes place through several processes, including atom inversion, bond rotation, acid-base, nucleophile-electrophile competitions. These diverse phenomena were studied to provide a clearer picture of the mechanism of this valuable reaction, especially in terms of stereochemistry considerations. According to the results, the enthalpy of the reaction was -45.9 and -41.2 kcal/mol for the dominant product in gas phase and in methanol. The stereoselectivity of the reaction was under the kinetic control of nucleophilic attack of isocyanide to less hindered si-face (E a = 4.1 compared to 7.4 kcal/mol for re-face) of more stable chiral (E)-iminium in methanol. DOI: http://dx.doi.org/10.17807/orbital.v11i1.1214

Organocatalytic Synthesis of α,α–Diaryl Substituted α–Amino Acid Derivatives by an Interrupted Three-Component Ugi Reaction

An organocatalytic interrupted three-component Ugi reaction for the synthesis of α,α–diaryl α–amino acid derivatives is described. The transformation proceeds with a range of isocyanides and 3-aryl isoindolinone alcohols using Brønsted acid catalysts to afford products in good to excellent yields. Based on the obtained results, a reaction mechanism is proposed and discussed.

Multicomponent Approach to a Library of N-Substituted γ-Lactams.

The γ-lactam motif is often found in naturally occurring compounds with diverse biological activities. We prepared a 28-member library of N-substituted γ-lactams following a single-pot, three-component Ugi reaction comprising bifunctional building block, l-glutamic acid methyl ester. The reaction tolerates structurally diverse carbonyl and isocyanide components providing a robust access to functionalized γ-lactams. Antimicrobial susceptibility testing, including agar well diffusion assay, serial microdilution broth assay, and antibiofilm activity testing, identified a potent compound with antibiofilm activity against Staphylococcus aureus ATCC 6538.

Lewis Acid-Catalyzed Diastereoselective Synthesis of Multisubstituted N-Acylaziridine-2-carboxamides from 2 H-Azirines via Joullié-Ugi Three-Component Reaction.

A ZnCl2-catalyzed diastereoselective Joullié-Ugi three-component reaction from 2 H-azirines, isocyanides, and carboxylic acids was established. The protocol allows the preparation of highly and diversely functionalized N-acylaziridine-2-carboxamide derivatives in up to 82% isolated yields. Moreover, the applicability of N-acylaziridines is demonstrated through a variety of transformations.

Aza-Riley Oxidation of Ugi-Azide and Ugi-3CR Products toward Vicinal Tricarbonyl Amides: Two-Step MCR-Oxidation Methodology Accessing Functionalized α,β-Diketoamides and α,β-Diketotetrazoles.

Direct oxidative deamination of glyoxal-derived Ugi-azide and Ugi three-component reaction products readily affords vicinal tricarbonyls (α,β-diketoamides) and α,β-diketotetrazoles with two diversity elements. This significant extension of our previously described multicomponent reaction-oxidative deamination methodology is proposed to proceed through a mechanistically distinct SeO2-mediated C-N oxidation derived from an active enol of α-amino-β-ketone systems, effectively an aza-Riley oxidation. This methodology accesses diverse VTC systems from prototypical amines, glyoxaldehydes, and isocyanide building blocks in a mere two steps.

Synthesis of iminoisoindolinones via a cascade of the three-component Ugi reaction, palladium catalyzed isocyanide insertion, hydroxylation and an unexpected rearrangement reaction.

A robust ligand-free palladium-catalyzed cascade reaction for the synthesis of diversely substituted iminoisoindolinones has been developed. The cascade reaction involves isocyanide insertion into Ugi-3CR adducts, accompanied by unexpected hydroxylation and rearrangement.

Rapid access to reverse-turn peptidomimetics by a three-component Ugi reaction of 3,4-dihydroisoquinoline

Peptidomimetics have raised a considerable attention in the last decades due to their potential application as therapeutic agents. In this perspective, multicomponent reactions are an excellent tool to rapidly afford a large number of drug candidates having a great structural diversity. We report here on the use of the three-component Ugi reaction for the synthesis of a library of potential reverse-turn mimetics, based on the constrained tetrahydroisoquinoline heterocyclic scaffold. The ability of the target compounds to mimic secondary structure of peptides was evaluated by means of computational tools and NMR studies. We were able to demonstrate that by using the appropriate starting materials, a β-turn or a β-sheet mimetic is obtained.

Ugi three-component reaction of alcohols, amines and isocyanides: A new approach to the synthesis of cyclic amidines

We have developed a novel, simple, efficient and one pot synthetic protocol for the synthesis of cyclic amidines via Ugi three-component reaction of alcohols, amines, and isocyanides.

Enzymatic Ugi Reaction with Amines and Cyclic Imines.

The application of the Ugi reaction to the construction of new peptide scaffolds is an important goal of organic chemistry. To date, there are no examples of the Ugi reaction being performed with a cyclic imine and amine simultaneously. The application of 2-substituted cyclic imines in an enzymatic three-component Ugi-type reaction provides an elegant and attractive synthesis of substituted pyrrolidine and piperidine derivatives in up to 60 % yield. Results on studies of the selection of an enzyme, amount of water, and solvent used in a novel three-component Ugi reaction and the limitations thereof are reported herein. The presented methodology exploiting enzyme promiscuity in the multicomponent reaction fulfills the requirements associated with green chemistry. Several methods, such as isotope labeling and enzyme inhibition, were used to probe the possible mechanism of this complex synthesis. This research is the first example of an enzyme-catalyzed Ugi-type reaction with an imine, amine, and isocyanide.

Two-Step Route to Diverse N-Functionalized Peptidomimetic-like Isatins through an Oxidation/Intramolecular Oxidative-Amidation Cascade of Ugi Azide and Ugi Three-Component Reaction Products.

Two-step methodology described herein showcases the first example of an oxidation/oxidative amidation cyclization cascade of MCR products toward diverse N-functionalized isatins. Products of both the Ugi 3CR and the Ugi azide reactions are oxidatively cyclized through a postcondensation process utilizing selenium dioxide. This methodology was found to be applicable for the generation of bis-peptidomimetic-like isatins containing multiple points of diversification.

ChemInform Abstract: Revisited Mechanistic Implications of the Joullie—Ugi Three‐Component Reaction.

AbstractThe Joullie—Ugi three‐component reaction proceeds in hexafluoro‐2‐propanol through SN1‐type mechanism to generate the trans‐isomer, whereas in toluene the cis‐isomer is generated selectively via a SN2‐type mechanism.