The synthesis of 6-deoxy-6-fluoro-α,α-trehalose and related analogues

Selective acid-catalysed methanolysis of 2,3,2′,3′-tetra-O-benzyl-4,6:4′,6′-di-O-benzylidene-α,α-trehalose yielded the monobenzylidene derivative, which was converted into the 4,6-dimesylate. Selective nucleophilic displacement of the primary sulphonyloxy group then gave 2,3-di-O-benzyl-6-deoxy-6-fluoro-4-O-mesyl-α-d-glucopyranosyl 2,3-di-O-benzyl-4,6-O-benzylidene-α-d-glucopyranoside. Removal of the protecting groups then yielded 6-deoxy-6-fluoro-α,α-trehalose. In addition, 6-deoxy-6-fluoro-4-O-mesyl-α,α-trehalose and a derivative of 4-chloro-4,6-dideoxy-6-fluoro-α-d-galactopyranosyl α-d-glucopyranoside were also prepared from the same substrate. Iodide displacement of 2,3-di-O-benzyl-4,6-di-O-mesyl-α-d-glucopyranosyl 2,3-di-O-benzyl-4,6-di-O-mesyl-α-d-glucopyranoside afforded the 6-iodide and 6,6′-di-iodide in yields of 31 and 36%, respectively. Similarly, the 6-azide and 6,6′-diazide were isolated in yields of 17 and 21%, respectively.     

The synthesis of racemic purpurosamine B

Starting from methyl 4,6-dichloro-4,6-dideoxy-α-D-galactopyranoside (1), D-chalcose (4,6-dideoxy-3-O-methyl-D-xcylo-hexopyranose) (5) was prepared by dechlorination with tributyltin hydride, selective benzoylation with benzoyl cyanide at O-2, methylation at O-3, and acid hydrolysis. D-Chalcose (5) was obtained as well by direct methylation of 1 with diazomethane at O-3, reduction with tin hydride, and hydrolysis. Chalcosyl bromide prepared from 5 was not very suitable for β-glycoside synthesis under Koenigs-Knorr conditions, and better results were obtained with 2- O-acetyl-4,6-dichloro-4,6-dideoxy-3-O-methyl-α-D-galactopyranosyl bromide, which gave β-glycosides with methanol, cyclohexanol, benzyl alcohol, 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose, and methyl 2,3-di-O-benzyl-6-deoxy-α-D-glucopyranoside. After dechlorination with tributyltin hydride, the corresponding β-glycosides of D-chalcose were obtained in good yield.     

3′,6′-anhydro-6-O-corynomycoloyl trehalose: Synthesis and identification as the impurity in synthetic cord factor preparations

Acylation of 2,3,4,2′,3′,4′-hexa-O-benzyl-6,6′-di-O-methanesulphonyl-α-α-trehalose (1) with a reduced amount of potassium corynomycolate yielded a mixture which consisted mainly of 2,3,4,2′,3′,4′-hexa-O-benzyl-6-O-corynomycoloyl-6′-O-methanesulphonyl-α,α-trehalose (2). Catalytic hydrogenolysis of 2 gave the mono-mesylate 4 which was converted into 3′,6′-anhydro-6-O-corynomycoloyl-α,α-trehalose (5) but treatment with sodium hydride. The structure of 5 was studied by mass-spectroscopy. Compound 5 was found to be identical with the byproduct obtained in the acylation of 6,6′-di-O-p-toluenesulphonyl-α,α-trehalose with potassium corynomycolate.     

Sucrochemistry : Part X. 1′,4,6′-tri-O-mesylsucrose penta-acetate: A comparison of the reactivity at the 4 and 1′ positions

The 1′,4,6′-trisulphonate 2, obtained by mesylation of sucrose 2,3,3′,4′,6-penta-acetate (1), undergoes nucleophilic substitution with sodium benzoate in hexamethylphosphoric triamide at positions 1′,4, and 6′ to give 1,6-di-O-benzoyl-β-D-fructofuranosyl 4-O-benzoyl-α-D-galactopyranoside penta-acetate (3), and selectively at positions 4 and 6′ to give 6-O-benzoyl-1-O-mesyl-β-D-fructofuranosyl 4-O-benzoyl-α-D-galactopyranoside penta-acetate (4). The products 3 and 4 were identified from their ¹H-n.m.r. spectra and by O-deacylation to give β-D-fructofuranosyl α-D-galactopyranoside (5) and its 1-methanesulphonate 6, respectively. Treatment of the trisulphonate 2 with sodium azide gave analogous products, namely, 1,6-diazido-1,6-dideoxy-β-D-fructofuranosyl 4-azido-4-deoxy-α-D-galactopyranoside penta-acetate (8) and 6-azido-6-deoxy-1-O-mesyl-β-D-fructofuranosyl 4-azido-4-deoxy-α-D-galactopyranoside penta-acetate (7).     

Synthesis of derivatives of methyl β-sophoroside

Selective tritylation of methyl β-sophoroside (1) and subsequent acetylation gave the 3,4,2′,3′,4′-penta-O-acetyl-6,6′-di-O-trityl derivative, which was O-detritylated, and the product p-toluenesulfonylated, to give methyl 3,4,2′,3′,4′-penta-O-acetyl-6,6′-di-O-p-tolylsulfonyl-β-sophoroside (4) in 63% net yield. Compound 4 was also obtained in 69% yield by p-toluenesulfonylation of 1, followed by acetylation. Several, 6,6′-disubstituted derivatives of 1 were synthesized by displacement reactions of 4 with various nucleophiles. Treatment of 4 with sodium methoxide afforded methyl 3,6:3′,6′-dianhydro-β-sophoroside. Several 6- and 6′-monosubstituted derivatives of 1 were prepared, starting from the 4,6-O-benzylidene derivative of 1.     

The first replacement of a chlorosulphonyloxy group by chlorine at C-2 in methyl α-D-glucopyranoside and sucrose derivatives

Treatment of methyl 3-O-acetyl-4,6-O-benzylidene-α-D-glucopyranoside 2-chlorosulphate (2), 3,4,6,3′,4′,6′-hexa-O-acetylsucrose 2,1′-bis(chlorosulphate), 3,4,6,3′,4′,6′-hexa-O-acetyl-1′-O-benzoylsucrose 2-chlorosulphate, and 3,4,3′,4′-tetra-O-acetyl-6,6′-dichloro-6,6′-dideoxysucrose 2,1′-bis(chlorosulphate) with lithium chloride in hexamethylphosphoric triamide gave the corresponding chlorodeoxy-manno derivatives. Treatment of the 2-chlorosulphate 2 with such nucleophilic reagents as lithium bromide, sodium azide, sodium chloride, and sodium benzoate in hexamethylphosphoric triamide gave the 2-hydroxy compound as a major product. Selective chlorination at C-1′ was achieved when 3,4,6,3′,4′,6′-hexa-O-acetylsucrose was treated with sulphuryl chloride in a mixture of pyridine and chloroform.     

Use of positively charged,leaving groups in the synthesis of α-D-linked galactosides. Attempted synthesis of 3-O-α-(D-(galactopyranosyl)-D-galactose

Quaternary ammonium and phosphonium salts were readily obtained by treating 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide with tertiary amines and phosphines in various solvents under anhydrous conditions. Optical rotations and n.m.r. spectra of the hygroscopic syrups indicated that they exist mainly in the β-D configuration. Several dialkyl sulfides reacted very slowly with the galactosyl bromide and no conclusive evidence for sulfonium salt formation was obtained. 2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl chloride failed to react with any of the nucleophiles.Methanolysis reactions of the phosphonium salts were too slow to be practical and were not studied extensively. Methanolyses of several quaternary ammonium salts in various solvents were not completely stereospecific, but gave good yields of methyl 2,3,4,6-tetra-O-benzyl-α-D-galactopyranoside. Attempted reactions of benzyl 2-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside with quaternary ammonium salts derived from 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide failed to produce the corresponding derivative of 3-O-(α-D-galactopyranosyl)-D-galactose.     

Reaction of methanesulphonyl chloride-N,N-dimethylformamide with partially esterified derivatives of sucrose

Treatment of sucrose 2,3,3′,4′,6-penta-acetate (1) with methanesulphonyl chloride-N,N-dimethylformamide (reagent A) gave the 1′,4,6′-trichloride 2, the 1′-O-formyl-4,6′-dichloride 3, the 4,6′-dichloride 4, and the 1′,4-di-O-formyl-6′-chloride 5. De-esterification of 3 afforded the unsubstituted 4,6′-dichloride 6 which, on acetylation, gave the corresponding hexa-acetate 7, also prepared by acetylation of 4. In compounds 2, 3, and 4, substitution at C-4 by chloride ion occurred with inversion of configuration. The structure of 5 was confirmed by conversion into the known 6′chloro-6′-deoxysucrose hepta-acetate by de-esterification followed by acetylation. Treatment of sucrose 1′,2,3,3′,4′,6′-hexa-acetate (10) with the reagent gave the 4,6-dichloride 11 and 4-O-formyl-6-chloride 12. The formyl group in 12 was selectively removed by using an anion-exchange resin to give 16. De-esterification of 12 with methanolic sodium methoxide gave 6-chloro-6-deoxysucrose (13) which, on acetylation and benzoylation, afforded the hepta-acetate 14 and the hepta-benzoate 15, respectively. Alternatively, 15 was prepared by the reaction of 1′,2,3,3′,4,4′,6′-hepta-O-benzoylsucrose with reagent A. Treatment of 14 with sodium methoxide in methanol followed by acetylation gave 3,6-anhydrosucrose hexa-acetate (24). Reaction of sucrose 2,3,3′,4,4′-pentabenzoate (17) with reagent A gave the known 1′,6,6′-trichloro-1′,6,6′-trideoxysucrose pentabenzoate (18) and 1′-O-formyl-6,6′-dichloride 19. Treatment of 19 with anion-exchange resins selectively removed the formyl group to give 20. The structure of 20 was confirmed by conversion into the 1′-chlorosulphate-6,6′-dichloride (21). Treatment of sucrose 1′,2,3,3′,4,4′-hexabenzoate (22) with reagent A gave the expected 6,6′-dichloride (23).     

The preparation of 4,6-dichloro-4,6-dideoxy-α-d-galactopyranosyl 6-chloro-6-deoxy-,β-d-fructofuranoside and the conversion of chlorinated derivatives into anhydrides

Under carefully controlled conditions, sucrose is converted by selective reaction with sulphuryl chloride into either 6-chloro-6-deoxy-α-d-glucopyranosyl 6-chloro-6-deoxy-β-d-fructofuranoside or 4,6-dichloro-4,6-dideoxy-α-d-galactopyranosyl 6-chloro-6-deoxy-β-d-fructofuranoside, which could be isolated without recourse to chromatography. Treatment of the dichloride with sodium methoxide gave 3,6-anhydro-β-d-glucopyranosyl, 3,6-anhydro-β-d-fructofuranoside in high yield. In contrast, 4,6-dichloro-4,6-dideoxy-α-d-galactopyranosyl 6-chloro-6-deoxy-β-d-fructofuranoside gave, in two distinct stages, 3,6-anhydro-4-chloro-4-deoxy-α-d-galactopyranosyl 6-chloro-6-deoxy-β-d-fructofuranoside and 3,6-anhydro-4-chloro-4-deoxy-α-d-galactopyranosyl 3,6-anhydro-β-d-fructofuranoside. The structures of these products were ascertained by ¹H-n.m.r. and mass spectrometry.     

Derivatives of β-D-fructofuranosyl α-D-galactopyranoside

De-etherification of 6,6′-di-O-tritylsucrose hexa-acetate (2) with boiling, aqueous acetic acid caused 4→6 acetyl migration and gave a syrupy hexa-acetate 14, characterised as the 4,6′-dimethanesulphonate 15. Reaction of 2,3,3′4′,6-penta-O-acetylsucrose (5) with trityl chloride in pyridine gave a mixture containing the 1′,6′-diether 6 the 6′-ether 9, confirming the lower reactivity of HO-1′ to tritylation. Subsequent mesylation, detritylation, acetylation afforded the corresponding 4-methanesulphonate 8 1′,4-dimethanesulphonate 11. Reaction of these sulphonates with benzoate, azide, bromide, and chloride anions afforded derivatives of β-D-fructofuranosyl α-D-galactopyranoside (29) by inversion of configuration at C-4. Treatment of the 4,6′-diol 14 the 1,′4,6′-triol 5, the 4-hydroxy 1′,6′-diether 6 with sulphuryl chloride effected replacement of the free hydroxyl groups and gave the corresponding, crystalline chlorodeoxy derivatives. The same 4-chloro-4-deoxy derivative was isolated when the 4-hydroxy-1′,6′-diether 6 was treated with mesyl chloride in N,N-dimethylformamide.     

Further applications of selective displacements in an unsymmetrical ditriflate. Synthesis of new triamino and tetraamino disaccharides of the trehalose type

Although the known ring-opening with sodium azide in 2,3-anhydro-4,6-O-benzylidene-α-d-allopyranosyl 2,3-anhydro-4,6-O-benzylidene-α-d-allopyranoside gave mainly symmetrical 2-azido-4,6-O-benzylidene-2-deoxy-α-d-allopyranosyl 2-azido-4,6-O-benzylidene-2-deoxy-α-d-allopyranoside (2), the unsymmetrical 2,3′-diazido isomer 3 having the α-d-altro, α-d-gluco configuration was shown to be a second product that can be conveniently isolated on a preparative scale. The ditriflate 4 derived from 3 was subjected to regioselective displacement in the altro moiety with sodium azide, followed by displacement with sodium benzoate in the gluco moiety, to give a 2,3,3′-triazide having the α-d-manno, α-d-manno configuration. Alternatively, 4 was subjected to displacement first with benzoate and then with azide, thus providing the regioisomeric 2,3,2′-triazide of the same configuration. The ditriflate obtained from 2 furnished the corresponding 2,3,2′,3′-tetraazido derivative. Minor proportions of elimination products also arose in these reactions. The protected azido sugars were converted by standard methods into the 2,3,2′- and 2,3,3′-triamino derivatives and the 2,3,2′,3′-tetraamino derivative of α-d-mannopyranosyl α-d-mannopyranoside.     

Synthesis of 3-amino-3-deoxy-α-d-mannopyranosyl α-d-mannopyranoside by way of a regioselective Sn2 displacement in an unsymmetrical,disecondary ditriflate of a disaccharide

3-Amino-3-deoxy-α-d-mannopyranosyl α-d-mannopyranoside was synthesized from known 2-O-benzyl-4,6-O-benzylidene-α-d-altropyranosyl 3-O-benzyl-4,6-O-benzylidene-α-d-glucopyranoside, which is available in four steps from commercial α,α-trehalose. The 3,2′-ditriflate of the blocked disaccharide was first treated with sodium azide under phase-transfer conditions, which effected regioselective displacement of the 3-triflyloxy group, and subsequent reaction with sodium benzoate in N,N-dimethylformamide displaced the 2′-triflyloxy group. The blocked, 3-azido-2′-O-benzoyl derivative of α-d-mannopyranosyl α-d-mannopyranoside so obtained was conventionally debenzoylated and debenzylidenated, and subsequent, palladium-catalyzed transfer hydrogenation with formic acid effected reduction of the azido group and cleavage of the benzyl protecting groups, to give the title disaccharide in 13% over-all yield.     

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%.     

Untersuchungen zur modifikation der cellobiose und synthese von methyl-2,6-didesoxy-4-O-(6-desoxy-β-D-glucopyranosyl)-α-D-arabino-hexopyranosid (methyl-4-O-β-D-chinovosyl-α-D-olivosid)

Starting with cellobiosides, several different procedures were employed to prepare 6,6′-dichloro-6,6′-dideoxy, 6,6′-dibromo-6,6′-dideoxy, and 6,6′-dideoxy-6,6′-diiodo derivatives. Reduction with lithium aluminum hydride or nickel boride afforded peracetyl derivatives of methyl, phenyl, and benzyl 6-deoxy-4-O-(6-deoxy-β-D-glucopyranosyl)-β-D-glucopyranoside. Following acetolysis or hydrogenolysis, the glycosyl halide and the corresponding-glycal 40 were prepared. Iodomethoxylation of 40 and subsequent reduction gave the title compound. Alternatively, the halomethoxylation products of cellobial hexaacetate gave, by various procedures, the 2,6,6′-trideoxy-2,6,6′-trihalo derivatives, which, in turn, could be reduced to the title compound. The structures of the derivatives prepared were unequivocally assigned by n.m.r. spectroscopy. The various reaction sequences were compared with respect to the number of steps and the yields obtained.     

The synthesis of 4′,6′-diacetamido-4′,6′-dideoxycellobiose hexa-acetate from lactose

Reaction of methyl 4′,6′-di-O-mesyl-β-lactoside pentabenzoate (8), synthesised via the 4′,6′-O-benzylidene derivative (6), with sodium azide in hexamethylphosphoric triamide gave three products. In addition to the required 4′,6′-diazidocellobioside (9), an elimination product, methyl 4-O-(6-azido-2,3-di-O-benzoyl-4,6-dideoxy-α-L-threo-hex-4-enopyranosyl)-2,3,6-tri-O-benzoyl-β-D-glucopyranoside (12), and an unexpected product of interglycosidic cleavage, methyl 2,3,6-tri-O-benzoyl-β-D-glucopyranoside (13), were formed. The origin of the latter product is discussed. The diazide 9 was converted into 4′,6′-diacetamido-4′,6′-dideoxycellobiose hexa-acetate (16) by sequential debenzoylation, catalytic reduction, acetylation, and acetolysis.     

Oxazoline synthesis of 1,2-trans-2-acetamido-2-deoxyglycosides. Glycosylation with 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-D-galactopyrano)-[2′,1′:4,5]-2-oxazoline

The glycosylating activity of 2-methyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-α-D-galactopyrano)-[2′,1′:4,5]-2-oxazoline has been tested in reaction with partially protected saccharides having free primary or secondary hydroxyl groups or with hydroxy amino acids. 3-O-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-galactopyranosyl)-N-benzyloxycarbonyl-L-serine benzyl ester (3), 6-O-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-D-galactopyranose (5), p-nitrophenyl 2-acetamido-6-O-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-2-deoxy-β-D-glucopyranoside (7), 6-O-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-D-glucose (9), and 3-O-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-D-glucose (11) were synthesized in high yield.     

The synthesis of chlorodeoxyhexofuranoid derivatives

The reaction of 1,2-O-isopropylidene-α- d-glucofuranose with sulfuryl chloride at 0° and at 50° afforded 6-chloro-6-deoxy-1,2-O-isopropylidene-α- d-glucofuranose 3,5-bis(chlorosulfate) ( 3) and 5,6-dichloro-5,6-dideoxy-1,2-O-isopropylidene-β- l-idofuranose 3-chlorosulfate ( 7, not characterised), respectively. Dechlorosulfation of 3 afforded the hydroxy derivative, whereas treatment of 3 with pyridine gave the 3,5-(cyclic sulfate). Dechlorosulfation of 7 afforded 5,6-dichloro-5,6-dideoxy-1,2-O-isopropylidene-β- l-idofuranose which, on acid hydrolysis, was converted into 3,6-anhydro-5-chloro-5-deoxy- l-idofuranose. 5-Chloro-5-deoxy-α- l-idofuranosidurono-6,3-lactone and 5-chloro-5-deoxy-β- l-idofuranurono-6,3-lactone derivatives were also prepared.     

An Improved Synthesis of dl-Histidine

The 5-O-(2,6-diamino-2,6-dideoxy-α-d-glucopyranosyl)-2-deoxystreptamine derivative and its related compounds were synthesized by a modified Königs-Knorr condensation of 3,4-di-O-acetyl-2,6-dideoxy-2-(2′,4′-dinitroanilino)-6-phthalimido-α-d-glucopyranosyl bromide (I) with 4,6-di-O-acetyl-N,N′-dicarbobenzoxy-2-deoxystreptamine (V) and the corresponding streptamine (XI). The aglycons (V) and (XI) were prepared by selective acetylation of the aminocyclitol derivatives by taking advantage of the reactivity difference between the hydroxyl groups at C₅ and C₄ or C₆. The condensed products were converted to N-acetyl derivatives and were shown to have the α-configuration by PMR spectroscopy.     

Synthesis and reactions of cyclic acetal derivatives of 6,6′-dichloro-6,6′-dideoxysucrose

Treatment of 6,6′-dichloro-6,6′-dideoxysucrose with a combination of 2,2-dimethoxypropane, N,N-dimethylformamide, and toluene-p-sulphonic acid (reagent A), followed by acetylation, gave the 1′,2:3,4-diacetal 1 (39%) and the 1′,2-acetal 2 (37%). A similar reaction of methyl 6-chloro-6-deoxy-α-D-glucopyranoside with reagent A yielded the corresponding 2,3- and 3,4-acetal derivatives in yields of 29% and 9%, respectively. The structures of 1 and 2 have been confirmed by ¹H-n.m.r. spectroscopy and by chemical transformations.     

Purification and properties of an endo-(1 leads to 3)-beta-D-glucanase from malted barley

3,6-Anhydro-α-D-galactopyranose 1,2-(methyl orthoacetate) and its 4-acetate were synthesized from 2,3,4-tri-O-acetyl-6-O-tosyl-α-D-galactopyranosyl bromide. Condensation of the above-mentioned, acetylated ortho ester with 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose gave 6-O-(2,4-di-O-acetyl-3,6-anhydro-β-D-galactopyranosyl)-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose. The same disaccharide derivative was synthesised from 6-O-β-D-galactopyranosyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose by mono-O-tosylation followed by treatment with alkali and acetylation.