A short path to synthesis of 4-deoxy-4-fluoroglucosaminides: methylumbelliferyl N-acetyl-4-deoxy-4-fluoro-beta-D-glucosaminide

A convenient method of synthesis of 1,6-anhydro-4-deoxy-2-O-tosyl-4-fluoro-beta-D-glucopyranose by fusion of 1,6;3,4-dianhydro-2-O-tosyl-beta-D-galactopyranose with 2,4,6-trimethylpyridinium fluoride was found. By successive action of ammonia, methyl trifluoroacetate, and acetic anhydride, the resulting compound was transformed into 1,6-anhydro-3-O-acetyl-2,4-dideoxy-2-trifluoroacetamido-4-fluoro-beta-D-glucopyranose, which was converted into 3,6-di-O-acetyl-2,4-dideoxy-2-trifluoroacetamido-4-fluoro-alpha-D-glucopyranosyl fluoride by the reaction with HF/Py. The resulting fluoride was further used as a glycosyl donor in the synthesis of methylumbelliferyl N-acetyl-4-deoxy-4-fluoro-beta-D-glucosaminide.     

Synthesis of 4-Deoxy-4-C-hydroxymethyl-α-L-Lyxo-Pyranosyl Thymine

Abstract

The synthesis of 1-[4-deoxy-4-C-hydroxymethyl-α-L-lyxopyranosyl]thymine has been accomplished by two synthetic routes both starting from methyl 2, 3-O-isopropylidene-β-D-ribopyranoside. The first route makes use of a ring opening, ring closure reaction sequence to increase the proportion of the desired L-isomers. The second route utilizes the soft nucleophilic character of malonyl anions and ozonolytic cleavage of enol ether to introduce the branched chain. The newly obtained pyranosyl nucleoside obtains a ⁴C₁ conformation with an equatorially oriented thymine moiety.     

Synthesis of 2-Deoxy-4-thio-D-ribofuranose and Its 3-Azido Analogue from L-Arabinose; Intermediates in the Synthesis of 4′-Thiodeoxynucleosides

Abstract

1-O-Acetyl-3,5-di-O-benzoyl-2-deoxy-4-thio-α,β-D-ribofuranose and its 3-azido analogue have been prepared by an efficient route starting from L-arabinose. A key intermediate in this route is 2-deoxy-4,5-O-isopropylidene-L-erythro-pentose dibenzyl dithioacetal which is readily substituted in the 3-position thus offering extensive scope for the synthesis of 3-substituted 2-deoxy-4-thio-α,β-D-ribofuranoses and subsequent nucleoside derivatives.     

Synthesis and Biological Activity of 5-Azacytosine Nucleosides Derived from 4-Thio-2-Deoxy-L-threo-Pentofuranose and 4-Thio-2-Deoxy-D-erythro-Pentofuranose

Abstract

1-O-Acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-_d-erythro-pentofuranose and 2-deoxy-1,3,5-tri-O-acetyl-4-thio-_l-threo-pentofuranose were coupled with 5-azacytosine to obtain α and β anomers of nucleosides.     

Synthesis of some monodeoxyfluorinated methyl and 4-nitrophenyl alpha-D-mannobiosides and a related 4-nitrophenyl alpha-D-mannotrioside

Treatment of methyl 3,4,6-tri-O-benzyl-2-O-(2,3,4-tri-O-acetyl-alpha-D-mannopyranosyl)-alpha -D- mannopyranoside with N,N-diethylaminosulfur trifluoride (Et2NSF3), followed by O-deacetylation and catalytic hydrogenolysis, afforded methyl 2-O-(6-deoxy-6-fluoro-alpha-D-mannopyranosyl)-alpha-D-mannopyranoside (8). Methyl 6-deoxy-6-fluoro-2-O-alpha-D-mannopyranosyl-alpha-D-mannopyranoside (11) was similarly obtained from methyl 3-O-benzyl-2-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl-alpha-D- mannopyranoside. 1,2,3,4-Tetra-O-acetyl-6-deoxy-6-fluoro-beta-D-mannopyranose (13), used for the synthesis of the 4-nitrophenyl analogs of 8 and 11, as well as their 3-O-linked isomers, was obtained by treatment of 1,2,3,4-tetra-O-acetyl-beta-D-mannopyranose with Et2NSF3. Treatment of 13 with 4-nitrophenol in the presence of tin(IV) chloride, followed by sequential O-deacetylation, isopropylidenation, acetylation, and cleavage of the acetal group, afforded 4-nitrophenyl 4-O-acetyl-6-deoxy-6-fluoro-alpha-D-mannopyranoside (18). Treatment of 13 with HBr in glacial acetic acid furnished the 6-deoxy-6-fluoro bromide 19. Glycosylation of diol 18 with 20 gave 4-nitrophenyl 4-O-acetyl-6-deoxy-6-fluoro-3-O- (21) and -2-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-alpha-D- mannopyranoside (23) in the ratio of approximately 2:1, together with a small proportion of a branched trisaccharide. 4-Nitrophenyl 4,6-di-O-acetyl-alpha-D-mannopyranoside was similarly glycosylated with bromide 19 to give 4-nitrophenyl 4,6-di-O-acetyl-3-O- and -2-O-(2,3,4-tri- O-acetyl-6-deoxy-6-fluoro-alpha-D-mannopyranosyl)-alpha-D-mannopyranosid e. The various di- and tri-saccharides were O-deacetylated by Zemplén transesterification.     

Synthesis and Antiviral Evaluation of 2′-Deoxy-4′-thio-L-nucleosides and Their Phosphotriester Derivatives Bearing S-Acyl-2-thioethyl Bioreversible Phosphate-Protecting Groups

Abstract

A new route to 2-deoxy-4-thio-L-ribofuranose and the synthesis of some 4′-thio-L-nucleosides are reported. Also, the bis (SATE) phosphotriester derivatives of 2′-deoxy-4′-thio-L-cytidine and -adenosine were synthesized and their biological activities are discussed.     

Some biochemical effects of 4-deoxy-4-fluoro-D-glucose on Escherichia coli.

The uptake of 4-deoxy-4-fluoro-D-glucose (4FG), without subsequent catabolism, by resting cells of Escherichia coli (ATCC 11775) is 0.06 mg/mg dry weight. In frozen-thawed cells of this organism, 4FG is a substrate for the phosphoenolpyruvate phosphotransferase system with a rate of phosphorylation twice that found for the isomeric 3-deoxy-3-fluoro-D-glucose. 4FG is not a carbon source for growth of this organism and it inhibits the extent of growth of cells in the presence of glucose. The inhibition of growth of E. coli K12 on lactose by 4FG is also observed and this is considered to be consistent with the fact that 4FG is an uncompetitive inhibitor of beta-galactosidase (EC 3.2.1.23) activity and that 4FG or 4-deoxy-4-fluoro-D-glucose-6 phosphate repress beta-galactosidase synthesis. These results support the view that catabolite repression may be produced by compounds which are not necessarily metabolised further than hexose-6-phosphates.     

Synthesis and Biological Activity of 4′-Thio-2′-deoxy Purine Nucleosides

Abstract

Coupling of 1-O-acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-_d-ribofuranose with 6-chloropurine and 2,6-dichloropurine gave a mixture of 9α and 9β anomers as major products. These anomers were separated and converted to 2′-deoxy-4′-thio analogues of adenosine, inosine, guanosine, 2-amino-adenosine, and 2-chloro adenosine as well as their α-anomers.     

Synthesis and Anti-cancer Activity of Some Novel 5-Azacytosine Nucleosides

Abstract

1-O-Acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-D-erythro-pentofuranose and 2-deoxy-1,3,5-tri-O-acetyl-4-thio-L-threo-pentofuranose were coupled with 5-azacytosine to obtain α and β anomers of nucleosides. All four nucleosides were reduced to the corresponding dihydro derivatives and deblocked to give target compounds. All eight target compounds were evaluated in a series of human cancer cell lines in culture. Only 2′-deoxy-4′-thio-5-azacytidine (3β) was found to be cytotoxic in all the cell lines and was further evaluated in vivo. Details of the synthesis and biological activity are reported.     

PREPARATION OF BASE-DEUTERATED 2′-DEOXYADENOSINE NUCLEOSIDES AND THEIR SITE-SPECIFIC INCORPORATION INTO DNA

We report a four-step synthesis of 2′-deoxy-2-deuteroadenosine from 2′-deoxyadenosine in 38% overall yield. The more accessible 2′-deoxy-8-deuteroadenosine was also prepared and incorporated into DNA by automated solid phase synthesis (80% deuterium) using N ⁶-benzoyl-2′-deoxy-8-deuteroadenosine-3′-O-(2-cyanoethyl-N,N-diisopropylphosphoramidite) in combination with acetyl-protected deoxycytidine and phenoxyacetyl-protected purine phosphoramidites.     

Synthesis and Biological Activity of 4′-Thionucleosides of 2-Chloroadenine1

Abstract

1,2,3,5-Tetra-O-acetyl-4-thio-D-riboruranose, prepared from 2,3,5-tri-O-benzyl-D-ribofuranose in four steps, was converted to the corresponding 2-chloroadenine nucleoside (8), which was deoxygenated to obtain 2-chloro-2′-deoxy-4′-thioadenosine (12). This is the first report of a 2′-deoxy-4′-thioribonucleoside of a purine rather than a pyrimidine. These novel nucleosides (8 and 12) were cytotoric to several human tumor cell lines in culture.     

Modified Nucleosides. II.1 Economical Synthesis of 2′,3′-Dideoxycytidine

Abstract

An economical two pot synthesis of 2′,3′-dideoxycytidine (2) from N⁴-acetyl-cytidine (4) has been developed. The key feature of this sequence is the in situ reductive elimination of a mixture of 1-(3-bromo-3-deoxy-2,5-di-O-acetyl-β-D-xylofuranosyl)-N⁴-acetylcytosine (5) and 1-(2-bromo-3-deoxy-3,5-di-O-acetyl-β-D-arabinofuranosyl)-N⁴-acetylcytosine (6) and subsequent hydrogenation of the resultant olefin over palladised charcoal.     

Keto-fluorothiopyranosyl nucleosides: a convenient synthesis of 2- and 4-keto-3-fluoro-5-thioxylopyranosyl thymine analogs

A novel series of fluorinated keto-β-d-5-thioxylopyranonucleosides bearing thymine as the heterocyclic base have been designed and synthesized. Deprotection of 3-deoxy-3-fluoro-5-S-acetyl-5-thio-d-xylofuranose (1) and selective acetalation gave the desired isopropylidene 5-thioxylopyranose precursor 3. Acetylation and isopropylidene removal followed by benzoylation led to 3-deoxy-3-fluoro-1,2-di-Ο-benzoyl-4-O-acetyl-5′-thio-d-xylopyranose (6). This was condensed with silylated thymine and selectively deacetylated to afford 1-(2′-Ο-benzoyl-3′-deoxy-3′-fluoro-5′-thio-β-d-xylopyranosyl)thymine (8). Oxidation of the free hydroxyl group in the 4′-position of the sugar led to the formation of the target 4′-keto compound together with the concomitant displacement of the benzoyl group by an acetyl affording, 1-(2′-O-acetyl-3′-deoxy-3′-fluoro-β-d-xylopyranosyl-4′-ulose)thymine (9). Benzoylation of 3 and removal of the isopropylidene group followed by acetylation, furnished 3-deoxy-3-fluoro-1,2-di-Ο-acetyl-4-O-benzoyl-5′-thio-d-xylopyranose (12). Condensation of thiosugar 12 with silylated thymine followed by selective deacetylation led to the 1-(4′-Ο-benzoyl-3′-fluoro-5′-thio-β-d-xylopyranosyl)thymine (14). Oxidation of the free hydroxyl group in the 2′-position and concomitant displacement of the benzoyl group by an acetyl gave target 1-(4′-O-acetyl-3′-deoxy-3′-fluoro-β-d-xylopyranosyl-2′-ulose)thymine (15).     

Oligonucleotides containing substituted 4-nitroindoles: Synthesis and study of their DNA duplexes

The synthesis of oligonucleotides containing 1-(2-deoxy-β-D-ribofuranosyl)-2-methyl-4-nitroindole and 1-(2-deoxy-β-D-ribofuranosyl)-2-phenyl-4-nitroindole is described. The synthesized modified oligonucleotides were used for studying the stability of intermolecular DNA duplexes with one unnatural strand and for evaluation of discriminating potential of 2-methyl-and 2-phenyl-4-nitroindoles toward nucleic bases. For comparison, an unmodified oligonucleotide and oligonucleotides bearing 5-nitroindole were used. It was shown that 2-methyl-4-nitroindole was only insignificantly inferior in stability to 5-nitroindole and characterized by a similar discriminating potential. 2-Phenyl-4-nitroindole provided a more pronounced duplex destabilization, the discrimination toward natural bases being decreased.     

Synthesis of the sugar moiety of TIME-EA4, a glycopeptide isolated from silkworm diapause eggs

We describe the efficient synthesis of the tetrasaccharide, 2-O-acetyl-3,4,6-tri-O-benzyl-alpha-D-mannopyranosyl-(1-->6)-2,4-di-O-acetyl-3-O-allyl-beta-D-mannopyranosyl-(1-->4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl-(1-->4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl azide, which is the protected form of the sugar unit of TIME-EA4 that is isolated from the diapausing eggs of the silkworm, Bombyx mori. The beta-linked D-mannoside of the tetrasaccharide was obtained using the conventional oxidation-reduction method for inversion of the configuration at the C-2 hydroxyl group of beta-D-glucoside. The reduction was effected with NaBH(4) in a methanolic solution in a ratio of 98:2 in favor of the beta-D-mannoside that was obtained in 87% yield.     

Deoxyfluoroketohexoses: 4-deoxy-4-fluoro- -sorbose and -tagatose and 5-deoxy-5-fluoro- -sorbose

4-Deoxy-4-fluoro-α- -sorbose (6) was prepared in crystalline form by the action of potassium hydrogen fluoride on 3,4-anhydro-1,2-O-isopropylidene-β- -psicopyranose (3) followed by deacetonation. Under identical conditions 3,4-anhydro-1,2-O-isopropylidene-β- -tagatopyranose (7) underwent epoxide migration to give 4,5-anhydro- 1,2-O-isopropylidene-β- -fructopyranose (12), which after deacetonation yielded 4-deoxy-4-fluoro- -tagatose (15) 5-deoxy-5-fluoro-α- -sorbopyranose (16) the latter as the crystalline free sugar. The action of glycol-cleavage reagents on the isopropylidene acetals of the deoxyfluoro sugars was consistent with the assigned structures. The structures were established by ¹³C n.m.r. studies of the free deoxyfluoro sugars 6 and 16 of the isopropylidene acetal 13, and by ¹H n.m.r. studies on the acetylated isopropylidene acetals 5 diacetate, 13 diacetate, and 14 diacetate. 5-Deoxy-5-fluoro- -sorbose (16) was biologically active producing in mice effects characteristic of deoxyfluorotrioses and of fluoroacetate. 4-Deoxy-4-fluoro- -tagatose (15) and 4-deoxy-4-fluoro- -sorbose (6) produced no apparent effects in mice up to a dose of 500 mg/kg. The implications of these findings with respect to transport phosphorylation, and the action of aldolase on ketohexoses are discussed.     

Syntheses of 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-d-glucopyranose (n-acetylmaltosamine) and 2-acetamido-2-deoxy-4-O-β-d-glucopyranosyl-α-d-glucopyranose

Condensation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside with 2,3,4,6-tetra-O-benzyl-1-O-(N-methyl)acetimidoyl-β-D-glucopyranose gave benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside which was catalytically hydrogenolysed to crystalline 2-acetamido-2-deoxy-4-O-α-D-glucopyranosyl-α-D-glucopyranose (N-acetylmaltosamine). In an alternative route, the aforementioned imidate was condensed with 2-acetamido-3-O-acetyl-1,6-anhydro-2-deoxy-β-D-glucopyranose, and the resulting disaccharide was catalytically hydrogenolysed, acetylated, and acetolysed to give 2-acetamido-1,3,6-tri-O-acetyl-2-deoxy-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-α-D-glucopyranose Deacetylation gave N-acetylmaltosamine. The synthesis of 2-acetamido-2-deoxy-4-O-β-D-glucopyranosyl-α-D-glucopyranose involved condensation of benzyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-α-D-glucopyranoside with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in the presence of mercuric bromide, followed by deacetylation and catalytic hydrogenolysis of the condensation product.     

Synthesis of 5′-deoxy-5′-ethoxycarbonylmethyl nucleosides,the precursors of oligonucleotides with the amide internucleoside bond C3′-NH-C(O)-CH<Subscript>2</Subscript>-C5′

A method for the synthesis of 5′-deoxy-5′-ethoxycarbonylmethyl nucleosides has been developed. 3-O-benzyloxymethyl-1,2-O-isopropylidene-α-D-allofuranose was oxidized by sodium periodate to form a 5′-aldo derivative, which was converted by the reaction with triethylphosphonoacetate in the presence of sodium hydride into a 5-deoxy-5-ethoxycarbonylmethylene derivative. The hydration of the unsaturated compound gave 5-deoxy-5-ethoxycarbonylmethyl-1,2-O-isopropylidene-α-D-ribofuranose. After the benzylation of 3-hydroxyl, the removal of the isopropylidene group by heating with acetic acid, and the subsequent acetylation, 1,2-di-O-acetyl-3-O-benzyl-5-deoxy-5-ethoxycarbonylmethyl-D-ribofuranose was obtained, which reacted with persilylated nucleic acid bases to form 5′-deoxy-5′-ethoxycarbonylmethyl nucleosides.     

Total synthesis and properties of prostaglandins. XXI. Synthesis of a 4,4-dimethyl-4-sil analog of 11-deoxyprostaglandin E1

Total synthesis of a new prostaglandin analogue, 11-deoxy-4,4-dimethyl-4-sil-prostaglandin E1, is carried out through synthesis of a silicon-containing alpha-chain precursor and a 2-substituted cyclopentenone derivative followed by their cuprate-induced interaction.     

The synthesis and antiviral activity of some 4'-thio-2'-deoxynucleoside analogues.

A practical 7-step synthesis of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside is described and the product has been used in the synthesis of some 4'-thio-2'-deoxynucleosides. These novel nucleoside analogues have potentially useful biological activity and are resistant to phosphorolysis.