Anomeric Oxygen Research Articles

Design and Synthesis of α-Anomeric Diacetylene-Containing Glycosides as Photopolymerizable Molecular Gelators.

Glycolipids with diacetylene functional groups are fascinating compounds with many practical uses. Among these, diacetylene-containing gelators are especially important because they can form photopolymerizable gels, which are useful stimuli-responsive materials. Inspired by the unique properties of diacetylene-containing gelators and to understand the structural influences especially the location of the diacetylene functional groups on the self-assembling properties, a series of 15 novel N-acetyl-d-glucosamine derivatives with the diacetylene functional group introduced at the anomeric position were designed and synthesized. The diacetylene function is attached to the sugar through α-glycosylation with the distance from the anomeric oxygen being varied from one, two, and three methylene groups, and the other side contains hydroxyl, carboxyl, phenyl, and alkyl substituents. Remarkably, all compounds can form self-assembled gels in one or more selected solvents. A majority of these synthesized diacetylene glycosides are effective gelators for ethanol/water (v/v 1:1), dimethyl sulfoxide/water (v/v 1:1), and toluene, and one compound also formed a hydrogel at 1.0 wt %. Typically, these glycosides form gels that are photopolymerizable to afford red-colored gels. Scanning electronic microscopy indicated that the gelators formed helices, fibers, and planar sheet-like morphologies. The chemical structures of the derivatives affected their gelation properties and responses to UV treatment. The carboxylic acid-functionalized derivative 17 was able to immobilize basic solutions and form transparent gels. We expect that these diacetylene glycosides especially the hydroxyl and carboxylic acid derivatives will be useful as stimuli-responsive glycolipids for biomedical research.

Glucosamine to gold nanoparticles binding studied using Raman spectroscopy

The binding of glucosamine to gold in water solutions of glucosamine hydrochloride mixed with clean colloidal gold nanoparticles obtained by laser ablation in liquid was studied using surface-enhanced Raman scattering (SERS), dynamic light scattering (DLS) and UV–VIS spectroscopy. The purpose of this study was to establish whether the binding of charged aminogroup to gold nanoparticles (AuNPs) is taking place, and if it does, how can it be identified by means of SERS.The average size of dried gold nanoparticles was (20 ± 4) nm determined by averaging the sizes observed in transmission electron microscopy micrographs, which is smaller than the average size of gold nanoparticles in water solution as determined by DLS: (52 ± 2) nm. Upon adding the glucosamine solutions to gold colloid, average hydrodynamic diameter of ions was slightly larger for 0.1 mM glucosamine solution (55 ± 2 nm), while it increased to (105 ± 22) nm in the case of 1 mM solution, and was (398 ± 54) nm when 10 mM glucosamine solution was added.Most prominent Raman bands observed both for 0.1 mM and 1 mM glucosamine solutions were located at 1165 cm−1, 1532 and 1586 cm−1 and assigned to C-N coupled with C-C stretching, and C-NH3+ deformation angles bending. In SERS spectrum of 1 mM GlcN+ solution, two strong bands at 999 and 1075 cm−1 were found and attributed to C-Oring stretching coupled with C-NH3+ bending (999 cm−1) and to dominantly C-O stretching vibration. The differences in SERS spectra are attributed to different number of glucosamine molecules that attach to gold nanoparticles and their orientation with respect to the metal particle surface, partly due to presence of beta anomers protonated at anomeric oxygen position. The assignment of glucosamine bands was further corroborated by comparison with vibrational spectra of alpha and beta glucose and of polycrystalline powder of glucosamine hydrochloride. For all three substances comprehensive calculation of vibrational density of states was conducted using density functional theory. Benchmark bands for polycrystalline glucose anomers distinction are 846 and 915 cm−1 for alpha glucose, and 902 cm−1 for beta glucose. However, the bands observed in SERS spectra of 0.1 mM glucosamine solution at 831, 899, and 946 cm−1 or in 1 mM solution at 934 cm−1 cannot be easily identified as belonging either to alpha or beta glucosamine anomer, due to complexity of atomic motions involved. The identification of vibrational bands associated with –CNH3+ group will aid SERS studies on amino acids, especially in cases when several atomic groups could possibly bind to AuNPs.

Formulation of anomerization and protonation in d-glucosamine, based on 1H NMR

The major anomer of non-protonated neutral d-glucosamine GlcN0 is the β-form, while the α-anomer is dominant for protonated cationic glucosamine GlcNH+. The present work confirmed correlation between the anomerization and the protonation by simultaneous determination of signal intensity and chemical shift in pD-variation 1H NMR, and formulated the equilibrium constants between subspecies α-GlcN0, β-GlcN0, α-GlcND+, and β-GlcND+ to interpret the correlation. The individual anomerization constants, Kan = [βGlcN]/[αGlcN] and KanD = [βGlcND+]/[αGlcND+], are linked to each other through the relation KDα∙KanD = KDβ∙Kan with the deuteration constants KDα and KDβ of the anomers. The anomer populations are stimulated by OD− and D+ ions in the dose−response form. The acidic deuteron in α-GlcND+ is populated mostly at the nitrogen atom, whereas the population in β-GlcND+ is comparable at nitrogen and anomeric oxygen; this difference is consistent with the basicity of the nitrogen and the anomerization process of glucosamine.

Synthesis and Conformation of Pentopyranoside Nucleoside Phosphonates.

In contrast to natural nucleosides, where the nucleobase is positioned at the anomeric center, we report the synthesis of pentopyranoside nucleosides with a phosphonate functionality at the 1'-anomeric oxygen. Starting from l-arabinose, key functionalized l- glycero- and l- erythro-pentopyranose carbohydrate synthons were prepared and further elaborated into the final six-membered ring nucleosides via nucleobase incorporation and phosphonomethylation reactions. NMR analysis demonstrated that these nucleoside phosphonates exist in solution as conformers predominantly adopting a chair structure in which the base moiety is equatorially positioned. Such conformation prevents unfavorable 1,3-diaxial steric and electronic interactions. Notably, the stereochemical outcome of the Vorbrüggen glycosylation step utilized en route to the thymine analogue clearly suggests the absence of anchimeric assistance, as opposed to what is usually observed during nucleoside synthesis using protected furanose precursors. The finding that the diphosphates of the compounds developed in this study are recognized by DNA polymerases is important in view of the future selection of artificial genetic systems and dedicated polymerases as well as applications in therapy.

Identification, characterization, and structural analyses of a fungal endo-β-1,2-glucanase reveal a new glycoside hydrolase family

endo-β-1,2-Glucanase (SGL) is an enzyme that hydrolyzes β-1,2-glucans, which play important physiological roles in some bacteria as a cyclic form. To date, no eukaryotic SGL has been identified. We purified an SGL from Talaromyces funiculosus (TfSGL), a soil fungus, to homogeneity and then cloned the complementary DNA encoding the enzyme. TfSGL shows no significant sequence similarity to any known glycoside hydrolase (GH) families, but shows significant similarity to certain eukaryotic proteins with unknown functions. The recombinant TfSGL (TfSGLr) specifically hydrolyzed linear and cyclic β-1,2-glucans to sophorose (Glc-β-1,2-Glc) as a main product. TfSGLr hydrolyzed reducing-end-modified β-1,2-gluco-oligosaccharides to release a sophoroside with the modified moiety. These results indicate that TfSGL is an endo-type enzyme that preferably releases sophorose from the reducing end of substrates. Stereochemical analysis demonstrated that TfSGL is an inverting enzyme. The overall structure of TfSGLr includes an (α/α)6 toroid fold. The substrate-binding mode was revealed by the structure of a Michaelis complex of an inactive TfSGLr mutant with a β-1,2-glucoheptasaccharide. Mutational analysis and action pattern analysis of β-1,2-gluco-oligosaccharide derivatives revealed an unprecedented catalytic mechanism for substrate hydrolysis. Glu-262 (general acid) indirectly protonates the anomeric oxygen at subsite -1 via the 3-hydroxy group of the Glc moiety at subsite +2, and Asp-446 (general base) activates the nucleophilic water via another water. TfSGLr is apparently different from a GH144 SGL in the reaction and substrate recognition mechanism based on structural comparison. Overall, we propose that TfSGL and closely-related enzymes can be classified into a new family, GH162.

Fragmentation Pathways of Lithiated Hexose Monosaccharides.

We characterize the primary fragmentation reactions of three isomeric lithiated D-hexose sugars (glucose, galactose, and mannose) utilizing tandem mass spectrometry, regiospecific labeling, and theory. We provide evidence that these three isomers populate similar fragmentation pathways to produce the abundant cross-ring cleavage peaks (0,2A1 and 0,3A1). These pathways are highly consistent with the prior literature (Hofmeister et al. J. Am. Chem. Soc. 113, 5964-5970, 1991, Bythell et al. J. Am. Soc. Mass Spectrom. 28, 688-703, 2017, Rabus et al. Phys. Chem. Chem. Phys. 19, 25643-25652, 2017) and the present labeling data. However, the structure-specific energetics and rate-determining steps of these reactions differ as a function of precursor sugar and anomeric configuration. The lowest energy water loss pathways involve loss of the anomeric oxygen to furnish B1 ions. For glucose and galactose, the lithiated α-anomers generate ketone structures at C2 in a concerted reaction involving a 1,2-migration of the C2-H to the anomeric carbon (C1). In contrast, the β-anomers are predicted to form 1,3-anhydroglucose/galactose B1 ion structures. Initiation of the water loss reactions from each anomeric configuration requires distinct reactive conformers, resulting in different product ion structures. Inversion of the stereochemistry at C2 has marked consequences. Both lithiated mannose forms expel water to form 1,2-anhydromannose B1 ions with the newly formed epoxide group above the ring. Additionally, provided water loss is not instantaneous, the α-anomer can also isomerize to generate a ketone structure at C2 in a concerted reaction involving a 1,2-migration of the C2-H to C1. This product is indistinguishable to that from α-glucose. The energetics and interplay of these pathways are discussed. Graphical Abstract ᅟ.

Synthesis of a library of variously modified 4-methylumbelliferyl xylosides and a structure-activity study of human β4GalT7.

Proteoglycans (PGs) are complex macromolecules that are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein through a tetrasaccharide linker. The biosynthesis of PGs is complex and involves a large number of glycosyltranferases. Here we present a structure-activity study of human β4GalT7, which transfers the first Gal residue onto a xyloside moiety of the linkage region. An efficient and regiocontrolled synthesis of a library of modified analogs of 4-methylumbelliferyl xyloside (XylMU) is reported herein. Hydroxyl groups at the position C-2, C-3 or C-4 have been epimerized and/or replaced by a hydrogen or a fluorine, while the anomeric oxygen was replaced by either a sulfur or a sulfone. The effect of these compounds on human β4GalT7 activity in vitro and on GAG biosynthesis in cellulo was then evaluated.

The Antiadhesive Strategy in Crohn's Disease: Orally Active Mannosides to Decolonize Pathogenic Escherichia coli from the Gut.

Blocking the adherence of bacteria to cells is an attractive complementary approach to current antibiotic treatments, which are faced with increasing resistance. This strategy has been particularly studied in the context of urinary tract infections (UTIs), in which the adhesion of pathogenic Escherichia coli strains to uroepithelial cells is prevented by blocking the FimH adhesin expressed at the tips of bacteria organelles called fimbriae. Recently, we extended the antiadhesive concept, showing that potent FimH antagonists can block the attachment of adherent-invasive E. coli (AIEC) colonizing the intestinal mucosa of patients with Crohn's disease (CD). In this work, we designed a small library of analogues of heptyl mannoside (HM), a previously identified nanomolar FimH inhibitor, but one that displays poor antiadhesive effects in vivo. The anomeric oxygen atom was replaced by a sulfur or a methylene group to prevent hydrolysis by intestinal glycosidases, and chemical groups were attached at the end of the alkyl tail. Importantly, a lead compound was shown to reduce AIEC levels in the feces and in the colonic and ileal mucosa after oral administration (10 mg kg(-1) ) in a transgenic mouse model of CD. The compound showed a low bioavailability, preferable in this instance, thus suggesting the possibility of setting up an innovative antiadhesive therapy, based on the water-soluble and non-cytotoxic FimH antagonists developed here, for the CD subpopulation in which AIEC plays a key role.

ChemInform Abstract: Total Syntheses of Laevigatins A and E.

We describe the first total syntheses of two ellagitannins, laevigatins A and E. Laevigatin A comprises a 2,3-O-(S)-hexahydroxydiphenoyl-α-D-glucose unit, whose anomeric oxygen atom forms a dehydrodigalloyl ester. Laevigatin E is a dimeric ellagitannin with structural motifs similar to those of laevigatin A. A recently developed method for synthesizing C–O digallates allowed the synthesis of more than 1 g of laevigatin A. The abundant supply allowed the synthesis of laevigatin E, an achievement that implies that more complex ellagitannins could be accessible.

Total Syntheses of Laevigatins A and E

AbstractWe describe the first total syntheses of two ellagitannins, laevigatins A and E. Laevigatin A comprises a 2,3‐O‐(S)‐hexahydroxydiphenoyl‐α‐D‐glucose unit, whose anomeric oxygen atom forms a dehydrodigalloyl ester. Laevigatin E is a dimeric ellagitannin with structural motifs similar to those of laevigatin A. A recently developed method for synthesizing C–O digallates allowed the synthesis of more than 1 g of laevigatin A. The abundant supply allowed the synthesis of laevigatin E, an achievement that implies that more complex ellagitannins could be accessible.

Synthesis of new steroidal inhibitors of P-glycoprotein-mediated multidrug resistance and biological evaluation on K562/R7 erythroleukemia cells.

A simple route for improving the potency of progesterone as a modulator of P-gp-mediated multidrug resistance was established by esterification or etherification of hydroxylated 5α/β-pregnane-3,20-dione or 5β-cholan-3-one precursors. X-ray crystallography of representative 7α-, 11α-, and 17α-(2'R/S)-O-tetrahydropyranyl ether diastereoisomers revealed different combinations of axial-equatorial configurations of the anomeric oxygen. Substantial stimulation of accumulation and chemosensitization was observed on K562/R7 erythroleukemia cells resistant to doxorubicin, especially using 7α,11α-O-disubstituted derivatives of 5α/β-pregnane-3,20-dione, among which the 5β-H-7α-benzoyloxy-11α-(2'R)-O-tetrahydropyranyl ether 22a revealed promising properties (accumulation index 2.9, IC50 0.5 μM versus 1.2 and 10.6 μM for progesterone), slightly overcoming those of verapamil and cyclosporin A. Several 7α,12α-O-disubstituted derivatives of 5β-cholan-3-one proved even more active, especially the 7α-O-methoxymethyl-12α-benzoate 56 (accumulation index 3.8, IC50 0.2 μM). The panel of modulating effects from different O-substitutions at a same position suggests a structural influence of the substituent completing a simple protection against stimulating effects of hydroxyl groups on P-gp-mediated transport.

The Tyrosine Gate as a Potential Entropic Lever in the Receptor-Binding Site of the Bacterial Adhesin FimH

Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infections. During infection, UPEC adhere to mannosylated glycoreceptors on the urothelium via the FimH adhesin located at the tip of type 1 pili. Synthetic FimH antiadhesives such as alkyl and phenyl α-D-mannopyranosides are thus ideal candidates for the chemical interception of this crucial step in pathogenesis. The crystal structures of the FimH lectin domain in its ligand-free form and in complexes with eight medium- and high-affinity mannopyranoside inhibitors are presented. The thermodynamic profiles of the FimH-inhibitor interactions indicate that the binding of FimH to α-D-mannopyranose is enthalpy-driven and has a negative entropic change. Addition of a hydrophobic aglycon influences the binding enthalpy and can induce a favorable entropic change. The alleviation of the entropic cost is at least in part explained by increased dynamics in the tyrosine gate (Tyr48 and Tyr137) of the FimH receptor-binding site upon binding of the ligand. Ligands with a phenyl group directly linked to the anomeric oxygen of α-D-mannose introduce the largest dynamics into the Tyr48 side chain, because conjugation with the anomeric oxygen of α-D-mannose forces the aromatic aglycon into a conformation that comes into close contact (≈2.65 Å) with Tyr48. A propargyl group in this position predetermines the orientation of the aglycon and significantly decreases affinity. FimH has the highest affinity for α-D-mannopyranosides substituted with hydrophobic aglycons that are compatible in shape and electrostatic properties to the tyrosine gate, such as heptyl α-D-mannose.

A highly efficient deprotection of the 2,2,2-trichloroethyl group at the anomeric oxygen of carbohydrates

Commercially available zinc dust in the presence of ammonium chloride in acetonitrile at reflux removes the 2,2,2-trichloroethyl (TCE) group at anomeric centers with excellent yields (>95%) in short reaction times. This present method is easily implemented on substrates containing acyl and benzyl groups and large-scale reactions also proceed in high yield.

Stereoelectronic factors in the stereoselective epoxidation of glycals and 4-deoxypentenosides.

Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-π frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.

ChemInform Abstract: Diastereoselective Anomeric Oxygen to Carbon Rearrangements of Silyl Enol Ether Derivatives of Lactols.

ChemInform Abstract: Diastereoselective Anomeric Oxygen to Carbon Rearrangements of Silyl Enol Ether Derivatives of Lactols.

ChemInform Abstract: Anomeric Oxygen to Carbon Rearrangements of Alkynyl Tributylstannane Derivatives of Lactols.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: A Short and Efficient Stereoselective Synthesis of the Potent 5-Lipoxygenase Inhibitor CMI-977.

Abstract A short and efficient synthesis of the potent 5-lipoxygenase inhibitor CMI-977 is described using as the key step a stereoselective anomeric oxygen to carbon rearrangement of an alkynyl stannane tetrahydrofuranyl ether derivative mediated by boron trifluoride etherate.

2-Nitroglycals as Powerful Glycosyl Donors: Application in the Synthesis of Biologically Important Molecules

[Reaction: see text]. The biological significance of oligosaccharides and glycoconjugates is profound and wide-ranging. For example, the mucins have attracted attention because of their role in fundamental cellular processes such as fertilization, parasitic infection, inflammation, immune defense, cell growth, and cell-cell adhesion. Increased expression of mucins is implicated in malignant transformation of cells. Antifreeze glycoproteins also are of interest because they are important for the survival of many marine teleost fishes that live in polar and subpolar waters. The synthesis of glycoconjugates requires methods for glycoside bond formation, the most difficult aspect of which is the assembly of monosaccharide building blocks. This Account discusses a valuable addition to the repertoire of methods for glycoconjugate synthesis: an approach that involves 2-nitroglycal concatenation. For a long time, methods for glycosylation via glycosyl donor generation required either an anomeric oxygen exchange reaction or anomeric oxygen retention. In the case of an anomeric oxygen exchange reaction, activation of the glycosyl donors demands a promoter in at least equimolar amounts. However, anomeric oxygen retention, such as base-catalyzed formation of O-glycosyl trichloroacetimidates, can be activated by catalytic amounts of acid or Lewis acid. Alternatively, glycals, which are readily available from sugars, can be an attractive starting material for glycoside bond formation. Their nucleophilic character at C-2 permits reactions with oxygen, nitrogen, and sulfur electrophiles that under high substrate stereocontrol generally lead to three-membered rings; ring opening under acid catalysis furnishes the corresponding glycosides, whichdepending on the electrophile Xare also employed for 2-deoxyglycoside synthesis. Glycals also can be transformed into derivatives that have at C-2 an electron-withdrawing group and are amenable to Michael-type addition. A good example are 2-nitroglycals. In this case, glycoside bond formation is achieved under base catalysis and leads to 2-deoxy-2-nitroglycosides. These intermediates are readily converted into 2-amino-2-deoxyglycosides, which are constituents of almost all glycoconjugates. This 2-nitroglycal concatenation has been extensively investigated with 2-nitrogalactal derivatives. When alcohols are used as nucleophiles and strong bases used as catalysts, the result is primarily or exclusively the alpha-galacto-configured adducts. Some studies show that weaker bases may lead to preferential formation of the beta-galacto-configured products instead. The reaction was very successfully extended to other nucleophiles and also to other 2-nitroglycals that undergo base-catalyzed stereoselective Michael-type additions. Thus, 2-nitroglycals are versatile synthons in glycoconjugate and natural-products synthesis, and it is foreseeable that many more applications will be based on these readily available and highly functionalized skeletons.

Synthesis of the C1-phosphonate analog of UDP-GlcNAc

We describe the first synthesis of the C1-phosphonate analog of UDP-GlcNAc, based on a new preparation of the corresponding glycosyl phosphonate. This C-glycosyl analog is shown to be a very weak inhibitor (Ki>10mM) of fungal chitin synthase, indicating that at least in this case the replacement of the anomeric oxygen with a methylene group is not an innocent substitution.

Novel Oxygen Chirality Induced by Asymmetric Coordination of an Ether Oxygen Atom to a Metal Center in a Series of Sugar-Pendant Dipicolylamine Copper(II) Complexes

Six sugar-pendant 2,2'-dipicolylamine (DPA) ligands (L1-3 and L'1-3) have been prepared. OH-protected and unprotected D-glucose, D-mannose, and D-xylose were attached to a DPA moiety via an O-glycoside linkage. X-ray crystallography of the copper(II) complexes (1-5) with these ligands revealed that the anomeric oxygen atom is coordinated to the metal center in the solid state, generating a chiral center at the oxygen atom. The CD spectra of these copper complexes in methanol or aqueous solution exhibit Cotton effects in the d-d transition region, which indicates that the ether oxygen atoms remain coordinated to the metal center and the oxygen-atom chirality is preserved even in solution. For complexes 1 and 2, the inverted oxygen-atom chirality and chelate-ring conformation in the solid state are well correlated with the mirror-image CD spectra in methanol solution. The concomitant inversion of the asymmetric configuration around the copper center was also observed in a methanol solution of complex 3 and a pyridine solution of complex 2. The square-pyramidal/octahedral copper(II) centers also exhibited characteristic absorption and CD spectra.