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 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.     

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.     

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 .     

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).     

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.     

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.     

Synthesis of certain 1,2,4-triazole nucleoside derivatives

The syntheses of 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and its 2′-deoxy analog 8b as well as 5-amino-2-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-3-one ( 12 ) have been accomplished. Compounds 8a and 8b were synthesized via glycosylation of 3-bromo-5-nitro-1,2,4-triazole which was followed by replacement in three steps of the 3-bromo function to yield 3-nitro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 4a ) and its 2′-deoxy analog 4b . Compounds 4a and 4b were methylated at N², hydrogenated and deblocked to give 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and the 2′-deoxy analog 8b . Compound 12 was synthesized by glycosylation of 3-amino-1-methyl-1,2,4-triazolin-5(2H)-one ( 10 ). The structures of 8b and 12 were confirmed by single crystal X-ray diffraction analysis.     

The synthesis of some 5-methoxypyrimidine nucleosides

The synthesis of 5-methoxyuridine ( 3 ), 5-methoxycytidine ( 6 ), 1-(2-deoxy-β-D-erythropento-furanosyl)-5-methoxyuracil ( 14 ), 5-methoxy-1-β-D-ribofuranosyl-4-thiopyrimidin-2-one ( 5 ), 1-β-D-arabinofuranosyl-5-methoxycytosine ( 12 ), 1-β-D-arabinofuranosyl-5-methoxyuracil ( 8 ) and 1-β-D-arabinofuranosyl-5-methoxy-4-thiopyrimidin-2-one ( 11 ) have been accomplished. Both 3 and 14 were synthesized by alkylation of 2,4-bis(trimethyIsilyI)-5-methoxyuracil ( 1 ) with the appropriately blocked halosugars. Synthesis of the corresponding 5-methoxy-1-β-D-arabinofuranosyl derivatives was accomplished through the intermediate 2,2 -anhydro-1-β-D-arabinofuranosyl-5-methoxyuracil ( 7 ). The cytosine and 4-thiouracil derivatives in both the arabino- and ribo- series were prepared by thiation followed by amination.     

9-deazapurine nucleosides. The synthesis of certain N-5-2′-deoxy-β-D-erythropentofuranosyl and N-5-β-D-arabinofuranosylpyrrolo[3,2-d]pyrimidines

A number of 2,4-disubstituted pyrrolo[3,2-d]pyrimidine N-5 nucleosides were prepared by the direct glycosylation of the sodium salt of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (3) using 1-chloro-2-deoxy-3,5-di-O-(p-toluoyl)-α-D -erythropentofuranose (1) and 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose (11) . The resulting N-5 glycosides, 2,4-dichloro-5-(2-deoxy-3,5-di-O-(p-toluoyl) -β-D-erythropentofuranosyl)-5H-pyrrolo-[3,2-d]pyrimidine (4) and 2,4-dichloro-5-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl-5H -pyrrolo [3,2-d)pyrimidine (12) , served as versatile key intermediates from which the N-7 glycosyl analogs of the naturally occurring purine nucleosides adenosine, inosine and guanosine were synthesized. Thus, treatment of 4 with methanolic ammonia followed by dehalogenation provided the adenosine analog, 4-amino-5-(2-deoxyerythropentofuranosyl) -5H-pyrrolo[3,2-d]pyrimidine (6) . Reaction of 4 with sodium hydroxide followed by dehalogenation afforded the inosine analog, 5-(2-deoxy-β-D-erythropentofuranosyl) -5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one (9) . Treatment of 4 with sodium hydroxide followed by methanolic ammonia gave the guanosine analog, 2-amino-5-(2-deoxy-β-D-erythropentofuranosyl) -5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one (10) . The preparation of the same analogs in the β-D-arabinonucleoside series was achieved by the same general procedures as those employed for the corresponding 2′-deoxy-β-D-ribonucleoside analogs except that, in all but one case, debenzylation of the sugar protecting groups was accomplished with cyclohexene-palladium hydroxide on carbon, providing 4-amino-5-β-D-arabinofuranosyl-5H-pyrrolo [3,2-d]pyrimidin-4(3H)-one (18) . Structural characterization of the 2′-deoxyribonucleoside analogs was based on uv and proton nmr while that of the arabinonucleosides was confirmed by single-crystal X-ray analysis of 15a . The stereospecific attachment of the 2-deoxy-β-D-ribofuranosyl and β-D-arabinofuranosyl moieties appears to be due to a Walden inversion at the C₁ carbon by the anionic heterocyclic nitrogen (S_N2 mechanism).     

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 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.     

The synthesis of imidazole-2-thione nucleosides

Ribosylation of the trimethylsilyl derivative ( 1b ) of imidazole-2-thione ( 1a ) using either stannic chloride or silver perchlorate as catalyst resulted in the formation of the acylated derivatives of 1-(β-D-ribofuranosyl)imidazole-2-thione ( 3c ) and 1,3-di-(β-D-ribofuranosyl)imidazole-2-thione ( 4c ) with the latter predominating ( 4c:3c , ca. 2:1 ). The diribosylated nucleoside 4c was shown to be the N,N-disubstituted product rather than the N,S-disubstituted product by ¹H nmr and ¹³C nmr spectroscopy. Employment of the iodine-catalyzed fusion procedure reversed the aforementioned product ratios and provided the monoriboside 3c in excellent yield. When the trimethylsilyl derivative ( 5b ) of 2-methylthioimidazole ( 5a ) was reacted with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2d ) in acetonitrile, the major product was 1,3-di-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-imidazole-2-thione ( 4b ). The formation of 4b in this reaction is thought to arise via the Hilbert-Johnson mechanism.     

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 of ribonucleosides of 4(5)-cyano-5(4)-methylimidazole and related 4-substituted-5-methylimidazole ribosides

4-Cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-5-methylimidazole ( 4 ) and its corresponding 5-cyano-4-methyl substituted isomer ( 5 ) have been obtained by ribosylation of 4(5)-cyano-5(4)-methylimidazole ( 3 ) via the mercuric cyanide method or by ribosylation of the trimethylsilyl derivative of 3 . Treatment of 4 with methanolic ammonia, ammonium chloride in liquid ammonia and potassium hydrosulfide provided 4-cyano-1-β-D-ribofuranosyl-5-methylimidazole ( 6 ), 1-β-D-ribofuranosyl-5-methylimidazole-4-carboxamide ( 2 ) and 1-β-D-ribofuranosyl-5-methylimidazole-4-thiocarboxamide ( 11 ) respectively. Reaction of 6 with hydroxylamine afforded the corresponding 4-carboxamidoxime substituted nucleoside ( 13 ) which on catalytic reduction in the presence of ammonium chloride, was transformed into 1-β-D-ribofuranosyl-5-methylimidazole-4-carboxamidine ( 14 ) as hydrochloride salt.     

Synthesis of 6-amino-1,2,3-triazolo[4,5-c] pyridin-4(5H)one (8-aza-3-deazaguanine) and 6-amino-1-(β-D-ribofuranosyl)-1,2,3-triazolo[4,5-c] pyridin-4(5H)one (8-Aza-3-deazaguanosine) via novel ring closure procedures

The total synthesis of 6-amino-1,2,3-triazolo[4,5-c]pyridin-4(5H)one (8-aza-3-deazaguanine, 3 ) and 6-amino-1-(β-D-ribofuranosyl)-1,2,3-triazolo[4,5-c]pyridin-4(5H)one (8-aza-3-deazaguano-sine, 22 ) has been described for the first time by a novel base-catalyzed ring closure of 4(5)-cyanomethyl-1,2,3-triazole-5(4)carboxamide (14) and methyl 5-cyanomethyl-1-(2,3,5-tri-O-ben-zoyl-β-D-ribofuranosyl)-1,2,3-triazole-4-carboxylate (17) , respectively. Under the catalysis of DBU, 2,4-dinitrophenylhydrazone of dimethyl 1,3-acetonedicarboxylate (7) was converted to methyl 5-methoxycarbonylmethyl-1-(2,4-dinitroanilino)-1,2,3-triazole-4-carboxylate (12) via dimethyl 2-diazo-3-iminoglutarate (8) . Catalytic reduction of 12 gave methyl 4(5)methoxycar-bonylmethyl-1,2,3-triazole-5(4)carboxylate (11) from which methyl 4(5)carbamoylmethyl-1,2,3-triazole-5(4)carboxylate (10) was obtained by ammonolysis. Dehydration of 10 provided methyl 4(5)cyanomethyl-1,2,3-triazole-5(4)carboxylate (13) which on amination gave 14 . The 1,2,3-triazole nucleosides 17, 18 and 19 were obtained from the stannic chloride-catalyzed condensation of the trimethylsilyl 13 and a fully acylated β-D-ribofuranose. The yield and ratio of the ribofuranosyl derivatives of 13 markedly depends on the ratio of stannic chloride used. The structures of the nucleosides 22 and 23 were established by a combination of NOE, ¹H-nmr and ¹³C-nmr spectroscopy.     

Synthesis of certain 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridines structurally related to nicotinamide ribonucleoside

Several substituted 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridines have been prepared as congeners of nicotinamide ribonucleoside. Direct glycosylation of the silylated 3-ethylcarboxylate 5 or 3-carbamoyl 6 derivative of 1,2-dihydro-2-oxopyridine with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose ( 7 ) in the presence of trimethylsilyl triflate gave the corresponding blocked nucleosides 8 and 9 , respectively in good yield. Ammonolysis of 8 and 9 with methanolic ammonia furnished 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridine-3-carboxa-mide ( 10 ), the structure of which was established by single-crystal X-ray diffraction analysis. Thiation of 9 with Lawesson's reagent and subsequent deacetylation of the thiated product 11 with methanolic ammonia furnished 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridine-3-thiocarboxamide ( 12 ). Modification of the carbo-nitrile function of 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2-dihydro-2-oxopyridine-4-carbonitrile ( 13 ) gave a series of 4-substituted-1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridines, in which the 4-substituent is a thiocarboxamide 15 , carboxamide 16 , carboxamidoxime 17 , carboxamidine 18 and aminomethyl 19 group. None of these compounds exhibited any significant antitumor or antiviral effects in vitro.     

Polyazanaphthylene nucleosides II. Synthesis of β-D-ribofuranosyl derivatives of 4-quinazolone

The preparation of N¹ (2,3-O-isopropylidene-β-D-ribofuranosyl)-4-quinazolone ( 6 ) and N³-β-D-ribofuranosyI-4-quinazolone ( 3b ) are reported. The N³ derivative was prepared by the direct condensation of 4-trimethylsilyloxyquinazoline ( 2 ) and 2,3,5-tri-O-benzoyl- D - ribofuranosyl bromide. The N¹ derivative was prepared from the previously reported N¹ -β-D-ribofuranosyl-2,4-quinazolinedione via the cyclonucleoside 4 .     

Adamantylazoles: X. Reactions of 1,2,4-Triazole-3-thione with 1-Adamantanol in Acid Solutions

1,2,4-Triazole-3-thione reacts with 1-adamantanol in concentrated sulfuric acid to form 1-(1-adamantyl)-1,2,4-triazole-3-thione, which transforms into 1-(1-adamantyl)-3-(1-adamantyl)sulfanyl-1,2,4-triazole or is oxidized with atmospheric oxygen dissolved in sulfuric acid into 3,3′-disulfanediylbis[1-(1-adamantyl)- 1,2,4-triazole]. 3-(1-Adamantyl)sulfanyl-1,2,4-triazole was prepared by adamantylation of 1,2,4-triazole-3-thione in a mixture of phosphoric and acetic acid (weight ratio 4 : 1).     

Synthesis and single-crystal X-ray diffraction analysis of 2-sulfamoyladenosine (6-amino-9-β-D-ribofuranosylpurine-2-sulfonamide)

2-Amino-9-β-D-ribofuranosylpurine-2-sulfonamide (2-sulfamoyladenosine, 4 ), a congener of sulfonosine ( 3 ), was synthesized by four different routes. Acid catalyzed fusion of 6-chloropurine-2-sulfonyl fluoride ( 5 ) with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose ( 8 ) gave a good yield of 6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine-2-sulfonyl fluoride ( 9 ). Ammonolysis of 9 furnished 4 . Lewis acid catalyzed glycosylation of the trimethylsilyl derivative of either 6-chloropurine-2-sulfonamide ( 6 ) or 6-aminopurine-2-sulfonamide ( 7 ) with 8 gave the corresponding N9-glycosylated products, 10 and 11 , respectively, which on ammonolysis gave 4 . Amination of 2-thioadenosine ( 12 ) with chloramine solution gave the sulfenamide derivative 13 , which on subsequent oxidation with m-chloroperoxybenzoic acid furnished an alternate route to 4 . The structure of 4 was established by single-crystal X-ray diffraction studies. 2-Sulfamoyladenosine ( 4 ) is devoid of significant inhibitory activity against L1210 leukemia in mice.