Efficient Syntheses of Methyl 2-Amino-2-Deoxy-3,4,6-Tri-O-Benzyl-α-D-Glucopyranoside and its 2-tert-Butoxycarbonylamino- and 2-Methylamino Derivatives from N-Acetyl-D-Glucosamine

ABSTRACT

The synthesis of the title compounds started with N-acetylglucosamine which was converted into the corresponding methyl glycoside and O-protected with benzyl groups. Subsequent N-protection as its N-BOC-N-acetyl derivative and sequential removal of the N-acetyl group and of the BOC group led in good yield to the target compounds in multigram amounts.     

Synthesis of Methyl 6′-Deoxy- and 6′-Thiolactosaminides and Their Inhibitory Activity Toward CMP-NeuNAc:D-galactoside-(2→6)-α-D-sialyltransferase

Abstract

Specific inhibitors of glycosyltransferases have become of interest1 not only for investigation of carbohydrate-participating cell-surface phenomena but also for practical use such as chemotherapeutic reagents. Glycosyltransferases catalyze the transfer of glycosyl moieties from nucleotide donors to oligosaccharide acceptors. Therefore, two kinds of substrate-analog inhibitors are possible. The donor analogs have been rather well studied, but are not specific. On the other hand, glycosyltransferases have in general smct acceptor specifkity. Recently, acceptor analogs which inhibit the corresponding glycosyltransferases were reported^2-5 and as expected were acceptor-specific inhibitors.     

Syntheses of Methyl 2-O-, 3-O- and 6-O-(2′-Hydroxypropyl)-α-D-Glucopyranosides 1

Abstract

Methyl 6-O-, 3-O- and 2-O-(2′-hydroxypropyl)-α-D-glucopyranosides (4,8, and 12) were synthesized starting from methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside (1), methyl 4,6-O-benzylidene-α-D-glucopyranoside (5), and methyl 3-O-benzyl-4,6-O-benzylidene-D-glucopyranoside (9), respectively. Overall yields were 88%, 6% and 26% of 4, 8 and 12, respectively, with the 2-ether (12) being crystalline and the 3-ether (8) a single diastereomer.

     

Stereocontrolled Conversion of Allylic Alcohols Into Vicinal Cis-Diols: New Syntheses of Methyl α-L-Digitoxoslde and Methyl 2-Deoxy-α-L-Fucoside

A synthetic process is outlined in which an allylic alcohol is converted into its primary urethane derivative, which is then subjected to iodonium ion induced cyclization to give a single iodo-carbonate. The carbonate is then deiodinated reductively and hydrolyzed to afford the vicinal diol. By use of this process the two title sugars have been prepared from methyl 2.3.6-trideoxv-α-L-ervthro-hex-2-enopvranoside and its α-L-threo counterpart.     

Analogues of Moranoline and Mdl 73945. Methyl 6(5)-Deoxy-6(5)-(Morpholin-4-Yl)-α-D-Glycosides as Glucosidase Inhibitors

ABSTRACT

Methyl 2,3,4-tri-O-acetyl-6-O-(p-tolylsulfonyl)-α-D-glucopyranoside (6), or its iodo analogue 7, were subjected to nucleophilic displacement with morpholine to give 8, deacetylation of which gave methyl 6-deoxy-6-(morpholin-4-yl)-α-D-glucopyranoside (3). Similarly, 11, 12 and 21 were prepared. The 6-deoxy-6-iodo derivative 16 was subjected to nucleophilic displacement with morpholine and subsequent acetylation to give 15. Deacetylation of 15 gave 17. The kinetic studies for the inhibition of β-D-glucosidase from sweet almond and using o-nitrophenyl β-D-glucopyranoside as substrate exhibited a K _i value for 21 on the same order as 1-deoxynojirimycin whereas for 3, a K _i value of lesser order was observed.     

Stereocontrolled Synthesis of 6′-Deoxy-6′-Fluoro Derivatives of Methyl α-Sophoroside, α-Laminaribioside, α-Kojibioside and α-Nigeroside

Abstract

Sequential tritylation, benzoylation and detritylation of D-glucose, followed by resolution of the crude product by chromatograpEy gave crystalline 1,2,3,4-tetra-O-benzoyl-α- (1) and β-D-glucopyranose (2). Compound 1, 2, and the corresponding methyl α-glycoside 5 were treated with dimethylaminosulfur trifluoride (methyl DAST) to give, respectively, the 6-deoxy-6-fluoro derivatives 3, 4, and 6. Crystalline 2,3,4-tri-O-benzoyl-6-deoxy-6-fluoro-α-D-glucopyranosyl chloride (10) could be obtained from either 3, 4, or 5 by reaction with dichloromethyl methyl ether in the presence of anhydrous zinc chloride. Silver trifluoromethanesulfonate-promoted reaction of 10 with methyl 2-O-(9) and 3-O-benzyl-4,6-O-benzylidene-α-D-glucopyranoside (8) gave the corresponding, (β-linked disaccharidës in high yield. Subsequent deprotection afforded the 6′-deoxy-6′-fluoro derivatives of methyl α-sophoroside (13) and methyl 6′ -deoxy-o′-fluoro-α-laminaribioside (16). Condensation of 8 and 9 with 6-O-acetyl-2,3,4-tri-O-benzyl-α-D-glucopyranosyl chloride in the presence of silver perchlorate was highly stereoselective and produced the α-linked disaccharidës 17 and 21, respectively, in excellent yield. Deacetylation of 17 and 21, followed by fluorination of the resulting alcohols 18 and 22 with methyl DAST and subsequent hydrogenolysis, gave 6′-deoxy-6′-fluoro derivatives of methyl α-kojibioside and methyl α-nigeroside 20 and 24, respectively.     

Syntheses of O-(2-Acetamido-2-Deoxy-α-D-Galactopyranosyl)-Myo-Inositols

ABSTRACT

The structure of an O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol isolated from human pregnancy urine has previously been identified as that of 1-O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol. In order to ascertain the absolute configuration in the inositol part of the compound, the 1D- and 1L- isomers were synthesised. Since none of these two stereoisomers corresponded to the natural product, the corresponding 2-O-, the mixture of the two 1DL-4-O-, and 5-O- isomers were also synthesised. None of these gave ¹H NMR spectra corresponding to the natural product, the structure of which therefore remains unresolved.     

Synthesis of the 4-Deoxy-2-Deutero-4-Fluoro Analog of Methyl O-β-D-Galactopyranosyl-(1→6)-β-D-Galactopyranoside

ABSTRACT

Methyl 4-deoxy-4-fluoro-6-O-(β-D-galactopyranosyl)-(2-²H)-β-D-galactopyranoside was prepared by the condensation of 2,3,4,6-tetra-O-benzoyl-α-D-galactopyranosyl bromide and methyl 2-O-benzoyl-3-O-benzyl-4-deoxy-4-fluoro-(2-²H)-β-D-galactopyranoside (17), followed by deprotection. The introduction of deuterium at C-2 in an intermediate methylhexopyranoside was achieved by a double inversion, brought about by oxidation of C-2 of a derivative of methyl α-D-glucopyranoside, to give the corresponding ketone, and subsequent reduction thereof with NaBD₄, to give a derivative with the D-manno configuration (8). Inversion of the configuration at C-2 of the latter was achieved by displacement with sodium benzoate of the O-trifluoromethanesulfonyl (triflyl) group in the 2-O-triflyl derivative of 8. The resulting synthon was converted, conventionally, to methyl 2-O-benzoyl-3-O-benzyl-6-O-trityl-(2-²H)-β-D-glucopyranoside. Its conversion into the 6-O-trityl derivative of 17, unsuccessful by treatment with dimethylaminosulfur trifluoride, was readily accomplished by the displacement of the triflyl group with fluoride ion contained in an ion-exchange resin.     

Synthesis of Specifically Fluorinated Methyl β-Glycosides of (1→6)-β-D-Galactooligosaccharides II. Methyl 4-Deoxy-4-fluoro-6-O-(β-D-galactopyranosyl)-β-D-galactopyranoside

Abstract

Condensation of methyl 2,3-di-O-benzyl-4-deoxy-4-fluoro-β-D-galactopyranoside with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide in the presence of mercuric cyanide in benzene afforded, in excellent yield, the β-linked product. Its deblocking, effected by hydrogenolytic cleavage of the benzyl groups followed by deacecylation or, alternatively, via a pathway where the sequence of the deblocking reactions was reversed, gave crystalline title disaccharide 10. The structures of the compounds involved in the synthesis were confirmed by C NMR spectroscopy.     

Synthesis of 5-Deoxy-5-Acyloxyiminoavermectin B1 Derivatives

The avermectins1 are a unique collection of naturally occurring macrocyclic lactones with broad spectrum of anthelmintic and insecticidal activities. Their remarkable biological activity and complex molecular architecture stimulated significant interest in the scientific community. Much research has been carried out on these compounds. Many derivatives of avermectin have much more bioactivities and have been commercially utilized2-5. Here we describe the synthesis of 5-deoxy-5-acyloxyimi…     

Ab Initio Calculations on Nitramide and Its Methyl Derivatives( Ⅱ )——The Harmonic Force Fields and Vibrational Spectra of Nitramide and Its Isotopic Derivatives

The harmonic force field and the vibrational spectrum of nitramide were calculated by using the ab initio gradient program TEXAS at the Hartree-Fock level with a 4-21G basis set. The directly computed theoretical harmonic force field was scaled by using empirical scale factors which are transferred from other molecules and provided an a priori prediction of fundamental frequencies and intensities. The average deviations between predicted vibrational frequencies of nitramide and experimental IR spectrum in an argon matrix are 63 cm-1 for symmetric vibrations and 41 cm-1 for antisymmetric modes. A new set of scale factors was optimized in this paper. These scale factors reduced the average deviations to 2. 3 cm-1 for symmetric modes and 0. 8 cm-1 for antisymmetric ones. The vibrational spectra of three isotopic derivatives of nitramide were predicted by using the force field resulted from the optimized set of scale factors, which are in good agreement with their experimental data in an argon matrix.     

Synthetic Studies on Sialoglycoconjugates 23: Total Synthesis of Sialyl-α(2↠6)-Lactotetraosylceramide and Sialyl-α(2↠6)-Neolactotetraosylceramide

ABSTRACT

The first total syntheses of sialyl-α(2→6)-lactotetraosylceramide (29, IV⁶NeuAcLc₄Cer) and sialyl-α(2→6)-neolatotetraosylceramide (33, IV⁶NeuAcnLc₄Cer) are described. Methyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonulopyranosylonate)-(2→6)-2,4-di-O-benzoyl-3-O-benzyl-1-thio-ß-D-galactopyranoside (11), the key glycosyl donor was prepared, via glycosylation of 2-(trimethylsilyl)ethyl 3-O-benzyl-ß-D-galactopyranoside (2) with the methyl α-thioglycoside 3 of N-acetylneuraminic acid, benzoylation, replacement of the 2-(trimethylsilyl)ethyl group by acetyl, and introduction of the methylthio group with (methylthio)trimethylsilane. Each coupling of 2-(trimethylsilyl)ethyl O-(2-acetamido-4,6-O-benzylidene-2-deoxy-ß-D-glucopyranosyl)-(1→3′)-per-O-benzyl-ß-lactoside (12) or 2-(trimethylsilyl)ethyl O-(2-acetamido-3-O-acetyl-6-O-benzyl-2-deozy-ß-D-glucopyranosyl)-(1→3′)-per-O-benzyl-ß-D-lactoside (14) prepared from 12 by O-acetylation and reductive opening of the benzylidene acetal, with 11 gave the pentasaccharides 16 and 20 in good yields. Compounds 16 and 20 were converted into the corresponding α-trichloroacetimidates 19 and 24 which, on coupling with (2S, 3R, 4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (25), gave the ß-glycosides 26 and 30, respectively. Finally, 26 and 30 were transformed, via selective reduction of the azide group, condensation with octadecanoic acid, O-deacylation, and hydrolysis of the methyl ester group, into 29 and 33, respectively.     

Syntheses of 4- and/or 4′-Phosphate Derivatives of Methyl 3-O-l-Glycero-α-d-manno-heptopyranosyl-l-glyceroα-d-manno-heptopyranoside and Their 2-(4-Trifluoro-acetamidophenyl)ethyl Glycoside Analogues.

Abstract

Syntheses are described of the three disaccharides: methyl 3-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-manno-heptopyranoside 4-phosphate, methyl 3-O-(L-glycero-α-D-manno-heptopyranosyl 4-phosphate)-L-glycero-α-D-manno-heptopyranoside, and methyl 3-O-(L-glycero-α-D-manno-heptopyranosyl 4-phosphate)-L-glycero-α-D-manno-heptopyranoside 4-phosphate together with their 2-(4-trifluoroacetamidophenyl)ethyl glycoside analogues. These correspond to phosphorylated structures found in the inner core region of lipopolysaccharides from Salmonella. The known derivative methyl 6,7-di-O-acetyl-2,3,4-tri-O-benzyl-L-glycero-α-D-manno-heptopyranoside was used as a common heptose precursor. Phosphorylation on suitably protected disaccharide derivatives was performed by treatment with phosphorus triimidazolate in dichloromethane followed by the addition of benzyl alcohol and in situ oxidation with m-chloroperbenzoic acid to give the dibenzyltriester phosphate derivatives, which after deprotection gave the target compounds.     

Synthesis and Reactions of 2,3,4,6-Tetra-O-Acetyl-1-S-(N-Acylaminoacyl)-1-Thio-β-D-Glucopyranoses

Abstract

Fully acetylated 1-thio-β-D-glucopyranosyl esters of N-protected amino acids (4–13) were prepared in high yields by condensation of 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose (1) with a pentachlorophenyl esters of N-protected amino acids (2) in the presence of imidazole, or bN-protected amino acids (3) in the presence of DCC + imidazole. High tendency of the S-acyl aglycon group in 4–13 to undergo S → O and S → N migrations was demonstrated in reactions with several alcohols and amines.     

Synthesis and Anti-HIV Activity of Further Examples of 1-[3-Deoxy-3-(N-hydroxyamino)-β-d-threo-(and β-d-erythro)-pentofuranosyl]thymine Derivatives1

Abstract

Upon sodium cyanoborohydride reduction followed by de-O-silylation, the O-methyloxime and N-benzylnitrone of 5′-TBDMS-3′-ketothymidine gave resolvable epimeric mixtures of 1-[2,3-dideoxy-3-(N-methoxyamino)-β-d-threo-and β-d-erythro-pentofuranosyl]thymine and 1-[3-(N-benzyl-N-hydroxyamino)-2,3-dideoxy-β-d-threo- and β-d-erythro-pentofuranosyl]thymine respectively. These compounds were inactive against HIV. On the other hand, 1-[2,3-dideoxy-3-(N-hydroxyamino)-5-O-TBDMS-β-d-threo-pentofuranosyl]thymine, upon treatment with acetone, then de-O-silylation, gave the bicyclonucleoside analogue 15, slightly more active against HIV in vitro than DDI.     

Dimerization by Hetero Diels-Alder Reaction of Methyl 4,6-O-Benzylidene-3-Deoxy-3-C-Methylene-α-D-Erythro-Hexopyranosid-2-Ulose

Abstract

The dimerization by hetero Diels-Alder reaction of methyl 4,6-O-benzylidene-3-deoxy-3-C-methylene-α-D-erythro-hexopyranosid-2-ulose was found to be regio and stereospecific. The structure of the cycloadduct was assigned from NMR spectrographic and X-ray crystallographic results. These results indicated that this cycloaddition occurred by a concerted hetero Diels-Alder reaction with inverse electron demand.     

Derivatives Of α-Cyclodextrin and the Synthesis of 6-O-α-D-Glucopyranosyl-α-Cyclodextrin

Abstract

Regioselective silylation of α-cyclodextrin with tert-butyl-dimethylsilyl chloride in N, N-dimethylformamide in the presence of imidazole gave, in 75% yield, the hexakis(6-O-tert-butyldimethylsilyl) derivative 2, which was transformed into the hexakis(2,3-di-O-methyl, 6-O-methyl, 2,3-di-O-propyl, and 2,3-di-O-acetyl) derivatives. On methanesulfonylation and p-toluenesulfonylation, the hexakis(2,3-di-O-acetyl) derivative 16 afforded the hexakis(2,3-di-O-acetyl-6-O-methylsulfonyl 17 and 2,3-di-O-acetyl-6-O-p -tolylsulfonyl 18) derivatives, respectively. Nucleophilic displacement of 17 and 18 with iodide, bromide, chloride, and azide ions afforded the hexakis(6-deoxy-6-iodo 19, 6-bromo-6-deoxy, 6-chloro-6-deoxy, and 6-azido-6-deoxy) derivatives, respectively, of α-cyclodextrin dodeca-acetate. The hexakis (2, 3-di-O-acetyl-6-deoxy) derivative was prepared from 19. Selective glucosylation of 16 with 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide under catalysis by halide ion, followed by removal of protecting groups, furnished 6-O-α-D-glucopyranosyl-α-cyclodextrin.     

Crystal Structure and Solid State 13C Nmr Analysis of Methyl 3,4,6-Tri-O-Acetyl-2-Deoxy-2-(3-Phenylureido)-β-D-Glucopyranoside

ABSTRACT

The X-ray diffraction analysis of methyl 3,4,6-tri-O-acetyl-2-deoxy-(3-phenylureido)-β-D-glucopyranoside was performed and showed that the molecules are associated by two NHz.O=C hydrogen bonds. One molecule with disorder of an acetyl group at C-4 was found in the asymmetric crystal unit. The signals in ¹³C CPMAS NMR spectrum are duplicated indicating that local symmetry is lower than those of the crystal.