Oligosaccharide synthesis by the thioglycoside scheme on soluble and insoluble polystyrene supports

The solid-phase synthesis of a disaccharide via the thioglycoside approach is described. Treatment of (chloromethyl)polystyrene, either cross-linked (1-X) or linear (1-L), with the 1-thio sugar 4 gave resins (6-X, 6-L) carrying thioglycosidically bound 2,3,4-tri-O-benzyl-D-glucopyranosyl groups. Alternatively, the conversion of 1-X into (mercaptomethyl)polystyrene (3-X) and reaction of this with the glucosyl chloride 5 gave 6-X. By repeated treatments with 6-O-acetyl-2,3,4-tri-O-benzyl-α-D-glucopyranosyl bromide, a second D-glucose residue was coupled to 74–92% of the first sugar residues. The action of methyl iodide—benzyl alcohol in refluxing benzene quantitatively cleaved the sugars from the polystyrene support, forming benzyl glycosides (13, 7) and, from the unreacted monosaccharide residues, the 1,6-anhydro sugar 9. The coupling product was 92–95% α-linked. Deprotection and purification gave isomaltose.     

Synthesis of 2,4-diacetamido-2,4,6-trideoxy-D-Galactose

Treatment of benzyl 2-acetamido-3-O-benzyl-2,6-dideoxy-4-O-(methylsulfonyl)-α-D-glucopyranoside (1) with sodium azide in hexamethylphosphoric triamide gave the 4-azido-α-D-galacto derivative (2), which was converted into benzyl 2,4-di-acetamido-3-O-benzyl-2,3,6-trideoxy-α-D-galactopyranoside (3) by hydrogenation and subsequent acetylation. Hydrogenolysis of 3 at atmospheric pressure afforded benzyl 2,4-diacetamido-2,4,6-tridcoxy-α-D-galactopyranoside (4), which was acetylated to give the 3-O-acetyl derivative (5). The n.m.r. spectrum of 5 was in agreement with the assigned structure and different from that of benzyl 2,4-di-acetamido-3-O-acetyl-α-D-glucopyranoside (9), which was prepared from the known benzyl 2,4-diacetamido-3-O-benzyl-2,4,6-trideoxy-α-D-glucopyranoside. Catalytic hydrogenolysis of 4 gave 2,4-diacetamido-2,4,6-trideoxy-D-galactose (6).     

Copper(II) complexes of new pentadentate bis(benzimidazolyl)-dithioether ligands: synthesis, structure, spectra and redox properties

Copper(II) complexes of a series of linear pentadentate ligands containing two benzimidazoles, two thioether sulfurs and a amine nitrogen, viz. N,N^′-bis{4^′-(2″-benzimidazolyl)(methyl)-3^′-thiabutyl}amine(L¹), N,N^′-bis{4^′-(2″-benzimidazolyl)(methyl)-3^′-thiabutyl}N-methylamine (L²), 2,6-bis{4^′-(2″-benzimidazolyl)(methyl)-3^′-thiabutyl}pyridine(L³), N,N^′-bis{4^′-(2″-benzimidazolyl)-2^′-thiabutyl}amine (L⁴), N,N^′-bis{4^′-(2″-benzimidazolyl)-2^′-thiabutyl}N-methylamine (L⁵) and 2,6-bis{4^′-(2″-benzimidazolyl)-2^′-thiabutyl}-3pyridine (L⁶) have been isolated and characterized by electronic absorption and EPR spectroscopy and cyclic and differential pulse voltammetry. Of these complexes, [Cu(L¹)](BF₄)₂ (1) and [Cu(L²)](BF₄)₂ (4) have been structurally characterized by X-ray crystallography. The coordination geometries around copper(II) in 1 and 4 are described as trigonal bipyramidal distorted square based pyramidal geometry (TBDSBP). The distorted CuN₃S basal plane in them is comprised of amine nitrogen, one thioether sulphur and two benzimidazole nitrogens and the other thioether sulfur is axially coordinated. The ligand field spectra of all the complexes are consistent with a mostly square-based geometry in solution. The EPR spectra of complexes [Cu(L¹)](BF₄)₂ (1), [Cu(L¹)](NO₃)₂ (2), [Cu(L²)](BF₄)₂ (4) and [Cu(L³)](ClO₄)₂ (6) are consistent with two species indicating the dissociation/disproportionation of the complex species in solution. All the complexes exhibit an intense CT band in the range 305-395 nm and show a quasireversible to irreversible Cu^II/Cu^I redox process with relatively positive E_1/2 values, which are consistent with the presence of two-coordinated thioether groups. The addition of N-methylimidazole (mim) replaces the coordinated thioether ligands in solution, as revealed from the negative shift (222-403 mV) in the Cu^II/Cu^I redox potential. The present study reveals that the effect of incorporating an amine nitrogen donor into CuN₂S₂ complexes is to generate an axial copper(II)-thioether coordination and also to enforce lesser trigonality on the copper(II) coordination geometry.     

Synthesis of new 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles: A search for novel nitric oxide donor anti-inflammatory agents

A group of 1-(4-methane(amino)sulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles (12a–f) was synthesized and evaluated as anti-inflammatory agents. While all the compounds (20 mg/kg) showed significant anti-inflammatory activity after 3 h of inflammation induction (69–89%) as compared to celecoxib (80%), 1-(4-methanesulfonylphenyl)-5-(4-methylaminomethylphenyl)-3-trifluoromethyl-1H-pyrazole (12a) was found to be the most effective one (89%). The synthesis of model hybrid nitric oxide donor N-diazen-1-ium-1,2-diolate derivatives of 1-(4-methanesulfonylphenyl)-5-(4-substituted-aminomethylphenyl)-3-trifluoromethyl-1H-pyrazoles (10a–f) requires further investigation since the reaction of N-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)ethanamine (12b) or 1-(4-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)piperazine (12c) with nitric oxide furnished N-nitroso derivatives (13 and 14), respectively, rather than the desired N-diazen-1-ium-1,2-diolate derivatives (10b and 10c).     

Insulin-like,and insulin-antagonistic,carbohydrate derivatives. The synthesis of aryl and aralkyl d-mannopyranosides and 1-thio-d-mannopyranosides

A number of novel, aryl and aralkyl d-mannopyranosides and 1-thio-d-mannopyranosides were synthesized for evaluation of insulin-like and insulin-antagonistic properties. The substituted-phenyl α-d-mannopyranosides were prepared by the general procedure of Helferich and Schmitz-Hillebrecht, the substituted-phenyl 1-thio-α-d-mannopyranosides by a method corresponding to the Michael synthesis of aromatic glycosides, and the aralkyl 1-thio-α-d-mannopyranosides by aralkylation of 2,3,4,6-tetra-O-acetyl-1-thio-α-d-mannopyranose (15) and subsequent O-deacetylation. Compound 15 was obtained by basic cleavage of the amidino group in 2-S-(tetra-O-acetyl-α-d-mannopyranosyl)-2-thiopseudourea hydrobromide, the product of the reaction of tetra-O-acetyl-α-d-mannosyl bromide with thiourea. Benzyl 1-thio-β-d-mannopyranoside, obtained by reaction of the sodium salt of 1-thio-β-d-mannopyranose with α-bromotoluene, and benzyl 1-thio-α-l-mannopyranoside were also synthesized, in order to assess the stereospecificity of the biological activities measured.     

Derivatives of phosphonate and vinyl phosphate analogs of D-ribose 5-phosphate

Propanal thiosemicarbazone (1a) showed activity in preventing anaphylactic shock in a mouse test-system; it also had some activity in stunting the growth of Botrytis allii. Hexanal thiosemicarbazone (1b) was active in the Botrytis allii test-system, and citral thiosemicarbazone (2) and citral guanylhydrazone nitrate (3) showed some activity in the same test-system. Heptanal guanylhydrazone nitrate (4) had some antibacterial activity against Staphylococcus aureus, and D-threo-pentosulose bis(thiosemicarbazone) (5) prevented anaphylactic shock in the mouse test-system. D-glycero-Tetrosulose bis(thiosemicarbazone) (6), D-lyxo-hexosulose bis-(guanylhydrazone) nitrate (7), D-galacto-heptosulose bis(thiosemicarbazone) (8), and D-galacto-heptosulose bis(guanylhydrazone) sulfate (9) showed some activity in stunting the growth of Botrytis allii. The copper chelate (10a) of D-arabino-hexosulose bis(thiosemicarbazone), and the copper (11a) and palladium (11b) chelates of 6-deoxy-L-arabino-hexosulose bis(thiosemicarbazone) showed antitumor activity in the KB cell-culture test-system. The palladium chelate 11b also showed some activity in the leukemia p-388 mouse test-system.     

Nucleocyclitols. Synthesis of 3-(adenin-9-yl)-3-deoxy-1,5,6-tri-O-(methylsulfonyl)-muco-inositol

The reaction of 2,3-di-O-acetyl-1,4,5,6-tetra-O-(methylsulfonyl)-myo-inositol (1) with sodio-adenine in HCONMe₂ for 24 h at 100° gave, in 53.7% yield, the title compound, whose structure was ascertained by physical methods. Other parallel, secondary reactions were the aromatization of compound 1 to give 2,4-di-O-(methylsulfonyl)-1,2,4-benzenetriol (13.8%), and the formation of 1,5,6-tri-O-(methylsulfonyl)-muco-inositol (17.8%).     

Synthesis of 3-(2-aminoethylthio)propyl glycosides

Anomeric pairs of 3-(2-aminoethylthio)propyl d-galactopyranoside (4, 4a), d-glucopyranoside (5, 5a), and 2-acetamido-2-deoxy-d-glucopyranoside (6, 6a) were prepared by addition of 2-aminoethanethiol to the corresponding, anomeric, allyl glycosides. The allyl α-glycosides were prepared by refluxing the sugars with allyl alcohol in the presence of an acid catalyst; the allyl β-glycosides were prepared by the reaction of acetylated glycosyl bromides with allyl alcohol in the presence of mercuric cyanide, followed by O-deacetylation. The rate of thiol addition to the allylic group was found to be different for each glycoside.     

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.     

Syntheses of some purine nucleosides by the fusion method,by the condensation of acetylated chlorides,and from 1-acetates in the presence of titanium tetrachloride: a comparison

9-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-6-benzamidopurine (9) and 6-benzamido-9-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)purine (11) have been prepared by three synthetic routes: (a) the fusion procedure, (b) direct condensation of 6-benzamido(chloromercuri)purine with the acetylated chloride, or (c) with the chloride formed in situ from the 1-acetate in the presence of titanium tetrachloride. The results obtained are briefly discussed; the direct condensation of the mercuri salt with chlorides proved to be the most convenient.Whereas, in the condensation with acetylated chlorides, only products having the β-d anomeric configuration were isolated, the chloride protected with non-participating groups (benzyl) afforded both anomers. The removal of the benzyl groups should be preceded by hydrolytic cleavage of the benzamido group. A simple procedure for fractionation, on small columns of silica gel, of reaction mixtures obtained in the fusion reactions is described.     

Synthesis of myo- and muco-inositol esters,and some nitrogen derivatives thereof

Starting from myo-inositol, 1,2-O-isopropylidene-3,4,5,6-tetra-O-(methylsulfonyl)-, 1,4,5,6-tetra-O-(methylsulfonyl)-, and 2,3-di-O-acetyl-1,4,5,6-tetra-O-(methylsulfonyl)-myo-inositol (3) were synthesized. Compound 3 was treated with sodium azide to give 3-azido-3-deoxy-1,5,6-tri-O-(methylsulfonyl)-muco-inositol, reduction of whose diacetate led to a mixture of 3-amino-3-deoxy- and 3-acetamido-2-O-acetyl-3-deoxy-1,5,6-tri-O-(methylsulfonyl)-muco-inositol. The configurations and conformations of these compounds were ascertained by n.m.r. spectroscopy. 3-Acetamido-3-deoxy-1,5,6-tri-O-(methylsulfonyl)-muco-inositol and its 2,4-diacetate are also described.     

Syntheses of p-aminophenyl α-d-talopyranoside and 1-thio α-d-talopyranoside as analogs of glycosidase substrates

p-Nitrophenyl and p-aminophenyl α-d-talopyranoside and 1-thio-α-d-talopyranosides were prepared for studies on specificity of glycosidases. Reaction of α-d-talopyranose pentaacetate with p-nitrophenol gave exclusively p-nitrophenyl 2,3,4,6-tetra-O-acetyl-α-d-talopyranoside (2) in 63% yield. A similar reaction with p-nitrobenzenethiol afforded the 1-thio analog (3) of 2 in 41.8% yield; the p-nitrophenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-d-talopyranoside (6) was also obtained in low yield (6.7%). The two α-d-talosides 2 and 3 were catalytically deacetylated in near-quantitative yields by methanolic sodium methoxide. The p-nitrophenyl α-d-talopyranoside (4) and 1-thio-α-d-talopyranoside (5) were reduced with palladium on barium sulfate catalyst to the corresponding p-aminophenyl talosides. The acetylated p-nitrophenyl d-talosides 2, 3, and 6 were determined, from their 250-MHz n.m.r. spectra, to exist in the ⁴C₁ (d) conformation in chloroform solution.     

Synthesis of 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine)-d-glucopyranoses

Five 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine)-d-glucopyranoses (lipophilic, muramoyl dipeptide analogs) were synthesized from benzyl 2-(benzyloxycarbonylamino)-3-O-(d-1-carboxyethyl)-2-deoxy-5,6-O-isopropylidene-β-dglucopyranoside (1). Methanesulfonylation of 3, derived from the methyl ester of 1 by O-deisopropylidenation, gave the 6-methanesulfonate (4). (Tetrahydropyran-2-yl)ation of 4 gave benzyl 2-(benzyloxycarbonylamino)-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-6-O-(methylsulfonyl)-5-O-(tetrahydropyran-2-yl)-β-d- glucofuranoside, which was treated with sodium azide to give the corresponding 6-azido derivative (6). Condensation of benzyl 6-amino-2-(benzyloxycarbonyl-amino)-2,6-dideoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-5-O-(tetrahydropyran-2-yl)-β-d-glucofuranoside, derived from 6 by reduction, with the activated esters of octanoic, hexadecanoic, and eicosanoic acid gave the corresponding 6-N-fatty acyl derivatives (8–10). Coupling of the 2-amino derivatives, obtained from compounds 8, 9, and 10 by catalytic reduction, with the activated esters of the fatty acids, gave the 2,6-(diacylamino)-2,6-dideoxy derivatives (11–15). Condensation of the acids, formed from 11–15 by de-esterification, with the benzyl ester of l-alanyl-d-isoglutamine, and subsequent hydrolysis, afforded benzyl 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine benzyl ester)-β-d-glucofuranosides. Hydrogenation of the dipeptide derivatives thus obtained gave the five lipophilic analogs of 6-amino-6-deoxymuramoyl dipeptide, respectively, in good yields.     

Debenzylation of carbohydrate benzyl ethers and benzyl glycosides via free-radical bromination

The dealkylation of benzylated carbohydrates by free-radical bromination and hydrolysis has been further examined. Free-radical bromination of methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (1) methyl 2,3-di-O-benzyl-α-D-glucopyranoside (2) 6-O-benzyl-3,5-O-benzylidene-1,2-O-isopropylidene-α-D-glucofuranose (4) and 6-O-benzyl-D-glucose (3) appears to be quantitative. Spectroscopic evidence of a CBr bond indicates that an α-bromobenzyl ether is the product. Alkaline hydrolysis yielded methyl α-D-glucopyranoside from 1 and 2 and D-glucose from 3 and 4. A benzyl group present as an aglycon could be removed in the same way. Reaction of benzyl α-D-glucopyranoside tetraacetate (6) with bromine and chlorine under free-radical conditions and examination of the products by t.l.c. and i.r. spectrophotometry indicated that the first product was an α-halobenzyl glycoside and that the aglycon could be displaced by Br^- or Cl^- to form the tetra-O-acetyl-D-glucopyranosyl halide, undoubtedly with anomerization. Treatment of the mixture of products with moist ether and silver carbonate yielded only 2,3,4,6-tetra-O-acetyl-D-glucopyranose.     

Preparation and characterization of cobalt(II), nickel(II) and copper(II) complexes with water-soluble macrocyclic N4-ligands: 6,15-diethyl-4,13-dihydro-1,10-dimethyl-(E)-dipyridinio [b,i] [1,4,8,11] tetraazacyclotetradecine iodide or methyl sulfate

The mixture of 6,15-diethyl-4,13-dihydro-(E)-dipyrido [b,i] [1,4,8,11] tetraazacyclotetradecine (2-E) and 6,15-diethyl-4,13-dihydro-(Z)-dipyrido [b,i][1,4,8,11] tetraazacyclotetradecine (2-Z) was prepared by cyclization of 3,4-diaminopyridine and 2-ethyl-3-ethoxyacrolein. Two kinds of isomers were separated by repeated recrystallization from chloroform. Methylation of pyridine comprised in 2-E using iodomethane or dimethyl sulfate afforded the corresponding dimethylated product (2-E-I or 2-E-S), which is soluble in water. The cobalt(II), nickel(II) and copper(II) complexes of 2-E-I and 2-E-S were prepared. The absorption bands appearing in the energy range greater than 18 000 cm⁻¹ were attributed to the π → π* transitions within a ligand molecule and CT transitions from metal to ligand. Since the d → d* bands for nickel(II) and copper(II) complexes were obscured by the π → π* and CT bands, no significant absorption bands were found in the region more than 18000 cm⁻¹. One of the d → d* bands for the cobalt(II) complex was observed at around 13 000 cm⁻¹. These complexes assume the square- planar structures. A strong IR band due to the CN stretching mode of the macrocycle moiety was observed at ca. 1640 cm−1 and shifted slightly toward lower energy upon metal-coordination, cis (2-Z) and trans (2-E) isomers in the present macrocycle can be judged by the amine proton signals of NMR spectra. All proton signals except for amine protons show downfield shifts due to the deshielding effect of the positive charge provided by methylation of pyridine contained in the metal-free macrocycle. Upon formation of the nickel(II) complex all proton signals, except the aromatic protons adjacent to the nitrogen atom of a pyridine ring, also show a downfield shift, which is attributed to the deshielding effect based on the positive charge given by nickel(II). The intensity change of the electronic spectrum at 425 nm is available for the determination of copper(II) concentrations in the aqueous solution using the water-soluble macrocycles (2-E-I and 2-E-S) and a good linear correlation is observed up to 8 × 10⁻⁶ mol dm⁻³.     

Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation

To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[¹¹C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([¹¹C]1) and N-(4-[¹¹C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([¹¹C]MPPA, [¹¹C]4) were prepared from their corresponding precursors 2 and 5 with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A_M) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.     

2-Substituted fortimicins by ring opening of 2-deoxy-1,2-epimino-2-epi-fortimicin B and by nucleophilic displacements of 2-O-(methylsulfonyl)fortimicin derivatives

Opening of the aziridine ring of 2-deoxy-1,2-epimino-2-epi-fortimicin B (10) has been effected with both chloride and azide. The reactions are both stereo- and regiospecific and give 2-chloro-2-deoxyfortimicin B (2c) and 2-azido-2-deoxy-fortimicin B (2d). The nucleophilic displacements of the methanesulfonate groups of some 1-N-benzyloxycarbonyl-2-O-(methylsulfonyl)fortimicin derivatives with chloride, azide, and cyanide in N,N-dimethylformamide are dependent both on the nature of the nucleophile and the specific 1-N-benzyloxycarbonyl-2-methanesulfonate employed as the substrate. Striking differences in the stereochemistry of the azide displacements with different 2-methanesulfonates are believed to have a conformational basis. 2-Amino-2-deoxyfortimicin A (1c) and both of the 2-epimeric 2-chloro-2-deoxyfortimicins A (1b) and (5) were prepared for antibacterial assay and the in vitro results are reported.     

Chemical modification of the carbohydrate moiety in N-acetylmuramoyl-l-alanyl-d-isoglutamine,and the immunoadjuvant activity

Five carbohydrate analogs of N-acetylmuramoyl-l-alanyl-d-isoglutamine have been synthesized from benzyl 2-acetamido-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-α-d-glucopyranoside (1) and the corresponding 6-O-benzoyl derivative (2). Chlorination of 1 and 2 with triphenylphosphine in carbon tetrachloride gave the 4,6-dichloro compound 3 and the 6-O-benzoyl-4-chloro compound (4), which were treated with tributyltin hydride, to yield benzyl 2-acetamido-2,4,6-trideoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-α-d-xylo-hexopyranoside (6) and benzyl 2-acetamido-6-O-benzoyl-2,4-dideoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-α-d-xylo-hexopyranoside (7), respectively. Methanesulfonylation of 8, derived from 7 by debenzoylation, gave the 6-methanesulfonate, which underwent displacement with azide ion to afford benzyl 2-acetamido-6-azido-2,4,6-trideoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-α-d-xylo-hexopyranoside (10). Hydrolysis of the methyl ester group in compounds 3, 5 (debenzoylated 4), 6, 8, and 10 gave the corresponding free acids, which were coupled with l-alanyl-d-isoglutamine benzyl ester, to yield the dipeptide derivatives in excellent yields. Hydrogenation of the dipeptide derivatives thus obtained gave the five carbohydrate analogs of N-acetylmuramoyl-l-alanyl-d-isoglutamine, respectively, in good yields. The immunoadjuvant activity of the N-acetylmuramoyl-dipeptide analogs was examined.     

The action of Bacillus subtilis liquefying amylase on 6-deoxy-6-iodoamylose

Benzyl 2-acetamido-2-deoxy-3-O-β-D-galactopyranosyl-α-D-glucopyranoside (1) was chosen as a model bioside to develop a standard procedure for the selective cleavage of glycosidic linkages in polysaccharides containing 2-amino-2-deoxyhexose residues. Treatment of 1 with hydrazine in the presence of hydrazine sulphate resulted in quantitative N-deacetylation with the formation of benzyl 2-amino-2-deoxy-3-O-β-D-galactopyranosyl-α-D-glucopyranoside (2). The galactosyl glycosidic linkage in 2 could be selectively cleaved by acid hydrolysis. Oxidation of 2 with periodate destroyed the galactose residue. Treatment of 2 with nitrous acid cleaved the 2-amino-2-deoxy-D-glucosyl linkage to give 2,5-anhydro-3-O-β-D-galactopyranosyl-D-mannose (3) and benzyl alcohol.     

Synthesis of 2,4-diacetamido-2,4,6-trideoxy-L-altrose, -L-idose, and -L-talose from benzyl 6-deoxy-3,4-O-isopropylidene-beta-L-galactopyranoside

Acetylation of benzyl 6-deoxy-3,4O-isopropylidene-β-L-galactopyranoside gave benzyl 2-O-acetyl-6-deoxy-3,4-O-isopropylidene-β-L-galactopyranoside (1). Removal of the isopropylidene group afforded benzyl 2-O-acetyl-6-deoxy-β-L-galactopyranoside (2), which was converted into benzyl 2-O-acetyl-6-deoxy-3,4-di-O-(methyl-sulfonyl)-β-L-galactopyranoside (3). Benzyl 2,3-anhydro-6-deoxy-4-O-(methyl-sulfonyl)-β-L-gulopyranoside (4) was obtained from 3 by treatment with alkali. Reaction of 4 with sodium azide in N,N-dimethylformamide gave a mixture of two isomeric benzyl 2,4-diazido-2,4,6-trideoxy hexoses, the syrupy diazido derivative 5 and the crystalline benzyl 2,4-diazido-2,4,6-trideoxy-β-L-idopyranoside (6). Acetylation of 6 afforded a compound whose n.m.r. spectrum was completely first order and in agreement with the structure of benzyl 3-O-acetyl-2,4-diazido-2,4,6-trideoxy-β-L-idopyranoside (7). Lithium aluminium hydride reduction of 5, followed by acetylation, afforded a crystalline product (8), shown by n.m.r. spectroscopy to be benzyl 2,4-diacetamido-3-O-acetyl-2,4,6-trideoxy-β-L-altropyranoside. Similar treatment of the diazido derivative 6 afforded benzyl 2,4-diacetamido-3-O-acetyl-2,4,6-trideoxy-β-L-idopyranoside (9). Compounds 8 and 9 could also be obtained from 4 by treatment of the crude diazido mixture with lithium aluminium hydride, with subsequent N-acetylation. The syrupy benzyl 2,4-diacetamido-2,4,6-trideoxy-β-L-altropyranoside (10) and the crystalline benzyl 2,4-diacetamido-2,4,6-trideoxy-β-L-idopyranoside (11) thus obtained were then O-acetylated to give 8 and 9 respectively. Benzyl 2,4-diacetamido-2,4,6-trideoxy-β-L-talopyranoside (15) was obtained from 11 by treatment with methanesulfonyl chloride and subsequent solvolysis. Compound 15 was O-acetylated to yield benzyl 2,4-diacetamido-3-O-acetyl-2,4,6-trideoxy-β-L-talopyranoside (16). the n.m.r. spectrum of which was in full agreement with the assigned structure. The mass spectra of compounds 8–11, 15, and 16 were also in agreement with their proposed structures. Removal of the benzyl groups from 10, 11 and 15 afforded the corresponding 2,4-diacetamido-2,4,6-trideoxyhexoses 12, 13, and 17, having the L-altro, L-ido, and L-talo configurations, respectively.