Synthesis of derivatives of 3-amino-2,3-dideoxy-l-hexoses related to daunosamine (3-amino-2,3,6-trideoxy-l-lyxo-hexose)

The synthesis is described of 3-amino-2,3-dideoxy-l-arabino-hexose (10), methyl 2,3-dideoxy-3-trifluoroacetamido-α-l-lyxo-hexopyranoside (17), methyl 3-amino-2,3-dideoxy-α-l-ribo-hexopyranoside (21), methyl 2,3-dideoxy-3-trifluoroacetamido-α-l-xylo-hexopyranoside (26), and certain derivatives from methyl 4,6-O-benzylidene-2-deoxy-α-l-arabino-hexopyranoside (3). Conversion of 2-deoxy-l-arabino-hexose into 3 by modified, standard procedures, and on a large scale, gave a 75% yield.     

An approach to stereoselective preparation of 3-C-glycosylated d- and l-glucals

An approach to stereoselective synthesis of α- or β-3-C-glycosylated l- or d-1,2-glucals starting from the corresponding α- or β-glycopyranosylethanals is described. The key step of the approach is the stereoselective cycloaddition of chiral vinyl ethers derived from both enantiomers of mandelic acid. The preparation of 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl)methyl]-l-arabino-hex-1-enitol, 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4,6-tetra-O-benzyl-β-d-glucopyranosyl)methyl]-d-arabino-hex-1-enitol, and 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-C-[(2,3,4-tri-O-benzyl-α-l-fucopyranosyl)methyl]-d-arabino-hex-1-enitol serves as an example of this approach.     

Synthesis of alkyl 4,6-di-o-acetyl-2,3-dideoxy-α-d-threo-hex-2- enopyranosides from 3,4,6-tri-o-acetyl-1,5-anhydro-2-deoxy- d-lyxo-hex-1-enitol (3,4,6-tri-o-acetyl-d-galactal)

3,4,6-Tri-O-acetyl-d-galactal, on treatment in 1,2-dichloroethane with alcohols and stannic chloride as catalyst, readily undergoes allylic rearrangement-substitution, forming alkyl 4,6-di-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosides in yields of 43-92%. Alkyl 3,4,6-tri-O-acetyl-2-deoxy-αβ-d-lyxo-hexopyranosides are formed as side-products in yields of 2-14 %. Stannic chloride-catalysis is also useful in allylic rearrangement of 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-arabino- hex-l-enitol (3,4,6-tri-O-acetyl-d-glucal) which, with methanol or ethanol, affords the corresponding alkyl 4,6-di-O-acetyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranosides in yields of 83 and 94%.     

Silylmethylene radical cyclization. A stereoselective approach to branched sugars

Ethyl 6-O-benzyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside (2) was converted, in three steps and in 73% overall yield, into ethyl 6-O-benzyl-2,3-dideoxy-3-C-(hydroxymethyl)-α-d-ribo-hex-2-enopyranoside. This transformation involved silylation of 2 with (bromomethyl)chlorodimethylsilane and application of the Nishiyama-Stork radical cyclisation, followed by Tamao oxidation of the sila cycle. Ethyl 6-O-benzyl-2,3-dideoxy-α-d-threo-hex-2-enopyranoside and benzyl 2,6-di-O-benzyl-α-l-threo-hex-4-enopyranoside were similarly transformed into, respectively, ethyl 6-O-benzyl-2,3-dideoxy-3-C-(hydroxymethyl)-α-d-lyxo-hex-2-enopyranoside (50%), and benzyl 2,6-di-O-benzyl-4-deoxy-4-C-(hydroxymethyl)-β-d-galactopyranoside (71%).     

β-Elimination in aldonolactones. Synthesis of 3,6-dideoxy L-arabino-hexose (ascarylose)

Benzoylation of L-rhamnono-1,5-lactone (1) with an excess of benzoyl chloride and pyridine for 16 h afforded 2,4-O-benzoyl-3,6-dideoxy-L-erythro-hex-2-enono-1,5-lactone (2). Catalytic hydrogenation of 2 was stereoselective and gave crystalline 2,4-di-O-benzoyl-3,6-dideoxy-L-arabino-hexono-1,5-lactone (3). Reduction of the lactone 3 with disiamylborane afforded 2,4-di-O-benzoyl-3,6-dideoxy-L-arabino-hexopyranose (4) which, on debenzoylation, gave 3,6-dideoxy-L-arabino-hexose (ascarylose) (7) in good overall yield. The sugar was identified as the corresponding alditol (ascarylitol) and by convertion into methyl 3,6-dideoxy-α-L-arabino-hexopyranoside (methyl ascaryloside, 6).     

The deamination of methyl 5-amino-5,6-dideoxy-2,3-O-isopropylidene-α-L-talo- and -β-D-allo-furanoside with nitrous acid

Deamination of methyl 5-amino-5,6-dideoxy-2,3-O-isopropylidene-α-L-talofuranoside (6) with sodium nitrite in 90% acetic acid at ≈0° gave methyl 6-deoxy-2,3-O-isopropylidene-α-L-talofuranoside (8a) and methyl 6-deoxy-2,3-O-isopropylidene-β-D-allofuranoside (9a) (combined yield, 12.3%), the corresponding 5-acetates 8b (2.9%) and 9b (26.4%), and the unsaturated sugar methyl 5,6-dideoxy-2,3-O-isopropylidene-β-D-ribo-hex-5-enofuranoside (10) (43.5%). Similar deamination of methyl 5-amino-5,6-dideoxy-2,3-O-isopropylidene-β-D-allofuranoside (7) gave 8a and 9a (combined yield, 20.4%), 8b (12.5%), 9b (25.8%), 10 (7.7%), and the rearranged products 6-deoxy-2,3-O-isopropylidene-5-O-methyl-L-talofuranose (13a, 17.5%) and the corresponding 1-acetate 13b (14.1%). A synthesis of 13a was accomplished by successive methylation and debenzylation of the conveniently prepared benzyl 6-deoxy-2,3-O-isopropylidene-α-L-talofuranoside (15b). Differences between the two sets of deamination products can be rationalized by assuming that the carbonium-ion intermediate reacts in the initial conformation assumed, before significant interconversion to other conformations occurs.     

Nucleophilic displacement reactions in carbohydrates : Part XX. Displacements on alkyl α-l-talopyranoside 4-sulphonate derivatives

The azide displacement reaction on methyl 6-deoxy-4-O-methanesulphonyl-2,3-di-O-methyl-α-l-talopyranoside (6) in N,N-dimethylformamide yielded methyl 4,6-dideoxy-2,3-di-O-methyl-α-l-threo-hex-3-enopyranoside (7, ca. 50%), methyl 4,6-dideoxy-2,3-di-O-methyl-β-d-erythro-hex-4-enopyranoside (8, ca. 10%), and methyl 4-azido-4,6-dideoxy-2,3-di-O-methyl-α-l-mannopyranoside (9, ca. 40%). The corresponding azide 14 (20%) and the unsaturated sugars 12 (68%) and 13 (12%) were obtained from a comparable reaction on benzyl 6-deoxy-4-O-methanesulphonyl-2,3-di-O-methyl-α-l-talopyranoside (11).     

Synthesis of acetylenic sugars and uronic acids via two-carbon chain extension of d-ribose

Treatment of methyl β-d-ribofuranoside with acetone gave methyl 2,3-O-isopropylidene-β-d-ribofuranoside (1, 90%), whereas methyl α-d-ribofuranoside gave a mixture (30%) of 1 and methyl 2,3-O-isopropylidene-α-d-ribofuranoside (1a). On oxidation, 1 gave methyl 2,3-O-isopropylidene-β-d-ribo-pentodialdo-1,4-furanoside (2), whereas no similar product was obtained on oxidation of 1a. Ethynylmagnesium bromide reacted with 2 in dry tetrahydrofuran to give a 1:1 mixture (95%) of methyl 6,7-dideoxy-2,3-O-isopropylidene-β-d-allo- (3) and -α-l-talo-hept-6-ynofuranoside (4). Ozonolysis of 3 and 4 in dichloromethane gave the corresponding d-allo- and l-talo-uronic acids, characterized as their methyl esters (5 and 6) and 5-O-formyl methyl esters (5a and 6a). Ozonolysis in methanol gave a mixture of the free uronic acid and the methyl ester, and only a small proportion of the 5-O-formyl methyl ester. Malonic acid reacted with 2 to give methyl 5,6-dideoxy-2,3-O-isopropylidene-β-d-ribo-trans-hept-5-enofuranosiduronic acid (7).     

Synthèses et réductions de sucres fonctionnels mono et diinsaturés

Attempts to prepare 1,2:5,6 and 2,3:5,6 di-unsaturated sugars starting from 3,4,6-tri-O-acetyl-1,5-anhydro-1,2-dideo xy-d-arabino-hex-1-enitol or from ethyl 4,6-di-O-acetyl-1,5-anhydro-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside led to 1,5-anhydro-1,2,6-trideoxy-l-threo-hex-5-enitol and its 3,4-diacetate. Hydrogenation and hydrogenolysis of the unsaturated chloro and fluoro derivatives afforded 1,5-anhydro-1,2,6-trideoxy-d-arabino-hexitol and ethyl 4-O-acetyl-2,3,6-trideoxy-α-d-erythro-hexopyranoside.     

Synthesis of 1-deoxy-3-C-methyl-d-fructose and 1-deoxy-3-C-methyl-d-sorbose

Hydroxylation of trans-1,3,4-trideoxy-5,6-O-isopropylidene-3-C-methyl-d-glycero-hex-3-enulose with osmium tetraoxide gave a mixture of 1-deoxy-5,6-O-isopropylidene-3-C-methyl-d-arabino- and -d-xylo-hexulose that was partially resolved by acetonation to give 1-deoxy-2,3:4,5-di-O-isopropylidene-3-C-methyl-β-d-fructopyranose (4), 1-deoxy-3,4:5,6-di-O-isopropylidene-3-C-methyl-keto-d-fructose (5), and 1-deoxy-2,3:4,6-di-O-isopropylidene-3-C-methyl-α-d-sorbofuranose (6). Treatment of a mixture of 4 and 5 with sodium borohydride gave, after column chromatography, 4 and 1-deoxy-3,4:5,6-di-O-isopropylidene-3-C-methyl-d-manno- and -d-gluco-hexitol. Deuterated derivatives corresponding to 4–6 were obtained when isopropylidenation was carried out with acetone-d₆. Deacetonation of 4 and 5 yielded 1-deoxy-3-C-methyl-d-fructose, and 6 similarly afforded 1-deoxy-3-C-methyl-d-sorbose.     

Synthesis of 4-deoxy-d-xylo-hexose and 4-azido-4-deoxy-d-glucose and their effects on lactose synthase

Syntheses are reported of 4-deoxy-d-xylo-hexose and 4-azido-4-deoxy-d-glucose as potential inhibitors for lactose synthase [uridine 5′-(α-d-galactopyranosyl pyrophosphate):d-glucose 4-β-d-galactopyranosyltransferase, EC 2.4.1.22]. These syntheses involved SN2 displacement of the 4-methylsulfonyloxy group of methyl 2,3,6-tri-O-benzoyl-4-O-methylsulfonyl-α-d-galactopyranoside by iodide and azide ions. In both cases, inversion in configuration was observed. The resulting intermediates, methyl 2,3,6-tri-O-benzoyl-deoxy-4-iodo-α-d-glucopyranoside and methyl 4-azido-2,3,6-tri-O-benzoyl-deoxy-α-d-glucopyranoside, were obtained in crystalline form. Both 4-deoxy-d-xylo-hexose and 4-azido-4-deoxy-d-glucose were found to be inhibitors for lactose synthase in the presence of α-lactalbumin, but had no effect in the absence of α-lactalbumin. Both d-glucose analogues bind to the enzyme system far more weakly than d-glucose, suggesting that the recognition of the 4-OH group of the acceptor substrate is an important factor in binding.     

Synthesis of 3-amino-2,3,6-trideoxy-ll-lyxo-hexose (daunosamine) hydrochloride from d-glucose

Three different approaches starting from 1,2-O-isopropylidene-α-d-glucofuranose were tested for the synthesis of daunosamine hydrochloride (24), the sugar constituent of the antitumor antibiotics daunomycin and adriamycin. The third route, affording 24 in ~5% overall yield in 11 steps, constitutes a useful, preparative synthesis, 3,5,6-Tri-O-benzoyl-1,2-O-isopropylidene-α-d-glucofuranose was converted via methyl 2,3-anhydro-β-d-mannofuranoside into methyl 2,3:5,6-dianhydro-α-l-gulofuranoside, the terminal oxirane ring of which was split selectively on reduction with borohydride, to afford methyl 2,3-anhydro-6-deoxy-α-l-gulofuranoside (31). Compound 31 was converted into methyl 2,3-anhydro-5-O-benzyl-6-deoxy-α-l-gulofuranoside, which was selectively reduced at C-2 on treatment with lithium aluminum hydride, affording methyl 5-O-benzyl-2,6-dideoxy-α-l-xylo-hexofuranoside. Subsequent mesylation, and replacement of the mesoloxy group by azide, with inversion, afforded methyl 3-azido-5-O-benzyl-2,6-dideoxy-α-l-lyxo-hexofuranoside, which could be converted into either 24 or methyl 3-acetamido-5-O-acetyl-2,3,6-trideoxy-α-l-lyxo-hexofuranoside, which can be used as a starting material for the synthesis of daunomycin analogs.     

Synthesis of 3-amino-2,3,6-trideoxy-d-ribo- and -l-lyxo-hexofuranoses suitable for nucleoside synthesis

N-Acetylepidaunosamine (3-acetamido-2,3,6-trideoxy-d-ribo-hexopyranose) was converted into the diethyl dithioacetal and this was cyclized with HgCi₂, HgO, and MeOH, to give methyl 3-acetamido-2,3,6-trideoxy-α- and -β-d-ribo-hexofuranoside (4 and 5). These anomers were acetylated or (p-nitrobenzoyl)ated, and the esters were subjected to acetolysis, to afford 3-acetamido-1,5-di-O-acetyl-2,3,6-trideoxy-d-ribo-hexofuranose and 3-acetamido-1-O-acetyl-2,3,6-trideoxy-5-O-(p-nitrobenzoyl)-d-ribo-hexofuranose, respectively. Alternatively, compounds 4 and 5 were hydrolyzed to the free bases with barium hydroxide, and these were converted into the trifluoroacetamido derivatives which, on (p-nitrobenzoyl)ation and acetolysis, afforded 1-O-acetyl-2,3,6-trideoxy-5-O-(p-nitrobenzoyl)-3-(trifluoroacetamido)-d-ribo-hexofuranose. To prepare the corresponding daunosamine derivative, 2,3,6-trideoxy-3-(trifluoroacetamido)-l-lyxo-hexopyranose was converted into the diethyl dithioacetal, and this was cyclized in the same way, to afford methyl 2,3,6-trideoxy-3-(trifluoroacetamido)-α- and -β-l-lyxo-hexofuranoside. On (p-nitrobenzoyl)ation and acetolysis, both afforded 1-O-acetyl-2,3,6-trideoxy-5-O-(p-nitrobenzoyl)-3-(trifluoroacetamido)-l-lyxo-hexofuranose.     

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.     

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.     

An approach to branched-chain amino sugars,particularly derivatives of l-vancosamine (3-amino-2,3,6-trideoxy-3-C-methyl-l-lyxo-hexose) and its d enantiomer,via the cyanohydrin route

Methyl 4,6-O-benzylidene-2-deoxy-α-d-erythro-hexopyranosid-3-ulose reacted with potassium cyanide under equilibrating conditions to give, initially, methyl 4,6-O-benzylidene-3-C-cyano-2-deoxy-α-d-ribo-hexopyranoside (7), which, because it reverted slowly to the thermodynamically stable d-arabino isomer, could be crystallised directly from the reaction mixture. The mesylate derived from the kinetic product 7 could be converted by published procedures into methyl 3-acetamido-2,3,6-trideoxy-3-C-methyl-α-d-arabino-hexopyranoside, which was transformed into methyl N-acetyl-α-d-vancosaminide on inversion of the configuration at C-4. A related approach employing methyl 2,6-dideoxy-4-O-methoxymethyl-α-l-erythro-hexopyranosid-3-ulose gave the kinetic cyanohydrin and thence, via the spiro-aziridine 27, methyl 3-acetamido-2,3,6-trideoxy-3-C-methyl-α-l-arabino-hexopyranoside, a known precursor of methyl N-acetyl-α-l-vancosaminide.     

Reaction of methyl β-d-glycero-l-manno-heptopyranoside with cyclohexanone: Synthesis of the 4- and 6-methyl ethers of d-glycero-l-manno-heptitol

Acid-catalysed condensation of methyl β-d-glycero-l-manno-heptopyranoside with cyclohexanone yielded an approximately 3:1 mixture of the 2,3:6,7- and 2,3:4,7-di-O-cyclohexylideneheptosides (1 and 2), which could be separated either as their benzoates (3 and 4) or as their methyl ethers (5 and 6). The latter compounds afforded the 4- and 6-methyl ethers (7 and 8) of d-glycero-l-manno-heptitol.     

Synthesis of methyl 4,6-O-methylene-D-glycopyranosides

Methyl 4,6-O-methylene-D-glycopyranosides having the α-D-altro, α- and β-D-gluco, α-D-manno, and α-D-galacto configurations were prepared in 3.4 to 27.4% yields by condensing formaldehyde from 1,3,5-trioxane with the methyl glucosides in anhydrous 1,4-dioxane at 95° with boron trifluoride as the catalyst. A crystalline methyl 2,3:4,6-di-O-methylene-α-D-mannopyranoside was also isolated. Crystalline methyl 4,6-O-methylene 2,3-di-O-p-tolylsulfonyl-α-D-galacto- and α-D-glucopyranosides were prepared in 78 and 54.4% yields. N.m.r. coupling constants of the 2,3-di-O-acetyl derivatives of the 4,6-O-methylene glycosides were used to establish the Cl(D) conformation for each derivative.     

Cation-Exchange resin-catalyzed addition of methanol to benzoylated 1,5-anhydro-2-deoxy-d-hex-1-enitols

1,5-Anhydro-3,4,6-tri-O-benzoyl-2-deoxy-d-arabino-hex-1-enitol (1) was boiled under reflux with methanol and AG 50W-X8 cation-exchange resin. A two-product mixture of glycosides (2 and 3) was obtained in 38% yield, together with 19% of unreacted material. 1,5-Anhydro-3,6-di-O-benzoyl-2-deoxy-d-arabino-hex-1-enitol (7) was prepared from 1,5-anhydro-2-deoxy-d-arabino-hex-1-enitol by selective benzoylation, from which the corresponding 4-methanesulfonate 8 was obtained. Treatment of 8 with sodium benzoate in hexamethylphosphoric triamide for 72 h at 100° afforded 1,5-anhydro-3,4,6-tri-O-benzoyl-2-deoxy-d-lyxo-hex-1-enitol (9) in 52% yield. An unknown byproduct (B), tentatively shown to be a tri-O-benzoyl-d-hex-2-enopyranose analog, was also isolated in 14% yield. The 270-MHz n.m.r. spectrum of B was analyzed in terms of its J_1,3, J_2,4, and J_4,5 coupling constants in relation to the various configurational and conformational possibilities for hex-2-enopyranoses, and was identified as 1,4,6-tri-O-benzoyl-2,3-dideoxy-α-d-threo-hex-2-enopyranose having the ^oH₅ conformation. The analysis presented should also be applicable to pent-2-enopyranose systems. When 9 was treated with methanol in the presence of AG 50W-X8 cation-exchange resin, a mixture of glycosides 4 and 5 was obtained in 47% yield. The low yields were attributed to methanolysis of the benzoyl groups during the reaction.     

Synthesis of crystalline derivatives of 6-deoxy-d-allo- and -l-talo-furanosyl bromide suitable for nucleoside synthesis

6-Deoxy-2,3,5-tri-O-(p-nitrobenzoyl)-β-d-allo- and -α-l-talo-furanosyl bromide (6 and 11) have been synthesized from methyl 2,3-O-isopropylidene-β-d-ribo-pentodialdo-1,4-furanoside (1). Treatment of 1 with methyl Grignard reagent, followed by (p-nitrobenzoyl)ation, afforded two 5-epimers, methyl 6-deoxy-2,3-O-isopropylidene-5-O-(p-nitrobenzoyl)-β-d-allo- and -α-l-talo-furanosides (3 and 8) which were fractionally recrystallized. The l-talo isomer (8) separated first, and was treated with acid to remove the isopropylidene group, the product (p-nitrobenzoyl)ated, and the ester reacted with hydrogen bromide in acetic acid, to afford crystalline compound 11. The mother liquor from the fractional recrystallization was treated with acid, whereby methyl 6-deoxy-5-O-p-nitrobenzoyl)-d-allofuranoside was isolated. It was (p-nitrobenzoyl)ated, and the ester treated with hydrogen bromide in acetic acid, to afford crystalline bromide 6.