Isocyanide-based Multicomponent Reactions Research Articles

Isocyanide-Based Multicomponent Reaction: Cascade α-Acyloxylation/Carboxamidation and [3 + 1+1] Cyclization of I(III)/S(VI)-Ylides.

A metal-free cascade of α-acyloxylation/carboxamidation of I(III)/S(VI)-ylides, carboxylic acids, and isonitriles via a Passerini-like multicomponent reaction is reported. Unexpectedly, [3 + 1+1] cyclization involving I(III)/S(VI)-ylides and two molecules of ethyl isocyanoacetate was observed. The strategy allows for the synthesis of unsymmetrical α,α-disubstituted ketones and functionalized pyrroles with up to 99% yield and wide substrate compatibility. Notably, the procedure has been extended to the late-stage modification of drugs and natural products, offering an elegant complement to the classic Passerini reaction.

Atom-economical synthesis, antimicrobial assessment, and molecular dynamics of indole-derived peptidomimetics for improved therapeutic insights

The emergence of multi-drug resistant strains spanning bacteria, fungi, viruses, and parasites poses a severe threat to public health and the economy. Tackling antimicrobial resistance requires swiftly identifying new agents with unique mechanisms. Multicomponent reactions offer a vital method to produce diverse analogs in various heterocyclic compounds, with broad medicinal applications. This study synthesized a range of peptidomimetics using isocyanide-based multicomponent Ugi reactions. These analogs were screened for antimicrobial efficacy against both Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Staphylococcus aureus IGMS-01), with ampicillin as a reference antibiotic, and for antifungal activity against Candida albicans, using fluconazole as a reference. The compounds showed moderate but significant efficacy across all tests. Docking analysis with microbial proteins revealed notable binding affinities for peptidomimetics 5h (N-(2-(1H-indol-3-yl)ethyl)-N-(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)stearamide) and 5i (N-(2-(1H-indol-3-yl)ethyl)-N-(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)oleamide). Molecular dynamics simulations confirmed stable interactions between the ligands and proteins. Furthermore, the long alkyl chain analogs demonstrated the ability to form organo/hydrogels, facilitating the incorporation of silver sulfadiazine for controlled antimicrobial release. This innovative approach enhances drug dispersion within the gel structure, effectively inhibiting microbial growth. These findings highlight the potential of these adaptable materials to advance drug development efforts in the foreseeable future.

The effect of carbon chain length of cross-linking agent on the functionality of carrier- free immobilized Thermomyces lanuginosa lipase particles

The cross-linked enzyme (CLEs) of Thermomyces lanuginosa lipase (TLL) was prepared in an isocyanide-based multi-component reactions (ICMRs) platform by applying three di-acidic cross-linkers to unveil more factors contributing to the functional properties of CLEs. The linkers were 1,11-undecanedicarboxylic acid, azelaic acid, and adipic acid with 11, 7, and 4 carbon lengths, respectively, providing a proper tool to investigate the effect of linker length on the activity, stability, and selectivity of the resulting CLEs. The immobilization yields of 60–90 % and the specific activities of 168, 88.4 and 49 U/mg were obtained for the CLEs of 1,11-undecanedicarboxylic acid, azelaic acid, adipic acid, respectively. The lower activity of azelaic and adipic acid-mediated CLEs compared to the soluble TLL (110 U/mg) was explained by in silico calculations. The results revealed that as opposed to 1,11-undecanedicarboxylic acid, both linkers tended to penetrate the enzyme active site, thus resulting in a major inhibitory effect on the enzyme functionality. The thermal and co-solvent stability of the immobilized derivatives improved compared to those of free TLL. The selectivity of CLEs was also examined by catalytic release of main omega-3 fatty acids from fish oil, presenting the highest selectivity of 22 for the CLEs of azelaic acid.

Isocyanide-Based Multicomponent Reactions Coupled One-Pot Process: Efficient Tools to Diversity-Oriented Synthesis of Structural Peptidomimetics.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Isocyanide-based Multicomponent Reactions (IMCRs) in Water or Aqueous Biphasic Systems.

Isocyanide is an intriguing one-carbon synthon that is frequently employed in a variety of carbon-carbon and carbon-heteroatom bond-forming reactions. Isocyanide-based multicomponent reactions (IMCRs) are effective synthetic tools in organic synthesis for the preparation of complex heterocyclic molecules. The IMCRs in water have become an attractive research direction, enabling simultaneous growth of both IMCRs and green solvents towards ideal organic synthesis. The goal of this review is to provide a general overview of IMCRs in water or biphasic aqueous systems for accessing various organic molecules, as well as an examination of their benefits and mechanistic insights. High atom economies, mild reaction conditions, high yields, and catalyst-free processes are crucial features of these IMCRs in water or biphasic aqueous systems.

Combined cross-linking of Rhizomucor miehei lipase and Candida antarctica lipase B for the effective enrichment of omega-3 fatty acids in fish oil

The incorporation of a non-specific lipase and a sn-1,3 specific one in a single immobilized system can be a promising approach for the exploitation of both lipases. A one-step immobilization platform mediated by an isocyanide-based multi-component reaction was applied to create co-cross-linked enzymes (co-CLEs) of lipases from Rhizomucor miehei (sn-1,3 specific) and Candida antarctica (non-specific). Glutaraldehyde was found to be effective cross-linker by producing specific activity of 16.9 U/mg and immobilization yield of 99 %. High activity recovery of up to 404 % was obtained for immobilized derivatives. Leaking experiment showed covalent nature of the cross-linking processes. BSA had considerable effect on the immobilization process, providing 87–100 % immobilization yields and up to 10 times improvement in the specific activity of the immobilized derivatives. Scanning electron microscopy images showed flower-like and rod-like structures for the CLEs prepared by glutaraldehyde and undecanedicarboxylic acid, respectively. The prepared co-CLEs were examined in non-selective enrichment of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil, showing capability of releasing up to 100 % of both omega-3 fatty acids within 8 h of the reaction. The reusability of co-CLEs in five successive cycles presented retaining 63–72 % of their initial activities after the fifth reuse cycle in the hydrolysis reaction.

Isocyanide-based multicomponent reactions for the synthesis of benzopyran derivatives with biological scaffolds.

Benzopyrans (BZPs) are among the most privileged and influential small O-heterocycles that form the core of many natural compounds, commercial drugs, biological compositions, agrochemicals, and functional materials. BZPs are divided into six general categories including coumarins, chromans, 2H-chromenes, 4H-chromenes, chromones, and 4-chromanones, each of which is abundant in many plants and foods. These oxygenated heterocyclic compounds are fascinating motifs and have extensive applications in biology and materials science. Hence, numerous efforts have been made to develop innovative approaches for their extraction and synthesis. However, most of them are step-by-step or multi-step strategies that suffer from waste material generation and a tedious extraction process. Isocyanide-based multicomponent reactions (I-MCRs) offer a highly efficient method for overcoming these problems. The I-MCR is a simple and environmentally friendly one-pot domino procedure that does not require intermediate isolation or workup and is generally more efficient in material usage. This review covers all research articles related to I-MCRs for synthesizing BZP derivatives from the beginning to the middle of the year 2023. This strategy will be useful for organic and pharmaceutical chemists to design new drugs and optimize the synthesis steps of biological compounds and commercial drugs with benzopyran cores.

Ultrasound-assisted diastereoselective green synthesis of spiro-fused-γ-lactams functionalized with an amide bond heterocyclic bioisostere via the Ugi azide/domino process coupled strategy.

A series of linked-type 1,5-disubstituted tetrazoles (1,5-DS-Ts) were synthesised via an isocyanide-based multicomponent reaction (IMCR) and used as synthetic platforms to access bound-type polyheterocycles containing an epoxyisoindol-1(6H)-one scaffold under green conditions. This rapid sonochemical synthetic strategy includes a double domino process using an orthogonal heterocyclic input in the Ugi-azide (UA) reaction. DFT calculations and NBO analysis were performed to understand the pseudopericyclic reaction involved in the 1,5-electrocyclization of the UA mechanism.

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction.

An efficient protocol for the synthesis of polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity. The reaction was finished by in situ generation of activated 5-(alkylimino)cyclopenta-1,3-dienes from addition of alkyl isocyanide to two molecules of but-2-ynedioates and sequential formal [3 + 2] cycloaddition reaction with 5,6-unsubstituted 1,4-dihydropyridine.

Submicron polymer particles loaded with piperine: Preparation from fucoidan and evaluation of morphology, release profile, and antioxidant activity

A combination of two methods, polyelectrolyte self-assembly of fucoidan–chitosan and isocyanide-based multicomponent reactions, was used to obtain submicron polymer particles suitable for lyophilization. Piperine, an alkaloid and the major bioactive compound found in black pepper, is endowed with numerous biological activities; however, its application is hindered by low solubility and poor delivery. To overcome this problem, piperine was loaded into the submicron polymer particles obtained. These particles were subjected to lyophilization to assess their ability to redisperse in aqueous solution after drying and their stability. The characterization of the nanoparticles by dynamic light scattering revealed particle sizes of 219.67 ± 0.61 and 355.63 ± 14.49 nm for fucoidan–chitosan nanoparticles and piperine-loaded nanoparticles, respectively. Also, an irregular spherical piperine-loaded nanoparticle was found using atomic force microscopy. An encapsulation efficiency of 92.78% ± 0.02% was measured with UV/visible spectroscopy. In vitro, the release profile of piperine from the nanoparticles showed a significant release and faster dissolution rate than free piperine. For the release mechanism of piperine from the nanoparticle, the Korsmeyer–Peppas model was the best fit with a correlation coefficient (R2) close to 1. The antioxidant activity of the piperine-loaded nanoparticles was significantly higher than that of the unformulated piperine. The piperine-loaded nanoparticles also exhibited positive stability against stress from lyophilization. Therefore, fucoidan–chitosan nanoparticles to improve the bioavailability of piperine, as well as enhance antioxidant activity, and could be used as a nutraceutical.

The Discovery of Novel Antimicrobial Agents through the Application of Isocyanide-Based Multicomponent Reactions.

Multicomponent reactions (MCR) have been used to synthesize a wide range of analogs from several classes of heterocyclic compounds, with multifaceted medicinal uses. The synthesis of highly functionalized molecules in a single pot is a unique property of MCR, allowing researchers to quickly assemble libraries of compounds of biological interest and uncover novel leads as possible therapeutic agents. Isocyanide-based multicomponent reactions have proven to be extremely effective at swiftly specifying members of compound libraries, particularly in the discovery of drugs. The understanding of structure-activity correlations that drive the development of new goods and technology requires structural variety in these libraries. In today's world, antibiotic resistance is a major ongoing problem that poses risks to public health. The implementation of isocyanide-based multicomponent reactions upholds a significant potential in this regard. By utilizing such reactions, new antimicrobial compounds can be discovered and subsequently used to fight against such concerns. This study discusses the recent developments in antimicrobial medication discovery using isocyanide-based multicomponent reactions (IMCRs). Furthermore, the article emphasizes the potential of IMCRs (Isocyanide-based multicomponent based reactions) in the near future.

Isocyanide Heterodimerization-Triggered Three-Component Reaction: Diversity-Oriented Synthesis of Quinoxalines.

Known isocyanide-based multicomponent reactions (IMCRs) are usually triggered by addition of the isocyano group to the strong electrophilic component. We herein report a new isocyanide-based three-component reaction, in which an unprecedented quinoxaline-based zwitterionic intermediate is generated from the chemoselective heterodimerization of weak electrophilic ortho-diisocyanoarenes and common isocyanides. This reactive zwitterion could react in situ with various trapping agents to furnish a range of structurally diverse quinoxalines.

Isocyanide-based multi-component reactions for carrier-free and carrier-bound covalent immobilization of enzymes.

Strategies for the covalent immobilization of enzymes depend on the type of functional group selected to perform the coupling reaction, and on the relative importance of selectivity, loading capacity, immobilization time and activity/stability of the resulting immobilized preparation. However, no single strategy is applicable for all covalent immobilization methods or can meet all these criteria, exemplifying the challenge of introducing a versatile process broadly compatible with the residues on the surface of proteins and the functional groups of common linkers. Here, we describe the use of isocyanide-based multi-component reactions for the carrier-bound and carrier-free covalent immobilization of enzymes. Isocyanide-based multi-component reactions can accept a wide variety of functional groups such as epoxy, acid, amine and aldehyde, as well as many commercially available bi-functional linkers, and are therefore suitable for either covalent coupling of enzymes on a solid support or intermolecular cross-linking of enzymes. In this strategy, an isocyanide is directly added to the reaction medium, the enzyme supplies either the exposed amine or carboxylic acid groups, and the support (in carrier-bound immobilization) or the bi-functional cross-linking agent (in carrier-free immobilization) provides another reactive functional group. The protocol offers operational simplicity, high efficiency and a notable reduction in time over alternative strategies, and can be performed by users with expertise in chemistry or biology. The immobilization reactions typically require 1-24 h.

The vital use of isocyanide-based multicomponent reactions (MCR) in chemical synthesis

Abstract Multicomponent (MCRs) reactions are classified as one-pot reaction where more than two starting materials are employed to form a single product that contains the building blocks of the starting components. MCRs are considered a convenient approach in synthetic chemistry and have many advantages over the traditional one or two-component reaction, by reducing the number of sequential multiple steps required and often producing better yields. This chapter dissects the use of isocyanide-based MCRs and the elegant chemistry that they offer to build useful scaffolds in the chemical synthetic field. In addition MCRs are considered as one of the recognisable options for increasing “greenness” during the synthesis of pharmaceutical and industrial products.

Ugi Four-Component Reactions Using Alternative Reactants.

The Ugi four-component reaction (Ugi-4CR) undoubtedly is the most prominent multicomponent reaction (MCRs) that has sparked organic chemists' interest in the field. It has been widely used in the synthesis of diverse heterocycle molecules such as potential drugs, natural product analogs, pseudo peptides, macrocycles, and functional materials. The Ugi-4CRs involve the use of an amine, an aldehyde or ketone, an isocyanide, and a carboxylic acid to produce an α-acetamido carboxamide derivative, which has significantly advanced the field of isocyanide-based MCRs. The so-called intermediate nitrilium ion could be trapped by a nucleophile such as azide, N-hydroxyphthalimide, thiol, saccharin, phenol, water, and hydrogen sulfide instead of the original carboxylic acid to allow for a wide variety of Ugi-type reactions to occur.β In addition to isocyanide, there are alternative reagents for the other three components: amine, isocyanide, and aldehyde or ketone. All these alternative components render the Ugi reaction an aptly diversity-oriented synthesis of a myriad of biologically active molecules and complex scaffolds. Consequently, this review will delve deeper into alternative components used in the Ugi MCRs, particularly over the past ten years.

Isocyanide-Based Multicomponent Reactions Promoted by Visible Light Photoredox Catalysis.

Isocyanide-based multicomponent reactions claim a one century-old history of flourishing developments. On the other hand, the enormous impact of recent progresses in visible light photocatalysis has boosted the identification of new straightforward and green approaches to both new and known chemical entities. In this context, the application of visible light photocatalytic conditions to multicomponent processes has been promoting key stimulating advancements. Spanning from radical-polar crossover pathways, to photoinduced and self-catalyzed transformations, to reactions involving the generation of imidoyl radical species, the present literature analysis would provide a general and critical overview about the potentialities and challenges of exploiting isocyanides in visible light photocatalytic multicomponent reactions.

Cross-linked lipase particles with improved activity; application of a non-toxic linker for cross-linking

The preparation of cross-linked enzymes is often performed through enzyme aggregation or crystallization prior to cross-linking by glutaraldehyde as the most common linker. Isocyanide-based multi-component reactions (ICMRs) provide a one-step process to prepare cross-linked preparations of enzymes directly from their soluble forms. ICMRs accept a variety of functional groups to be involved in the coupling reaction. We here introduce cysteamine as a novel non-toxic alternative for glutaraldehyde to be used as a cross-linker in cross-linking reactions implemented by ICMRs. The cross-linked enzymes (CLEs) of Rhizomucor miehei lipase (RML) and Thermomyces lanuginosa lipase (TLL) were prepared with high immobilization yields (up to 97%). The results showed the maximum activities of 43.7 U/mg and 213.35 U/mg for the immobilized derivatives of RML and TLL, respectively, presenting an 11-fold and 10-fold improvement compared to the activity of the corresponding soluble lipases. The immobilized derivatives showed improved thermal and co-solvent stability. Additionally, the CLEs of TLL showed a selectivity of 19.9 in the selective hydrolysis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil. The used linker provides an alternative strategy for CLEs production, particularly where the traditional cross-linking method has the possible risk of reaction contamination by weakly bonded glutaraldehyde molecules.

First-row transition metal for isocyanide-involving multicomponent reactions (IMCR).

First-row transition metal catalyzed transformations that are able to construct complex molecules from simple, readily obtainable feedstocks have become a keystone of modern synthetic organic chemistry. Particularly, the multicomponent reaction (MCR) involving carbon-carbon (C-C) as well as carbon-heteroatom (C-X) bond formation plays an essential role in many chemical conversions, and insurgencies in these reactions powerfully improve the overall synthetic efficiency. Recently, MCRs emerges rapidly because of its greener sides like eco-friendly nature, swift and straightforward execution, high atom/step economy, and construction of aimed product with lowest or no by-product, usually in quantitative yield. Curiously, the exceptional divalent carbon atoms of isocyanides make them predominantly useful components in multicomponent reactions. As a result of widespread research over the past few decades, numerous well-designed and effective procedures for the first-row TM-catalyzed MCR to afford the various entities have been reported. These aspects are summarized in this review article. A particular focus on comparative discussion of various first-row transition-metal catalyzed isocyanide-based multicomponent reactions through mechanistic details included in the review article.

Enantiopure β-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure β-substituted β-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the β-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.Graphical abstract

Isocyanide-Based Multicomponent Reactions in Water: Advanced Green Tools for the Synthesis of Heterocyclic Compounds.

Reaction rate acceleration using green methods is an intriguing area of research for chemists. In this regard, water as a "green solvent" plays a crucial role in the acceleration of some organic transformations and reveals exclusive selectivity and reactivity in comparison with conventional organic solvents. In particular, multicomponent reactions (MCRs) as sustainable tools lead to the rapid generation of small-molecule libraries in water and aqueous media due to the prominent role of the hydrophobic effect. MCRs, as diversity-oriented synthesis (DOS) methods, have great efficiency with simple operations, atom, pot, and step economy synthesis, and mechanistic beauty. Among diverse classes of MCRs, isocyanide-based multicomponent reactions (I-MCRs), as sustainable and versatile reactions, have gained considerable attention in the synthesis of diverse heterocycle rings, especially in drug design because of the peculiar nature of isocyanide as a particular active reactant. I-MCRs that are performed in water are mild, environmentally friendly, and easily controlled, and have a reduced number of workup, purification, and extraction steps, which fit well with the advantages of "green" chemistry. Performing these powerful organic transformations in water and aqueous media is accompanied by acceleration owing to negative activation volumes, which originate from connecting several reactants together to generate a single product. It should be noted that the combination of MCR strategy and aqueous phase reaction is of growing interest for the development of sustainable synthetic techniques in organic conversions. However, an exclusive account focusing on the recent progress in eco-friendly I-MCRs for the construction of heterocycles in water and aqueous media is particularly lacking. This review highlights the progress of various kinds of I-MCRs in water and aqueous media as benign methods for the efficient construction of vital heterocyclic scaffolds, with a critical discussion of the subject in the period 2000-2021. We hope that this themed collection will be of interest and beneficial for organic and pharmaceutical chemists and will inspire more reaction development in this fascinating field.