Monomolar acetalations of methyl α-d-mannosides—synthesis of methyl α-d-talopyranoside

Methyl α-d-mannopyranoside (1 mole) reacts with 2,2-dimethoxypropane (1 mole), to give the 4,6-O-isopropylidene derivative (2) which rearranges to the 2,3-O-isopropylidene derivative (4). Compound4 can also be prepared by graded hydrolysis of methyl 2,3:4,6-di-O-isopropylidene-α-d-mannopyranoside. Successive benzoylation, oxidation, and reduction of4 provides a useful route to a number ofd-talopyranoside compounds. Methyl α-d-mannofuranoside (1 mole) reacts with 1–2 moles of 2,2-dimethoxypropane to give the 5,6-O-isopropylidene derivative (16) in 90% yield.     

A synthesis of methyl 4,6-di-O-Methyl-α-d-mannopyranoside

A new route is described for preparing methyl 4,6-di-O-methyl-α-d-mannopyranoside (5) via methyl 2,3-di-O-p-tolylsulfonyl-α-d-mannopyranoside (3) as an intermediate. The retention of the mannopyranoside configuration and ring form was confirmed by proton n.m.r. spectroscopy and by m.s. of peracetylated aldononitrile derivatives. Mass-spectral fragmentation-pathways previously proposed were confirmed for 5-O-acetyl-2,3,4,6-tetra-O-methyl-, 2,5-di-O-acetyl-3,4,6-tri-O-methyl-, and 3,5-di-O-acetyl-2,4,6-tri-O-methyl-d-mannononitrile.     

Synthesis and 13C-N.M.R. spectroscopy of 2-O- and 6-O-acetyl-3-O-α-l-rhamnopyranosyl-d-galactose,constituents of bacterial cell-wall polysaccharides

Benzyl 2-O-acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-acetyl-α-l-rhamnopyranosyl)-β-d-galactopyranoside (11) has been synthesised by two routes. Partial deacetylation of 11 and then acid hydrolysis yielded benzyl 2-O-acetyl-3-O-α-l-rhamnopyranosyl-β-d-galactopyranoside, catalytic hydrogenolysis of which gave the first title compound in excellent yield. Benzyl 4,6-O-benzylidene-3-O-α-l-rhamnopyranosyl-β-d-galactopyranoside was benzylated, and hydrogenolysis (LiAlH₄-AlCl₃) of the product gave the disaccharide derivative 16 with only HO-6 unsubstituted. Acetylation of 16 followed by catalytic hydrogenolysis gave the crystalline, second title compound. As model compounds for comparative n.m.r. studies, 2-O-, 3-O-, and 6-O-acetyl-d-galactose were also synthesised.     

The acid-catalyzed hydrolysis of β-d-xylofuranosides

The rate constants for the hydrolysis of six alkyl and four aryl β-d-xylofuranosides in aqueous perchloric acid at various temperatures have been measured. The effects of varying the aglycon structure on the hydrolysis rate are interpreted in terms of two concurrent reactions. Either, the substrate, protonated on the glycosidic oxygen atom, undergoes a rate-limiting heterolysis to form a cyclic oxocarbonium ion, or, an initial rapid protonation of the ring oxygen is followed by a unimolecular cleavage of the five-membered ring, all subsequent reactions being fast. It is suggested that xylofuranosides having strongly electron-attracting aglycon groups react mainly by the former pathway, whereas the latter is more favourable for substrates having electron-repelling aglycon groups. The negative entropies of activation obtained with the latter compounds are attributed to the rate-limiting opening of the five-membered ring. The rate variations of the hydrolyses of alkyl β-d-xylofuranosides in aqueous perchloric acid-methyl sulfoxide mixtures are interpreted as lending further support for the suggested chance in mechanism.     

A synthesis of 3-O-(α-d-mannopyranosyl)-d-mannose and its protein conjugate

Methods for the synthesis of 3-O-(α-d-mannopyranosyl)-d-mannose and 2-(4-aminophenyl)ethyl 3-O-(α-d-mannopyranosyl)-α-d-mannopyranoside have been investigated by a number of sequences. Glycosidations with 2,3-di-O-acetyl-4,6-di-O-benzyl-d-mannopyranosyl and 2-O-benzoyl-3,4,6-tri-O-benzyl-d-mannopyranosyl p-toluenesulfonates were found to give better yields than the Helferich modification, the use of a peracylated d-mannopyranosyl halide, or the use of triflyl leaving group. Only the α anomer was obtained. Factors influencing glycosidation reactions are discussed. A mercury(II) complex was used for selective 2-O-acylation of 4,6-di-O-benzyl-α-d-mannopyranosides. A disaccharide—protein conjugate was prepared by the isothiocyanate method.     

Conformational analysis of 1,2:3,4-di-O-isopropylidene-α-d-galacto-octopyranose derivatives: a 1H- and 13C-N.M.R.-spectral and x-ray comparative study

The pyranoid conformations of 7-acetamido-6,7,8-trideoxy-1,2:3,4-di-O-isopropylidene-d-glycero-α-d-galacto-octopyranose (3) and 7-acetamido-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-l-threo-α-d-galacto-octopyranose (4) in solution have been determined by calculation of the dihedral angles from the vicinal, proton-proton coupling-constants, using three modifications of the Karplus equation. Of these, only the equation ³J(HCCH)(φ)  (7.48  0.74 -ΣδE_x)  (2.03  0.17 ΣE_x)cos φ + (4.60  0.23 ΣδE_x)cos 2φ + 0.06 (Σ ± ΔE_x)sin φ + 0.62 (Σ ± ΔE_x)sin 2φ indicates that the pyranoid part of 3 and 4 has the °S₂ conformation, very slightly distorted towards °H₅, in agreement with the conformations determined for the crystalline state. Analysis of the ¹H-n.m.r. data for a series of 1,2:3,4-di-O-isopropyl-idene-α-d-galacto-octopyranose derivatives shows that the pyranoid parts of these compounds adopt the same conformation as that found for 3 and 4.     

Synthesis of p-isothiocyanatophenyl 3-O-(3,5-dideoxy-α-d-ribo-hexopyranosyl)-α-d-mannopyranoside

The synthesis of the title disaccharide derivative (1C), corresponding to the Salmonella O-factor 2¹, is described. Treatment of 2-O-benzyl-4-O-p-nitrobenzoyl-α-paratosyl bromide (5) with p-nitrophenyl 2-O-benzyl-4,6-O-benzylidene-α-d-mannoside in dichloromethane, in the presence of mercuric cyanide, gave the α- and β-linked disaccharide derivatives (6a and 6b) in yields of 34 and 5%, respectively. The disaccharide derivative 10 can react with free amino groups in proteins to produce artificial antigens useful in studies on Salmonella immunology.     

β-d-glucosidase-catalysed transfer of the glycosyl group from aryl β-d-gluco- and β-d-xylo-pyranosides to phenols

The effect of phenols on the hydrolysis of substituted phenyl β-d-gluco- and β-d-xylo-pyranosides by β-d-glucosidase from Stachybotrys atra has been investigated. Depending on the glycon part of the substrate and on the phenol substituent, the hydrolysis is either inhibited or activated. With aryl β-d-xylopyranosides, transfer of the xylosyl residue to the phenol, with the formation of new phenyl β-d-xylopyranosides, is observed. With aryl β-d-glucopyranosides, such transfer does not occur when phenols are used as acceptors, but it does occur with anilines. A two-step mechanism, in which the first step is partially reversible, is proposed to explain these observations. A qualitative analysis of the various factors determining the overall effect of the phenol is given.     

β-Elimination of 2-O-(4-O-methyl-α-d-glucopyranosyluronic acid)-d-xylose with methylsulphinyl carbanion and hydrolysis of the hex-4-enopyranosiduronic linkage

On treatment with m sodium methylsulphinylmethanide at 25°, 2-O-(4-O-methyl-α-d-glucopyranosyluronic acid)-d-xylose (1) was rapidly degraded by β-elimination, to form 2-O-(4-deoxy-β-l-threo-hex-4-enopyranosyluronic acid)-d-xylose (2). The kinetics of hydrolysis of 1 and 2 in 0.5m sulphuric acid have been studied. Compound 2 was hydrolysed 70 times faster than 1. Compared with the rate coefficients of other related compounds, 2 was hydrolysed at approximately the same rate as 2-O-(4-O-methyl-α-d-glucopyranosyl)-d-xylose, 3.5 times more slowly than xylobiose, and twice as fast as the xylosidic bond in O-(4-O-methyl-α-d-glucopyranosyluronic acid)-(1→2)-O-β-d-xylopyranosyl-(1→4)-d-xylose.     

The use of 1-O-tosyl-d-glucopyranose derivatives in α-d-glucoside synthesis

1-O-Tosyl-d-glucopyranose derivatives having a nonparticipating benzyl group at O-2 have been shown to react rapidly in various solvents with low concentrations of alcohols, either methanol or methyl 2,3,4-tri-O-benzyl-α-d-glucopyranoside. The stereospecificity of the glucoside-forming reaction could be varied from 80% of β to 100% of α anomer by changing the solvent or modifying the substituents on the 1-O-tosyl-d-glucopyranose derivative. 2,3,4-Tri-O-benzyl-6-O-(N-phenylcarbamoyl)-1-O-tosyl-α-d-glucopyranose in diethyl ether gave a high yield of α-d-glucoside. Kinetic measurements of reaction with various alcohols (methanol, 2-propanol, and cyclohexanol) show a high rate even at low concentrations of alcohol, and give some insight into the reaction mechanism. The high rate and stereoselectivity of their reaction suggest that the 1-O-tosyl-d-glucopyranose derivatives may be used as reagents for oligosaccharide synthesis.     

The synthesis of methyl 4-O-(4-O-α-d-galactopyranosyl-β-d-galactopyranosyl)-β-d-glucopyranoside: The methyl β-glycoside of the trisaccharide related to Fabry's disease

As part of a program to synthesize the ceramide trisaccharide (1) related to Fabry's disease, methyl 4-O-(4-O-α-$\text{d}$-galactopyranosyl-β-$\text{d}$-galactopyranosyl)-β-$\text{d}$-glucopyranoside (12) was prepared. Methyl β-lactoside (2) was converted into methyl 4-O-(4,6-O-benzylidene-β-$\text{d}$-galactopyranosyl)-β-$\text{d}$-glucopyranoside (4). Methyl 2,3,6-tri-O-benzoyl-4-O-(2,3,6-tri-O-benzoyl-β-$\text{d}$-galactopyranosyl)-β-$\text{d}$-glucopyranoside (7) was synthesized from 4 through the intermediates methyl 2,3,6-tri-O-benzoyl-4-O-(4,6-O-benzylidene-2,3-di-O-benzoyl-β-$\text{d}$-galactopyranosyl)-β-$\text{d}$-glucopyranoside (5) and methyl 2,3,6-tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-β-$\text{d}$-galactopyranosyl)-β-$\text{d}$-glucopyranoside (6). The halide-catalyzed condensation of 7 with 2,3,4,6-tetra-O-benzyl-$\text{d}$-galactopyranosyl bromide (8) gave methyl 2,3,6-tri-O-benzoyl-4-O-[2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzyl-α-$\text{d}$-galactopyranosyl)- β-$\text{d}$-galactopyranosyl]-β-$\text{d}$-glucopyranoside (10). Stepwise deprotection of 10 led to 12, the methyl β-glycoside of the trisaccharide related to Fabry's disease.     

α-D-Mannosidase-catalyzed hydrolysis of substituted phenyl α-D-mannopyranosides

The influence substituents on the hydrolysis of substituted phenyl α-D-mannopyranosides by α-D-mannosidase from Medicago sativa L. has been investigated. As indicated by structure-activity relations, the electronic effect of the substituent has an influence on the rate of formation of the intermediate mannosyl-enzyme complex. This effect depends not only on the nature of the substituent, but also on its position (meta or para) and on the temperature of the experiment. Hammett-type linear free energy relationships show that the reaction constant p changes its sign at ～27°. Substrates with strong electron-withdrawing groups show values of log V that are linearly related to 1/T, whereas the Arrhenius plots for other substrates are severely curved. This complex behaviour is tentatively explained by assuming that some meta-substituents have an unusual, temperature- and substituent-dependent influence on the formation of the Michaelis—Menten complex.     

The use of positively charged leaving-groups in the synthesis of α-D-linked glucosides. Synthesis of methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside

Quaternary ammonium and triphenylphosphonium salts of 2,3,4-tri-O-benzyl-6-O-(N-phenylcarbamoyl)-D-glucopyranosyl bromide were readily prepared by reaction with tertiary amines and triphenylphosphine under anhydrous conditions. Methanolysis of these salts was studied to determine the conditions of solvent and temperature that would produce the highest yields of α-D-glucosides. The quaternary ammonium salts gave the highest yields with solvents of low dielectric constant and room temperature. The phosphonium salts gave moderate yields with diethyl ether at 50°. The synthesis of methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside by treatment of the quaternary ammonium salt of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide with methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside was studied as a model for the synthesis of oligosaccharides. The anomeric composition of the disaccharide product could be easily determined from the optical rotation since the specific rotations of both the final product and of the gentiobioside analog are known. Under the best conditions, the yield of disaccharide was low (50%) and the reactions were not completely stereoselective.     

Identification of neoschaftoside as 6-C-β-d-glucopyranosyl-8-C-β-l-arabinopyranosylapigenin

The structure of neoschaftoside is shown for the first time to be 6-C-β-d-glucopyranosyl-8-C-β-l-arabinopyranosylapigenin. A variety of chemical and spectroscopic techniques are involved.     

Synthesis of phenyl O-α-l-fucopyranosyl-(1→2)-O-β-d-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-α-d-galactopyranoside

phenyl 2-acetamido-2-deoxy-4,6-O-(p-methoxybenzylidene)-3-O-[4,6-O-(p-methoxybenzylidene)-β-d-alactopyranosyl]-α-d-galactopyranoside (3) was prepared from phenyl 2-acetamido-2-deoxy-4,6-O-(p-methoxybenzylidene)-3-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-α-d-galactopyranoside by zemplén deacetylation, followed by reaction with p-methoxybenzaldehyde in the presence of anhydrous zinc chloride. The selective benzoylation of 3 gave the 3′-benzoate which, on condensation with 2,3,4-tri-O-benzyl-α- l-fucopyranosyl bromide under catalysis by halide ion, afforded a crystalline trisaccharide from which the title trisaccharide was obtained by debenzoylation followed by catalytic hydrogenolysis.     

Derivatives of β-D-fructofuranosyl α-D-galactopyranoside

De-etherification of 6,6′-di-O-tritylsucrose hexa-acetate (2) with boiling, aqueous acetic acid caused 4→6 acetyl migration and gave a syrupy hexa-acetate 14, characterised as the 4,6′-dimethanesulphonate 15. Reaction of 2,3,3′4′,6-penta-O-acetylsucrose (5) with trityl chloride in pyridine gave a mixture containing the 1′,6′-diether 6 the 6′-ether 9, confirming the lower reactivity of HO-1′ to tritylation. Subsequent mesylation, detritylation, acetylation afforded the corresponding 4-methanesulphonate 8 1′,4-dimethanesulphonate 11. Reaction of these sulphonates with benzoate, azide, bromide, and chloride anions afforded derivatives of β-D-fructofuranosyl α-D-galactopyranoside (29) by inversion of configuration at C-4. Treatment of the 4,6′-diol 14 the 1,′4,6′-triol 5, the 4-hydroxy 1′,6′-diether 6 with sulphuryl chloride effected replacement of the free hydroxyl groups and gave the corresponding, crystalline chlorodeoxy derivatives. The same 4-chloro-4-deoxy derivative was isolated when the 4-hydroxy-1′,6′-diether 6 was treated with mesyl chloride in N,N-dimethylformamide.     

Synthesis of 4-O-α-d-galactopyranosyl-l-rhamnose and 4-O-α-d-galactopyranosyl-2-O-β-glucopyranosyl-l-rhamnose using dioxolane-type benzylidene acetals as temporary protecting-groups

The Halide ion-catalysed reaction of benzyl exo-2,3-O-benzylidene-α-l-rhamnopyranoside with tetra-O-benzyl-α-d-galactopyranosyl bromide and hydrogenolysis of the exo-benzylidene group of the product 2 gave benzyl 3-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-α-d-galactopyranosyl)-α-l-rhamnopyranoside (6). Compound 2 was converted into 4-O-α-d-galactopyranosyl-l-rhamnose. The reaction of 6 with tetra-O-acetyl-α-d-glucopyranosyl bromide and removal of the protecting groups from the product gave 4-O-α-d-galactopyranosyl-2-O-β-d-glucopyranosyl-l-rhamnose.     

The oxidation of methyl α-D-glucopyranoside with methyl sulproxide and acetic anhydride

The relative proportions of carbonyl, O-acetyl, and O-(methylthio)methylsugars resulting from the partial oxidation of methyl α-D-glucopyranoside with methyl sulphoxide and acetic anhydride have been investigated@ the preparation of the 2- and 6-(methylthio)methyl ethers of methyl α-D-glucopyranoside is described.     

The synthesis of 5-O-(2-acetamido-2-deoxy-α-D-glucopyranosyl)-β-D-glucofuranose

Condensation of dimeric 3,4,6-tri-O-acetyl-2-deoxy-2-nitroso-α-D-glucopyranosyl chloride (1) with 1,2-O-isopropylidene-α-D-glucofuranurono-6,3-lactone (2) gave 1,2-O-isopropylidene-5-O-(3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-α-D-arabino-hexopyranosyl)-α-D-glucofuranurono-6,3-lactone (3). Benzoylation of the hydroxyimino group with benzoyl cyanide in acetonitrile gave 1,2-O-isopropylidene-5-O-(3,4,6-tri-O-acetyl-2-benzoyloxyimino-2-deoxy-α-D-arabino-hexopyranosyl)-α-D-glucofuranurono-6,3-lactone (4). Compound 4 was reduced with borane in tetrahydrofuran, yielding 5-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-1,2-O-isopropylidene-α-D-glucofuranose (5), which was isolated as the crystalline N-acetyl derivative (6). After removal of the isopropylidene acetal, the pure, crystalline title compound (10) was obtained.