Glycosyl Azides Research Articles

Access to Reverse Glycosyl Azides and Rare Sugar-Based Glycosyl Azides via Radical Decarboxylative Azidation: Divergent Synthesis of 4'-C-Azidonucleosides as Potential Antiviral Agents.

The radical decarboxylative azidation of structurally diverse uronic acids has been established as an efficient approach to reverse glycosyl azides and rare sugar-derived glycosyl azides under the action of Ag2CO3, 3-pyridinesulfonyl azide, and K2S2O8. The power of this method has been highlighted by the divergent synthesis of 4'-C-azidonucleosides using Vorbrüggen glycosylation of nucleobases with 4-C-azidofuranosyl acetates. The antiviral assessment of the resulting nucleosides revealed one compound as a potential inhibitor of covalently closed circular DNA.

Synthesis of Novel Propynyl Monoterpene Analogues and their Conjugates with β-DGlucopyranosides

Abstract: Camphor and carvone exhibit a broad spectrum of biological activity, which determines the prospect of their use as a platform for functionalization to obtain the analogues as potential drugs. The functionalization of camphor and carvone often involves changes to the skeleton of the molecules or their fragmentation. Therefore, in modern medicinal chemistry, research aimed at the development of effective approaches to the synthesis of semisynthetic derivatives of camphor and carvone with preservation of the native framework, demonstrating high biological activity, is in demand. The present work is aimed at the synthesis of new propynyl analogues of camphor and carvone, as well as their conjugates with mono- and disaccharides via Cu-catalyzed cycloaddition of acetylenes and azides (Cu- AAC). Alkylation of camphor and carvone with propargyl bromide in the presence of the base KN(SiMe3)2–Et3B in 1,2-dimethoxyethane (DME) at room temperature provides the target products with yields of 69% and 47%, respectively. Glycosyl azides were obtained by the reaction of peracetylated sugars with trimethylsilyl azide in the presence of SnCl4.The synthesis of 1,2,3-triazolyl glycoconjugates of camphor and carvone with mono- and disaccharides was carried out through Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides to acetylenes (CuAAC) in the presence of Cu and CuSO4·5H2O. The structures of the synthesized compounds were determined by NMR. The new propynyl-substituted camphor and carvone, as well as their 1,2,3- triazolylglycoconjugates, can be used as promising building blocks for medicine chemistry.

Synthesis of N-glycosyl amides: conformational analysis and evaluation as inhibitors of β-galactosidase from E. coli.

The synthesis of N-glycosyl amides typically involves the use of glycosyl amines as direct precursors, resulting in low yields due to hydrolysis and the loss of stereocontrol through anomerization processes. In this study, a sequential synthesis of N-glycosyl amides is proposed, employing glycosyl amines as intermediates obtained from glycosyl azides. Derivatives with gluco, galacto, or xylo configurations were synthesized. Hexose derivatives were obtained under stereocontrol to give only the β anomer, while the xylo derivatives provided a mixture of α and β anomers. Conformational analysis revealed that all β anomers adopted the 4C1 conformation, while α anomers were found in the 1C4 chair as the major conformer. After de-O-acetylation, the derivatives containing a galactose unit were evaluated as inhibitors of β-galactosidase from E. coli and were found to be moderate inhibitors.

Synthesis and chiroptical properties of β‐1,2‐linked glycopolymers prepared by click polymerization

AbstractThis article describes the design, synthesis, and folding behaviors of β‐1,2‐linked glycopolymers as a bioconjugate‐based foldamer. The synthesis of alkyne‐containing β‐glycosyl azides has been achieved via anomeric substitution using tetrabutylammonium azide (Bu4NN3) to 1,2‐anhydro sugar and subsequent esterification with 5‐hexynoic acid. Copper‐catalyzed alkyne‐azide 1,3‐dipolar cycloaddition of the glycosyl azide leads to the formation of β‐1,2‐linked glycopolymer alternating 4‐triazolyl butanoate and tribenzylated d‐galactose (PolyGal) or d‐glucose unit (PolyGlu). The folding and chiroptical properties of the polymers are discussed through UV–vis and CD spectroscopy and anisotropic factors of CD (gCD) values. The results suggest that PolyGal would adopt a helically folded structure in ClCH2CH2Cl (DCE) or THF. Thermal stability of the folded structure of PolyGal in less polar DCE appears to increase compared with that in THF. It is found that the folded structure of PolyGal in THF denatures to a random coil above 40°C. It is indicated that PolyGlu can possibly form the helically folded structure in DCE and adopt a random coil structure at high temperature region. In polar THF, PolyGlu does not fold the conformation at all the observed temperature region. Such phenomena suggest a special role of stereochemistry at the 4 position on the folding behaviors.

Relevant Advances in the Synthesis and Applications of N‐Glycopyranosides

AbstractN‐glycosides are produced when an aglycone is connected, for example, using a glycosylation reaction, to the sugar moiety via linkage of C−N bond at anomeric carbon. N‐glycosides are obtained from different precursors, including glucals, 1‐azido glycosides, glycosyl azide, glycosyl isothiocyanate, 2‐deoxy‐2‐iodo‐N‐glycoside, glycosyl‐1H‐1,2,3‐triazol, and 2‐nitroglucal. The biological relevance of N‐glycopyranosides has drowned attracted the attention of several researchers. The scope of this review covers the literature from 2010 to 2022. Recent advances focused on the natural occurrence, synthesis, mechanism, and pharmacological applications of N‐glycopyranosides are discussed.

Organocatalyzed Regioselective Synthesis of 1,5-Disubstituted 1,2,3-Triazolyl Glycoconjugates.

A novel organocatalyzed [3+2] cycloaddition reaction of nitroolefins with glycosyl azides as well as organic azides has been developed for successful construction of 1,5-disubstituted triazolyl glycoconjugates. This metal-free and acid-free, regioselective synthetic protocol proceeds in the presence of only Schreiner thiourea organocatalysts, which enable the required activation of nitroolefins through double hydrogen bonding. The straightforward, operationally simple, and regioselectivity of this methodology, complementing to the classical RuAAC catalyzed synthesis of 1,5-disubstituted 1,2,3-triazoles. In the presence of catalytic amount of Schreiner thiourea organocatalyst, organic azides react with a broad array of nitroolefins producing a series of diverse 1,5-disubstituted 1,2,3- triazoles in good yields with excellent regioselectivity.

Stereoselective synthesis of glycosyl azides from anomeric hydroxides via protecting group manipulations

Herein, we report the direct conversion of anomeric hydroxides to glycosyl azides in one step using diphenylphosphoryl azide. Protecting group manipulations on the hexose sugars have enabled the stereoselective synthesis of either the α-glycosyl azides or the β-anomeric azides in moderate to very good yields. The reaction has also been successfully used to enable the synthesis of β-2-deoxy-2-aminoglucosyl azides.

One-Pot Synthesis of 2-C-Branched Glycosyl Triazoles by Integrating 1,2-Cyclopropanated Sugar Ring-Opening Azidation and CuAAC Reaction.

A series of 2-C-branched glycosyl triazoles including triazole-tethered oligosaccharides and glycopeptides were synthesized in one pot from 1,2-cyclopropanated sugars or 2'-acetonyl-2-O-Ts-C-furanosides, NaN3, and alkynes using PEG-400 as a single solvent. Nucleophilic ring-opening azidation of 1,2-cyclopropanated sugars (or 2'-acetonyl group 1,2-migration-azidation of C-furanosides) obtained glycosyl azides, which upon reaction with alkynes under CuAAC conditions achieved glycosyl triazoles in good yields and high stereoselectivity without the need to change the solvent and isolate any intermediates.

Pyridyl Glycosyl Triazole/CuI-Mediated Domino/Tandem Synthesis of Quinazolinones.

The glycosyl 1,2,3-triazoles are expediently accessible from readily available sugar-derived glycosyl azide by utilizing modular CuAAC "Click Chemistry", and the resulting glycohybrid skeleton possesses efficient metal-coordinating centers that support a wide range of metal-mediated efficient catalysis in various imperative organic transformations. Here, we designed and developed pyridyl glycosyl triazoles by employing the CuAAC reaction of d-glucose-derived glycosyl azides and alkynyl pyridines. These pyridyl glycosyl triazoles with Cu(I) salt were explored as an efficient catalyst to successfully assemble 2-amino-3-substituted and 3-substituted quinazolinones by the domino/tandem cross-coupling reaction of various N-substituted o-halobenzamides with cyanamide and formamide, respectively. The devised protocol has some notable features, including biocompatibility, low cost, easily accessible starting materials for the glycosyl ligands, high yield, broad spectrum, low catalytic loading, and mild reaction conditions.

Synthesis and anti-inflammatory effects of Δ7-Cholestenol and Δ8(14)-Cholestenol derivatives

In this study, O-glycosides of cholesterol derivatives Δ7-cholestenol and Δ8(14)-cholestenol were prepared by Schmidt glycosylation with various glycosyl imidates. In addition, 1,2,3-triazole-linked N-glycosides of Δ8(14)-cholestenol were prepared via the “click” reaction of proparzylic Δ8(14)-cholestenol with glycosyl azides. The anti-inflammatory activities of these molecules were investigated for inhibitory mRNA expression activity of CCL17 and CCL22, which are important biomarkers of atopic dermatitis. Both the O- and N-glycosides Δ7-cholestenol and Δ8(14)-cholestenol were observed to exhibit good anti-inflammatory activity in vitro. In particular, the 1,2,3-triazole-linked N-glycoside of Δ8(14)-cholestenol exhibited anti-inflammatory activity similar to that of O-glycoside in vitro and is expected to be more potent in vivo due to better stability.

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

Click-Chemistry-Based Free Azide versus Azido Sugar Detection Enables Rapid In Vivo Screening of Glycosynthase Activity.

Engineering of carbohydrate-active enzymes such as glycosynthases to enable chemoenzymatic synthesis of bespoke oligosaccharides has been limited by the lack of suitable ultrahigh-throughput screening methods capable of robustly detecting either starting substrates or end-products of the glycosidic bond formation reaction. Currently, there are limited screening methods available for rapid and highly sensitive single-cell-based screening of glycosynthase enzymes employing azido sugars as activated donor glycosyl substrates. Here, we report a fluorescence-based approach employing click-chemistry for the selective detection of glycosyl azides as substrates versus free inorganic azides as reaction products that facilitated an ultrahigh-throughput in vivo single-cell-based assay of glycosynthase activity. This assay was developed based on the distinct differences observed in relative fluorescence intensity of the triazole-containing fluorophore product formed during the click-chemistry reaction of organic glycosyl azides versus inorganic azides. This discovery formed the basis for proof of concept validation of a directed evolution methodology for screening and sorting glycosynthase mutants capable of synthesis of targeted fucosylated oligosaccharides. Our screening approach facilitated fluorescence-activated cell sorting of an error-prone polymerase chain reaction-based mutant library of fucosynthases expressed in Escherichia coli to identify several novel mutants that showed increased activity for β-fucosyl azide-activated donor sugars toward desired acceptor sugars (e.g., pNP-xylose and lactose). Finally, we discuss avenues for improving this proof of concept in vivo assay method to identify better glycosynthase mutants and further demonstrate the broader applicability of this screening methodology for synthesis of bespoke glycans.

Synthesis of biologically important 4‐Phenyl‐C‐glycosyl‐1,2,3‐triazole derivatives by Cu(I)‐catalyzed azide–alkyne cycloaddition

AbstractA new series of 4‐phenyl‐C‐glycosyl‐1,2,3‐triazoles were synthesized using Cu(I)‐ catalyzed azide–alkyne cycloaddition. The key step in the synthesis involved the coupling of unprotected glycosyl azides with substituted C‐glycosylated phenyl acetylenes. Using o‐phenylenediamine as a ligand, we could significantly reduce the reaction time, improve the product yield, and simplify the purification process. Broad substrate scope in terms of sugars was achieved.

Synthesis and evaluation of porphyrin glycoconjugates varying in linker length: preliminary effects on the photodynamic inactivation of Mycobacterium smegmatis.

Porphyrins have served as common photosensitizing agents in photomedicine due to their unique properties and broad therapeutic potential. While photodynamic therapy (PDT) offers a promising avenue for novel drug development, limitations in application due to selectivity, and the inherent hydrophobicity and poor solubility of porphyrins and other organic photosensitizers has been noted. Porphyrin glycoconjugates have recently gained attention for their potential to overcome these limitations. However, little has been done to explore the effects of the linker between the carbohydrate and porphyrin analog. Here we report the synthesis of over 30 new carbohydrate–porphyrin conjugates which vary in the nature of the sugar (Gal, Glc, GalNAc, GlcNAc, Lac and Tre) and the distance between the porphyrin macrocycle and the carbohydrate. Porphyrin glycoconjugates were synthesized in three steps from a readily available meso-brominated diphenylporphyrin analog by (i) C–O coupling of an appropriate TMS-protected alkynol consisting of two to six carbon spacers (ii) removal of the TMS protecting group, and (iii) CuAAC conjugation with an appropriate glycosyl azide. First studies with trehalose-based glycoporphyrins and M. smeg were used to determine the effects of the linker in photodynamic inactivation (PDI) studies. Preliminary results demonstrated an increase in photodynamic inactivation with a decrease in linker length. Investigations are underway to determine the mechanism for these results.

An Overview on the ChemicalN‐Functionalization of Sugars and Formation ofN‐Glycosides

Its even more than a centennial that the systematic researches of chemical alteration of sugars have been advancing. Out of all the interest in the field ofN‐glycoside has assembled pace over the past few years. Therefore,N‐functionalization of sugar is one of the most fundamental modifications along with other group like azide, amide etc also play a remarkable role in the field of glycoscience. Different approaches to access structurally modifiedN‐glycosides in carbohydrate derivatives are reviewed. The goal of this review is to provide an overview of different way ofN‐functionalization of amino sugar and induction of nitrogen scaffolds for the synthesis of various orthogonal protective groups of theN‐glycoside. TheN‐functionalization of sugars designate as follows: (a) glycosylamine, (b) glycosyl azide, and (c) introduction ofN‐functionality to the sugar for formation ofN‐glycosides. This is the first review focus onN‐functionalization of sugars which will be a future scope that influence the readers to work in this area further.

Design, Synthesis and Anticancer Activity of New Thiazole-Tetrazole or Triazole Hybrid Glycosides Targeting CDK-2 via Structure-Based Virtual Screening.

The target tetrazole glycosides were synthesized by construction of ring system by cycloaddition reaction of benzothiazole-linked nitrile derivative and sodium azide followed by N-glycosylation process and deprotection. The triazole glycosides were prepared by applying click approach involving dipolar cycloaddition of benzothiazole possessing alkyne functionality and different glycosyl azides. The products incorporating acyclic analogs of sugar moieties were synthesized through alkylation using acyclic oxygenated halides. The anticancer activity was studied against human breast adenocarcinoma cells (MCF-7) and human normal Retina pigmented epithelium cells (RPE-1). High activities were revealed by three compounds with IC50 values 11.9-16.5 µM compared to doxorubicin (18.6 µM) in addition to other four derivatives with good inhibition activities. Enzyme docking investigation was performed into cyclin-dependent kinase 2 (CDK2); a potential target for cancer medication. Compounds which have possessed highest activities revealed good fitting inside the binding site of the protein molecular surface and showed minimum binding energy.

Organocatalyzed preparation of 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives.

Organocatalytic coupling of glycosyl azides with enolates of active ketones and esters through azide-enolate [3 + 2] cycloaddition in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives in excellent yield. The reaction condition is simple and can be scaled-up. Graphical abstract Coupling of glycosyl azides with active ketones through azide-enolate [3 + 2] cycloaddition in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) furnished 1,4,5-trisubstituted-glycosyl-1,2,3-triazole derivatives in excellent yield.

Sugar Composition in Asparagus Spears and Its Relationship to Soil Chemical Properties.

Glycoside hydrolases require carboxyl groups as catalysts for their activity. A retaining xylanase from Streptomyces olivaceoviridis E-86 belonging to glycoside hydrolase family 10 possesses Glu128 and Glu236 that respectively function as acid/base and nucleophile. We previously developed a unique mutant of the retaining xylanase, N127S/E128H, whose deglycosylation is triggered by azide. A crystallographic study reported that the transient formation of a Ser–His catalytic dyad in the reaction cycle possibly reduced the azidolysis reaction. In the present study, we engineered a catalytic dyad with enhanced stability by site-directed mutagenesis and crystallographic study of N127S/E128H. Comparison of the Michaelis complexes of N127S/E128H with pNP-X2 and with xylopentaose showed that Ser127 could form an alternative hydrogen bond with Thr82, which disrupts the formation of the Ser–His catalytic dyad. The introduction of T82A mutation in N127S/E128H produces an enhanced first-order rate constant (6 times that of N127S/E128H). We confirmed the presence of a stable Ser–His hydrogen bond in the Michaelis complex of the triple mutant, which forms the productive tautomer of His128 that acts as an acid catalyst. Because the glycosyl azide is applicable in the bioconjugation of glycans by using click chemistry, the enzyme-assisted production of the glycosyl azide may contribute to the field of glycobiology.

Bivalent glycoconjugates based on 1,5-diazabicyclo[3.3.0]octa-3,6-diene-2,8-dione (“bimane”) as a central scaffold

The heteroaromatic fused diazabicyclic “bimane” ring system, discovered four decades ago, is endowed with remarkable chemical and photophysical properties. No carbohydrate derivatives of bimanes have, however, been described thus far. Here we report on the syntheses of a range of bimanes decorated with various glycosyl residues. Mono- and disaccharide residues were attached to syn- or anti-bimane central cores via thio-, disulfido- or selenoglycosidic linkages to obtain novel fluorescent or nonfluorescent glycoconjugates. Cu(I)-catalyzed cycloaddition of glycosyl azides to a bimane diethynyl derivative furnished further bivalent glycoconjugates with sugar residues linked to the central bimane core via 1,2,3-triazole rings. We have determined the crystal and molecular structures of several glycosylated and non-glycosylated bimanes and report fluorescence data for the new compounds.

Chemistry of 1,2-Anhydro Sugars.

The 1,2-anhydro sugars are a class of valuable and versatile intermediates in carbohydrate chemistry. In the first part of this article, a review is given on preparation methods of 1,2-anhydro sugars that are suitably protected. Protected 1,2-anhydro sugars have been widely used as glycosyl donors for the synthesis of glycosyl compounds such as oligosaccharides and nucleosides. In the second part, a brief history and the chemistry of unprotected 1,2-anhydro sugars is described. In the past few years, our research group has developed protection-free methods for synthesis of glycosyl compounds through unprotected 1,2-anhydro sugars as reactive intermediates based on the concept of 'direct anomeric activation'. In this article, the one-step preparation of glycosyl compounds such as thioglycoside derivatives and glycosyl azides by using formamidinium-type dehydrating agents is presented. Furthermore, the initial results on the first detection of unprotected 1,2-anhydro sugar intermediates by NMR measurements are shown along with their full structure characterizations.