Conrad Schuerch

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

Abstract 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.

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

Abstract 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.

The use of 2,3,4,6-tetra-O-benzyl-α-d-glycopyranosyl iodides in α-glycoside synthesis

Abstract 2,3,4,6-Tetra-O-benzyl-α- d -gluco- and -α- d -galactopyranosyl iodides react rapidly in acetonitrile and other solvents with limited excesses of methanol, ethanol, 2-propanol, and cyclohexanol in the presence of 2,6-lutidine. The products obtained from the lower alcohols, contain a high proportion of α glycoside. The highest ratios of α- to β-anomer are obtained at low concentrations of alcohol. The high rates, stereoselectivity, and lack of side-reactions observed suggest that the alcoholysis of glycosyl iodides should be tested as a route to oligosaccharide synthesis.

The influence of reactant structure and solvent on galactoside syntheses from galactosyl sulfonates

Abstract The glycosidation of some 2-O-allyl- and 2-O-benzyl- D -galactopyranosyl sulfonates was studied as a function of alcohol, solvent, leaving group at C-1, and substituent groups at C-3, -4, and -6. In the 2,3,4-tri-O-benzyl series, no combinations of these parameters lead to high α-stereoselectivity, and high β-stereoselectivity was observed only in methanolyses with the trifluoromethanesulfonate leaving-group. With 2,3-di-O-benzyl-4,6-di-O-(N-phenylcarbamoyl)- D -galactopyranosyl p-toluene-sulfonate, high α-specificity (>90%) was achieved on methanolysis and, with the corresponding trifluoromethanesulfonate, high β-stereoselectivity. Results with 2-O-allyl- and 2-O-benzyl-3,4-di-O-(N-phenylcarbamoyl)-6-O-acetyl- D -galactopyranosyl sulfonates were comparable to each other. In general methane- and p-toluene-sulfonates in solvents of the ether type gave high α-stereoselectivity (>90%) with a number of alcohols of widely different structures, including saccharides. Thus, appropriately substituted D -galactopyranosyl sulfonates, reacting overnight with an equivalent amount of alcohol, formed α-glycosides in high yield and steric purity, as has previously been observed with related glucose derivatives. The nature of the substituents at C-3, C-4, and C-6 has a profound influence on the steric course of the glycosidation reaction.

Synthesis and characterization of methyl 6-O-β-d-galactopyranosyl-β-d-galactopyranoside and methyl O-β-d-galactopyranosyl-(1→6)-O-β-d-galactopyranosyl-(1→6)-β-d-galactopyranoside☆

Abstract 6- O -Acetyl-2- O -benzoyl-3,4-di- O -benzyl-α- d -galactopyranosyl chloride ( 8 ) was prepared from 1,6-anhydro-2- O -benzoyl-3,4-di- O -benzyl-β- d -galactopyranose via the corresponding 1,6-di- O -acetyl derivative 7 . The glycosyl chloride 8 was converted into the 1- O -tosyl derivative ( 9 ) which was allowed to react with methanol in acetonitrile to form methyl 6- O -acetyl-2- O -benzoyl-3,4-di- O -benzyl-β- d -galactopyranoside ( 10 ). Compound 10 was O -deacetylated with ammonium hydroxide in methanol to give 11 . Reaction of 9 with 11 under the same conditions of glycosidation gave the corresponding disaccharide derivative 12 . O -Deacetylation of 12 followed by glycosidation with 9 gave the corresponding trisaccharide derivative 16 . Appropriate deblocking sequences gave the title compounds. The structures of the glycosides were determined with the aid of both 1 H- and 13 C-n.m.r. spectroscopy. No evidence of α- d linkages was found.

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

Abstract 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.

Stereoselective syntheses of 1,2-cis- and 1,2-trans-d-mannopyranosides

Abstract 3,4,6-Tri- O -allyl-β- d -mannose 1,2-(methyl orthoacetate) has been prepared from the corresponding tri- O -acetyl derivative and used as a precursor for stereo-controlled synthesis of both the 1,2- cis - and trans - d -mannopyranosides. The allyl groups were selected and tested as temporary blocking groups which allow suitable deprotection under mild conditions following glycosidation. Hydrolysis of the orthoester ring afforded 3,4,6-tri- O -allyl- d -mannose. The latter was converted into 3,4,6-tri- O -allyl-2- O -mesyl-α- d -mannopyranosyl chloride, whose coupling with methanol and cyclohexanol afforded stereoselectively the β anomers as the major products. Methanolysis of the orthoester afforded the α anomer as the major product. The determination of the anomeric configuration is discussed and the 1 H-n.m.r. and 13 C-n.m.r. spectral data are correlated.

The synthesis of trisaccharide antigenic determinants for the branch points in natural dextrans and their protein conjugates

Abstract Three O -allyl-di- O -benzyl-6- O -( N -phenylcarbamoyl)-1- O -tosyl- d -glucopyranose derivatives were coupled with 2-[4-( p -toluenesulfonamido)phenyl]ethanol to give the corresponding α- d -glucopyranosides. Decarbanilation and deallylation gave the corresponding 2,3-, 2,4-, and 3,4-di- O -benzyl-α- d -glucopyranosides. Reaction of the diols with two equivalents of 2,3,4-tri- O -benzyl-6- O -( N -phenylcarbamoyl)-1- O -tosyl- d -glucopyranose gave the branched trisacchalides having an α- d -glucopyranosyl group at O-6 and one at either O-2, O-3, or O-4. The oligosaccharides were deblocked with sodium in liquid ammonia to give the 2-(4-aminophenyl)ethyl α- d -glucoside, which were converted into the isothiocyanate derivatives with thiophosgene. The functionalized oligosaccharides were coupled to bovine serum albumin to give protein conjugates.

The synthesis of α- and β-(1 → 2)- and -(1 → 3)-linked glucopyranose disaccharides and their protein conjugates

Abstract 2,3,4-Tri- O -benzyl-6- O -( N -phenylcarbamoyl)-1- O -tosyl- d -glucopyranose and 3,4,6-tri- O -benzyl-2- O - p -nitrobenzoyl-1- O -tosyl- d -glucopyranose were allowed to react with partially blocked 2-[4-( p -toluenesulfonamido)phenyl]ethyl α- and β- d -glucopyranosides. Disaccharides having the structure α- d -Glc p -(1 → 2)-α- d -Glc p , α- d -Glc p -(1 → 3)-α- d -Glc p , β- d -Glc p -(1 → 2)-β- d -Glc p , and β- d -Glc p -(1 → 3)-α- d -Glc p were synthesized. The oligosaccharides were debenzylated with sodium in liquid ammonia to give disaccharides having a free primary aromatic amino group, which were converted into isothiocyanate derivatives and then coupled to various proteins to give the corresponding conjugates.

Chemical synthesis of a (1→2)-d-glucopyranan

Abstract 1,2-Anhydro-3,4,6-tri- O -benzyl-α- d -glucopyranose was polymerized with a number of Lewis acids. Phosphorus pentafluoride at −60° caused polymerization to a product rich in β linkages. Other Lewis acids at higher temperatures gave perbenzylated polysaccharides of lower molecular weight with less stereoselectivity. Debenzylation of the most-regular derivative gave a polysaccharide whose specific rotation was +14.7° and whose 13 C-n.m.r. spectrum had six absorptions corresponding to those of natural (1→2)-β- d -glucopyranans and additional minor peaks presumably due to some α-anomeric configurations. It was estimated to have ∼90% of β linkages.