One-pot Multistep Reaction Research Articles

The Mn-doped CeO2 nanoparticles with enhanced peroxidase-like activity for one-pot analysis of glucose at neutral pH based on bio-inorganic cascade reactions

Enzyme catalytic cascade reactions based on peroxidase nanozymes and natural enzymes have aroused extensive attention in analytical fields. However, a majority of peroxidase nanozymes perform well only in acidic environments, resulting in their optimal pH mismatch with a neutral pH of natural enzymes, further restricting their application in biochemical sensing. Herein, Mn-doped CeO2 (Mn/CeO2) performing enhanced peroxidase-like activity at neutral conditions was prepared via a facile and feasible strategy. An effective enzyme cascade catalysis system via integrating glucose oxidase (GOx) with Mn/CeO2 was developed for one-pot detection of glucose in serum at neutral conditions. Using one-pot multistep catalytic reactions, this work provided a detection platform that allows for faster detection and easier operations than traditional methods. Under optimized conditions, our assay performed a sensitive detection of glucose ranging from 2.0 μΜ to 300 μΜ and a low detection limit of 0.279 μΜ. Notably, favorable analytical outcomes for glucose detection in serum samples were obtained, exhibiting potential applications in clinical diagnosis.

Bayesian Optimization for an ATP-Regenerating In Vitro Enzyme Cascade

Enzyme cascades are an emerging synthetic tool for the synthesis of various molecules, combining the advantages of biocatalysis and of one-pot multi-step reactions. However, the more complex the enzyme cascade is, the more difficult it is to achieve adequate productivities and product concentrations. Therefore, the whole process must be optimized to account for synergistic effects. One way to deal with this challenge involves data-driven models in combination with experimental validation. Here, Bayesian optimization was applied to an ATP-producing and -regenerating enzyme cascade consisting of polyphosphate kinases. The enzyme and co-substrate concentrations were adjusted for an ATP-dependent reaction, catalyzed by mevalonate kinase (MVK). With a total of 16 experiments, we were able to iteratively optimize the initial concentrations of the components used in the one-pot synthesis to improve the specific activity of MVK with 10.2 U mg−1. The specific activity even exceeded the results of the reference reaction with stoichiometrically added ATP amounts, with which a specific activity of 8.8 U mg−1 was reached. At the same time, the product concentrations were also improved so that complete yields were achieved.

Continuous process technology for bottom-up synthesis of soluble cello-oligosaccharides by immobilized cells co-expressing three saccharide phosphorylases

BackgroundContinuous processing with enzyme reuse is a well-known engineering strategy to enhance the efficiency of biocatalytic transformations for chemical synthesis. In one-pot multistep reactions, continuous processing offers the additional benefit of ensuring constant product quality via control of the product composition. Bottom-up production of cello-oligosaccharides (COS) involves multistep iterative β-1,4-glycosylation of glucose from sucrose catalyzed by sucrose phosphorylase from Bifidobacterium adeloscentis (BaScP), cellobiose phosphorylase from Cellulomonas uda (CuCbP) and cellodextrin phosphorylase from Clostridium cellulosi (CcCdP). Degree of polymerization (DP) control in the COS product is essential for soluble production and is implemented through balance of the oligosaccharide priming and elongation rates. A whole-cell E. coli catalyst co-expressing the phosphorylases in high yield and in the desired activity ratio, with CdP as the rate-limiting enzyme, was reported previously.ResultsFreeze-thaw permeabilized E. coli cells were immobilized in polyacrylamide (PAM) at 37–111 mg dry cells/g material. PAM particles (0.25–2.00 mm size) were characterized for COS production (~ 70 g/L) in mixed vessel with catalyst recycle and packed-bed reactor set-ups. The catalyst exhibited a dry mass-based overall activity (270 U/g; 37 mg cells/g material) lowered by ~ 40% compared to the corresponding free cells due to individual enzyme activity loss, CbP in particular, caused by the immobilization. Temperature studies revealed an operational optimum at 30 °C for stable continuous reaction (~ 1 month) in the packed bed (volume: 40 mL; height: 7.5 cm). The optimum reflects the limits of PAM catalyst structural and biological stability in combination with the requirement to control COS product solubility in order to prevent clogging of the packed bed. Using an axial flow rate of 0.75 cm− 1, the COS were produced at ~ 5.7 g/day and ≥ 95% substrate conversion (sucrose 300 mM). The product stream showed a stable composition of individual oligosaccharides up to cellohexaose, with cellobiose (48 mol%) and cellotriose (31 mol%) as the major components.ConclusionsContinuous process technology for bottom-up biocatalytic production of soluble COS is demonstrated based on PAM immobilized E. coli cells that co-express BaScP, CuCbP and CcCdP in suitable absolute and relative activities.

One-pot multistep Henry-Michael reaction with notable upshots using reduced graphene oxide supported bifunctional catalysts

We concocted peculiar and exceedingly sound bifunctional MNPs/AA-rGO (MNPs = Fe and/or Nb2O5 nanoparticles; AA = aromatic and/or aliphatic primary amine derivatives such as benzene-1,4-diamine (BD) or ethylenediamine (ED); rGO = reduced graphene oxide) catalysts with an acid-base twofold activation mechanism bestowing base characteristics by the amine scaffold and Lewis acidic sites triggered by MNPs doped on the peripheral of rGO. Surprisingly, Nb2O5/BD-rGO demonstrated excellent performance for one-pot Henry-Michael reaction via acid-base supportive effect with 90.6 and 88.9% conversions of benzaldehyde and β-nitrostyrene, respectively, and an admirable product selectivity (i.e., 93.2%) of 2-(2-nitro-phenylethyl)malononitrile.

Solid acid-catalyzed one-pot multi-step cascade reaction: Multicomponent synthesis of indol-3-yl acetates and indol-3-yl acetamides in water

A solid acid-catalyzed cascade reaction of condensation/intermolecular nucleophilic addition/intramolecular cyclization, esterification and amination has been developed to rapidly construct complex polysubstituted indole compounds. This one-pot, three-step five-component cascade reaction affords a series of 2-(4-oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl) acetamide derivatives with good yield under mild conditions. The present procedure exhibited some attractive features, including inexpensive and easy available reagents, large substrate scope, separable intermediate products, recyclable solid acid catalyst, and more importantly, it can be conveniently performed by simple one-pot three-step procedure, involving the sequential mixture of 3-(arylamino)cyclohex-2-en-1-ones, 2,2-dihydroxy-1-arylethan-1-ones, meldrum acid, and alcohols, anilines in the of solid acid at 80 °C. Significantly, this strategy not only expands the application range of solid acid, but also provides a series of 2-(4-oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)acetate/acetamide derivatives.

High Value Utilization of an Avermectin Fermentation Byproduct: Novel B2a Derivatives as Pesticide Candidates.

In an effort to develop novel molecules with suitable insecticidal activities, 23,24-alkene-avermectin B2a derivatives have been synthesized via a one-pot multistep reaction using avermectin B2a, a byproduct of avermectin fermentation, as a starting material. All products and intermediates were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry. Bioassay results showed that the LC50 values of compounds 4 and 9 against Meloidogyne incognita were 0.63 and 0.50 mg/L, respectively, similar to that of avermectin (0.46 mg/L). Importantly, the LC50 values of compound 9 against Tetranychus cinnabarinus and Mythimna separate were 0.0067 and 0.047 mg/L, respectively, superior to that of avermectin. Through field experiments, it could be found that spraying 0.25% water-dispersible granules of compound 9 345 g ha-1 could effectively control M. incognita outbreaks, with an efficacy of 84.9%. Combined with toxicity experiments, it could be further inferred that compound 9 may be useful as a low-toxicity pesticide. In summary, we efficiently synthesized a new B2a derivative as a potential pesticide and offered an important way for improving the utilization efficiency of avermectin fermentation products. In doing so, the environmental pollution associated with fermentation byproducts may be greatly reduced, potentially enabling a sustainable avermectin fermentation process.

Study on the Lubricating Properties of Castor (Ricinus communis) and Hydroxylated Rubber (Hevea brasiliensis) Seed Oil.

Rubber seed oil (RSO) (Hevea brasiliensis) was extracted from rubber seeds by chemical means. The effect of temperature on the oil yield was investigated. The experiment suggested that the maximum yield of the oil occurs at 60 °C. This is a result of the proximity to the boiling point of n-hexane, which is about 68 °C. Epoxidized and hydroxylated RSOs were further synthesized by performic acid generated in situ by the reaction of formic acid with 30% hydrogen peroxide. The physiochemical properties of the epoxidized rubber seed oil (ERSO) and hydroxylated rubber seed oil (HRSO) were determined. A separate study was also carried out on castor seed oil (CSO). The improved products were characterized with respect to their configuration and properties. Spectroscopic analysis was carried out on the oil base stocks (RSO, CSO, ERSO, and HRSO). All of the experimental findings were compared with one another. The lubricating properties of CSO and HRSO are further studied as a result of their common hydroxyl nature to ascertain their suitability as a lubricant base. Both oils can be categorized as a nondrying oil with saponification values of 179.52 and 255.25 mgKOH/g, respectively, and as such possess advantageous properties for industrial application. When compared to one another, HRSO appears to be a more effective choice as a lubricant base. This is because of its higher viscosity index of 380.65. The outcomes of this study indicate that hydroxylated and epoxidized RSO with high oxirane content can be synthesized concurrently by one-pot multistep reactions.

A Highly Efficient Three-Liquid-Phase-Based Enzymatic One-Pot Multistep Reaction System with Recoverable Enzymes for the Synthesis of Biodiesel.

A three-liquid-phase system (TLPS) was developed and used as a novel enzymatic one-pot multistep reaction (EOMR) system. In this system, lipase and phospholipase were enriched in a single liquid phase with a high recovery (ca. 98%) and then used for the simultaneous catalysis of mutually inhibiting and interfering reactions (hydrolysis of phospholipids and glyceride in crude oil). A novel emulsion containing the two dispersed droplets (W2/O/W2 and W1/W2 emulsion structures) could be the key reason for this phenomenon because the emulsion system not only provided a new catalytic interface but also relieved the product inhibition. As a result, the content of free fatty acid (main hydrolysate of the glyceride) and the removal of phospholipid from the crude oil could be increased to 96 and 95%, respectively, within 1 h. The product obtained from the EOMR was directly used in the production of biodiesel via enzymatic esterification, and the content of fatty acid methanol ester could be increased to 93% within 2 h. Furthermore, the enzymes in the middle phase could also be reused, at least for eight rounds without significant loss in catalytic efficiency. Therefore, the TLPS could be considered as an ideal catalytic platform for the EOMR.

Unexpected Ethyltellurenylation of Epoxides with Elemental Tellurium under Lithium Triethylborohydride Conditions

The one-pot multistep ethyltellurenylation reaction of epoxides with elemental tellurium and lithium triethylborohydride is described. The reaction mechanism was experimentally investigated. Dilithium ditelluride and triethyl borane, formed from elemental tellurium and lithium triethylborohydride, were shown to be the key species involved in the reaction mechanism. Epoxides undergo ring-opening reaction with dilithium ditelluride to afford β-hydroxy ditellurides, which are sequentially converted into the corresponding β-hydroxy-alkyl ethyl tellurides by transmetalation with triethyl borane, reasonably proceeding through the SH2 mechanism.

Efficient photocatalytic one-pot hydrogenation and N-alkylation of nitrobenzenes/benzonitriles with alcohols over Pd/MOFs: Effect of the crystal morphology & “quasi-MOF” structure

One-pot multi-step reactions over visible-light induced catalysis feature the sustainable green process. Here, ligand structure change and 2-MI coordinated modulation were adapted to adjust the crystal size, morphology and crystalline structure of Fe-MOFs; double solvent impregnation was employed for the Pd loading; “quasi-MOF” materials with retained morphology were formed with calcination under N2. Above modified materials were employed as multifunctional photocatalysts for highly efficient one-pot hydrogenation and N-alkylation of nitrobenzenes or benzonitriles with alcohols after in situ Pd photoreduction. Photocatalytic performance was evidently affected by the Fe-MOFs crystal size, morphology, crystalline structure alteration and “quasi-MOF” construction. One-pot hydrogenation and N-alkylation of benzonitriles with alcohols was achieved with excellent catalytic performance firstly in heteroegeneous catalysis. Reaction mechanism was proposed with the assistance of in situ DRIFTS.

Highly Mesoporous Metal-Organic Frameworks as Synergistic Multimodal Catalytic Platforms for Divergent Cascade Reactions.

Rational engineering and assimilation of diverse chemo- and biocatalytic functionalities in a single nanostructure is highly desired for efficient multistep chemical reactions but has so far remained elusive. Here, we design and synthesize multimodal catalytic nanoreactors (MCNRs) based on a mesoporous metal-organic framework (MOF). The MCNRs consist of customizable metal nanocrystals and stably anchored enzymes in the mesopores, as well as coordinatively unsaturated cationic metal MOF nodes, all within a single nanoreactor space. The highly intimate and diverse catalytic mesoporous microenvironments and facile accessibility to the active site in the MCNR enables the cooperative and synergistic participation from different chemo- and biocatalytic components. This was shown by one-pot multistep cascade reactions involving a heterogeneous catalytic nitroaldol reaction followed by a [Pd/lipase]-catalyzed chemoenzymatic dynamic kinetic resolution to yield optically pure (>99 % ee) nitroalcohol derivatives in quantitative yields.

Surface modification of regenerated cellulose membrane based on thiolactone chemistry – A novel platform for mixed mode membrane adsorbers

Mixed-mode membrane chromatography (MMC) is an effcient separation technology for protein purification. However, tedious preparation methods and difficulty on ligand density control for its stationary phase limit the application of MMC. Herein we explored a one-pot multistep reaction based on the thiolactone chemistry as a platform for membrane surface modification design toward mixed mode membrane adsorbers. The regenerated cellulose (RC) membrane was modified by the atom transfer radical polymerization (ATRP) of styrene-thiolactone (St-Tla), followed by the amine-thiol-ene conjugation. N-butylamine/methacrylic acid and octylamine/methacrylic acid were selected as the modifier to prepare two different mixed mode membrane adsorbers, RC-HIC/IEC (hydrophobic/ion-exchange) and RC-RPC/IEC (reversed phase/ion-exchange). SEM, FT-IR and XPS results showed that the membrane adsorbers were successfully prepared. The RC-HIC/IEC membrane had a statistic adsorption capacity of 73.5 µg/cm2 for human immunoglobulin G (IgG) under the conditions of pH = 8 and 0.5 mol/L NaCl in PB buffer. The RC-RPC/IEC membrane showed a capacity of 70 µg/cm2 for α-chymotrypsin (α-CTP) under the conditions of pH = 6.5 in PB buffer. The feasibility of tethering multi functions onto membrane surface via the thiolactone chemistry was demonstrated in this work.

High-Throughput Preparation of Antibacterial Polymers from Natural Product Derivatives via the Hantzsch Reaction.

SummaryThe Hantzsch and free-radical polymerization reactions were combined in a one-pot high-throughput (HTP) system to simultaneously prepare 30 unique polymers in parallel. Six aldehydes derived from natural products were used as the starting materials to rapidly prepare the library of 30 poly(1,4-dihydropyridines). From this library, HTP evaluation methods led to the identification of an antibacterial polymer. Mechanistic studies revealed that the dihydropyridine group in the polymer side-chain structure plays an important role in resisting bacterial attachment to the polymer surface, thus leading to the antibacterial function of this polymer. This research demonstrates the value of multicomponent reactions (MCRs) in interdisciplinary fields by discovering functional polymers for possible practical applications. It also provides insights to further developing new functional polymers using MCRs and HTP methods with important implications in organic chemistry, polymer chemistry, and materials science.

Biocatalytic selective functionalisation of alkenes via single-step and one-pot multi-step reactions.

Alkenes are excellent starting materials for organic synthesis due to the versatile reactivity of C[double bond, length as m-dash]C bonds and the easy availability of many unfunctionalised alkenes. Direct regio- and/or enantioselective conversion of alkenes into functionalised (chiral) compounds has enormous potential for industrial applications, and thus has attracted the attention of researchers for extensive development using chemo-catalysis over the past few years. On the other hand, many enzymes have also been employed for conversion of alkenes in a highly selective and much greener manner to offer valuable products. Herein, we review recent advances in seven well-known types of biocatalytic conversion of alkenes. Remarkably, recent mechanism-guided directed evolution and enzyme cascades have enabled the development of seven novel types of single-step and one-pot multi-step functionalisation of alkenes, some of which are even unattainable via chemo-catalysis. These new reactions are particularly highlighted in this feature article. Overall, we present an ever-expanding enzyme toolbox for various alkene functionalisations inspiring further research in this fast-developing theme.

Manganese oxide catalyzed synthesis of anti-HIV N-substituted benzimidazoles via a one-pot multistep process

1, 2-Disubstituted benzimidazoles are drug discovery targets and play an important role in many areas. Herein, non-noble-metal α-MnO2 prepared using urea as the additive was found to be an efficient catalyst for the synthesis of antiviral 1,2-disubstituted benzimidazoles via one-pot multistep reactions using dimethyl carbonate and air as green solvent and oxidant, respectively. The catalytic system could tolerate 1, 2-diol or alcohols as raw via cascade oxidation/cyclization/alkylation to realize the desired products in moderate to good yields. The catalyst was characterized by ICP-AES, XRD, BET, SEM, TEM and XPS, which indicates that the surface oxygen species seriously affected the catalytic performance. And the leaching of Na/K ions in tunnels of the catalyst caused loss of catalytic activity of retrieved α-MnO2.

A new and informative [a,b,c,d] nomenclature for one-pot multistep transformations: a simple tool to measure synthetic efficiency.

Domino, cascade and tandem reactions constitute the most efficient and creative chemical transformations with a huge domain of synthetic utility and applications. A number of reactions may be achieved in a single pot, accompanied by the formation of new rings and new bonds, leading towards higher molecular complexity. A lack of one unified, yet informative descriptor often understates the synthetic ingenuity of certain highly creative transformations. In this review, we propose a new tetra-coordinated [a,b,c,d] nomenclature which takes into account and displays the basic parameters which generally indicate the level of efficiency of a chemical transformation. An almost exhaustive set of one-pot multistep reactions may be described by this system and this review is an attempt to display the one-pot multistep transformations reported from our group and to classify them based on our proposed descriptor.

Rapid, chemical-free breaking of microfluidic emulsions with a hand-held antistatic gun.

Droplet microfluidics can form and process millions of picoliter droplets with speed and ease, allowing the execution of huge numbers of biological reactions for high-throughput studies. However, at the conclusion of most experiments, the emulsions must be broken to recover and analyze their contents. This is usually achieved with demulsifiers, like perfluorooctanol and chloroform, which can interfere with downstream reactions and harm cells. Here, we describe a simple approach to rapidly and efficiently break microfluidic emulsions, which requires no chemicals. Our method allows one-pot multi-step reactions, making it useful for large scale automated processing of reactions requiring demulsification. Using a hand-held antistatic gun, we pulse emulsions with the electric field, coalescing ∼100 μl of droplets in ∼10 s. We show that while emulsions broken with chemical demulsifiers exhibit potent PCR inhibition, the antistatic-broken emulsions amplify efficiently. The ability to break emulsions quickly without chemicals should make our approach valuable for most demulsification needs in microfluidics.

Enantioselective Organocatalytic Synthesis of a Secoyohimbane-Inspired Compound Collection with Neuritogenic Activity.

Natural products provide evolutionary validated core structures to inspire the synthesis of new compound collections endowed with neurite growth-promoting activity. Rhynchophylline is the major component of Uncaria species, and has been used to treat neurological diseases in Chinese traditional medicine. Based on the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide a tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers, in a one-pot multistep reaction sequence. A compound collection of derived secoyohimbanes was synthesized and expanded by decorating the periphery of the basic scaffold with additional substituents to increase the diversity. Evaluation of the different subcollections of secoyohimbanes for modulation of neurite outgrowth in the SH-SY5Y human cell line led to the discovery of new compounds that promote neurite outgrowth.

Facile access to versatile functional groups from alcohol by single multifunctional reusable catalyst

Tandem oxidation processes enabling one-pot multistep reactions received great attention as an efficient synthetic methodology for construction of complex molecules from simple substrates by a single operation. We report here tandem oxidative transformations of seven different functional groups (imine, imidazole, cyanide, amide, lactone, ester and olefin) from a single substrate (alcohol) by a single cesium promoted mesoporous manganese oxide catalyst (meso Cs/MnOx). High conversions were obtained with a broad range of substrates including aliphatic long chain alcohols. The catalyst can be reused without any loss of catalytic activity. We also demonstrated a unique multiple esterification reaction from a single aliphatic alcohol under aerobic atmospheric conditions catalyzed by meso Cs/MnOx.

“On Water” MW-Assisted Synthesis of Hydroxytyrosol Fatty Esters

A new “on water” MW-assisted esterification protocol using fatty chlorides and acetonidehydroxytyrosol as starting materials, giving rise to a one-pot multistep reaction, without any added catalyst is described. The reaction took place at the interface oil/water thus being strictly dependent on the lipophilicity of the fatty acid acyl chloride. The potential scale-up of the method was also reported.