Synthesis of 8-amino-4-methylthio-6-methyl-2-(β-D-ribofuranosyl)-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene and an unusual reductive ring-opening of the 1,2,3,5,6,7-hexaazaacenaphthylene ring system

The tricyclic nucleoside 8-amino-4-methylthio-6-methyl-2-(β-D-ribofuranosyl)-1,2,3,5,6,7-hexaazaacenaphthylene ( 3 ) was synthesized from 3-cyano-4,6-bis(methylthio)-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 1 ). Attempts to synthesize 8-amino-6-methyl-2-(β-D-ribofuranosyl)-1H-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene ( 5 ) ([an aza analog of 6-amino-4-methyl-8-(β-D-ribofuranosyl)-1,3,4,5,8-pentaazaacenaphthylene (TCN)], which is a potent antitumor agent), by the treatment of 3 with Raney nickel did not afford the desired aza analog of TCN. Instead, it was established that a reductive cleavage of the pyridazine moiety of 3 had occurred to give 4-methylamino-6-methylthio-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 6 ). Assuming that solubility was a problem in the reductive step, the isopropylidene derivative of 3 , 8-amino-6-methyl-4-methylthio-2-(2,3-O-isopropylidene-β-D-ribofuranosyl)-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene ( 8 ), was treated with Raney nickel, only to observe that a similar reductive ring cleavage of 8 had occurred to afford 4-methylamino-6-methylthio-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 10 ) and 4-methylamino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 11 ). Structural assignments for all products were established by physico-chemical procedures.     

Synthesis of 2-(β-D-ribofuranosyl)pyrimidines,A new class of C-nucleosides

A new C-glycosyl precursor for C-nucleoside synthesis, 2,5-anhydroallonamidine hydrochloride ( 4 ) was prepared and utilized in a Traube type synthesis to prepare 2-(β-D-ribofuranosyl)pyrimidines, a new class of C-nucleosides. The anomeric configuration of 4 was confirmed by single-crystal X-ray analysis. Reaction of 4 with ethyl acetoacetate gave 6-methyl-2-(β-D-ribofuranosyl)pyrimidin-4-(1H)-one ( 5 ). Reaction of 4 with diethyl sodio oxaloacetate gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxylic acid ( 6 ). Esterification of 6 with ethanolic hydrogen-chloride gave the corresponding ester 7 which when treated with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxamide ( 8 ). Condensation of 2,5-anhydroallonamidine hydrochloride ( 4 ) with ethyl 4-(dimethylamino)-2-oxo-3-butenoate ( 9 ), gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboxylate ( 10 ). Treatment of 10 with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ). Single-crystal X-ray analysis confirmed the β-anomeric configuration of 11. Acetylation of 11 followed by treatment with phosphorus pentasulfide and subsequent deprotection with sodium methoxide gave 2-(β-D-ribofuranosyl)pyrimidine-4-thiocarboxamide ( 14 ). Dehydration of the acetylated amide 12 with phosphorous oxychloride provided 2-(β-D-ribofuranosyl)pyrimidine-4-carbonitrile ( 15 ). Treatment of 15 with sodium ethoxide gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboximidate ( 16 ), which was converted to 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamidine hydrochloride ( 17 ) by treatment with ethanolic ammonia and ammonium chloride. Treatment of 16 with hydroxylamine yielded 2-(β-D-ribofuranosyl)pyrimidine-4-N-hydroxycarboxamidine ( 18 ). Treatment of 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ) with phosphorus oxychloride gave the corresponding 5′-phosphate, 19 , Coupling of 19 with AMP using the carbonyldiimidazole activation procedure gave the corresponding NAD analog, 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide-(5′ ? 5′)-adenosine pyrophosphate ( 20 ).     

Synthesis of 2-(β-D-ribofuranosyl)[1,3,5]triazines

The synthesis of the first [1,3,5]triazine carbon linked nucleosides are reported. 4-Amino-6-(β-D-ribofuranosyl)[1,3,5]triazin-2(1H)-one ( 8 ), an analog of 5-azacytidine and pseudoisocytidine was prepared. 2,5-Anhydro-D-allonamidine hydrochloride ( 3 ) was condensed with dimethyl cyanoiminodithiocarbonate ( 4 ) to give 4-methylthio-6-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 5 ). Compound 5 was reacted with m-chloroperbenzoic acid to give 4-methylsulfinyl-6-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 6 ). Displacement of the methyl sulfinyl with the appropriate nucleophile gave 6-(β-D-ribofuranosyl)[1,3,5]triazine-2,4-diamine ( 7 ), 4-amino-6-(β-D-ribofuranosyl)[1,3,5]triazin-2(1H)-one ( 8 ), and 4-amino-6-(β-D-ribofuranosyl)[1,3,5]triazine-2(1H)-thione ( 9 ). Dethiation of compound 5 with Raney nickel gave 4-(β-D-ribofuranosyl)[1,3,5]triazin-2-amine ( 10 ). The crystal structure of 7 was determined by single crystal X-ray.     

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 and PMR study of certain 3-substituted 2-(β-D-Ribofuranosyl)indazoles

The synthesis of 3-cyano-2-(β-D-ribofuranosyl)indazole (4) has been accomplished by a condensation of N-trimethylsilyl-3-cyanoindazole (1) with 2,3,5-tri-O-aeetyl-D-ribofuranosyl bromide (2) followed by subsequent deacetylation. The reactivity of the 3-cyano group was demonstrated by the conversion of 4 to 2-(β-D-ribofuranosyl)indazole-3-carboxamide (5) and 2-(β-D-ribofuranosyl)indazole-3-thiocarboxamide (6). The site of ribosylation and the assignment of anomeric configuration for 4 is discussed. The magnetic anisotropy effect of the exocyclic group at C3 on the anomeric proton as determined by pmr spectroscopy is discussed.     

An unexpected product from the cyclodesulfurization of 5-[1-(3-methoxycarbonyl)thioureido]-1-(β-D-ribofuranosyl)imidazole-4- carboxamide with dicyclohexylcarbodiimide

The treatment of 5-[1-(3-methoxycarbonyl)thioureido]-1-(β-D-ribofuranosyl)imidazole-4-carboxamide with N,N'-dicyclohexylcarbodiimide in N,N-dimethylformamide has afforded 4-cyano-5-[1-(3-methoxycarbonyl)-ureido]-1-(β-D-ribofuranosyl)imidazole.     

Synthesis of New Nucleosides by coupling of chloropurines with 2- and 3-deoxy derivatives of N-methyl-D-ribofuranuronamide

The synthesis of new deoxyribose nucleosides by coupling chloropurines with modified D -ribose derivatives is reported. The methyl 2-deoxy-N-methyl-3-O-(p-toluoyl)-α-D -ribofuranosiduronamide (α-D - 8 ) and the corresponding anomer β-D - 8 were synthesized starting from the commercially available 2-deoxy-D -ribose ( 1 ) (Scheme 1). Reaction of α-D - 8 with the silylated derivative of 2,6-dichloro-9H-purine ( 9 ) afforded regioselectively the N⁹-(2′-deoxyribonucleoside) 10 as anomeric mixture (Scheme 2), whereas β-D - 8 did not react. Glycosylation of 9 or of 6-chloro-9H-purine ( 17 ) with 1,2-di-O-acetyl-3-deoxy-N-methyl-β-D -ribofuranuronamide ( 13 ) yielded only the protected β-D -anomers 14 and 18 , respectively (Scheme 3). Subsequent deacetylation and dechlorination afforded the desired nucleosides β-D - 11 , β-D - 12,15 , and 16 . The 3′-deoxy-2-chloroadenosine derivative 15 showed the highest affinity and selectivity for adenotin binding site vs. A₁ and A_2A adenosine receptor subtypes.     

Purine nucleosides XXVIII. The synthesis of 7-(2′-deoxy-α- and β-d-ribofuranosyl)purines from 2′-deoxyribofuranosylimidazoles. Preparation of the 2′-deoxy derivative of the nucleoside from pseudovitamin B12 factor G

The synthesis of 1-(2′-deoxyribofuranosyl)imidazoles have been achieved for the first time via the fusion method of glycosidation. 4-Amino-5-carboxamido-1-(2′-deoxy-α-D-ribofuranosyl)-imidazole ( 8 ) and 4-amino-5-carboxamido-1-(2′-deoxy-β-D-ribofuranosyl)imidazole ( 10 ) have been obtained and their structures established by spectroscopic methods. The first examples of 7-(2′-deoxyglycosyl)purines [7-(2′-deoxy-α-D-ribofuranosyl)hypoxanthine ( 6 ) and 7-(2′-deoxy-β-D-ribofuranosyl)hypoxanthine ( 11 )] have been obtained from the requisite 2′-deoxyribofuranosylimidazoles. The preparation of 6 has furnished the 2′-deoxy derivative (α-configuration) of the nucleoside from pseudovitamin B₁₂ Factor G, which constitutes the first 2′-deoxy derivative of any nucleoside isolated from the various naturally occurring pseudovitamin B₁₂ factors.     

A facile synthesis of certain 4- and 4,5-disubstituted 1-β-d-ribofuranosylpyrazoles

A number of pyrazole ribonucleosides, structurally related to AICA riboside and ribavirin have been prepared and evaluated for their biological activity in vitro. Deisopropylidenation of 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 6 ) with aqueous trifluoroacetic acid gave 5-amino-1-(β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 7 ). Conventional transformation of the carbonitrile function of 7 gave the AICA riboside congener ( 2 ) and related 5-amino-1-(β-D-ribofuranosyl)-pyrazoles ( 8–10 ). Acetylation of 7 at low temperature gave the versatile intermediate 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 15 ). Non-aqueous diazotization of 15 with isoamylnitrite in dibromomethane or diiodomethane gave the corresponding C₅-bromo 13 and C₅-iodo 16 derivatives. Compounds 13 and 16 were subsequently transformed into 5-bromo-1-(β-D-ribofuranosyl)pyrazole-4-carboxamide ( 11 ) and the 5-iodo analog 25 . However, a similar nonaqueous diazotization of 15 in dichloromethane afforded the deaminated product 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrazole-4-carbonitrile ( 22 ). Treatment of 22 with ammonium hydroxide/hydrogen peroxide gave the ribavirin congener 1-(β-D-ribofuranosyl)pyrazole-4-carboxamide ( 18 ). Similar treatment of 22 with hydrogen sulfide in pyridine or hydroxylamine in ethanol gave the 4-thiocarboxamide 19 and 4-carboxamidoxime 20 derivatives, respectively. Catalytic hydrogenation of 20 afforded 1[β-D-ribofuranosyl)pyrazole-4-carboxamidine ( 21 ). These pyrazole nucleosides are devoid of any significant antiviral or antitumor activity in vitro.     

C-Glycoside Analogues of N4-(2-Acetamido-2-deoxy-β-D-glucopyranosyl)-L-asparagine: Synthesis and conformational analysis of a cyclic C-glycopeptide

The synthesis of C-glycosidic analogues 15–22 of N⁴-(2-acetamido-2-deoxy-β-D -glucopyranosyl)-L -asparagine (Asn(N⁴GlcNAc)) possessing a reversed amide bond as an isosteric replacement of the N-glycosidic linkage is presented. The peptide cyclo(-D -Pro-Phe-Ala-CGaa-Phe-Phe-) (CGaa = C-glycosylated amino acid; 24 ) was prepared to demonstrate that 3-[(3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-β-D -glycero-D -guloheptonoyl)amino]-2-[(9H-fluoren-9-yloxycarbonyl)amino]propanoic acid ( 22 ) can be used in solid-phase peptide synthesis. The conformation of 24 was determined by NMR and molecular-dynamics (MD) techniques. Evidence is provided that the CGaa side chain interacts with the peptide backbone. The different C-glycosylated amino acids 15–21 were prepared by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-β-D -glycero-D -gulo-heptonic acid ( 4 ) with diamino-acid derivatives 8–14 in 83–96% yield. The synthesis of 4 was performed from 2-(acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D -glucopyranosyl) tributylstannane ( 2 ) by treatment with BuLi and CO₂ in 83% yield. Similarly, propyl isocyanat yielded the glycoheptonamide 7 in 52% from 2 . Compound 2 was obtained from 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-D -glucopyranose ( 1 ) by chlorination and addition of tributyltinlithium in 74% yield. A procedure for a multigram-scale synthesis of 1 is given.     

Nucleosides CV. Synthesis of the 8-((β-D-ribofuranosyl)pyrazolo[1,5-a]-1,3,5-triazine isosteres of adenosine and inosine

Reaction of ethyl N-cyanoformimidate ( 3 ) and of ethyl N-carbelhoxyformimidate ( 5 ) with 3-aminopyrazole ( 2 ) gave 4-amino- and 4-oxo-3H-pyrazolo[1,5-a]-1,3,5-triazine ( 4 and 7 ), respectively. Reaction of 3-amino-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)pyrazole ( 8 ) with the same reagents similarly gave the blocked 4-amino-8-ribosyl- and 4-oxo-3H-8-ribosyl-pyrazolo[ 1,5-a]-1,3,5-triazine ( 9 and 15 ), respectively. Deblocking in acid finally afforded the unblocked products 10 (an isostere of adenosine and formycin) and 16 (an isostere of inosine and formycin B). The corresponding derivatives in the a series were made by identical procedures for confirming all structural assignments. Preliminary in vitro testing results of 10 are included.     

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 2-amino-6-chloro- and 2,6-diammopunne 3-oxides

N-Oxidation of 2-amino-6-chloropurine to the 3-oxide provided a convenient intermediate for the synthesis of 2-amino-6-substituted purine 3-oxides, including the previously unavailable 2,6-diaminopurine 3-oxide. Thiation of the 6-halogen was accompanied by reduction of the N-oxide. The properties of the 1- and 3-oxides of 2,6-diaminopurine are compared.     

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).     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.     

Synthesis of 3-(β-D-ribofuranosyl)pyrazolo[3,2-i]-purine derivatives and their cytotoxic activities

9-Amino-3-(β-D-ribofuranosyl)pyrazolo[3,2-i|purine ( 6 ) has been prepared from a fully protected 3-(β-D-ribofuranosyl)pyrazolo[3,2-i]purine ( 2 ) and the 9-bromo substituted derivative 3 by nitration, followed by reduction. Reaction of 9-bromo-3-(β-D-ribofuranosyl)pyrazolo[3,2-i)purine ( 1b ) with alkali gave the (pyrazol-3-yl)imidazole derivative, followed by diazocyclization with sodium nitrate to give 9-bromo-3-(β-D-ribofuran-osyl)imidazolo[4,5-d]pyrazolo[2,3-c][1,2,3]triazine ( 10 ) after deacetylation. Compounds 6 and 10 exhibited cytotoxic activity against leukemia cells.     

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-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.     

The synthesis of certain ribofuranosylindazoles

The synthesis of 1-(β-D-ribofuranosyl)indazole (4), 2-(β-D-ribofuranosyl)indazole (5) and 6-, 5-, and 4-nitro-2-(β-D-ribofuranosyl)indazole (8a, 8b, and 8c, respectively), has been accomplished in good yield by the condensation of the appropriate N-trimethylsilylindazole (1, 6a, 6b, and 6c) with 2,3,5-tri-O-acetyl-D -ribofuranosyl bromide (2) followed by subsequent deacetylation of the reaction products. The site of ribosylation and the assignment of anomeric configuration for all nucleosides reported is discussed. This has furnished the first indazole nucleosides with assigned anomeric configurations and the site of ribosylation has been established on the basis of uv comparisons with model methyl compounds.     

Syntheses of 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one,an isostere of oxanosine,and the guanosine analog 6-amino-1-(β-d-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one via ring closure of pyrazole-5-thioureido intermediates

6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 4 ), an isostere of the nucleoside antibiotic oxanosine has been synthesized from ethyl 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxylate ( 6 ). Treatment of 6 with ethoxycarbonyl isothiocyanate in acetone gave the 5-thioureido derivative 7 , which on methylation with methyl iodide afforded ethyl 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-ethoxycarbonyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxylate ( 8 ). Ring closure of 8 under alkaline media furnished 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]-1,3-oxazin-4-one ( 10 ), which on deisopropylidenation afforded 4 in good yield. 6-Amino-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 5 ) has also been synthesized from the AICA riboside congener 5-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)pyrazole-4-carboxamide ( 12 ). Treatment of 12 with benzoyl isothiocyanate, and subsequent methylation of the reaction product with methyl iodide gave 1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-5-[(N'-benzoyl-S-methylisothiocarbamoyl)amino]pyrazole-4-carboxamide ( 15 ). Base mediated cyclization of 15 gave 6-amino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one ( 14 ). Deisopropylidenation of 14 with aqueous trifluoroacetic acid afforded 5 in good yield. Compound 4 was devoid of any significant antiviral or antitumor activity in culture.