An efficient synthesis of quinoxaline derivatives from 4-chloro-4-deoxy-alpha-D-galactose and their cytotoxic activities

A novel and efficient method for the synthesis of quinoxaline derivatives has been developed. Isopropylidenation of 4-chloro-4-deoxy-alpha-D-galactose with 2,2-dimethoxypropane, followed by selective hydrolysis, afforded 2,3-O-isopropylidene-4-chloro-4-deoxy-D-galactose di-methyl acetal (3) as a sole product. Oxidation of compound 3 with (Bu3Sn)2O-Br2 gave corresponding hex-5-ulose derivative in high yields. The hex-5-ulose derivative reacted with o-phenylenediamines under neutral conditions to afford quinoxaline derivatives in reasonable yields. The in vitro cytotoxic activities of these quinoxaline derivatives were investigated.     

Some non-anomerically C-C-linked carbohydrate amino acids related to leucine-synthesis and structure determination

(5'R)-5'-Isobutyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-L-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione was synthesised starting from methyl 2,3-O-isopropylidene-alpha-D-lyxo-pentodialdo-1,4-furanoside via methyl 6-deoxy-6-isopropyl-2,3-O-isopropylidene-alpha-D-lyxo-hexofuranosid-5-ulose applying the Bucherer-Bergs reaction. Its 5'-R configuration was confirmed by X-ray crystallography. Corresponding alpha-amino acid-methyl (5R)-5-amino-5-C-carboxy-5,6-dideoxy-6-isopropyl-alpha-D-lyxo-hexofuranoside (alternative name: 2-[methyl (4R)-beta-L-erythrofuranosid-4-C-yl]-D-leucine) was obtained from the above hydantoin by acid hydrolysis of the isopropylidene group followed by basic hydrolysis of the hydantoin ring. Analogous derivatives with 5S configuration, formed in a minority, were also isolated and characterised.     

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).     

A new and efficient entry to D-xylo-hexos-4-ulose and some derivatives thereof through epoxidation of the 3,4-hexeno derivative of diacetone-D-glucose

A new preparation of D-xylo-hexos-4-ulose (1) and of its 3-m-chlorobenzoate (2) has been devised using the epoxidation of 3-deoxy-1,2:5,6-di-O-isopropylidene-D-erythro-hex-3-enofuranose (6) as the key step. The epoxidation of 6 in CH2Cl2 furnished with high yield 1,2:5,6-di-O-isopropylidene-3-O-m-chlorobenzoyl-4-C-hydroxy-D-xylo-hexos-4-ulo-1,4-furanose as a mixture of C-4 hemiacetal anomers (7a,b), which, on acid hydrolysis, gave a tautomeric mixture of 3-O-m-chlorobenzoyl-D-xylo-hexos-4-ulose (2) with an overall 60% yield from 6. The formation of 4-C-methoxy-diacetone-D-glucose derivatives (11a,b) through epoxidation-methanolysis of 6, took place with reduced yield because of the competition between m-chlorobenzoic acid (MCBA) and methanol to the opening by attack at C-4 of the intermediate epoxide and the formation of acyclic products arising from the alternative nucleophilic attack at C-1. Acid hydrolysis of derivatives 11 gave D-xylo-hexos-4-ulose (1) with a 35% overall yield from 6. NMR analysis showed that 2 is composed, in CD3CN, mainly by a 7:3 mixture of 4-keto-alpha- and beta-pyranose forms, while 1, in D2O, is present as a more complex mixture constituted mainly by 4-keto-alpha- and beta-pyranoses and their respective hydrates in a 17:15:34:34 ratio.     

Synthesis of 3-deoxy-4-O-β-D-galactopyranosyl-D-erythro-hexos-2-ulose and of some of its derivatives from lactose

3-Deoxy-4-O-β-D-galactopyranosyl-D-erythro-hexos-2-ulose (1) was obtained from lactose by reaction with benzoylhydrazine in the presence of a slightly acidic solution of p-toluidine, followed by hydrazinolysis of the product, 3-deoxy-4-O-β-D-galactopyranosyl-D-erythro-hexos-2-ulose bis(benzoylhydrazone) (3), with benzaldehyde. A variety of derivatives of 1 and 3 was prepared. Lactose aroylhydrazones were also prepared. Quantitative determination of the oxidant during the periodate oxidation of 3 was studied. Periodate oxidation of monosaccharide arylhydrazones gave glyoxal mono(arylhydrazones) which afforded the corresponding, mixed bis(hydrazones).     

A synthesis of l-ristosamine and a derivative of its C-4 epimer

A synthesis of l-ristosamine from l-rhamnal is described, involving the sequence of reactions: methoxymercuration, tosylation, azide displacement, and reduction, which gave methyl α-l-ristosaminide (10). Acid hydrolysis then afforded l-ristosamine hydrochloride. Trifluoroacetylation of the hydrochloride of 10 followed by saponification and oxidation with ruthenium tetraoxide gave methyl 2,3,6-tri-deoxy-3-trifluoroacetamido-α-l-erythro-hexopyranosid-4-ulose (17). Borohydride reduction of 17 gave a separable, 1:1 mixture of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α-l-ribo- and α-l-xylo-hexopyranoside.     

Synthesis and structure determination of some sugar amino acids related to alanine and 6-deoxymannojirimycin.

(5'R)-5'-Methyl-5'-[methyl (4S)-2,3-O-isopropylidene-beta-L-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione was synthesised starting from methyl 6-deoxy-2,3-O-isopropylidene-alpha-D-lyxo-hexofuranosid-5-ulose applying the Bucherer-Bergs reaction. Its 5'-R configuration was confirmed by X-ray crystallography. Corresponding alpha-amino acid-methyl (5R)-5-amino-5-C-carboxy-5,6-dideoxy-alpha-D-lyxo-hexofuranoside (alternative name: 2-[methyl (4S)-2,3-O-isopropylidene-beta-L-erythrofuranosid-4-C-yl]-D-alanine) was obtained from the above hydantoin by acid hydrolysis of the isopropylidene group followed by basic hydrolysis of the hydantoin ring. Total deprotection afforded 5-C-carboxy-6-deoxymannojirimycin. Analogously, methyl (5S)-5-amino-5-C-carboxy-5,6-dideoxy-alpha-L-lyxo-hexofuranoside and 5-C-carboxy-6-deoxy-L-mannojirimycin were prepared from the corresponding (5'S)-5'-methyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-D-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione starting from methyl 6-deoxy-2,3-O-isopropylidene-alpha-L-lyxo-hexofuranosid-5-ulose.     

Synthesis of 3-hexuloses from 1,2:5,6-di-O-isopropylidenehexitols

A simple, but low-yielding method for the synthesis of 3-hexuloses has been elaborated. Oxidation of 1,2:5,6-di-O-isopropylidenehexitols with bromine in the presence of barium carbonate, followed by mild-acid hydrolysis of the oxidation products gave the free hexuloses. Oxidation occurred at only one of the carbon atoms bearing free hydroxyl groups. From the D-mannitol derivative, D-arabino-3-hexulose was obtained via the di-O-isopropylidene derivative, whereas the D-glucitol derivative gave a mixture of the 1,2:5,6-di-O-isoprpylidene derivatives of L-xylo- and D-ribo-3-hexulose, separable by column chromatography. Mild-acid hydrolysis of the oxidation products afforded the free hexuloses.     

Synthesis and structure determination of some nonanomerically C-C-linked serine glycoconjugates structurally related to mannojirimycin

The Bucherer-Bergs reaction of methyl 2,3-O-isopropylidene-alpha-d-lyxo-hexofuranosid-5-ulose gave (4'S)-4'-carbamoyl-4'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-oxazolidin-2'-one instead of expected hydantoins. A mixture of hydantoins--(5'R)-triphenylmethoxymethyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione and (5'S)-triphenylmethoxymethyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione was obtained from the 5-ulose having protected primary OH group at C-6. The 4'-S configuration of 2 as well as 5'-S configuration of (5'S)-hydroxymethyl-5'-[methyl (4R)-2,3-O-isopropylidene-beta-l-erythrofuranosid-4-C-yl]-imidazolidin-2',4'-dione (9) was confirmed by X-ray crystallography. Corresponding alpha-amino acid--methyl (5S)-5-amino-5-C-carboxy-5-deoxy-alpha-d-lyxo-hexofuranoside (alternative name: 2-[methyl (4R)-beta-l-erythrofuranosid-4-C-yl]-l-serine) (11) was obtained from the hydantoin 9 by acid hydrolysis of the isopropylidene and trityl groups followed by basic hydrolysis of the hydantoin ring. Analogous derivatives with 5-R configuration, formed in a minority, were also isolated and characterised.     

Synthesis of 2,6,7-trideoxy-7-C-(2,4-dichlorophenyl)-D-xylo-heptonic acid and 6-(2,4-dichlorophenyl)-D-xylo-2,3,4-tri-hydroxyhexanesulfonic acid.

2,4-O-Benzylidene-L-xylose was converted via a Wittig reaction into Z-2,4-O-benzylidene-5,6-dideoxy-6-C-(2,4-dichlorophenyl)-D-xylo-hex-5-++ +enitol (17), which, on hydrogenation, gave 5,6-dideoxy-6-C-(2,4-dichlorophenyl)-D-xylo- hexitol (33). tert-Butyldimethylsililation of the primary hydroxyl group of 33, followed by 4-methoxybenzylation, and desilylation afforded 5,6-dideoxy-6-C-(2,4-dichlorophenyl)-2,3,4-tri-O-(4-methoxybenzyl)-D-xyl o- hexitol (54). A Mitsunobu-type reaction of 54 replaced HO-1 by cyanide to give, after hydrolysis and hydrogenolysis, 2,6,7-trideoxy-7-C-(2,4- dichlorophenyl)-D-xylo-heptono-1,4-lactone (55). Mesylation of 33 and then acetylation gave 2,3,4-tri-O-acetyl-5,6-dideoxy- 6-C-(2,4-dichlorophenyl)-1-O-methanesulfonyl-D-xylo-hexitol (63), which was converted via its 1-thiobenzoate into bis[1,5,6-trideoxy-6-C-(2,4-dichlorophenyl)-D-xylo-hexitol] 1,1'-disulfide (65). Acetylation of 65, followed by permanganate oxidation and deacetylation, afforded sodium 6-(2,4-dichlorophenyl)-D-xylo- 2,3,4-trihydroxy-hexanesulfonate (67). Both 57 (obtained from 55 by hydrolysis with NaOH) and 67 are weak inhibitors of HMG-CoA reductase.     

Synthesis of non-glycosidic 4,6'-thioether-linked disaccharides as hydrolytically stable glycomimetics

Michael addition of 1,2:3,4-di-O-isopropylidene-6-thio-alpha-D-galactose (2) to 2-propyl 6-O-acetyl-3,4-dideoxy-alpha-D-glycero-hex-3-enopyranosid-2-ulose (1) afforded, as the major diastereoisomer, 2-propyl 6-O-acetyl-3-deoxy-4-S-(6-deoxy-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranos-6-yl)-4-thio-alpha-D-threo-hexopyranosid-2-ulose (3, 91% yield). Reduction of the carbonyl group of 3, followed by O-deacetylation gave the two epimers 7 (alpha-D-lyxo) and 8 (alpha-D-xylo) in a 1:2 ratio. On removal of the protecting groups of 8 by acid hydrolysis, formation of an 1,6-anhydro bridge was observed in the 3-deoxy-4-thiohexopyranose unit (10). The free non-glycosidic thioether-linked disaccharide 3-deoxy-4-S-(6-deoxy-alpha,beta-D-galactopyranos-6-yl)-4-thio-alpha,beta-D-xylo-hexopyranose (11) was obtained by acetolysis of 10 followed by O-deacetylation. A similar sequence starting from the enone 1 and methyl 2,3,4-tri-O-benzoyl-6-thio-alpha-D-glucopyranoside (12) led successfully to 2-propyl 3-deoxy-4-S-(methyl 6-deoxy-alpha-D-glucopyranos-6-yl)-4-thio-alpha-D-lyxo-hexopyranoside (17) and its alpha-D-xylo analog (19, major product). In this synthetic route, orthogonal sets of protecting groups were employed to preserve the configuration of both reducing ends and to avoid the formation of the 1,6-anhydro ring.     

Inhibitors of sterol synthesis. Chemical syntheses and spectral properties of 26-oxygenated derivatives of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells.

26-Oxygenated derivatives of delta 8(14)-15-ketosterols have been synthesized from (25R)-3 beta,26-diacetoxy-5 alpha-cholest-8(14)-en-15-one (IX) as part of a program to prepare potential metabolites and analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism. Partial hydrolysis of IX gave a mixture, from which the 3 beta,26-diol II and the 26-acetate (XI) and 3 beta-acetate (X) monoesters were isolated. Mitsunobu reaction of XI followed by hydrolysis gave (25R)-3 alpha,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one (VI). Oxidation of XI with pyridinium chlorochromate followed by hydrolysis of the acetate gave (25R)-26-hydroxy-5 alpha-cholest-8(14)-ene-3,15-dione (VII). Oxidation of X with Jones reagent followed by hydrolysis of the acetate gave (25R)-3 beta-hydroxy-15-keto-5 alpha-cholest-8(14)-en-26-oic acid (IVa). Jones oxidation of II gave (25R)-3,15-diketo-5 alpha-cholest-8(14)-en-26-oic acid (VII). 1H and 13C nuclear magnetic resonance assignments and analyses of mass spectral fragmentation data are presented for each of the new compounds and their derivatives. The 3,15-diketone VII was found to be highly active in lowering the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells, with a potency comparable to that of I. In contrast, 3 alpha,26-diol VI was less potent than I or VII. The two carboxylic acid analogs IVa and VIII were considerably less potent than VI in lowering the levels of HMG-CoA reductase activity.     

Stereospecific synthesis of a new class of compounds: bis-homoconduritol-A, -D, and -F

Bis-homoconduritol derivatives with conduritol-A, -D, and -F structures have been synthesized starting from cyclooctatetraene. The photooxygenation of trans-7,8-dibromo- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-dienes afforded the bicyclic endoperoxides. Reduction of the endoperoxides with thiourea followed by acetylation gave the corresponding diacetates. The KMnO(4) oxidation and epoxidation of the diacetates followed by acetylation gave the tetraacetates. Removal of the halides either with zinc-dust or Na-anthracene followed by the ammonolysis of tetraacetates afforded the bis-homoconduritol derivatives in high yield.     

The synthesis of -xylo-hexos-4-ulose and some derivatives

D-xylo-Hexos-4-ulose has been synthesised, characterised chromatographically, and methyl α- -xylo-hexopyranosid-4-ulose has been shown to be stable in neutral aqueous solution, contrary to a previous report. Glycosyl phosphate derivatives are also reported.     

The synthesis of D-xylo-hexos-4-ulose and some derivatives

D-xylo-Hexos-4-ulose has been synthesised, characterised chromatographically, and methyl α-D-xylo-hexopyranosid-4-ulose has been shown to be stable in neutral aqueous solution, contrary to a previous report. Glycosyl phosphate derivatives are also reported.     

Synthesis and antitumour activity of derivatives of curdlan and lichenan branched at C-6.

Derivatives of curdlan and lichenan, linear (1----3)-beta-D- and (1----3/1----4)-beta-D-glucans, respectively, have been synthesised having alpha-L-arabinofuranosyl, alpha-L-rhamnosyl, beta-D-glucosyl, and beta-gentiobiosyl side chains attached at positions 6. These water-soluble derivatives, obtained by condensation of the 2,4- and 2,4-/2,3-di-O-phenylcarbamoyl derivatives of curdlan and lichenan, respectively, with appropriate ortho esters followed by saponification, were characterised by methylation analysis, g.p.c., and interaction with Congo Red. The curdlan derivatives and the lichenan derivative with few glucosyl branches were active against the Sarcoma 180.     

Synthesis of D-manno-3-heptulose,D-ido-3-heptulose,and some aldoheptoses via isopropylidene derivatives of heptitols

D-manno-3-Heptulose (5) was synthesized by dimethyl sulfoxide-phosphorus pentaoxide oxidation of 1,2:3,4:6,7-tri-O-isopropylidene-D-glycero-D-manno-heptitol (3, prepared from volemitol), followed by hydrolysis. D-ido-3-Heptulose (8) was synthesized similarly by oxidation of 1,2:4,5:6,7-tri-O-isopropylidene-D-glycero-l-galacto-heptitol (7, prepared from D-glycero-l-galacto-heptitol, 6). Another tri-O-isopropylidene derivative (11), having a free primary hydroxyl group, was produced in larger amount than 7, and 11 yielded D-glycero-l-galacto-heptose (14). Compound 8 was also synthesized by way of 1,2:4,5.6,7-tri-O-isopropylidene-D-glycero-l-gulo-heptitol (15). The production of 15 from D-glycero-l-gulo-heptitol (13) was accompanied by a larger amount of 2,3:4,5:6,7-tri-O-isopropylidene-D-glycero-D-ido-heptitol (17) which, upon oxidation followed by hydrolysis, yielded D-glycero-D-ido-heptose (18). One of the two tri-O-isopropylidene derivatives obtained by acetonation of perseitol, 2,3:4,5:6,7-tri-O-isopropylidene-D-glycero-D-galacto-heptitol (19), yielded D-glycero-D-galacto-heptose (20).     

Structure of a -D-glucan from the mycelial wall of Basidiomycete QM 806

A water-soluble β-D-glucan has been isolated from the mycelial wall of Basidiomycete QM 806. The structure of this glucan was investigated by methylation, periodate, and enzymic studies. Hydrolysis of the methylated glucan gave 2,3,4,6-tetra-, 2,4,6-, 2,3,4- and 2,3,6-tri-, and 2,4-di-O-methyl-D-glucose in the following molar proportions: 1.0:1.0:O.8:1.2:1.0. Periodate oxidation of the glucan followed by reduction and mild acid hydrolysis gave glycerol, erythritol, and D-glucose in the molar proportions, 2.1, 1.0, and 2.0, respectively. The glucan was degraded to the extent of 38% by an exo-β-(1→3)-glucanase isolated from the same organism, though the branch points (joined through O-1, O-3, and O-6) appeared to be resistant to the enzyme whereas the (1→4) linkages were not. On the basis of these findings, the structure of the glucan and the possible role of the glucanase are discussed.     

Exomethylene pyranonucleosides: efficient synthesis and biological evaluation of 1-(2,3,4-trideoxy-2-methylene-beta-d-glycero-hex-3-enopyranosyl)thymine

A new series of unsaturated pyranonucleosides with an exocyclic methylene group and thymine as heterocyclic base have been designed and synthesized. d-Galactose (1) was readily transformed in three steps into the corresponding 1-(beta-d-galactopyranosyl)thymine (2). Selective protection of the primary hydroxyl group of 2 with a t-butyldimethylsilyl (TBDMS) group, followed by specific acetalation, and oxidation gave 1-(6-O-t-butyldimethylsilyl-3,4-O-isopropylidene-beta-d-lyxo-hexopyranosyl-2-ulose)thymine (5). Wittig reaction of the ketonucleoside 5, deprotection and tritylation of the 6'-hydroxyl group gave 1-(2-deoxy-2-methylene-6-O-trityl-beta-d-lyxo-hexopyranosyl)thymine (9). Exomethylene pyranonucleoside 9 was converted to the olefinic derivative 10, which after detritylation afforded the title compound 1-(2,3,4-trideoxy-2-methylene-beta-d-glycero-hex-3-enopyranosyl)thymine (11). These novel synthesized compounds were evaluated for antiviral activity against rotaviral infection and cytotoxicity in colon cancer. As compared to AZT, compounds 1-(2-deoxy-2-methylene-beta-d-lyxo-hexopyranosyl)thymine (7) and 1-(beta-d-lyxo-hexopyranosyl-2-ulose)thymine (8) showed to be more efficient, in rotavirus infections and in treatment of colon cancer.