Glycal Formation Research Articles

Synthesis of 1,5-Anhydro-d-glycero-d-gluco-heptitol Derivatives as Potential Inhibitors of Bacterial Heptose Biosynthetic Pathways

A series of 1,5-anhydro-d-glycero-d-gluco-heptitol derivatives have been prepared from 3-O-benzyl-1,2-O-isopropylidene-d-glycero-d-gluco-heptofuranose via conversion into anomeric bromide and thiophenyl derivatives, followed by glycal formation and reductive desulfurization, respectively. Global deprotection of the protected intermediates afforded the 1,5-anhydro derivatives of the d-glycero-d-gluco- and 1,2-dideoxy-d-altro- configuration as well as the 1,5-anhydro-2-deoxy-d-altro-hept-1-enitol. In addition, the 7-O-phosphorylated d-glycero-d-gluco-heptose and its 1,5-anhydro analogue were prepared in good yields utilizing phosphoramidite chemistry. A novel heptitol analogue based on a 1-deoxynojirimycin scaffold was also elaborated via a Wittig­-type chain elongation followed by dihydroxylation, separation of the resulting epimers, and global deprotection. The target compounds, however, were not active as inhibitors of the bacterial sedoheptulose-7-phosphate isomerase GmhA.

Synthesis of a biotinylated keratan sulfate tetrasaccharide composed of dimeric Galβ1-4GlcNAc6Sβ

We successfully synthesized the biotinylated keratan sulfate tetrasaccharide, Galβ1-4GlcNAc6Sβ1-3Galβ1-4GlcNAc6Sβ in a stereocontrolled manner. The suitably protected Galβ1-4GlcNPhth unit was converted to the corresponding donor and acceptor. Optimization in 2 + 2 coupling using AgOTf, CuBr2, and n-Bu4NBr in CH3NO2 at a low temperature afforded the desired tetrasaccharide that suppressed glycal formation. The subsequent chemoselective removal of the protecting group at O-6 of two GlcNAcs, sulfation, and deprotection procedures as well as biotinylation gave the target compound.

Reaction of Glyconitriles with Organometallic Reagents: Access to Acyl β-C-Glycosides.

A new strategy for the synthesis of acyl β-C-glycosides is described. The reactivity of glyconitriles toward organometallic reagents such as organomagnesium or organolithium derivatives was studied, affording acyl β-C-glycosides in moderate to good yields. In this study, glycal formation was efficiently prevented by deprotonating the hydroxyl group in position 2 of the glyconitriles during the process.

Azidonitration of Di-O-acetyl-L-fucal: X-Ray Crystal Structures of Intermediate Azidodeoxysugars and of the Bacterial Aminosugar N-Acetyl-L-fucosamine

The azidonitration of di-O-acetyl-l-fucal has previously been shown to be an efficient route to the bacterial aminosugar N-acetyl-l-fucosamine. Upon repeating this sequence, with updated versions of the glycal formation and amide installation steps, we have obtained X-ray crystal structures of several of the addition products, which are now reported along with the solid-state structure of N-acetyl-l-fucosamine itself.

ChemInform Abstract: Unexpected Formation of Glycals Upon Attempted C-Alkylation of Protected Glycosylacetylenes.

Abstract Treatment of 3,7-anhydro-4,5,6,8-tetra- O -benzyl-1,2-dideoxy- d - glycero - d - galacto- oct-1-ynitol (β- d -mannosyl acetylene, 1 ) with 5 equivalents of n -butyllithium at either 0 or −78 °C resulted in the elimination of benzyl alcohol to yield 3,7-anhydro-5,6,8-tri- O -benzyl-1,2,4-trideoxy- d - arabino- oct-3-en-1-ynitol (glycal acetylene, 3 ) as the major product. Additional studies showed that 3 is also produced from two isomers of 1 with α- d -mannosyl and β- d -glucosyl stereochemistry, but in lower yields. Furthermore, substrates in which the acetylene moiety is replaced by either a methyl or phenyl group do not produce a glycal product under these conditions. Finally, treatment of 1 with phenyllithium provides 3 in low yield. Deuterium labeling studies suggest that the reaction proceeds through an E2, rather than an E1cB, mechanism.

Glycal Formation in Crystals of Uridine Phosphorylase,

Uridine phosphorylase is a key enzyme in the pyrimidine salvage pathway. This enzyme catalyzes the reversible phosphorolysis of uridine to uracil and ribose 1-phosphate (or 2'-deoxyuridine to 2'-deoxyribose 1-phosphate). Here we report the structure of hexameric Escherichia coli uridine phosphorylase treated with 5-fluorouridine and sulfate and dimeric bovine uridine phosphorylase treated with 5-fluoro-2'-deoxyuridine or uridine, plus sulfate. In each case the electron density shows three separate species corresponding to the pyrimidine base, sulfate, and a ribosyl species, which can be modeled as a glycal. In the structures of the glycal complexes, the fluorouracil O2 atom is appropriately positioned to act as the base required for glycal formation via deprotonation at C2'. Crystals of bovine uridine phosphorylase treated with 2'-deoxyuridine and sulfate show intact nucleoside. NMR time course studies demonstrate that uridine phosphorylase can catalyze the hydrolysis of the fluorinated nucleosides in the absence of phosphate or sulfate, without the release of intermediates or enzyme inactivation. These results add a previously unencountered mechanistic motif to the body of information on glycal formation by enzymes catalyzing the cleavage of glycosyl bonds.

Stereoselective Synthesis of α-Keto-deoxy-D-glycero-D-galacto-nonulosonic Acid Glycosides by Means of the 4,5-O-Carbonate Protecting Group

A 1-adamantyl thioglycoside derivative of KDN, derived from N-acetylneuraminic acid, carrying a 3,4-O-carbonate protecting group is a highy efficient and α-selective KDN donor on activation with NIS and TfOH in dichloromethane and acetonitrile at −78 °C. Glycosylations conducted with this protecting group do not suffer from competing glycal formation. Seven examples are given, including the use of galactose 3- and 6-hydroxy groups.

A Facile Synthesis of N‐Acetylneuraminic Acid Glycal.

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A Facile Synthesis of N-Acetylneuraminic Acid Glycal

Treatment of the readily available peracetylated N-acetylneuraminic acid glycosyl chloride [methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-trideoxy-β-d-glycero-d-galactononulopyranosonate)] with anhydrous Na2HPO4 in refluxing MeCN quantitatively affords the peracetylated N-acetylneuraminic acid glycal [methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2,6-anhydro-d-glycero-d-galacto-non-2-enonate], which can be isolated from the reaction mixture by simple filtration and subsequent evaporation of the solvent. No glycal formation was detected at room temperature even after prolonged treatment with Na2HPO4. The method proposed is experimentally simple and allows ready preparation of substantial amounts of the title compound, which is an important intermediate in sialic acid chemistry.

Chemical Mechanism and Specificity of the C5-Mannuronan Epimerase Reaction

C5-mannuronan epimerase catalyzes the formation of alpha-L-guluronate residues from beta-D-mannuronate residues in the synthesis of the linear polysaccharide alginate. The reaction requires the abstraction of a proton from C5 of the residue undergoing epimerization followed by re-protonation on the opposite face. Rapid-mixing chemical quench experiments were conducted to determine the nature of the intermediate formed upon proton abstraction in the reaction catalyzed by the enzyme from Pseudomonas aeruginosa. Colorimetric and HPLC analysis of quenched samples indicated that shortened oligosaccharides containing an unsaturated sugar residue form as transient intermediates in the epimerization reaction. This suggests that the carbanion is stabilized by glycal formation, concomitant with cleavage of the glycosidic bond between the residue undergoing epimerization and the adjacent residue. The time dependence of glycal formation suggested that slow steps flank the chemical steps in the catalytic cycle. Solvent isotope effects on V and V/K were unity, consistent with a catalytic cycle in which chemistry is not rate-limiting. The specificity of the epimerase with regard to neighboring residues was examined, and it was determined that the enzyme showed no bias for mannuronate residues adjacent to guluronates versus those adjacent to mannuronates. Proton abstraction and sugar epimerization were irreversible. Existing guluronate residues already present in the polysaccharide were not converted to mannuronates, nor was incorporation of solvent deuterium into existing mannuronates observed.

Efficient glycosidation of a phenyl thiosialoside donor with diphenyl sulfoxide and triflic anhydride in dichloromethane.

The formation of sialic acid glycosides with a thiosialic acid derivative, diphenyl sulfoxide, and trifluoromethanesulfonic anhydride is reported. With an excess of diphenyl sulfoxide, glycal formation can be completely suppressed and excellent yields are obtained for coupling to a wide range of primary, secondary, and tertiary acceptors.

Glycosyl azides of sugar 2-sulfonic acids

Phenyl and trityl 2- O-sulfonyl-1-thio-α- d-manno- and β- d-glucopyranosides were reacted with sodium azide to yield 2- S-phenyl or 2- S-trityl- d-gluco- and d-mannopyranosyl azides, respectively. Usually, both anomers were formed in approximately equal amounts and formation of glycals was also observed in some cases. The product distribution of these reactions depends on the nature of the aglycone, the applied reagent and also on the solvent. These results can be rationalised by the intermediacy of episulfonium as well as oxocarbenium ions. Oxidation of the 2- S-trityl-α- d-glucopyranosyl or α- d-mannopyranosyl azides by Oxone ®, gave sodium 2-sulfonato-α- d-gluco- and α- d-mannopyranosyl azides, respectively.

Study of interhalogens/silver trifluoromethanesulfonate as promoter systems for high-yielding sialylations.

We have studied interhalogen/silver trifluoromethanesulfonate (IX/AgOTf) promoted glycosylations and found differences in the sensitivity of the formed oxocarbenium ions (e.g. from compounds with or without participating groups) toward halide nucleophiles. These differences can be explained using the HSAB theory. By applying this theory on sialylations, we increased the yield for a model reaction from a highly unpredictable 35-46% using ICl to 74% using IBr. We have also showed that the most prominent role of the silver ions is lowering the concentration of the halide nucleophile rather than activating the interhalogen compound and, by increasing the amount of AgOTf from 1 to 1.5 equiv (with respect to IBr), the yield in the model reaction improved from 74% to 89%. A comparison of two different anomeric leaving groups showed that glycal formation can be minimized using a thiophenyl donor instead of xanthate. By combining these observations, we were able to increase the yield of the model reaction to 97%.

ChemInform Abstract: Electrochemical Formation of Glycals in THF.

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Electrochemical formation of glycals in THF

A new method is presented to produce unsaturated sugars from glycosyl bromides. This work offers a simplification of existing electrochemical approaches to these types of species and is amenable to scale up for large-scale production. In addition, this work is intended to provide a means of employing electrochemistry that can be duplicated in most organic chemistry laboratories using readily available glassware and equipment.

Unexpected formation of glycals upon attempted C-alkylation of protected glycosylacetylenes

Treatment of 3,7-anhydro-4,5,6,8-tetra- O-benzyl-1,2-dideoxy- d- glycero- d- galacto-oct-1-ynitol (β- d-mannosyl acetylene, 1) with 5 equivalents of n-butyllithium at either 0 or −78 °C resulted in the elimination of benzyl alcohol to yield 3,7-anhydro-5,6,8-tri- O-benzyl-1,2,4-trideoxy- d- arabino-oct-3-en-1-ynitol (glycal acetylene, 3) as the major product. Additional studies showed that 3 is also produced from two isomers of 1 with α- d-mannosyl and β- d-glucosyl stereochemistry, but in lower yields. Furthermore, substrates in which the acetylene moiety is replaced by either a methyl or phenyl group do not produce a glycal product under these conditions. Finally, treatment of 1 with phenyllithium provides 3 in low yield. Deuterium labeling studies suggest that the reaction proceeds through an E2, rather than an E1cB, mechanism.

Facile Preparation of Protected Furanoid Glycals from Thymidine

The synthesis of O-silyl- and O-acyl-protected furanose glycals from free thymidine was investigated. The method of glycal formation reported by Pedersen et al. was successfully expanded to include 5-ester (toluoyl) protected glycals as well as various combinations of 5‘-ester and 3- and 5-tert-butyldimethylsilyl and tert-butyldiphenylsilyl protection. Gram quantities of furanoid glycals can be prepared in a few days in two−four synthetic steps in overall yields ranging from 17 to 80%.

α-selectivity and glycal formation are temperature dependent in glycosylation with sialic acid. Synthesis of a Neu5Acα(2-6)Gal thioglycoside building block

The glycosylation with the N-acetylneuraminic acid (Neu5Ac) donor 1 of the 6-OH position of D-galactose in various nitriles promoted by methylsulfenyl triflate at different temperatures is reported. The proportion of α-sialoside increased and glycal 5 decreased at lower temperatures. A short route to a Neu5Acα(2-6)Gal thioglycoside building block is also described.