Studies on the stereoselective synthesis of a protected α-d-Gal-(1→2)-d-Glc fragment

A novel 1,2-cis stereoselective synthesis of protected α-d-Gal-(1→2)-d-Glc fragments was developed. Methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (13), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-α-d-glucopyranoside (15), methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside (17), and methyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-α-d-galactopyranosyl-(1→2)-3,4,6-tri-O-benzoyl-β-d-glucopyranoside (19) were favorably obtained by coupling a new donor, isopropyl 2-O-acetyl-3-O-allyl-4,6-O-benzylidene-1-thio-β-d-galactopyranoside (2), with acceptors, methyl 3-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (4), methyl 3,4,6-tri-O-benzoyl-α-d-glucopyranoside (5), methyl 3-O-benzoyl-4,6-O-benzylidene-β-d-glucopyranoside (8), and methyl 3,4,6-tri-O-benzoyl-β-d-glucopyranoside (12), respectively. By virtue of the concerted 1,2-cis α-directing action induced by the 3-O-allyl and 4,6-O-benzylidene groups in donor 2 with a C-2 acetyl group capable of neighboring-group participation, the couplings were achieved with a high degree of α selectivity. In particular, higher α/β stereoselective galactosylation (5.0:1.0) was noted in the case of the coupling of donor 2 with acceptor 12 having a β-CH₃ at C-1 and benzoyl groups at C-4 and C-6.     

Studies on Phenolic Lactones

The synergistic action of phenolic lactones on allethrin and pyrethrin were investigated from the mortality of synergized pyrethroids against rice-weevil by petri-dish method.

In the series of α-benzylidene-γ-butyrolactones, (±) hibalactone and α-piperonylidenebutyrolactone were appreciably sy~ergistic on allethrin although less effective than piperonyl butoxide. (±) Hinokinin, 2-piperonylidene-3-piperonyl-l,4-butanediol also showed week activation, but α-benzylidene-, α-anisylidene-, α-veratrylidene-butyrolactone, α-piperonylidenea-α’-piperonyl-tetrahydrofuran, α-trirnethoxybenzylidene-β-trimethoxybenzyl-butyrolactone were not synergistic on the insecticidal action.

In the series of synergized pyrethrin, (±) hibalactone and α-piperonylidene-butyrolactone showed week synergism but the other test compounds showed no appreciable synergism.     

Novel synthesis of methyl 4,6-O-benzylidenespiro[2-deoxy-α-d-arabino-hexopyranoside-2,2′-imidazolidine] and its homologue and sugar-γ-butyrolactam derivatives from methyl 4,6-O-benzylidene-α-d-arabino-hexopyranosid-2-ulose

Novel methyl 4,6-O-benzylidenespiro[2-deoxy-α-d-arabino-hexopyranoside-2,2′-imidazolidine] and its homologue methyl 4,6-O-benzylidene-3′,4′,5′,6′-tetrahydro-1′H-spiro[2-deoxy-α-d-arabino-hexopyranoside-2,2′-pyrimidine] have been synthesized in good yields by reaction of methyl 4,6-O-benzylidene-α-d-arabino-hexopyranosid-2-ulose with 1,2-diaminoethane and 1,3-diaminopropane. The results are completely different from the reaction with arylamines or alkylamines. One-pot synthesis of novel (E)-methyl 4-[hydroxy (methoxy)methylene]-5-oxo-1-alkyl-(4,6-O-benzylidene-2-deoxy-α-d-glucopyranosido)[3,2-b]pyrrolidines has been achieved by the reaction of alkylamines with the butenolide-containing sugar, derived from the aldol condensation of methyl 4,6-O-benzylidene-α-d-arabino-hexopyranosid-2-ulose with diethyl malonate. These sugar-γ-butyrolactam derivatives are potential GABA receptor ligands.     

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.     

Studies on the structure of a polysaccharide from Epidermophyton floccosum and approach to a synthesis of the basic trisaccharide repeating units

An alkali-soluble polysaccharide, designated as S-Iawe, has been isolated from the maycelia of Epidermophyton floccosum. Methylation, periodate oxidation, and acetolysis studies suggested that S-lawe is composed of (1→6)-Oα-d-mannopyranosyl-(1→6)-O-[α-d-mannopyranosyl-(1→2)]-O-α-d-mannopyranosyl repeating units. Condensation of 2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl bromide with methyl 3-O-benzyl-4,6-O-benzylidene-α-d-mannopyranoside in the presence of mercuric cyanide gave in 70% yield methyl 3-O-benzyl-4,6-O-benzylidene-2-O-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-α-d-mannopyranoside. Condensation of the debenzylidenated disaccharide with 2,3,4,6-tetra-O-acctyl-α-d-mannopyranosyl bromide afforded the corresponding trisaccharide repeating unit.     

Reaktionen von kohlenhydraten mit dichlormethylendimethylammoniumchlorid: ein neuer weg zu 2-chlor-2-desoxy-, und 3-chlor-3-desoxyhexose-, und 3-chlor-3-desoxypentosederivaten

Treatment of methyl 4,6-O-benzylidene-α-D-mannopyranoside with dichloromethylenedimethylammonium chloride gave methyl 4,6-O-benzylidene-3-chloro-3-deoxy-2-(N,N-dimethylcarbamoyl)-α-D-altropyranoside and methyl 4,6-O-benzy]idene-2-chloro-2-deoxy-3-(N,N-dimethylcarbamoyl)-α-D-glucopyranoside. Methyl 4,6-O-benzylidene-α-D-allopyranoside gave under analogous conditions the corresponding 2-chloro-3-(N,N-dimethylcarbamoyl)-α-D-altrose and 3-chloro-2-(N,N-dimethylcarbamoyl)-α-D-glucose derivatives. Methyl 5-O-benzyl-α,β-D-ribofuranoside and methyl 5-O-methyl-β-D-ribofuranoside gave only the corresponding methyl 3-chloro-2-(N,N-dimethylcarbamoyl)-α-D-xylofuranoside derivatives.     

The synthesis and degradation of benzyl 4,6-O-benzylidene-2,3-dideoxy-3-C-ethyl-2-C-hydroxymethyl-α-d-glucopyranoside and -mannopyranoside

The use of carbohydrates for establishing, by synthesis, the absolute configuration of branched aliphatic alcohols is demonstrated by the synthesis and degradation of carbohydrate derivatives that contain two branch points. Benzyl 4,6-O-benzylidene-2,3-dideoxy-3-C-ethyl-2-C-hydroxymethyl-α-d-glucopyranoside (23) and -mannopyranoside (24) were formed from benzyl 2,3-anhydro-4,6-O-benzylidene-α-d-mannopyranoside (17) by a reaction sequence that involved ring-opening with ethylmagnesium chloride, oxidation, epimerisation, methylenation, and hydroboronation. The gluco isomer 23 was converted into (+)-(R)-2,3-bisacetoxymethylpentyl acetate (1) by sequential hydrogenolysis, borohydride reduction, periodate oxidation, borohydride reduction, and acetylation. The synthesis of 1 provides confirmatory evidence for the absolute configuration of the alkaloid pilocarpine (2). Unidentified products, and not the expected free-sugars, were obtained by acidic hydrolysis of methyl 4,6-O-benzylidene-2,3-dideoxy-3-C-ethyl-2-C-hydroxymethyl-α-d-glucopyranoside (8) and -mannopyranoside (9). Convenient syntheses of benzyl α-d-glucopyranoside derivatives are described.     

Synthèse de trithioorthocarbonates de pyranosides par thermolyse de bis(dithiocarbonates)

The thermal decomposition of methyl 4,6-O-benzylidene-2,3-di-O-[(methylthio)-thiocarbonyl]-α-d-glucopyranoside afforded methyl 4,6-O-benzylidene-2-thio-α-d-mannopyranoside 3-O,2-S-(S,S-dimethyl trithioorthocarbonate) and methyl 4,6-O-benzylidene-3-thio-α-d-allopyranoside 2-O,3-S-(S,S-dimethyl trithioorthocarbonate) in good yield. This decomposition can be generalized to 1,3-diols derived from sugars. Thus methyl 2,3-di-O-methyl-4,6-di-O-[(methylthio)thiocarbonyl]-α-d-glucopyranoside afforded in the same way the corresponding trithioorthocarbonates, following a regioselective process. The structures of these trithioorthocarbonates are confirmed by spectral and chemical proofs.     

Synthesis of 8-(hydroxyalkyl)adenines

Treatment of methyl 4,6-O-benzylidene-2-O-p-tolylsulfonyl-α-D-ribo-hexopyranosid-3-ulose (1) with triethylamine-methanol at reflux temperature yields methyl 2,3-anhydro-4,6-O-benzylidene-3-methoxy-α-D-allopyranoside (2), a derivative (3) of 3-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one, and methyl 4,6-O-benzylidene-α-D-ribo-hexopyranosid-3-ulose dimethyl acetal (4). The reaction of methyl 4,6-O benzylidene-3-O-p-tolylsulfonyl-α-D-arabino-hexopyranosid-2-ulose (12) with triethylamine-methanol afforded methyl 4,6-O-benzylidene-α-D-ribo-hexopyranosid-2-ulose dimethyl acetal (19) and methyl 2,3-anhydro-4,6-O-benzylidene-2-methoxy-α-D-allopyranoside (20); from the reaction of the β-D anomer (13) of 12, methyl 4,6-O-benzylidene-β-D-ribo-hexopyranosid-2-ulose dimethyl acetal (21) was isolated. Syntheses of the α-keto toluene-p-sulfonates 12 and 13 are described. Mechanisms for the formation of the compounds isolated from the reactions with triethylamine-methanol are proposed.     

Galactan sulfate from the test of tunicates

Methyl and benzyl 3-O-β-d-xylopyranosyl-α-d-mannopyranoside were prepared by way of d-xylosylation (Koenigs-Knorr) of methyl and benzyl 4,6-O-benzylidene-α-d-mannopyranoside (1 and 17). Analogous 2-O-β-d-xylopyranosyl-α-d-mannopyranosides could not be prepared efficiently by this procedure. However, methyl and benzyl 3-O-acetyl-4,6-O-benzylidene-α-d-mannopyranoside, prepared by limited acetylation of 1 and 17, respectively, could be d-xylosylated by the same method, and afforded, after removal of protective groups, methyl and benzyl 2-O-β-d-xylopyranosyl-α-d-mannopyranoside. Hydrogenolysis of benzyl 2-O- and 3-O-β-d-xylopyranosyl-α-d-mannopyranoside yielded the corresponding, reducing disaccharides. In addition to these disaccharides, disaccharides containing an α-d-xylopyranosyl group, and trisaccharides having d-xylopyranosyl groups at both O-2 and O-3 were obtained as minor products.     

Configurational assignments of C-nitromethyl-C-hydroxy branched-chain carbohydrate derivatives by use of a europium shift-reagent in 1 H-N.M.R. spectroscopy

Configurational assignments for the tertiary alcoholic centers of four branched-chain 3-C-nitromethylglycopyranosides, namely, methyl 2-benzamido-4,6-O-benzylidene-2-deoxy-3-C-nitromethyl-α-D-allopyranoside (1), benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-C-nitromethyl-α-D-glucopyranoside (4), benzyl 2-acetamido-4,6-O-benzylidene-2-deoxy-3-C-nitromethyl-α-D-allopyranoside (5), and methyl 4,6-O-benzylidene-3-C-nitromethyl-2-O-p-tolylsulfonyl-α-D-glucopyranoside (8), were made on the basis of the downfield chemical shifts of their identifiable protons per molar equivalent of added Eu(fod)₃, as compared with those of model compounds, of known configuration, having a close structural relationship. In some cases, the assignments were corroborated by the position of the acetyl resonances in the unshifted 60-MHz p.m.r. spectra of the corresponding O-acetyl derivatives.     

Preparation of O-Aminoacyl Sugars as Enzymatically Removable Protections for Hydroxyl Groups in Carbohydrates

To confirm the potential usefulness of amino acid residues as the protecting group of sugar hydroxyls, N-(benzyloxycarbonyl) and N-(t-butoxycarbonyl) amino acids were condensed with methyl 4,6-O-benzylidene-α-d-glucopyranoside (1) and methyl 2,3-di-O-methyl-α-d-glucopyranoside (2), and the conditions were studied for the removal of aminoacyl groups from sugar moieties. The aminoacyl groups were easily removed by enzymatic hydrolysis using pronase E, trypsin and chymotrypsin, as well as alkaline treatment as with conventional acyls. We determined the utility of aminoacyl sugars as new protecting groups having some useful characteristics which never exist in normal circumstances.     

Synthesis and cytotoxic evaluation of halogenated α-exo-methylene-lactones

α-exo-Methylene-γ-butyrolactones and α-exo-methylene-δ-valerolactones constitute an important group of natural and bioactive products. A simple and general protocol of halolactonization of dienoic acids to obtain various α-exo-methylene-lactones in excellent yields is described. The resulting halogenated α-exo-methylene-lactones were found to exhibit potent cytotoxic activities.     

The synthesis of 3-amino-3-deoxy-α-d-glucopyranosyl α-d-glucopyranoside (3-amino-3-deoxy-α,α-trehalose

The preparation of 2,3-di-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranosyl-2-O-benzoyl-4,6-O-benzylidene-α-d-ribo-hexopyranosid-3-ulose (3) from 4,6:4′,6′-di-O-benzylidene-α,α-trehalose (1) via the 2,3,2′-tribenzoate 2 has been improved. Reduction of 3 with sodium borohydride gave 2-O-benzoyl-4,6-O-benzylidene-α-d-allopyranosyl 2,3-di-O-benzoyl-4,6-O-benzylidene-α-d-glucopyranoside (4), which was converted into the methanesulfonate 5 and trifluoromethanesulfonate 6. Displacement of the sulfonic ester group in 6 with lithium azide was very facile and afforded a high yield of 3-azido-2-O-benzoyl-4,6-O-benzylidene-3-deoxy-α-d-glucopyranosyl 2,3-di-O-benzoyl-4,6-O-benzylidene-α-d-glycopyranoside (7), whereas similar displacement in 5 proceeded sluggishly, giving a lower yield of 7 together with an unsaturated disaccharide (8). The azido sugar 7 was converted by conventional reactions into the analogous 2,3,2′-triacetate 9, the corresponding 2,3,2′-triol 10, and deprotected 3-azido-3-deoxy-α-d-glucopyranosyl α-d-glucopyranoside (11). Hydrogenation of 11 over Adams' catalyst furnished crystalline 3-amino-3-deoxy-α,α-trehalose hydrochloride (12), the overall yield from 3 being 35%.     

Synthesis of the allo-analogue of trehalose

Selective benzoylation of HO-2 and HO-2′ of 4,6-O-benzylidene-α-D-glucopyranosyl 4,6-O-benzylidene-α-D-glucopyranoside with N-benzoylimidazole led to the exclusive formation of 2-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranosyl 2-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside. Oxidation of either the dibenzoate or the corresponding ditosylate with methyl sulphoxide-phosphorus pentaoxide gave the 3,3′-diulose, and subsequent reduction with borohydride gave the 3,3′diepimers having the allo-allo configuration. De-esterification and hydrolysis of the benzylidene substituents gave α-D-allopyranosyl α-D-allopyranoside.     

Synthese der “repeating unit” der O-spezifischen kette des lipopolysaccharides aus Aeromonas salmonicida

8-Methoxycarbonyloctyl 2-azido-4,6-O-benzylidene-2-deoxy-β-d-mannopyranoside reacted with 2,3,4-tri-O-acetyl-α-l-rhamnopyranosyl bromide to give a disaccharide from the which the glycosyl-acceptor 8-methoxycarbonyloctyl 2-azido-4,6-O-benzylidene-2-deoxy-3-O-(2,4,-di-O-acetyl-α-l-rhamnopyranosyl)-β-d-manno pyranoside (19) was obtained. This glycosyl-acceptor with 2,3,4,6-tetra-O-benzyl-α-d-glucopyranosyl chloride to give trisaccharide derivative 22 and with 2,3,6-tri-O-(α-²H₂)benzyl-4-O-(2,3,4,6-tetra-O-(α-²H₂)benzyl-α-d-glucopyranosyl)-α-d-glucopyranosyl chloride to give tetrasaccharide derivative 29. Deblocking of 22 yielded 8-methoxycarbonyloctyl O-(α-d-glucopyranosyl)-(1→3)-O-α-l-rhamnopyranosyl-(1→3)-2-acetamido-2-deoxy-β-d-mannopyranoside and deblocking of 29 8-methoxycarbonyloctyle O-α-d-glucopyranosyl-(1→4)-O-α-d-glucopyranosyl-(1→3)-O-α-l-rhamnopyranosyl- (1→3)-2-acetamido-2-deoxy-β-d-mannopyranoside. Both oligosaccharides represent the “repeating unit” of the O-specific chain of the lipopolysaccharide from Aeromonas salmonicida.     

Synthesis and 13C-N.M.R. spectroscopy of 2-O- and 6-O-acetyl-3-O-α-l-rhamnopyranosyl-d-galactose,constituents of bacterial cell-wall polysaccharides

Benzyl 2-O-acetyl-4,6-O-benzylidene-3-O-(2,3,4-tri-O-acetyl-α-l-rhamnopyranosyl)-β-d-galactopyranoside (11) has been synthesised by two routes. Partial deacetylation of 11 and then acid hydrolysis yielded benzyl 2-O-acetyl-3-O-α-l-rhamnopyranosyl-β-d-galactopyranoside, catalytic hydrogenolysis of which gave the first title compound in excellent yield. Benzyl 4,6-O-benzylidene-3-O-α-l-rhamnopyranosyl-β-d-galactopyranoside was benzylated, and hydrogenolysis (LiAlH₄-AlCl₃) of the product gave the disaccharide derivative 16 with only HO-6 unsubstituted. Acetylation of 16 followed by catalytic hydrogenolysis gave the crystalline, second title compound. As model compounds for comparative n.m.r. studies, 2-O-, 3-O-, and 6-O-acetyl-d-galactose were also synthesised.     

Synthesis of a Spacer-Linked Derivative of Heptopyranosyl(α1-3)heptopyranose Expressed in Lipooligosaccharide and Lipopolysaccharide

Glycosylation of penta-O-acetyl heptopyranosyl trichloroacetimidate with the 3-OH acceptor, methyl 2-O-benzyl-4,6-O-benzylidene-7,8-dideoxy-α-D-manno-oct-7-enopyranoside, gave the desired α1-3-linked disaccharide in a 94% yield. The oct-enopyranoside moiety of the disaccharide was converted to the heptoside by oxidative cleavage with osmium tetroxide/NaIO₄ and subsequent reduction with NaBH₄. The resulting α1-3-linked heptose disaccharide was converted to a tricholoroacetaimidate derivative containing a benzoyl group at C-2. This donor was glycosylated with 2-(carbobenzoxyamino)-1-ethanol to give an α spacer-linked disaccharide derivative in a 90% yield. Zemplén deacylation of the derivative and subsequent hydrogenolysis gave a 2-aminoethyl glycoside of heptopyranosyl(α1-3)heptopyranose.     

Desulfonyloxylations of some secondary p-toluenesulfonates of glycosides by lithium triethylborohydride; a high-yielding route to 2- and 3-deoxy sugars

Lithium triethylborohydride (LTBH) reacts readily with p-toluenesulfonates of methyl 4,6-O-benzylidene-α-d-glucopyranoside (4) to give deoxyglycosides in > 90% yield. Thus, the 2,3-ditosylate (1) and the 3-monotosylate (2) thereof afford methyl 4,6-O-benzylidene-2-deoxy-α-d-ribo-hexopyranoside (7) in highly regio- and stereo-selective reactions that proceed via methyl 2,3-anhydro-4,6-O-benzylidene-α-d-allopyranoside (6), and the 2-monotosylate (8) of 4 gives the 3-deoxy-α-d-arabino isomer (12) of 7via the corresponding 2,3-anhydro-α-d-mannopyranoside 11. In the series of the corresponding β anomers, the 3-monotosylate 14 and the 2-monotosylate 16 are similarly desulfonyloxylated, with equal ease, but furnish mixtures of regioisomeric deoxyglycosides, namely, the 3- and 2-deoxy-β-d-ribo derivatives 20 and 21, and 2- and 3-deoxy-β-d-arabino derivatives 22 and 23, respectively. It could be shown that this difference is due to the failure of the intermediary, β-glycosidic epoxides 18 and 19 (the anomers of 6 and 11) to obey the Fürst-Plattner rule in their reductive ring-opening with LTBH. The β-glycosidic 2,3-ditosylate 15 reacts less readily, and gives 20–23, with 20 preponderating. The 2-O-methyl-3-O-tosyl-β-d-glucopyranoside 24 is partly desulfonylated and partly desulfonyloxylated, whereas its 3-O-methyl-2-O-tosyl isomer 27 undergoes desulfonylation exclusively. The reductions of 1, 2, and 8 by LTBH are compared with those previously effected by lithium aluminum hydride, which are slower, involve considerable desulfonylation, and afford lower yields of deoxyglycosides, with the main products differing from those obtained by the action of LTBH. Mechanistic differences associated with the two reductants are discussed.     

Synthèse des l-fucose et l-(3-2H)fucose à partir du d-mannose

Oxidation with the dimethyl sulfoxide-acetic anhydride reagent of methyl 2-O-acetyl-4,6-O-benzylidene-α-d-mannopyranoside, obtained in quantitative yield from the corresponding 4,6-benzylidene acetal by stereoselective opening of a 2,3-orthoester, led in good yield to methyl 2-O-acetyl-4,6-O-benzylidene-α-d-arabino-hexopyranosid-3-ulose, which was reduced with either sodium borohydride or sodium borodeuteride into a methyl 4,6-O-benzylidene-α-d-altropyranoside or its 3-²H derivative. A sequence involving a C-6 halogenation-dehydrohalogenation followed by catalytic hydrogenation of the resulting methyl 6-deoxy-α-d-arabino-hex-5-enopyranoside gave methyl 6-deoxy-β-l-galactopyranoside (methyl β-l-fucopyranoside) and then α-l-fucose, with an overall yield of 24% with respect to the starting methyl α-d-mannopyranoside.