Addition of halogenoazides to glycals

Addition of chloroazide to 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-lyxo- (1) and -d-arabino-hex-1-enitol (2) under u.v. irradiation proceeds regio- and stereo-selectively yielding mainly O-acetyl derivatives of 2-azido-2-deoxy-d-galactopyranose and -d-glucopyranose, respectively. 3,4,6-Tri-O-acetyl-2-chloro-2-deoxy-α-d-galactopyranosyl azide and 3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-d-talopyranose (from 1), and 1,3,4,6-tetra-O-acetyl-2-chloro-2-deoxy-α-d-glucopyranosyl azide and 1,3,4,6-tetra-O-acetyl-2-azido-2-deoxy-α-d-mannopyranose (from 2) are byproducts. 1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-d-lyxo- and -d-arabino-hex-1-enitol reacted more rapidly with chloroazide, to give, under irradiation, derivatives of 2-azido-2-deoxy-d-galactose and -d-glucose, respectively. However, reaction in the dark gave mainly O-benzyl derivatives of 2-chloro-2-deoxy-α-d-galacto- and -α-d-glucopyranosyl azide. The difference between the products obtained may depend on the existence of two parallel processes, one radical (under irradiation), and the other ionic (reaction in the dark).     

Synthesis of 2-deoxy-2-fluorohexoses by fluorination of glycals in aqueous media

1,5-Anhydro-2-deoxy-d-arabino- (d-glucal), 1,5-anhydro-2-deoxy-d-lyxo- (d-galactal), and 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) were fluorinated in water and organic solvent-water with molecular fluorine and, for ¹⁸F-labelled compounds, with [¹⁸F]fluorine. Chemical yields of 40 and 10% were obtained for 2-deoxy-2-fluoro-d-glucose and 2-deoxy-2-fluoro-d-mannose, respectively, and 35 and 5% for 2-deoxy-2-fluoro-d-galactose (12) and 2-deoxy-2-fluoro-d-talose (13), respectively. In the fluorination of 3, the chemical yields of 12 and 13 were 38 and 6%, respectively. An l.c. separation of 2-deoxy-2-fluoro-d-hexoses is described.     

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.     

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 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).     

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     

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%.     

Synthesis of C-arabinofuranosyl compounds. Phosphonate and carboxylate isosteres of d-arabinose 1,5-bisphosphate

Electrophile-mediated cyclization of 3,4,6-tri-O-benzyl-1,2-dideoxy-d-arabino-hex-1-enitol with N-bromosuccinimide yielded primarily 2,5-anhydro-3,4,6-tri-O-benzyl-1-bromo-1-deoxy-d-glucitol (10). This apparently kinetically controlled reaction was of key importance in the successful synthesis of a phosphonate analog of β-d-arabinose 1,5-bisphosphate (1), namely, 2,5-anhydro-1-deoxy-1-phosphono-d-glucitol 6-phosphate (4), whith high stereoselectivity. By contrast, condensation of the sodium salt of tetraethyl methylenediphosphonate and 2,3,5-tri-O-benzyl-d-arabinose (7) gave a phosphonate compound slightly enriched in the 2,5-anhydro-d-mannitol (α) isomer. In the Wittig—Michael reaction of stabilized phosphoranes with 7, the α isomer preponderated. Since equilibration of methyl 3,6-anhydro-4,5,7-tri-O-benzyl-2-deoxy-d-glycero-d-galacto- (33) and -d-gulo-heptonate (34) (5:1) resulted in a 1:1 α:β ratio, the preference for the 2,5-anhydro-d-mannitol (α) isomer probably reflects a kinetic bias. The carbomethoxy anomers were converted independently into the α and β carboxylate isosteres (5 and 6, respectively) of d-arabinose 1,5-diphosphate. Empirical force field calculations (MMP2) and n.m.r. experiments were conducted on the pairs of diastereomers 9 and 10, and 33 and 34. The calculations predict that the α and β anomers of each pair have similar energies, differing by only 2.1 kJ/mol. Compounds 4, 5, and 6 were evaluated for biological activity.     

Additions comparées des halogenès sur le 3,4,6-tri-O-acétyl-1,5-anhydro-1,5-didésoxy-, d-arabino-hex-1-énitol et l'analogue 3,4,6-tri-O-benzylé; effets de solvant sur la formation spécifique des dérivés 1,2-didésoxy-1,2-dihalogéno-α-d-glucopyranoses

Comparison of the addition of chlorine and bromine to 3,4,6-tri-O-acetyl-1,5-anhydro-1,5-dideoxy-d-arabino-hex-l-enitol (1) and to the 3,4,6-tri-O-benzyl analog (2) shows a greater stereoselectivity for 2 in the formation of 1,2-dideoxy-1,2-dihalo-geno-α-d-glucopyranose derivatives. Stereospecific addition took place in nonpolar solvents, and a quantitative correlation was established between the polarity of the solvent and the stereospecificity of the addition of chlorine to 1 and 2. Similar results were observed for the halogenomethoxylation of 1 and 2.     

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.     

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.     

Preparation of some acylated D-arabino-hexopyranosuloses and 4-deoxy-D-glycero-hex-3-enopyranosuloses

Oxidation of 1,3,4,6-tetra-O-benzoyl-α- and β-D-glucopyranose gave the tetra-O-benzoyl-α- and -β-D-arabino-hexopyranosuloses (3α and β), from which benzoic acid was readily eliminated to give the anomeric tri-O-benzoyl-4-deoxy-D-glycero-hex-3-enopyranosuloses (4α and β). The anomeric 1-O-acetyl-tri-O-benzoyl-D-arabino-hexopyranosuloses (7α and β) were obtained as very unstable syrups which readily lost benzoic acid. Treatment of tetra-O-benzoyl-2-O-benzyl-D-glucopyranose (1) with hydrogen bromide gave 3,4,6-tri-O-benzoyl-α-D-glucopyranosyl bromide (5) in one step.     

1,4-Rearrangement of 7-(2-acetamido-2,3-dideoxyhex-2-enopyranosyl)theophylline derivatives

Treatment of 7-2(-acetamido-2,3-dideoxyhex-2-enopyranosyl)theophylline derivatives with boron trifluoride etherate in boiling methanol led to the isolation of 7-(methyl 2-acetamido-2,3,4-trideoxyhex-2-enopyranosid-4-yl)theophylline derivatives. Some mechanistic features of this 1,4-rearrangement followed by solvolysis are discussed, and a rationalization of the formation of the C-4′ derivatives in the fusion reaction of 2-acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-l-enitol with theophylline is offered.     

Isolation and identification of products in the reaction of 2-acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enitol with theophylline

Fusion of 2-acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-d-arabino-hex-1-enitol with theophylline, in the presence of boron trifluoride etherate as the catalyst, caused condensation to occur. This reaction afforded a variety of products of nucleosidic character, which were successively separated by repeated chromatography on silica gel. The structures of the products were determined, on the basis of X-ray crystallographic analysis (for three compounds) and by means of n.m.r.-spectral data and mass spectrometry, as the following: 7-(2-acetamido-4,6-di-O-acetyl-2,3-dideoxy-β-d-erythro-hex-2-enopyranosyl)theophylline, the corresponding α- and β-d-threo derivatives, and 7-(2-acetamido-6-O-acetyl-2,3-dideoxy-α-d-threo-hex-2-enopyranosyl)theophylline and its β anomer.In addition to these 2′,3′-unsaturated nucleosides having the base linked at C-1′, three products of a new type, having the base attached at C-4′, were also isolated: 7-(methyl 2-acetamido-6-O-acetyl-2,3,4-trideoxy-β-d-erythro-hex-2-enopyranosid-4-yl)theophylline, and the corresponding α-d-threo and α-d-erythro isomers.The correlation of the data obtained by X-ray structure analysis and proton nuclear magnetic spectroscopy, together with their application for the determination of configuration and conformation of these compounds, are discussed. It appears that the ¹H-n.m.r. data alone do not suffice for unambiguous and correct structure determination for these classes of compounds.     

Aminodesoxyzucker und glycosylamin-synthesen durch oxyaminierung von hex-2-enopyranosiden und hex-1-enitolen. Synthese des N-acetylmycosamins

The vicinal cis-oxyamination of ethyl 4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside (1) and of methyl 4-O-acetyl-2,3,6-trideoxy-α-D-erythro-hex-2-enopyranoside (11) as well as of 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-(17) and -D-lyxo-hex-1-enitol (23) with Chloramine T-osmium tetraoxide was investigated (Sharpless reaction). The hex-2-enopyranosides 1 and 11 yielded the corresponding 3-deoxy-3-p-toluenesulfonamido-and 2-deoxy-2-p-toluenesulfonamido-hexopyranosides with the manno configuration in the ratio 2:1. The glycals 17 and 23 reacted with formation of the corresponding α-D-gluco and α-D-galactoN-tosyl-glycosylamines and of the 2-deoxy-2-p-toluenesulfonamidoglycoses in the ratio 3:1. The stereospecifity and the regioselectivity of the reactions are discussed. Quantum chemical calculations on models for the hex-2-enopyranosides 1 and 11 suggest a [3+2] cycloaddition of the N-tosylimido osmium(VIII) oxide in preference to a [2+2] mechanism with participation of the metal species. The preparative importance of the oxyamination reaction is demonstrated by a simple synthesis of N-acetyl-mycosamine.     

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 synthesis of the α-d-anomers of “homonucleosides”: derivatives of 2,5-anhydro-d-altritol

Reaction of 2,3,5-tri-O-benzyl-d-ribofuranosyl bromide with mercuric cyanide afforded an anomeric mixture of cyanides (3) and 1,4-anhydro-2,3,5-tri-O-benzyl-d-erythro-pent-1-enitol (6). Reduction of 3 with lithium aluminum hydride gave a pair of epimeric amines (4 and 5), which were separated by chromatography and characterized by conversion into the known 2,5-anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-ureido-d-allitol (7) and its epimer, 2,5-anhydro-3,4,6-tri-O-benzyl-1-deoxy-1-ureido-d-altritol (8). Compound 8 and its precursor were used for the synthesis of various “α-homonucleosides”.     

Nitrous acid deamination of conformationally inverted aminodeoxyhexopyranoses

Nitrous acid deamination of 2-amino-1,6-anhydro-2-deoxy-β-D-glucopyranose (1) in the presence of weakly acidic, cation-exchange resin gave 1,6:2,3-dianhydro-β-D-mannopyranose (3) and 2,6-anhydro-D-mannose (6), characterized, respectively, as the 4-acetate of 3 and the per-O-acetylated reduction product of 6, namely 2,3,4,6- tetra-O-acetyl-1,5-anhydro-D-mannitol, obtained in the ratio of 7:13. Comparative deaminatior of the 4-O-benzyl derivative of 1 led to similar qualitative results. Deamination of 3-amino-1,6-anhydro-3-deoxy-β-D-glucopyranose gave 1,6:2,3- and 1,6:3,4-dianhydro-β-D-allopyranose (13 and 16), characterized as the corresponding acetates, obtained in the ratio of 31:69, as well as the corresponding p-toluenesulfonates. Deamination of 4-amino-1,6-anhydro-4-deoxy-β-D-glucopyranose and of its 2-O-benzyl derivative gave the corresponding 1,6:3,4-D-galacto dianhydrides as the only detectable products. 2,5-Anhydro-D-glucose, characterized as the 1,3,4,6-tetra-O- acetyl derivative of the corresponding anhydropolyol, was obtained in 39% yield from the same deamination reaction performed on 2-amino-1,6-anhydro-2-deoxy-β-D- mannopyranose (24). In 90% acetic acid, the nitrous acid deamination of 24, followed by per-O-acetylation, gave only 1,3-4-tri-O-acetyl-2,5-anhydro-α-D-glucoseptanose. In the case of 1,6-anhydro-3,4-dideoxy-3,4-epimino-β-D-altropyranose, only the corresponding glycosene was formed, namely, 1,6-anhydro-3,4-dideoxy-β-D-threo--hex-3-enopyranose.     

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.     

Derivatives of 2,5-anhydroallitol and 2,5-anhydroaltritol

Two routes to protected derivatives of 2,5-anhydroallitol were investigated. The first route, involving a two-step reduction of 2,5-anhydro-6-O-benzoyl-3,4-O-isopropylidene-D-allonitrile (4), gave a mixture of 2,5-anhydro-6-O-benzoyl-3,4-O-isopropylidene-D-altritol (7) and a lesser amount of the desired 2,5-anhydro-6-O-benzoyl-3,4-O-isopropylidene-D-allitol (6). Isomerization was shown to occur in the first reduction step—treatment of the nitrile 4 with Raney nickel, sodium hypophosphite, and acetic acid. The second route gave isomerically pure 2,5-anhydro-3,4,6-tri-O-benzyl-D-allitol (21) via reduction of the corresponding ethyl allonate (18).