Triple Cascade Reaction Research Articles

Triple enzymatic cascade reaction to produce hydroxytyrosol acetate from olive leaves using integrated membrane bioreactors.

An integrated system of three membrane bioreactors (MBRs) has been developed that cascades three different enzymatic reactions. The integrated system was applied to produce hydroxytyrosol acetate from oleuropein extracted from olive leaves. Different reactor configurations for each reaction were tested and individually optimized to select the MBR to ensure high conversion and continuous production of oleuropein aglycone (OA), hydroxytyrosol (HY) and hydroxytyrosol acetate (HA). Based on this study, the most performing configuration of the integrated system was identified. In the first reaction, oleuropein was converted to OA using a biocatalytic membrane reactor (BMR) with immobilized β-glucosidase in polymeric membranes (conversion 98%). The OA was then fed to another BMR, where it was converted to HY (conversion: 70%) by an immobilized mutant of the promiscuous hydrolase/acyltransferase (PestE) (from the thermophilic archaeon Pyrobaculum calidifontis VA1). The HY produced was then acetylated using PestE immobilized on magnetic nanoparticles in a multiphase MBR (conversion: 98%) and simultaneously extracted (extraction: 98%) in ethyl acetate. The work demonstrates that continuous cascade enzymatic reactions can be engineered using artificial membranes to tailor enzyme compartmentalization, mass transport and phase contact according to reaction requirements. Besides, environmental factors proved the sustainability of the integrated membrane bioreactive system.

Complex Droplet Microreactor for Highly Efficient and Controllable Esterification and Cascade Reactions.

A highly efficient complex emulsion microreactor has been successfully developed for multiphasic water-labile reactions, providing a powerful platform for atom economy and spatiotemporal control of reaction kinetics. Complex emulsions, composing a hydrocarbon phase (H) and a fluorocarbon phase (F) dispersed in an aqueous phase (W), are fabricated in batch scale with precisely controlled droplet morphologies. A biphasic esterification reaction between 2-bromo-1,2-diphenylethane-1-ol (BPO) and perfluoro-heptanoic acid (PFHA) is chosen as a reversible and water-labile reaction model. The conversion reaches up to 100 % under mild temperature without agitation, even with nearly equivalent amounts of reactants. This efficiency surpasses all reported single emulsion microreactors, i. e., 84~95 %, stabilized by various emulsifiers with different catalysts, which typically necessitate continuous stirring, a high excess of one reactant, and/or extended reaction time. Furthermore, over 3 times regulation threshold in conversion rate is attained by manipulating the droplet morphologies, including size and topology, e. g., transition from completely engulfed F/H/W double to partially engulfed (F+H)/W Janus. Addition-esterification, serving as a model for triple phasic cascade reaction, is also successfully implemented under agitating-free and mild temperature with controlled reaction kinetics, demonstrating the versatility and effectiveness of the complex emulsion microreactor.

Study of lawsone and its modified disperse dyes derived by triple cascade reaction: dyeing performance on nylon and polyester fabrics

Purpose This paper aims to develop a novel protocol for the synthesis of disperse dyes derived by a triple cascade reaction with lawsone in presence of Zn acetate as a catalyst. The developed novel scaffolds have efficient dyeing properties on nylon and polyester fibers. Design/methodology/approach This report demonstrates an effectual triple cascade protocol for the synthesis of novel disperse dyes derived from various polynuclear carbaldehyde, urea and lawsone. The Zn acetate was found to be an effective catalyst for this reaction. Their dyeing performance has been studied on nylon and polyester fabrics. The wash fastness, sublimation fastness, color assessment, determination of percentage exhaustion and fixation properties were applied to both the dyed fabrics. Findings The obtained results indicate that the Zn acetate is an efficient catalyst for the developed triple cascade protocol. The prepared novel disperse dye greatly impacted their dyeing properties on nylon and polyester fibers. They have shown brilliant shades, higher affinity, adsorption capacity, superior tinctorial strength than the lawsone. The percentage exhaustion value, fixation value, color strength (K/s) value, washing and sublimation fastness properties have been found very well in all dyed nylon samples compared to polyester samples. These results discloses that these disperses dyes are very useful to the growing importance of nylon and polyester fibers. Research limitations/implications The present protocol synthesizes the racemic mixture of the prepared molecules. Practical implications Developed protocol can be used for various other triple cascade processes. Also these molecules can be used for dyeing of other fabrics. Social implications With the help of commercialization of prepared molecules, it may provide the better alternative of the current disperse dyes. This may affect the various segments of society. Originality/value This report represents a novel protocol for the synthesis of modified novel disperse dyes with an efficient dyeing properties on nylon and polyester fibers.

Synthesis of Multi-Substituted 4,5-Dihydrofurans: Microwave Assisted Reaction of β-Ketonitriles, Aldehydes and Pyridinium Phenacyl Salts via [1+1+3] Knoevenagel-Michael-Oxa-Michael Cyclization Triple Cascade Sequence

A microwave assisted protocol for the development of fully substituted dihydrofurans has been explained as a three component triple cascade reaction between pyridinium ylide, phenacyl nitriles and aldehydes. This [1+1+3] annulation protocol produced the dihydrofurans having two stereocentres. A total of 14 molecules have been synthesized with high chemical yields.

Biocatalysis tips another domino: A single-enzyme Enders triple cascade reaction

Multi-enzyme cascades are increasingly popular, but single-enzyme cascades, which avoid issues of catalyst compatibility, are still rare. A new article by Melchiorre and co-workers in Angewandte Chemie describes the design and engineering of an enzyme capable of catalyzing the Enders triple cascade reaction, resulting in four new stereocenters. Multi-enzyme cascades are increasingly popular, but single-enzyme cascades, which avoid issues of catalyst compatibility, are still rare. A new article by Melchiorre and co-workers in Angewandte Chemie describes the design and engineering of an enzyme capable of catalyzing the Enders triple cascade reaction, resulting in four new stereocenters.

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products.

A representative number of decalin and hydrindane derivatives 2a–l were prepared in 11–91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael–Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the 1H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the 1H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.

An efficient triple cascade process for synthesis of novel disperse dyes from lawsone: A modification of natural colorant

This article describes the synthesis of novel dihydropyrimidone derivatives that have been paid attention in organic, medicinal, dyes and many other chemistry disciplines. Here we have developed an efficient triple cascade process to prepare novel disperses dyes with dihydropyrimidine-thiones scaffold. These 3, 4-dihydropyrimidin-2-(1H)-thione derivatives were prepared by simple triple cascade reaction via formal [1+2+3] cyclization among 2-hydroxy-1, 4-naphthoquinone, thiourea and various aromatic aldehyde. This process has varied substrate scope and shortened reaction duration with isolated yield up to 95% resulting in situ formation of one carbon–carbon as well as two carbon–nitrogen bonds. The structures of all the prepared molecules are confirmed with NMR, HRMS and IR spectroscopies. The color properties, UV visible spectral studies are also performed with all the prepared molecules.

Organocascade Synthesis of Spiro[chroman‐3,2′‐indanedione] Scaffolds via [4+2] or [1+1+4] Cyclisation

AbstractA simple and convenient protocol has been demonstrated for the construction of spiro[chroman‐3,2′‐indanedione] via Oxa‐Michael/Michael cascade reaction sequence using 2‐arylidene‐1,3‐indanedione and (E)‐2‐(2‐nitrovinyl)phenol. This [4+2] cyclisation protocol results in the generation of two stereocentres along with an all carbon quaternary centre in good to high chemical yields of upto 93 %. A triple cascade reaction approach was carried out for the construction of spiro[chroman‐3,2′‐indanedione] using [1+1+4] cyclisation protocol.

Asymmetric organocatalytic vinylogous Michael addition triggered triple-cascade reactions of 2-hydroxycinnamaldehydes and vinylogous nucleophiles: construction of benzofused oxabicyclo[3.3.1]nonane scaffolds.

An organocatalytic vinylogous Michael addition triggered triple-cascade reaction has been developed. 2-Hydroxycinnamaldehydes worked under iminium activation with either acyclic or cyclic ketone-derived α,α-dicyanoalkenes, yielding the benzofused oxabicyclo[3.3.1]nonanes bearing one quaternary stereocenter with excellent stereoselectivities.

Organocascade Synthesis of Bicyclo[3.3.1]nonan‐9‐ones Initiated by an Unusual 1,6‐Addition of Cyclohexanones to (E)‐2‐(3‐Arylallylidene)‐1H‐indene‐1,3(2H)‐diones

AbstractAn efficient organocatalytic cascade reaction for the synthesis of the bicyclo[3.3.1]nonan‐9‐one skeleton is reported. The cascade reaction proceeds smoothly between prochiral 4‐substituted cyclohexanones and (E)‐2‐(3‐arylallylidene)‐indene‐1,3‐diones involving a 1,6‐/γ‐protonation/1,4‐addition sequence to construct bicyclic products that contain five stereogenic centers in good to high chemical yields and excellent diastereo‐ and enantioselectivity (up to >20:1 dr and 97% ee) in the presence of a thioether‐linked l‐prolinol‐camphor‐derived organocatalyst at ambient temperature. An interesting organocatalytic three‐component triple cascade reaction has been performed to produce a bicyclo[2.2.2]octan‐2‐one in a favorable chemical yield and stereoselectivity (>19:1 dr and 97% ee) starting from 1,3‐indanedione, an enal, and cyclohexenone in the presence of a primary amine organocatalyst.magnified image

Asymmetric Organocatalytic Michael/Michael/Henry Sequence to Construct Cyclohexanes with Six Vicinal Stereogenic Centers

An efficient, asymmetric, catalytic, triple-cascade reaction between α-keto esters and nitroalkenes to construct cyclohexanes with six vicinal stereogenic centers in good yields and with high enantioselectivities has been established. A bifunctional guanidine–amide organocatalyst proved to be useful for the Michael/Michael/Henry sequence through Bronsted base and hydrogen-bonding cooperative catalysis.

Highly Enantioselective Synthesis of Alkylpyridine Derivatives through a Michael/Michael/Aldol Cascade Reaction

A method for the synthesis of pyridine derivatives based on a triple cascade reaction catalyzed by chiral secondary amines was developed. The resulting cyclohexenes (three C–C bonds were formed) were obtained in good yields with good diastereoselectivities and excellent enantioselectivities.

Novel Functional Hollow and Multihollow Organic Microspheres: Enhanced Efficiency in a Complex, Heterogeneous, Asymmetric, Three‐Component/Triple Organocascade Reaction

AbstractThe pioneered construction of monodisperse hollow and multihollow Jørgensen–Hayashi‐functionalized microspheres with a well‐defined spherical morphology, high surface area, and large pore volume were developed by initial dispersion copolymerization of the Jørgensen–Hayashi organocatalyst with acrylamide and styrene monomers cross‐linked by p‐divinylbenzene and ethylene glycol dimethacrylate, respectively, on the surface of poly(styrene/acrylic acid) (PS) microspheres to form core–shell structures, followed by removal of the PS core by etching in organic solvents. The as‐prepared hollow and multihollow microspheres were able to achieve better mass transfer in a complex heterogeneous asymmetric three‐component/triple cascade reaction and provided the products in good yields (31–61 %) with excellent stereoselectivities (80:20–93:7 dr, >99 % ee).

Iodine(III)-Catalyzed Cascade Reactions Enabling a Direct Access to β-Lactams and α-Hydroxy-β-amino Acids.

In the presented method, a one-pot metal-free access to β-lactams is provided. The developed strategy employs a hypervalent iodine(III)-triggered bromination/rearrangement/cyclization cascade reaction that allows the straightforward synthesis of a broad range of structurally different lactams from cheap and easily available imides. This triple cascade reaction is furthermore extendable by an in situ ring-opening reaction, giving direct access to isoserine derivatives from simple imines in a four-step, one-pot reaction.

Triple cascade reactions: An ultrasensitive and specific single tube strategy enabling isothermal analysis of microRNA at sub-attomole level

Sensitive and specific analysis of microRNAs (miRNAs) in a single tube without the need of thermal cycler instrument would greatly facilitate the investigation of miRNA-associated regulatory circuits and diseases. Homogeneous isothermal amplification assays are attractive in conducting single tube assays that can minimize contamination-prone steps and simplifies assay procedures. However, the relative low amplification efficiency and high detection background remain as bottlenecks restricting their more versatile applications. In this work, we have developed a novel isothermal exponential enzymatic amplification (IEEA) strategy for miRNAs analysis. By rational triple cascade amplification cycles of target recycling, nicking-replication reaction, and DNAzyme catalysis, the strategy exhibited high signal amplification efficiency (104–109 folds of amplification in 1h) with very low detection background and excellent specificity. As a result, the miR-27a target model was rapidly determined with a limit of detection down to 0.79 aM (S/N=3), corresponding to 94 copies of the miRNA molecule in a 200μL sample solution. The levels of miR-27a in atherosclerotic sprague-dawley rats were accurately quantified. The strategy is anticipated to have an important impact on the development of simple and rapid molecular diagnostic applications for any short oligonucleotides.

ChemInform Abstract: An Efficient Combinatorial Synthesis of Allocolchicine Analogues via a Triple Cascade Reaction and Their Evaluation as Inhibitors of Insulin Aggregation.

AbstractA total of 21 different analogues is synthesized.

Vinylogous Organocatalytic Triple Cascade Reaction: Forging Six Stereocenters in Complex Spiro‐Oxindolic Cyclohexanes

AbstractWe report a triple vinylogous cascade reaction, yielding valuable spiro‐oxindolic cyclohexane derivatives. The three‐component domino process proceeds by way of a catalyzed Michael/1,6‐addition/vinylogous aldol sequence affording the products with six stereogenic centers and very high control over the stereochemistry. The chemistry is based on a rare example of asymmetric 1,6‐addition to linear 2,4‐dienals proceeding with complete δ‐site selectivity. Key to the reaction development was a directing group positioned at the β‐dienal position, which was essential for achieving highly predictable reaction outcomes.magnified image

An Efficient Combinatorial Synthesis of Allocolchicine Analogues via a Triple Cascade Reaction and their Evaluation as Inhibitors of Insulin Aggregation

A controlled cascade: A divergent, diastereoselective and efficient one-pot synthesis of allocolchicinoids via a cascade Suzuki-Michael addition-Carbocyclization sequence is described. The utility of the compounds as possible inhibitors of insulin aggregation is also presented.

A Straightforward Route to Homoallyl‐Homocrotylamines Promoted by a Titanium Complex

Abstractπ‐Allyltitanium complexes, generated in situ from 1,3‐dienes and [Cp2TiH], react with benzotriazole derivatives to give homoallylic amines in good yields. Under similar conditions, triple cascade reactions (allyltitanation followed by cationic 2‐aza‐Cope rearrangement followed by a second allyltitanation) occur from bis(benzotriazolyl) compounds affording a straightforward route to homoallyl‐(E)‐homocrotylamines. A theoretical study provides further insight into the factors that govern the selectivity of this sequence of reactions.

Diastereoselective Multicomponent Cascade Reaction Leading to [3.2.0]-Heterobicyclic Compounds

A general three-component triple cascade reaction through an iminium-enamine-iminium sequential activation initiated by a hetero-Michael addition to α,β-unsaturated aldehydes affords [3.2.0]heterobicycles in high diastereoselectivity. The rate and diastereoselectivity of the reaction depended on the (E)-4-heterocrotonate and size of the secondary amine. The enantiomers of the major diastereoisomer of oxa- and azabicyclo[3.2.0]heptane derivatives were separated by enzymatic kinetic resolution with immobilized Candida antarctica Lipase B (CALB), with E values up to 153. The absolute configuration of the nonacylated enantiomer of oxabicyclo[3.2.0]heptane was determined by single crystal X-ray analysis.