Synthesis and transformations of new annulated pyranosides using the Pauson-Khand reaction

The synthesis and transformations of new annulated pyranosides are described. These adducts were prepared by Pauson-Khand reaction on differently functionalized prop-2-ynyl-2,3-dideoxy-alpha-D-erythro-hex-2-enopyranosides (1-8). Compound 1 with a free hydroxyl group at C-4 afforded significant amounts of the hydrogenolysis product 12 in addition to the normal adduct 13. The C-4 O-protected similar precursors (2-8) gave PK products in yields ranging from 39 to 63%. Pauson-Khand adduct 19 provided intermediate 23 after selective manipulation. The oxidation plus decarbonylation synthetic sequence applied to intermediate 23 gave a poor yield of compound 24 using Wilkinson's catalyst. The t-butyl hydroperoxide promoted decarbonylation of product 23 afforded formate 25 in a typical Baeyer-Villiger rearrangement. The Ferrier-II reaction on intermediate 45, readily available from compound 9, afforded the hydrindane-type derivative 46 in 34% yield using a Ferrier-II type reaction.     

Short and efficient synthesis of (2S,3R,4R,5R) and (2S,3R,4R,5S)-tetrahydroxyazepanes via the Henry reaction

The Henry reaction with the easily available alpha-d-xylo-pentodialdose afforded a diastereomeric mixture of nitroaldoses with the alpha-d-gluco- and beta-l-ido-configuration, respectively, in good yield. When n-BuLi was used as the base, the reaction afforded the alpha-d-gluco-nitroaldose as the only product. The reduction of the nitro group in the alpha-d-gluco- and beta-l-ido-nitroaldoses, removal of the protecting groups and intramolecular reductive cyclo-amination afforded the corresponding (2S,3R,4R,5R) and (2S,3R,4R,5S) tetrahydroxyazepanes.     

Novel Nucleoside Analogues: First Synthesis of Pyridine-4-Thioglycosides and Their Cytotoxic Evaluation

The reaction of sodium 2,2-dicyanoethene-1,1-bis(thiolate) with 2-cyano-N-arylacetamides afforded sodium pyridine-4-thiolates, coupling of the latters with 2,3,4,6-tetra-O-acetyl-D-gluco- and D-galactopyranosyl bromides, respectively, afforded new pyridine-4-thioglycosides. Ammonolysis of the latter compounds afforded the free thioglycosides. The antitumor activities of the synthesized compounds were tested against human tumor cell lines; lung (A549), colon (HCT116), liver (HEPG2), and prostate (PC3).     

Synthesis of AZT analogues: 7-(3-azido-2-hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-,7-(3-triazolyl-2-hydroxypropyl)theophylline

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Isolation and identification of the intermediates during pyrazole formation of some carbohydrate hydrazone derivatives

Reaction of the oxidation product of L-ascorbic acid, dehydro-L-ascorbic acid, with o-phenylenediamine, followed by 2,4,6-trichlorophenylhydrazine (3) afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (4), whose structure was deduced from studying its periodate oxidation, which gave the glyoxal derivative 3-[1-(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one (5) that upon reduction afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-2-hydroxyethy-1-yl]quinoxalin-2(1H)one (6). The reaction of 5 with 3 afforded the bishydrazone 3-[1,2-bis(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one. The reaction of 5 with acetic anhydride in pyridine afforded the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-acetoxy-3-[2-acetyl-2-(2,4,6-trichlorophenyl)hydrazono)]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 4 with acetic anhydride in pyridine afforded the acyclic diacetate intermediate 3-[3,4-di-O-acetyl-2-deoxy-1-(2,4,6-trichlorophenylhydra-zono)but-2-en-1-yl]quinoxalin-2(1H)one (12), which was also obtained from the reaction of 4 with boiling acetic anhydride. Compound 12 rearranged under the reaction conditions to give the pyrazole derivatives 3-[5-(ace-toxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (14) and 2-acetoxy-3-[5-(acetoxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl)]quinoxaline (15), as well as the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-(2-acetoxyethen-2-yl)-3-[2-(2,4,6-trichlorophenyl)hydrazono]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 3-[5-(hydroxymethyl)-l-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (16) with acetic anhydride in pyridine or 12 with boiling acetic anhydride afforded 15 and 16, respectively. Treatment of 4 with diluted sodium hydroxide afforded the pyrazolo[2,3-b]quinoxaline (flavazole) derivative 1-(2,4,6-trichlorophenyl)-3-(L-threo-glycerol-1-yl)pyrazolo[2,3-b]quinoxaline whose acetylation afforded the acetyl derivative 3-(2,3,4-tri-O-acetyl-L-threo-glycerol-1-yl)-1-(2,4,6-trichlorophenyl)pyrazolo[2,3-b]quinoxaline. The assigned structures were based on spectral analysis. The activity of compound 4 against hepatitis B virus has been studied.     

A glycosidic eudesmanolide from Hyaloseris salicifolia

The flowers of Hyaloseris salicifolia afforded known ivasperin, while the leaves afforded ivasperin and 2-O-(6'-O-acetyl-beta-D-glucopyranosyl)-ivasperin, whose structure was determined by spectroscopic methods.     

Labdane derivatives from hemizonia species

The investigation of three Hemizonia species afforded in addition to known compounds seven new labdane derivatives, all derived from labd-13-en-15-ol. The absolute configuration of these diterpenes was determined by degradation of the triol by periodate cleavage, which afforded a known norditerpene ketone. From H. fitchii two new chromene esters and the cis-isomer of a known coumarate were isolated. H. congesta afforded in addition to labdane derivatives a hydroxycubebol.     

Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa

A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.     

Malaria: a vaccine concept based on sickle haemoglobin's augmentation of an innate autoimmune process to band 3

The protection from malaria afforded by sickle haemoglobin (and certain other haemoglobinopathies) suggests that it may be possible to utilise a common property that their erythrocytes share with both malaria-infected erythrocytes and senescent erythrocytes to develop a vaccine. All three conditions cause clustering of a specific protein molecule, band 3, on their erythrocyte's surface and this protein, when present on senescent erythrocytes at least, results in the immune recognition and removal of these by naturally occurring antibodies. It is hypothesised that if an up-regulated immune response to this protein on sickle cells is responsible for the benefit afforded to malaria patients then a vaccine using antigenic band 3 peptides may provide similar protection.     

Helifulvanolsäkure—ein neues diterpen mit anomalem kohlenstoffgerüst aus Helichrysum fulvum

The aerial parts of Helichrysum fulvum afforded, in addition to beyerenic acid and ent-kaurenic acid, two new diterpenic acids with the hitherto unknown carbon skeleton of an isotrachylobane type. The structures of these acids, isolated as their methyl esters, were elucidated by extensive NMR studies, some chemical transformations and by X-ray structural analysis of the corresponding acetate. The related alcohol on reaction with pyridinochlorochromate afforded a homoconjugated diene probably formed by fragmentation of a cyclopropyl carbinol. The possible biogenesis of the new carbon skeleton is discussed briefly.     

Acyl migration on nucleic acid compounds related to adenosine

Treatment of N6,N6-di-p-toluyl-2',3'-O-isopropylideneadenosine (7) with ZnBr2 in 1,4-dioxane afforded a 8,5'-O-cycloadenosine derivative 8 exclusively. Reaction of 2',3'-O-isopropylideneadenosine (1) with p-cyanobenzoyl chloride in a CH2Cl2-Et3N mixture afforded a ring-cleaved compound 11 as the main product.     

Photolysis of 3-Hydroxyisoxazoles

Photolysis of 3-hydroxy-5-phenylisoxazole in methanol with a low-pressure mercury lamp afforded 5-phenyl-4-oxazolin-2-one, together with small amounts of benzoic acid and benzoylacetamide. Similarly, 3-hydroxy-5-methylisoxazole in distilled water afforded 5-methyl-4-oxazolin-2-one as the major product. Both isoxazoles were stable in sunlight for up to 20 days.     

A concise synthesis of 3-fluoro-5-thio-xylo- and glucopyranoses, useful precursors towards their corresponding pyranonucleoside derivatives

The chemical synthesis of 1,2,4-tri-O-acetyl-3-deoxy-3-fluoro-5-thio-D-xylopyranose, 1,2,4,6-tetra-O-acetyl-3-deoxy-3-fluoro-5-thio-alpha-D-glucopyranose and their corresponding nucleosides of thymine is described. Treatment of 3-fluoro-5-S-acetyl-5-thio-D-xylofuranose, obtained by hydrolysis of the isopropylidene group of 3-fluoro-1,2-O-isopropylidene-5-S-acetyl-5-thio-D-xylofuranose, with methanolic ammonia and direct acetylation, led to triacetylated 3-deoxy-3-fluoro-5-thio-D-xylopyranose. Condensation of acetylated 3-fluoro-5-thio-D-xylopyranose with silylated thymine afforded the corresponding nucleoside. Selective benzoylation and direct methanesulfonylation of 3-fluoro-1,2-O-isopropylidene-alpha-D-glucofuranose gave the 6-O-benzoyl-5-O-methylsulfonyl derivative, which on treatment with sodium methoxide afforded the 5,6-anhydro derivative. Treatment of the latter with thiourea, followed by acetolysis, gave the 3-fluoro-5-S-acetyl-6-O-acetyl-1,2-O-isopropylidene-5-thio-alpha-D-glucofuranose. 3-fluoro-5-S-acetyl-6-O-acetyl-5-thio-D-glucofuranose, obtained after hydrolysis of 5-thiofuranose isopropylidene, was treated with ammonia in methanol and directly acetylated, giving tetraacetylated 3-deoxy-3-fluoro-5-thio-alpha-D-glucopyranose. Condensation of the latter with silylated thymine afforded the desired 3-deoxy-3-fluoro-5-thio-beta-D-glucopyranonucleoside analogue.     

Towards alpha- or beta-D-C-glycosyl compounds by tin-catalyzed addition of glycosyl radicals to acrylonitrile and vinylphosphonate,and flexible reduction of tetra-O-acetyl-alpha-D-glucopyranosyl bromide with cyanoborohydride

Photo-induced radical addition of acetylated alpha-D-glucopyranosyl bromide (1). to acrylonitrile or diethyl vinylphosphonate, in the presence of catalytic amounts of tri-n-butyltin chloride and sodium (or tetra-n-butylammonium) cyanoborohydride in excess, allowed efficient preparations of alpha-configurated nonononitrile and 2-(alpha-D-glucopyranosyl)-ethylphosphonate (79, 70% yields, respectively). These conditions led to 2-(alpha-D-manno-, and galactopyranosyl)-ethylphosphonates in 68 and 76% yields. Similarly, radical addition of acetylated 1-bromo-beta-D-glucopyranosyl chloride (2). to acrylonitrile or diethyl vinylphosphonate afforded mainly intermediate chlorides which, upon radical reduction with excess tri-n-butyltin hydride, afforded the corresponding beta anomers (40 and 38%, respectively) by sequential C-C and C-H bond formation. Stereocontrol relies on the alpha-stereoselective quenching of D-glycopyranos-1-yl radicals. We found also that UV light irradiation of 1 with excess NaBH(3)CN in tert-butanol afforded either 1,3,4,6-tetra-O-acetyl-2-deoxy-alpha-D-arabino-hexopyranose (65% after crystallization) or, when 10% mol thiophenol was added, 2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-glucitol (79%). These are simple, tin-free, and easily controlled conditions, which compare well with known preparations of these reduced sugars.     

Enzymatic regioselective deprotection of peracetylated mono- and disaccharides

Selective enzymatic hydrolysis of the peracetylated disaccharides, namely cellobiose, lactose, maltose and melibiose, with lipase from Asperilligus niger in aqueous buffer and organic solvent for 30 min afforded exclusively the corresponding heptaacetates with a free hydroxyl group at C-1 in high yield. Prolonged reaction of the β-1,4 linked cellobiose and lactose peracetates afforded selectively their hexaacetates with free hydroxyl groups at C-1,2, whereas the α-1,4 linked disaccharides maltose and melibiose peracetate gave a complex mixture of products. The reaction of 2-acetamido-2-deoxy-1,3,4,6-tetra-O-acetylglucopyranose (11) for 22 h afforded as the major product the diacetate 12 with free hydroxyl groups at C-1,4.     

Synthesis of N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione-N-nucleosides and S-glycosylated derivatives

Fusion of the N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thiones 1-4 with the peracylated ribose 5 in the presence of iodine afforded the N-nucleosides 6-9 in moderate yields. Deblocking with NaOMe/MeOH gave the free nucleosides 10-13. Alternatively, silylation of 4 followed by ribosylation with 5 in the presence of TMSOTf as catalyst afforded 9 in moderate yield. Ribosylation of 4 with the chlorodeoxyribose derivative 15 as well as 5 in the presence of NaH in DMF afforded the thioglycosides 16 and 18, respectively. Deblocking of 16 and 18 with NaOMe/MeOH gave the free S-thioglycosides 17 and 19, respectively. Thermal rearrangement of 19 at high temperature in the presence of iodine furnished 13 in low yield. The new free nucleosides and thioglycosides were inactive against HIV-1 and HIV-2 induced cytopathicity in human MT-4 lymphocyte cells.     

Stereoselective syntheses of a di-, tri-, and tetra-saccharide fragment of Shigella dysenteriae type 1 O-antigen using 3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-glucopyranosyl chloride as a glycosyl donor.

Methyl 2,4-di-O-benzoyl-alpha-L-rhamnopyranoside (1) furnished a crystalline 3-O-bromoacetyl derivative that was treated with the dichloromethyl methyl ether-ZnCl2 reagent to give 2,4-di-O-benzoyl-3-O-bromoacetyl-alpha-L-rhamnopyranosyl chloride (3). Compounds 1 and 3 were condensed under the conditions of base-deficient, silver trifluoromethanesulfonate-mediated glycosylation to give a fully protected rhamnobioside, which on O-debromoacetylation afforded the disaccharide nucleophile 10. Similar condensation of 3 with methyl 3-O-benzoyl-4,6-O-benzylidene-alpha-D-galactopyranoside, followed by O-debromoacetylation and condensation of the thus formed methyl O-(2,4-di-O-benzoyl-alpha-L-rhamnopyranosyl)-(1----2)-4,6-O-benzylidene- 3-O-benzoyl-alpha-D-galactopyranoside again with 3, gave the trisaccharide glycoside. Subsequent O-debromoacetylation gave 17, having only HO-3(3) unsubstituted. Silver perchlorate-mediated glycosylations of 1, 10, and 17 with 3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-glucopyranosyl chloride afforded, with high alpha stereoselectivity, protected di-, tri-, and tetra-saccharide glycosides. Subsequent hydrogenation, followed by N-acetylation and O-deacylation, afforded three oligosaccharide glycosides having nonreducing terminal 2-acetamido-2-deoxy-alpha-D-glucopyranosyl residues and comprising successively larger portions of the repeating unit of Shigella dysenteriae type 1 O-antigen.     

Application of solid-phase chemistry for the synthesis of 3'-fluoro-3'-deoxythymidine

Reported solution-phase methods for the synthesis of 3'-fluoro-3'-deoxythymidine (FLT) are cumbersome, require purification of intermediates, and include several protecting/deprotecting steps. To circumvent these problems, a solid-phase strategy was designed for the synthesis of FLT. Thymidine was immobilized on trityl resin via the 5'-hydroxyl group. The subsequent mesylation of the free 3'-hydroxyl group in the presence of methanesulfonyl chloride afforded the polymer-bound 3'-O-mesylthymidine. Nucleophilic substitution of the mesyl moiety by hydroxyl group in the presence of sodium hydroxide produced the polymer-bound threothymidine. Fluorination with diethylaminosulfur trifluoride followed by acidic cleavage of the polymer-bound FLT in the presence of trifluoroacetic acid afforded FLT.     

Preparation and ring-opening reactions of a 2,3-anhydride derived from sucrose

Selective tosylation of 6,1′,6′-tri-O-tritylsucrose afforded the 2-O-tosyl derivative and not the 3-O-tosyl derivative as previously claimed. Treatment of the 2-tosylate with base afforded mainly (40%) the 2,3-manno-epoxide together with the 3,4-altro-epoxide which arose by migration of the epoxide ring. Ring-opening of the 2,3-epoxide with a variety of nucleophilic anions took place exclusively at C-3 to give altropyranosyl derivatives, whereas reaction of the epoxide with ammonium thiocyanate afforded the 2,3-allo-episulphide. Ring-opening of the 2,3-manno-epoxide with lithium iodide in ether gave 37% of the 3-deoxy-3-iodomannopyranosyl isomer, which arose by prior rearrangement of the 2,3-epoxide to the 3,4-epoxide.     

Nucleosides 7(9): synthesis, structure, and biological activity of new 6-arylidenamino-2-thio- and 2-benzylthiopyrimidine N-nucleosides

The condensation of 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidine-4-one [compound (1)] with aromatic aldehydes (2) afforded azomethine derivatives (3). The formed azomethines underwent glycosidation with α-acetobromoglucose (4) to form the corresponding pyrimidine N-glycosides (6) and not S-glycosides (5). The interaction of (3) with 1-O-acetyl-2, 3, 5-tri-O-benzoyl-β-D-ribofuranose (8) afforded the corresponding pyrimidine N-riboside (10) and not S-riboside (9). Deacetylation and debenzoylation of each of (6) and (10) by using methanolic sodium methoxide afforded the corresponding free N-nucleosides (7) and (11), respectively. Next, the reaction of 2-benzylthio-6-benzylidenaminouracil (13) with (4) and (8) did not yield the corresponding protected N-nucleosides (14) and (17), whereas it afforded (15) and (18), respectively. The latter compounds (15) and (18) were stirred in methanolic sodium methoxide to yield the corresponding free N-nucleosides (16) and (19), respectively. The structures of products have been elucidated and reported and also some of the products were screened for their antimicrobial activity. Graphical Abstract: