Alkali and oxygen-alkali treatment of D-arabino-hexosulose and O-β-D-glucopyranosyl-(1 → 4)-d-arabino-hexosulose.

Benzilic acid rearrangement of D-arabino-hexosulose (1) and O-β-D-glucopyranosyl-(1→4)-D-arabino-hexosulose (2) favours formation of mannonic acid and mannonic acid moieties, respectively. The results show that formation of aldonic acid end-groups via terminal aldosulose moieties is of little importance during oxygen-hydrogencarbonate treatment of (1→4)-linked polysaccharides. The major reaction of 1 in the absence of oxygen involves loss of C-1 as formic acid. The enediol intermediate gives rise to pentoses and pentuloses (degraded completely at high alkalinity), and 3-deoxypentonic acids. The yield of 3-deoxypentonic acids is decreased in the presence of oxygen, whereas that of arabinonic, erythronic, and glycolic acids is increased. The main reaction of 2 giving rise to aliphatic hydroxy acids is β-elimination of the glucose moiety, yielding a tricarbonyl intermediate (3) which, in sodium hydrogencarbonate, is decomposed mainly to 3,4-dihydroxybutanoic and glycolic acids. In sodium hydroxide, 3-deoxypentonic acids are among the major reaction products. In addition, a complex mixture of u.v.-absorbing solutes is formed, some of which are held irreversibly by anion exchangers.     

Dehydration of 2-(d-arabino-tetrahydroxybutyl)furans : Part II. The steric course and mechanism of the reaction

Acid-catalyzed dehydration of methyl and ethyl 2-methyl-5-(d-arabino-tetrahydroxybutyl)-3-furoate (4a, b) takes place preferentially with inversion of configuration at C-1′, yielding the corresponding 5-(1,4-anhydro-d-ribo-tetrahydroxybutyl)-2-methyl-3-furoate (6a, b), and, to a much smaller extent, with retention of configuration giving the isomeric d-arabino anhydro-derivative (5a, b). The reaction is reversible, the equilibrium being set up when there is a high concentration of the thermodynamically more-stable d-ribo anhydro-derivative in the presence of the d-arabino isomer, the starting (d-arabino-tetrahydroxybutyl)furan (4a, db), and a compound thought to be methyl (or ethyl) 2-methyl-5-(d-ribo-tetrahydroxybutyl)-3-furoate (13). A mechanism is proposed for this reaction which involves the C-1′ carbonium ion 15 as the key intermediate. The anhydro derivatives of the d-ribo and d-arabino configurations can be distinguished by their optical rotations, the chemical shifts of H-1′, and the J_1′,2′ coupling constants.     

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.     

Stereocontrolled preparation of C-2-deoxy-α- and -β-d-glucopyranosyl compounds from tributyl-(2-deoxy-α- and -β-d-glucopyranosyl)stannanes

tributylstannyllithium treatment of 3,4,6-tri-O-benzyl-2-deoxy-α-d-arabino-hexopyranosyl chloride (2) provided selectively tributyl (3,4,6-tri-O-benzyl-2-deoxy-β-d-arabino-hexopyranosyl)stannane (3) in 85% yield. Isomeric tributyl (3,4,6-tri-O-benzyl-2-deoxy-α-d-arabino-hexopyranosyl)stannane (6) could be prepared in 70% yield by reductive lithiation of 2 and reaction with tributyltin chloride. Tin—lithium exchange reaction, performed on 3 and 6 with butyllithium in oxolane at −78°, generated the corresponding, configurationally stable 2-deoxy-β- and -α-d-hexopyranosyllithium compounds which reacted with electrophilic compounds with retention of configuration. Addition to these glycosyllithium reagents to prochiral carbonyl compounds gave variable degrees of facial selectivity. A significant diastereofacial discrimination (10:1) was observed by condensation of 3,4,6-tri-O-benzyl-2-deoxy-α-d-arabino-hexopyranosyllithium reagent with hexanal and isobutyraldehyde. The structure of all C-glycopyranosyl compounds obtained was established by ¹H-n.m.r. spectroscopy.     

The formation of end groups in cellulose during alkali cooking

Cotton that had been subjected to alkali cooking at 170° was hydrolysed to determine the car?ylic acid end-groups. Large proportions of 3-deoxy-ribo-hexonic, 3-deoxy-arabino-hexonic, and 2-C-methylglyceric acids, together with a minor proportion of 2-C-methylribonic acid, were isolated and identified. Reduction of the cellulose end-groups and subsequent analysis of the hydrolysate revealed 3-deoxy-ribo-hexitol, 3-deoxy-arabino-hexitol, 2-C-methylglycerol, and a small proportion of 2-C-methylribitol. It is concluded from these results that, in addition to 3-deoxyhexonic acid end-groups, significant quantities of terminal 2-C-methylglyceric and minor amounts of 2-C-methylribonic acid groups are formed during the alkali cooking. No alditol end-groups were detected in the unreduced cellulose.     

Acid-catalysed monoacetalation of some 2-deoxyalditols

Acid-catalysed monobutylidenation of 2-deoxy-D-arabino-hexitol, 2-deoxy-D-lyxo-hexitol, and 2-deoxy-D-erythro-pentitol yielded a 1,3-monoacetal as a kinetic product in each reaction. The thermodynamic products were 4,6-monoacetals from 2-deoxy-D-arabino-hexitol and 2-deoxy-D-lyxo-hexitol, and a 3,5-monoacetal from 2-deoxy-D-erythro-pentitol 2-Deoxy-D-lyxo-hexitol also yielded diastereoisomeric 4,5-monoacetals.     

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.     

Synthesis of some C-glycosyl- and polyhydroxyalkyl-pyridazines

Photo-oxygenation of 3-hydroxymethyl-5-(2,3-O-isopropylidene-β-d-erythrofuranosyl)-2-methylfuran, 5-(1,2:3,4-di-O-isopropylidene-d-arabino-tetritol-1-yl)-3-(1-hydroxyethyl)-2-methylfuran (8a), and 2-methyl-5-(1,2,3,4-tetra-O-acetyl-d-arabino-tetritol-1-yl)-3-furoic acid (8b) yielded the corresponding endo-peroxides, which were transformed into 4-hydroxymethyl-6-(2,3-O-isopropylidene-β-d-erythrofuranosyl)-3-methylpyridazine, 6-(1,2:3,4-di-O-isopropylidene-d-arabino-tetritol-1-yl)-4-(1-hydroxyethyl)-3-methylpyridazine, and 6-(d-arabino-tetritol-1-yl)-3-methylpyridazine by treatment with hydrazine. The γ-di-ketones (Z)-1-(1,2:3,4-di-O-isopropylidene-d-arabino-tetritol-1-yl)-3-(1-hydroxyethyl)pent-2-ene-1,4-dione and d-arabino-6,7,8,9-tetraacetoxy-4-methoxynonane-2,5-dione can be obtained by reduction of the endo-peroxides 9a and 9b (derived from 8a and 8b, respectively) with dimethyl sulphide. The C → O rearrangement reported for C-glycosyl endo-peroxides was also observed for 9a.     

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.     

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 entry reaction of the plant shikimate pathway is subjected to highly complex metabolite-mediated regulation

The plant shikimate pathway directs bulk carbon flow toward biosynthesis of aromatic amino acids (AAAs, i.e. tyrosine, phenylalanine, and tryptophan) and numerous aromatic phytochemicals. The microbial shikimate pathway is feedback inhibited by AAAs at the first enzyme, 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase (DHS). However, AAAs generally do not inhibit DHS activities from plant extracts and how plants regulate the shikimate pathway remains elusive. Here, we characterized recombinant Arabidopsis thaliana DHSs (AthDHSs) and found that tyrosine and tryptophan inhibit AthDHS2, but not AthDHS1 or AthDHS3. Mixing AthDHS2 with AthDHS1 or 3 attenuated its inhibition. The AAA and phenylpropanoid pathway intermediates chorismate and caffeate, respectively, strongly inhibited all AthDHSs, while the arogenate intermediate counteracted the AthDHS1 or 3 inhibition by chorismate. AAAs inhibited DHS activity in young seedlings, where AthDHS2 is highly expressed, but not in mature leaves, where AthDHS1 is predominantly expressed. Arabidopsis dhs1 and dhs3 knockout mutants were hypersensitive to tyrosine and tryptophan, respectively, while dhs2 was resistant to tyrosine-mediated growth inhibition. dhs1 and dhs3 also had reduced anthocyanin accumulation under high light stress. These findings reveal the highly complex regulation of the entry reaction of the plant shikimate pathway and lay the foundation for efforts to control the production of AAAs and diverse aromatic natural products in plants.

Characterization of Arabidopsis 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase enzymes and mutants revealed highly complex metabolite-mediated feedback regulation of the plant shikimate pathway.     

Improved preparation and synthetic uses of 3-deoxy-d-arabino-hexonolactone: an efficient synthesis of Leptosphaerin

Acetylation of d-glucono-1,5-lactone and subsequent treatment with triethylamine gave 2,4,6-tri-O-acetyl-d-erythro-hex-2-enono-1,5-lactone. Hydrogenation of the latter in the presence of palladium on carbon yielded 2,4,6-tri-O-acetyl-3-deoxy-d-arabino-hexono-1,5-lactone (5) in almost quantitative yield calculated from gluconolactone. Catalytic hydrogenation of 5 with platinum on carbon in the presence of triethylamine gave 2,4,6-tri-O-acetyl-3-deoxy-d-arabino-hexopyranose in quantitative yield. Deacetylation of 5 gave 3-deoxy-d-arabino-hexono-1,4-lactone, which was converted into 3-deoxy-5,6-O-isopropylidene-2-O-methanesulfonyl-d-arabino-hexono-1,4-lactone (10). The latter was converted into 2-acetamido-2,3-dideoxy-d-erythro-hex-2-enono-1,4-lactone (Leptosphaerin). When 10 was boiled in water in the presence of acid, it gave a high yield of 2,5-anhydro-3-deoxy-d-ribo-hexonic acid.     

Synthesis of 3-deoxy-d-arabino-2-heptulosonic acid 7-phosphate by phosphorylation of methyl (methyl 3-deoxy-d-arabino-heptulopyranosid)onate

3-Deoxy-d-arabino-2-heptulosonic acid 7-phosphate (5), the first committed intermediate in aromatic amino acid biosynthesis, has been synthesized in good yield by treatment of methyl (methyl 3-deoxy-d-arabino-2-heptulopyranosid)onate with diphenylphosphoric chloride under mild conditions to give the 7-diphenyl phosphate. Catalytic removal of the phenyl residues, followed by base-catalyzed hydrolysis resulted in formation of (methyl 3-deoxy-d-arabino-2-heptulopyranosid)onic acid dihydrogen 7-phosphate (4), which yielded a crystalline tris-(cyclohexylammonium) salt. Acid-catalyzed hydrolysis of 4 afforded 5, which was used to purify 3-dehydroquinate synthase.     

Synthesis of D-ristosamine and its derivatives

A convenient preparative route involving eleven steps starting from D-glucose is described for the synthesis of D-ristosamine (15) hydrochloride. Methyl 2-deoxy-β-D-arabino-hexopyranoside, prepared from 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex- 1-enitol, was benzylidenated, and the product mesylated to give methyl 4,6-O-benzylidene-2-deoxy-3-O-methylsulfonyl-β-D-arabino-hexopyranoside. Azidolysis of this compound and subsequent opening of the 1,3-dioxane ring with N-bromosuccinimide gave methyl 3-azido-4-O-benzoyl-6-bromo-2,3,6-trideoxy-βD-ribo-hexopyranoside. Simultaneous reduction of the azido and bromo groups gave a mixture that was benzoylated to give methyl N,O-dibenzoyl-β-D-ristosaminide and then hydrolyzed to 15 hydrochloride (3-amino-2,3,6-trideoxy-D-ribo-hexopyranose hydrochloride).     

Basic structure of the oligosaccharide repeating-unit of the Shigella flexneri O-antigens.

The reaction of sodium D-glucuronate with a synthetic peptide, AcTyrLysGlyNH₂ acetate, under physiological conditions, gave as major product the sodium salt of AcTyr-N-(D-arabino-5-carboxy-2,3,4,5-tetrahydroxy-1-pentenyl)-N-(D-arabino- 5-carboxy-3,4,5-trihydroxy-2-oxopentylidene)LysGlyNH₂ (2). The structure was elucidated on the basis of p.m.r., ¹³C-n.m.r., i.r., and u.v. spectra, and pH titration. Compound 2 is the product of oxidation of the sodium salt of AcTyr-N,N-bis(D- arabino-5-carboxy-2,3,4,5-tetrahydroxy-1-pentenyl)LysGlyNH₂, the bis-enol form of the di-D-fructuronic acid peptide obtained through the Amadori rearrangement. A new type of condensation that gives a product having a conjugated enol-keto-immonium group might take place when D-glucuronic acid reacts with peptides or proteins containing a lysine residue.     

The 13C-n.m.r. spectra of peracetylated cello-oligosaccharides

The reaction of 1,4-anhydro-2-deoxy-5,6-O-isopropylidene-d-arabino-hex-1-enitol (1) with m-chloroperbenzoic acid in ethanol gives 2,3-unsaturated ethyl glycosides together with saturated ethyl glycosides formed by trans-ring opening of 1,2-epoxide intermediates. Similar results are obtained on peroxidation of 1,4-anhydro-2-deoxy-3-O-(2,3:5,6-di-O-isopropylidene-α-d-mannofuranosyl)-5,6-O-isopropylidene-d-arabino-hex-1-enitol (2). Products resulting from osmylation of 1 and 2 and cleavage of the osmate esters are also described. 2-Deoxy derivatives are prepared from 1 and 2 by methoxymercuration-demercuration and also by reduction of 2-bromo-2-deoxy derivatives obtained by ethoxybromination.     

Solid-phase de novo synthesis of a (±)-2-deoxy-glycoside

The solid-phase synthesis of methyl 2-deoxy-3-O-benzyl-d,l-arabino-hexopyranoside was achieved in a six-step sequence via a de novo strategy based on the hetero-Diels-Alder reaction of a vinyl ether supported on an azalactone-functionalized polystyrene resin, followed by the functional modification of the heteroadduct and the final release of the methyl glycoside by acidic solvolysis.     

Degradation of 2-deoxyaldoses by alkaline hydrogen peroxide

Reaction of 2-deoxy-D-arabino-hexose, 2-deoxy-D-lyxo-hexose, and 2-deoxy-D-erythro-pentose with alkaline hydrogen peroxide in the presence of magnesium hydroxide afforded the corresponding 2-deoxyaldonic acid, the 1,4-lactone, and the 1-O-formyl derivative of the next lower alditol. The 2-deoxyaldonic acids were separated in 60–80% yields, as new, crystalline lithium salts. The 1,4-lactones were obtained under conditions that precluded intermidiate formation of the free acids: presumably, the reaction proceeded by way of an intermediate, furanosyl hydroperoxide, which was converted into the lactone by elimination of water. With an excess of alkaline hydrogen peroxide, in the absence of magnesium hydroxide, the substrates were degraded to formic acid, with concurrent decomposition of hydrogen peroxide. It is shown that decomposition of hydrogen peroxide is catalyzed by hydroperoxide anion, and that it takes place by both a chain, and a non-chain, process. The decomposition reactions afford an abundant source of hydroxyl radical capable of oxidizing a wide variety of compounds.     

Photo-oxygenation of polyhydroxyalkylfurans: rearrangement of O-acetyl derivatives

The photo-oxygenation of ethyl 2-methyl-5-(1,2,3,4-tetra-O-acetyl-d-lyxo-tetritol-1-yl)-3-furoate, ethyl 2-methyl-5-(1,2,3,4-tetra-O-acetyl-d-arabino-tetritol-1-yl)-3-furoate, 3-acetyl-2-methyl-5-(1,2,3,4-tetra-O-acetyl-d-arabino-tetritol-1-yl)furan, and ethyl 5-(1,4-di-O-acetyl-2,3-O-isopropylidene-d-lyxo-tetritol-1-yl)-2-methyl-3-furoate yielded the corresponding 1,4-endo-peroxides (3a–3d as pairs of diastereomers). Each diastereomer of the pairs 3a and 3d was isolated by fractional crystallisation. The rearrangement of the endo-peroxides at room temperature, by dissolution in CDCl₃, yielded the corresponding diepoxides and monoepoxides. The reduction of 3a–3d with methyl sulphide yielded the corresponding γ-diketones, ethyl (E)-2-C-acetyl-5,6,7,8-tetra-O-acetyl-2,3-dideoxy-d-lyxo-oct-2-en-4-ulosonate, ethyl (E)-2-C-acetyl-5,6,7,8-tetra-O-acetyl-2,3-dideoxy-d-arabino-oct-2-en-4-ulosonate, 3-C-acetyl-6,7,8,9-tetra-O-acetyl-1,3,4-trideoxy-d-arabino-non-3-eno-2,5-diulose, and ethyl (E)-2-C-acetyl-5,8-di-O-acetyl-2,3-dideoxy-6,7-O-isopropylidene-d-lyxo-oct-2-en-4-ulosonate, which can isomerise into the corresponding Z isomers.     

Some reactions of a furanoid 2-aminoglycal derivative

Some reactions, catalyzed by p-toluenesulfonic acid, of 2-acetamido-1,4-anhydro-2-deoxy-5,6-O-isopropylidene-d-arabino-hex-1-enitol (1), a furanoid 2-aminoglycal derivative, were examined. Reaction with methyl and with benzyl alcohol gave the corresponding furanoid 2,3-unsaturated glycosides (2 and3) in good yield. Similar reaction with water, followed by acetylation, gave 2-acetamido-1,4,6-tri-O-acetyl-2,3-dideoxy-d-ribo-hex-2-enopyranose, which was hydrogenated to 2-acetamido-1,4,6-tri-O-acetyl-2,3-dideoxy-d-ribo-hexopyranose (an N-acetyllividosamine derivative) and its arabino analog. Addition of a catalytic amount of p-toluenesulfonic acid to a solution of 1 in dry 1,4-dioxane afforded furanoid, (1→3)-disaccharides in high yield. Tosylation of 1 to yield a furan derivative was, however, unsuccessful. Hydrogenation of methyl 2-acetamido-2,3-dideoxy-5,6-O-isopropylidene-d-erythro-hex-2-enofuranoside (2) was examined by use of palladium-on-carbon, as well as platinum oxide, as the catalyst