Reaktionen der glucuronsäure : 7. Mitt. Oxidationen an d-glucofuranosidurono-6,3-lactonen

Methyl α-D- (1) and methyl β-D-glucofuranosidurono-6,3-lactone (5) were oxidized at C-2 or C-5, 1,2-O-isopropylidene-α-D- (10) and 1,2-O-cyclohexylidene-α-D-glucofuranurono-6,3-lactone (11) at C-5 by various methods to the corresponding D-arabino- or D-xylo-hexulofuranosiduronolactones. In contrast to the starting materials 5, 10, and 11, the 5-uloses 15, 17, and 18 do not exhibit reducing power in alkaline Cu²⁺ solutions. Methyl 5-O-benzyl-α-D- and methyl 5-O-benzyl-β-D-arabino-2-hexulofuranosidurono-6,3-lactone reduce Benedict solution at room temperature.     

The synthesis of 5-O-(2-acetamido-2-deoxy-α-D-glucopyranosyl)-β-D-glucofuranose

Condensation of dimeric 3,4,6-tri-O-acetyl-2-deoxy-2-nitroso-α-D-glucopyranosyl chloride (1) with 1,2-O-isopropylidene-α-D-glucofuranurono-6,3-lactone (2) gave 1,2-O-isopropylidene-5-O-(3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-α-D-arabino-hexopyranosyl)-α-D-glucofuranurono-6,3-lactone (3). Benzoylation of the hydroxyimino group with benzoyl cyanide in acetonitrile gave 1,2-O-isopropylidene-5-O-(3,4,6-tri-O-acetyl-2-benzoyloxyimino-2-deoxy-α-D-arabino-hexopyranosyl)-α-D-glucofuranurono-6,3-lactone (4). Compound 4 was reduced with borane in tetrahydrofuran, yielding 5-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-1,2-O-isopropylidene-α-D-glucofuranose (5), which was isolated as the crystalline N-acetyl derivative (6). After removal of the isopropylidene acetal, the pure, crystalline title compound (10) was obtained.     

Synthesis of 5-O-α-and-β-d-glucopyranosyl-d-glucofuranose and 5-O-α-d-glucopyranosyl-d-fructopyranose (leucrose)

Reaction of 1,2-O-cyclopentylidene-α-d-glucofuranurono-6,3-lactone (2) with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (1) gave 1,2-O-cyclopentylidene- 5-O-(2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl)-α-d-glucofuranurono-6,3-lactone (3, 45%) and 1,2-O-cyclopentylidene-5-O-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-α-d-glucofuranurono-6,3-lactone (4, 38%). Reduction of 3 and 4 with lithium aluminium hydride, followed by removal of the cyclopentylidene group, afforded 5-O-α-(9) and -β-d-glucopyranosyl-d-glucofuranose (12), respectively. Base-catalysed isomerization of 9 yielded crystalline 5-O-α-d-glucopyranosyl-d-fructopyranose (leucrose, 53%).     

The synthesis of chlorodeoxyhexofuranoid derivatives

The reaction of 1,2-O-isopropylidene-α- d-glucofuranose with sulfuryl chloride at 0° and at 50° afforded 6-chloro-6-deoxy-1,2-O-isopropylidene-α- d-glucofuranose 3,5-bis(chlorosulfate) ( 3) and 5,6-dichloro-5,6-dideoxy-1,2-O-isopropylidene-β- l-idofuranose 3-chlorosulfate ( 7, not characterised), respectively. Dechlorosulfation of 3 afforded the hydroxy derivative, whereas treatment of 3 with pyridine gave the 3,5-(cyclic sulfate). Dechlorosulfation of 7 afforded 5,6-dichloro-5,6-dideoxy-1,2-O-isopropylidene-β- l-idofuranose which, on acid hydrolysis, was converted into 3,6-anhydro-5-chloro-5-deoxy- l-idofuranose. 5-Chloro-5-deoxy-α- l-idofuranosidurono-6,3-lactone and 5-chloro-5-deoxy-β- l-idofuranurono-6,3-lactone derivatives were also prepared.     

2-amino-2-desoxy-6-O-(D-glykofuranosylurono-6,3-lacton)-D-galaktopyranosen

Condensation of 2-amino-2-deoxy-D-galactopyranose with D-glucuronic acid or D-mannurono-6,3-lactone in the presence of hydrochloric acid gave the corresponding 2-amino-2-deoxy-6-O-(D-glycofuranosylurono-6,3-lactone)-D-galactopyranoses. The α-D configuration of the disaccharide derived from D-glucuronic acid was determined by its resistance towards β-D-glucuronidase.     

Synthesis of l-idofuranurono-6,3-lactone and its derivatives via hexodialdodifuranoses

1,2-O-Alkylidene-β-l-idofuranurono-6,3-lactones were obtained from the corresponding 5-O-toluene-p-sulphonyl-α-d-glucofuranurono-6,3-lac tones by a sequence involving lactone reduction, benzoylation of HO-6, inversion of configuration at C-5, deacylation, and lactol oxidation. Hydrogenolysis or methanolysis of 1,2-O- benzylidene-β-l-idofuranurono-6,3-lactone gave l-idofuranurono-6,3-lactone and a mixture of its methyl glycosides, respectively.     

Beta-anomeric selectivity in the glycosidation of D-mannofuranurono-6,3-lactone catalyzed by boron trifluoride diethyl etherate

The BF3-promoted glycosylation of D-mannofuranurono-6,3-lactone with dodecanol or methanol afforded n-alkyl beta-D-mannofuranosidurono-6,3-lactone. Reduction of n-dodecyl beta-D-mannofuranosidurono-6,3-lactone with sodium borohydride yielded the corresponding alkyl beta-D-mannofuranoside.     

The preparation of some bromodeoxy- and dibromodideoxy-pentonolactones

Brief reaction of d-lyxono-1,4-lactone (1) with hydrogen bromide in acetic acid (HBA) yields 2-bromo-2-deoxy-d-xylono-1,4-lactone (2), and a similar treatment of d-ribono-1,4-lactone (8) gives 2-bromo-2-deoxy-d-arabinono-1,4-lactone (12). On longer reaction with HBA, 1 is converted into 2,5-dibromo-2,5-dideoxy-d-xylono-1,4-lactone, whereas 8 forms a mixture of 2,5-dibromolactones. Reduction of 2 and 12 gives 2-bromo-2-deoxy-d-xylose and -d-arabinose, respectively. On hydrogenolysis, 2 and 12 are converted into 2-deoxy-d-threo- and 2-deoxy-d-erythro-pentono-1,4-lactone, respectively. The 2,5-dibromolactones can be selectively hydrogenolysed to 5-bromo-2,5-dideoxy-d-pentono-1,4-lactones.     

Conformations of the d-glucarolactones and d-glucaric acid in solution

The conformations of d-glucaric acid (1), d-glucaro-1,4-lactone (2), d-glucaro-6,3-lactone (3), and d-glucaro-1,4:6,3-dilactone (4) in solution were investigated by ¹H-n.m.r. and ¹³C-p.F.t., n.m.r. spectroscopy. The solvents used were deuterium oxide, methanol-d₄, and dimethyl sulfoxide-d₆, and praseodymium chloride was employed as a lanthanide shift-reagent. For 2, it was found that the conformational equilibrium ³E(d)

E₃(d) exists in solution, and that the OH-5 group tends to occupy the position over the lactone ring in the favored E₃(d),gg conformation. The n.m.r. data for 3 indicated that the conformational equilibrium is shifted in favor of the ⁴E(d)

E₄(d),gt conformation in solution. The dienvelope conformation ³E:E₄(d) was found to be the favored conformation of 4. For 1, a conformational equilibrium between one planar, zigzag form and two sickle forms was indicated by the n.m.r. data observed. ¹³C-N.m.r. spectroscopy proved to be a convenient method for monitoring the lactonization of 1, and the hydrolysis of its lactones. Lactones other than 2–4 were not found in solutions prepared from 1–4, either during their mutarotation or after equilibration at 30°.     

Biosynthesis of chondroitin sulfate. Purification of UDP-D-xylose:core protein beta-D-xylosyltransferase by affinity chromatography

Silver carbonate on Celite (the Fetizon reagent) was shown to be selective as an oxidizing agent, and convenient for the preparation of various aldonolactones. Whereas substituted aldoses having the 1-hydroxyl group free were readily converted into the corresponding lactones, partially protected 2-acetamido-2-deoxypyranoses having more than one free hydroxyl group were selectively oxidized at C-1. The oxidation was carrried out in boiling benzene or 1,4-dioxane. A series of partially protected 2-acetamido-2-deoxy-1,5-aldonolactones [2-acetamido-4,6-O-benzylidene-2-deoxy-D-mannono-1,5-lactone (13),2-acetamido-4,6-O-benzylidene-2-deoxy-D-glucono-1,5-lactone (15), 2-acetamido-2-deoxy-4,6-O-isopropylidene-D-glucono-1,5-lactone (18), 2-acetamido-2-deoxy-4,6-O-isopropylidene-D-mannono-1,5-lactone (20), 2-acetamido-2-deoxy-3,4-di-O-methyl-D-mannono-1,5-lactone (24), and 2-acetamido-2-deoxy-3,4-di-O-methyl-D-glucono-1,5-lactone (25)] was thus prepared; for these, the oxidation was accompanied by two side-reactions: (a) an elimination (dehydration) that gave the unsaturated lactones [2-acetamido-4,6-O-benzylidene-2,3-dideoxy-D-erythro-hex-2-enono-1,5-lactone (12), 2-acetamido-2,3-dideoxy-4,6-O-isopropylidene-D-erythro-hex-2-enono-1,5-lactone (17), and 2-acetamido-2,3-dideoxy-4-O-methyl-D-erythro-hex-2-enono-1,5-lactone (23)], and (b) partial gluco-to-manno epimerization occurring during the oxidation of 2-acetamido-4,6-O-benzylidene-2-deoxy-D-glucopyranose (14), 2-acetamido-2-deoxy-4,6-O-isopropylidene-D-glucopyranose (16), and 2-acetamido-2-deoxy-3,4-di-O-methyl-D-glucopyranose (22).The free unsaturated lactone, 2-acetamido-2,3-dideoxy-D-erythro-hex-2-enono-1,5-lactone (26), was obtained on hydrolysis of the isopropylidene group in lactone 17.     

3-desoxyhex-2-enono-1,4-lactone aus D-hexofuran(osid)- urono-6,3-lactonen

The yield of 2-O-benzyl-3-deoxy-L-threo-hex-2-enono-1,4-lactone by reaction of 5-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranurono-6,3-lactone with sodium borohydride was improved by variation of the aprotic dipolar solvent and temperature. The general validity of this elimination—reduction reaction was ascertained by conversion of eleven other D-hexofuran(osid)urono-6,3-lactones into various 3-deoxy-hex-2-enono-1,4-lactones by treatment with sodium borohydride in hexamethyl phosphoric triamide.     

The inhibitory activity of 2-acetamido-2-deoxy-D-gluconolactones and their isopropylidene derivatives on 2-acetamido-2-deoxy-beta-D-glucosidase

2-Acetamido-2-deoxy-D-glucono-1,4-lactone (1) and 2-acetamido-2-deoxy-D-gluconic acid (3) have been examined for inhibitory activity against 2-acetamido-2-deoxy-β-D-glucosidase from bull epididymis. Crystalline 1 and 3 were compared with the known, crystalline 2-acetamido-2-deoxy-D-glucono-1,5-lactone (2), and a correlation of the activities of these compounds with various factors is presented. The inhibition constant of the 1,5-lactone 2 is lower (0.45μM) than that (4.43μM) of the 1,4-lactone 1. The effect of time is the opposite; whereas the activity of solutions of 2 decreases with time, solutions of 1 show an increase in inhibitory power, but both reach an equilibrium after 5 h. The free acid 3 exhibits no inhibitory activity. 2-Acetamido-2-deoxy-5,6-O-isopropylidene-D-glucono- 1,4-lactone (4) and 2-acetamido-2-deoxy-4,6-O-isopropylidene-D-glucono-1,5-lactone (5), which are appropriately protected to prevent conversion into the other lactone isomer, were also tested; 4 has 1/1000th the activity of 5.     

β-elimination in aldonolactones. Synthesis of 2-deoxy-D-lyxo-hexose and 2-deoxy-D-arabino-hexose

Benzoylation of D-glycero-L-manno-heptono-1,4-lactone (1) with benzoyl chloride and pyridine for 2 h afforded crystalline penta-O-benzoyl-D-glycero-L-manno-heptono-1,4-lactone (2), but a large excess of reagent during 8 h also led to 2,5,6,7-tetra-O- benzoyl-3-deoxy-D-lyxo-hept-2-enono-1,4-lactone (3). Catalytic hydrogenation of 3 was stereoselective and gave 2,5,6,7-tetra-O-benzoyl-3-deoxy-D-galacto-heptono-1,4-lactone (4). Debenzoylation of 4 followed by oxidative decarboxylation with ceric sulfate in aqueous sulfuric acid gave 2-deoxy-D-lyxo-hexose (5). Application of the same reaction to 3-deoxy-D-gluco-heptono-1,4-lactone afforded 2-deoxy-D-arabino-hexose (6).     

The preparation of some bromodeoxy- and dibromodideoxy-pentonolactones

Treatment of ammonium d-xylonate with hydrogen bromide in acetic acid yields 2,5-dibromo-2,5-dideoxy-d-lyxono-1,4-lactone (2a), whereas similar treatment of potassium d-arabinonate gives 5-bromo-5-deoxy-d-arabinono-1,4-lactone (8a) as the main product. Two isomeric 2,5-dibromo-2,5-dideoxy-1,4-lactones are also formed in minor amounts. Selective hydrogenolysis of 2a affords 5-bromo-2,5-dideoxy-d-threo-pentono-1,4-lactone, while prolonged treatment results in the formation of 3-hydroxypentanoic acid. Similarly, hydrogenolysis of 8a produces a 2,3-dihydroxypentanoic acid together with smaller amounts of 5-deoxy-d-arabinono-1,4-lactone; the latter also results from hydrogenolysis of 5-deoxy-5-iodo-d-arabinono-1,4-lactone with Raney nickel.     

The conversion of d-glucono-1,5-lactone into an α-pyrone derivative

Treatment of d-glucono-1,5-lactone (3) with excess of acetic anhydride in anhydrous pyridine at room temperature afforded the tetra-acetate and 2,4,6-tri-O-acetyl-3-deoxy-d-erythro-hex-2-enono-1,5-lactone (1). On prolonged reaction or at 80°, 3-acetoxy-6-acetoxymethylpyran-2-one (5) was the unexpected main product. The mechanistic implications of the conversion of 1 → 5 are discussed.     

Improved preparation and synthetic uses of 3-deoxy-d-arabino-hexonolactone: an efficient synthesis of Leptosphaerin

Acetylation of d-glucono-1,5-lactone and subsequent treatment with triethylamine gave 2,4,6-tri-O-acetyl-d-erythro-hex-2-enono-1,5-lactone. Hydrogenation of the latter in the presence of palladium on carbon yielded 2,4,6-tri-O-acetyl-3-deoxy-d-arabino-hexono-1,5-lactone (5) in almost quantitative yield calculated from gluconolactone. Catalytic hydrogenation of 5 with platinum on carbon in the presence of triethylamine gave 2,4,6-tri-O-acetyl-3-deoxy-d-arabino-hexopyranose in quantitative yield. Deacetylation of 5 gave 3-deoxy-d-arabino-hexono-1,4-lactone, which was converted into 3-deoxy-5,6-O-isopropylidene-2-O-methanesulfonyl-d-arabino-hexono-1,4-lactone (10). The latter was converted into 2-acetamido-2,3-dideoxy-d-erythro-hex-2-enono-1,4-lactone (Leptosphaerin). When 10 was boiled in water in the presence of acid, it gave a high yield of 2,5-anhydro-3-deoxy-d-ribo-hexonic acid.     

The conversion of d-glucono-1,5-lactone into an α-pyrone derivative

Treatment of d-glucono-1,5-lactone (3) with excess of acetic anhydride in anhydrous pyridine at room temperature afforded the tetra-acetate and 2,4,6-tri-O-acetyl-3-deoxy-d-erythro-hex-2-enono-1,5-lactone (1). On prolonged reaction or at 80°, 3-acetoxy-6-acetoxymethylpyran-2-one (5) was the unexpected main product. The mechanistic implications of the conversion of 1 → 5 are discussed.     

Studies on dehydro-l-ascorbic acid 3-oxime 2-phenylhydrazone: Conversion into substituted triazoles

l-threo-2,3-Hexodiulosono-1,4-lactone 3-oxime 2-(phenylhydrazone) (1) gave 2-(p-bromophenyl)-4-(l-threo-1,2,3-trihydroxypropyl)-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone (2), and this gave a diacetyl and a dibenzoyl derivative. On treatment of 2 with liquid ammonia, methylamine, or dimethylamine, the corresponding triazole-5-carboxamides (5–7) were obtained. Periodate oxidation of 5 gave 2-(p-bromophenyl)-4-formyl-1,2,3-triazole-5-carboxamide (10), and, on reduction, 10 gave 2-(p-bromophenyl)-4-(hydroxymethyl)-1,2,3-triazole-5-carboxamide, characterized as its monoacetate. Condensation of 10 with phenylhydrazine gave the triazole hydrazone. Acetonation of 2 gave the isopropylidene derivative. Reaction of 2 with HBr-HOAc gave 4-(l-threo-2-O-acetyl-3-bromo-1,2-dihydroxypropyl)-2-(p-bromophenyl)-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone. Similar treatment of 1 with HBr-HOAc gave 5-O-acetyl-5-bromo-6-deoxy-l-threo-2,3-hexodiulosono-1,4-lactone 3-oxime 2-(phenylhydrazone). This was converted into 4-(l-threo-2-O-acetyl-3-bromo-1,2-dihydroxypropyl)-2-phenyl-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone on treatment with boiling acetic anhydride. On reaction of 1 with benzoyl chloride in pyridine, dehydrative cyclization occurred, with the formation of 4-(l-threo-2,3-dibenzoyloxy-1-hydroxypropyl)-2-phenyl-1,2,3-triazole-5-carboxylic acid 5,1¹-lactone, which was converted into the amide on treatment with ammonia.     

Some studies on dehydro-d-ascorbic acid 2-(phenylhydrazone)

Reaction of hydroxylamine with d-erythro-2,3-hexodiulosono-1, 4-lactone 2-(phenylhydrazone) (2) gave the 3-oxime 2-(phenylhydrazone) (3). On boiling with acetic anhydride, 3 gave 4-(d-erythro-2,3-diacetoxy-l-hydroxypropyl)-2-phenyl-1,2, 3-triazoIe-5-carboxylic acid 5,1′-lactone. Compound 3 was also converted into the related, unacetylated 2-(p-bromophenyl)triazole with bromine. Treatment of 2 with boiling acetic anhydride gave an optically inactive, olefinic compound, assigned the structure 4-(2-acetoxyethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(phenylhydrazone). The 2-(phenylhydrazone) 2 gave the corresponding 2,3-bis(phenylhydrazone) on condensation with phenylhydrazine.     

β-Elimination in aldonolactones. Synthesis of 3,6-dideoxy L-arabino-hexose (ascarylose)

Benzoylation of L-rhamnono-1,5-lactone (1) with an excess of benzoyl chloride and pyridine for 16 h afforded 2,4-O-benzoyl-3,6-dideoxy-L-erythro-hex-2-enono-1,5-lactone (2). Catalytic hydrogenation of 2 was stereoselective and gave crystalline 2,4-di-O-benzoyl-3,6-dideoxy-L-arabino-hexono-1,5-lactone (3). Reduction of the lactone 3 with disiamylborane afforded 2,4-di-O-benzoyl-3,6-dideoxy-L-arabino-hexopyranose (4) which, on debenzoylation, gave 3,6-dideoxy-L-arabino-hexose (ascarylose) (7) in good overall yield. The sugar was identified as the corresponding alditol (ascarylitol) and by convertion into methyl 3,6-dideoxy-α-L-arabino-hexopyranoside (methyl ascaryloside, 6).