Application of Phenyl 1-Selenoglycosides in the Synthesis of a Cell-Wall Tetrameric Fragment of Proteus Vulgaris Strain 5/43

Abstract

DAST-assisted rearrangement of 3-O-allyl-4-O-benzyl-α-l-rhamnopyranosyl azide followed by treatment of the generated fluorides with ethanethiol and BF₃·OEt₂ gave glycosyl donor ethyl 3-O-allyl-2-azido-4-O-benzyl-2,6-dideoxy-1-thio-α/β-l-glucopyranoside. Stereoselective glycosylation of methyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucopyranoside with ethyl 3-O-allyl-2-azido-4-O-benzyl-2,6-dideoxy-1-thio-α/β-l-glucopyranoside, under the agency of NIS/TfOH afforded methyl 3-O-(3-O-allyl-2-azido-4-O-benzyl-2,6-dideoxy-α-l-glucopyranosyl)-4,6-O-benzyli-dene-2-deoxy-2-phthalimido-β-D-glucopyranoside. Removal of the allyl function of the latter dimer, followed by condensation with properly protected 2-azido-2-deoxy-glucosyl donors, in the presence of suitable promoters, yielded selectively methyl 3-O-(3-O-[6-O-acetyl-2-azido-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranosyl]-2-azido-4-O-benzyl-2,6-dideoxy-α-l-glucopyranosyl)-4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucopyranoside. Deacetylation and subsequent glycosylation of the free HO-6 with phenyl 2,3,4,6-tetra-O-benzoyl-1-seleno-β-D-glucopyranoside in the presence of NIS/TfOH furnished a fully protected tetrasaccharide. Deprotection then gave methyl 3-O-(3-O-[6-O-{β-D-glucopyranosyl}-2-acetamido-2-deoxy-β-D-glucopyranosyl)-2-acetamido-2,6-dideoxy-α-L-glucopyranosyl)-2-acetamido-2-deoxy-β-D-glucopyranoside.     

Studies on the Thioglycosides of N-Acetylneuraminic Acid 7: Synthesis of S-(α-Sialyl)-(2↠6)-β-D-Hexopyranosyl and -(2↠6)-β-D-Lactosyl Ceramides and their Biological Activity

ABSTRACT

The coupling of the sodium salt of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3, 5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosonate (17) with 2-(trimethylsilyl)ethyl 2,3,4-tri-O-acetyl-6-bromo-6-deoxy-β-D-galactopyranoside (5), glucopyranoside (10), and 2-(trimethylsilyl)ethyl 2,3,6,2′,3′,4′-hexa-O-acetyl-6′-bromo-6′-deoxy-β-D-lactoside (16), gave the corresponding α-thioglycosides 18, 21, and 24 of the 2-thio-N-acetyl-neuraminic acid derivative in good yields, which were converted, via selective removal of the 2-(trimethylsilyl)ethyl group, trichloroacetimidation, and coupling with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (27), into the ß-glycosides 28, 32, and 36, respectively.

Compounds 28, 32, and 36 were transformed, via selective reduction of the azide group, coupling with octadecanoic acid, O-deacetylation, and de-esterification, into the title compounds 31, 35, and 39, which showed potent inhibitory effect for sialidases from influenza and other viruses.     

Synthesis of 5′-azido- and 5′-amino-2′,5′-dideoxynucleosides from quinazoline-2,4(1H,3H)-diones

Quinazoline-2,4(1H,3H)-diones 4 were silylated and condensed with methyl 5-azido-2,5-dideoxy-3-O-(4-methylbenzoyl)-α,β-D-erythro-pentofuranoside (3) using trimethylsilyl trifluoromethanesulfonate (TMS triflate) as the catalyst to afford the corresponding 5′-azidonucleosides 5 . 1-(5-Azido-2,5-dideoxy-α-D-erythro-pentofuranosyl)quinazoline-2,4(1H,3H)-diones 6 and the corresponding β anomers were obtained by treating 5 with sodium methoxide in methanol at room temperature. 6-Methyl-1-(5-amino-2,5-dideoxy-β-D-erythro-pentofuranosyl)quinazoline-2,4(1H,3H)-dione (8) was obtained by treatment of the corresponding azido derivative 7 with triphenylphosphine in pyridine, followed by hydrolysis with ammonium hydroxide.     

Strukturelle Abwandlungen an partiell silylierten Kohlenhydraten mittels Triphenylphosphin/Azodicarbonsäure-diäthylester. 3. Mitteilung [1]

Structural Modification on Partially Silylated Carbohydrates by Means of Triphenylphosphine/Diethyl Azodicarboxylate Reaction of methyl 2, 6-bis-O-(t-butyldimethylsilyl)-β-D -glucopyranoside ( 1a ) with triphenylphosphine (TPP)/diethyl azodicarboxylate (DEAD) and Ph₃P · HBr or methyl iodide yields methyl 3-bromo-2, 6-bis-O-(t-butyldimethylsilyl)-3-deoxy-β-D -allopyranoside ( 3a ) and the corresponding 3-deoxy-3-iodo-alloside 3c (Scheme 1). By a similar way methyl 2, 6-bis-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 2a ) can be converted to the 4-bromo-4-deoxy-galactoside 4a and the 4-deoxy-4-iodo-galactoside 4b . In the absence of an external nucleophile the sugar derivatives 1a and 2a react with TPP/DEAD to form the 3,4-anhydro-α- or -β-D -galactosides 5 and 6a , respectively, while methyl 4, 6-bis-O-(t-butyldimethylsilyl)-β-D -glucopyranoside ( 1b ) yields methyl 2,3-anhydro-4, 6-bis-O-(t-butyldimethylsilyl)-β-D -allopyranoside ( 7a , s. Scheme 2). Even the monosilylated sugar methyl 6-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 2b ) can be transformed to methyl 2,3-anhydro-6-O-(t-butyldimethylsilyl)-β-D -allopyranoside ( 8 ; 56%) and 3,4-anhydro-α-D -alloside 9 (23%, s. Scheme 3). Reaction of 1c with TPP/DEAD/HN₃ leads to methyl 3-azido-6-O-(t-butyldimethylsilyl)-3-deoxy-β-D -allopyranoside ( 10 ). The epoxides 7 and 8 were converted with NaN₃/NH₄Cl to the 2-azido-2-deoxy-altrosides 11 and 13 , respectively, and the 3-azido-3-deoxy-glucosides 12 and 14 , respectively (Scheme 4 and 5). Reaction of 7 and 8 with TPP/DEAD/HN₃ or p-nitrobenzoic acid afforded methyl 2,3-anhydro-4-azido-6-O-(t-butyldimethylsilyl)-4-deoxy-α- and -β-D -gulopyranoside ( 15 and 17 ), respectively, or methyl 2,3-anhydro-6-O-(t-butyldimethylsilyl)-4-O-(p-nitrobenzoyl)-α- and -β-D -gulopyranoside ( 16 and 18 ), respectively, without any opening of the oxirane ring (s. Scheme 6). - The 2-acetamido-2-deoxy-glucosides 19a and 20a react with TPP/DEAD alone to form the corresponding methyl 2-acetamido-3,4-anhydro-6-O-(t-butyldimethylsilyl)-2-deoxy-galactopyranosides ( 21 and 22 ) in a yield of 80 and 85%, respectively (Scheme 7). With TPP/DEAD/HN₃ 20a is transformed to methyl 2-acetamido-3-azido-6-O-(t-butyldimethylsilyl)-2,3-didesoxy-β-D -allopyranoside ( 25 , Scheme 8). By this way methyl 2-acetamido-3,6-bis-O-(t-butyldimethylsilyl)-α-D -glucopyranoside ( 19b ) yields methyl 2-acetamido-4-azido-3,6-bis-O-(t-butyldimethylsilyl)-2,4-dideoxy-α-D -galactopyranoside ( 23 ; 16%) and the isomerized product methyl 2-acetamido-4,6-bis-O-(t-butyldimethylsilyl)-2-deoxy-α-D -glucopyranoside ( 19d ; 45%). Under the same conditions the disilylated methyl 2-acetamido-2-deoxy-glucoside 20b leads to methyl 2-acetamido-4-azido-3,6-bis-O-(t-butyldimethylsilyl)-2,4-dideoxy-β-D -galactopyranoside ( 24 ). - All Structures were assigned by ¹H-NMR. analysis of the corresponding acetates.     

Synthesis of Sialic Acid Analogues with the Oxime Group at C-4 Or C-5 of KDN 1

Abstract

The readily available methyl (methyl 3-deoxy-5,8:7,9-di-O-isopropylidene-β-D-glycero-D-galacto-2-nonulopyranosid)onate (7) was converted in five synthetic steps into methyl (methyl 4-acetamido-3,4-dideoxy-β-D-glycero-D-talo-2-nonulopyranosid)onate (11). Selective protection of the C-4, C-7, C-8 and C-9 hydroxy groups of methyl (methyl 3-deoxy-8,9-O-isopropylidene-β-D-glycero-D-galacto-2-nonulpyranosid)onate (2) followed by oxidation of the C-5 hydroxy group and then its oximination gave 5-hydroxyimino derivatives (15 and 16).

     

Non-Glycosidic Azides of D-Altro- and D-Gulopyranose

ABSTRACT

Starting with methyl 2-O-cyclohexylcarbamoyl-3,4-O-(2,2,2-trichloroethylidene)-α-D-altropyranoside (1), methyl 4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-β-D-gulopyranoside (12), and methyl 6-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-β-D-gulopyranoside (21), the 6-azido-6-deoxyaltroses 4, 6, 11, the 6-azido-6-deoxy-D-gulose 14, the 4-azido-4,6-dideoxy-D-gulose 20, and the 4-azido-4-deoxy-D-gulose 26 were synthesised via iodinated or tosylated precursors. Additionally, two gluco-configured azides, the 3-azido-3,6-dideoxy-D-glucose (19) and the 3-azido-3-deoxy-D-glucose (25), were obtained besides the desired 4-azido-4-deoxy-D-gulosides 20 and 26, when methyl 6-deoxy-4-O-tosyl-β-D-gulopyranoside (18) and methyl 6-O-cyclohexylcarbamoyl-4-O-tosyl-β-D-gulopyranoside, respectively, were reacted with sodium azide. An X-ray analysis is presented for methyl 2,4-di-O-acetyl-3-azido-3,6-dideoxy-zl-D-glucose (19).     

An Unusual Behavior of Methyl or Benzyl 3-Azido-5-O-Benzoyl-3,6-Di-Deoxy-α-L-Talofuranoside with (Dimethylamino)Sulfur Trifluoride; Migration of the Alkoxyl Group from the C-1 to the C-2 Position

The reaction of methyl or benzyl 3-azido-5-0-benzoyl-3,6-di-deoxy-α-L-talofuranoside with (diethylamino)sulfur trifluoride (DAST) in toluene at 60°C resulted in the formation of 3-azido-5-0-benzoyl-3,6-dideoxy-2-0-methyl (or 2-0-benzyl)-3β-L-galactofuranosyl fluoride in good yield. In this reaction the alkoxyl group at C-1 migrated to the C-2 position and a fluorine atom entered into the C-1 position. The furanosyl fluoride was converted, via reduction of the azido group followed by N-trifluoroacetylation, acetolysis, and O-deacetylation, into 3,6-dideoxy-2-0-methyl-3-trifluoroacet-amido-L-galactopyranose (2-methoxy-Daunosamine derivative).     

Synthesis of 5-benzyl and 5-benzyloxybenzyl-3′-azido-2′,3′-dideoxyuridine and their analogues as potential anti-AIDS agents

5-Benzyl and 5-benzyloxybenzyl-substituted 3′-azido-2′,3′-dideoxyuridine, ( 8a and 8b ), 3′-halogeno-2′,3′-dideoxyuridine, 9a, 9b, 10a, 10b, 11a and 11b , and 2′,3′-dideoxyuridine, 12a and 12b , of Scheme I were synthesized as potential anti AIDS agents. Synthesis of epimers of 8a and 8b , 5-benzyl- and 5-benzyloxybenzyl-1-(3′-azido-2′,3′-dideoxy-β-D-threo-pentafuranosyl)uracil, 15a and 15b , and 5-benzyl- and 5-benzyloxy-5′-azido-2′,5′-dideoxyuridine, 16a and 16b , shown in Scheme II, were also reported.     

Rearrangement of allylic azide and phenylthio groups of 3′-azido- or 3′-phenylthio-4′,5′-didehydro-5′-deoxyarabinofuranosyluridines

The reversible intramolecular [3,3]-sigmatropic rearrangement between 1-(3-azido-3,5-dideoxy-β-d-threo-pent-4-enofuranosyl)uracil (3) and 1-(5-azido-3,5-dideoxy-β-d-glycero-pent-4-enofuranosyl)uracil (4) and irreversible radical rearrangement of 1-(3,5-dideoxy-3-phenylthio-β-d-threo-pent-4-enofuranosyl)uracil (5) and 1-[3,5-dideoxy-3-(4-tolyl)thio-β-d-threo-pent-4-enofuranosyl]uracil (7) into 1-(3,5-dideoxy-5-phenylthio-β-l-glycero-pent-4-enofuranosyl)uracil (6) and 1-[3,5-dideoxy-5-(4-tolyl)thio-β-l-glycero-pent-3-enofuranosyl]uracil (8) were attained at room temperature.     

SYNTHESIS OF THE C-DISACCHARIDE α-C(1→3)-L-FUCOPYRANOSIDE OF N-ACETYLGALACTOSAMINE[1]

Radical C-glycosidation of racemic 5-exo-benzeneselenyl-6-endo-chloro-3-methylidene-7-oxabicyclo[2.2.1]heptan-2-one ((±)-2) with α-acetobromofucose (3) provided a mixture of α-C-fucosides that were reduced with NaBH₄ to give two diastereomeric alcohols that were separated readily. One of them ((?)-6) was converted into (?)-methyl 2-acetamido-4-O-acetyl-2,3-dideoxy-3-C-(3′,4′,5′-tri-O-acetyl-2′,6′-anhydro-1′,7′-dideoxy-α-L-glycero-D-galacto-heptitol-1′-C-yl)-α -D-galactopyranuronate ((?)-11) and then into (?)-methyl 2-acetamido-2,3-dideoxy-3-C-(2′,6′-anhydro-1′,7′-dideoxy-α-L-glycero-D-galacto-heptitol-1′-C-yl)-β -D-galactopyranoside ((?)-1), a new α-C(1→3)-L-fucopyranoside of N-acetylgalactosamine. Its ¹H NMR data shows that this C-disaccharide (α-L-Fucp-(1→3)CH₂-β-D-GalNAc-OMe) adopts a major conformation in solution similar to that expected for the corresponding O-linked disaccharide, i.e., with antiperiplanar σ(C-3′,C-2′) and σ(C-1′,C-3) bonds.     

Synthetic Studies on Sialoglycoconjugates 53: Synthesis of Novel N-Methyl-1-Deoxynojirimycincontaining Sialo-Oligosaccharides Related to Ganglioside GM3 Active as a Biosignal Mediator

Abstract

O-(6-O-Benzoyl-β-d-galactopyranosyl)-(1→4)- and O-(2, 3, 4-tri-O-acetyl-β-d-galactopyranosyl)-(1→4)-2, 3, 6-tri-O-benzyl-N-benzyloxycarbonyl-1, 5-dideoxy-1, 5-imino-d-glucitols (4 and 12) were each coupled with methyl (methyl 5-acetamido-4, 7, 8, 9-tetra-O-acetyl-3, 5-dideoxy-2-thio-d-glycero-d-galacto-2-nonulopyranosid)onate (5) in acetonitrile medium in the presence of dimethyl(methylthio)sulfonium triflate (DMTST) or N-iodosuccinimide/trifluoromethanesulfonic acid to give the corresponding α-sialyl-(2 → 3)- and α-sialyl-(2 → 6)-glycosides (6 and 13α), which were converted to novel ganglioside GM3-related trisaccharides (9 and 15) containing N-methyl-1-deoxynojirimycin.     

Synthesis and Properties of 1-(3,4-DI-O-Acetyl-2-Deoxy-2-Hydroxyimino-D-Threo-Pentopyranosyl)Pyrazoles

ABSTRACT

3,4-Di-O-acetyl-2-deoxy-2-nitroso-α-D-xylo-pentopyranosyl chloride (2) reacts with pyrazole to afford 1-[3,4-di-O-acetyl-2-deoxy-2-(Z)-hydroxyimino-α- (3) and β-D-threo-pentopyranosyl]pyrazole (4). The products of condensation were modified at C-2 or C-3 to give pyrazole derivatives with 3-azido-2,3-dideoxy-2-hydroxyimino-pentopyranosyl (5,7,8,9,10), 2-acetoxyimino-2,3-dideoxy-β-D-glycero-pentopyranosyl (12,13), β-D-lyxo- (14), β-D-xylopentopyranosyl (15) structures and 2,3-dihydro-2-pyrazol-1-yl-6H-pyran-3-one oximes (6,11). The conformation of the sugar residue and configuration at the anomeric centre and of the hydroxyimino group were established on the basis of ¹H NMR and polarimetric data.     

Synthetic Studies on Sialoglycoconjugates 14: Synthesis of Ganglioside GM3 Analogs Containing The Carbon 7 And 8 Sialic Acids

ABSTRACT

Ganglioside GM₃ analogs, containing 5-acetamido-3, 5-dideoxy-L-arabino-heptulosonic acid and 5-acetamido-3, 5-dideoxy-D-galacto-octulosonic acid have been synthesiyed. Glycosylation of 2-(trimethylsilyl)ethyl 0-(6-0-benzoyl-ß-D-galactopyranosyl)-(l→4)-2, 6-di-0-benzoyl-ß-D-glucopyranoside (5), with methyl (methyl 5-acetamido-4, 7-di-0-acetyl-3, 5-dideoxy-2-thio-ß-L-arabino-2-heptulo-pyranosid)onate (2) or with methyl (methyl 5-acetamido-4, 7, 8-tri-0-acetyl-3, 5-dideoxy-2-thio-α-D-galacto-2-octulopyranosid)onate (4), which were respectively prepared from the corresponding 2-S-acetyl derivatives (1 and 3) by selective 2-S-deacetylation and subsequent S-methylation, using dimethyl(methylthio)sulfonium triflate as a glycosyl promoter, gave 2-(trimethylsilyl)ethyl 0-(methyl 5-acet-amido-4, 7-di-0-acetyl-3, 5-dideoxy-ß-L-arabino-2-heptulopyranosyl-onate)-(2→3)-0-(6-0-benzoyl-ß-D-galactopyranosyl)-(1→4)-2, 6-di-0-benzoyl-ß-D-glucopyranoside (6) and 2-(trimethylsilyl)ethyl (0)-(methyl 5-acetamido-4, 7, 8-tri-0-acetyl-3, 5-dideoxy-α-D-galacto-2-octulopyranosylonate)-(2→3)-0-(6-0-benzoyl-ß-D-galactopyranosyl)-(l-4)-2, 6-di-0-benzoyl-ß-D-glucopyranoside (10), respectively. Compounds 6 and 10 were converted, via 0-acetylation, selective removal of the 2-(trimethylsilyl)ethyl group, and subsequent imidate formation, into the corresponding trichloroacetimidates 9 and 13, respectively.

Glycosylation of (2S, 3R, 4E)-2-azido-3-0-benzoyl-4-octadecen1, 3-duik (14) with 9 or 13 affored the ß-glcosides (15 and 18), which were converted, via selective reduction of the azide group, coupling with octadecanoic acid, 0-deacylation, and deesterification, into the title compounds, respectively.     

Réactions inhabituelles dans la synthèse et la substituition d'un triflate osdique

Triflation of methyl 3-azido-3,4-dideoxy-α or β-DL-threo-pentopyranoside with triethylamine as acid acceptor in dichloromethane, gave the two isomers of a 1:2′ , 2:1′ dianhydride. Benzoate displacement of the α triflate occured with a pyranose to furanose contraction reaction at C-2.     

Enantiomeric forms of 9-(5,6-dideoxy-α-d-arabino-hex-5-enofuranosyl)adenine and preparation of 9-(6-deoxy-β-d-galactofuranosyl)adenine: Further results with the acetolysis of hexofuranosides

Acetolysis of methyl 5,6-dideoxy-2,3-0-isopropylidene-β-d-ribo-hex-5-enofuranoside (1) and condensation of the product with 6-benzamidochloromercuripurine by the TiCl₄ method, gave 9-(5,6-dideoxy-α-d-arabino-hex-5-enofuranosyl) adenine (3) in low yield after removal of blocking groups. The main product was the D ribo nucleoside which was selectively destroyed by periodate oxidation to facilitate chromatographic purification of 3. The enantiomer 6 was prepared from methyl 5,6-dideoxy-2,3-0-isopropylidene-β-l-ribo-hex-5-enofuranoside (5) by the exact same route. The acetolysis reaction, in contrast to most previous experience, failed to epimerize C-2 of the sugar completely. An improved preparation of 6 is described which started from D-galactose. In addition, the latter pathway was used to prepare 9-(6-deoxy-β-d-galactofuranosyl)adenine (17).     

2′, 3′-Dideoxy-3′-fluorotubercidin and Related Dideoxyribonucleosides:. Synthesis via a 2′-deoxy-3′-oxoribofuranoside intermediate and conformation studies

An efficient synthesis of the unknown 2′-deoxy-D-threo-tubercidin ( 1b ) and 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4-chloro-7-(2-deoxy-β-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine ( 5 ) with (tert-butyl)diphenylsilyl chloride yielded 6 which gave the 3′-keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH₄ reduction (→ 8 ) followed by deprotection with Bu₄NF(→ 9a )and nucleophilic displacement at C(6) afforded 1b as well as 7-deaza-2′-deoxy-D-threo-inosine ( 9b ). Mesylation of 4-chloro-7-{2-deoxy-5-O-[(tert-butyl)diphenylsilyl]-β-D-threo-pentofuranosyl}-7H-pyrrolo[2,3-d]-pyrimidine ( 8 ), treatment with Bu₄NF (→ 12a ) and 4-halogene displacement gave 2′, 3′-didehydro-2′, 3′-dideoxy-tubercidin ( 3 ) as well as 2′, 3′-didehydro-2′, 3′-dideoxy-7-deazainosne ( 12c ). On the other hand, 2′, 3′-dideoxy-3′-fluorotubercidin ( 2 ) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→ 10a ), subsequent 5′-de-protection with Bu₄NF (→ 10b ), and Cl/NH₂ displacement. ¹H-NOE difference spectroscopy in combination with force-field calculations on the sugar-modified tubercidin derivatives 1b , 2 , and 3 revealed a transition of the sugar puckering from the ^3′T_2′ conformation for 1b via a planar furanose ring for 3 to the usual ^2′T_3′ conformation for 2.     

Total Synthesis of the Gastroprotective Substance AI-77-B and of Analogues

The Diels-Alder adducts 8 of furan to 1-cyanovinyl acetate were converted into (Methyl 3-chloro)-5-O-(3-chlorobenzoyl)-2, 3-dideoxy-α-dl-arabino-hexofuranosid)uronic acid ((α)- 18a ) and into (methyl 3-azido-5-O-(3-chlorobenzoyl_-2,3-dideoxy-α-dl-ribo-hexofuranosid)uronic acid ((α)- 41a ). These compounds were condensed to (3S)-3-[(1′S)-1′-amino-3′-methylbutyl]-3,4-dihydro-8-hydroxyisocoumarin hydrochloride ((?)- 2 ); the resulting mixtures of diastereoisomeric amides were transformed and separated to give the gastroprotective substance AI-77- B ((?)- 1 ) and analogues.     

Synthetic Studies on Sialoglycoconjugates 66: First Total Synthesis of a Cholinergic Neuron-Specific Ganglioside GQ1bα1

Abstract

A first total synthesis of a cholinergic neuron-specific ganglioside, GQ1bα (IV³Neu5Acα, III⁶Neu5Acα, II³Neu5Acα₂-Gg₄Cer) is described. Regio- and stereo-selective monosialylation of the hydroxyl group at C-6 of the GalNAc residue in 2-(trimethylsilyl)ethyl O-(2-acetamido-2-deoxy-3,4-O-isopropylidene-β-d-galactopyranosyl)-(1→4)-O-(2,6-di-O-benzyl-β-dgalactopyranosyl)-(1→4)- O-2,3,6-tri-O-benzyl-β-dglucopyranoside (4) with methyl (phenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-d glycero-d galacto-2-nonulopyranosid) onate (5), and subsequent dimericsialylation of the hydroxyl group at C-3 of the Gal residue with methyl [phenyl 5-acetamido-8-O-(5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d glycero-α-d galacto-2-nonulopyranosylono-1′,9-lactone)-4, 7-di-O-acetyl-3,5-dideoxy-2-thio-d glycero-d galacto-2-nonulopyranosid]onate (7), using N-iodosuccinimide (NIS)-trifluoromethanesulfonic acid (TfOH) as a promoter, gave the desired hexasaccharide 8 containing α-glycosidically-linked mono- and dimeric sialic acids. This was transformed into the acceptor 9 by removal of the isopropylidene group. Condensation of methyl O-(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d glycero-α-d galacto-2-nonulopyranosylonate)-(2→3)-2,4,6-tri-O-benzoyl-1-thio-β-dgalactopyranoside (10) with 9, using dimethyl(methylthio)sulfonium triflate (DMTST) as a promoter, gave the desired octasaccharide derivative 11 in high yield. Compound 11 was converted into α-trichloroacetimidate 14, via reductive removal of the benzyl groups, O-acetylation, removal of the 2-(trimethylsilyl)ethyl group, and treatment with trichloroacetonitrile, which, on coupling with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (15), gave the β-glycoside 16. Finally, 16 was transformed, via selective reduction of the azido group, coupling with octadecanoic acid, O-deacylation, and hydrolysis of the methyl ester group, into the title ganglioside 18 in good yield.     

Participation by C-3 Substituents in Disaccharide Formation

Abstract

Four reactions were conducted in order to study the ability of a C-3 acyloxy group to control the stereoselectivity of glycosidation reactions in which the glycosyl donors were unsubstituted at c-2. These donors differed in the structure of the acyloxy group attached to C-3 (benzoyloxy or p-methoxybenzoyloxy) and in the identity of the leaving group (chloro or thiomethoxy) attached to the anomeric carbon. The stereoselectivity in all reactions was low; for example, treatment of 3,4-di-O-benzoyl-2,6-dideoxy-D-ribo-hexopyranosyl chloride (6) with methyl 4-O-benzoyl-2,6-dideoxy-α-D-lyxo-hexopyranoside (7) yielded a 2.2/1 (α/β) ratio of methyl 4-O-benzoyl-3-O-(3,4-di-O-benzoyl-2,6-dideoxy- α-D-ribo-hexopyranosyl-2,6-dideoxy-α-D-ribo-hexopyranoside (8) and methyl 4-O-benzoyl-3-O-(3,4-di-O-benzoyl-2,6-dideoxy-α-D-lyxo-hexopyranoside-2,6-dideoxy-α-D-lyxo-hexopyranoside (9). Formation of 1,5-anhydro-3,4-di-O-benzoyl-2,6-dideoxy-D-ribo-her-1-enitol (10) was a significant additional reaction. In reactions involving the thioglycosides only trace amounts of glycals were formed and approximately equal amounts of α and β anomers were produced. The significance of these reactions to participation by C-3 acyloxy groups is discussed.     

Nucleotides. Part XXXI. Modified Oligomeric 2′–5′ A Analogues: Synthesis of 2′–5′ oligonucleotides with 9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine and 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)adenine as modified nucleosides

A series of new 2′–5′ oligonucleotides carrying the 9-(3′-azido-3′deoxy-β-D-xylofuranosyl)adenine moiety as a building block has been synthesized via the phosphotriester method. The use of the 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) blocking groups for phosphate, amino, and hydroxy protection guaranteed straightforward syntheses in high yields and easy deblocking lo form the 2′–5′ trimers 21 , 22 , and 25 and the tetramer 23 . Catalytic reduction of the azido groups in [9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine]2′-yl-[2′-(O^p-ammonio)→ 5′]-[9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenin]-2′-yl-[2′-(O^p-ammonio)→ 5′]-9-(3′-azido-3′-deoxy-β-D-xylofuranosyl)adenine ( 21 ) led to the corresponding 9-(3′-amino-3′-deoxy-β-D-xylofuranosyl)-adenine 2′–5′ trimer 26 in which the two internucleotidic linkages are formally neutralized by intramolecular betaine formation.