One-pot Cascade Reaction Research Articles

Multienzyme Synthesis of Glycyrrhetic Acid 3-O-mono-β-d-glucuronide by Coupling UGT73F15 to UDP-Glucuronic Acid Regeneration Module

Glycyrrhetic acid 3-O-mono-β-d-glucuronide (GAMG), a rare and innovative compound in licorice, exhibits high-potency sweetness and improved physiological activities. However, low amounts of GAMG from plants cannot meet the demands of growing markets. In this study, an efficient one-pot multienzyme cascade reaction for GAMG biosynthesis was constructed using a coupled catalysis of glycosyltransferase and uridine 5′-diphosphate (UDP) glucuronic acid (GlcA) regeneration system. The Glycyrrhiza uralensis glycosyltransferase UGT73F15 was expressed in Escherichia coli BL21 (DE3). The optimal reaction conditions of UGT73F15 were found to be pH 7.5 and 35 °C. The catalytic efficiency (kcat/Km) for glycyrrhetic acid (GA) was 2.14 min−1 mM−1 when using UDP-GlcA as sugar donor. To regenerate costly UDP-GlcA, the one-pot multienzyme cascade reaction including UGT73F15, sucrose synthase, UDP-glucose dehydrogenase, and lactate dehydrogenase was adopted to synthesize GAMG from GA on the basis of the UDP-GlcA regeneration system. By optimizing the cascade reaction conditions, the GAMG production successfully achieved 226.38 mg/L. Our study developed an economical and efficient one-pot multienzyme cascade method for facile synthesis of GAMG and other bioactive glucuronosides.

One-pot sonochemical synthesis and in silico/in vitro antitubercular evaluation of 1-methyl-3-propyl-1H-pyrazole containing polynuclear fused N-heteroarenes

A series of molecules containing the fragment based on 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide were explored as the potential inhibitors of chorismate mutase (or CM that plays an important role in the survival of bacteria). These molecules were evaluated in silico via their docking at the interface site of MtbCM (PDB: 2FP2). Prompted by the promising docking results the ultrasound assisted one-pot synthesis of target molecules i.e. 6-arylpyrazolo[4′,3′:4,5]pyrimido[2,1-a]isoquinolin-8(9H)-one derivatives were undertaken. The methodology involved Sonogashira coupling of 2-iodobenzaldehyde with a terminal alkyne to afford the 2-alkynylbenzaldehyde intermediate in situ that on Yb(III)-catalyzed sequential reaction with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide afforded the desired product in good to acceptable yield. To build a small library of compounds, a range of terminal alkynes as well as 2-iodobenzaldehydes were employed and the one-pot cascade reaction proceeded well in all these cases. The strategy was also used to prepare 6-aryl-8H-isoquinolino[1,2-b]quinazolin-8-ones. Three derivatives i.e. 4b, 4h and 4l that participated in good interaction with MtbCM (including a common H-bond with SER70) in silico with the docking score in the range -91 to -84 kcal/mol, exhibited encouraging (60–67%) inhibition at 10 µM in vitro. Further, a brief SAR within the series and in silico ADME prediction for best active compounds are presented. The compound 4l seemed to be of further interest form the view point of discovery and development of new anti-tubercular agents. 2009 Elsevier Ltd. All rights reserved.

One-pot sequential cascade reaction for selective gluconic acid production from cellulose photobiorefining.

We demonstrate the feasibility of cellulose photobiocatalytic conversion with >75% cellulose conversion and >75% gluconic acid selectivity from converted glucose. This process is realized via a one-pot sequential cascade reaction by cellulase enzymes and a carbon nitride photocatalyst that can realize selective glucose photoreforming into gluconic acid. Cellulase enzymes breakdown cellulose into glucose, which will subsequently be converted into gluconic acid by essential oxidative species (˙O2- and ˙OH) via a selective photocatalysis process with simultaneous H2O2 formation. This work demonstrates a good example to realize direct cellulose photobiorefining into value-added chemicals via the photo-bio hybrid system.

Carboxamide functionality grafted entangled Co(II) framework as a unique hydrogen-bond-donor catalyst in solvent-free tandem deacetalization-Knoevenagel condensation with pore-fitting-mediated size-selectivity.

Concerning environmentally benign catalysis with reduced chemical usage, less energy consumption, and waste minimization, metal-organic frameworks (MOFs) with spatially isolated task-specific functionalities not only execute atom-economic important reactions but also enable size-exclusive catalysis at the interface of structure-function synergy. Herein, we synthesized a bipillar-layer Co(II) MOF from the dicarboxylate ligand and carboxamide moiety grafted pyridyl linker. The framework contains a [Co2(COO)4N4] secondary building unit (SBU) and shows excellent hydrolytic stability due to ample non-covalent interactions among the highly conjugated aromatic struts. Notably, the carboxamide functionalities remain free and are perfectly positioned throughout the one-dimensional channels of the framework, wherein three-fold interpenetration of the structure largely increases their density along the pore wall. Benefiting from these structural features, the activated MOF acts as an unprecedented organocatalyst in tandem deacetalization-Knoevenagel condensation towards electronically assorted substrates that were additionally characterized using single-crystal X-ray diffraction. Importantly, the reaction occurs under solvent-free mild conditions, and high catalyst reusability is recorded. In this one-pot cascade reaction, substrates with molecular dimensions larger than that of the three-fold interpenetration generated optimized pore-aperture undergo insignificant conversion, and therefore a rare molecular-dimension-induced size-selectivity is demonstrated. The catalytic route is detailed based on a battery of control experiments, including juxtaposing the performance of an isostructural MOF without any linker functionalization. Compared to the common Lewis acid mediated route, the results explicitly corroborate the first-ever substrate activation via hydrogen bonding to prepare coumarin derivatives via a tandem pathway, and shed light on this futuristic unconventional catalysis using contemporary materials and avoiding major operative glitches.

One-pot cascade reactions for the synthesis of dinitroalkanes in aqueous buffer

A one-pot combination of biocatalysis and organocatalysis converts aliphatic alcohols to dinitroalkanes in mild conditions at room temperature.

Selective Construction of Spiro or Fused Heterocyclic Scaffolds via One-pot Cascade Reactions of 1-Arylpyrazolidinones with Maleimides.

Presented herein is a controllable selective construction of spiro or fused heterocyclic scaffolds through the one-pot cascade reactions of 1-phenylpyrazolidinones with maleimides. To be specific, succinimide spiro pyrazolo[1,2-a]pyrazolones were effectively formed via [4 + 1] spiroannulation of 1-phenylpyrazolidinones with maleimides through simultaneous C(sp2)-H bond activation/functionalization and intramolecular cyclization along with the traceless fusion of the pyrazolidinonyl unit into the final product. In this reaction, air acts as a cost-effective and environmentally sustainable oxidant to assist the regeneration of the Rh(III) catalyst. Alternatively, succinimide-fused pyrazolidinonylcinnolines were formed from the same starting materials through an initial [4 + 1] spiroannulation followed by base-promoted skeleton rearrangement of the in situ formed spiro product without isolation. Notable features of these protocols include easily tunable selectivity, broad substrate scope, cost-effective and sustainable oxidant, excellent atom economy, and facile scalability.

Metal-free one-pot synthesis of 2-substituted benzimidazoles from N-aryl imines and TMSN3

Iodine-catalysed efficient synthesis of 2-substituted benzimidazoles has been developed under aerobic condition. The one-pot oxidative cascade reactions of anilines, aldehydes and trimethylsilyl azide (TMSN3) lead to the benzimidazoles derivatives in the presence of tert-butyl hydroperoxide (TBHP). Iodine efficiently promoted the cross-coupling strategy to achieve the desired compounds via the sequential CH functionalization and cyclization. The present method features a greener approach, readily accessible reagents, broad substrate scope, high yields of the products, shorter reaction time and mild conditions.

Enzyme-metal-single-atom hybrid catalysts for one-pot chemoenzymatic reactions

Combining enzymatic and single-metal-atom catalysis is a promising approach for green chemical synthesis. We herein report a one-pot chemoenzymatic cascade reaction to asymmetric synthesize (R)-1-(4-biphenyl) ethanol by using the highly active and selective enzyme-metal-single-atom hybrid as the catalyst. We demonstrate that the Pd single atoms anchored lipase (Pd1/CALB-P) can efficiently drive one-pot cascade reactions in aqueous solution at 30 °C to achieve facile synthesis of chiral biaryl alcohols, which are important pharmaceutical intermediates that traditionally require complex synthesis procedures. The rate of (R)-1-(4-biphenyl) ethanol formation catalyzed by Pd1/CALB-P is more than 30-fold higher than that of the combination of commercial palladium on carbon (Pd/C) and lipase-pluronic conjugate (CALB-P). The enzyme-metal-single-atom hybrid catalyst provides a promising strategy for effectively merging the enzymatic and single-atom catalysis.

Polymeric organophosphate-hafnium unconventional MOFs nanohybrids enable high-efficiency upgrading of biomass feedstocks via cascade catalytic transfer hydrogenation-dehydration

Efficiently selective catalytic conversion of biomass into biofuels and high-value chemicals using robust and porous catalysts is of great significance for valorization of renewable carbon resources. With respect to this, to reduce the supply dependence on natural oils, heterogeneous catalysis provides the opportunity for versatile anethole (AN) synthesis from bio-derived 4′-methoxypropiophenone (4-MOPP) via the one-pot cascade reactions of catalytic transfer hydrogenation (CTH) followed by dehydration, using an alcohol hydrogen donor and a Lewis/Brønsted acid catalyst. Herein, a sustainable and green strategy for catalytic upgrading of 4-MOPP to AN was developed via the cascade CTH-dehydration process, which was remarkably promoted by polymeric organophosphate unconventional MOFs-hafnium nanohybrids (PDVP-Hf) prepared via a simple solvothermal method. Interestingly, Brønsted/Lewis acidity, Lewis basicity, and hydrophobicity of PDVP-Hf could be effectively regulated by simply adjusting the composite components, among which PDVP-Hf-3 having an amorphous and porous inorganic-organic framework structure (with mesopores centered at 6.52 nm), an enhanced acidity of a suitable B/L molar ratio with lower basicity, and a strong hydrophobicity (water contact angle of 113°), was demonstrated to be efficient for selective conversion of 4-MOPP to AN with a maximum yield of 98.9% using 2-pentanol as hydrogen donor. Moreover, this developed catalytic system exhibited broad substrate generality, and could be employed for reductive upgrading of various carbonyl compounds to alcohols, or further coupled with dehydration to afford olefins. The catalyst synergistic roles of L acid-base couple sites (Hf 4+ -O 2− ) and B acid species (-OH) contributed to its pronounced performance, while high thermostability and robust hydrophobicity of PDVP-Hf-3 endowed its superior reusability, with no significant decline in reactivity for five consecutive recycles. The involved catalytic mechanisms and reaction pathways were explicitly elucidated by control experiments and theoretical calculations. This work sheds light on the appropriate design of unconventional MOF-polymer nanohybrids by combining both advantages for enhanced biomass upgrading via tough cascade reactions. • Hf-containing UMOFs-polymer hybrids were prepared via a simple solvothermal method. • PDVP-Hf-3 enabled biomass transformation of cascade CTH-dehydration. • Synergy of acid-base sites in PDVP-Hf-3 contributed up to 99.7% conversion. • PDVP-Hf-3 was highly reusable due to robust UMOFs-polymer and strong hydrophobicity. • DFT calculations and GC-MS revealed the reaction mechanism and pathways.

Multicomponent Cascade Reaction of 3-Cyanochromones: Highly Site-Selective Synthesis of 2-(1H-Imidazol-1-yl)-4H-chromen-4-one Derivatives.

A method for the synthesis of 2-(1H-imidazol-1-yl)-4H-chromen-4-one derivatives (IMCMs) from 3-cyanochromones and α-isocyanoacetates via a one-pot cascade reaction involving a 1,2-addition, Michael reaction, ring-closing, tautomerization, ring-opening, and [3 + 2] cyclization was enabled by refluxing a mixture of the starting materials in THF in the presence of Ag2CO3 as a catalyst. The cascade reaction resulted in the formation of five bonds and the cleavage of two bonds, including a triple bond, in one pot. This protocol enabled not only the synthesis of functionalized imidazoles (i.e., IMCMs) but also the synthesis of functionally useful enamine building blocks. This strategy is suitable for combinatorial and parallel syntheses of IMCMs.

Deep eutectic solvent-driven self-assembly of metal mercaptide complexes with enzyme-mimicking activities for detection of uric acid through one-step cascade catalytic reaction

This work presents a generic strategy to create a series of metal mercaptides complexes via coordination self-assembly between transition metals (Mn, Cu, Co, Fe, and Ni) and cysteine (Cys) by forming the sulfur-metal bridges. This strategy involves dissolving metal chlorides and Cys into deep eutectic solvents (DES), followed by the precipitation of metal mercaptides complexes (such as Cys-Mn) by adding water as an antisolvent, where DES serves as the solvent, shape directing, and capping agent, thereby preventing the formation of other metal impurities. Interestingly, the prepared complexes possess both laccase and peroxidase-like properties, allowing the design of a technique for the detection of L-3,4-dihydroxyphenylalanine (l-DOPA) and uric acid, respectively. The prepared Cys-Mn can linearly oxidize l-DOPA with its concentrations from 0.1 to 130 μM and the detection limit was calculated to be 75.5 nM. Additionally, the Cys-Mn can mimic the activity of peroxidase towards oxidization of o-phenylenediamine at neutral pH, allowing single-step and one-pot cascade reactions for visual and fluorometric measurements of uric acid (UA) that could work in the range of 0.2–500 μM UA with a detection limit of 0.06 μM and 0.054 μΜ, respectively. The assay was successful in detecting UA in serum and urine samples with relative standard deviation (RSD) ranging from 7.3% to 10.2% and 3.0%–8.5% respectively, suggesting that it may prove useful in medical diagnostic testing.

Enzyme-bimetallic hybrid catalyst for one-pot chemoenzymatic reactions

To overcome the intrinsic incompatibility between enzyme and chemical catalysts in one-pot chemoenzymatic cascade reactions, an enzyme-bimetallic hybrid catalyst was constructed by in situ reduction of ultrafine PdCu naonoclusters on the cross-linked lipase aggregates. The PdCu nanoalloy showed excellent activity in the Sonogashira coupling reaction because of the strong bimetallic synergistic effect between Pd and Cu within PdCu/CALB CLEAs. The activity of 3.4Pd1.7Cu/CALB CLEAs was 2.6-fold of Pd/CALB CLEAs in the synthesis of (R)-N-[1-(4-(phenylethynyl)phenyl)ethyl] acetamide. The highly active PdCu/CALB CLEAs rendered the one-pot chemoenzymatic reaction to perform at a lower temperature.

Recent advances on bifunctional catalysts for one-pot conversion of furfural to γ-valerolactone

γ-Valerolactone (GVL) is one of the most valuable compounds derived from furfural (FAL), which has been industrially produced from agricultural byproducts like corn cobs. It is extremely challenging to synthesize GVL from FAL efficiently via a one-pot cascade reaction due to the need for multiple active sites in a single pot. By focusing on the aspects of one-pot synthesis of GVL from FAL, the authors aim to shed light on the rational design and utilization of environmentally friendly bifunctional catalysts with high efficiency in this reaction. Perspectives regarding future research opportunities in bi- or multi-functional catalysts for one-pot GVL synthesis are also discussed.

Transition‐Metal‐Free Synthesis of Functionalized Quinolines by Direct Conversion of β‐O‐4 Model Compounds

Direct production of heterocyclic aromatic compounds from lignin β-O-4 models remains a huge challenge due to the incompatible catalysis for aryl ether bonds cleavage and heterocyclic ring formation. Herein, the first example of quinoline synthesis from β-O-4 model compounds by a one-pot cascade reaction is reported in yields up to 89 %. The reaction pathway involves selective cleavage of C-O bonds, dehydrogenation, aldol condensation, C-N bond formation along with heterocyclic aromatic ring construction. The control experiments suggest that both imine and chalcone were identified as the key intermediates, and the rate determining step as well as the preferred pathway were experimentally clarified and supported by density functional theory (DFT) calculations. Based on this protocol, the conversion of β-O-4 polymer delivered 56 wt % yield of quinoline derivative in three steps. This transformation provides a potential petroleum-independent choice for heterocyclic aromatic chemicals.

Strategies to Improve the Biosynthesis of β-Lactam Antibiotics by Penicillin G Acylase: Progress and Prospects.

β-Lactam antibiotics are widely used anti-infection drugs that are traditionally synthesized via a chemical process. In recent years, with the growing demand for green alternatives, scientists have turned to enzymatic synthesis. Penicillin G acylase (PGA) is the second most commercially used enzyme worldwide with both hydrolytic and synthetic activities toward antibiotics, which has been used to manufacture the key antibiotic nucleus on an industrial level. However, the large-scale application of PGA-catalyzed antibiotics biosynthesis is still in the experimental stage because of some key limitations, such as low substrate concentration, unsatisfactory yield, and lack of superior biocatalysts. This paper systematically reviews the strategies adopted to improve the biosynthesis of β-lactam antibiotics by adjusting the enzymatic property and manipulating the reaction system in recent 20 years, including mining of enzymes, protein engineering, solvent engineering, in situ product removal, and one-pot reaction cascade. These advances will provide important guidelines for the future use of enzymatic synthesis in the industrial production of β-lactam antibiotics.

Three-Component One-Pot Construction of 2-Aryl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidines Using Solid Calcium Carbide as a Surrogate of Gaseous Acetylene.

A concise method for the construction of 2-aryl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidines using solid calcium carbide instead of gaseous acetylene as an alkyne source and 2-aminobenzothiazoles and aromatic aldehydes as substrates through one-pot three-component cascade reactions is described. The salient features for this protocol are the use of an inexpensive and easy-to-handle alkyne source, noble-metal-free condition, wide substrate scope and functional tolerance, satisfactory yield, and simple workup procedure.

Water accelerated activity of Ru NPs in sequential hydrogenation of nitrobenzene to cyclohexylamine

It is difficult to balance the two separate and connected reaction steps in the sequential hydrogenation of nitrobenzene (NB) to cyclohexylamine (CHA) via only tuning the active sites. In this work, we optimize the activity of supported Ru NPs in the one-pot NB hydrogenation to CHA by tuning the surface hydrophobicity of the catalysts and by investigating the solvation effect. The Ru supported on hydrophobic mesoporous silicas is more active than that on hydrophilic mesoporous silicas, which may be attributed to the enrichment effect of the former one for hydrophobic NB. Furthermore, the activity of Ru is significantly promoted with the addition of H2O in the reaction system. Systematic studies suggest that the water promotion effect is mainly related with the decreased adsorption strength of NB on Ru surface and the water accelerated H* transfer during the NB hydrogenation process. Our primary results suggest that the modification of the surface properties of the catalysts and the deeper understanding of the solvation effect play an important role in one-pot cascade reactions.

A Versatile Chemoenzymatic Nanoreactor that Mimics NAD(P)H Oxidase for the In Situ Regeneration of Cofactors.

Herein, we report a multifunctional chemoenzymatic nanoreactor (NanoNOx) for the glucose-controlled regeneration of natural and artificial nicotinamide cofactors. NanoNOx are built of glucose oxidase-polymer hybrids that assemble in the presence of an organometallic catalyst: hemin. The design of the hybrid is optimized to increase the effectiveness and the directional channeling at low substrate concentration. Importantly, NanoNOx can be reutilized without affecting the catalytic properties, can show high stability in the presence of organic solvents, and can effectively oxidize assorted natural and artificial enzyme cofactors. Finally, the hybrid was successfully coupled with NADH-dependent dehydrogenases in one-pot reactions, using a strategy based on the sequential injection of a fuel, namely, glucose. Hence, this study describes the first example of a hybrid chemoenzymatic nanomaterial able to efficiently mimic NOx enzymes in cooperative one-pot cascade reactions.

Copper-catalyzed cascade reaction of indole and benzimidazole radicals to synthesize 3-haloindole-benzimidazole compounds

A one-pot multi-component cascade reaction strategy between benzimidazole, indole, and N-halosuccinimides was developed through the combination of the Cu(II) catalyst and (bis(trifluoroacetoxy)iodo)benzene, mediated by initiating the formation of benzimidazole nitrogen-centered radicals. This strategy realizes the formation of nitrogen radicals centered on the aromatic nitrogen atoms in the ring. On this basis, the radical-level combined synthesis of substituted 3-haloindole-benzimidazole compounds was achieved. Furthermore, this study provides a reference direction for subsequent work utilizing nitrogen radicals.

Transition-metal-free synthesis of pyrimidines from lignin β-O-4 segments via a one-pot multi-component reaction

Heteroatom-participated lignin depolymerization for heterocyclic aromatic compounds production is of great importance to expanding the product portfolio and meeting value-added biorefinery demand, but it is also particularly challenging. In this work, the synthesis of pyrimidines from lignin β-O-4 model compounds, the most abundant segment in lignin, mediated by NaOH through a one-pot multi-component cascade reaction is reported. Mechanism study suggests that the transformation starts by NaOH-induced deprotonation of Cα-H bond in β-O-4 model compounds, and involves highly coupled sequential cleavage of C-O bonds, alcohol dehydrogenation, aldol condensation, and dehydrogenative aromatization. This strategy features transition-metal free catalysis, a sustainable universal approach, no need of external oxidant/reductant, and an efficient one-pot process, thus providing an unprecedented opportunity for N-containing aromatic heterocyclic compounds synthesis from biorenewable feedstock. With this protocol, an important marine alkaloid meridianin derivative can be synthesized, emphasizing the application feasibility in pharmaceutical synthesis.