Stereo- and regioselective glycosylation of 4-deoxy-ε-rhodomycinone

A method for the glycosylation of anthracyclines featuring benzoylated imidate donors has been developed and utilized in the synthesis of glycosylated 4-deoxy-ε-rhodomycinone derivatives. Due to its high efficiency, regioselectivity, stereoselectivity, and operational simplicity, the method should prove valuable to researchers working with glycosylation of tetracyclic compounds.     

Syntheses of 2-acetamido-2-deoxy-4-O-βD-galacto-pyranosyl-D-mannose and -D-glucose and of 2-acetamido-2-deoxy-4-O-βD-mannopyranosyl-D-mannose and -D-glucose

2-acetamido-2-deoxy-4-O-β-D-galactopyranosyl-D-mannose (6) and -D-glucose (7) were prepared by addition of nitromethane to 3-O-β-D-galactopyranosyl-D-arabinose, followed by acetylation, ammonolysis, and application of the Nef reaction. Similarly, 2-acetamido-2-deoxy-4-O-β-D-mannopyranosyl-D-mannose (14) and -D-glucose (15) were prepared by the same scheme from 3-O-β-D-mannopyranosyl-D-arabinose. In the two series of experiments, 6 and 14 were the respective major products. Epimerization of the 2-acetamido-2-deoxy-D-mannose residue in 6 and 14 yielded 7 and 15, respectively.     

3-Azido-3-deoxy-α-d-altrose

The synthesis of (±)-epilupinine from trans-1-cyanoquinolizidines (IVa) and (IVb), the intermediates of the (±)-lamprolobine synthesis is described.     

4-deoxy-4-fluoro-1,2-O-isopropylidene-β-D-xylo-hexulopyranose

A 5-stage synthesis of the title compound (11), the first example of a secondary deoxyfluoroketose, is described. The synthesis comprised the following reaction sequence: D-fructose→1,2:4,5-di-O-isopropylidene-β-D-fructopyranose (4)→1,2:4,5-di-O-isopropylidene-3-O-tosyl-β-D-fructopyranose (3)→ 3,4-anhydro-1,2-O-isopropylidene-β-D-ribo-hexulopyranose (9)→4-deoxy-fluoro-1,2-O-isopropylidene-β-D-xylo-hexulopyranose (11). Fluoride displacement at C-4 in 9 was effected with tetrabutyl-ammonium fluoride in methyl cyanide. Similar treatment of either 3 or 1,2:4,5-di-O-isopropylidene-3-O-tosyl-β-D-ribo-hexulopyranose (5) failed to yield a fluoro derivative. Compound 5 was prepared by the sequence 4→1,2:4,5-di-O-isopropylidene-β-D-erythro-hexo-2,3-diulopyranose (6)→1,2:4,5-di-O-isopropylidene-β-D-ribo-hexulopyranose (7)→5.     

A new synthesis and an antiviral assessment of the 4′-fluoro derivative of 4′-deoxy-5′-noraristeromycin

A synthetic route to (1S,2S,3R,5S)-3-(6-amino-9H-purin-9-yl)-5-fluorocyclopentane-1,2-diol (that is, the 4′-fluoro derivative of 4′-deoxy-5′-noraristeromycin, 3) is described via a fluorinated cyclopentanol, which is in contrast to existing schemes where fluorination occurred once the purine ring was present. Compound 3 was assayed versus a number of viruses. A favorable response was observed towards measles (IC₅₀ of 1.2 μg/mL in the neutral red assay and 14 μg/mL by the visual assay) but this was accompanied by cytotoxicity in the CV-1 host cells (21–36 μg/mL). Among the viruses unaffected by 3 were human cytomegalovirus and the poxviruses (vaccinia and cowpox), which are three viruses that were inhibited by the 4′,4′-difluoro analog of 3 (that is, 2).     

New 4-deoxy-(1→3)-β-D-glucan-based oligosaccharides and their immunostimulating potential

(1→3)-β-D-Glucans are well-established natural biological immunomodulators. However, problems inherited with the natural origin of these polysaccharides bring about significant setbacks, including batch-to-batch heterogeneity and significant differences based on the source and isolation techniques. In this study, we tried to overcome these problems by preparation of a quantitatively new set of oligo-(1→3)-β-D-glucan-based synthetic immunomodulators. Some of these non-natural oligosaccharides showed biological activities, such as stimulation of phagocytosis, modulation of gene expression, and anti-cancer activity, which were superior to natural glucans.     

Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs

Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-d-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC₅₀ values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3 (K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug.     

A novel synthesis of 2-deoxy-α-glycosides

The key step of the synthesis involves the reaction of glycals [3,4,6-tri-O-acetyl-d-glucal (1), the new glycal derivative 4-O-acetyl-1,5-anhydro-2,6-dideoxy-3-C-methyl-3-O-methyl-l-ribo-hex-l-enitol (2), and 3-acetamido-4,6,-di-O-acetyl-1,5-anhydro-2,3-dideoxy-d-arabino-hex-l-enitol (3)] with 1.5 molar equivalents of several alcohols in the presence ofN-bromosuccinimide in acetonitrile to give mainly the corresponding 2-bromo-2-deoxy-α-glycopyranosides (4-21). The glycopyranosides (4-8 and16-21) from1 and3 have the α-d-manno configuration and those (10-15) from2 have the α-l-altro configuration. The yields are high from1, virtually quantitative from2, and moderate from3. Debromination of the 2-bromo-2-deoxy compounds with tributylstannane and a radical initiator gives the corresponding 2-deoxy-α-glycopyranosides (22-38) in quantitative yields. In particular, the branched-chain glycal2 reacts with alcohols to give exclusively the corresponding α-glycopyranosides (27-32) of cladinose in strikingly high overall yields. The stereoselectivity and regiospecificity of the bromination reaction are described. 1,3-Dibromo-5,5-dimethylhydantoin andN-bromoacetamide are also found to be useful for the reaction.     

A surprising C-4 epimerization of 5-deoxy-5-sulfonylated pentofuranosides under Ramberg-Bäcklund reaction conditions

Treatment of methyl 5-deoxy-2,3-O-isopropylidene-5-(benzylsulfonyl)-β-d-ribofuranoside with CBr₂F₂-KOH/Al₂O₃ afforded the corresponding olefinic sugar. The methyl- and the isopropyl-analogues in contrast underwent epimerization at C-4 to generate the α-l-lyxo derivatives.     

Photochemical addition of 2-propanol and of acetone to methyl 5-deoxy-2,3-O-isopropylidene-β-d-erythro-pent-4-enofuranoside

High-capacity adsorbents for lectins, including Lotus tetragonolobusl-fucose-binding protein, were readily prepared by conjugation of monosaccharides with commercially available, epoxy-activated Sepharose. Purified, radioiodinated lectins were bound to cells of the mosquito Aedes aegyptii and of human KB tumour. Relative to human KB cells, mosquito cells bound less of lectins specific for the sugars (l-fucose and d-galactose) that are terminal residues in many mammalian glycoproteins, whereas the number of binding sites of lectins specific for core-region sugars (d-mannose and 2-acetamido-2-deoxy-d-glucose) were similar. Neuraminidase, which greatly enhanced binding of peanut agglutinin or soybean agglutinin to human KB cells, had negligible effects on binding of these lectins to mosquito cells. The comparative structures of surface oligosaccharides of mosquito and KB cells are discussed in relation to the lectin-binding studies.     

Microbial transformation of 1,6-dichloro-1,6-dideoxy-β,D-fructofuranosyl-4-chloro-4-deoxy-α,D-galactopyranoside (TGS) by soil populations

Summary Soil microorganisms from one site were shown to be consistently capable of the transformation of 1,6-dichloro-1,6-dideoxy-,d-fructofuranosyl-4-chloro-4-deoxy-,d-galactopyranoside (TGS) in laboratory batch cultures. With fresh soils, all of the available chloride ions were released from the molecule. Subcultures of a TGS-dehalogenating bacterial community produced a progressive decline in the dehalogenating capabilities towards the substrate. The soil organisms did not utilise TGS as a carbon source. The transformation was achieved by co-metabolism and was probably supported by an unknown component in the soil. Four bacterial species were isolated from the TGS-dehalogenating soil community: twoBacillus species, anAcinetobacter group isolate and aMicrococcus group isolate. Thin-layer chromatography confirmed the disappearance of the chlorosugar and high-performance liquid chromatography demonstrated that neither of the constituent monosaccharides—1,6-dichlorofructose nor 4-chlorogalactosucrose was accumulated as an intermediate.

---

Resumen Microorganismos de suelo de cierto lugar demostraron consistemente ser capaces de realizar la transformación de 1,6-dicloro-1,6 dideoxi--D-fructofuranosil-4-cloro-4-deoxi-,D-alactopiranosa (TGS) in culturas de laboratorio de tipo discontinuo. Con muestras frescas de suelo, todos los iones cloruro fueron liberados de la molecula. Subculturas de una comunidad bacterial capaz de dehalogenizar TGS produjeron una declinación progresiva de la capacidad de dehalogenizar el substrato. Los microorganismos no utilizaron el TGS como fuente de carbono. La transformación se realiza por co-metabolismo y probablemente se base en un componente del suelo, no determinado. Cuatro especies bacteriales fueron aisladas de la comunidad de bacterias de suelo con capacidad de dehalogenar el TGS: dos especies deBacilo, unaAcinelobacteria y unMicrococo. Estudios de cromatografía de capa delgada confirmaron la desaparición del clorosacárido, y estadios de cromatografía liquida demostraron que ninguno de los componentes monoscáridos — 1,6-diclorofructuosa y 4-clorogalactosucrosa — eran acumulados como productors intermedios.

---

Résumé Les microorganismes du sol d'un certain endroit ont été démontrés être capable, sans exception, de la transformation de 1,6-dichloro-1,6-dideoxy-,D-fructofuranosyl-4-chloro-4-deoxy-,D-galactopyranoside (TGS) en cultures de laboratoire du type discontinu. Avec des prélèvements frais du sol, tous les ions disponibles de chlorure ont été libérés de la molécule. Des souscultures d'une communauté bactérienne capable de déhalogeniser le TGS ont produit un déclin progressif de la capacité de déhalogeniser le substrat. Les microorganismes du sol n'ont pas utilisé le TGS comme source de carbone. La transformation s'est accomplie par cometabolisme et, probablement, s'est basée sur un component indéterminé du sol. Quatre espèces bactériennes ont été isolées de la communauté de bactéries du sol capable de déhalogeniser le TGS: deux espèces deBacillus, unAcinetobacter et unMicrococcus. Des études de chromatographie de couches fines ont confirmées la disparition du chlorosaccharide, tandis que des études de chromatographie liquide de haut rendement ont démontrées que, des monosaccharides constituants, ni 1,6-dichlorofructose ni 4-chlorogalactosucrose, n'ont été accumulés comme produits intermédiaires.

     

o-nitrophenyl 6-deoxy-3-O-(6-deoxy-β-d-xylo-hex-5-enopyranosyl)-β-d-xylo-hex-5-enopyranoside,the major product of β-d-glucosidase action on o-nitrophenyl 6-deoxy-β-d-xylo-hex-5-enopyranoside

Incubation of o-nitrophenyl 6-deoxy-β-d-xylo-hex-5-enopyranoside (1) with emulin β-d-glucosidase gave, instead of the expected 6-deoxy-d-xylo-hexos-5-ulose (3), o-nitrophenyl 6-deoxy-3-O-(6-deoxy-β-d-xylo-hex-5-enopyranosyl)-β-d-xylo-hex-5-enopyranoside (2) in high yield (≈90% under optimal conditions). The structure of 2 was established from spectroscopic data and by correlation with compounds synthesised definitively. The specificity of the transfer reaction is discussed as an argument for an acceptor or aglycon binding-site.     

Synthesis of benzyl 2-acetamido-2-deoxy-3-O-β-d-fucopyranosyl-α-d-galactopyranoside and benzyl 2-acetamido-6-O-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-2-deoxy-3-O-β-d-fucopyranosyl-α-d-galactopyranoside

Condensation of benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-galactopyranoside with 2,3,4-tri-O-acetyl-α-d-fucopyranosyl bromide in 1:1 nitromethane-benzene, in the presence of powdered mercuric cyanide, afforded benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4-tri-O-acetyl-β-d-fucopyranosyl)-α-d-galactopyranoside (3). Cleavage of the benzylidene group of 3 with hot, 60% aqueous acetic acid afforded diol 4, which, on deacetylation, furnished the disaccharide 5. Condensation of diol 4 with 2-methyl-(3,4,6-tri-O-acetyl-1,2-di-deoxy-α-d-glucopyrano)-[2,1-d]-2-oxazoline in 1,2-dichloroethane afforded the trisaccharide derivative (7). Deacetylation of 7 with Amberlyst A-26 (OH^?) anion-exchange resin in methanol gave the title trisaccharide (8). The structures of 5 and 8 were confirmed by ¹³C-n.m.r. spectroscopy.     

Stereoselective synthesis of β-N-glycosides through 2-deoxy-2-nitroglycal

An efficient, base-free protocol has been developed for the β-stereoselective synthesis of N-glycosides from 2-nitroglycal and secondary amines. Simple protection and deprotection manipulations on the N-glycosides pave a way for the synthesis of biologically significant1,2-diaminosugars and glycopeptides.     

Synthesis of 3,6-di-O-acetyl-2-deoxy-2-phthalimido-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-β-d-glucopyranosyl chloride

A lactosaminyl donor, 3,6-di-O-acetyl-2-deoxy-2-phthalimido-4-O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)-β-d- glucopyranosyl chloride, was synthesized in 10 steps, starting from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranose. Benzyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-d-glucopyranoside was prepared by regioselective benzylation at the primary hydroxyl group by the stannyl method, and was used as a key intermediate.

     

Synthesis of 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose

Condensation of 4,6-di-O-acetyl-2,3-O-carbonyl-α-d-mannopyranosyl bromide with benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside (2) gave an α-d-linked disaccharide, further transformed by removal of the carbonyl and benzylidene groups and acetylation into the previously reported benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-O-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-α-d-glucopyranoside. Condensation of 3,4,6-tri-O-benzyl-1,2-O-(1-ethoxyethylidene)-α-d-glucopyranose or 2-O-acetyl-3,4,6-tri-O-benzyl-α-d-glucopyranosyl bromide with 2 gave benzyl 2-acetamido-3-O-(2-O-acetyl-3,4,6-tri-O-benzyl-β-d-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-α-d-glucopyranoside. Removal of the acetyl group at O-2, followed by oxidation with acetic anhydride-dimethyl sulfoxide, gave the β-d-arabino-hexosid-2-ulose 14. Reduction with sodium borohydride, and removal of the protective groups, gave 2-acetamido-2-deoxy-3-O-β-d-mannopyranosyl-d-glucose, which was characterized as the heptaacetate. The anomeric configuration of the glycosidic linkage was ascertained by comparison with the α-d-linked analog.     

2′-Azido-2′-deoxy- and 2′-amino-2′-deoxy-β-d-arabino-furanosyl purine nucleosides

A general method for the preparation of 2′-azido-2′-deoxy- and 2′-amino-2′-deoxyarabinofuranosyl-adenine and -guanine nucleosides is described. Selective benzoylation of 3-azido-3-deoxy-1,2-O-isopropylidene-α-d-glucofuranose afforded 3-azido-6-O-benzoyl-3-deoxy-1,2-O-isopropylidene-α-d-glucofuranose (1). Acid hydrolysis of 1, followed by oxidation with sodium metaperiodate and hydrolysis by sodium hydrogencarbonate gave 2-azido-2-deoxy-5-O-benzoyl-d-arabinofuranose (3), which was acetylated to give 1,3-di-O-acetyl-2-azido-5-O-benzoyl-2-deoxy-d-arabinofuranose (4). Compound 4 was converted into the 1-chlorides 5 and 6, which were condensed with silylated derivatives of 6-chloropurine and 2-acetamido-hypoxanthine. The condensation reaction gave α and β anomers of both 7- and 9-substituted purine nucleosides. The structures of the nucleosides were determined by n.m.r. and u.v. spectroscopy, and by correlation of the c.d. spectra of the newly prepared nucleosides with those published for known purine nucleosides.