Synthesis of nucleoside-based antiviral drugs in ionic liquids

Nucleoside-based antiviral drugs have been synthesized using imidazolium-based ionic liquids as reaction medium. The ionic liquids were proved to be better solvents for all the nucleoside in terms of solubility and reaction medium as compared to conventional molecular solvents.     

Green microwave-assisted synthesis of cellulose/calcium silicate nanocomposites in ionic liquids and recycled ionic liquids

Fabrication of biomass materials by a microwave-assisted method in ionic liquids allows the high value-added applications of biomass by combining three major green chemistry principles: using environmentally preferable solvents, using an environmentally friendly method, and making use of renewable biomass materials. Herein, we report a rapid and green microwave-assisted method for the synthesis of the cellulose/calcium silicate nanocomposites in ionic liquids and recycled ionic liquids. These calcium silicate nanoparticles or nanosheets as prepared were homogeneously dispersed in the cellulose matrix. The experimental results confirm that the ionic liquids can be used repeatedly. Of course, the slight differences were also observed using ionic liquids and recycled ionic liquids. Compared with other conventional methods, the rapid, green, and environmentally friendly microwave-assisted method in ionic liquids opens a new window to the high value-added applications of biomass.     

Recent advances of enzymatic reactions in ionic liquids

The tremendous potential of room temperature ionic liquids as an alternative to environmentally harmful ordinary organic solvents is well recognized. Ionic liquids, having no measurable vapor pressure, are an interesting class of tunable and designer solvents, and they have been used extensively in a wide range of applications including enzymatic biotransformation. In fact, ionic liquids can be designed with different cation and anion combinations, which allow the possibility of tailoring reaction solvents with specific desired properties, and these unconventional solvent properties of ionic liquids provide the opportunity to carry out many important biocatalytic reactions that are impossible in traditional solvents. As compared to those observed in conventional organic solvents, the use of enzymes in ionic liquids has presented many advantages such as high conversion rates, high enantioselectivity, better enzyme stability, as well as better recoverability and recyclability. To date, a wide range of pronounced approaches have been taken to further improve the performance of enzymes in ionic liquids. This review presents the recent technological developments in which the advantages of ionic liquids as a medium for enzymes have been gradually realized.     

Toward advanced ionic liquids. Polar,enzyme-friendly solvents for biocatalysis

Ionic liquids, also called molten salts, are mixtures of cations and anions that melt below 100°C. Typical ionic liquids are dialkylimidazolium cations with weakly coordinating anions such as (MeOSO₃) or (PF₆). Advanced ionic liquids such as choline citrate have biodegradable, less expensive, and less toxic anions and cations. Deep eutectic solvents are also included in the advanced ionic liquids. Deep eutectic solvents are mixtures of salts such as choline chloride and uncharged hydrogen bond donors such as urea, oxalic acid, or glycerol. For example, a mixture of choline chloride and urea in 1:2 molar ratio liquefies to form a deep eutectic solvent. Their properties are similar to those of ionic liquids. Water-miscible ionic liquids as cosolvents with water enhance the solubility of substrates or products. Although traditional water-miscible organic solvents also enhance solubility, they often inactivate enzymes, while ionic liquids do not. The enhanced solubility of substrates can increase the rate of reaction and often increases the regioor enantioselectivity. Ionic liquids can also be solvents for non-aqueous reactions. In these cases, they are especially suited to dissolve polar substrates. Polar organic solvent alternatives inactivate enzymes, but ionic liquids do not even when they have similar polarities. Besides their solubility properties, ionic liquids and deep eutectic solvents may be greener than organic solvents because ionic liquids are nonvolatile, and can be made from nontoxic components. This review covers selected examples of enzyme catalyzed reaction in ionic liquids that demonstrate their advantages and unique properties, and point out opportunities for new applications. Most examples involve hydrolases, but oxidoreductases and even whole cell reactions have been reported in ionic liquids.     

Use of salt hydrate pairs to control water activity for enzyme catalysis in ionic liquids

Salt hydrate pairs were used to control water activity in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate. It was shown that salt hydrate pairs behave essentially the same in ionic liquids as they do in organic solvents as long as they do not dissolve. Initial rate-water activity profiles were prepared for the immobilized Candida antarctica lipase catalyzed synthesis of 2-ethylhexyl methacrylate. The ability to use salt hydrate pairs for the control of water activity in ionic liquids should allow for improved comparison of enzyme activity and specificity in ionic liquids and conventional solvents.     

Enzyme catalysis in ionic liquids

Ionic liquids offer new possibilities for the application of solvent engineering to biocatalytic reactions. Although in many cases ionic liquids have simply been used to replace organic solvents, they have often led to improved process performance. Unlike conventional organic solvents, ionic liquids possess no vapor pressure, are able to dissolve many compounds, and can be used to form two-phase systems with many solvents. To date, reactions involving lipases have benefited most from the use of ionic liquids, but the use of ionic liquids with other enzymes and in whole-cell processes has also been described. In some cases, remarkable results with respect to yield, (enantio)selectivity or enzyme stability were observed.     

Biocatalysis in ionic liquids - advantages beyond green technology

In recent years researchers have started to explore a particular class of organic solvents called room temperature ionic liquids - or simply ionic liquids - to identify their unique advantages for biocatalysis. Because they lack vapour pressure, ionic liquids hold potential as green solvents. Furthermore, unlike organic solvents of comparable polarity, they often do not inactivate enzymes, which simplifies reactions involving polar substrates such as sugars. Biocatalytic reactions in ionic liquids have also shown higher selectivity, faster rates and greater enzyme stability; however, these solvents present other challenges, among them difficulties in purifying ionic liquids and controlling water activity and pH, higher viscosity and problems with product isolation.     

Biocatalysis in semi-aqueous and nearly anhydrous conditions

In the past few years there have been prolific advances in activating enzymes for nonaqueous biocatalysis. Molecular dynamics simulations complement recent experimental results and offer new insights into the deleterious effects of organic solvents, such as water stripping and active-site penetration. Methods for activating enzymes in semi-aqueous or nonaqueous media include protein engineering, chemical modification, and co-lyophilization with non-buffer salts. Enzyme immobilization on novel polymeric supports and the use of zeolite molecular sieves can also increase solvent tolerance, enhance activity, and improve enantioselectivity. The recent implementation of enzymes in ionic liquids has also led to better long-term stability relative to traditional organic solvents and the simultaneous solubilization of enzymes, cofactors and substrates.     

离子液体的性能及应用

离子液体不仅可用作环境友好的“绿色溶剂”,而且在生物合成和有机反应中能表现出特殊的催化、促进效应。在介绍离子液体种类、性质、合成方法的基础上,重点综述离子液体功能化方法、离子液体／超临界CO2体系和其在生物催化反应中应用的最新研究进展。     

Nucleosides Containing Selenium1 II

Abstract

The chemistry of nucleoside analogs with antiviral and antitumor activity is well known. These properties have prompted considerable attention to new developments in synthetic methodology, especially in the field of modification of heterocyclic functions. One such class of methods is introduction of sulfur and selenium into the purine or pyrimidine bases. While thio-substituted nuclesides, are well known, their selenium counterparts are relatively less known in contrast to their potential importance as antitumor agents, as has been reported. The fact that the chemistry of selenium nucleosides is relatively unexplored encouraged review of the literature in this field.     

Thermodynamically based solvent design for enzymatic saccharide acylation with hydroxycinnamic acids in non-conventional media

Enzyme-catalyzed synthesis has been widely studied with lipases (EC 3.1.1.3), but feruloyl esterases (FAEs; EC 3.1.1.73) may provide advantages such as higher substrate affinity and regioselectivity in the synthesis of hydroxycinnamate saccharide esters. These compounds are interesting because of their amphiphilicity and antioxidative potential. Synthetic reactions using mono- or disaccharides as one of the substrates may moreover direct new routes for biomass upgrading in the biorefinery. The paper reviews the available data for enzymatic hydroxycinnamate saccharide ester synthesis in organic solvent systems as well as other enzymatic hydroxycinnamate acylations in ionic liquid systems. The choice of solvent system is highly decisive for enzyme stability, selectivity, and reaction yields in these synthesis reactions. To increase the understanding of the reaction environment and to facilitate solvent screening as a crucial part of the reaction design, the review explores the use of activity coefficient models for describing these systems and - more importantly - the use of group contribution model UNIFAC and quantum chemistry based COSMO-RS for thermodynamic predictions and preliminary solvent screening. Surfactant-free microemulsions of a hydrocarbon, a polar alcohol, and water are interesting solvent systems because they accommodate different substrate and product solubilities and maintain enzyme stability. Ionic liquids may provide advantages as solvents in terms of increased substrate and product solubility, higher reactivity and selectivity, as well as tunable physicochemical properties, but their design should be carefully considered in relation to enzyme stability. The treatise shows that thermodynamic modeling tools for solvent design provide a new toolbox to design enzyme-catalyzed synthetic reactions from biomass sources.     

Enzyme Catalysed Synthesis in Ambient Temperature Ionic Liquids

The activity of three different lipases, a glycosidase and a protease in ionic liquids has been studied. Ambient temperature ionic liquids are a new class of solvents that are nonvolatile and nonflammable and thus an interesting alternative to classical organic solvents. Monitoring the synthesis of a simple ester, all lipases were found to exhibit both excellent activity and stability in the non-polar ionic liquid 1-butyl-3-methylimidazohum hexaflurophosphate ([bmin][PF₆], 1). Furthermore, β-galactosidase from E. coli and the Subtilisin protease Savinase^TM were both found to exhibit a hydrolytic activity in a 50% aqueous solution of the water-miscible ionic liquid 1-butyl-3-methyhmidazoUum tetra-fluoroborate ([bmin][BF₄], 2) comparable to the activity observed in 50% aqueous solutions of ethanol and acetonitrile.     

Biocatalytic synthesis of ascorbyl esters and their biotechnological applications

Ascorbyl fatty acid esters act both as antioxidants and surfactants. These esters are obtained by acylation of vitamin C using different acyl donors in presence of chemical catalysts or lipases. Lipases have been used for this reaction as they show high regioselectivity and can be used under mild reaction conditions. Insolubility of hydrophilic ascorbic acid in non-polar solvents is the major obstacle during ascorbic acid esters synthesis. Different strategies have been invoked to address this problem viz. use of polar organic solvents, ionic liquids, and solid-phase condensation. Furthermore, to improve the yield of ascorbyl fatty acid esters, reactions were performed by (1) controlling water content in the reaction medium, (2) using vacuum to remove formed volatile side product, and (3) employing activated acyl donors (methyl, ethyl or vinyl esters of fatty acids). This mini-review offers a brief overview on lipase-catalyzed syntheses of vitamin C esters and their biotechnological applications. Also, wherever possible, technical viability, scope, and limitations of different methods are discussed.     

Over-stabilization of Candida antarctica lipase B by ionic liquids in ester synthesis

Four different ionic liquids, based on dialkylimidazolium cations associated with perfluorinated and bis(trifluoromethyl)sulfonyl amide anions were used as reaction media for butyl butyrate synthesis catalyzed by free Candida antarctica lipase B at 2% (v/v) water content and 50 °C. Lipase had enhanced synthetic activity in all ionic liquids in comparison with two organic solvents (hexane, and 1-butanol), the enhanced activity being related to the increase in polarity of ionic liquids. The continuous operation of lipase with all the assayed ionic liquids showed over-stabilization of the enzyme. The reuse of free lipase in 1-butyl-3-methylimidazolium hexafluorophosphate in continuous operation cycles showed a half-life time 2300 times greater than that observed when the enzyme was incubated in the absence of substrate (3.2 h), and a selectivity higher than 90%.     

Chiral ionic liquids: synthesis and applications

Over the last ten years, interest and publications involving ionic liquids have expanded exponentially. Thus far, they have predominantly been used in organic synthesis and separations. However, their use is rapidly expanding into other areas of science and technology. Research involving chiral ionic liquids has been much more limited and only recently has come to the forefront. In this work, we review the synthesis of chiral ionic liquids and their use. Today, this is an area of research that is poised for rapid development and expansion.     

Chemical modification with functionalized ionic liquids: a novel method to improve the enzymatic properties of Candida rugosa lipase

Chemical modification of lysine residues in Candida rugosa lipase (CRL) was carried out using five different functional ionic liquids, and about 15.4–25.0 % of the primary amino groups of lysine were modified. Enzymatic properties of the native and modified CRLs were investigated in olive oil hydrolysis reaction. Improved thermal stability, catalytic activity in organic solvents, and adaptability to temperature and pH changes were achieved compared with the native enzyme. CRL modified by [choline][H₂PO₄] showed the best results, bearing a maximum improvement of 16.7 % in terms of relative activity, 5.2-fold increase in thermostability (after incubation at 45 °C for 5 h), and 2.3-fold increase in activity in strong polar organic solvent (80 % dimethyl sulfoxide) compared with the native enzyme. The results of ultraviolet, circular dichroism and fluorescence spectroscopy suggested that the change of the secondary and tertiary structures of CRL caused by the chemical modification resulted in the enhancement of enzymatic performance. The modification of CRL with functional ionic liquids was proved to be a novel and efficient method for improving the enzymatic properties of CRL.     

Enzymatic selective acylation of glycosides in ionic liquids: significantly enhanced reactivity and regioselectivity

The enzymatic selective acylations of carbohydrates in ionic liquids were explored in both organic solvents and ionic liquids to see any significant differences in terms of reactivity and regioselectivity between two different classes of reaction media. Monoprotected glycosides (methyl-6-O-trityl-glucosides and galactosides) were chosen as the substrates with Candida rugosa lipase as an acylation enzyme. Two organic solvents, THF and chloroform, and two ionic liquids, [BMIM]⁺PF₆⁻ ([BMIM]⁺ = 1-butyl-3-methylimidazolium) and [MOEMIM]⁺PF₆⁻ ([MOEMIM]⁺ = 1-methoxyethyl-3-methylimidazolium), were employed as reaction media. The enzymatic reactions were performed in the presence of vinyl acetate at room temperature. It was observed that the reactions in ionic liquids took place more rapidly and more selectively than those in conventional organic solvents.     

Activity and stability of cross-linked tyrosinase aggregates in aqueous and nonaqueous media

Cross-linked tyrosinase aggregates were prepared by precipitating the enzyme with ammonium sulfate and subsequent cross-linking with glutaraldehyde. Both activity and stability of these cross-linked enzyme aggregates (CLEAs) in aqueous solution, organic solvents, and ionic liquids have been investigated. Immobilization effectively improved the stability of the enzyme in aqueous solution against various deactivating conditions such as pH, temperature, denaturants, inhibitors, and organic solvents. The stability of the CLEAs in various organic solvents such as tert-butanol (t(1/2)=326.7h at 40°C) was significantly enhanced relative to that in aqueous solution (t(1/2)=5.5h). The effect of thermodynamic water activity (a(w)) on the CLEA activity in organic media was examined, demonstrating that the enzyme incorporated into CLEAs required an extensive hydration (with an a(w) approaching 1.0) for optimizing its activity. The impact of ionic liquids on the CLEA activity in aqueous solution was also assessed.     

Ionic liquids in biotechnology: applications and perspectives for biotransformations

Ionic liquids are considered as an alternative to organic solvents for catalysis. The literature in this field is reviewed with focus on advantageous use of ionic liquids in biocatalysis and biotransformations. The overview reveals that the exploration and mapping of ionic liquids with respect to biocatalysis is still sketchy. It is apparent that advantages can be gained in view of activity, stability and selectivity. Furthermore, integration of reaction and separation has a high potential in the field. The review presents quantitative data on the productivities, space–time yields, as well as stability as far as they can be extracted from the literature. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.