Chemoenzymatic polymer-supported liquid phase synthesis of glucose γ-aminobutyric ester

A concise, polymer-supported solution synthesis of 6-O-(γ-aminobutyryl)-d-glucose has been achieved. Glucose was attached to polyethylene glycol monomethyl ether (MPEG) through an α,α′-dioxyxylyl diether linker, and, subsequently, the HO-6 hydroxyl of the glucose was regioselectively esterified with γ-aminobutyric acid by a lipase-catalyzed reaction.     

An unusual twist conformation of 2-O-methyl-1,3,4,5-tetrakis-O-tert-butyldiphenylsilyl-myo-inositol

The ring conformation of 2-O-methyl-1,3,4,5-tetrakis-O-tert-butyldiphenylsilyl-myo-inositol was in a twist form both in solid state and in solution. This is the first observation of a stable twist conformer induced by the introduction of bulky silyl protecting groups.     

Cyclodextrin chemistry. Selective modification of all primary hydroxyl groups of α- and β-cyclodextrins

Two efficient methods are described for the selective modification of all six primary hydroxyl groups of α-cyclodextrin (α-CD, 1 1 ). One, using an indirect strategy, involves protection of all 18 hydroxyl functions as benzoate esters, followed by selective deprotection of the six primary alcohol groups. The other, using a direct strategy, involves selective activation of the primary hydroxyl groups via a bulky triphenylphosphonium salt, which is then substituted by azide anion as the reaction proceeds. A number of modified α-cyclodextrin derivatives have been prepared and fully characterized, among which are: the useful intermediate α-cyclodextrin-dodeca (2, 3) benzoate ( 3 ); hexakis (6-amino-6-deoxy)-α-cyclodextrin hexahydrochloride ( 7 ); hexakis (6-amino-6-deoxy)-dodeca (2, 3)-O-methyl-α-cyclodextrin hexahydrochloride ( 9 ), hexa (6)-O-methyl-α-cyclodextrin ( 13 ). The direct substitution is shown to be even more efficient for β-cyclodextrin ( 16 ), giving the heptakis (6-azido-6-deoxy)-β-CD-tetradeca (2, 3)acetate ( 17 ), while the indirect strategy fails. The compounds are characterized by extensive use of ¹³C- and ¹H-NMR. spectroscopy. The steric and statistical problems of selective polysubstitution reactions for the cyclodextrins are discussed, and possible reasons for the observed differences in reactivity between α- and β-cyclodextrins are examined. The dodecabenzoate 3 presents a very marked solvent effect on physical properties (IR. and NMR. spectra, optical rotation); the effects observed may be ascribed to an unusually strong intramolecular network of hydrogen bonds which severely distorts the α-cyclodextrin ring and lowers the symmetry from six-fold to three-fold.     

Solid-phase synthesis of O-sulfated glycopeptide by the benzyl-protected glycan strategy

To expand the repertoire of our benzyl-protection strategy for solid-phase glycopeptide synthesis, an O-sulfated glycopeptide was chosen as the synthetic target. Trisaccharyl serine derivatives (Galβ1-4-GlcNAcβ1-2-Manα1-3-Ser) carrying (4-methoxyphenyl)methyl (MPM) groups at either 3-O or 6-O of the Gal residue were prepared through three stereoselective glycosylations. Cleavage of MPM followed by reaction with Me₃N·SO₃ efficiently afforded 3-O- and 6-O-sulfo-glycoserines, respectively. A preliminary debenzylation study using the sulfated glycoserines revealed that the sulfate groups persisted under ‘low-acidity TfOH’ conditions, when using a limited amount of TfOH and extending the reaction period. The 3-O-sulfo-glycoserine was then introduced into an icosapeptide modeled after an α-dystroglycan fragment by a combination of automated and manual solid-phase peptide synthesis procedures. The synthesized glycopeptide was successfully debenzylated by the low-acidity TfOH cocktail with slight damage to the sulfate functionality.     

Armed-disarmed effect of remote protecting groups on the glycosylation reaction of 2,3-dideoxyglycosyl donors

The armed-disarmed effect of remote protecting groups at the C-4 and/or C-6 position(s) on the glycosylation reactions of 2,3-dideoxyglycosyl donors was investigated. It was found that under various glycosylation conditions, 4- or 6-O-Bn 2,3-dideoxyglycosyl donors were much more reactive than the corresponding 4,6-di-O-Bz 2,3-dideoxyglycosyl donors. Based on these results, an effective and chemoselective glycosylation reaction using 4,6-di-O-Bn glycosyl acetate and 4-OH-6-O-Bz glycosyl acetate was realized, producing a 2,3-dideoxydisaccharide in good yield with high α-stereoselectivity.     

Significant solvent effect in anomerization reaction of pyranosides with 2,3-trans carbamate and carbonate

A pronounced solvent effect was observed in the anomerization reaction of pyranosides carrying 2,3-trans carbamate or carbonate. While significant anomerization from the β- to α-direction was observed in CH₃CN, none was observed in ether.     

Synthesis of three regioisomers of the pentasaccharide part of the Skp1 glycoprotein of Dictyostelium discoideum

Three regioisomers of the linear pentasaccharide part of the Skp1 glycoprotein, found in Dictyostelium discoideum, were prepared in the form of (2-trimethylsilyl)ethyl glycosides by means of 2+3 block syntheses using the disaccharide donor at the non-reducing end, and three different trisaccharide acceptors at the reducing end. Fucosylation of (2-trimethylsilyl)ethyl 3,4,6-tri-O-benzyl-β-d-galactopyranosyl-(1→3)-4,6-O-benzylidene-2-deoxy-2-NPhth-β-d-glucopyranoside with different fucosyl donors carrying an O-(2-naphthyl)methyl ether as a temporary-protecting group at positions C2, C3 or C4 gave rise to the protected core trisaccharides. After selective removal of the (2-naphthyl)methyl group, the resulting acceptors were glycosylated with the α(1→6) linked digalactosyl donor to yield the respective three regioisomeric pentasaccharides. Transformation of the phthalimido moiety into an N-acetyl group, followed by catalytic hydrogenation of the reducible-protecting groups furnished the free target pentasaccharides, which should be able to assist during the elucidation of the exact structure of the natural pentasaccharide.     

Synthese des substances de groupe sanguin—IX: Une synthese du 2-o-(α-l-fucopyranosyl)-3-o-(α-d-galactopyranosyl)-d-galactose,le determinant antigenique du groupe sanguin b

The trisaccharide 2-O-(α-L-fucopyranosyl)-3-O-(α-D-galactopyranosyl)-D-galactose has been synthesised stereospecifically using the imidate procedure. Allyl 3-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside was first α-L-fucosylated by 1-O-(N-methyl)-acetimidyl-2,3,4-tri-O-benzyl-β-L-fucopyranose then, after O-debenzoylation, α-D-galactosylated by 1-O-(N-methyl)-acetimidyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranose. The resulting tri-saccharide has also been obtained from allyl 2-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside after α-D-galactosylation, O-debenzoylation and α-L-fucosylation. The glycosylations were performed at room temperature in nitromethane in the presence of p-toluenesulfonic acid. Deallylation followed by catalytic hydrogenolysis gave the B blood-group antigenic determinant. The allyl group was also selectively transformed into hydroxyethyl group.     

The first synthesis of secondary sugar sulfonic acids by nucleophilic displacement reactions

The 4-deoxy-4-C-sulfonic acid and 6-deoxy-6-C-sulfonic acid derivatives of methyl α-d-gluco- and α-d-galactopyranosides were prepared by triflate-mediated nucleophilic displacement reactions, either with NaHSO₃ or with AcSK. The triflate esters of methyl 2,3,4-tri-O-benzyl- 1, methyl 2,3,6-tri-O-benzyl-α-d-glucopyranoside 9 and methyl 2,3,6-tri-O-benzyl-α-d-galactopyranoside 5 provided methyl 6-deoxy-6-C-sulfo-α-d-glucopyranoside 4, methyl 4-deoxy-4-C-sulfo-α-d-galactopyranoside 12 and α-d-glucopyranoside 8, respectively. The triflate derivative of methyl 2,3,4-tri-O-benzyl-α-d-galactopyranoside 13 gave methyl 3,6-anhydro-2,4-di-O-benzyl-α-d-galactopyranoside 14. Formation of the 3,6-anhydro derivative was prevented by using 3,4-O-isopropylidene acetal protection to obtain methyl 6-deoxy-6-C-sulfo-α-d-galactopyranoside 19. The aim of the research is to replace the sulfate esters by sulfonic acids in the repeating oligosaccharide units of glycosaminoglycans or in different oligosaccharide ligands.     

Synthesis and enantiomeric recognition studies of dialkyl-substituted 18-crown-6 ethers containing an acridine fluorophore unit

Selectivity of the reported dimethyl-substituted (R,R)-1, the diisobutyl-substituted (R,R)-2 acridino-18-crown-6 ethers and the newly synthesized acridino-crown ether (S,S)-3 containing the methyl groups one carbon-carbon bond further away from the acridine unit was studied towards the enantiomers of the hydrogen perchlorate salts of α-phenylethylamine, α-(1-naphthyl)ethylamine, phenylglycine methyl ester and phenylalanine methyl ester using fluorescence.     

Glycosyl azides of sugar 2-sulfonic acids

Phenyl and trityl 2-O-sulfonyl-1-thio-α-d-manno- and β-d-glucopyranosides were reacted with sodium azide to yield 2-S-phenyl or 2-S-trityl-d-gluco- and d-mannopyranosyl azides, respectively. Usually, both anomers were formed in approximately equal amounts and formation of glycals was also observed in some cases. The product distribution of these reactions depends on the nature of the aglycone, the applied reagent and also on the solvent. These results can be rationalised by the intermediacy of episulfonium as well as oxocarbenium ions. Oxidation of the 2-S-trityl-α-d-glucopyranosyl or α-d-mannopyranosyl azides by Oxone^®, gave sodium 2-sulfonato-α-d-gluco- and α-d-mannopyranosyl azides, respectively.     

Synthesis of enantiomerically pure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol present in the liver oil of cartilaginous fish

Synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol 1, the principal methoxylated glyceryl ether found in Nature, is described by a highly convergent five-step process taking place in 27% overall yield. The synthesis is based on an ether bond formation between the chiral synthon (R)-2,3-O-isopropylidene-sn-glycerol and (Z)-(R)-1-chlorohexadec-4-en-2-ol employing ground potassium hydroxide and tetra-n-butylammonium bromide as a catalyst under solvent free conditions.     

Two additional 1,9-diarylnonanoid 3-glucosides from Erica cinerea among which an unusual α-dione in conformational equilibrium

Continuation of the phytochemical analysis of Erica cinerea fresh aerial parts resulted in the isolation of two new compounds with a very close chromatographic behavior. On the basis of spectroscopic evidence (UV, MS and NMR), the structures were established as (−)-(3S,6E)-1,9-bis(p-hydroxyphenyl)-3-hydroxynon-6-en-5-one 3-O-β-d-glucoside named 6,7-anhydroericaone 3-O-β-d-glucoside and (−)-(3S)-1,9-bis(p-hydroxyphenyl)-3-hydroxynonan-5,6-dione 3-O-β-d-glucoside named α-ericadione 3-O-β-d-glucoside. Unanticipated by its α-alkadione type structure —a very unusual feature in the plant kingdom— the latter metabolite was found as a mixture of the minor s-cis and the major s-trans conformers. Moreover, the GC-MS analysis of the aglycone moieties of such glucosides, pointed out the permanent absence of the molecular ion and the constant hydroxybenzylium base peak, as well as the conversion of the α-dione into the major α-keto-enol tautomer.     

Unusual α-glycosylation with galactosyl donors with a C2 ester capable of neighboring group participation

Glycosylation of 4-methoxyphenyl 2,3,6-tri-O-benzoyl-β-d-glucopyranoside (2) with isopropyl 3-O-allyl-2,4,6-tri-O-benzoyl- (9) or 6-O-allyl-2,3,4-tri-O-benzoyl-1-thio-β-d-galactopyranoside (7) as the donor, afforded an α- and β-linked mixture, whereas with isopropyl 3-O-chloroacetyl-2-O-benzoyl-4,6-O-benzylidene- (13) and isopropyl 3-O-allyl-2-O-benzoyl-4,6-O-benzylidene-1-thio-β-d-galactopyranoside (15) as the donor, glycosylation of 2 gave α-linked products only, indicating that 4,6-O-benzylidenation led to α-stereoselectivity in spite of the C2 ester capable of neighboring group participation. Using 15 as the donor, glycosylation of mannose derivatives with 2- or 3-OH's, glucose with 2- or 3-OH's, galactose with 2-, or 3-, or 4-OH's, glucosamine and glucuronic acid with a 4-OH, and a lactose derivative with a 4-OH, also furnished α-linked products. However, when using 15 as the donor, glycosylation of aglycon alcohol or sugars with 6-OH's yielded normal β-linked products.     

Exocyclic vinyl ethers of ketofuranosides

Exocyclic vinyl ether derivatives of sugars are found in biosynthetic pathways and may serve as useful synthetic intermediates. The ketose subfamily of sugars is the least characterized in this field. Thus, the synthesis of exocyclic vinyl ether derivatives of ketohexoses via β-elimination was studied with respect to the nature of the 6-O leaving group and the protection of the 4-hydroxy group. We applied this study to protected l-sorbofuranoside and d-tagatofuranoside sugar derivatives in which the 4-hydroxy group and the 6-O-leaving group are in the syn configuration. Some reactions involving deprotection and reductive rearrangement of the tagatose-derived vinyl ether product were also studied.     

Solvation effects on stereochemistry of reduction of 3,3,5-trimethylcyclohexanone with lithium aluminum tri-t-butoxyhydride

Specific solvation effects on stereoselectivity in the reduction of a cyclohexanone by lithium aluminum tri-t-butoxyhydride have been studied by adding measured quantities of diethyl ether, tetrahydrofuran (THF) and methyl-substituted tetrahydrofurans to benzene solvent, and various amounts of THF to diethyl ether solvent. A steric hindrance effect in the case of bulky addends was observed, and a significant increase in stereoselectivity for less bulky addends was found. The results have been explained in terms of complexing, or steric hindrance to complexing, of the lithium cation.     

Highly diastereoselective synthesis of α-trifluoromethylated α-propargylamines by acetylide addition to chiral CF3-substituted N-tert-butanesulfinyl ketimines

A convenient and practical method for the preparation of enantiomerically pure α-trifluoromethylated α-propargylamines is described. A range of enantiopure α-trifluoromethylated α-propargyl sulfinamides were obtained by the addition of lithium acetylides generated in situ with n-BuLi and terminal alkynes to diverse chiral CF₃-substituted (S)-N-tert-butanesulfinyl ketimines in moderate to excellent yields (56–97%) and with uniformly excellent diastereoselectivities (>99:1) by using Ti(OⁱPr)₄ as the catalyst and THF as the polar solvent. Enantiomerically pure α-trifluoromethylated α,α-dibranched propargyl amines were then readily obtained in excellent yields (87–97%) by acidic cleavage of the tert-butanesulfinyl group.     

Use of Ferric Chloride in Carbohydrate Reactions.1 Iv. Acetolysis of Benzyl Ethers of Sugars

Acetolysis of benzyl ethers of sugars has been carried out with anhydrous ferric chloride in acetic anhydride. By employing this reagent, benzyl ether groups variously placed in sugars or in their glycosides could be removed with ease and replaced by acetyl groups. By controlled acetolysis, preferential removal of certain benzyl groups was possible. The results show that in D-glucose the relative ease of removal of benzyl ether groups by acetolysis follows the order C-6 > C-4 > C-3 > C-2 and that the rate of acetolysis is 6-O-Bn : 3-O-Bn : 2-O-Bn = 125 : 24 : 1. The corresponding methyl ethers were very sluggish towards acetolysis.     

Synthesis of anomerically pure vinyl sulfone-modified pent-2-enofuranosides and hex-2-enopyranosides: a group of highly reactive Michael acceptors for accessing carbohydrate based synthons

Syntheses of the benzyl or the trityl protected α- and β-anomers of vinyl sulfone-modified pent-2-enofuranosides have been initiated by the ring opening of the suitably masked methyl α-lyxofuranosyl-epoxide or methyl β-ribofuranosyl-epoxide or by the nucleophilic displacement of the leaving groups in benzyl protected 3-O-tosyl xylofuranoside and 3-O-mesyl ribofuranoside by p-thiocresol. In case of the latter set of starting materials, α- and β-methyl glycosides formed in almost equal ratio only from the derivatives of d-xylose. For the synthesis of α- and β-anomers of vinyl sulfone-modified hex-2-enopyranosides, a d-glucose derivative was selected over a d-allose derivative as the starting material because the former almost exclusively produced the required methyl pyranosides whereas the latter produced a mixture. All sulfides were converted to vinyl sulfone-modified carbohydrates by the sequential application of oxidation, mesylation and base induced elimination reactions.     

Stereoselective synthesis of 1,2-cis galactosides: synthesis of a glycolipid containing Galα1-6Gal component from Zygomycetes species

An α-selective galactosylation was demonstrated under various conditions. Among these α-galactoside approaches, high α-selectivity was achieved by the virtue of 4,6-O-di-tert-butylsilylene (DTBS) group. Yield was further improved by the influence of a 2-O-benzylated donor compared to 2-O-benzoylated donor. This method was then applied to the first highly stereoselective synthesis of a newly found trisaccharide glycosphingolipid in Zygomycetes species.