An approach to the synthesis of branched-chain amino sugars from c-methylene sugars

The reaction of 1,2:5,6-di-O-isopropylidene-3-C-methylene-α-D-ribo-hexofuranose (4) with mercuric azide in hot 50% aqueous tetrahydrofuran yielded, after reductive demercuration, 3-azido-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-methyl-α-D-glucofuranose (5). Partial, acid hydrolysis of5 afforded the diol7, which gave 3-azido-3-deoxy-1,2-O-isopropylidene-5,6-di-O-methanesulphonyl-3-C-methyl-α-D-glucofuranose (8) on sulphonylation. On hydrogenation over a platinum catalyst and N-acetylation, the dimethanesulphonate 8 furnished 3,6-acetylepimino-3,6-dideoxy-1,2-O-isopropylidene-5-O-methanesulphonyl-3-C-methyl-α-D-glucofuranose (9), which was also prepared by an analogous sequence of reactions on 3-azido-3-deoxy-1,2-O-isopropylidene-5-O-methanesulphonyl-3-C-methyl-6-O-toluene-p-sulphonyl-α-D-glucofuranose (13). The formation of the N-acetylepimine 9 establishes the D-gluco configuration for 5.1,2-O-Isopropylidene-3-C-methylene-α-D-ribo-hexofuranose (20) reacted with mercuric azide in aqueous tetrahydrofuran at ≈85° to give 3,6-anhydro-1,2-O-isopropylidene-3-C-methyl-α-D-glucofuranose (22) as a result of intramolecular participation by the C-6 hydroxyl group in the initial intermediate.     

The synthesis of 5-O-(2-acetamido-2-deoxy-α-D-glucopyranosyl)-β-D-glucofuranose

Condensation of dimeric 3,4,6-tri-O-acetyl-2-deoxy-2-nitroso-α-D-glucopyranosyl chloride (1) with 1,2-O-isopropylidene-α-D-glucofuranurono-6,3-lactone (2) gave 1,2-O-isopropylidene-5-O-(3,4,6-tri-O-acetyl-2-deoxy-2-hydroxyimino-α-D-arabino-hexopyranosyl)-α-D-glucofuranurono-6,3-lactone (3). Benzoylation of the hydroxyimino group with benzoyl cyanide in acetonitrile gave 1,2-O-isopropylidene-5-O-(3,4,6-tri-O-acetyl-2-benzoyloxyimino-2-deoxy-α-D-arabino-hexopyranosyl)-α-D-glucofuranurono-6,3-lactone (4). Compound 4 was reduced with borane in tetrahydrofuran, yielding 5-O-(2-amino-2-deoxy-α-D-glucopyranosyl)-1,2-O-isopropylidene-α-D-glucofuranose (5), which was isolated as the crystalline N-acetyl derivative (6). After removal of the isopropylidene acetal, the pure, crystalline title compound (10) was obtained.     

Chain elongation of sugars with ethyl isocyanoacetate

Addition of ethyl isocyanoacetate to 3-O-benzyl-1,2-O-isopropylidene-α-D-ribo-pentodialdo-1,4-furanose in ethanolic sodium cyanide gave two oxazolines that were hydrolysed during chromatography to two isomeric ethyl 3-O-benzyl-6-deoxy-6-formamido-1,2-O-isopropylidene-heptofuranuronates. Similarly, 1,2-O-isopropyl-idene-3-O-methyl-α-D-xylo-pentodialdo-1,4-furanose gave the 3-O-methyl-heptofuranuronates 7 and 11. Reduction of 7 and 11 gave N-methylamino esters that exhibited Cotton effects from which the configurations at C-6 of 7 and 11 were deduced. The chiralities at C-5 of 7 and 11 were established by tetrahydropyranlation of 7 and 11, followed by consecutive treatment with bis(2-methoxyethoxy)aluminium hydride, periodate, sodium borohydride, and dilute acid, to give 1,2-O-isopropylidene-3-O-methyl-α-D-glucofuranose and its β-L-ido epimer, respectively. Attempts to methylate HO-5 of 7 and 11 resulted in elimination. On formylaminomethylenation (ethyl isocyanoacetate and potassium hydride in tetrahydrofuran), 3-O-benzyl-1,2-O-isopropylidene-α-D-ribo-pentodialdo-1,4-furanose and its 3-O-methyl-α-D-xylo epimer each gave (E)- and (Z)-mixtures of alkenes that were hydrogenated to give mixtures of 5,6-dideoxy-6-formamido-heptofuranuronates.     

The synthesis of new deoxynitroinositols by cyclization of 6-deoxy-3-O-methyl-6-nitro-d-allose and -l-talose

6-Deoxy-3-O-methyl-6-nitro-d-allose (5) and -l-talose (6) were synthesized from 1,2-O-isopropylidene-3O-methyl-α-d-allofuranose (1) by the nitromethane method via their furanoid, 1,2-O-isopropylidene derivatives (2 and 3). The barium hydroxide-catalyzed cyclization of the free nitrohexoses (5 and 6) was investigated. Under conditions favoring kinetic control (pH ～8, 0°), 5 gave mainly 1d-5-deoxy-2-O-methyl-5-nitro-allo-inositol (7), with the 1l-epi-1 (8) and epi-6 (9) stereoisomers as minor products. Compound 6 afforded a high yield of the myo-5-isomer (11); the 1l-allo-5 (13) and 1d-epi-1 (14) isomers were formed in small proportions but not isolated. The thermodynamically controlled, mutual interconversion of the stereoisomeric products was studied, as was the formation of nitronate salts and the regeneration of free nitroinositols. Upon immediate acidification, the nitronate obtained from 11 gave 11 and the neo-2 epimer (12) in a ratio of 2:3. The nitronate produced by 7 underwent rapid β-epimerization. The five isolated deoxynitroinositol monomethyl ethers were further characterized as tetra-acetates (7a, 9a, 11a, and 12a) and isopropylidene derivatives (7b, 8b, and 9b).     

C-4′-Branched-chain sugar nucleosides: synthesis of isomers of psicofuranine

Photoamidation of 3-O-acetyl-1,2:5,6-di-O-isopropylidene-α-d-erythro-hex-3-enofuranose (1) afforded 3-O-acetyl-4-C-carbamoyl-1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2) and 3-O-acetyl-3-C-carbamoyl-1,2:5,6-di-O-isopropylidene-d-α-allofuranose (3) in 65 and 26% yields, respectively (based on consumed1). Treatment of2 with 5% hydrochloric acid in methanol yielded the spiro lactone5, which was deacetylated to yield7. Reduction of5 with sodium borohydride afforded 4-C-(hydroxymethyl)-1,2-O-isopropylidene-α-d-gulofuranose (9) in 79% yield. Oxidation of9 with sodium metaperiodate afforded a dialdose that was reduced with sodium borohydride to give 4-C-(hydroxymethyl)-1,2-O-isopropylidene-α-d-erythro-pentofuranose (11) in 88% yield. Treatment of the acetate12, derived from11, with trifluoroacetic acid, followed by acetylation, afforded the branched-chain sugar acetate14. Condensation of the glycosyl halide derived from14 withN⁶-benzoyl-N⁶, 9-bis-(trimethylsilyl)adenine yielded an equimolar anomeric mixture of protected nucleosides15 and16 in 40% yield. Treatment of the latter compounds with sodium methoxide in methanol afforded 9-[4-C-(hydroxymethyl)-β-d-erythro-pentofuranosyl]-adenine (17) and the α-d anomer18. The structure of3 was determined by correlation with the known 5,3′-hemiacetal of 3-C-(hydroxymethyl)-1,2-O-isopropylidene-α,α′-d-ribo-pentodialdose (25).     

Synthesis of 3-O Substituted D-Mannoses

1,2,4,6-Tetra-O-acetyl-3-O-benzyl-α-D-mannopyranose (7) was obtained in good yield from 3,4,6-tri-O-benzyl-1,2-O-(1-methoxyethylidene)-β-D-mannopyranose (1) by acetolysis. Hydrogenolysis of 7 afforded 1,2,4,6-tetra-O-acetyl-α-D-mannopyranose which is a versatile intermediate for the preparation of other 3-O-substituted D-mannoses, such as 3-O-methyl-D-mannose and 3-O-α-D-mannopyranosyl-D-mannose. 3,4-Di-O-methyl-D-mannose was readily prepared from 1,2,6-tri-O-acetyl-3,4-di-O-benzyl-α-D-mannopyranose, which was also obtained from 1 by controlled acetolysis.     

6-thio- and -seleno-D-galactose esters of dimethylarsinous acid

The syntheses of 1,2:3,4-di-O-isopropylidene-6-S-dimethylarsino-6-thio-α-D-galactopyranose (2), methyl 6-S-dimethylarsino-6-thio-D-galactopyranoside (3), and 1,2:3,4-di-O-isopropylidene-6-Se-dimethylarsino-6-seleno-α-D-galactopyranose (8) are reported. The attempted preparation of 6-Se-dimethylarsino-6-seleno-D-galactopyranose (9) is also discussed. The n.m.r. spectra of these compounds are unexceptional, except for the slight downfield shift of the arsenic methyl resonances for the selenium compound as compared to the sulfur compound, confirming previous observations. The mass spectra of these compounds showed molecular ions for 2, 3, and 8. The u.v. spectra of the X-As (X = S, Se) chromophore are discussed in terms of a simplified MO model. 1,2:3,4-Di-O-isopropylidene-6-S-dimethylarsino-6-thio-α-D-galactopyranose (2) showed carcinostatic activity in the P388 system (mouse lymphocytic leukemia).     

6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases

6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli PNP. The prototype MeP releasing prodrug, 9-(β-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction with E. coli PNP. In this work, we report on the synthesis of 9-(6-deoxy-β-d-allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-β-d-ribo-hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl-α-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C-methyl-β-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O-isopropylidine-α-d-glucofuranose in 9 and 11 steps, respectively. Coupling of 10 and 15 with silylated 6-methylpurine under Vorbrüggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5′-C-methylated-6-methylpurine nucleosides 3 and 4, respectively. Unlike 9-(6-deoxy-α-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity with E. coli PNP mutant (M64V), the β-d-allo-furanosyl derivative 3 and the 5′-di-C-methyl derivative 4 were poor substrates for all tested glycosidic bond cleavage enzymes.     

The cyclization of 3-O-benzyl-6-deoxy-6-nitro-D-glucose and -L-idose to O-benzyldeoxynitroinositols,and epimerizations related thereto

3-O-Benzyl-1,2-O-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose (1) was found to give, with nitromethane under catalysis by sodium methoxide, 3-O-benzyl-6-deoxy-1,2-O-isopropylidene-6-nitro- α-D-glucofuranose (2) as the kinetically favored product. Subsequent, spontaneous epimerization led to a 2:1 mixture of 2 and its β-L-ido isomer (3), from which crystalline 3 was isolated. The free nitro hexoses (4 and 5) obtained by deacetonation of 2 and 3 were subjected to barium hydroxide-catalyzed cyclization (internal Henry reaction) to give mixtures of O-benzyldeoxynitroinositols. Under conditions of kinetic control, the α-D-gluco derivative 4 furnished 6-O-benzyl-3-deoxy-3-nitro-muco-inositol (6) and optically active 4-O-benzyl-1-deoxy-1-nitro-L-myo-inositol (L-7) in a ratio of 3:1. The β-L-ido derivative 5 gave the enantiomer (D-7) of the myo compound and 4-O-benzyl-1-deoxy-1-nitro-scyllo-inositol (8) in a similar ratio. Slow, thermodynamically controlled epimerization led from each individual nitro inositol to mixtures of the same composition, with 17–18% of 6, 68–69% of DL-7, and 11–12% of 8. All of the nitroinositol benzyl ethers were isolated crystalline and characterized further as crystalline tetraacetates (6a–8a). The muco isomer 6 gave a di-O-isopropylidene derivative (6b).     

Synthesis of a 6-c-nitro-d-glucopyranose derivative having phosphorus in the hemiacetal ring

5,6-Dideoxy-6-C-nitro-5-(phenylphosphino)-d-glucopyranose was prepared by addition of phenylphosphine to 3-O-acetyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-α-d-xylo-hex-5-enofuranose, followed by hydrolysis of the resulting 3-O-acetyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-(phenylphosphino)-d-glucofuranose (10). Acetylation of 10 gave the crystalline 1,2,3,4-tetraacetate (16). 5,6-Dideoxy-6-C-nitro-5-(phenylphosphinyl)-d-glucopyranose (15) was obtained by oxidation of 10, and hydrolysis of the resulting 5-phenylphosphinyl compound. Acetylation of 15 gave the 1,2,3,4-tetraacetate (17). Although the n.m.r. spectrum of 17 was complex, the n.m.r. spectrum of 16 was rather simple. The n.m.r. data showed that 16 is the α anomer in the ⁴C₁(d) conformation.     

Routes to higher-carbon sugar derivatives having keto-acetylenic and -alkenic,and α,β-unsaturated aldehyde functionality

Oxidative dimerization of 7,8-dideoxy-1,2:3,4-di-O-isopropylidene-d-glycero-α-d-galacto-oct-7-ynopyranoside (1) gave a high yield of the diyne 2, readily reduced by lithium aluminum hydride to the trans,trans-diene (4). The structures of 2 and 4 were established spectroscopically and by degradation of 4 to d-glycero-d-galacto-heptitol (perscitol). A mixture of the alkyne 1 and its 7-epimer 10 was readily oxidized by dimethyl sulfoxide-acetic anhydride to the 6-ketone 11, and the 8-alkene analog was similarly prepared from the alkenes derived from 1 and 10. Likewise, oxidation of 6,7-dideoxy-1,2-O-isopropylidene-α-d-gluco(and β-L-ido)-hept-6-enopyranose gave the corresponding 5-ketone. The acetylenic ketone 11 gave a crystalline oxime and (2,4-dinitrophenyl)hydrazone, the latter being accompanied by the product of attack of the reagent at the acetylene terminus (C-8). Previous work had shown that formyl-methylenetriphenylphosphorane did not convert 1,2:3,4-di-O-isopropylidene-6-aldehydo-α-d-galacto-hexodialdo-1,5-pyranose into the corresponding C₈ unsaturated aldehyde, although the latter was obtainable via1 and 10 by an ethynylation-hydroboration sequence. The Wittig route with formylmethylenetriphenylphosphorane is shown to be satisfactory for obtaining C₇ unsaturated aldehydes from 3-O-benzyl-1,2-O-isopropylidene-5-aldehydo-α-d-xylo-pentodialdo-1,4-furanose (22) and the 3-epimer of 22, respectively. These reactions provide convenient access to higher-carbon sugars and chiral dienes for synthesis of optically pure products of cyclo-addition reactions.     

Reactions of carbohydrate α-nitroepoxides with dimethylamine and with methylmagnesium iodide

Methyl 2,3-anhydro-4,6-O-benzylidene-3-C-nitro-β-d-allopyranoside (1), as well as its β-d-manno (2) and α- d-manno (3) isomers, reacted with dimethylamine to give the same, crystalline 3-(dimethylamino) adduct (4) of 1,5-anhydro-4,6-O-benzylidene-2-deoxy-2-(dimethylamino)-d-erythro-hex-1-en-3-ulose (5). The enulose 5 was obtained from 4 by the action of silica gel. Similarly, the β-d-gulo (6) and α-d-talo (7) stereoisomers of 1–3 afforded a 3-(dimethylamino) adduct (8) of the d-threo isomer (9) of 5. Reaction of dimethylamine with 5,6-anhydro-1,2-O-isopropylidene-6-C-nitro-α-d-glucofuranose (10) yielded a mixture of two diastereoisomeric (possibly anometic at C-6) 5-deoxy-5-(dimethylamino)-1,2-O-isopropylideric-α-d-hexodialdo-1,4:6,3-difuranoses (11). The β-glycoside 1 and the α-glycoside 3 reacted with methylmagnesium iodide to produce methyl 4,6-O-benzylidene-3-deoxy-3-C-methyl-3-(N-hydroxy-N-methylamino)-β- and -α-d-hexopyranosides (12) and (13), respectively; both products had the 1,2-trans configuration, but their configurations at the quaternary center C-3 have not been determined.     

Chemical constituents from the roots of Fallopia multiflora var. Ciliinerve

Phytochemical investigations on the roots of Fallopia multiflora var. Ciliinerve led to the isolation of eighteen compounds, including six chromones [2-methyl-5- carboxymethyl-7-hydroxychromone (1), 2-methyl-5-methylcarboxymethyl-7- hydroxychromone (2), 2,5-dimethyl-7-hydroxychromone (3), 2-methyl-5-hydroxymeth-yl-7-hydroxychromone (4), 2-methyl-5-carboxylicacid-7-hydroxy-chromone (5), and 2,5-dimethyl-7-hydroxychromone-7-O-β-D-glucopyranoside (6)], three lignans [Isolariciresinol (8), 5-[4-(3,4-dimethoxyphenyl)-2,3-dimethylbutyl]-1,3-benzodioxole (9), and isolariciresinol-9-O-β-D-xylopyranoside (10)], four anthraquinones [physcion-8-O-β-D-glucopyranoside (11), emodin-8-O-β-D-glucopyranoside (12), Rhein (13), and Chrysophanol (14)], three isobenzofurans [5,7-dihydroxy-isobenzofuran (15), 5-methoxy-7-hydroxy-isobenzofuran (16), and 5-methoxy-isobenzofuran-7-O-β-D-glucoside (17)], one phenolic acid [2,5-diacethylhy-droquinone (7)], and one pyran [Zanthopyranone (18)]. Among them, compounds 1, 3, 6, 13 and 14 were reported from F. multiflora var. Ciliinerve for the first time, compounds 2, 8, 10 and 15–17 were isolated from the genus Fallopia for the first time, and compounds 4, 9 and 18 were isolated for the first time from Polygonaceae family. Furthermore, the isolation of compounds 5 and 7 were reported for the first time in plants. Their structures were identified by spectroscopic methods and compared with those previously published. The chemotaxonomic significance of these isolated compounds has also been discussed.     

Synthesis of higher-carbon sugars via vinyltin derivatives of simple monosaccharides

6-O-Benzyl-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-l-glycero-α-d-galacto-oct-7-ynopyranose reacted with tributyltin hydride to afford (Z-6-O-benzyl-7,8-dideoxy-1,2:3,4-di-O-isopropylidene-8-(tributylstannyl)-l-glycero-α-d-galacto-oct-7-enopyranose, which was subsequently isomerized to the E-olefin 4. Replacement of the tributyltin moietey with lithium in 4 afforded the vinyl anion which reacted with 3-O-benzyl-1,2-O-isopropylidene-α-d-xylo-pentodialdo-1,4-furanose, furnishing 3-O-benzyl-6-C-[(E)-6-O-benzyl-7-deoxy-1,2:3,4-di-O-isopropylidene-l-glycero-α-d-galacto-heptopyranos-7-ylidene] -60-deoxy-1,2-O-isopropylidene-α-d-gluco- (6) and -β-l-ido-furanose (7) in yields of ∼70 or ∼87% (depending on the temperature of the reaction). The configurations of the new chiral centers in 6 and 7 were determined by their conversion into 3-O-benzyl-1,2-O-isopropylidene-α-d-gluco- and -β-l-ido-furanose, respectively. Oxidation of 6 and 7 gave the same enone, 3-O-benzyl-6-C-[(E)-6-O-benzyl-7-deoxy-1,2:3,4-di-O-isopropylidene-l-glycero-α-d-galacto- heoptopyranos-7-ylidene]-6-deoxy-1,2-O-isopropylidene-α-d-xylo-hexofuranos-5-ulose.     

5-thio-l-rhamnose

Two routes for the synthesis of methyl 5-S-acetyl-6-deoxy-2,3-O-isopropylidene-5-thio-l-mannofuranoside (8) have been examined. Reaction of l-rhamnose with methanol in the presence of the cation-exchange resin gives methyl 6-deoxy-α-l-mannofuranoside (2), which on conventional acetonation yields methyl 6-deoxy-2,3-O- isopropylidene-α-l-mannofuranosides (3). Compounds 3 is also obtained by acetonation of l-rhamnose followed by treatment with a mixture of methanol, acetonation, Amberlite IR-120(H⁺) resin. Chlorination of 3 with triphenylphosphine-carbon tetrachloride gives methyl 5-chloro-5,6-dideoxy-2,3-O-isopropylidene-β-d-gulofuranoside (7), which reacts with potassium thioacetate to give 8. Alternatively, 3 is iodized with ruthenium tetraoxide to methyl 6-deoxy-2,3-O-isopropylidene-α-l-lyxo-hexofuranosid-5-ulose (9), which reduced by sodium borohydride mainly to methyl 6-deoxy-2,3-O-isopropylidene-β-d-gulofuranoside (10). The O-tosyl derivative of 10 reacts with potassium thioacetate to produced 8. Hydrolysis of 8 with 90% aqueous triflouroacetic acid, followed by acetolysis with a solution of acetic acid, acetic anhydride, and sulfuric acids gives an anomeric mixture of 1,2,3,4,-tetra-O-acetyl-6-deoxy-5-thio-l-mannopyranoses (12), together with a small proportion of 1,2,3,-tri-O-acetyl-5-S-acetyl-6-deoxy-5-thio-β-l-mannofuranose (13). Deacetylation of 12 or 13 gives 5-thio-l-rhamnose (6), from which crystalline 1,2,3,4-tetra-O-(p-nitrobenzoyl)-5-thio-β-l-rhamnopyranose (14) is obtained.     

Synthesis of new branched-chain aminodeoxyhexoses related to daunosamine (3-amino-2,3,6-trideoxy-l-lyxo-hexose)

Addition of methylmagnesium iodide to methyl 2,3,6-trideoxy-3-trifluoro-acetamido-α-l-threo-hexopyranosid-4-ulose (3) gave methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-l-lyxo-hexopyranoside (4) and its l-arabino analogue, depending upon the reaction temperature and the solvent. The corresponding 4-O-methyl derivatives were obtained by treatment of 4 and 5 with diazomethane in the presence of boron trifluoride etherate. Treatment of 4 with thionyl chloride, followed by an alkaline work-up, gave methyl, 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoro-acetamido-α-l-threo-hexopyranoside (8), which was stereoselectively reduced to methyl 2,3,4,6-tetradeoxy-4-C-methyl-3-trifluoroacetamido-α-l-arabino-hexopyranoside. Epoxidation of 8 with 3-chloroperoxybenzoic acid gave the corresponding 4,4₁-anhydro-4-C-hydroxymethyl-l-lyxo derivative (10), which was also prepared by treatment of 3 with diazomethane. Azidolysis of 10, followed by catalytic hydrogenation and N-trifluoroacetylation, gave methyl 2,3,6-trideoxy-3-trifuloroacetamido-4-C-trifluoroacetamidomethyl-α-l-lyxo-hexopyranoside.     

Synthesis of 5-O-α-and-β-d-glucopyranosyl-d-glucofuranose and 5-O-α-d-glucopyranosyl-d-fructopyranose (leucrose)

Reaction of 1,2-O-cyclopentylidene-α-d-glucofuranurono-6,3-lactone (2) with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide (1) gave 1,2-O-cyclopentylidene- 5-O-(2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl)-α-d-glucofuranurono-6,3-lactone (3, 45%) and 1,2-O-cyclopentylidene-5-O-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-α-d-glucofuranurono-6,3-lactone (4, 38%). Reduction of 3 and 4 with lithium aluminium hydride, followed by removal of the cyclopentylidene group, afforded 5-O-α-(9) and -β-d-glucopyranosyl-d-glucofuranose (12), respectively. Base-catalysed isomerization of 9 yielded crystalline 5-O-α-d-glucopyranosyl-d-fructopyranose (leucrose, 53%).     

Grignard addition-reactions to glycosulose derivatives

The course of Grignard addition-reactions to 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranos-3-ulose (1) has been examined as a function of the nature of the reagent, the solvent, the halide, and the temperature. Ethylmagnesium bromide in ether at — 14° converted 1 into 60% of the 3-C-ethyl-D-allo adduct 2. The latter was convertible in 90% yield into the 3-benzyl ether 6, despite the tertiary nature of the hydroxyl group. The use of tetrahydrofuran (THF) or THF-ether at higher temperatures, or of ethylmagnesium iodide, lowered the yield of 2 and gave substantial proportions of such side products as 1,2:5,6-di-O-isopropylidene-α-D-allofuranose (3). 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (4), and the hydrate (5) of the starting ketone 1. Phenylmagnesium bromide in ether or THF converted 1 into the 3-C-phenyl-D-allo derivative 7 in 84% yield, accompanied by only minor proportions of side products; the latter were the 3-C-phenyl-D-gluco adduct 8 and the product (9) of 5,6-dioxolane ring-opening. The structures of 8 and 9 were confirmed by an acetylation-deacetylation sequence, and by n.m.r. spectroscopy. The 3-C-phenyl-D- allo derivative 7 could be converted in 95% yield into its 3-benzyl ether 10. Cyclohexylmagnesium bromide reacted with 1 in ether or THF at various temperatures to give 3-C-cyclohexyl-1,2:5,6-di-O-isopropylidene-α-D)-allofuranose (11) in low yields; the main product generally encountered was 3. with variable proportions of 4, 1,2-O-isopropylidene-α-D-allofuranose (18), the hydrate 5, and a dimeric product 19 (further characterized as its oxime 20). Compound 11 was, however, obtainable in >95% yield by reducing 7 with hydrogen in the presence of rhodium-on-alumina. Phenylmagnesium bromide reacted with the 4-ketone derivative 25 in THF at 0° to give 83% of 1,6-anhydro-2,3-O-isopropylidene-3-C-phenyl-β-D-talopyranose (26), and no side-products were detected.     

O-benzylated thio sugars: 2,3,4- and 2,4,6-tri-O-benzyl-1-thio-β-d-galactopyranose

The 2,3,4- (9) and 2,4,6-tribenzyl (19) ethers of 1-thio-β-d-galactopyranose were prepared from the corresponding O-benzylated normal (1-hydroxyl) sugars 4 and 15 via the sequence: normal sugar → diacetate → O-acetylglycosyl bromide → O-acetyl-glycosyl ethylxanthate → 1-thio sugar. 2,3,4-Tri-O-benzyl-α-d-galactopyranose (4) is most advantageously made from allyl 6-O-allyl-α-d-galactopyranoside (2) by a published synthesis. An improved synthesis of 2,4,6-tri-O-benzyl-d-galactopyranose (15) was devised; it involves the selective 3-O-benzoylation of allyl 2,6-di-O-benzyl-α-d-galactopyranoside (10).     

Synthesis of 1,2,4-tri-O-acetyl-5-deoxy-3-O-methyl-5-C-[(R)- and -(S)-phenylphosphinyl]-β-d-ribopyranose

5-Deoxy-1,2-O-isopropylidene-5-C-(methoxyphenylphosphinyl)-3-O-methyl-α-d-ribofuranose (4) was prepared from 1,2-O-isopropylidene-3-O-methyl-α-d-ribo-pentodialdo-1,4-furanose by an addition reaction with methyl phenylphosphinate, followed by deoxygenation of the terminal HOCHP group of the adduct by successive reaction with 1,1′-thiocarbonyldiimidazole and tributyltin hydride. Treatment of 4 with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by deacetonation with mineral acid, and acetylation with acetic anhydride—pyridine, gave mainly the two title compounds, which were isolated by column chromatography on silica gel, and characterized by 90-MHz, ¹H-n.m.r.-spectral analysis.