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).     

The cyclization of 3-O-benzyl-6-deoxy-6-nitro-D-glucose and -L-idose to O-benzyldeoxynitroinositols,and epimerizations related thereto

3-O-Benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (1) was found to give, with nitromethane under catalysis by sodium methoxide, 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-6-nitro- α-D-glucofuranose (2) as the kinetically favored product. Subsequent, spontaneous epimerization led to a 2:1 mixture of 2 and its β-L-ido isomer (3), from which crystalline 3 was isolated. The free nitro hexoses (4 and 5) obtained by deacetonation of 2 and 3 were subjected to barium hydroxide-catalyzed cyclization (internal Henry reaction) to give mixtures of O-benzyldeoxynitroinositols. Under conditions of kinetic control, the α-D-gluco derivative 4 furnished 6-O-benzyl-3-deoxy-3-nitro-muco-inositol (6) and optically active 4-O-benzyl-1-deoxy-1-nitro-L-myo-inositol (L-7) in a ratio of 3:1. The β-L-ido derivative 5 gave the enantiomer (D-7) of the myo compound and 4-O-benzyl-1-deoxy-1-nitro-scyllo-inositol (8) in a similar ratio. Slow, thermodynamically controlled epimerization led from each individual nitro inositol to mixtures of the same composition, with 17–18% of 6, 68–69% of DL-7, and 11–12% of 8. All of the nitroinositol benzyl ethers were isolated crystalline and characterized further as crystalline tetraacetates (6a–8a). The muco isomer 6 gave a di-O-isopropylidene derivative (6b).     

Synthesis of 3,4-anhydro-1-deoxy-3-C-methyl-d-hexulose derivatives

Epoxidation of (E)-1,3,4-trideoxy-5,6-O-isopropylidene-3-C-methyl-d-glycero-hex-3-enulose by alkaline hydrogen peroxide gave a mixture of 3,4-anhydro-1-deoxy-5,6O-isopropylidene-3-C-methyl-d-arabino- (2) and -d-xylo-hexulose (3) that was resolved by chromatography. From the reaction of 2 with 3-chloroperbenzoic acid, the Baeyer-Villiger rearrangement product (2R)-2-O-acetyl-2,3-anhydro-1-deoxy-4,5-O-isopropylidene-d-eythro-pentulose hydrate was isolated. The structures and configurations of the above products were established on the basis of chemical transformations and anlytical and spectroscopic data.     

Synthesis and structural analysis of 6-deoxy-6-hydroxyphosphinyl-D-fructopyranose derivatives

3,4-Di-O-benzyl-6-deoxy-6-diethoxyphosphinyl-1,2-O-isopropylidene-beta-D-fructofuranose (13) was prepared from the known 1,2-O-isopropylidene-6-O-tosyl-beta-D-fructofuranose in five steps. Reduction of 13 with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of hydrochloric acid and then hydrogen peroxide, afforded the 6-deoxy-6-hydroxyphosphinyl-D-fructopyranose derivative. This was converted into the 1,2,3,4,5-penta-O-acetyl-6-deoxy-6-methoxyphosphinyl-D-fructopyranoses, whose structure and conformation were established by 1H NMR spectroscopy.     

Synthesis of 6-deoxy-5-thio- -glucose

Three routes were investigated for the conversion of -glucose into the title compound. In the first approach, reduction of the 5,6-thürane ring of 5,6-dideoxy-5,6-epithio-1,2-O-isopropylidene α- -glucofuranose (17) as well as that of its 3-O-allyl derivative (13) with lithium aluminium hydride was investigated; 17 afforded the corresponding 6-deoxy derivative besides di-, tri-, and poly-mers, whereas only polymers were formed from 13. In the second approach, the oxirane ring of

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was reduced by sodium borohydride and the resulting 6-deoxy derivative was converted into the 5-thiobenzoate; the corresponding hex-4-enofuranose was formed as a byproduct. In the third approach partial mesylation of methyl 5-thio-α- -glucopyranoside was attempted, but the 6-mesylate 27 could be isolated only in modest yield (28%) together with rearranged 2,5-thioanhydromannofuranoside derivatives. The mechanism of this rearrangement is discussed in detail. The 6-mesylate 27 was converted via the 6-iodo derivative into the title compound.     

Synthesis and stereochemistry of 6-deoxy-6-halogeno-D-glucofuranose cyclic phosphates.

1, 2-O-Cyclohexylidene- and 1, 2-O-isopropylidene-alpha-D-glucofuranose react with hexa-alkylphosphorous triamides to give the corresponding 3, 5, 6-phosphites. Treatment of the latter compounds with chlorine and bromine affords 1, 2-substituted 6-deoxy-6-halogeno-alpha-D-glucofuranose 3, 5-phosphorohalogenidates. Replacement of halogen at phsophorus by hydroxyl and amino groups has been investigated. Cyclic phosphorohalogenidates isomerize in N, N-dimethylformamide. The stereochemistry of the compounds investigated was established by using 1H- and 13C-n.m.r. data.     

Synthesis of 6-deoxy-6-chloro and 6-deoxy-6-bromo derivatives of scleroglucan as intermediates for conjugation with methotrexate and other carboxylate containing compounds

Polysaccharides are widely used as carriers in the field of drug delivery. We present a methodology to obtain water soluble drug-conjugates based on scleroglucan. Selective C-6 halogenation gives access to C-6 esters; conjugates between methotrexate and scleroglucan are described, potentially useful for antitumour therapy or in rheumatoid arthritis treatment.     

Stability of hydroxylamino- and amino-intermediates from reduction of 2,4,6-trinitrotoluene, 2,4-dinitrotoluene, and 2,6-dinitrotoluene

Hydroxylamines, produced as intermediates in the reductive metabolism of 2,4,6-trinitrotoluene, 2,4-dinitrotoluene, and 2,6-dinitrotoluene between nitroaromatic parent compounds and corresponding amines, were unstable in aqueous solution in the presence of O₂. Reactions of hydroxylamines to compounds other than amines may be the major cause of poor mass balance observations in bioremediation systems where only aminated products are monitored. Results demonstrate the formation of azoxy compounds as products of abiotic aryl-hydroxylamine reactions.     

Preparation of 6-deoxy-6-fluorocellulose

6-Deoxy-6-fluorocellulose was prepared from cellulose 2,3-diacetate (1) or cellulose 2,3-dibenzoate (2) in various solvents, and was characterized by ¹⁹F and ¹³C NMR measurements. The best product, having ds of 0.95 at C-6 and 0.04 at C-3, was prepared from cellulose 2,3-dibenzoate in nitrobenzene. Other combinations of starting material and solvent gave a lower (≈ 0.8) ds of fluorine at C-6 and higher (≈ 0.12) at C-2 or C-3. Substitution at C-2 was observed when the combination of 1 and 1,4-dioxane, or 2 and chloroform was used. The products substituted at C-2 by fluorine were relatively resistant to acid hydrolysis.     

Synthesis of 1-deoxy-3-C-methyl-d-fructose and 1-deoxy-3-C-methyl-d-sorbose

Hydroxylation of trans-1,3,4-trideoxy-5,6-O-isopropylidene-3-C-methyl-d-glycero-hex-3-enulose with osmium tetraoxide gave a mixture of 1-deoxy-5,6-O-isopropylidene-3-C-methyl-d-arabino- and -d-xylo-hexulose that was partially resolved by acetonation to give 1-deoxy-2,3:4,5-di-O-isopropylidene-3-C-methyl-β-d-fructopyranose (4), 1-deoxy-3,4:5,6-di-O-isopropylidene-3-C-methyl-keto-d-fructose (5), and 1-deoxy-2,3:4,6-di-O-isopropylidene-3-C-methyl-α-d-sorbofuranose (6). Treatment of a mixture of 4 and 5 with sodium borohydride gave, after column chromatography, 4 and 1-deoxy-3,4:5,6-di-O-isopropylidene-3-C-methyl-d-manno- and -d-gluco-hexitol. Deuterated derivatives corresponding to 4–6 were obtained when isopropylidenation was carried out with acetone-d₆. Deacetonation of 4 and 5 yielded 1-deoxy-3-C-methyl-d-fructose, and 6 similarly afforded 1-deoxy-3-C-methyl-d-sorbose.     

Synthesis and glycosidase inhibitory activity of some N-substituted 6-deoxy-5a-carba-beta-DL- and L-galactopyranosylamines

Chemical modification of 5a-carba-beta-DL-fucopyranosylamine (3) generated six N-substituted derivatives 9a-f, among which N-octyl 9b, decyl 9c, and phenylbutyl ones 9f were found to be very strong beta-galactosidase as well as beta-glucosidase inhibitors. The inhibitory activity appeared attributable to D-enantiomers from biological assays of prepared L-enantiomers. Therefore, 6-deoxy-5a-carba-beta-D-galactopyranosylamine (D-3) might be a promising lead compound for further design of new carba sugar-type beta-galactosidase inhibitors.     

Fungal transformation of 2,4-dinitrotoluene and 2,4,6-trinitrotoluene.

Screening of 190 fungi representing 98 genera showed that the ability to transform 2,4,6-trinitrotoluene was common, whereas transformation of 2,4-dinitrotoluene was rare.     

The synthesis of 5-C-(6-deoxy-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranos-6-yl)-2 ,3-O-isopropylidene-D-allo-pentofuranose [deaminotri-O-isopropylidene tunicamine]

Three approaches to the synthesis of deaminotunicamine and derivatives were developed. Tin tetrachloride condensation of 6-deoxy-1,2:3,4-di-O-isopropylidene-alpha-D-galacto-heptodialdo-1, 5-pyranose with 2-(trimethylsilyloxy)furan gave a mixture of stereoisomeric precursors. Condensation of 1,2:3,4-di-O-isopropylidene-alpha-D-galacto-hexodialdo-1,5-pyranos e with the phosphate carbanion obtained from diethyl (2-furyl)methoxymethyl phosphonate led to 6-deoxy-7-C-(2-furyl)-1,2:3,4-di-O-isopropylidene-L-glycero-alpha-D- galactoheptopyranose (13). This was converted, via the "delta 2"-butenolide route, to a mixture of stereoisomeric 5-C-(6-deoxy-alpha-D-galactopyranos-6-yl)-pentono-1,4-lacton es of the D-allo and D-talo configuration. In the third approach, 13 was transformed by the "enulose" approach to deamino-tri-(O-isopropylidene)tunicamine.     

Purin-6-yl 6-deoxy-1-thio-beta-D-glucopyranoside. Enzymology, chemistry, and cytotoxicity

Purin-6-yl 6-deoxy-1-thio-beta-D-glucopyranoside (4) is a substrate for almond beta-glucosidase and a weak competitive inhibitor of bovine liver beta-D-glucuronidase (Ki approximately 20mM). Both 4 and purine-protonated 4 undergo hydrolysis catalyzed by dilute acid in the pH range 0.17-2.59. These results are compared with those previously obtained with ammonium (purin-6-yl 1-thio-beta-D-glucopyranosid)uronate, (purin-6-yl 1-thio-beta-D-glucopyranosid)uronamide, purin-6-yl 1-thio-beta-D-glucopyranoside, and purin-6-yl 2-deoxy-1-thio-beta-D-glucopyranoside, and it is concluded that the data support an involvement of substituents at C-5 in producing productive Michaelis-complex conformers. The 6-deoxyglucoside is more active than the D-glucosiduronic acid in an L1210 mouse screen.     

Synthesis of 7-(2,4-dichlorophenyl)-D-erythro-3-hydroxy-5-heptanolide, 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexane-1-sulfonic acid, and 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexylphosphonic acid.

6-(2,4-Dichlorophenyl)-D-erythro-1,2,4-hexanetriol, synthesised from D-glucose, was partially silylated, then reacted with 2-methoxypropene to afford 1-O-tert-butyldimethylsilyl-6-(2,4- dichlorophenyl)-2,4-O-isopropylidene-D-erythro-1,2,4-hexanetriol (17). Desilylation of 17 gave 6-(2,4-dichlorophenyl)-2,4-O-isopropylidene-D- erythro-1,2,4-hexanetriol, which was converted into the 1-tosylate 18 and the 1-bromo derivative 19. Reaction of 18 with potassium thiolbenzoate gave, after debenzoylation, oxidation, and deprotection, 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexane-1-sulfonic acid (4). Reaction of 18 or 19 with triethyl phosphite gave, after deprotection, 6-(2,4-dichlorophenyl)-D-erythro-2,4-dihydroxyhexyl-phosphonic acid (5), and reaction of 19 with potassium cyanide gave, after subsequent hydrolysis and deprotection, 7-(2,4-dichlorophenyl)-D-erythro-3-hydroxy-5-heptanolide (3).