Friedel-Crafts reactions for biomolecular chemistry.

Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions. Friedel-Crafts alkylation and acylation are arguably some of the most well-known and used synthetic methods for the preparation of small molecules but their use in biological and medical fields is relatively less frequent than the other reactions, possibly owing to the notion of their plausible incompatibility with biological systems. This review demonstrates advances in Friedel-Crafts alkylation and acylation reactions in a variety of biomolecular chemistry fields. With the discoveries and applications of numerous biomolecule-catalyzed or -assisted processes, these reactions have garnered considerable interest in biochemistry, enzymology, and biocatalysis. Despite the challenges of reactivity and selectivity of biomolecular reactions, the alkylation and acylation reactions demonstrated their utility for the construction and functionalization of all the four major biomolecules (i.e., nucleosides, carbohydrates/saccharides, lipids/fatty acids, and amino acids/peptides/proteins), and their diverse applications in biological, medical, and material fields are discussed. As the alkylation and acylation reactions are often fundamental educational components of organic chemistry courses, this review is intended for both experts and nonexperts by discussing their basic reaction patterns (with the depiction of each reaction mechanism in the ESI) and relevant real-world impacts in order to enrich chemical research and education. The significant growth of biomolecular Friedel-Crafts reactions described here is a testament to their broad importance and utility, and further development and investigations of the reactions will surely be the focus in the organic biomolecular chemistry fields.

Halo-1,2,3-triazoles: Valuable Compounds to Access Biologically Relevant Molecules.

1,2,3-triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4-disubstituted 1,2,3-triazole molecules however 1,4,5-trisubstituted 1,2,3-triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction have been developed to access halo-triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late-stage modification of halo-triazole derivatives by metal-mediated cross-coupling or halo-exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5-trisubstituted halo-1,2,3-triazoles in biologically relevant molecules.

New syntheses of thiosaccharides utilizing substitution reactions.

Novel synthetic methods published since 2005 affording carbohydrates containing sulfur atom(s) are reviewed. The review is divided to subchapters based on the position of sulfur atom(s) in the sugar molecule. Only those methods that take advantage of substitution are discussed.

Optochemical Control of Bacterial Gene Expression: Novel Photocaged Compounds for Different Promoter Systems.

Photocaged compounds are applied for implementing precise, optochemical control of gene expression in bacteria. To broaden the scope of UV-light-responsive inducer molecules, six photocaged carbohydrates were synthesized and photochemically characterized, with the absorption exhibiting a red-shift. Their differing linkage through ether, carbonate, and carbamate bonds revealed that carbonate and carbamate bonds are convenient. Subsequently, those compounds were successfully applied in vivo for controlling gene expression in E. coli via blue light illumination. Furthermore, benzoate-based expression systems were subjected to light control by establishing a novel photocaged salicylic acid derivative. Besides its synthesis and in vitro characterization, we demonstrate the challenging choice of a suitable promoter system for light-controlled gene expression in E. coli. We illustrate various bottlenecks during both photocaged inducer synthesis and in vivo application and possibilities to overcome them. These findings pave the way towards novel caged inducer-dependent systems for wavelength-selective gene expression.

Synthesis and Applications of Carbohydrate-Based Organocatalysts.

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed in benign solvents and do not require anhydrous conditions. It is well-known that most of the above-mentioned reactions are promoted by a simple aminoacid, l-proline, or, to a lesser extent, by the more complex cinchona alkaloids. However, during the past three decades, other enantiopure natural compounds, the carbohydrates, have been employed as organocatalysts. In the present exhaustive review, the detailed preparation of all the sugar-based organocatalysts as well as their catalytic properties are described.

Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.

This article describes studies on the regioselective acetal protection of monosaccharide-based diols using chiral phosphoric acids (CPAs) and their immobilized polymeric variants, (R)-Ad-TRIP-PS and (S)-SPINOL-PS, as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various d-glucose-, d-galactose-, d-mannose-, and l-fucose-derived 1,2-diols and could be carried out in a regiodivergent fashion depending on the choice of chiral catalyst. The polymeric catalysts were conveniently recycled and reused multiple times for gram-scale functionalizations with catalytic loadings as low as 0.1 mol %, and their performance was often found to be superior to the performance of their monomeric variants. These regioselective CPA-catalyzed acetalizations were successfully combined with common hydroxyl group functionalizations as single-pot telescoped procedures to produce 32 regioisomerically pure differentially protected mono- and disaccharide derivatives. To further demonstrate the utility of the polymeric catalysts, the same batch of (R)-Ad-TRIP-PS catalyst was recycled and reused to accomplish single-pot gram-scale syntheses of 6 differentially protected d-glucose derivatives. The subsequent exploration of the reaction mechanism using NMR studies of deuterated and nondeuterated substrates revealed that low-temperature acetalizations happen via a syn-addition mechanism and that the reaction regioselectivity exhibits strong dependence on the temperature. The computational studies indicate a complex temperature-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and another via concerted asynchronous formation of an acetal, that results in syn-addition products. The computational models also explain the steric factors responsible for the observed C2 selectivities and are consistent with experimentally observed selectivity trends.

Nucleophilic substitution at the anomeric position of furanose carbohydrates. The case of the C-allylations.

Taking advantage of the locked conformation of cyclic furanose form, carbohydrate derivatives have been transformed into relevant tetrahydrofuran moieties through a chemical operation commonly known as C-glycosylation reaction. Consequently, a large number of total synthesis of naturally occurring products containing this heterocycle have been accomplished by applying this reaction. In this regard, the C-allylation reaction of furanose carbohydrates provides flexible routes for stereoselective anomeric functionalization by incorporating an allyl group, which is eventually re-functionalized into advanced natural product intermediates. Therefore, this mini review deals with the description of the origin of the stereoselectivity and synthetic applications of this type of glycosylation reaction, which can be also called as: "Nucleophilic Substitution at the Anomeric Position", conducted by various research groups including our own group.

Recent advances in (chemo)enzymatic cascades for upgrading bio-based resources.

Developing (chemo)enzymatic cascades is very attractive for green synthesis, because they streamline multistep synthetic processes. In this Feature Article, we have summarized the recent advances in in vitro or whole-cell cascade reactions with a focus on the use of renewable bio-based resources as starting materials. This includes the synthesis of rare sugars (such as ketoses, L-ribulose, D-tagatose, myo-inositol or aminosugars) from readily available carbohydrate sources (cellulose, hemi-cellulose, starch), in vitro enzyme pathways to convert glucose to various biochemicals, cascades to convert 5-hydroxymethylfurfural and furfural obtained from lignin or xylose into novel precursors for polymer synthesis, the syntheses of phenolic compounds, cascade syntheses of aliphatic and highly reduced chemicals from plant oils and fatty acids, upgrading of glycerol or ethanol as well as cascades to transform natural L-amino acids into high-value (chiral) compounds. In several examples these processes have demonstrated their efficiency with respect to high space-time yields and low E-factors enabling mature green chemistry processes. Also, the strengths and limitations are discussed and an outlook is provided for improving the existing and developing new cascades.

Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity.

NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α, as an interesting hit exhibiting significant NK1R antagonist effect (kinact 0.209 ± 0.103 µM) and high binding affinity for NK1R (IC50 = 50.4 nM, Ki = 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.

Novel carbohydrate-based sulfonamide derivatives as selective carbonic anhydrase II inhibitors: Synthesis, biological and molecular docking analysis.

A series of sulfonamides containing glucosamine moieties had been prepared and investigated for the inhibition of the zinc enzyme carbonic anhydrases (CAs, EC 4.2.1.1). Compared to their parent compound p-sulfamoylbenzoic acid, target compounds showed two order of magnitude improvement in their binding affinities against hCA II in vitro. Moreover, they also showed great selectivity toward hCA II enzyme with the ratios for inhibiting hCA II over hCA I in the range 20-96 and for inhibiting hCA II over hCA IX in the range 4.3-9. Due to the introduction of glucosamine moieties, all of compounds displayed good water solubility (in the range of 2.0-2.5%) and the pH values of the obtained solutions is neutral (7.0-7.2). Compared to the clinically available and relatively highly acidic dorzolamide (pH 5.5), target compounds are more likely to be less irritating to the eye when applied to topical glaucomatous drugs. Then, cytotoxicity evaluation suggested that all target compounds did not display any appreciable toxicity against human cornea epithelial cell. In addition, molecular docking studies elucidated the binding modes of those compounds toward hCA II. Collectively, these results suggest that target compounds represented a promising scaffold to treat glaucoma without major topical side effects.

Bismuth(iii) triflate as a novel and efficient activator for glycosyl halides.

Presented herein is the discovery that bismuth(iii) trifluoromethanesulfonate (Bi(OTf)3) is an effective catalyst for the activation of glycosyl bromides and glycosyl chlorides. The key objective for the development of this methodology is to employ only one promoter in the lowest possible amount and to avoid using any additive/co-catalyst/acid scavenger except molecular sieves. Bi(OTf)3 works well in promoting the glycosidation of differentially protected glucosyl, galactosyl, and mannosyl halides with many classes of glycosyl acceptors. Most reactions complete within 1 h in the presence of only 35% of green and light-stable Bi(OTf)3 catalyst.

En Route to the Transformation of Glycoscience: A Chemist's Perspective on Internal and External Crossroads in Glycochemistry.

Carbohydrate chemistry is an essential component of the glycosciences and is fundamental to their progress. This Perspective takes the position that carbohydrate chemistry, or glycochemistry, has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author's and other laboratories. The first of these potential inflexion points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the experimental evidence supports bimolecular SN2-like mechanisms for typical glycosylation reactions over unimolecular ones involving stereoselective attack on naked glycosyl oxocarbenium ions. Similarly, it is argued that the experimental evidence does not support long-range stereodirecting participation of remote esters through bridged bicyclic dioxacarbenium ions in organic solution in the presence of typical counterions. Rational design and improvement of glycosylation reactions must take into account the roles of the counterion and of concentration. A second crossroads is that between mainstream organic chemistry and glycan synthesis. The case is made that the only real difference between glycan and organic synthesis is the formation of C-O rather than C-C bonds, with diastereocontrol, strategy, tactics, and elegance being of critical importance in both areas: mainstream organic chemists should feel comfortable taking this fork in the road, just as carbohydrate chemists should traveling in the opposite direction. A third crossroads is that between carbohydrate chemistry and medicinal chemistry, where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the past decade or so, but creativity, input, and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.

Temporary ether protecting groups at the anomeric center in complex carbohydrate synthesis.

The synthesis of a carbohydrate building block usually starts with introduction of a temporary protecting group at the anomeric center and ends with its selective cleavage for further transformation. Thus, the choice of the anomeric temporary protecting group must be carefully considered because it should retain intact during the whole synthetic manipulation, and it should be chemoselectively removable without affecting other functional groups at a late stage in the synthesis. Etherate groups are the most widely used temporary protecting groups at the anomeric center, generally including allyl ethers, MP (p-methoxyphenyl) ethers, benzyl ethers, PMB (p-methoxybenzyl) eithers, and silyl ethers. This chapter provides a comprehensive review on their formation, cleavage, and applications in the synthesis of complex carbohydrates.

The scientific legacy of Frieder W. Lichtenthaler.

This article presents a selection of topics from Professor Frieder W. Lichtenthaler's scientific lifework. It describes his contributions to, and further development of, the nitromethane cyclization of dialdehydes leading to amino sugars and amino nucleosides, as well as a new coupling methodology for purine nucleosides. A number of chiral building blocks derived from sugars like the "sugar enolones," enollactones, hydroxyhexenals, and their synthetic applications in natural product syntheses are covered. The article further describes the chemistry of "ulosyl bromides" and their glycosidation reactions, including those with bifunctional acceptors, which led to the synthesis of spectinomycin and gomphoside. Lichtenthaler's work on the preparation of synthetically useful building blocks from disaccharides that are readily available in bulk quantities, and his studies on the reactivity, as well as the selective O-functionalization of sucrose, higher oligosaccharides, and cyclodextrins based on computer simulations, are highlighted. The article also presents his research on the syntheses of chiral building blocks from readily available ketoses and their synthetic applications. Finally the chapter concludes with his significant contributions in the field of the history of carbohydrate chemistry.

Design, synthesis and biological evaluation of novel carbohydrate-based sulfonamide derivatives as antitumor agents.

A series of novel carbohydrate-based sulfonamides were designed and synthesized by the sugar-tail approach. The classical aromatic sulfonamide pharmacophore (ArSO2NH2) was directly linked to a hydrophilic sugar-tail moiety through a rigid 1, 2, 3-triazole linker by the click chemistry reaction. The inhibitory activity against three carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I, hCA II and hCA IX) of all new compounds so designed were investigated in vitro and efficient inhibition against all three CA isoforms, especially the tumor-associated hCA IX, were observed. These glycoconjugate sulfonamide derivatives displayed better inhibitory efficacy in comparison with the starting segments (SA and p-hydroxybenzene sulfonamide). In particular, compound 12g was found to be the most effective and rather selective inhibitor of hCA IX with inhibitory constant (IC50) value of 7 nM, being four times more potent than the clinical used agent acetazolamide (AAZ) (IC50 = 30 nM). Meanwhile, almost all compounds showed moderate antiproliferative activities against two cancer cell lines (HT-29 and MDA-MB-231) in both hypoxic and normoxic conditions while compound 12g also exhibited the most prominent antitumor activity. Furthermore, evident recovery (20-35% reduction of IC50 values) of cytotoxic efficiency of doxorubicin with the combination of compounds 12d, 12g and 22d as CAIs were detected on MDA-MB-231 cell line under hypoxic environment. In addition, docking studies revealed that the sugar-tail fragment of the target compounds participated in interactions with hydrophilic subpocket at the surface of hCA IX active site and supported the CA IX inhibitory activities of carbohydrate-based sulfonamide derivatives.

A single-step preparation of carbohydrate functionalized monoliths for separation and trapping of polar compounds.

A single-step copolymerization strategy was developed for the preparation of carbohydrate (glucose and maltose) functionalized monoliths using click reaction. Firstly, novel carbohydrate-functionalized methacrylate monomers were synthesized through Cu(I)-catalyzed 1,3-dipolar cycloaddition (alkyne-azide reaction) of terminal alkyne with azide of carbohydrate derivatives. The corresponding carbohydrate functionalized monolithic columns were then prepared through a single-step in-situ copolymerization. The physicochemical properties and performance of the fabricated monolithic columns were evaluated using scanning electron microscopy, Fourier-transform infrared spectroscopy, and nano-liquid chromatography. For the optimized monolithic column, satisfactory column permeability and good separation performance were demonstrated for polar compounds including nucleoside, phenolic compounds and benzoic acid derivatives. The monolithic column is also highly useful for selective and efficient enrichment of glycopeptides from human IgG tryptic digests. This study not only provided a novel hydrophilic column for separation and selective trapping of polar compounds, but also proposed a facile and efficient approach for preparing carbohydrate functionalized monoliths.

A light- and heat-driven glycal diazidation approach to nitrogenous carbohydrate derivatives with antiviral activity.

The aminated mimetics of 2-keto-3-deoxy-sugar acids such as the anti-influenza clinical drugs oseltamivir (Tamiflu) and zanamivir (Relenza) are important bioactive molecules. Development of synthetic methodologies for accessing such compound collections is highly desirable. Herein, we describe a simple, catalyst-free glycal diazidation protocol enabled by visible light-driven conditions. This new method requires neither acid promoters nor transition-metal catalysts and takes place at ambient temperature within 1-2 hours. Notably, the desired transformations could be promoted by thermal conditions as well, albeit with lower efficacy compared to the light-induced conditions. Different sugar acid-derived glycal templates have been converted into a range of 2,3-diazido carbohydrate analogs by harnessing this mild and scalable approach, leading to the discovery of new antiviral agents.

The synthesis of non-structural carbohydrates under the network security model.

In order to explore the pathway of non-structural carbohydrate synthesis, an analysis of the pathway of non-structural carbohydrate synthesis under the network security model was proposed. Taking non-structural carbohydrates as the research object, the experimental materials and equipment were selected under the network security model. Through the establishment of detection methods, the preparation of freeze-dried carbohydrates, the influence of synthesis pathway-specific inhibitors on the synthesis of non-structural carbohydrates, the influence of precursors and intermediates in the pathway on the synthesis of non-structural carbohydrates, the effect of multiple factors on the synthesis of non-structural carbohydrates, the influence of polysaccharide synthesis, the treatment of reaction solution for detection, the preparation of detection sample, the detection conditions of a liquid phase, the detection conditions of LC-MS and the determination of carbohydrate biomass were studied. The results showed that the synthesis of nonstructural carbohydrates requires the participation of the glycolysis, shikimic acid and phenylpropane pathways, but not the polyketone pathway.

Impact of bagasse lignin-carbohydrate complexes structural changes on cellulase adsorption behavior.

Pretreatment technology has attracted much attention as an effective method for the conversion of sugarcane bagasse into biochemicals. However, residual lignin-carbohydrate complexes (LCC) can negatively impact the subsequent enzymatic hydrolysis of bagasse. In this work, the changes in bagasse LCC after pretreatment with hot water and dilute acid were characterized by component analysis, 13C NMR and 1H-13C HSQC NMR to reveal the correlation between LCC structure and cellulase adsorption. A real-time dynamic model of LCC affecting adsorption of cellulase was constructed using a quartz crystal microbalance (QCM-D). The QCM-D results demonstrated that cellulase exhibited different adsorption characteristics on different LCCs. For example, the maximum adsorption capacities for cellulase onto the raw material LCC (RW-LCC), hot water pretreated LCC (LHW-LCC), and dilute acid pretreated LCC (AP-LCC) at 4 °C were 29.0 ng/cm2, 94.9 ng/cm2 and 129.8 ng/cm2, respectively. In addition, the adsorption rate constants for cellulase on RM-LCC, LHW-LCC and AP-LCC at 4 °C were 0.09, 0.14 and 0.19, respectively.