Synthesis of 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose

Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-α-d-mannopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside (2) gave an α-d-linked disaccharide, further transformed by removal of the carbonyl and benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-α-d-glucopyranoside. Condensation of 3,4,6-tri-O-benzyl-1,2-O-(1-ethoxyethylidene)-α-d-glucopyranose or 2-O-acetyl-3,4,6-tri-O-benzyl-α-d-glucopyranosyl bromide with 2 gave benzyl 2-acetamido-3-O-(2-O-acetyl-3,4,6-tri-O-benzyl-β-d-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside. Removal of the acetyl group at O-2, followed by oxidation with acetic anhydride-dimethyl sulfoxide, gave the β-d-arabino-hexosid-2-ulose 14. Reduction with sodium borohydride, and removal of the protective groups, gave 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose, which was characterized as the heptaacetate. The anomeric configuration of the glycosidic linkage was ascertained by comparison with the α-d-linked analog.     

Synthesis of phenyl 2-acetamido-2-deoxy-3-O-α-l-fucopyranosyl-β-d-glucopyranoside and related compounds

The reaction of phenyl 2-acetamido-2-deoxy-4,6- O-(p-methoxybenzylidene)-β-d-glucopyranoside with 2,3,4-tri-O-benzyl-α-l-fucopyranosyl bromide under halide ion-catalyzed conditions proceeded readily, to give phenyl 2-acetamido-2-deoxy-4,6-O-(p-methoxybenzylidene)-3-O-(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)-β-d-glucopyranoside (8). Mild treatment of 8 with acid, followed by hydrogenolysis, provided the disaccharide phenyl 2-acetamido-2-deoxy-3-O-α-l-fucopyranosyl-β-d-glucopyranoside. Starting from 6-(trifluoroacetamido)hexyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranoside, the synthesis of 6-(trifluoroacetamido)hexyl 2-acetamido-2-deoxy-3-O-β-l-fucopyranosyl-β-d-glucopyranoside has been accomplished by a similar reaction-sequence. On acetolysis, methyl 2-acetamido-2-deoxy-3-O-α-l-fucopyranosyl-α-d-glucopyranoside gave 2-methyl-[4,6-di-O-acetyl-1,2-dideoxy-3-O-(2,3,4-tri-O-acetyl-α-l-fucopyranosyl)-α-d-glucopyrano]-[2, 1-d]-2-oxazoline as the major product.     

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.     

Synthesis of 4-deoxy-d-xylo-hexose and 4-azido-4-deoxy-d-glucose and their effects on lactose synthase

Syntheses are reported of 4-deoxy-d-xylo-hexose and 4-azido-4-deoxy-d-glucose as potential inhibitors for lactose synthase [uridine 5′-(α-d-galactopyranosyl pyrophosphate):d-glucose 4-β-d-galactopyranosyltransferase, EC 2.4.1.22]. These syntheses involved SN2 displacement of the 4-methylsulfonyloxy group of methyl 2,3,6-tri-O-benzoyl-4-O-methylsulfonyl-α-d-galactopyranoside by iodide and azide ions. In both cases, inversion in configuration was observed. The resulting intermediates, methyl 2,3,6-tri-O-benzoyl-deoxy-4-iodo-α-d-glucopyranoside and methyl 4-azido-2,3,6-tri-O-benzoyl-deoxy-α-d-glucopyranoside, were obtained in crystalline form. Both 4-deoxy-d-xylo-hexose and 4-azido-4-deoxy-d-glucose were found to be inhibitors for lactose synthase in the presence of α-lactalbumin, but had no effect in the absence of α-lactalbumin. Both d-glucose analogues bind to the enzyme system far more weakly than d-glucose, suggesting that the recognition of the 4-OH group of the acceptor substrate is an important factor in binding.     

Studies on the stereoselective synthesis of a protected α-d-Gal-(1→2)-d-Glc fragment

A novel 1,2-cis stereoselective synthesis of protected α-d-Gal-(1→2)-d-Glc fragments was developed. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-α-d-glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside (17), and methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-β-d-glucopyranoside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-1-thio-β-d-galactopyranoside (2), with acceptors, methyl 3-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl-α-d-glucopyranoside (5), methyl 3-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-β-d-glucopyranoside (12), respectively. By virtue of the concerted 1,2-cis α-directing action induced by the 3-O-allyl and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group participation, the couplings were achieved with a high degree of α selectivity. In particular, higher α/β stereoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12 having a β-CH₃ at C-1 and benzoyl groups at C-4 and C-6.     

Synthesis of a series of fully methylated aldobiouronic acids,and β-elimination reactions of their synthetic precursors

Treatment of methyl 2,3,4-tri-O-acetyl-l-bromo-l-deoxy-α-d-glucopyranuronate severally with 2,4,6-, 2,3,6-, and 2,3,4-tri-O-methyl derivatives of methyl α-d-glucopyranoside and with methyl 4,6-O-benzylidene-3-O-methyl-α-d-glucopyranoside, in the presence of silver carbonate, afforded crystalline aldobiouronic acid derivatives in high yield. Deacetylation followed by methylation gave a series of fully methylated derivatives of laminaribiouronic, cellobiouronic, and gentiobiouronic acids, and the (1 → 2)-linked analogue. Methylation with methyl iodide and silver oxide in N,N-dimethylformamide was invariably accompanied by a small amount ofβ-elimination, with the formation of olefinic disaccharides which were also obtained by β-elimination reactions of the precursor acetates followed by methylation. Methyl 4,5-unsaturated 4-deoxyhexopyranosyluronate derivatives were the main products of the reaction, but these underwent further degradation with cleavage of the interglycosidic linkage and formation of 6-methoxycarbonyl-4-pyrone.     

Conversion of allyl 2-acetamido-2-deoxy-β-d-glucopyranoside into 2-methyl-(3,4,6-tri-O-benzoyl-1,2-dideoxy-α-d- galactopyrano)-[2′,1′:4,5]-2-oxazoline

2-Methyl-(3,4,6-tri-O-benzoyl-1,2-dideoxy-α-d-galactopyrano)-[2′,1′:4,5]-2-oxazoline (7) was prepared from 1-propenyl 2-acetamido-3,4,6-tri-O-benzoyl-2- deoxy-β-d-galactopyranoside (6). The latter was prepared from allyl 2-acetamido-2-deoxy-β-d-glucopyranoside (1) through selective benzoylation at O-3 and O-6, conversion into the 4-p-bromobenzenesulfonate 4, inversion of configuration at C-4 to afford allyl 2-acetamido-3,4,6-tri-O-benzoyl-β-d-galactopyranoside (5), and subsequent isomerization with palladium-charcoal to give 6.     

Synthesis of 3- and 2′-fucosyl-lactose and 3,2′-difucosyl-lactose from partially benzylated lactose derivatives

O-β-d-Galactopyranosyl-(1→4)-O-[α-l-fucopyranosyl-(1→3)]-d-glucose has been synthesised by reaction of benzyl 2,6-di-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-β-d-galactopyranosyl)-β-d-glucopyranoside with 2,3,4-tri-O-benzyl-α-l-fucopyranosyl bromide in the presence of mercuric bromide, followed by hydrogenolysis. Benzylation of benzyl 3′,4′-O-isopropylidene-β-lactoside, via tributylstannylation, in the presence of tetrabutylammonium bromide or N-methylimidazole, gave benzyl 2,6-di-O-benzyl-4-O-(6-O-benzyl-3,4-O-isopropylidene-β-d-galactopyranosyl)-β-d-glucopyranoside (6). α-Fucosylation of 6 in the presence of tetraethylammonium bromide provided either benzyl 2,6-di-O-benzyl-4-O-[6-O-benzyl-3,4-O-isopropylidene-2-O-(2,3,4-tri-O-benzyl-α-l-fucopyransoyl)-β-d- galactopyranosyl]-β-d-glucopyranoside (13, 73%) or a mixture of 13 (42%) and benzyl 2,6-di-O-benzyl-4-O-[6-O-benzyl-3,4,-O-isopropylidene-2-O-(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)-β-d- galactopyranosyl-3-O-(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)-β-d-glucopyranoside (16, 34%). α-Fucosylation of 13 in the presence of mercuric bromide and 2,6-di-tert-butyl-4-methylpyridine gave 16 (73%). Hydrogenolysis and acid hydrolysis of 13 and 16 afforded O-α-l-fucopyranosyl-(1→2)-O-β-d-galactopyranosyl-(1→4)-d-glucose and O-α-l-fucopyranosyl-(1→2)-O-β-d-galactopyranosyl-(1→4)-O-[α-l-fucopyranosyl-(1→3)]-d-glucose, respectively.     

Synthesis of 1,2-trans-disaccharides via sugar thio-orthoesters

The reaction of sugar 1,2-thio-orthoesters in the d-gluco, d-galacto, d-manno, and l-rhamno series with primary and secondary trityl ethers of monosaccharides, in the presence of triphenylmethylium perchlorate as catalyst, affords, stereospecifically, derivatives of 1,2-trans-disaccharides in good yields. 4-Trityl ethers of benzyl 2-acetamido-3,6-di-O-acetyl-2-deoxy-α-d-glucopyranoside and methyl 2,3,6-tri-O-benzoyl-α-d-galactopyranoside exhibit low reactivity in glycosylation by thio-orthoesters. A reaction scheme for the glycosylation is discussed.     

Galactan sulfate from the test of tunicates

Methyl and benzyl 3-O-β-d-xylopyranosyl-α-d-mannopyranoside were prepared by way of d-xylosylation (Koenigs-Knorr) of methyl and benzyl 4,6-O-benzylidene-α-d-mannopyranoside (1 and 17). Analogous 2-O-β-d-xylopyranosyl-α-d-mannopyranosides could not be prepared efficiently by this procedure. However, methyl and benzyl 3-O-acetyl-4,6-O-benzylidene-α-d-mannopyranoside, prepared by limited acetylation of 1 and 17, respectively, could be d-xylosylated by the same method, and afforded, after removal of protective groups, methyl and benzyl 2-O-β-d-xylopyranosyl-α-d-mannopyranoside. Hydrogenolysis of benzyl 2-O- and 3-O-β-d-xylopyranosyl-α-d-mannopyranoside yielded the corresponding, reducing disaccharides. In addition to these disaccharides, disaccharides containing an α-d-xylopyranosyl group, and trisaccharides having d-xylopyranosyl groups at both O-2 and O-3 were obtained as minor products.     

The synthesis of O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→4)-N-acetylnormuramoyl-l-α-aminobutanoyl-d-isoglutamine

Benzyl 2-acetamido-3-O-allyl-6-O-benzyl-2-deoxy-4-O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl)- α-d-glucopyranoside (4) was obtained in high yield on using the silver triflate method in the absence of base. Compound 4 was converted in six steps into benzyl 2-acetamido-4-O-(2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-d-glucopyranosyl)-6-O-benzyl-3-O-(carboxymethyl)-2-deoxy-α-d- glucopyranoside, which was coupled with the benzyl ester of l-α-aminobutanoyl-d-isoglutamine and the product hydrogenolyzed to afford the title compound. O-Benzylation of benzyl 2-acetamido-4-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-3-O-allyl-6-O-benzyl-2-deoxy-α-d-glucopyranoside with benzyl bromide and barium hydroxide in N,N-dimethylformamide is strongly exhanced by sonication of the reaction mixture.     

Selective benzylation of some D-galactopyranosides. Unusual relative reactivity of the hydroxyl group at C-4

Partial benzylation of methyl 2,3-di-O-benzyl-α-D-galactopyranoside gave methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside as the major product, whereas the isomeric 2,6-di-O-benzyl ether gave a mixture of products in which the ratio of methyl 2,4,6- to methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside was ≈4:1. The proportion of unreacted starting-material was low in both cases, whereas after a similar reaction of methyl 2,6-di-O-benzyl-β-D-galactopyranoside more than 50% of the dibenzyl ether was recovered unchanged. In this case also, considerably higher reactivity was exhibited by the hydroxyl group at C-4 than that at C-3. Acid hydrolysis of the methyl glycosides of the tribenzyl ethers afforded crystalline 2,4,6-tri-O-benzyl-α-D-galactose and syrupy 2,3,6-tri-O-benzyl-D-galactose. Structures of intermediates were established by acetylation, examination of their n.m.r. spectra, and conversion into the known 3-O and 4-O-methyl-D-galactose.     

Synthesis of a model of an inner chain of cell-wall proteoheteroglycan isolated from Piricularia oryzae: Branched d-mannopentaosides

Efficient syntheses are described of the branched d-mannopentaosides methyl 2,6-di-O-(2-O-α-d-mannopyranosyl-α-d-mannopyranosyl)α-d-mannopyranoside and methyl 2,4-di-O-(2-O-α-d-mannopyranosyl-α-d-mannopyranosyl)-α-d-mannopyranoside, starting from the glycosyl acceptors methyl 3,4-di-O-benzyl-α-d-mannopyranoside and methyl 3,6-di-O-benzyl-α-d-mannopyranoside, and employing the protected d-mannotriosides methyl 3,4-di-O-benzyl-2,6-di-O-(3,4,6-tri-O-benzyl-α-d-mannopyranosyl)-α-d-mannopyranoside, and methyl 3,6-di-O-benzyl-2,4-di-O-(3,4,6-tri-O-benzyl-α-d-mannopyranosyl)-α-d-mannopyranoside as key intermediates.     

Synthèse de trithioorthocarbonates de pyranosides par thermolyse de bis(dithiocarbonates)

The thermal decomposition of methyl 4,6-O-benzylidene-2,3-di-O-[(methylthio)-thiocarbonyl]-α-d-glucopyranoside afforded methyl 4,6-O-benzylidene-2-thio-α-d-mannopyranoside 3-O,2-S-(S,S-dimethyl trithioorthocarbonate) and methyl 4,6-O-benzylidene-3-thio-α-d-allopyranoside 2-O,3-S-(S,S-dimethyl trithioorthocarbonate) in good yield. This decomposition can be generalized to 1,3-diols derived from sugars. Thus methyl 2,3-di-O-methyl-4,6-di-O-[(methylthio)thiocarbonyl]-α-d-glucopyranoside afforded in the same way the corresponding trithioorthocarbonates, following a regioselective process. The structures of these trithioorthocarbonates are confirmed by spectral and chemical proofs.     

Synthesis of di-, tri-, and tetra-saccharides corresponding to receptor structures recognised by Streptococcus pneumoniae

Syntheses are described for methyl 2-acetamido-2-deoxy-4-O-β-d-galactopyranosyl-α-d-glucopyranoside, methyl 2-acetamido-2-deoxy-4-O-β-d-galactopyranosyl-β-d-glucopyranoside, methyl 3-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl-β-d-galactopyranoside, methyl 3-O-(2-acetamido-2-deoxy-4-O-β-d-galactopyranosyl-β-d-glucopyranosyl)-β-d-galactopyranoside, and methyl 4-O-[3-O-(2-acetamido-2-deoxy-4-O-β-d-galactopyranosyl-β-d-glucopyranosyl)-β-d-galactopyranosyl]- β-d-glucopyranoside.     

Synthesis of N-[2-O-(2-acetamido-2,3-dideoxy-5-thio-d-glucopyranose-3-yl)-d-lactoyl]-l-alanyl-d-isoglutamine

N-[2-O-(2-Acetamido-2,3-dideoxy-5-thio-d-glucopyranose-3-yl)-d-lactoyl]-l-alanyl-d-isoglutamine, in which the ring-oxygen atom of the sugar moiety in N-acetylmuramoyl-l-alanyl-d-isoglutamine (MDP) has been replaced by sulfur, was synthesized from 2-acetamido-2-deoxy-5-thio-α-d-glucopyranose (1). O-Deacetylation of the acetylated acetal, derived from the methyl α-glycoside of 1 by 4,6-O-isopropylidenation and subsequent acetylation, gave methyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-5-thio-α-d-glucopyranoside (4). Condensation of 4 with l-2-chloropropanoic acid, and subsequent esterification, afforded the corresponding ester, which was converted, viaO-deisopropylidenation, acetylation, and acetolysis, into 2-acetamido-1,4,6-tri-O-acetyl-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-5-thio-α-d-glucopyranose (12). Coupling of the acid, formed from 12 by hydrolysis, with the methyl ester of l-alanyl-d-isoglutamine, and de-esterification, yielded the title compound.     

Synthesis of the tetrasaccharide repeating-unit of the O-specific polysaccharide from Salmonella senftenberg

The oligosaccharide β-d-Man-(1 → 4)-α-l-Rha (1 → 3)-d-Gal-(6 ← 1)-α-d-Glc, which is the repeating unit of the O-specific polysaccharide chain of the lipopolysaccharide from Salmonella senftenberg, was obtained by glycosylation of benzyl 2,4-di-O-benzyl-6-O-(2,3,4-tri-O-benzyl-6-O-p-nitrobenzoyl-α-d-glucopyranosyl)-β-d-galactopyranoside or benzyl 2-O-acetyl-6-O-(2,3,4-tri-O-benzyl-6-O-p-nitrobenzoyl-α-d-glucopyranosyl)-β-d-galactopyranoside with 3-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-d-mannopyranosyl)-β-l-rhamnopyranose 1,2-(methyl orthoacetate) followed by removal of protecting groups.     

Synthesis of a branched d-mannopentaoside and a branched d-mannohexaoside: Models of the outer chain of the glycan of soybean agglutinin

Synthetic routes are described to the d-mannopentaoside methyl 3-O-(3,6-di-O-α-d-mannopyranosyl-α-d-mannopyranosyl)-6-O-α-d-mannopyranosyl-α-d-mannopyranoside, and the d-mannohexaoside methyl 3-O-(3,6-di-O-α-d-mannopyranosyl-α-d-mannopyranosyl)-6-O-(2-O-α-d-mannopyranosyl-α-d-mannopyranosyl)-α- d-mannopyranoside, formed in a regio- and stereo-controlled way by employing the properly protected d-mannobioside methyl 2,4-di-O-benzyl-3-O-(2,4-di-O-benzyl-α-d-mannopyranosyl)-α-d-mannopyranoside and d-mannotrioside methyl 2,4-di-O-benzyl-3-O-(2,4-di-O-benzyl-α-d-mannopyranosyl)-6-O-(3,4,6-tri-O-benzyl-α-d- mannopyranosyl)-α-d-mannopyranoside as key intermediates.     

Furostanol glycosides from Trigonella foenum-graecum seeds

Two new furostanol glycosides, trigofoenosides F and G, have been isolated as their methyl ethers from the methanolic extract of Trigonella foenum-graecum seeds (Leguminosae). The structures of the original glycosides have been determined as (25R)-furost-5-en-3β,22,26-triol, 3-O-α-l-rhamnopyranosyl (1 → 2)β-d-glucopyranosyl (1 → 6)β-d-glucopyranoside; 26-O-β-d-glucopyranoside and (25R)-furost-5en-3β,22,26-triol, 3-O-α-L-rhamnopyranosyl (1 → 2) [β-d-xylopyranosyl (1 → 4)]β-d-glucopyranosyl (1 → 6)β-d-glucopyranoside; 26-O-β-d-glucopyranoside, respectively.     

Synthesis and bioactivity of novel methyl 6-deoxy-6-(N'-alkyl/aryl-N'-benzothiazol-2-yl)guanidino-alpha-D-glucopyranosides

A series of new methyl 6-deoxy-6-[N′-alkyl/aryl-N″-(benzothiazol-2-yl)]guanidino-α-d-glucopyranosides were obtained from the reaction of an alkyl/aryl amine in the presence of HgCl₂ and sugar-thiourea derivatives, followed by the removal of protecting groups. The sugar-thiourea derivatives were obtained from the treatment of 2-aminobenzothiazole derivatives with methyl 2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-α-d-glucopyranoside in dry pyridine. Some of the synthesized guanidines displayed anti-influenza activity.