The synthesis of 3-(β-D-ribofuranosyl)imidazo[4,5-c] pyridazines

7-Chloro-3-(β- D -2,3,5-tri-O-benzoylribofuranosyl)imidazo[4,5-c] pyridazine ( 3 ), obtained from the condensation of 7-chloro-3-trimethylsilylimidazo[4,5-c] pyridazine ( 1 ) with 2,3,5-tri-O-benzoyl- D -ribofuranosyl bromide ( 2 ), served as the percursor of 7-chloro- ( 4 ), 7-amino- ( 8 ), and 7-mercapto-3-(β- D -ribofuranosyl)imidazo[4,5-c] pyridazine ( 9 ). 3-(β- D -ribofuranosyl)imidazo[4,5-c] pyridazine ( 7 ) was obtained from 3-(β- D -2,3,5-tri-O-benzoylribofuranosyl)imidazo-[4,5-c]pyridazine ( 6 ). The site of ribosidation is based upon uv spectral comparisons with model methyl compounds. The assignment of the anomeric configuration is derived from pmr spectral data.     

Pyrrolopyridazine nucleosides. The synthesis of certain 1-β-D-ribofuranosyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-ones

Nucleosides of pyrrolo[2,3-d]pyridazin-4(5H)-ones were prepared by the single-phase sodium salt glycosylation of appropriately functionalized pyrrole precursors. The glycosylation of the sodium salt of ethyl 4,5-dichloro-2-formyl-1H-pyrrole-3-carboxylate ( 4 ), or its azomethino derivative 7 , with 1-bromo-2,3,5-tri-O-benzoyl-D-ribofuranose in acetonitrile afforded the corresponding substituted pyrrole nucleosides ethyl 4,5-dichloro-2-formyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1H-pyrrole-3-carboxylate ( 5 ) and ethyl 4,5-dichloro-2-phenylazomethino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1H-pyrrole-3-carboxylate ( 8 ), respectively. The latter, upon treatment with hydrazine, afforded the annulated product 2,3-dichloro-1-β-D-ribofuranosyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one ( 6 ), in good yield. The unsubstituted analog 1-β-D-ribofuranosyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one ( 9 ), was obtained upon catalytic dehalogenation of 6 . This report represents the first example of the synthesis of nucleosides of pyrrolopyridazines.     

The synthesis of 2-chloro-1-β-D-ribofuranosyl-5,6-dimethylbenzimidazole and (certain related derivatives

The synthesis of 2-chloro-1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazole (3b) has been accomplished by a condensation of 1-trimethylsilyl-2-chloro-5,6-dimethylbenzimidazole (1) with 2,3,5-tri-O-acetyl-D -ribofuranosyl bromide (2) followed by subsequent deacetylation. Nucleophilic displacement of the 2-chloro group from 3b has furnished several interesting 2-substituted-1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazoles. 1-(β-D -Ribofuranosyl)-5,6-dimethylbenzimidazole (5) and 1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazole-2-thione (4) were prepared from 3b. Alkylation of 4 furnished certain 2-alkylthio-1-(β-D -ribofuranosyl)-5,6-dirnethylbenzimidazoles and oxidation of 4 with alkaline hydrogen peroxide produced 1-(β-D -ribofuranosyl)-5,6-dimethylbenzimidazole-2-one D The assignment of anomeric configuration for all nucleosides reported is discussed.     

Pyrazolopyrimidine nucleosides. Part VII. The synthesis of certain pyrazolo [3,4-d] pyrimidine nucleosides related to the nucleoside antibiotics toyocamycin and sangivamycin

The condensation of 4-acetamido-3-cyanopyrazolo[3,4-d]pyrimidine ( 5 ) with crystalline 2,3,5-tri-O-acetyl-β- D -ribofuranosyl chloride ( 6 ) has furnished a good yield of nucleoside material ( 7 ) which on treatment with sodium methoxide in methanol provided a high yield of nucleoside which was subsequently established as methyl 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]-pyrimidine-3-formimidate monohydrate ( 11 ). The formimidate function of 11 was found to be highly reactive and 11 was readily converted into the corresponding carhoxamidine ( 8 ), carboxamidoxime ( 14 ) and carboxamidrazone ( 15 ) when treated with the appropriate nucleophiles. Treatment of the imidate ( 11 ) with sodium hydrogen sulfide gave a high yield of the thiocarboxamide ( 12 ) which was then readily converted into 4-amino-3-cyano-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 16 ). Aqueous base transformed 11 into 4-amino-1-(β- D -ribofuranosyl)-pyrazolo[3,4-d]pyrimidine-3-carboxamide ( 10 ) while more vigorous basic hydrolysis provided the corresponding carboxylic acid ( 9 ) in nearly quantitative yield. Decarboxylation of 9 proceeded smoothly in hot sulfolane to provide the known 4-amino-1-(β- D -ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 13 ) in 68% yield which unequivocally established the site of ribosylation and anomeric configuration for all nucleosides reported in this investigation.     

Synthesis of 8-amino-9-β-D-ribofuranosylpurin-6-thione and related 6-substituted-8-aminopurine nucleosides

Acetylation of 8-amino-9-β-D-ribofuranosylpurin-6-one (III), followed by chlorination of the tetraacetyl derivative 8-acetamido-9-(2,3,5-tri-O-aeetyl-β-D-ribofuranosyl)purin-6-one (IV) with phosphorus oxychloride yielded 8-aeetamido-6-ehloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-purine (V). The 6-chloro substitutent of V was readily displaced with thiourea to give, after treatment with sodium methoxide 8-acetamido-9-β-D-ribofuranosylpurine-6-thione (VIII). Chlorination of 8-bromo-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purin-6-one (IX) yielded 6,8-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (X), which underwent nucleophilic displacement with ethanolic ammonia selectively in the 8 position. The resulting 8-amino-6-chloro-9-β-D-ribofuranosylpurine (VII) was converted to 8-amino-9-β-D-ribofuranosylpurine-6-thione (I), 8-amino-6-methylthio-9-β-D-ribofuranosylpurine (II), and to 8-amino-6-hydrazino-9-β-D-ribofuranosylpurine (XI).     

The synthesis of 2-chloro-1-(β-D-ribofuranosyl)benzimidazole and certain related derivatives

The synthesis of 2-chloro-1-(β-D-ribofuranosyl)benzimidazole (4b) has been accomplished by a condensation of 2-chloro-1-trimethylsilylbenzimidazole (1) with 2,3,5-tri-O-acetyl-D-ribofuranosyl bromide (2) followed by subsequent deacetylation. Nucleophilic displacement of the 2-chloro group has furnished several interesting 2-substituted-1-(β-D-ribofuranosyl)benzimidazoles. 1-(β-D-Ribofuranosyl)benzimidazole (5) and 1-(β-D-ribofuranosyl)benzimidazole-2-thione (6) were prepared from 4b and 6 was also prepared by condensation of 2 with silylated benzimidazole- 2-thione (3). Alkylation of 6 furnished certain 2-alkylthio-1-(β-D-ribofuranosyl)benzimidazoles and oxidation of 6 with alkaline hydrogen peroxide produced 1-(β-D-ribofuranosyl)benzimidazole-2-one (9). The assignment of anomeric configuration for all nucleosides reported is discussed.     

Synthesis of certain pyrazolo[3,4-d]pyrimidin-3-one nucleosides

Synthesis of the pyrazolo[3,4-d]pyrimidin-3-one congeners of guanosine, adenosine and inosine is described. Glycosylation of 3-methoxy-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 13 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 16 ) in the presence of boron trifluoride etherate gave 3-methoxy-6-methylthio-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 17 ) which, after successive treatments with 3-chloroperoxybenzoic acid and methanolic ammonia, afforded 6-amino-3-methoxy-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)one ( 18 ). The guanosine analog, 6-amino-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 21 ), was made by sodium iodide-chlorotrimethylsilane treatment of 6-amino-3-methoxy-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)one ( 19 ), followed by sugar deprotection. Treatment of the adenine analog, 4-amino-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( 11 ), according to the high temperature glycosylation procedure yielded a mixture of N-1 and N-2 ribosyl-attached isomers. Deprotection of the individual isomers afforded 4-amino-3-hydroxy-1-βribofuranosylpyrazolo-[3,4-d]pyrimidine ( 26 ) and 4-amino-2-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-3(7H)-one ( 27 ). The structures of 26 and 27 were established by single crystal X-ray diffraction analysis. The inosine analog, 1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 28 ), was synthesized enzymatically by direct ribosylation of 1H-pyrazolo[3,4-d]pyrimidine-3,4(2H,5H)-dione ( 8 ) with ribose-1-phosphate in the presence of purine nucleoside phosphorylase, and also by deamination of 26 with adenosine deaminase.     

Synthesis of imidazo[4,5-d]pyridazine nucleosides related to inosine

Several imidazo[4,5-d]pyridazine nucleosides which are structurally similar to inosine were synthesized. Anhydrous stannic chloride-catalyzed condensation of persilylated imidazo[4,5-d]-pyridazin-4(5H)one (1) and imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 16 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose ( 3 ) provided (after sodium methoxide deblocking) 6-β-D-ribo furanosylimidazo[4,5-d]pyridazin-4(5H)one (5) and 3,6-di-(β-D-ribofuranosyI)imidazo[4,5-d]pyridazin-4-one ( 7 ); and 1-(β-D-ribofuranosyl)imidazo[4,5-d]pyridazine-4,7(5H,6H)dione ( 19 ) and 1,5 or 6-di-(β-D-ribofuranosyl)imidazo[4,5-d ]pyridazine-4,7(5H or 6H)dione ( 21 ), respeeitvely. 4,7-Diehloro-1-β-D-ribofuranosylimidazo[4,5-d]pyridazine ( 12 ) and dimethyl 1-β-D-ribofuranosylimidazole-4,5-dicarboxylate ( 26 ), both prepared from stannic chloride-catalyzed ribosylations of the corresponding heterocycles, were converted in several steps to 3-β-D-ribo-furanosy limidazo[4,5-d]pyridazin-4(5H)one ( 14 ) and nucleosidc 19 , respectively. Acid-catalyzed isopropylidenation of mesomeric betaine 7 or nuclcoside 14 provided 3-(2,3-isopropylidene-β-D-ribofuranosyl)imidazo[4,5-d]pyrizin-4(5H)one ( 31 ). 1-β-D-Ribofuranosylimidazo[4,5-d]-pyridazine ( 29 ) was obtained in several steps from nueleoside 12 . The structure of the nucleosides was established by the use of carbon-13 and proton nmr.     

The synthesis of 2-substituted azino-3-(β-D-ribofuranosyl)-5-carboxymethylenethiazolidin-4- ones

2-(1-Isopropylidene)azino-3-β-D-ribofuranosyl-5- methoxycarbonylmethylenethiazolidin-4-one (IV) and 2-(1-methylbenzilidene)azino-3-β-D-ribofuranosyl-5-carboxymethylenethiazolidin-4-one were prepared by independent synthesis utilizing either acid catalyzed fusion of 2-(1-isopropylidene)azino-5-methoxycarbonylmethylenethiazolidin-3(H)-4-one (II) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, silylation procedure with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide or by cyclization of new isopropylidene and/or methylbenzilidene derivatives (VII) of 4-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiosemicarbazide (VI) with maleic anhydride and subsequent methylation. The synthetic approach has unambigously established the glycosilation site as well as anomeric configuration, which was additionally derived from pmr spectral data.     

The synthesis of 3-deazapyrimidine nucleosides related to uridine and cytidine and their derivatives

Condensation of 2,4-bis(trimethylsilyloxy)pyridine ( 1 ) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2 ) gave 4-hydroxy-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 3 ). Deblocking of 3 gave 4-hydroxy-1-β-D-ribofuranosyl-2-pyridone (3′-deazauridine) ( 4 ). Treatment of 4 with acetone and acid gave 2′,3′-O-isopropylidene-3-deazauridine ( 6 ). Reaction of 4 with diphenylcarbonate gave 2-hydroxy-1-β-D-arabinofuranosyl-4-pyridone-O₂←2′-cyclonucleoside ( 7 ) which established the point of gylcosidation and configuration of 4 . Base-catalyzed hydrolysis of 7 gave 4-hydroxy-1-β-D-arabinofuranosyl-2-pyridone (3-deazauracil arabinoside) ( 12 ). Fusion of 1 with 3,5-di-O-p-toluyl-2-deoxy-D-erythro-pentofuranosyl chloride ( 5 ) gave the blocked anomeric deoxynucleosides 8 and 10 which were saponified to give 4-hydroxy-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazauridine) ( 11 ) and its α anomer ( 9 ). Condensation of 4-acetamido-2-methoxypridine ( 13 ) with 2 gave 4-acetamido-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2-pyridone ( 14 ) which was treated with alcoholic ammonia to yield 4-acetamido-1-β-D-ribofuranosyl-2-pyridone ( 15 ) or with methanolic sodium methoxide to yield 4-amino-1-β-D-ribofuranosyl-2-pyridone (3-deazacytidine) ( 16 ). Condensation of 13 and 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride ( 17 ) gave the blocked nucleoside 22 which was treated with base and then hydrogenolyzed to give 4-amino-1-β-D-arabinofuranosyl-2-pyridone (3-deazacytosine arabinoside) ( 23 ). Fusion of 13 with 5 gave the blocked anomeric deoxynucleosides 18 and 20 which were deblocked with methanolic sodium methoxide to yield 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-2-pyridone (2′-deoxy-3-deazacytidine) ( 21 ) and its a anomer 19 . The 2′-deoxy-erythro-pentofuranosides of both 3-deazauracil and 3-deazacytosine failed to obey Hudson's isorotation rule but did follow the “quartet”-“triplet” anomeric proton splitting pattern in the ¹H nmr spectra.     

Synthesis of certain exocyclic thiazole nucleosides related to tiazofurin. Formation of a unique acycloaminonucleoside

Several thiazole nucleosides structurally related to tiazofurin (1) and ARPP (2) were prepared, in order to determine whether these nucleosides had enhanced antitumor/antiviral activities. Ring closure of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiourea (4) with ethyl bromopyruvate (5a) gave ethyl 2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosylamino)thiazole-4-carboxylate (6a) . Treatment of 6a with sodium methoxide furnished methyl 2-(β-D-ribopyranosylamino)thiazole-4-carboxylate (9) . Ammonolysis of the corresponding methyl ester of 6a gave a unique acycloaminonucleoside 2-[(1R, 2R, 3R, 4R)(1-benzamido-2,3,4,5-tetrahydroxypentane)amino]-thiazole-4-carboxamide (7a) . Direct glycosylation of the sodium salt of ethyl 2-mercaptothiazole-4-carboxylate (12) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (11) gave the protected nucleoside 10 , which on ammonolysis provided 2-(β-D-ribofuranosylthio)thiazole-4-carboxamide (3b) . Similar glycosylation of 12 with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride (13) , followed by ammonolysis gave 2-(2-deoxy-β-D-ribofuranosylthio)thiazole-4-carboxamide (3c) . The structural assignments of 3b, 7a , and 9 were made by single-crystal X-ray analysis and their hydrogen bonding characteristics have been studied. These compounds are devoid of any significant antiviral/antitumor activity in vitro.     

Synthesis of 4,6-disubstituted-7-β-D-ribofuranosyl- and arabinofuranosylpyrazolo[3,4-d]pyrimidines and certain related ribonucleosides

Several disubstituted pyrazolo[3,4-d]pyrimidine, pyrazolo[1,5-a]pyrimidine and thiazolo[4,5-d]pyrimidine ribonucleosides have been prepared as congeners of uridine and cytidine. Glycosylation of the trimethylsilyl (TMS) derivative of pyrazolo[3,4-d]pyrimidine-4,6(1H,5H,7H)-dione ( 4 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose ( 5 ) in the presence of TMS triflate afforded 7-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrazolo-[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 6 ). Debenzoylation of 6 gave the uridine analog 7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 3 ), identical with 7-ribofuranosyloxoallopurinol reported earlier. Thiation of 6 gave 7 , which on debenzoylation afforded 7-β-D-ribofuranosyl-6-oxopyrazolo[3,4-d]pyrimidine-4(1H,5H)-thione ( 8 ). Ammonolysis of 7 at elevated temperature gave a low yield of the cytidine analog 4-amino-7-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-6(1H)-one ( 11 ). Chlorination of 6 , followed by ammonolysis, furnished an alternate route to 11 . A similar glycosylation of TMS-4 with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride ( 12 ) gave mainly the N7-glycosylated product 13 , which on debenzylation provided 7-β-D-arabinofuranosylpyrazolo[3,4-d]pyrimidine-4,6(1H,5H)-dione ( 14 ). 4-Amino-7-β-D-arabinofuranosyl-pyrazolo[3,4-d]pyrimidin-6(1H)-one ( 19 ) was prepared from 13 via the C4-pyridinium chloride intermediate 17 . Condensation of the TMS derivatives of 7-hydroxy- ( 20 ) or 7-aminopyrazolo[1,5-a]pyrimidin-5(4H)-one ( 23 ) with 5 in the presence of TMS triflate gave the corresponding blocked nucleosides 21 and 24 , respectively, which on deprotection afforded 7-hydroxy- 22 and 7-amino-4-β-D-ribofuranosylpyrazolo[1,5-a]pyrimidin-5-one ( 25 ), respectively. Similarly, starting either from 2-chloro ( 26 ) or 2-aminothiazolo[4,5-d]pyrimidine-5,7-(4H,6H)-dione ( 29 ), 2-amino-4-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-5,7(6H)-dione ( 28 ) has been prepared. The structure of 25 was confirmed by single crystal X-ray diffraction studies.     

A comparison of two methods for the preparation of 3-Deazapurine ribonucleosides

The reaction of the trimethylsilyl derivative of 4,6-dichloroimidazo[4,5-c]pyridine with 2,3,5-tri-O-benzoyl- D -ribofuranosyl bromide gave four nucleosides-the α- and β-anomers of the 1-isomer and the α- and β-anomers of the 3-isomer (3.9:2.7:1.5:1). In contrast, the fusion reaction of 4,6-dichloroimidazo[4,5-c ]pyridine with 1,2,3,5-tetra-O-acetyl-β- D -ribofuranose gave a high yield of the 1-β-isomer, which was converted to the known 3-deazaadenosine (4-amino-l-β- D -ribofuranosylimidazo[4,5-c]pyridine).     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

A convenient synthesis of certain 1-(β-D-ribofuranosyl)benzotriazoles

The synthesis of 5,6-dichloro-1-(β-D -ribofuranosyl)benzotriazole ( 4a ), 5,6-dimethyl-1-(β-D -ribofuranosyl)benzotriazole ( 4b ) and 1-(β-D -ribofuranosyl)benzotriazole ( 4c ) in good yield has been accomplished by the condensation of the appropriate 1-trimethylsilylbenzotriazole ( 1a, 1b , and 1c ) with 2,3,5-tri-O-acetyl-D -ribofuranosyl bromide (2) followed by subsequent deacetylation of the reaction products. The assignment of anomeric configuration and site of glycosidation for all nucleosides reported is discussed.     

Synthesis of 1-(β-D-ribofuranosyl)indol-3-acetic acid

By condensation of ethyl indolin-3-acetate ( 4 ) and 2,3,5-tri-O-benzoylribofuranosyl-1-acetate ( 5 ), ethyl 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)indolin-3-acetate ( 6 ) was obtained in good yield. The indoline nucleoside 6 was aromatized to ethyl 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)indol-3-acetate ( 7 ) with DDQ. The treatment of the indole nucleoside with barium hydroxide and methanol gave the methyl ester 8 , which was further treated in water to give the desired 1-(β-D-ribofuranosyl)indol-3-acetic acid ( 9 ).     

Synthesis and single-crystal X-ray diffraction studies of 1-β-D-ribofuranosyl-1,2,4-triazole-3-sulfonamide and certain related nucleosides

1-β-D-Ribofuranosyl- 21 , 1-(2-deoxy-β-D-erytftro-pento fur anosyl)- 27 and 1-β-D-arabinofuranosyl- 29 derivatives of 1,2,4-triazole-3-sulfonamide ( 19 ) have been prepared. Glycosylation of the silylated 19 with 1,2,3,5-tetra-0-acetyl-β-D-ribofuranose ( 5 ) in the presence of trimethylsilyl triflate gave the corresponding blocked nucleoside ( 20 ), which on ammonolysis afforded 1-β-D-ribofuranosyl-1,2,4-triazole-3-sulfonamide ( 21 ). Stereospecific glycosylation of the sodium salt of 19 with either 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 22 ) or 1-chloro-2,3,5-tri-0-benzyl-α-D-arabinofuranose ( 23 ) provided the corresponding protected nucleosides 26 and 28. Deprotection of 26 and 28 furnished 1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,2,4-triazole-3-sulfonamide ( 27 ) and 1-β-D-arabinofuranosyl-1,2,4-triazole-3-sulfonamide ( 29 ), respectively. 2-0-D-Ribofuranosyl-1,2,4-triazole-3(4H)-thione ( 7 ) and 4-β-D-ribofuranosyl-1,2,4-triazole-3(2H)-thione ( 9 ) were also prepared utilizing either an acid catalyzed fusion of 1,2,4-triazole-3(1H,2H)-thione ( 4 ) with 5 , the reaction of 5 with silylated 4 in the presence of trimethylsilyl triflate, or by ring closure of 4-(2,3,5-tri-0-benzoyl-β-D-ribofuranosyl)thiosemicarbazide ( 10 ) with mixed anhydride and subsequent deacylation. The synthesis of 1-β-D-ribofuranosyl-3-benzylthio-1,2,4-triazole ( 15 ) has also been accomplished by the silylation procedure employing 3-benzylthio-1,2,4-triazole ( 13 ) and 5 to give 1-(2,3,5-tri-0-acetyl-β-D-ribofuranosyl)-3-benzylthio-1,2,4-triazole ( 14 ). Deacetylation of 14 furnished 15 . The structural assignments of 7, 14 and 21 were made by single-crystal X-ray diffraction analysis and their hydrogen bonding characteristics have been studied. The sulfonamido-1,2,4-triazole nucleosides are devoid of any significant antiviral or antitumor activity in cell culture.     

A synthesis of 2-β-D-ribofuranosyl-4-selenazolecarboxamide (selenazofurin) and certain N-substituted amide derivatives suitable for large scale syntheses

A new process suitable for large scale synthesis of the antitumor-antiviral agent, 2-β-D-ribofuranosyl-4-selenazolecarboxamide (selenazofurin, 1 ), has been developed. Thus, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose ( 3 ) was converted with cyanotrimethylsilane and stannic chloride to the crystalline 2,5-anhydro-3,4,6-tri-O-benzoyl-β-D-allononitrile ( 4 ) without chromatography. Cyanosugar 4 in ethanol was treated with hydrogen selenide gas to afford stereospecifically the unstable 2,5-anhydro-3,4,6-tri-O-benzoyl-β-D-allonoselenoamide ( 5 ) which was converted in situ by ethyl bromopyruvate to the stable ethyl 2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-4-selenazolecarboxylate ( 6). Selenazole ethyl ester 6 was deprotected with sodium methoxide affording methyl 2-β-D-ribofuranosyl-4-selenazolecarboxylate ( 7 ) which was aminated with ammonia to provide selenazofurin ( 1 ) or with other amines to provide N-substituted selenazofurin amides.     

Synthesis of β-D-ribo- and 2′-deoxy-β-D-ribofuranosyl derivatives of 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one by a ring closure of pyrazole nucleoside precursors

6-Amino-1-(2-deoxy-β-D-erthro-pentofuranosyl)pyrazolo[4,3-c]pyridin-4(5H)-one ( 5 ), as well as 2-(β-D-ribofuranosyl)- and 2-(2-deoxy-β-D-ribofuranosyl)- derivatives of 6-aminopyrazolo[4,3-c]pyridin-4(5H)-one ( 18 and 22 , respectively) have been synthesized by a base-catalyzed ring closure of pyrazole nucleoside precursors. Glycosylation of the sodium salt of methyl 3(5)-cyanomethylpyrazole-4-carboxylate ( 6 ) with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 8 ) provided the corresponding N-1 and N-2 glycosyl derivatives ( 9 and 10 , respectively). Debenzoylation of 9 and 10 with sodium methoxide gave deprotected nucleosides 14 and 16 , respectively. Further ammonolysis of 14 and 16 afforded 5(or 3)-cyanomethyl-1-(2-deoxy-β-D-erythro-pentofuranosyl)pyrazole-4-carboxamide ( 15 and 17 , respectively). Ring closure of 15 and 17 in the presence of sodium carbonate gave 5 and 22 , respectively. By contrast, glycosylation of the sodium salt of 6 with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 11 ) or the persilylated 6 with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose gave mainly the N-2 glycosylated derivative 13 , which on ammonolysis and ring closure furnished 18 . Phosphorylation of 18 gave 6-amino-2-β-D-ribofuranosylpyrazolo[4,3-c]pyridin-4(5H)-one 5′-phosphate ( 19 ). The site of glycosylation and the anomeric configuration of these nucleosides have been assigned on the basis of ¹H nmr and uv spectral characteristics and by single-crystal X-ray analysis of 16 .     

Synthese von Nucleosiden aus 2-substituierten Imidazolen

Synthesis of 2-Substituted Imidazole Nucleosides Condensation of the trimethylsilyl derivatives of 2-substituted diethyl and dimethyl imidazole-4,5-dicarboxylates ( 3–5 and 7–9 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D -ribofuranose ( 2 ) in the presence of trimethysilyl trifluoromethanesulfonate provided the 2-substituted diethyl and dimethyl 1-(2′,3′, 5′-tri-O-benzoyl-β-D -ribofuranosyl)imidazole-4, 5-dicarboxylates 10–15 . These were treated with ammonia to afford the 2-substituted 1-(β-D -ribofuranosyl)imidazole-4,5-dicarboxamides 16–21 . Treatment of 2-methyl-( 16 ) and 2-ethyl-1-(β-D -ribofuranosyl)imidazole-4,5-dicarboxamide ( 17 ) with fuming nitric acid in oleum at ?30° yielded the nitric acid esters 23 and 24 . Besides the esterification of the sugar hydroxyl groups one H-atom of the imidazolecarboxamide function at C(5) in these nucleosides was also substituted by the NO₂ group. The conformations in solution of 16 and 23 have been determined by ¹H- and ¹³C-NMR. spectroscopy. These studies indicate that the nucleosides exist in dimethyl-sulfoxide solution preferentially in the S-gg-syn-conformation ( 16 ) and N-gt-conformation ( 23 ). In the crystal structure of nucleoside 23 , the ribose was found to be in the O(1′)_endo, C(1′)_exo twist conformation. The conformation about C(4′), C(5′) is gauche-trans and the molecule exists in the syn form.