- An improved procedure for the analysis of linkage positions in 2- acetamido-2-deoxy-D-glucopyranosyl residues by the reductive-cleavage method
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The conditions of the reductive-cleavage method were modified to allow simultaneous analysis of 2-acetamido-2-deoxy-D-glucopyranosyl residues and monosaccharides of other classes. Methyl 2-deoxy-3,4,6-tri-O-methyl-2-(N- methylacetamido)-β-D-glucopyranoside was found to undergo transglycosidation under reductive-cleavage conditions when the reaction was quenched with an alcohol. Transglycosidation proceeded via an oxazolinium-ion intermediate, which then acted as a glycosyl donor to form an anomerically pure product. Time-course studies showed that in the presence of trimethylsilyl trifluoromethanesulfonate (Me3SiOSO2CF3), 4 h were required for complete conversion of the substrate into this intermediate, which was then trapped with methanol-d4. When the reaction was conducted in the presence of a mixture of trimethylsilyl methanesulfonate (Me3SiOSO2Me) and boron trifluoride etherate (BF3·OEt2) or with BF3·OEt2 alone, 24 h and 48 h, respectively, were required for complete conversion. The α anomer was unreactive after 24 h under all conditions, confirming earlier results. Reaction with racemic 2-butanol yielded a pair of diastereomers, in a 1:1 ratio, which were distinguishable by their GLC retention times and their 1H NMR spectra. Reaction with (S)-2-butanol gave only one of the diastereomeric products. These experiments demonstrated the feasibility of using the reductive-cleavage method to determine the absolute configuration of 2- acetamido sugars. The condition of the reductive-cleavage method were modified to allow simultaneous analysis of 2-acetamido-2-deoxy-D-glycopyranosyl residues and monosaccharides. These experiments demonstrated the feasibility of using the reductive-cleavage method to determine the absolute configuration of 2-acetamido sugars.
- D'Ambra,Gray
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- Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: Mechanistic and structural insights into inhibitor selectivity and transition state poise
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O-GlcNAcase catalyzes the cleavage of β-O-linked 2-acetamido-2-deoxy- β-D-glucopyranoside (O-GlcNAc) from serine and threonine residues of post-translationally modified proteins. Two potent inhibitors of this enzyme are O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2′-methyl-α-D-glucopyranoso[2,1-d]-Δ2′- thiazoline (NAG-thiazoline). Derivatives of these inhibitors differ in their selectivity for human O-GlcNAcase over the functionally related human lysosomal β-hexosamindases, with PUGNAc derivatives showing modest selectivities and NAG-thiazoline derivatives showing high selectivities. The molecular basis for this difference in selectivities is addressed as is how well these inhibitors mimic the O-GlcNAcase-stabilized transition state (TS). Using a series of substrates, ground state (GS) inhibitors, and transition state mimics having analogous structural variations, we describe linear free energy relationships of log(KM/kcat) versus log(KI) for PUGNAc and NAG-thiazoline. These relationships suggest that PUGNAc is a poor transition state analogue, while NAG-thiazoline is revealed as a transition state mimic. Comparative X-ray crystallographic analyses of enzyme-inhibitor complexes reveal subtle molecular differences accounting for the differences in selectivities between these two inhibitors and illustrate key molecular interactions. Computational modeling of species along the reaction coordinate, as well as PUGNAc and NAG-thiazoline, provide insight into the features of NAG-thiazoline that resemble the transition state and reveal where PUGNAc fails to capture significant binding energy. These studies also point to late transition state poise for the O-GlcNAcase catalyzed reaction with significant nucleophilic participation and little involvement of the leaving group. The potency of NAG-thiazoline, its transition state mimicry, and its lack of traditional transition state-like design features suggest that potent rationally designed glycosidase inhibitors can be developed that exploit variation in transition state poise.
- Whitworth, Garrett E.,Macauley, Matthew S.,Stubbs, Keith A.,Dennis, Rebecca J.,Taylor, Edward J.,Davies, Gideon J.,Greig, Ian R.,Vocadlo, David J.
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Read Online
- Chemoenzymatic Synthesis of Glycoconjugates Mediated by Regioselective Enzymatic Hydrolysis of Acetylated 2-Amino Pyranose Derivatives
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Highly regioselective deprotection of a series of 2-amino pyranose building blocks was achieved by enzymatic hydrolysis. These monodeprotected intermediates were successfully used in the synthesis of a variety of glycoconjugate derivatives with a core of glucosamine or galactosamine, including neo-glycoproteins and glycosphingolipids. The hydrolysis catalyzed by acetylxylan esterase from Bacillus pumilus (AXE) is suitable for the synthesis of neo-glycoproteins with an N-acetyl glucosamine core. The hydrolysis catalyzed by Candida rugosa lipase (CRL) was successfully applied in the preparation of new sialylated glycolipids starting from glucosamine building blocks protected as phthalimide. This chemoenzymatic approach can be used for the preparation of new glycoconjugate products with anticancer activity.
- Zheng, Changping,Bavaro, Teodora,Tengattini, Sara,Mascherpa, Andrea Gualla,Sollogoub, Matthieu,Zhang, Yongmin,Terreni, Marco
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supporting information
p. 3622 - 3631
(2019/06/17)
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- Nucleophilic Aromatic Substitution (SNAr) as an Approach to Challenging Carbohydrate-Aryl Ethers
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A general and practical route to carbohydrate-aryl ethers by nucleophilic aromatic substitution (SNAr) is reported. Upon treatment with KHMDS, C-O bond formation occurs between carbohydrate alcohols and a diverse range of fluorinated (hetero)ar
- Henderson, Alexander S.,Medina, Sandra,Bower, John F.,Galan, M. Carmen
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p. 4846 - 4849
(2015/10/12)
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- Direct glycosylation of unprotected and unactivated sugars using bismuth nitrate pentahydrate
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Bi(NO3)3, a low-cost, mild, and environmentally green catalyst, has been successfully utilized for Fischer glycosylation for the synthesis of alkyl/aryl glycopyranosides by reacting unprotected sugars, namely, D-glucose, L-rhamnose, D-galactose, D-arabinose, and N-acetyl-D-glucosamine with various alcohols in good to excellent yields. The glycosides were formed with high α-selectivity. Further, an expedient separation of α- and β-glycosides using silver nitrate-impregnated silica gel flash liquid chromatography has been developed.
- Polanki, Innaiah K.,Kurma, Siva H.,Bhattacharya, Asish K.
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p. 196 - 205
(2015/06/08)
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- Probing synergy between two catalytic strategies in the glycoside hydrolase O-GlcNAcase using multiple linear free energy relationships
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Human O-GlcNAcase plays an important role in regulating the post-translational modification of serine and threonine residues with β-O-linked N-acetylglucosamine monosaccharide unit (O-GlcNAc). The mechanism of O-GlcNAcase involves nucleophilic participation of the 2-acetamido group of the substrate to displace a glycosidically linked leaving group. The tolerance of this enzyme for variation in substrate structure has enabled us to characterize O-GlcNAcase transition states using several series of substrates to generate multiple simultaneous free-energy relationships. Patterns revealing changes in mechanism, transition state, and rate-determining step upon concomitant variation of both nucleophilic strength and leaving group abilities are observed. The observed changes in mechanism reflect the roles played by the enzymic general acid and the catalytic nucleophile. Significantly, these results illustrate how the enzyme synergistically harnesses both modes of catalysis; a feature that eludes many small molecule models of catalysis. These studies also suggest the kinetic significance of an oxocarbenium ion intermediate in the O-GlcNAcase-catalyzed hydrolysis of glucosaminides, probing the limits of what may be learned using nonatomistic investigations of enzymic transition-state structure and offering general insights into how the superfamily of retaining glycoside hydrolases act as efficient catalysts.
- Greig, Ian R.,Macauley, Matthew S.,Williams, Ian H.,Vocadlo, David J.
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supporting information; experimental part
p. 13415 - 13422
(2010/01/16)
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- Iminosugar glycoconjugates
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The iminosugar conjugates according to the invention are N-alkylated 1,5-dideoxy-1,5-iminohexitol or 1,5-dideoxy-1,5-iminopentitol derivatives. The iminosugar component can be, for example, D-gluco-, L-ido-, D-galacto-, D-manno-, 2-acetamido-2-deoxy-D-gluco- or xylo-configuration. The N-substituent is a protected L-α-aminoacid derivative, showing L-lysine-like structural features. The linkage between the carbohydrate and the peptide component is not via the usual glycosidic position, but shows structural features of a very stable tertiary amine. Thus the linkage is very stable. These new compounds are synthesised by using catalytic intramolecular reductive amination of dicarbonyl sugars with partially protected amino acids. The process of intramolecular reductive amination itself is carried out using Pearlman's catalyst (Pd(OH)2/C) and H2 at ambient pressure and room temperature. The resulting accessible class of iminosugar conjugate compounds is represented by the general structure shown in Figure 4(c). The alkyl chain length parameter n can be freely chosen from n=0 upwards. Preferably n is between 0 and 10, and more preferably n is 2, 3, or 4. Residue R1 can be chosen from H, OH, or NHAc, with Ac being Acetyl. R2 can be H, OH, or NHAc. R3, R4, R5, R6 can be H or OH. R7 and R8 can be H, CH2OH CH3, COQH, or COOR with R being Alkyl or Aryl. R9 and R10 can be chosen from H, NH2, NHR, with R being a protective group, an amino acid, a peptide, or a protein. R11 can be OH, O-Alkyl, O-Aryl, NH2, N-Alkyl, N-Aryl, amino acid or peptide, connected via an amide bond.
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Page/Page column 5
(2008/06/13)
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- Mild and efficient method for the cleavage of benzylidene acetals using HClO4-SiO2 and direct conversion of acetals to acetates
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HClO4-SiO2 has been used successfully for the deprotection of benzylidene acetals and the direct conversion of benzylidene acetals to the corresponding di-O-acetates. The reactions are very fast and yields are excellent.
- Agnihotri, Geetanjali,Misra, Anup Kumar
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p. 3653 - 3658
(2007/10/03)
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- Synthetic Peptidoglycan Substrates for Penicillin-Binding Protein 5 of Gram-Negative Bacteria
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The major constituent of the bacterial cell wall, peptidoglycan, is comprised of repeating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) with an appended peptide. Penicillin-binding proteins (PBPs) are involved in the final stages of bacterial cell wall assembly. Two activities for PBPs are the cross-linking of the cell wall, carried out by DD-transpeptidases, and the DD-peptidase activity, that removes the terminal D-Ala residue from peptidoglycan. The DD-peptidase activity moderates the extent of the cell wall cross-linking. There exists a balance between the two activities that is critical for the well-being of bacterial cells. We have cloned and purified PBP5 of Escherichia coli. The membrane anchor of this protein was removed, and the enzyme was obtained as a soluble protein. Two fragments of the polymeric cell wall of Gram-negative bacteria (compounds 5 and 6) were synthesized. These molecules served as substrates for PBP5. The products of the reactions of PBP5 and compounds 5 and 6 were isolated and were shown to be D-Ala and the fragments of the substrates minus the terminal D-Ala. The kinetic parameters for these enzymic reactions were evaluated. PBP5 would appear to have the potential for turnover of as many as 1.4 million peptidoglycan strands within a single doubling time (i.e., generation) of E. coli.
- Hesek, Dusan,Suvorov, Maxim,Morio, Ken-Ichiro,Lee, Mijoon,Brown, Stephen,Vakulenko, Sergei B.,Mobashery, Shahriar
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p. 778 - 784
(2007/10/03)
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- Furanodictine A and B: Amino sugar analogues produced by cellular slime mold Dictyostelium discoideum showing neuronal differentiation activity
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We investigated the constituents of Dictyostelium discoideum to clarify the diversity of secondary metabolites of Dictyostelium cellular slime molds and to explore biologically active substances that could be useful in the development of novel drugs. From a methanol extract of the multicellular fruit body of D. discoideum, we isolated two novel amino sugar analogues, furanodictine A (1) and B (2). They are the first 3,6-anhydrosugars to be isolated from natural sources. Their relative structures were elucidated by spectral means, and the absolute configurations were confirmed by asymmetric syntheses of 1 and 2. These furanodictines potently induce neuronal differentiation of rat pheochromocytoma (PC-12) cells.
- Kikuchi,Saito,Komiya,Takaya,Honma,Nakahata,Ito,Oshima
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p. 6982 - 6987
(2007/10/03)
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- New α-selective thermal glycosylation of acetyl-protected 2-acetamido-2-deoxy-β-D-glucopyranosyl diphenylphosphinate
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This paper describes new α-selective thermal glycosylation using acetyl-protected 2-acetamido-2-deoxy-β-D-glucopyranosyl diphenylphosphinate (4) as a glycosyl donor. When the glycosylation of 4 with 1-hexanol was carried out under various conditions, the conditions using trimethylsilyl trifluoromethanesulfonate as a promoter in nitromethane at reflux temperature were most suitable for the formation of the α anomer. The glycosylation of 4 with the other common alcohols gave corresponding α-glycosides in relatively high yields under the conditions. When cholesterol, a very steric hindered alcohol, was used as a glycosyl acceptor, α-glycoside was also produced predominantly. Copyright (C) 2000 Elsevier Science Ltd.
- Kadokawa, Jun-ichi,Nagaoka, Takeshi,Ebana, Jun,Tagaya, Hideyuki,Chiba, Koji
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p. 341 - 344
(2007/10/03)
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- The mild cleavage of 2-amino-2-deoxy-D-glucoside methoxycarbonyl derivatives.
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The conversion of methyl carbamate to the corresponding free amine is described for a series of 2-amino-2-deoxy-D-glucosamine derivatives. Cleavage of methoxycarbonyl moiety with MeSiCl(3) and triethylamine in dry THF at 60 degrees C and subsequent aqueou
- Yeung,Adamski-Werner,Bernard,Poulenat,Petillo
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p. 3135 - 3138
(2007/10/03)
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- Synthesis of carbohydrates with an anomeric thiol moiety for elaboration into metabolically stable thioglycosides
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The synthesis of thioglycosides for use as metabolically stable biological probes is an area of continued interest. This paper describes the synthesis of functionalised carbohydrates which contain an anomeric thio group. During the course of this work we have examined the most viable route into compounds such as the specifically functionalised carbohydrates 36 and 37, and have also investigated the usefulness of disulfides as protecting groups for anomeric thiols.
- Kiefel, Milton J.,Thomson, Robin J.,Radovanovic, Milica,Von Itzstein, Mark
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p. 937 - 959
(2007/10/03)
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- Carbohydrate Phosphinites as Practical Ligands in Asymmetric Catalysis: Electronic Effects and Dependence of Backbone Chirality in Rh-Catalyzed Asymmetric Hydrogenations. Synthesis of R- or S-Amino Acids Using Natural Sugars as Ligand Precursors
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Vicinal diarylphosphinites derived from carbohydrates are excellent ligands for the Rh(I)-catalyzed enantioselective asymmetric hydrogenation of dehydroamino acid derivatives, producing the highest enantioselectivity of any ligands directly prepared from natural products. The enantioselectivity can be enhanced by the appropriate choice of substituents on the aromatic rings of the phosphinites. For example, the use of phosphinites with electron-donating bis(3,5-dimethylphenyl) groups on phosphorus provides ee's up to 99% for a wide range of amino acids including some with easily removable N-protecting groups. Electron-withdrawing aryl substituents, on the other hand, decrease the enantioselectivity. Sense of chiral induction in the amino acid product depends on the relative juxtaposition of the vicinal diphosphinites on a given sugar backbone. When readily available D-glucopyranosides are used as the starting sugars, 2,3-phosphinites give the S-amino acids and 3,4-phosphinites give the R-amino acids. In the case of aromatic and heteroaromatic amino acids, enantioselectivities > 95% are consistently obtained. Practical considerations such as the ease of ligand synthesis, rates of reactions, catalyst turnover, and scope and limitations in terms of substrates are discussed. A possible explanation for the enhancement of enantioselectivity by electron-rich phosphinites is offered.
- RajanBabu,Ayers, Timothy A.,Halliday, Gary A.,You, Kimberly K.,Calabrese, Joseph C.
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p. 6012 - 6025
(2007/10/03)
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- Preparations and reactions of acylated and partially acylated glycosyl fluorides
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Partial acylation of glycosyl fluorides in the galacto (2 and 3) and gluco series (8-10) is readily achieved. Attempts to further alkylate these acyl derivatives failed. Treatment of 2 with Lewis acid, however, provided a facile route to the 1,4-anhydro derivative 5. Lewis acid-mediated glycosylation of 2-acetamido-3,4,6-tri-O-acetyl-α-D-glucopyranosyl fluoride 11 led to the simple glycosides and thioglycosides 12-16. Similarly, in the galacto series (17) an advantageous route to the β-galactosidase inhibitor 19 could be elaborated.
- Thiem, Joachim,Wiesner, Matthias
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p. 197 - 206
(2007/10/02)
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- A NEW SYNTHESIS OF 1,2-TRANS-2-ACETAMIDO-2-DEOXYGLYCOPYRANOSIDES VIA 1,2-TRANS-2-DEOXY-2-IODOGLYCOSYL AZIDES
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Trans-addition of iodoazide to the double bond of 3,4,6-tri-O-acetyl-1,5-anhydro-D-arabino-hex-1-enitol yielded 2-deoxy-2-iodoglycosyl azides, which are percursors of 1,2-trans-2-amino-2-deoxyglycopyranosides when treated by an alcohol in the presence of triphenylphosphine.
- Lafont, Dominique,Guilloux, Pascal,Descotes, Gerard
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- Cycloaddition Reaction of Dibenzyl Azodicarboxylate and Glycals
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The cycloaddition reaction of dibenzyl azodicarboxylate and glycals allows the stereoselective introduction of an amino function at C-2 of a carbohydrate.Very good results were obtained with both furanoid and pyranoid glycals, except when triacetylglucal (TAG) was used as the substrate.In some instances the course of the reaction was found to be concentration dependent.
- Leblanc, Yves,Fitzsimmons, Brian J.,Springer, James P.,Rokach, Joshua
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p. 2995 - 3000
(2007/10/02)
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- NOUVELLE VOIE D'ACCES AUX 1,2-trans-2-AMINO-2-DESOXY-GLYCOPYRANOSIDES PAR L'INTERMEDIAIRE DES PHOSPHORAMIDATES DE 1,2-trans-2-DESOXY-2-IODOGLYCOPYRANOSYLES
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1,2-trans-2-Deoxy-2-iodoglycopyranosyl phosphoramidates (prepared from the corresponding glycals by addition of iodoazide, followed by Staudinger reaction with a phosphite) led by treatment with an alcohol in the presence of a base to the corresponding 1,2-trans-2-deoxy-2-phosphoramidoglycopyranosides, after inversion of configuration at C-1 and C-2.The reaction proceeded by an aziridine intermediate, which was opened by the alcohol present in the medium.Use of simple alcohols yielded alkyl glycosides having β-D-gluco, β-D-xylo, α-D-manno, and α-D-lyxo configurations, respectively, starting from α-D-manno, α-D-lyxo, β-D-gluco-, and β-D-xylo phosphoramidates, with excellent yields.The same reaction with an alcohol derived from galactopyranose led to the expected disaccharide with a low yield.
- Lafont, Dominique,Descotes, Gerard
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- STANNOUS TRIFLATE MEDIATED GLYCOSIDATIONS. A STEREOSELECTIVE SYNTHESIS OF 2-AMINO 2-DEOXY-β-D-GLUCOPYRANOSIDES DIRECTLY WITH THE NATURAL N-ACETYL PROTECTING GROUP.
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Variuos 2-acetamido 2-deoxy β-D-glucopyranosides have been prepared in good yield from the crystalline 2-acetamido 3,4,6-tri-O-acetyl 2-deoxy α-D-glucopyranosyl chloride using stannous triflate as promoter.
- Lubineau, Andre,Gallic, Joelle Le,Malleron, Annie
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p. 5041 - 5044
(2007/10/02)
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- N-Allyloxycarbonyl derivatives of D-glucosamine as promotors of 1,2-trans-glucosylation in Koenigs-Knorr reactions and in Lewis acid catalysed condensations
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The use of suitably blocked D-glucosamine derivatives possessing the N-allyloxyxarbonyl protective group of the amino function represents potential new routes to 1,2-trans-glucosylations.Both 3,4,6-tri-O-acetyl-2-N-allyloxycarbonyl-2-amino-2-deoxy-α-D-glu
- Boullanger, Paul,Banoub, Joseph,Descotes, Gerard
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p. 1343 - 1348
(2007/10/02)
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- SYNTHESIS OF METHYL ETHERS OF METHYL 2-ACETAMIDO-2-DEOXY-α-D-GLUCOPYRANOSIDE
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A convenient method is proposed for the synthesis of all the individual methyl ethers of methyl 2-acetamido-2-deoxy-α-D-glucopyranoside based on the partial methylation of 2-acetamido-2-deoxy-α-D-glucopyranoside with dimethyl sulfate in an alkaline medium followed by preparative liquid column chromatography on silica gel of the resulting mixture of methyl ethers.
- Evtushenko, E. V.,Plisova, E. Yu.,Ovodov, Yu. S.
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p. 651 - 653
(2007/10/02)
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- Synthesis and biological activity of some 1-N-substituted 2-acetamido-2-deoxy-beta-D-glycopyranosylamine derivatives and related analogs.
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Several 1-N-substituted derivative [haloacetyl-, glycyl-, (dimethyl)amino-acetyl-, azidoacetyl-, trifluoroacetyl-, and trifluoromethylsulfonyl-] of 2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-beta-D-glucopyranosylamine (1) were synthesized as potential metabolic inhibitors of cellular-membrane glycoconjugates. Several fully acetylated derivatives were found to inhibit growth of mouse mammary adenocarcinoma TA3, leukemia L1210, or leukemia P-288 cells at 1-0.01 mM concentration in vitro. Some of these derivatives were less active after O-deacetylation. Analogs of 1 in which NH2-1 was replaced by OH- or OAc-1 were also active on the same cell systems. The growth-inhibitory activity was correlated with inhibition of the incorporation of 2-amino-deoxy-D-glucose and L-leucine into a macromolecular fraction.
- Paul,Bernacki,Korytnyk
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- Catalytic reduction of dimeric acetylated 2-deoxy-2-nitroso-α-D-glucopyranosyl chlorides
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Reduction of tri-O-acetyl-2-deoxy-2-nitroso-α-D-glucopyranosyl chloride dimer with hydrogen and platinum oxide in the presence of methanol or ethanol afforded the corresponding alkyl tri-O-acetyl-2-amino-2-deoxy-β-D-glucopyranoside hydrochloride.In the absence of an alcohol the product was tri-O-acetyl-2-amino-1,5-anhydro-2-deoxy-D-gucitol hydrochloride.The glycosylation/reduction process gave similar results with the galacto isomer.A method is described for the ready and large-scale synthesis of D-galactosamine hydrochloride.
- Nagabhushan, T. L.
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p. 2720 - 2723
(2007/10/02)
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