Current Organic Synthesis - Volume 8, Issue 6, 2011

Ionic liquids have advanced from the curiosity of ‘novel materials’ [1] of 1980s, ‘green solvents’ [2] of 1990s to the ‘designer chemicals’ [3] of the 21st century. This has been possible to a large extent due to realization that their physiochemical properties can be ‘tuned’ by judicious pairing of cations and anions. Of course, this feature has attracted scientists from various disciplines leading to phenomenal growth in our understanding of these materials. The scientific potential for research in ionic liquids is unlimited. Beyond the growing library of structures, the diversity of interdisciplinary research has helped in expanding the catalog of their applications. This is evident from the fact that Ionic liquids find wide ranging applications spanning for example, electrochemistry [4], synthesis [5], biochemistry [6], materials science [7, 8], pharmaceuticals and therapeutics [9]. Given the perceived toxicity issues, their utility as potential ‘therapeutics’ [10, 11] is very encouraging and promises unforeseen applications in the field of biomedical sciences. Among numerous advantages, the potential to manipulate their solvent properties has certainly helped in overcoming some of the challenges seen with conventional organic solvents in the synthesis of natural building blocks such as the carbohydrates, nucleosides, heterocycles etc. These achievements are highlighted in five review articles selected for this special issue of the Current Organic Synthesis. Topics covered include the utility of chloroferrate ILs as solvents and catalysts with a particular focus on reactions leading to pharmaceutically active compounds and intermediates (Bica et al.) The advantages using ionic liquids in the dissolution and transformation of carbohydrates are covered by Rosatella et al. Nucleosides derived molecules are biologically importantand found as active drugs. The effectiveness of ionic liquids in nucleoside chemistry is summarized by Kumar et al. Similarly, N-heterocyclic compounds are major building blocks for natural products with biological activity. The focus of article by Yadav et al. is on the advances made in the synthesis of these compounds using ionic liquids. Finally, the review by Pedro et al. highlights the synergistic applications of ILs with scCO2 in bio-catalytic systems allowing multistep organic synthesis in continuous flow processes.

Nucleoside chemistry represents an important research area for drug discovery, as many nucleoside analogues are prominent drugs that have been widely applied in cancer and viral chemotherapy. However, the synthesis of modified nucleosides presents a major challenge. Most of the currently available methods require toxic, high-boiling solvents, long reaction times and tedious workup methods. The situation is further aggravated by the poor solubility of the nucleosides in common organic solvents. There is a constant effort to develop process chemistry in alternative media to limit the use of organic solvents that are hazardous to the environment and can be deleterious to human health. Ionic liquids (ILs) are ‘designer materials’ with unique physico-chemical properties. The methodologies utilizing ionic liquids for the synthesis of pharmaceutically important nucleoside analogues, including some antiviral drugs, are highly convenient and efficient. This article is focused on the recent developments made in nucleoside chemistry using ILs as a reaction medium.

N-heterocyclic compounds, which constitute a major portion of heterocyclic compounds are present in many parmaceutical products that mimic the biological activity of natural products. Access to these complex structures became available through a variety of novel methods and the strategic deployment of known methods. Because of the current trend in environmental protection, which has resulted in more restrictive environmental regulations, as well as the high costs of waste treatment, removal and remediation, the exploration for the synthesis of pharmacophores has reached a new phase in research. Ionic liquids have been identified as having significant potential for contributing to this process. Although ionic liquids were initially introduced as an alternative green reaction media because of their unique chemical and physical properties, the fact that they play a significant role in controlling reactions as a solvent or catalyst directs the research toward the development of a number of viable strategies.

This review highlights the tool box for the development of continuous green/sustainable processes aimed at the synthesis of fine chemicals. By combining either chemical and/or biological catalysts with biphasic systems based on neoteric solvents, e.g. ionic liquids (ILs) and supercritical carbon dioxide (scCO2), interesting alternatives to organic solvents for designing continuous clean (bio)transformations methods are growing that directly provide pure products. The classical advantages of scCO2 -its ability to extract, dissolve and transport chemicals- are complemented by the high catalytic efficiency of enzymes in ILs. Enzyme behavior in scCO2 and ILs, as well as the phase behavior of ILs/scCO2, are key parameters for carrying out integral green bioprocesses in continuous operation. The preparation, main characteristics and advantages of monolithic microreactors and miniflow reactors for the synthesis of fine chemicals by continuous flow (bio)catalytic processes are underlined. Examples where the use of continuous flow techniques for multi-step synthesis enables multiple reaction steps to be combined into a single continuous operation are provided.

During the past few years, Lewis-acidic ionic liquids (ILs) have emerged from their role as mere reaction media toward a role as novel catalytic systems. Iron-containing chloroferrate ionic liquids in particular offer a novel approach to sustainable and environmentally benign catalysis and can be applied in a surprising diversity of transformations. In this review, we present this emerging topic and report the application of chloroferrate ILs as solvents, catalysts or catalytic systems for a variety of chemical processes, with a particular focus on reactions leading to pharmaceutically active compounds or intermediates.

Carbohydrates have a high number of hydroxyl groups, which makes them preferentially soluble in water, although this solvent is not always the most suitable. Polar organic solvents, such as pyridine, dimethylsulfoxide and dimethyformamide, are the few solvents able to dissolve carbohydrates however they have a higher impact in the environment and provide a less efficient solvent media due to deactivation in biocatalysis, for instance. A way to overcome these problems is to use Ionic Liquids (ILs). Data suggest that ILs can be acceptable solvents for carbohydrate dissolution and that they lead to higher yield and more selective reactions. In this review, we will focus mainly on monosaccharide dissolution and functional transformation, despite some references to polysaccharides, as an attempt to demonstrate ILs can be a suitable media for carbohydrate chemistry.

Our novel approach starts from a 1,1,3,4-tetrachloro-2,4-dinitrobuta-1,3-diene (5) being one of the most prominent members of this relatively new class of synthetic building blocks. Because of its multifunctional chemical behavior, polyhalogenated nitrobuta-1,3- dienes proved to be versatile reagents in the synthesis of a large variety of sulfurated, (hetero)cyclic, and acyclic derivatives. We describe our studies concerning successive nucleophilic vinylic substitution reactions of dinitrobuta-1,3-diene in order to establish the reactivity profile of this precursor and determine whether this precursor could be used for the synthesis of many dinitrodiene analogues offering new methodology for the synthesis of polyfunctional precursors that are difficult to access. Some of the resulting perfunctionalized 2,4- dinitrobuta-1,3-dienes are subjected to further transformations to give promising candidates with respect to biological activity.

Sugar and nucleoside identifications are important for the detection and treatment of dangerous diseases. In this study, a fluorescent boronic acid (3-(5-(dimethylamino)naphthalene-1-sulfonamido)phenyl)boronic acid (DNSBA) was bound to a diol quencher via a boronic ester linkage, and fluorescence recovery upon exposure to saccharides and nucleosides was demonstrated. Further, we successfully detected sugars and nucleosides in buffer systems. DNSBA expresses selectivity toward adenosine, fructose, sorbitol, and tartaric acid. Our investigations into the effects of pH on sensor sensitivity revealed that changes between the neutral and anionic forms of the boronic acid group, induced at high pH and/or in the presence of sugars or nucleosides, induce visible/optimal changes in DNSBA. DNSBA is responsive at pH = 8.21 whereas acidic media do not exhibit sensitivity. DNSBA can thus be useful in clinical applications as a novel sensor for sugars and nucleosides.

As focus is increasing on conducting chemistry in a greener fashion, this implies that chemists need to find new methods for synthetic transformations that are more efficient or open up the possibility for recycling. By such means less waste will be generated. Catalysts on solid supports are one of many avenues that are being explored in order to reach this goal. For the reasons just stated palladium on solid supports is gaining momentum in synthesis. More and more reaction conditions are being developed that enable the use of heterogenic catalysts and a range of solid supports are being explored. The use of a heterogenic catalyst, which can easily be removed post synthesis, has the advantage that it greatly simplifies the work-up of the reaction mixture. It also reduces the amount of palladium remaining in the product. The latter benefit is highly important when the product is a pharmaceutical. Another benefit with having the catalyst on solid supports is that it also offers the opportunity to relatively easily recycle the catalyst. This review will present some of the latest developments in solid supports for palladium, and highlight the use of palladium on solid supports in organic synthesis.

New synthetic approaches to the functionally substituted nitriles as well as the chemical reactivity profiles of these substances are reviewed.

Ephedra compounds are well known due to their biological activity. They have been widely used in asymmetric synthesis during the last decades. To our knowledge no review about acyclic ephedra derivative compounds has appeared in the literature. In this paper, the synthetic methodologies to access ephedrines and chiral compounds derived from them are summarized, including those by substitution of the hydroxy group by chlorine, sulfur, nitrogen or phosphorous containing groups. Ephedrines and some ephedra derivatives have displayed biological activity. Some of them have been used as asymmetric inductor ligands or catalysts in asymmetric synthesis. Clearly the ephedra derivatives are potential candidates to be used in both areas.