Unprotected Sugars Research Articles

Design of Knölker‐Type Catalysts for the Anomeric Oxidation of Unprotected Mono‐ and Disaccharides

AbstractKnölker complexes have been recently used to perform the catalytic C1‐oxidation of unprotected sugars into sugar lactones. This oxidation method remained limited by the stability of the catalyst with the polyhydroxylated substrates. Our objective is now to overcome these limitations and extend this method to more challenging substrates such as disaccharides. We proposed in this paper two original designs of Knölker‐type complexes conceived to promote secondary H‐bond interactions with the OH groups of the substrates to stabilise the system and favour the transformation. In total, 8 novel pre‐catalysts were synthesised, fully characterised and applied in the anomeric oxidation of several sugar derivatives. Two of these new complexes proved to be more efficient than the Knölker complex for the oxidation of disaccharides. Moreover, a preliminary DFT study revealed the presence of H‐bonds interactions between the substrate and the oxygen atom on the ligand arm of the best complexes suggesting a beneficial role of this heteroatom on the catalytic efficiency.

Site-Selective Palladium-catalyzed Oxidation of Unprotected Aminoglycosides and Sugar Phosphates.

The site-selective modification of complex biomolecules by transition metal-catalysis is highly warranted, but often thwarted by the presence of Lewis basic functional groups. This study demonstrates that protonation of amines and phosphates in carbohydrates circumvents catalyst inhibition in palladium-catalyzed site-selective oxidation. Both aminoglycosides and sugar phosphates, compound classes that up till now largely escaped direct modification, are oxidized with good efficiency. Site-selective oxidation of kanamycin and amikacin was used to prepare a set of 3'-modified aminoglycoside derivatives of which two showed promising activity against antibiotic-resistant E. coli strains.

Synthesis of 3-arylamino-2-polyhydroxyalkyl-substituted indoles from unprotected saccharides and anilines

A simple and efficient one-pot synthetic protocol has been developed for the synthesis of structurally diverse indole derivatives by using unprotected sugars and aromatic amines.

Electrochemical nickel-catalyzed cross-coupling of glycosyl thiols with preactivated phenols and ketones.

An efficient electrochemical nickel-catalyzed cross-coupling reaction has been reported here for the synthesis of S-glycosides from preactivated phenols and ketones under mild conditions. Various glycosyl thiols, including unprotected sugar, and a diverse range of aryl/alkenyl triflates, including some complex biorelevant phenols and ketones, were well tolerated in this method.

Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

Site‐Selective Electrochemical Oxidation of Carbohydrates

AbstractThe site‐selective transformation of unprotected sugars poses significant challenges to synthetic chemists but comes with a reward of step‐economic and energy efficient protocols. By replacing stoichiometric oxidants with electricity, greener processes are anticipated. To date, mostly C3‐ and C6‐selective transformations have been developed urging for further developments. Herein, we call for action to synthetic chemists to tackle the associated challenges of site‐selective transformations of unprotected sugars toward challenging C2 and C4 regioisomers fueled by mild electroorganic transformations.

Stereoselective protecting-group-free synthesis of alkyl glycosides using dibenzyloxy triazine type glycosyl donors

Chemical O-glycosylation is a key step for the synthesis of sugar-containing molecules such as glycolipids. However, traditional carbohydrate chemistry is characterized by extensive use of protective groups, resulting in laborious manipulations and poor atom economy. Here, we present a protecting-group-free glycosylation strategy employing dibenzyloxy-1,3,5-triazin-2-yl glycosides (DBT-glycosides) as glycosyl donors. The DBT-glycosyl donors could be prepared directly through an alkaline nucleophilic substitution from unprotected sugars in aqueous media. The O-glycosylation of alcohols by using DBT-glycosyl donors has been carried out under mild hydrogenolytic conditions, affording the corresponding alkyl glycosides stereo-selectively in good yields.

Investigations into the Aqueous Synthesis of Selenoglycoconjugates

AbstractGlycosylation of bioactive molecules has been found to improve the pharmacokinetic properties of the parent molecule. However, their syntheses often require tedious protecting group manipulations. The development of methodologies which allow direct aqueous conversion of unprotected sugars into glycosides is therefore an ambitious goal. Herein, we present a broadly applicable method for the synthesis of selenoglycosides in water. We show the ease of direct conjugation of unprotected glycosyl diselenides with various biomolecules, including resorcinol, resveratrol, and the antitumor agent, gimeracil, furnishing the corresponding selenoglycoconjugates in up to 96 % yield. We also demonstrate the oxidatively‐triggered release of the bioactive drug from the sugar, priming these molecules for medicinal applications. The generality and broad substrate scope of this novel transformation will provide access to various selenium‐containing glycomimetics and glycoconjugates.

Regioselective and Stereospecific β-Arabinofuranosylation by Boron-Mediated Aglycon Delivery.

Regio- and stereoselective formation of the 1,2-cis-furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and β-stereospecific d-/l-arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding β-arabinofuranosides (β-Arbf) in high yields with complete β-stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted SN i mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments.

Regioselective and Stereospecific β‐Arabinofuranosylation by Boron‐Mediated Aglycon Delivery

AbstractRegio‐ and stereoselective formation of the 1,2‐cis‐furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and β‐stereospecific d‐/l‐arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding β‐arabinofuranosides (β‐Arbf) in high yields with complete β‐stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted SNi mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments.

Synthesis of pyranobenzopyrans from D-glucal using ionic liquids

Imidazolium room temperature ionic liquids (RTILs) were used as solvents in the Lewis acid-catalyzed cycloaddition reactions of D-glucal with substituted salicylaldehydes. These reactions selectively led to various, novel, cis-pyrano [4,3-b]benzopyrans in modest yields, different products than those isolated from analogous solution studies. Furan diol was isolated as the major byproduct from all the reactions. The use of RTILs facilitated the use of unprotected sugars in these reactions.

The Development of DNA-Compatible S-Glycosyl Transformations.

In this study, we revealed two distinct S-glycosyl transformations in a DNA-encoded library (DEL)-compatible environment. The first approach involves 2-chloro-1,3-dimethylimidazolidinium chloride (DMC)-mediated S-glycosylation, which is facilitated by the coupling of unprotected sugar units with the thiol residue of the DNA-linked compounds. However, this methodology falls short of the requirement for DEL construction due to its limited substrate scope. We further investigated a photoinduced DNA-compatible S-glycosyl transformation through a radical process. In this alternative approach, allyl sugar sulfones serve as sugar donors and are conjugated to DNA-linked compounds upon irradiation with green light. Encouragingly, this on-DNA glycosyl chemistry demonstrated excellent compatibility with functional groups presented in both sugar units and peptides, affording the desired DNA-linked glycosyl derivatives with good to excellent conversions. This pioneering DNA-compatible S-glycosyl transformation represents a valuable tool, facilitating the preparation of glycosyl DELs and offering avenues for the exploration of sugar-incorporated delivery systems.

Synthesis and Nuclear Magnetic Resonance Structural Evaluation of Oxime-Linked Oligosialic Acid-Based Glycodendrimers.

A series of four oxime-linked octavalent sialic acid and oligosialic acid poly(ether amidoamine) glycodendrimers were synthesized. In the attachment of the sialic acids to the dendrimer core, chemoselective oxime bonds were formed between the unprotected sugars (sialic acid or α-2,8-linked di- through tetra-sialic acids) and the aminooxy-terminated dendrimer core in a microwave-mediated reaction, resulting in good to excellent yields (58-100%) of the fully functionalized octavalent glycodendrimers. Next, using a combination of 1D and 2D nuclear magnetic resonance and working from the inside outward, we employed a systematic method to assign the proton and carbon signals starting with the smallest linkers and dendrimer cores and moving gradually up to the completed octavalent glycodendrimers. Through this approach, the assignment of the protons and carbons was possible, including the E- and Z-isomers related to the oxime dendrimer to sugar connections and relative quantities of each. These glycodendrimers were designed as broad-spectrum inhibitors of viral pathogens.

Selective Anomeric Acetylation of Unprotected Sugars with Acetic Anhydride in Water.

Unprotected sugars are selectively acetylated simply by stirring in aqueous solution in the presence of acetic anhydride and a weak base such as sodium carbonate. The reaction is selective for acetylation of the anomeric hydroxyl group of mannose, 2-acetamido, and 2-deoxy sugars and can be performed on a large scale. Competitive intramolecular migration of the 1-O-acetate to the 2-hydroxyl group when these two substituents are cis causes over-reaction and the formation of product mixtures.

Preparation, characterizations, and application of (MWCNTs)-COOH/Fe3O4-CaO hybrid as an effective magnetic catalyst for direct C-glycosylation reactions

Modification of acid-functionalized multiwalled carbon nanotubes (MWCNTs)-COOH with Fe3O4-CaO nanoparticles using FeSO4 and eggshell, produced an efficient magnetic catalyst for the synthesis of some C-glycosides. The condensation of dimedone with unprotected sugars in ethanol in the presence of a catalytic amount of (MWCNTs)-COOH/Fe3O4-CaO gave 3,4,5,6,7,9-hexahydro-1H-xanthene-1,8 (2H)-dione derivatives in good yields. The products were identified by CHN analysis, NMR, and FTIR spectra. Conversely, synthesis of Fe3O4-CaO nanoparticles and their conjugation on the surface of (MWCNTs)-COOH have been confirmed by FTIR, scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and energy-dispersive X-ray spectroscopy.

Glycosyl benzoates as novel substrates for glycosynthases.

The development of a procedure for the one-pot synthesis of glycosyl benzoates directly from unprotected sugars in aqueous media using 2-chloro-1,3-dimethylimidazolium chloride (DMC), thiobenzoic acid, and triethylamine is reported. These glycosyl donors are excellent substrates for wild-type and mutant glycosidases. β-Glucosyl benzoate was hydrolysed by the GH1 β-glucosidase derived from Halothermothrix orenii (HorGH1). Subsequent use of this substrate in thioligase-mediated glycosylation of p-nitrothiophenol demonstrated their superiority as donors compared to their p-nitrophenol counterparts with excellent conversions. Using a series of arene nucleophiles, we also demonstrate good to excellent conversions (up to 94%) of β-glucosyl benzoate to the corresponding p-nitrophenyl- and thioglycosides.

Selective One-Pot Cascade Synthesis of N-Substituted Highly Functionalized Pyrroles from Unprotected Sugars, Primary Amines, and Oxoacetonitriles.

A one-pot, three-component cascade reaction between unprotected sugars, primary amines, and 3-oxoacetonitriles gave N-substituted 2,3,5-functionalized pyrroles or N-substituted 2,3,4-functionalized pyrroles in excellent yields and selectivities. The selectivity of the reaction was achieved by simple control of the sequence of substrate addition. The reaction showed a wide substrate scope, and various types of sugars, primary amines, and oxoacetonitriles reacted smoothly. The work demonstrates a highly desired simple reaction for embedding nitrogen into sugars to produce valuable N-heterocyclic compounds that are amenable to further modifications to natural products and drug intermediates.

An Organometallic Gold(III) Reagent for 18F Labeling of Unprotected Peptides and Sugars in Aqueous Media.

The 18F labeling of unprotected peptides and sugars with a Au(III)-[18F]fluoroaryl complex is reported. The chemoselective method generates 18F-labeled S-aryl bioconjugates in an aqueous environment in 15 min with high radiochemical yields and displays excellent functional group tolerance. This approach utilizes an air and moisture stable, robust organometallic Au(III) complex and highlights the versatility of designer organometallic reagents as efficient agents for rapid radiolabeling.

Fast and Efficient Mechanosynthesis of Aldonamides by Aminolysis of Unprotected Sugar Lactones

Sugar amides, such as aldonamides, are interesting, sugar-based molecules used in various fields, from detergency to medicine. Nevertheless, their valorization, especially as alternatives to petroleum-based substances, can be slowed down by their synthetic pathway, which is generally not in accordance with green chemistry principles, and is also not economically competitive. We propose herein a fast procedure for the synthesis of aldonamide-derived glycoconjugates with mechanochemistry. The conditions were first optimized with galactonolactone, used as a model lactone, and dodecylamine. After only 5 min of grinding of stoechiometric amounts of amine and lactone, in the presence of water used as a Liquid Assisted Grinding (LAG) agent, the corresponding galactonamide was isolated with a high yield (90%) after a simple aqueous work-up. The optimized conditions were then applied to a wide variety of amines and sugar lactones, showing the versatility of the methodology. Gluco- and ribono-lactone exhibited similarly excellent reactivity, showing that the procedure is not sugar-dependent. Furthermore, the procedure was shown to be compatible with various functional groups such as alkene, alkyne, thiol, ester and hydroxyl.

Inverse-electron demand Diels Alder Reactions between glycals and tetrazines

The inverse-electron demand Diels Alder reaction (IEDDA) of substituted tetrazines with 2,3-unsaturated sugars (glycals) has been investigated to prepare novel carbohydrate-based heterocycles. The cycloaddition reactions occurred in moderate to good, isolated yields and gave acyclic, C-linked pyranose diazines as the major products (33–90%). The effects of variations in sugars, sugar protecting groups, and reaction solvents on the yields and products obtained in these reactions were studied. Lower yields of adducts were isolated for TBDMS-protected glucals and for 4,6-O-benzylidene protected glucals. When unprotected sugars were used, the reactions failed to give the desired cycloadducts. A range of substituted tetrazines were also evaluated in these reactions. For comparison, HOMO-[LUMO + 1] gaps for glycal-tetrazine pairs were calculated using Density Functional (DFT) calculations at the B3LYP/631G+ level.