Synthesis of phenyl d-glucopyranosides; nucleophilic substitution of O-(2,3,4,6-tetra-O-benzyl-d-glucopyranosyl)-pseudoureas by phenols

A series of nucleophilic substitution-reactions of O-(2,3,4,6-tetra-O-benzyl-d-glucopyranosyl)pseudoureas by phenols was investigated as a novel procedure for the synthesis of phenyl d-glucopyranoside derivatives: these reactions were found to give the corresponding phenyl 2,3,4,6-tetra-O-benzyl-d-glucopyranosides in excellent yields. Reaction mechanisms were discussed on the basis of the results obtained.     

O-GLYCOSIDES OF N-HYDROXYINDOLES[1]

First O-glycosides of N-hydroxyindole were synthesized by the interaction of the indoles containing electron withdrowing substituents with acyl halogenoses in the presence of alkaline reagents. 1-O-β-D-Glucopyranosides of 1-hydroxy-5-(or 6)-nitroindoles, 1-O-β-D-ribofuranoside of 1-hydroxy-5-nitroindole and also 1-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)oxy]-2-methoxycarbonylindole were obtained. 1-[(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-oxy]-6-nitro-indole was transformed into 1-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-oxy]indole.     

Use of positively charged,leaving groups in the synthesis of α-D-linked galactosides. Attempted synthesis of 3-O-α-(D-(galactopyranosyl)-D-galactose

Quaternary ammonium and phosphonium salts were readily obtained by treating 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide with tertiary amines and phosphines in various solvents under anhydrous conditions. Optical rotations and n.m.r. spectra of the hygroscopic syrups indicated that they exist mainly in the β-D configuration. Several dialkyl sulfides reacted very slowly with the galactosyl bromide and no conclusive evidence for sulfonium salt formation was obtained. 2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl chloride failed to react with any of the nucleophiles.Methanolysis reactions of the phosphonium salts were too slow to be practical and were not studied extensively. Methanolyses of several quaternary ammonium salts in various solvents were not completely stereospecific, but gave good yields of methyl 2,3,4,6-tetra-O-benzyl-α-D-galactopyranoside. Attempted reactions of benzyl 2-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside with quaternary ammonium salts derived from 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide failed to produce the corresponding derivative of 3-O-(α-D-galactopyranosyl)-D-galactose.     

Ring-opening reactions of sucrose epoxides: Synthesis of 4′-derivatives of sucrose

The 2,1′-O-isopropylidene derivative (1) of 3-O-acetyl-4,6-O-isopropylidene-α-d-glucopyranosyl 6-O-acetyl-3,4-anhydro-β-d-lyxo-hexulofuranoside and 2,3,4-tri-O-acetyl-6-O-trityl-α-d-glucopyranosyl 3,4-anhydro-1,6-di-O-trityl-β-d-lyxo-hexulofuranoside have been synthesised and 1 has been converted into 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl 1,6-di-O-acetyl-3,4-anhydro-β-d-lyxo-hexulofuranoside (2). The S_N2 reactions of 2 with azide and chloride nucleophiles gave the corresponding 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl 1,3,6-tri-O-acetyl-4-azido-4-deoxy-β-d-fructofuranoside (6) and 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl 1,3,6-tri-O-acetyl-4-chloro-4-deoxy-β-d-fructofuranoside (8), respectively. The azide 6 was catalytically hydrogenated and the resulting amine was isolated as 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl 4-acetamido-1,3,6-tri-O-acetyl-4-deoxy-β-d-fructofuranoside. Treatment of 5 with hydrogen bromide in glacial acetic acid followed by conventional acetylation gave 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl 1,3,6-tri-O-acetyl-4-bromo-4-deoxy-β-d-fructofuranoside. Similar S_N2 reactions with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl 1,6-di-O-acetyl-3,4-anhydro-β-d-ribo-hexulofuranoside (12) resulted in a number of 4′-derivatives of α-d-glucopyranosyl β-d-sorbofuranoside. The regiospecific nucleophilic substitution at position 4′ in 2 and 12 has been explained on the basis of steric and polar factors.     

Glycosidation at C-4 of 2-acetamido-2-deoxy-D-glucopyranose derivatives by koenigs-knorr type condensations

The condensation of 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl bromide and 2,3,4,6-tetra-O-benzyl-D-mannopyranosyl chloride with benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside (1), under Koenigs-Knorr conditions, gave the fully benzylated derivatives of benzyl 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-D-glucopyranoside, benzyl 2-acetamido-2-deoxy-4-O-β-D-glucopyranosyl-α-D-glucopyranoside, and benzyl 2-acetamido-2-deoxy-4-O-α-D-mannopyranosyl-α-D-glucopyranoside. Three further compounds, namely, benzyl 2-acetamido-3-O-benzyl-2-deoxy-6-O-(2,3,4,6-tetra-O-benzyl-D-glucopyranosyl)-α-D-glucopyranoside, benzyl 2-acetamido-3-O-benzyl-2-deoxy-6-O-(2,3,4,6-tetra-O-benzyl-D)-mannopyranosyl)-α-D-glucopyranoside, and benzyl 2-acetamido-3-O-benzyl-2-deoxy-4,6-di-O-(2,3,4,6-tetra-O-benzyl-D-mannopyranosyl)-α-D-glucopyranoside, were formed by reaction of the respective glycosyl halide with benzyl 2-acetamido-3-O-benzyl-2-deoxy-α-D-glucopyranoside present as contaminant in 1.     

Practical Synthesis of the Disaccharide Epitope,D-Galactopyranosyl-α-1,3-D- galactopyranose,by using 1,2;5,6-Di-O-cyclohexylidene-α-D-galactofuranose as the Glycosyl Acceptor

D-Galactosyl-α-1,3-D-galactopyranose (1) was chemically prepared in a good yield by coupling phenyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside (5) or 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide (8) with 1,2:5,6-di-O-cyclohexylidene-α-D-galactofuranose (3) with subsequent de-O-benzylation and de-O-cyclohexylidenation of the resulting protected α-1,3-disaccharide.     

Oxidation of 2,3,4,6-tetra-O-methyl-d-glucose with alkaline hydrogen peroxide

Treatment of 2,3,4,6-tetra-O-methyl-d-glucose with 10 molar equivalents ofn 30% aqueous hydrogen peroxide and 2 molar equivalents of potassium hydroxide afforded, after chromatographic separation, 2,3,4,6-tetra-O-methyl-d-gluconolactone. 1-O-formyl-2,3,5-tri-O-methyl-d-arabinose methyl hemiacetal (7), 2,3,5-tri-O-methyl-d-arabinonolactone, methyl 2,3,5-tri-O-methyl-d-arabinoside, O-(2,4-di-O-methyl-d-erythrose)-(1'→3)-2,4-di-O-methyl-d-erythronic acid, and O-(2,4-di-O-methyl-d-erythrose)-(1′→2)-3-O-methyl-d-glyceraldehyde. The proportions of the products depended on the reaction conditions, especially the time, temperature, and the presence or absence of magnesium hydroxide. Formation of the products is explained by a series of reactions beginning with the addition of hydrogen peroxide to the carbonyl form of the methylated sugar. The adduct, with the help of superoxide radical and a molecule of hydrogen peroxide, breaks up in two ways, giving 2,3,4,6-tetra-O-methyl-d-gluconic acid and 7. The formic ester, on hydrolysis, gives 2,3,5-tri-O-methyl-d-arabinose, which undergoes a similar series of reactions, affording 2,3,5-tri-O-methyl-d-arabinonic acid, and presumably, 1-O-formyl-2,4-di-O-methyl-d-erythrose methyl hemiacetal. Apparently, the latter compound, on hydrolysis, forms a dimer, which, with alkaline hydrogen peroxide, undergoes a similar series of reactions, ultimately affording O-(2,4-di-O-methyl-d-erythrose)-(1→3)-2,4-di-O-methyl-d-erythronic acid and O-(2,4-di-O-methyl-d-erythrose)-(1→2)-3-o-methyl-d-glyceraldehyde. With a larger amount of alkali, under more-severe conditions, oxidation of 2,3,4,6-tetra-O-methyl-d-glucose proceeds further, with production of up to 3 moles of formic acid per mole of methylated sugar.     

Synthesis of Tropolone Glucopyranosides

Reactions of tropolone (1a) and 3-isopropenyl-, 3-acetyl-, 3- acetamido-, and 5-bromotropolones 1b-e with 2,3,4,6-tetra-O-acet- yl-α-d-glucopyranosyl bromide were carried out in the presence of silver carbonate at 80°C. Unsubstituted, 3′-/7′-isopropenyl-, 7′-acetyl-, 7′-acetamido-, and 5′-bromo-substituted 2′-troponyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosides were respectively obtained.     

5′-Uridyl derivatives of N-glycosyl allophanic acid and biuret

(2′,3′-O-Isopropylidene-5′-uridyl) 4-(2,3,4,6-tetra-O-acetyl-β-d-glycopyranosyl)allophanates were obtained in the reactions of 2′,3′-O-isopropylidene-uridine and O-peracetylated β-d-gluco-, galacto- and xylopyranosylamines, and OCNCOCl. 2,3,4,6-Tetra-O-acetyl-β-d-glucopyranosyl isocyanate and N-(2′,3′-O-isopropylidene-5′-uridyl)urea gave 1-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-5-(2′,3′-O-isopropylidene-5′-uridyl)biuret. Deprotection of the β-d-gluco configured allophanate and biuret was carried out by standard methods.     

Chemical Syntheses of 4-O-α and -β-D-galactopyranosyl-D-galactose and 3-O-α- and -β-D-galactopyranosyl-D-galactose

Reaction of 2,3-di-O-acetyl-1,6-anhydro-β-D-galactopyranose (2) with 2,3,4,6-tetra- O-acetyl-α-D-galactopyranosyl bromide in the presence of mercuric cyanide and subsequent acetolysis gave 1,2,3,6-tetra-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-α-D-galactopyranose (4, 40%) and 1,2,3,6-tetra-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-α-D-galactopyranose (5, 30%). Similarly, reaction of 2,4-di-O-acetyl-1,6-anhydro-β-D-galactopyranose (3) gave 1,2,4,6-tetra-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-α-D-galactopyranose (6, 46%) and 1,2,4,6-tetra-O-acetyl-3-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-α-D-galactopyranose (7, 14%). The anomeric configurations of 4-7 were assigned by n.m.r. spectroscopy. Deacetylation of 4-7 afforded 4-O-α-D-galactopyranosyl-D-galactose (8), 4-O-β-D-galactopyranosyl-D-galactose (9), 3-O-α-D-galactopyranosyl-D-galactose (10), and 3-O-β-D-galactopyranosyl-D-galactose (11), respectively.     

Glycosides for testing glycosidases: Vinyl,l-ethoxyethyl,and l-ethoxybut-3-enyl d-glucopyranosides

The reaction of ethyl vinyl ether and 2,3,4,6-tetra-O-acetyl-β-d-glucopyranose (1) in the presence of Hg-(OAc)₂ and toluene-p-sulphonic acid as catalysts yielded the acetylated vinyl, l-ethoxyethyl, and l-ethoxybut-3-enyl glycosides in varying proportions. Crystalline l-ethoxybut-3-enyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (2), vinyl 2,3,4,6-tetra-O-acetyl-α-d-glucopyranoside (3), and l-ethoxyethyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (4) were isolated by chromatography. Compound 4 was also prepared by the reaction of 1 with cold acetaldehyde diethyl acetal containing a trace of acetic acid, and its α anomer (5) by the reaction of 1 with boiling acetaldehyde diethyl acetal containing a trace of acetic acid. Each deacetylated d-glucoside was cleaved by the corresponding d-glucosidase, to yield d-glucose and either acetaldehyde (from deacetylated 3-5) or but-3-enal (from deacetylated 2).     

Synthesis of 2-(6-aminohexanamido)ethyl 1-thio-β-d-galactopyranoside and 1-thio-β-d-glucopyranoside,and related compounds

2-(6-Aminohexanamido)ethyl 1-thio-β-d-galactopyranoside (5) and 1-thio-β-d-glucopyranoside (9) were prepared by the following scheme: 2,3,4,6-tetra-O-acetyl-1-thio-β-d-aldopyranoses, generated from 2-S-(2,3,4,6-tetra-O-acetyl-β-d-aldopyranosyl)-2-thiopseudourea hydrobromides, were aminoethylated with ethylenimine, followed by N-acylation of the products with 6-(trifluoroacetamido)hexanoic acid (1), and O-deacylation. These reactions could be carried out consecutively without isolation of intermediates, and the products obtained after gel chromatography were de(trifluoroacetyl)ated to obtain the final products. The chain lengths of the aglycons were further extended by repeating the acylation and the de(trifluoroacetyl)ation. An analog containing glycerol in lieu of a sugar was prepared by a similar reaction-scheme.     

Studies on the structure of a polysaccharide from Epidermophyton floccosum and approach to a synthesis of the basic trisaccharide repeating units

An alkali-soluble polysaccharide, designated as S-Iawe, has been isolated from the maycelia of Epidermophyton floccosum. Methylation, periodate oxidation, and acetolysis studies suggested that S-lawe is composed of (1→6)-Oα-d-mannopyranosyl-(1→6)-O-[α-d-mannopyranosyl-(1→2)]-O-α-d-mannopyranosyl repeating units. Condensation of 2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl bromide with methyl 3-O-benzyl-4,6-O-benzylidene-α-d-mannopyranoside in the presence of mercuric cyanide gave in 70% yield methyl 3-O-benzyl-4,6-O-benzylidene-2-O-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-α-d-mannopyranoside. Condensation of the debenzylidenated disaccharide with 2,3,4,6-tetra-O-acctyl-α-d-mannopyranosyl bromide afforded the corresponding trisaccharide repeating unit.     

Application of the imidate procedure to α-d-galactosyltion

Using the imidate procedure, 2,3,4,6-tetra-O-benzyl-1-O-(N-methylacetimidoyl)-β-d-galactopyranose was condensed with various monosaccharides to provide, in good yield and with high stereoselectivity, α-linked disaccharides.     

Electrosyntheses of disaccharides from phenyl or ethyl 1-thioglycosides

Constant current electrolyses of the glycosyl donors phenyl and ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-d-glycopyranoside in dry acetonitrile in the presence of various primary and secondary sugar alcohols, performed in an undivided cell, gave β-linked disaccharide derivatives selectively in good yields. Phenyl 2,3,4,6-tetra-O-benzoyl-1-thio-β-d-glycopyranoside gave the β-glucosides exclusively in good to moderate yields.     

Synthesis of Some N-Galactosides of 3-Aryl-5-benzyl (or Substituted Benzyl)-1,2,4-triazin-6(1H)-/ones or Thiones of Expected Biological Activity

Abstract

The 1-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-3-aryl-5-benzyl (or substituted benzyl)-1,2,4-triazin-6(1H)-/ones or thiones were prepared via galactosidation of 3-aryl-5-benzyl (or substituted benzyl)-1,2,4-triazin-6(1H)-/ones or thiones with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide. The structure of the new galactosyl derivatives was based on both spectroscopic and chemical evidences.     

Synthesis of glycosyl halides and glycosides via 1-O-sulfonyl derivatives

The reaction of an aldose derivative containing a free anomeric hydroxyl group with trifluoromethanesulfonic anhydride or methanesulfonic anhydride, in the presence of halide ion and s-collidine, furnishes a glycosyl halide; if an alcohol is then introduced, glycoside synthesis is effected in an overall, “one-pot” reaction. Several α-d-glucopyranosides, including disaccharides, have been prepared in high yield by using 2,3,4,6-tetra-O-benzyl-d-glucose as the aldose, and generating the corresponding glycosyl bromide(s) in situ. As a halide-exchange step is incorporated in the reaction sequence, orthoacetate formation was favored in reactions of 2,3,4,6-tetra-O-acetyl-d-glucose, such as occurs with per-O-acetylglycosyl halides. Methanesulfonic anhydride promotes glycosidation or orthoester formation in the absence of halide ion, as well as in its presence, whereas formation of an intermediate glycosyl halide appears to be necessary in order to moderate the more vigorous reactions of the trifluoro derivative. The analogous reaction of methanesulfonyl chloride with an aldose provides a ready route to glycosyl chlorides. Under the conditions employed for these various syntheses, acid-sensitive protecting groups may be used, including cyclic and acyclic acetals and O-trityl substituents.     

Syntheses of 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-d-glucopyranose (n-acetylmaltosamine) and 2-acetamido-2-deoxy-4-O-β-d-glucopyranosyl-α-d-glucopyranose

Condensation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside with 2,3,4,6-tetra-O-benzyl-1-O-(N-methyl)acetimidoyl-β-D-glucopyranose gave benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside which was catalytically hydrogenolysed to crystalline 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-D-glucopyranose (N-acetylmaltosamine). In an alternative route, the aforementioned imidate was condensed with 2-acetamido-3-O-acetyl-1,6-anhydro-2-deoxy-β-D-glucopyranose, and the resulting disaccharide was catalytically hydrogenolysed, acetylated, and acetolysed to give 2-acetamido-1,3,6-tri-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-α-D-glucopyranose Deacetylation gave N-acetylmaltosamine. The synthesis of 2-acetamido-2-deoxy-4-O-β-D-glucopyranosyl-α-D-glucopyranose involved condensation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in the presence of mercuric bromide, followed by deacetylation and catalytic hydrogenolysis of the condensation product.     

Preparation of (aryl α-l-idopyranosid)uronic acids

The earlier preparation of cyclohexylammonium (phenyl α-l-idopyranosid)-uronate has been improved, and (4-methylumbelliferyl α-l-idopyranosid)uronic acid (14), a more sensitive substrate for α-l-iduronidase, has been synthesized by an analogous route. Zinc chloride-catalyzed condensation of 4-methylumbelliferone with 1,2,3,4,6-penta-O-acetyl-α-l-idopyranose (4) in 1,2-ethanediol diacetate gave crystalline 4-methylumbelliferyl 2,3,4,6-tetra-O-acetyl-α-l-idopyranoside (7). O-Deacetylation and catalytic oxidation gave 14, characterized as a cyclohexylammonium salt. The starting material 4 was prepared, in 21 % yield from l-glucose, by conversion of the intermediate 1,2,3,4,6-penta-O-acetyl-β-l-glucopyranose to 2,3,4,6-tetra-O-acetyl-β-l-glucopyranosyl chloride and acetoxonium ion rearrangement, as described for the D-series.     

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.