Synthesis of 1,5-Anhydro-D-Mannitol Nucleosides with a Purine Base Moeety

Abstract

D-Mannitol nucleosides with a purine base moiety have been conveniently synthesized strating from 1,5-anhydro-4,6-O-benzylidene-D-glucitol. The 3-OH function of 1,5-anhydro-4,6-O-benzylidene-D-glucitol was selectively protected with t-butyldimethylsilyl group and subsequently converted to the corresponding 0-triflate derivative for the introduction of the nucleobase moietes. These nucleoside derivatives were transformed to 1,5-Anhydro-6-O-MMTr-2-(N⁶-benzoyladenin-9-yl)-2-deoxy-3-O-TBDMS-D-mannitol and 1,5-Anhydro-6-O-MMTr-2-(N²-isobutyryl-guanin-9-yl)-2-deoxy-3-O-TBDMS-D-mannitol, useful as the building blocks for oligonucleotide synthesis. Also, the synthesis of the corresponding fully deprotected anhydrohexitol nucleosides were achieved for evaluation of antiviral activity test.     

Synthesis of 4-O-glycosylated 1,5-anhydro-d-fructose and of 1,5-anhydro-d-tagatose from a common intermediate 2,3-O-isopropylidene-d-fructose

Four novel disaccharides of glycosylated 1,5-anhydro-d-ketoses have been prepared: 1,5-anhydro-4-O-β-d-glucopyranosyl-d-fructose, 1,5-anhydro-4-O-β-d-galactopyranosyl-d-fructose, 1,5-anhydro-4-O-β-d-glucopyranosyl-d-tagatose, and 1,5-anhydro-4-O-β-d-galactopyranosyl-d-tagatose. The common intermediate, 1,5-anhydro-2,3-O-isopropylidene-β-d-fructopyranose, was prepared from d-fructose and was converted into the d-tagatose derivative by oxidation followed by stereoselective reduction to the 4-epimer. The anhydroketoses thus prepared were glycosylated and deprotected to give the disaccharides.     

1,5-Anhydro-2-Deoxy-D-Altritol Oligonucleotides as Conformationally Restricted Analogues of Rna

Abstract

As part of a project concerning the investigation of new hexitol nucleic acids (HNA), the 1,5-anhydro-2-deoxy-D-altritol nucleoside building blocks with a uracil, cytosine, adenine and guanine base moiety were synthesized. The uracil analogue was used for the automated synthesis of corresponding oligonucleotides. Hybridization capabilities of these altritol nucleic acids (ANA) are illustrated by the Tm values obtained for the (a ^hU)₁₃/(dA)₁₃ duplex.     

Synthèses et réductions de sucres fonctionnels mono et diinsaturés

Attempts to prepare 1,2:5,6 and 2,3:5,6 di-unsaturated sugars starting from 3,4,6-tri-O-acetyl-1,5-anhydro-1,2-dideo xy-d-arabino-hex-1-enitol or from ethyl 4,6-di-O-acetyl-1,5-anhydro-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside led to 1,5-anhydro-1,2,6-trideoxy-l-threo-hex-5-enitol and its 3,4-diacetate. Hydrogenation and hydrogenolysis of the unsaturated chloro and fluoro derivatives afforded 1,5-anhydro-1,2,6-trideoxy-d-arabino-hexitol and ethyl 4-O-acetyl-2,3,6-trideoxy-α-d-erythro-hexopyranoside.     

A revision of the structure of cucurbitacin S from Bryonia dioica

¹H NMR studies at 400 MHz on cucurbitacin S and its derivatives suggest that the structure of cucurbitacin S previously isolated from Bryonia dioica should be revised from (22S)-22, 25-anhydro-2,16α,22,25-tetrahydroxy-3,11,23-trioxo-cucurbita-1,5-diene to (24S)-16,24-anhydro- 2,16α,24,25-tetrahydroxy-3,11,22-trioxo-cucurbita-1,5-diene.     

Synthesis of some derivatives of 6-amino-1,5-anhydro-6-deoxy-d-glucitol and 2-amino-1,5-anhydro-2-deoxy-d-glucitol

6-Amino-1,5-anhydro-6-deoxy-d-glucitol (11) was prepared from 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (1) in six steps. Reduction of 1 with tributyltin hydride, followed by deacetylation, monomolar tosylation, and reacetylation, afforded 2,3,4-tri-O-acetyl-1,5-anhydro-6-O-toluene-p-sulfonyl-d-glucitol (9). Alternatively, tritylation of 1,5-anhydro-d-glucitol, followed by acetylation, detritylation, and tosylation, gave 9. Mesylation gave 8. Treatment of 8 or 9 with azide anion afforded the azide 10, reduction of which with tributyltin hydride gave 11, which was mesylated or tosylated, and then deacetylated to give the 6-methane-sulfonamido or 6-toluene-p-sulfonamido derivative. Similarly, mesylation or tosylation of 3,4,6-tri-O-acetyl-2-amino-1,5-anhydro-2-deoxy-d-glucitol (20) gave the 2-methanesulfonamido or 2-toluene-p-sulfonamido derivatives. Treatment of 11 and 20 with sulfur trioxide-pyridine afforded the sulfoamino derivatives, deacetylation of which gave sugar analogs of cyclamate-like compounds.     

Synthesis of 2-deoxy-2-fluorohexoses by fluorination of glycals in aqueous media

1,5-Anhydro-2-deoxy-d-arabino- (d-glucal), 1,5-anhydro-2-deoxy-d-lyxo- (d-galactal), and 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-lyxo-hex-1-enitol (3,4,6-tri-O-acetyl-d-galactal) (3) were fluorinated in water and organic solvent-water with molecular fluorine and, for ¹⁸F-labelled compounds, with [¹⁸F]fluorine. Chemical yields of 40 and 10% were obtained for 2-deoxy-2-fluoro-d-glucose and 2-deoxy-2-fluoro-d-mannose, respectively, and 35 and 5% for 2-deoxy-2-fluoro-d-galactose (12) and 2-deoxy-2-fluoro-d-talose (13), respectively. In the fluorination of 3, the chemical yields of 12 and 13 were 38 and 6%, respectively. An l.c. separation of 2-deoxy-2-fluoro-d-hexoses is described.     

Analysis of linkage positions in a polysaccharide containing nonreducing, terminal alpha-D-glucopyranosyluronic groups by the reductive-cleavage method

The fate of terminal (nonreducing) alpha-D-glucopyranosyluronic groups under reductive cleavage conditions was investigated by using the Klebsiella K2 (strain NCTC-418) capsular polysaccharide. Treatment of the fully methylated polysaccharide (1) with triethylsilane and a mixture of trimethylsilyl methanesulfonate (Me3SiOSO2CH3) and boron trifluoride etherate (BF3.Et2O) as the catalyst, resulted in complete cleavage of all glycosidic linkages to yield the expected products, namely 3-O-acetyl-1,5-anhydro-2,4,6-tri-O-methyl-D-glucitol (2), 3,4-di-O-acetyl-1,5-anhydro-2,6-di-O-methyl-D-mannitol (3), 4-O-acetyl-1,5-anhydro-2,3,6-tri-O-methyl-D-glucitol (4), and methyl 2,6-anhydro-3,4,5-tri-O-methyl-L-gulonate. Treatment of 1 with trimethylsilyl trifluoromethanesulfonate (Me3SiOSO2CF3) as the catalyst resulted in incomplete cleavage of the glycosidic linkage of the methylated D-glucopyranosyluronic group, to yield 4-O-acetyl-1,5-anhydro-2,6-di-O-methyl- 3-O-(methyl2,3,4-tri-O-methyl-alpha-D-glucopyranosyluronate )-D-mannitol (9). Reductive cleavage of 1 in the presence of BF3.Et2O resulted in incomplete cleavage of all glycosidic linkages and gave rise to all four dimers (including 9) that could be formed from a tetrasaccharide repeating unit. The proposed structures of these dimers are based upon their composition, as established by chemical ionization mass spectrometry and by the reported structure of the polysaccharide. A small proportion of 1,5-anhydro-2,4,6-tri-O-methyl-3-O-(methyl 2,3,4-tri-O-methyl-alpha-D-glucopyranosyluronate)-D-mannitol (12) was also detected in the products of the BF3.Et2O-catalyzed reductive cleavage. The presence of 12 is chemical evidence for the phase of the tetrasaccharide repeating unit in the polysaccharide. The reductive cleavage of 1 was also accomplished after reduction of its ester groups with lithium aluminum hydride. Complete cleavage of all glycosidic linkages was observed when either Me3SiOSO2CF3 or Me3SiOSO2CH3-BF3.Et2O was used to catalyze reductive cleavage, and anhydroalditols 2, 3, 4, and 6-O-acetyl-1,5-anhydro-2,3,4-tri-O-methyl-D-glucitol were produced, as expected.     

New Pyrimidine Cyclonucleosides with Hydrogenated Aglycones: Synthesis and X-Ray Structures

Abstract

Acid catalysed transformations of (6S)-6,5′-anhydro-6-hydroxy-1-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)hexahydropyrimidine-2-thione are studied. (6R)-6,2′-anhydro-6-hydroxy-1-(α-D-ribofuranosyl)hexahydropyrimidine-2-thione was formed as a thermodynamically stable product. Two intermediates, (6S)-6,5′-anhydro-6-hydroxy-1-(β-D-ribofuranosyl)hexahydropyrimidine-2-thione and 6-hydroxy-1-(D-ribosyl)hexahydropyrimidine-2-thione and products of cleavage of glycosidic bond were identified in the reaction mixtures. Results of X-ray structural determination of the synthesised nucleosides are presented.     

Photobromination of 1,5-Anhydro-2,3-O-isopropylidene-β-d-ribofuranose and Synthesis of (5R) and (5S)-(5-2H1)-d-Riboses

The photobromination of 1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose gave the corresponding (5S)-5-bromo compound. The reduction of the bromide with triphenyltindeuteride gave (5S)-(5-²H₁)-1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose, with a chiral purity of 76% at C-5, which was converted to (5R)- and (5S)-(5-²H₁)-d-riboses and other ribofuranose derivatives.     

1,5-Anhydro- -fructose: regioselective acylation with fatty acids

Regioselective acylation of 1,5-anhydro- -fructose was performed with dodecanoic acid to give 1,5-anhydro-6-O-dodecanoyl- -fructose, chemically in 50% yield and enzymatically in quantitative yield. Quantitative conversions were also obtained using hexadecanoic and octadecanoic acids as acyl donors.     

Analysis of Macrocystis pyrifera and Pseudomonas aeruginosa alginic acids by the reductive-cleavage method.

Permethylated alginic acids comprised of 4-linked D-mannopyranosyluronic acid and 4-linked L-gulopyranosyluronic acid residues undergo reductive cleavage to yield, after acetylation, methyl 3-O-acetyl-2,6-anhydro-4,5-di-O-methyl-D-mannonate (2b) and methyl 3-O-acetyl-2,6-anhydro-4,5-di-O-methyl-D-gluconate (3b) as major products. Small amounts (ca. 13%) of ring-contracted products, namely methyl 2-O-acetyl-3,6-anhydro-4,5-di-O-methyl-D-mannonate (9) and methyl 2-O-acetyl-3,6-anhydro-4,5-di-O-methyl-D-gluconate (10), were also observed in these experiments. These results are in marked contrast to previous results on the reductive cleavage of 4-linked D-glucopyranosyluronic acid residues, wherein the ring-contracted product was formed exclusively. Formation of the ring-contracted products could be completely eliminated by reduction (LiAlH4) of ester groups in the permethylated alginic acid prior to reductive cleavage. In the latter experiments, 4,6-di-O-acetyl-1,5-anhydro-2,3-di-O-methyl-D-mannitol (5b) and 4,6-di-O-acetyl-1,5-anhydro-2,3-di-O-methyl-L-gulitol (6b) were the sole products of reductive cleavage of the 4-linked ManA and 4-linked GulA residues, respectively. However, in the previous experiments it was noted that low yields of permethylated alginic acids were obtained and that extensive depolymerization occurred under methylation conditions. Depolymerization could be avoided and higher yields of permethylated polysaccharides could be obtained, by reduction of the carboxyl groups of the alginic acids prior to methylation. Reductive cleavage of the latter polysaccharides yielded the products expected from 4-linked D-mannopyranosyl and 4-linked L-gulopyranosyl residues, namely 4-O-acetyl-1,5-anhydro-2,3,6-tri-O-methyl-D-mannitol (13b) and 4-O-acetyl-1,5-anhydro-2,3,6-tri-O-methyl-L-gulitol (14b), respectively. Using the latter analytical strategy, it was established that the Macrocystis pyrifera alginate was comprised of 60% 4-linked ManA and 40% 4-linked GulA residues, whereas the Pseudomonas aeruginosa alginate was comprised of 80% 4-linked ManA and 20% 4-linked GulA residues.     

A new chemical synthesis of Ascopyrone P from 1,5-anhydro-D-fructose

The naturally occurring antioxidant Ascopyrone P (1,5-anhydro-4-deoxy-D-glycero-hex-1-en-3-ulose, 1) was prepared from the rare sugar 1,5-anhydro-D-fructose (AF, 3) in three steps in an overall yield of 36%. Thus, acetylation of 3 afforded the enolone 3,6-di-O-acetyl-1,5-anhydro-4-deoxy-D-glycero-hex-3-en-2-ulopyranose (4), which could be isomerised to 2,6-di-O-acetyl-1,5-anhydro-4-deoxy-D-glycero-hex-1-ene-3-ulose (6). Deacetylation of 6 under mild conditions gave crystalline Ascopyrone P (1).     

Reactivity of selenium-containing compounds with myeloperoxidase-derived chlorinating oxidants: Second-order rate constants and implications for biological damage

Hypochlorous acid (HOCl) and N-chloramines are produced by myeloperoxidase (MPO) as part of the immune response to destroy invading pathogens. However, MPO also plays a detrimental role in inflammatory pathologies, including atherosclerosis, as inappropriate production of oxidants, including HOCl and N-chloramines, causes damage to host tissue. Low molecular mass thiol compounds, including glutathione (GSH) and methionine (Met), have demonstrated efficacy in scavenging MPO-derived oxidants, which prevents oxidative damage in vitro and ex vivo. Selenium species typically have greater reactivity toward oxidants compared to the analogous sulfur compounds, and are known to be efficient scavengers of HOCl and other hypohalous acids produced by MPO. In this study, we examined the efficacy of a number of sulfur and selenium compounds to scavenge a range of biologically relevant N-chloramines and oxidants produced by both isolated MPO and activated neutrophils and characterized the resulting selenium-derived oxidation products in each case. A dose-dependent decrease in the concentration of each N-chloramine was observed on addition of the sulfur compounds (cysteine, methionine) and selenium compounds (selenomethionine, methylselenocysteine, 1,4-anhydro-4-seleno-L-talitol, 1,5-anhydro-5-selenogulitol) studied. In general, selenomethionine was the most reactive with N-chloramines (k₂ 0.8–3.4×10³ M^–1 s^–1) with 1,5-anhydro-5-selenogulitol and 1,4-anhydro-4-seleno-L-talitol (k₂ 1.1–6.8×10² M^–1 s^–1) showing lower reactivity. This resulted in the formation of the respective selenoxides as the primary oxidation products. The selenium compounds demonstrated greater ability to remove protein N-chloramines compared to the analogous sulfur compounds. These reactions may have implications for preventing cellular damage in vivo, particularly under chronic inflammatory conditions.     

An approach to stereoselective preparation of 3-C-glycosylated d- and l-glucals

An approach to stereoselective synthesis of α- or β-3-C-glycosylated l- or d-1,2-glucals starting from the corresponding α- or β-glycopyranosylethanals is described. The key step of the approach is the stereoselective cycloaddition of chiral vinyl ethers derived from both enantiomers of mandelic acid. The preparation of 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl)methyl]-l-arabino-hex-1-enitol, 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl)methyl]-d-arabino-hex-1-enitol, and 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)methyl]-d-arabino-hex-1-enitol serves as an example of this approach.     

Additions comparées des halogenès sur le 3,4,6-tri-O-acétyl-1,5-anhydro-1,5-didésoxy-, d-arabino-hex-1-énitol et l'analogue 3,4,6-tri-O-benzylé; effets de solvant sur la formation spécifique des dérivés 1,2-didésoxy-1,2-dihalogéno-α-d-glucopyranoses

Comparison of the addition of chlorine and bromine to 3,4,6-tri-O-acetyl-1,5-anhydro-1,5-dideoxy-d-arabino-hex-l-enitol (1) and to the 3,4,6-tri-O-benzyl analog (2) shows a greater stereoselectivity for 2 in the formation of 1,2-dideoxy-1,2-dihalo-geno-α-d-glucopyranose derivatives. Stereospecific addition took place in nonpolar solvents, and a quantitative correlation was established between the polarity of the solvent and the stereospecificity of the addition of chlorine to 1 and 2. Similar results were observed for the halogenomethoxylation of 1 and 2.     

Nucleosides. 145. Synthesis of 2,5′-Anhydro-2-Thiouridine and its Conversion to 3′-O-Acetyl-2,2′-Anhydro-5′-Chloro-5′-Deoxy-2-Thiouridine. Studies Directed Toward the Synthesis of 2′-Deoxy-2′-Substituted arabino Nucleosides (7)

Abstract

In an attempt to introduce a substituent at C-2′ in the “up” arabino configuration directly by nucleophilic displacement reaction of a preformed pyrimidine ribonucleoside, we synthesized 2,5′-anhydro-5′-deoxy-2-thiouridine (6) in three steps from uridine. Compound 6 was converted into the 3′-O-acetyl derivative 7. Upon treatment of 7 with triflyl chloride in methylene chloride in the presence of triethylamine and p-dimethylaminopyridine, 2,2′-anhydro-1-(3-O-acetyl-5-chloro-2,5-dideoxy-β-D-arabinofuranosyl)-2-thiouracil (9) was obtained as the only isolable product. Obviously, the intermediate 3′-O-acetyl-2,5′-anhydro-2′-O-triflyl-2-thiouridine (8) was attacked by the chloride nucleophile at C-5′ first giving the 2′-O-triflyl-2-thiouridine intermediate from which 9 was formed by intramolecular nucleopilic reaction.     

Reactions of Some 2,3-Anhydro Pyrimidine Nucleosides with Dilithium Tetrahalocuprates

Abstract

The reaction of 1-(2,3-anhydro-5-0-trityl-β-D-lyxofuranosyl)-2-0-methyluracil (2a) and its thymine analogue (2b) with dilithium tetrahalocuprates (Li₂CuX₄) revealed an excellent to perfect regioselectivity, yielding 2,2′-anhydro-3′-halonucleosides (3a-d), while the same reactions with 2,3-anhdro uracil and thymine nucleosides (5a,b) gave arabinosyl (6a-d) and xylosyl halohydrins (7a-d) with respective product ratios of 7:3 to 8:2 which were estimated after mesylation to 8a-d and 9a-d.     

Analysis by the reductive-cleavage method of linkage positions in a polysaccharide containing 4-linked D-glucopyranosyluronic residues

The fate of 4-linked D-glucopyranosyluronic residues under reductive-cleavage conditions was investigated by using the Klebsiella aerogenes type 54 strain A3 capsular polysaccharide. Treatment of the fully methylated polysaccharide with triethylsilane and trimethylsilyl trifluoromethanesulfonate in dichloromethane, followed by in situ acetylation, yielded 1,5-anhydro-2,3,4,6-tetra-O-methyl-D-glucitol, 3,4-di-O-acetyl-1,5-anhydro-2,6-di-O-methyl-D-glucitol, and 3-O-acetyl-1,5-anhydro-2,4-di-O-methyl-L-fucitol, as expected, but the expected product of reductive cleavage of the 4-linked D-glucopyranosyluronic residue, namely, methyl 3-O-acetyl-2,6-anhydro-4,5-di-O-methyl-L-gulonate, was not observed. Instead, methyl 2-O-acetyl-3,6-anhydro-4,5-di-O-methyl-L-gulonate (6) was identified as the sole product of reductive cleavage of the 4-linked D-glucopyranosyluronic residue. That compound 6 arose as a result of rearrangement during reductive cleavage rather than by reductive cleavage of a 5-linked D-glucofuranosyluronic residue, was established by reductive cleavage of the fully methylated polysaccharide following reduction of its ester groups with either lithium aluminum hydride or lithium aluminum deuteride. The products of the latter reductive cleavage were the same as before, except for the absence of 6 and the presence of 4,6-di-O-acetyl-1,5-anhydro-2,3-di-O-methyl-D-glucitol, or its 6,6-dideuterio isomer. Although the reductive-cleavage technique is suitable for the direct analysis of polysaccharides containing 4-linked D-glucopyranosyluronic residues, it does not establish whether the uronic residue is a 4-linked pyranoside or a 5-linked furanoside. The expected product is, however, derived from the 4-linked D-glucopyranosyluronic residue after sequential methylation, reduction of its ester group and reductive cleavage.     

Nitrous acid deamination of conformationally inverted aminodeoxyhexopyranoses

Nitrous acid deamination of 2-amino-1,6-anhydro-2-deoxy-β-D-glucopyranose (1) in the presence of weakly acidic, cation-exchange resin gave 1,6:2,3-dianhydro-β-D-mannopyranose (3) and 2,6-anhydro-D-mannose (6), characterized, respectively, as the 4-acetate of 3 and the per-O-acetylated reduction product of 6, namely 2,3,4,6- tetra-O-acetyl-1,5-anhydro-D-mannitol, obtained in the ratio of 7:13. Comparative deaminatior of the 4-O-benzyl derivative of 1 led to similar qualitative results. Deamination of 3-amino-1,6-anhydro-3-deoxy-β-D-glucopyranose gave 1,6:2,3- and 1,6:3,4-dianhydro-β-D-allopyranose (13 and 16), characterized as the corresponding acetates, obtained in the ratio of 31:69, as well as the corresponding p-toluenesulfonates. Deamination of 4-amino-1,6-anhydro-4-deoxy-β-D-glucopyranose and of its 2-O-benzyl derivative gave the corresponding 1,6:3,4-D-galacto dianhydrides as the only detectable products. 2,5-Anhydro-D-glucose, characterized as the 1,3,4,6-tetra-O- acetyl derivative of the corresponding anhydropolyol, was obtained in 39% yield from the same deamination reaction performed on 2-amino-1,6-anhydro-2-deoxy-β-D- mannopyranose (24). In 90% acetic acid, the nitrous acid deamination of 24, followed by per-O-acetylation, gave only 1,3-4-tri-O-acetyl-2,5-anhydro-α-D-glucoseptanose. In the case of 1,6-anhydro-3,4-dideoxy-3,4-epimino-β-D-altropyranose, only the corresponding glycosene was formed, namely, 1,6-anhydro-3,4-dideoxy-β-D-threo--hex-3-enopyranose.