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.     

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 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).     

β-Elimination in aldonolactones. the conversion of l-rhamnono-1-5-lactone into 3-benzoyloxy-6-methylpyran-2-one

Benzoylation of l-rhamnono-1,5-lactone (1) for 90 min at room temperature afforded 2,3,4-tri-O-benzoyl-l-rhamnono-I,5-Iactone (2). When an excess of benzoyl chloride and pyridine was used for 20 h, with subsequent sublimation of benzoic acid from the mixture at 120° in vacua, a double elimination took place and 3-benzoyloxy-6-methylpyran-2-one (4) was isolated as the main product. The conversion of 1, 2, and 2,4.-di-O-benzoyl-3,6-dideoxy-l-erythro-hex-2-enono-l,5-lactone (3) into the pyran-one derivative 4 under different conditions was monitored chromatographically.     

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.     

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.     

Conformational studies on aldonolactones by n.m.r. spectroscopy. Conformations of d-glucono-1,5-lactone and d-mannono-1,5-lactone in solution

The conformations of d-glucono-1,5-lactone (1) and d-mannono-1,5-lactone (2) in solution were investigated by ¹H- and ¹³C-n.m.r. spectroscopy. Conformational equilibria for 1 and 2 were found to lie strongly in favor of the ⁴H₃(d),gg and B_2,5(d),gg conformations, respectively.     

The conformation of 2,3,4-tri-O-acetyl-D-xylono-l,5-lactone

A conformational analysis of 2,3,4-tri-O-acetyl-D-xylono-1,5-lactone (5) has been performed by using ¹H-n.m.r. spectral data. Evidence is presented that the C-3 and C-4 acetoxyl groups are anti-periplanar. The possible contribution of attractive 1,3- and 1,4-interactions between the electropositive lactone-ring oxygen and the endo-acetoxyl groups at C-3 and C-4 to the conformational stability of 5 is discussed.     

Fungal hydroxylation of (−)-santonin and its analogues

Santonin (1) was incubated with separate growing cultures of Aspergillus niger ATCC 9142, Mucor plumbeus ATCC 4740, Whetzelinia sclerotiorum ATCC 18687, Cunninghamella echinulata var. elegans ATCC 8688a and Phanerochaete chrysosporium ATCC 24725. Three novel metabolites were isolated: 11β,13-dihydroxysantonin (3), 6,7-dehydosantonin (5) and 3,6-dihydroxy-9-keto-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (7). 11β-Hydroxysantonin (2), 14-hydroxysantonin (4) and 3,6,9-trihydroxy-9,10-seco-selina-1,3,5(10)-trien-12-oic acid-12,6-lactone (6) were also isolated. Hydroxylation at C-9 followed by a retro-aldol reaction was postulated to have produced 6 and 7. Through the synthesis and fermentation of the santonin analogues: tetrahydrosantonin (8) and α-desmotroposantonin (12), several new compounds were obtained; the most significant being 9-keto-desmotroposantonin (14), which was indicative of C-9 monohydroxylation.     

Novel antioxidant agents deriving from molecular combinations of vitamins C and E analogues: 3,4-dihydroxy-5(R)-[2(R,S)-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2(R,S)-yl-methyl)-[1,3]dioxolan-4(S)-yl]-5H-furan-2-one and 3-O-octadecyl derivatives

Molecular combinations of two antioxidants (i.e., ascorbic acid and the pharmacophore of α-tocopherol), namely the 2,3-dihydroxy-2,3-enono-1,4-lactone and the chromane residues, have been designed and tested for their radical scavenging activities. When evaluated for their capability to inhibit malondialdehyde (MDA) production in rat liver microsomal membranes, the 3,4-dihydroxy-5R-2(R,S)-(6-hydroxy-2,5,7,8-tetramethylchroman-2(R,S)yl-methyl)-1,3]dioxolan-4S-yl]-5H-furan-2-one (11a–d), exhibited an interesting activity. In particular the 5R,2R,2R,4S and 5R,2R,2S,4S isomers (11c,d) displayed a potent antioxidant effect compared to the respective synthetic α-tocopherol analogue (5) and natural α-tocopherol or ascorbic acid, used alone or in combination. Moreover, the mixture of stereoisomers 11a–d also proved to be effective in preventing damage induced by reperfusion on isolated rabbit heart, in particular at the higher concentration of 300 μM. In view of these results our study represents a new approach to potential therapeutic agents for applications in pathological events in which a free radical damage is involved. Design, synthesis and preliminary biological activity are discussed.     

Equilibria of the anomeric and ring forms of ammonium 3-deoxy-d-manno-octulosonate in deuterium oxide

The tautomeric composition of a solution of ammonium 3-deoxy-d-manno-octulosonate (KDO, 1a) in D₂O at 28° was assessed by means of ¹³ C-F.t.-n.m.r. spectroscopy. The results revealed the presence of 6?0 and 11 % of the α and β anomers of the pyranose, and 20 and 9 % of the two furanoses, and suggested, but did not unequivocally prove, that the major furanose form is the α anomer. To facilitate interpretation of the spectral results for 1, ammonium 3,5-dideoxy-d-arabino(or ribo)-octulosonate (3a) was prepared by the reaction of 5-deoxy-d-erythro-pentose with sodium oxalacetate at pH 11. A chromatographically homogeneous, noncrystalline sample of 3 was obtained by lyophilization, and characterized as its (4-nitrophenyl)hydrazone (m.p. 162-163°). The ¹³C-n.m.r. spectrum of a solution of 3a in D₂O revealed it to be substantially all in the α-pyranose form. No signals were obtained for the possible 1,4-lactone of 3. As the 1,5-lactone and furanose forms are impossible for 3, it exhibited no signals analogous to those attributed to furanoid 1. On the basis of these results for 3, the two lactone forms of 1 were excluded from consideration, and the three pairs of ¹³C-n.m.r. signals observed at ≈45, 86, and 104 p.p.m. were assigned to the furanose forms of 1.     

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.     

Studies on dehydro- -ascorbic acid 2-arylhydrazone 3-oximes: Conversion into substituted triazoles and isoxazolines

-threo-2,3-Hexodiulosono-1,4-lactone 2-(arylhydrazones) (2) were prepared by condensation of dehydro- -ascorbic acid with various arylhydrazines. Reaction of 2 with hydroxylamine gave the 2-(arylhydrazone) 3-oximes (3). On boiling with acetic anhydride, 3 gave 2-aryl-4-(2,3-di-O-acetyl- -threo-glycerol-l-yl)-1,2,3-triazole-5-carboxylic acid 5,4¹-lactones (4). On treatment of 4 with liquid ammonia, 2-aryl-4-( -threo-glycerol-l-yl)-1,2,3-triazole-5-carboxamides (5) were obtained. Acetylation of 5 with acetic anhydride-pyridine gave the triacetates, and vigorous acetylation with boiling acetic anhydride gave the tetraacetyl derivatives. Periodate oxidation of 5 gave the 2-aryl-4-formyl-1,2,3-triazole-5-carboxamides (8), and, on reduction, 8 gave the 2-aryl-4-(hydroxymethyl)-1,2,3-triazole-5-carboxamides, characterized as the monoacetates and diacetates. Controlled reaction of 2 with sodium hydroxide, followed by neutralization, gave 3-( -threo-glycerol-l-yl)-4,5-isoxazolinedione 4-(arylhydrazones), characterized by their triacetates. Reaction of 2 with HBr-HOAc gave 5-O-acetyl-6-bromo-6-deoxy- -threo-2,3-hexodiulosono-1,4-lactone 2-(arylhydrazones); these were converted into 4-(2-O-acetyl-3-bromo-3-deoxy- -threo-glycerol-l-yl)-2-aryl-1,2,3-triazole-5-carboxylic acid 5,4¹-lactones on treatment with acetic anhydride-pyridine.     

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.     

Studies in the sphingolipids series,XXXII : Synthesis and resolution into optical antipodes of C20-phytosphingosine

C₂₀-Phytosphingosine, D(+)-ribo-2-amino-1, 3, 4-trihydroxyeicosane (8a), is synthesized through the following intermediates: 2-Methoxyoctadecanoic acid chloride (1)→Ethyl 2-methoxyoctadecanoylacetoacetate (2)→Ethyl (2-p-nitrophenylhydrazono)-2,3-dioxo-4-methoxyeicosanoate (3)→Ethyl 2-acetamido-3-oxo-4-methoxyeicosanoate (4)→Ethyl 2-acetamido-3-hydroxy-4-methoxyeicosanoate (5)→2-Acetamido-3-hydroxy-4-methoxyeicosanoic acid (6), 2-Amino-3-hydroxyeicosanoic acid 1,4-lactone hydrobromide (7a, b)→DL-ribo (8a) and DL-xylo(?)-2-amino-1,3,4-trihydroxyeicosane (8b). The resolution of the racemic base (8a) has been effected through its salts with D-tartaric acid.     

A new sesquiterpene lactone from the roots of Saussurea lappa: structure-anticancer activity study

The dried roots of Saussurea lappa, called costus roots, are used in the traditional system of medicine for the treatment of cancer. In our investigation for the anticancer constituents from the hexane extract of this plant, a new sesquiterpene (1) was isolated along with the known compounds costunolide (2), β-cyclocostunolide (3), dihydro costunolide (4) and dehydro costuslactone (5). Their structures were established by the extensive spectroscopic analyses. In addition, costunolide and β-cyclocostunolide derivatives were synthesized using Michael-type addition reaction of NaOMe to the α-methylene-γ-lactone moiety. All the compounds were tested for their in vitro cytotoxic activity. Compound 1 exhibited potent cytotoxic activity and other compounds displayed moderate activity.     

Linear sesterterpenes from the Caribbean sponge Thorecta horridus with inflammatory activity

Two new linear sesterterpenes 1 and 2, containing an α,β-unsaturated γ-lactone ring, have been isolated from the Caribbean sponge Thorecta horridus, Hyatt 1877 (F. Thorectidae). The structures of the two new metabolites were established on the basis of spectral data including 2D NMR experiments. Compound 1 exhibits inflammatory activity.Structures of two new linear sesterterpenes 1 and 2 from the sponge Thorecta horridus, determined through HREIMS, 1D and 2D NMR experiments, are reported. Compound 1 exhibits inflammatory activity.     

1-(2-((Z)-6-(2-(Trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one as a new potent apoptosis agent

Compounds 4a–f, 5a–f and 6–9, showed significant growth inhibition activity against human tumor cell lines. Of these compounds, 1-(2-((Z)-6-(2-(trifluoromethyl)phenyl)hexa-3-en-1,5-diynyl)phenyl)piperidin-2-one (8) displayed the most potent growth inhibition activity. Compound 8 also arrested cancer cells in G2/M phase and induced apoptosis via activation of caspase-3 and -9. According to western-blotting analysis, compound 8 can up-regulate Bax, down-regulate Bcl-2 and XIAP, as well as promote cytochrome c release.     

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.     

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.