Ugi Multicomponent Reaction Research Articles

The Application of Multicomponent Ugi and Passerini Reactions for the One-Pot Synthesis of Pyrrolones and Butenolides

A new protocol for the one-pot synthesis of pyrrolones and butenolides involving an isocyanide-based multicomponent reaction (Ugi or Passerini) followed by a triethylamine-promoted cycloisomerization is described.

A carbohydrate-binding affinity ligand for the specific enrichment of glycoproteins

One challenge facing the production of glycoprotein therapeutics is the lack of stable and selective affinity ligands for their enrichment. Synthetic affinity ligands based on the solid phase multi-component Ugi reaction represent a desirable option, particularly those incorporating benzoboroxole and its derivatives, which have been shown to enrich glycoproteins under physiological conditions. Thus, an Ugi ligand, A21C11I8, comprising 5-amino-2-hydroxymethylphenylboronic acid was synthesised on aldehyde-functionalised Sepharose™. Immobilised A21C11I8 displayed affinity for the glycosylated protein, glucose oxidase (GOx), which bound primarily through its glycan moiety. The ligand had a preference for sugar alcohols and the furanose form of the monosaccharides tested. Compared with immobilised 3-aminophenylboronic acid and Concanavalin A, the Ugi ligand was able to purify GOx from spiked Escherichia coli supernatants with retention of its maximum enzymatic activity and protein recovery. Glycan profiles of human immunoglobulin G tested on A21C11I8 columns suggested that the adsorbent possesses the potential to resolve sialylated and neutral glycoforms. The benzoboroxole-functionalised Ugi ligand may find application in selective glycoform separation.

Fluorescent Peptoids as Selective Live Cell Imaging Probes.

This paper describes the synthesis of fluorescent peptoids using the Ugi multicomponent reaction (4CR). The four synthesized structures had their photophysical properties evaluated and their potential as biomarkers established. The peptidomimetics were used at very low concentrations (10 nM) to follow their internalization in breast cancer cells and had their localization precisely determined. One of the new peptoids displayed mitochondrial affinity and stained this important organelle selectively. Co-staining experiments using MitoTracker Red confirmed the localization inside live cells.

Synthesis of novel tetrahydroindeno[1,2-b]pyrrolidines via Ugi multicomponent and palladium-catalyzed aerobic oxidative cyclization

ABSTRACTNovel tetrahydroindeno[1,2-b]pyrrolidines were conveniently prepared in moderate to good yields via a sequential Ugi multicomponent reaction or Staudinger/aza-Wittig/Ugi combination, followed by the palladium-catalyzed aerobic oxidative cyclization of the resulting Ugi adducts.

New Antimycobacterial Leads from Multicomponent Hydrazino-Ugi Reaction.

Previously, modification of isoniazide- and pyrazinamide-derived pharmacophores via the Ugi multicomponent reaction proved to be an effective strategy to obtain efficacious and non-cytotoxic antimycobacterial leads. To apply the hydrazino-Ugi reaction developed in our group toward modifying these pharmacophores with similar appendages as reported previously; to create hydrolytically more stable compounds which are based on acyl hydrazine, rather than diamide backbone. Six hydrazino-Ugi products were synthesized and modified at the reactive nitrogen atom via reductive alkylation. Additionally, by conducting the hydrazino-Ugi reaction in methanol, three methyl ester by-products were obtained and tested alongside the main library. Compounds were screened against M. tuberculosis H37Rv strain and checked for cytotoxicity vs. HEK293 cells. Hydrolytic stability of a model Ugi and one of the newly synthesized hydrazino-Ugi products was compared in rat plasma stability experiments. 6 out of 20 compounds prepared and tested, displayed potent inhibition of M. tuberculosis growth and virtually no cytotoxicity in the testing concentration range. The stability of a sample hydrazino-Ugi product in rat plasma was over 3 times higher compared to that of one of the Ugi products reported earlier. Hydrazino-Ugi reaction represents an effective way to modify classical antitubercular chemotypes and generate compounds endowed with specific antimycobacterial activity. These are new, hydrolytically stable leads for the future antitubercular therapy development.

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction.

Enantiomerically pure β-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multicomponent reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three stereogenic centers, allowing the introduction of five diversity inputs.

Highly Convergent Synthesis of Intensively Blue Emissive Furo[2,3-c]isoquinolines by a Palladium-Catalyzed Cyclization Cascade of Unsaturated Ugi Products.

A convergent and diversity-oriented approach to the unusual furo[2,3-c]isoquinoline scaffold is presented. This serendipity-driven approach is characterized by an Ugi multicomponent reaction, which gives the substrate for a palladium-catalyzed insertion-alkynylation-cycloisomerization cascade to provide the furo[2,3-c]isoquinolines in moderate to high yield. Upon UV excitation, all representatives are intensively blue luminescent, as observed by the naked eye, and quantitative fluorescence spectroscopy reveals a considerable effect of the substitution pattern on the quantum yields. The electronic structure is semiquantitatively rationalized by DFT and time-dependent DFT calculations.

ChemInform Abstract: (Z)‐Stereoselective Synthesis of Mono‐ and Bis‐heterocyclic Benzimidazol‐2‐ones via Cascade Processes Coupled with the Ugi Multicomponent Reaction.

AbstractThe acid treatment of various Ugi adducts afford 1,5‐benzodiazepines which subsequently undergo a rearrangement affording benzimidazolones.

Multicomponent reactions of methyl substituted all-cis tetrafluorocyclohexane aldehydes.

This paper reports the preparation of methyl substituted all-cis tetrafluorocyclohexanes prepared from a Birch reduction of benzoic acid, worked up with a methyl iodide quench. The resultant methylcyclohexadiene carboxylic acid was reduced to the alcohol, protected as an ether and then a sequence of functional group manipulations carried out to introduce four fluorines. The cyclohexadienyl ring was then epoxidised and the C-O bonds sequentially converted through deoxyfluorination reactions to two sets of isomers of all-cis tetrafluorocyclohexane isomers. The blocking methyl group renders the ring safe to hydrogen fluoride elimination. Deprotection of the benzylic ether and then oxidation gave aldehydes which were then used in Ugi and Passerini multicomponent reactions, allowing this facially polarised cyclohexane to be incorporated into peptidic structural motifs.

Versatile Multicomponent Reaction Macrocycle Synthesis Using α-Isocyano-ω-carboxylic Acids.

The direct macrocycle synthesis of α-isocyano-ω-carboxylic acids via an Ugi multicomponent reaction is introduced. This multicomponent reaction (MCR) protocol differs by being especially short, convergent, and versatile, giving access to 12-22 membered rings.

Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction.

The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein—protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

Enantioselective Steglich Rearrangement of Oxindole Derivatives by Easily Accessible Chiral N,N-4-(Dimethylamino)pyridine Derivatives.

Chiral N,N-4-(dimethylamino)pyridine (DMAP) derivatives, which can be readily prepared by the Ugi multicomponent reaction in a one-pot manner, have been efficiently applied to the enantioselective Steglich rearrangement of oxindole derivatives to give the desired products bearing a quaternary carbon center in high yield (>98% yield) and with high enantioselectivity (up to 99:1 er).

Efficient Synthesis of Conformationally Restricted Apoptosis Inhibitors Bearing a Triazole Moiety.

Apoptosis is a biological process relevant to different human diseases that is regulated through protein-protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis/trans conformers of an exocyclic tertiary amide bond in slow exchange has been characterized. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3-triazole moiety, in which different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogues have been carried out through an Ugi multicomponent reaction followed by an intramolecular cyclization. The unexpected formation of a β-lactam scaffold prompted us to study the course of the intramolecular cyclization of the Ugi adducts. In order to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated.

Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction.

We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [(35)S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.

A Rapid One-Pot Ugi Reaction Based Route to Novel Imidazole-Fused Benzodiazepinones

A short and efficient synthetic approach has been developed for the synthesis of a variety of imidazole-fused benzodiazepinones. It is based on a Ugi multicomponent reaction strategy and uses various isocyanides to generate the key intermediates for a Mumm rearrangement process. The method is suitable for rapid syntheses of fused azaheterocycles of pharmacological interest.

N-(2-(Piperazin-1-yl)phenyl)arylamide Derivatives as β-Secretase (BACE1) Inhibitors: Simple Synthesis by Ugi Four-Component Reaction and Biological Evaluation.

A novel series of N-(2-(piperazin-1-yl)phenyl)aryl carboxamide derivatives were simply synthesized by Ugi-multicomponent reaction as β-secretase (BACE1) inhibitors. The BACE1 inhibitory activity of the synthesized compounds was examined using a Forester resonance energy transfer (FRET)-based assay. Among the tested compounds, the N-(5-bromo-2-(4-phenylpiperazine-1-yl)phenyl)thiophene-carboxamide derivative 14 containing the N-cyclohexyl indole acetamide moiety showed superior BACE1 inhibition at 10 and 40 µM. The results of the molecular docking study indicated that compound 14 establishes favorable hydrogen bonding interactions with the catalytic amino acid residues Asp228 and Thr72 and could be well accommodated in the flap region and P2 and P'2 pockets of the BACE1 active site.

ChemInform Abstract: What Do We Know about Multicomponent Reactions? Mechanisms and Trends for the Biginelli, Hantzsch, Mannich, Passerini and Ugi MCRs

AbstractReview: 50 refs.

Synthesis and structural characterization of monomeric and dimeric peptide nucleic acids prepared by using microwave-promoted multicomponent reactions.

A solution phase synthesis of peptide nucleic acid monomers and dimers was developed by using microwave-promoted Ugi multicomponent reactions. A mixture of a functionalized amine, a carboxymethyl nucleobase, paraformaldehyde and an isocyanide as building blocks generates PNA monomers which are then partially deprotected and used in a second Ugi 4CC reaction, leading to PNA dimers. Conformational rotamers were identified by using NMR and MD simulations.

Diversity-oriented synthesis of intensively blue emissive 3-hydroxyisoquinolines by sequential Ugi four-component reaction/reductive Heck cyclization.

A convergent approach to highly functionalized 3-hydroxyisoquinolines is reported. The key steps are an Ugi multicomponent reaction and a subsequent intramolecular reductive Heck reaction; these can also be performed as a one-pot procedure. The structures display very interesting properties as blue-fluorescence emitters. Photophysical studies on the absorption and static fluorescence indicate that the substitution pattern on the pyridyl part influences the optical properties only to a minor extent, unless the amide substituent becomes sterically demanding and leads to significant nonradiative deactivation. The donor substitution on the benzo core considerably enhances the fluorescence quantum yields and trimethoxy substitution causes a pronounced redshift of the emission bands. Protonation of the isoquinolyl nitrogen atom causes efficient static quenching of the fluorescence.

What do we know about multicomponent reactions? Mechanisms and trends for the Biginelli, Hantzsch, Mannich, Passerini and Ugi MCRs

The current manuscript describes the importance, mechanism propositions, evidence and controversies associated with multicomponent reactions (MCRs). The following multicomponent reactions are presented and critically evaluated: the Biginelli, Hantzsch, Mannich, Passerini and Ugi reactions. The aim of this review is to highlight what we already know about the mechanisms associated with these MCRs and the evidence supporting the proposed reaction pathways. Controversies and prospects are also discussed herein.