Synthesis of a 2-acetamido-5-amino-2,5-dideoxy- -xylopyranosyl derivative

2-Acetamido-5-amino-2,5-dideoxy- -xylopyranosyl hydrogensulfite (11) has been synthesized from benzyl 2-(benzyloxycarbonylamino)-2-deoxy-5,6-O-isopro-pylidene-β- -glucofuranoside (1). O-Deisopropylidenation of 1 gave the triol 2, which was converted, via oxidative cleavage at C-5-C-6 and subsequent reduction, into the related benzyl β- -xylofuranoside derivative (3). Catalytic reduction of benzyl 2-(benzyloxycarbonylamino)-2-deoxy-5-O-tosyl-β- -xylofuranoside, derived from 3 by selective tosylation, and subsequent N-acetylation, afforded benzyl 2-acetamido-2-deoxy-5-O-tosyl-β- -xylofuranoside, which was treated with sodium azide to give the corresponding 5-azido derivative (6). (Tetrahydropyran-2-yl)ation of the product formed by hydrolysis of 6 gave 2-acetamido-5-azido-2,5-dideoxy-1,3- di-O-(tetrahydropyran-2-yl)- -xylofuranose (9). Treatment of 2-acetamido-5-amino-2,5-dideoxy-1,3-di-O-(tetrahydropyran-2-yl)- -xylofuranose, derived from 9 by reduction, with sulfur dioxide in water gave 11. Hydrogenation of 6 and subsequent acetylation yielded 3-acetamido-4,5-diacetoxy-1-acetyl-xylo-piperidine. Evidence in support of the structures assigned to the new derivatives is presented.     

Synthesis of ethyl 2-acetamido-6-S-(5-amino-5-deoxy-beta-D- arabinopyranosyl)-2-deoxy-1,6-dithio-beta-D-glucopyranoside: a sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide

A novel pseudo-disaccharide having an imino sugar residue at the non-reducing end, namely, a sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide, which is a potential specific inhibitor for glycosidases that recognize not only the glycosidic linkage but also the aglycone moiety, was synthesized. Glycosidation of N-Boc-5-amino-5-deoxy-D-arabinose with ethyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-1,6-dithio-beta-D- glucopyranoside in the presence of TsOH gave exclusively the corresponding 1,2-cis-linked thioglycoside. The interglycosidic linkage proved stable enough under conditions for the deprotection of the N-Boc group with TFA. This pseudodisaccharide was unstable at pH > 5, but stable at lower pH. The sulfur-linked 5-amino-5-deoxyglycopyranosyl disaccharide was shown to be formed from 5-amino-5-deoxy-D-arabinose and ethyl 2-acetamido-2-deoxy-1,6-dithio-beta-D-glucopyranoside in an acidic buffer solution.     

Synthesis of 2-acetamido-2-deoxy-5-thio-d-glucopyranose

2-Acetamido-2-deoxy-5-thio-d-glucopyranose (12) has been synthesized from methyl 2-acetamido-2-deoxy-5,6-O-isopropylidene-β-d-glucofuranoside (1). Benzoylation of 1, followed by O-deisopropylidenation, gave methyl 2-acetamido-3-O-benzoyl-2-deoxy-β-d-glucofuranoside, which was converted, via selective benzoylation and mesylation, into methyl 2-acetamido-3,6-di-O-benzoyl-2-deoxy-5-O-mesyl-β-d-glucofuranoside (5). Treatment of 6, formed by the action of sodium methoxide in chloroform on 5, with thiourea gave methyl 2-acetamido-2,5,6-trideoxy-5,6-epithio-β-d-glucofuranoside (7), which was converted into the 5-thio compound 9 by cleavage of the epithio ring in 7 with potassium acetate. Alkaline treatment of 10, derived from 9 by hydrolysis, afforded the title compound. Evidence in support of the structures assigned to the new derivatives is presented.     

Structure of 2-acetamido-3-amino-2,3-dideoxy-d-glucofuranurono-6,3-lactam

An X-ray crystallographic analysis of the title compound, an N-acetyl derivative of the 2,3-diamino-2,3-dideoxy-d-glucofuranurono-6,3-lactam found in the hydrolyzate of Pseudomonas aeruginosa P14 lipopolysaccharide, was performed. The crystals are monoclinic, space group P2₁, a = 11.704(2), b = 5.333(1), c = 7.399(2) Å, β = 91.63(2)°, and Z = 2. The structure was solved by direct methods and refined by the block-diagonal least-squares method to a final R value of 0.046 for 796 independent reflections. The dihedral angle between the mean plane through the furanose ring and that through the γ-lactam ring is 106.2(2)°, the furanose ring is ¹T₂, and the C-3, C-4, C-6, and N-3 atoms of the γ-lactam ring are nearly coplanar. The conformation in aqueous solution is discussed, based on the ¹H-n.m.r. data.     

Synthesis of an ether-linked alkyl 5a-carba-beta-D-glucoside,a 5a-carba-beta-D-galactoside,a 2-acetamido-2-deoxy-5a-carba-beta-D-glucoside,and an alkyl 5a'-carba-beta-lactoside

For the purpose of providing biologically stable building blocks for the biocombinatorial synthesis using a living cell, some ether-linked alkyl 5a-carba-beta-D-glycoside primers were prepared. The key step of the synthesis was coupling of 1-bromo-n-alkanes with the 1-OH unprotected derivatives of 5a-carba-sugar analogues of D-glucose, D-galactose, and 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine), in DMF in the presence of sodium hydride. Alternatively, alkyl carba-lactoside was synthesized by incorporation of a 5a-carba-beta-D-galactose residue into the 4-position of dodecyl beta-D-glucopyranoside. A strong and specific inhibition of beta-galactosidase (K(i) 0.67 microM, bovine liver) was found for dodecyl 5a-carba-beta-D-galactopyranoside.     

Synthesis of p-nitrophenyl 2-acetamido-2-deoxy-O-beta-D-galactopyranosyl-beta-D-glucopyranosides.

Reaction of p-nitrophenyl 2-acetamido-2-deoxy-4,6-O-(p-methoxybenzylidene)-beta-D-glucopyranoside (2) with 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide (3) under the usual conditions, followed by removal of the p-methoxybenzylidene group and O-deacylation, produced crystalline p-nitrophenyl 2-acetamido-2-deoxy-3-O-beta-D-galactopyranosyl-beta-D-glucopyranoside (6). Starting from p-nitrophenyl 2-acetamido 3,4-di-O-acetyl-2-deoxy-beta-D-glucopyranoside, the synthesis of p-nitrophenyl 2-acetamido-2-deoxy-6-O-beta-D-galactopyranosyl-beta-D-glucopyranoside was also accomplished.     

Synthesis of 2-acetamido-2-deoxy-4-O-alpha-L-fucopyranosyl-alpha-D-glucopyranose]

Condensation of 2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl bromide with benzyl 2-acetamido-3,6-di-O-benzyl-alpha-D-glucopyranoside in dichloromethane-N,N-dimethylformamide, in the presence of tetraethylammonium bromide, diisopropylethylamine, and molecular sieve (halide ion-catalyzed reaction), gave benzyl 2-acetamido-3,6-di-O-benzyl-2 deoxy-4-O-(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)-alpha-D-glucopyranoside in crystalline form in 82% yield. Hydrogenolysis of the benzyl groups gave the title disaccharide, in crystalline form in 90% yield, which was characterized by a crystalline peracetylated alpha-D derivative.     

Synthesis of a 2-Amino-2,5-dideoxy-D-ribofuranoside Analogue

Benzyl 2-benzamido-2,5-dideoxy-α-D-ribofuranoside was synthesized via benzyl 2-amino-3-C-(branched-chain)-2,3,5-trideoxy-α-d-furanoside from an optically active 3-oxa-6-azabicyclo[3.2.0]-heptan-7-one derivative.     

Selective inhibition of herpes simplex virus by 5-amino-2,5-dideoxy-5-iodouridine.

5-Amino-2,5-dideoxy-5-iodouridine, a nel thymidine analogue, is a potent inhibitor of herpes simplex virus type 1 replication. In contrast to most other nucleoside analogues which possess antiviral activity, 5-amino-2,5-dideoxy-5-iodouridine exhibits little, if any, cellular toxicity. Preliminary evidence suggests that 5-amino-2,5-dideoxy-5-iodouridine selectively inhibits viral-specific DNA synthesis.     

Enzymic synthesis of 5-acetamido-9-azido-3,5,9-trideoxy-D-glycero-D-galacto-2-nonulosonic acid, a 9-azido-9-deoxy derivative of N-acetylneuraminic acid

N-Acetylneuraminate synthase from $\text{Neisseria meningitidis}$ 6OE catalyzes the conversion of phosphoenolpyruvate and 2-acetamido-6-azido-2,6-dideoxy-

-mannose into 5-acetamido-9-azido-3,5,9-trideoxy-

-$\text{glycero}$-

-$\text{galacto}$-2-nonulosonic acid. The product, a 9-azido-9-deoxy derivative of N-acetylneuraminic acid, is indistinguishable from a chemically synthesized sample by i. the thiobarbituric acid assay, ii. paper electrophoresis, and iii. paper electrophoresis following sodium borohydride reduction. Both the chemically and the enzymically synthesized samples are substrates of the reaction catalyzed by CTP:CMP-N-acetylneuraminate cytidylyl-transferase from $\text{Neisseria meningitidis}$ 6OE