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.     

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.     

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.     

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 .     

Synthesis and Biological Evaluation of 2-(2-Deoxy-β-D-ribofuranosyl)pyridine-4-carboxamide

A new protected 2-deoxy-D -ribose derivative, 5-O-[(tert-butyl)diphenylsilyl]-2-deoxy-3,4-O- isopropylidene-aldehydo-D -ribose ( 5 ), was synthesized starting from 2-deoxy-D -ribose. This compound was coupled with 2-lithio-4-(4,5-dihydro-4,4-dimethyloxazol-2-yl)pyridine giving a D /L -glycero-mixture 7 of 5-O-[(tert-butyl)diphenylsilyl]-2-deoxy-1-C-[4-(4,5 -dihydro-4,4-dimethyloxazol-2-yl)pyridin-2-yl]-3,4-O-isopropylidene- D -erythro-pentitol. The mixture 7 was 1-O-mesylated with methanesulfonyl chloride and subsequently treated with CF₃COOH/H₂O and ammonia to afford the α/β-D -anomers 10 of 2-(2-deoxy-D -ribofuranosyl)pyridine-4-carboxamide. Both anomers were purified and separated by HPLC and identified by NMR and DCI-MS. Anomer β-D - 10 was evaluated against a series of tumor-cell lines and a variety of viral strains. No antitumor or antiviral activity was observed.     

4-Oxa(thia)-9-oxa-2-azabicyclo[4.2.1]nonane-3-on(thion) derivatives

The synthesis of 7,8-dihydroxy-2-(2-methoxycarbonylethyl)-4,9-dioxa-2-azabicyclo[4.2.1]nonane- 3-thione ( 16 ) and of its parents 9-oxa-4-thia-3-thione 17 , and 9-oxa-4-thia-3-one 18 is described. The conversion of 5′-deoxy-5′-iodo-2′,3′-O, O-isopropylidene-5,6-dihydrouridin ( 1 ) into the 2-O-methyl-5,6-dihydrouridine 5 , the 5′-O-acetyl-5,6-dihydrouridine 4 , and into the N-(5-O-acetyl-2,3-O, O-isopropylidene-β-D -ribofuranosyl)-N-(2-methoxycarbonyl thyl)-urea ( 6 ) invoked 2′,3′-O, O-isopropylidene-2,5′-anhydro-5,6-dihydrouridine ( 2 ) as the common intermediate.     

Products from furans. VII. A General Route for the Synthesis of α-(1,2-cis) and β-(1,2-trans) Glycoconjugates via 1-O-Acyl and 1-O-Ethoxycarbonyl-2-azido-2,3-dideoxyglycopyranosides

A methodology for the synthesis of 2,3,6-trideoxy- and 2,3-dideoxy-2-aminoglycosides is presented. 2,3-Dideoxyhex-2-enopyranos-4-uloses (named also as 2H-pyran-3(6H)-ones) were used for the synthesis of 1-O-acetyl, 1-O-ethyloxycarbonyl and 1-S-phenyl-2,3,6-trideoxy-(or 2,3-dideoxy)-2-azidoglycopyranosyl donors. Glycosidation of the above thio-ethers with a variety of alcohols in the presence of N-bromosuccinimide as activator yielded predominantly α-glycosides, while acetates afforded β-glycosides when TMSOTf was used as a promoter. The coupling of carbonates using tin tetrachloride or TMSOTf proved to be the most successful procedure, yielding the β-glycoside as the predominant product. Thus, glycoconjugates of aminosugars, steroids and aminoacids have been synthesized.     

The dimeric and polymeric anhydride of 2,3-O-isopropylidene-β-D-ribofuranose. An NMR study

The ¹H- and ¹³C-NMR data of the dimeric anhydride 1 of 2,3-O-isopropylidene-β-D -ribofuranose are reported together with the ¹H-NOE values. The data show that the products of the polymerization of 1,5-anhydro-2,3-O-isopropylidene-β-D -ribofuranose are α- and β-D -ribofuranans and not an α-D -ribofuranan and a β-D -ribofuranan and a β D ribo-pyranan as claimed before [2] [3].     

Synthesis of 3- and 4-(β-D-ribofuranosyl)-s-triazolo[2,3-a] pyrimid-7-one,isomers of inosine containing a bridgehead nitrogen atom

The first synthesis of a purine nucleoside analog containing a bridgehead nitrogen atom is here reported. The direct glycosylation of the trimethylsilyl derivative of s-triazolo[2,3-a] pyrimid-7-one has been shown to give 3-(β-D-ribofuranosyl)-s-triazolo[2,3-a]pyrimid-7-one (V) and 4-(β-D-ribof'uranosyl)-s-lriazolo[2,3-α]pyrimid-7-one (VII). The nueleoside V may he considered a close analog of inosine in which the nitrogen N₁ and C₅ of inosine have been interchanged. Bro-minalion of the tri-O-acelyl derivative IV gave, after deblocking, 6-bromo-3-(β-D-ribofurnaosyl)-s-triazolo[2,3-a] pyrimid-7-one (IX). Structural assignments of the nucleosides were made on the basis of comparison of the ultraviolet absorption spectral characteristics with 3-methyl-s-triazolo-[2,3-a]pyrimid-7-one (XI) and 4-methyl-s-lriazolo[2,3-a Jpyrimid-7-one (XII) prepared by a standard procedure from 7-methoxy-s-triazolo(2,3-a] pyrimidine (X).     

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.     

Total synthesis of 2-(β-D-ribofuranosyl)thiazole-4-carboxamide (Tiazofurin) and of precursors of ribo-C-nucleosides

(1R,2S,4R)-2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl (1S′)-camphanate ( 5 ) was transformed into (?)-methyl 2,5-anhydro-3,4,6-O-tris[(tert-butyl)dimethylsilyl]-D -allonate ( 2 ), (+)-1,3-diphenyl-2-{2′,3′,5′-O-tris[(tert-butyl)dimethylsilyl]-β-D -ribofuranosyl}imidazolidine ( 3 ), and the benzamide 20 of 1-amino-2,5-anhydro-1-deoxy-3,4,6-O-tris-[((tert-butyl)dimethylsily)]-D -allitol. Compound 2 was converted efficiently into optically active tiazofurin ( 1 ).     

9-Deazapurine nucleosides. The synthesis of certain N-5-β-d-ribofuranosylpyrrolo[3,2-d]pyrimidines

Several N-5 ribofuranosyl-2,4-disubstituted pyrrolo[3,2-d]pyrimidine (9-deazapurine) nucleosides were prepared by the single phase sodium salt glycosylation of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine ( 3 ) using 1-chloro-2,3-O-isopropylidene-5-O-(t-butyl)dirnethylsilyl-α-D-ribofuranose ( 2 ). Use of 2 for the glycosylation avoided the formation of “orthoamide” products 1 and provided an excellent yield of the β nucleoside, 2,4-dichloro-5-[2,3-O-isopropylidene-5-O-(t-butyl)dimethylsilyl-β-D-ribofuranosyl]-5H-pyrrolo[3,2-d]pyrimidine ( 4 ), along with a small amount of the corresponding α anomer, 5 . Compound 4 served as the versatile intermediate from which the N-7 ribofuranosyl analogs of the naturally-occurring purine nucleosides adenosine, inosine and guanosine were synthesized. Thus, controlled amination of 4 followed by sugar deprotection and dehalogenation yielded the adenosine analog, 4-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidine ( 8 ) as the hydrochloride salt. Base hydrolysis of 4 followed by deprotection gave the 2-chloroinosine analog, 10 , and subsequent dehalogenation provided the inosine analog, 5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]-pyrimidin-4(3H)-one ( 11 ). Amination of 10 furnished the guanosine analog, 2-amino-5-β-D-ribofuranosyl-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one ( 12 ). Finally, the α anomer in the guanosine series, 16 , was prepared from 5 by the same procedure as that used to prepare 12 . The structural assignments were made on the basis of ultraviolet and proton nmr spectroscopy. In particular, the isopropylidene intermediates 9 and 14 were used to assign the proper configuration as β and α, respectively, according to Imbach's rule.     

2,4-Disubstituted Pyrrolo[2,3-d]pyrimidine α-D- and β-D-Ribofuranosides Related to 7-Deazaguanosine

Nucleobase-anion glycosylation (KOH, tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), MeCN) of the pyrrolo[2,3-d]pyrimidines 4a – d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribo-furanosyl chloride ( 5 ) gave the protected β-D -nucleosides 6a – d stereoselectively (Scheme 1). Contrary, the β-D -halogenose 8 yielded the corresponding α-D -nucleosides ( 9a and 9b ) apart from minor amounts of the β-D -anomers. The deprotected nucleosides 10a and 11a were converted into 4-substituted 2-aminopyrrolo[2,3-d]-pyrimidine β-D -ribofuranosides 1 . 10c , 12 , 14 , and 16 and into their α-D -anomers, respectively (Scheme 2). From the reaction of 4b with 5 , the glycosylation product 7 was isolated, containing two nucleobase moieties.     

Synthesis of 6-amino-4-aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles and their hydrogenated analogs. Molecular structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole

Substituted 3-hydroxypyrazoles, which were prepared based on ethyl esters of substituted 4-(pyridin-2-ylthio)- or 4-(1,4-dihydropyridin-2-ylthio)acetoacetic acids and hydrazine hydrate, were used in the synthesis of 6-amino-4-aryl-5-cyano-3-(pyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles. The molecular and crystal structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole was established by X-ray diffraction analysis.     

C-Nucleosides. 8. Synthesis of 5-hydroxy-2-(β-D-ribofuranosyl)pyridine

The synthesis of 5-hydroxy-2-(β-D-ribofuranosyl)pyridine ( 12 ) from 2-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)furan ( 1 ) is described. Treatment of 1 with α-methoxycarbamate in the presence of p-toluenesulfonic acid in benzene at reflux temperature afforded furfurylcarbamate ( 2 ) and its α-isomer in a 5/1 ratio. The anomerization was circumvented by treatment of 1 with α-methoxycarbamate in the presence of boron trifluoride in benzene at room temperature. Compound 2 was electrochemically oxidized to give dihydrofuran 4 . However, conversion of 4 into 11 was unsuccessful. Treatment of azide 8 with bromine and methanol afforded 9 . Reduction of 9 with zinc powder gave dihydrofurfurylamine 10 , in 80% yield. Treatment of this with concentrated hydrochloric acid in methanol yielded 11 , which on deblocking with 5% sodium hydroxide aqueous solution gave 12.     

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.     

Nucleosides and Nucleotides. Part 13. Synthesis and spectral properties of 1- (3′-O-Phosphoryl-2′-deoxy-β -D-ribofuranosyl)-2(1H)-pyridone-(3′-5′)-1-(2′-deoxy-β-D-ribofuranosyl)-2 (1H)-pyridone

The dinucleoside phosphate Π_dpΠ_d ( 4 ) was synthesized from the monomers 1-(5′-O-monomethoxytrityl - 2′ - deoxy - β - D - ribofuranosyl) - 2 (1 H) - pyridone ((MeOTr) Π_d, 2 ) and 1-(5′-O-phosphoryl-3′-O-acetyl-2′-deoxy-β-D -ribofuranosyl)-(1H)-pyridone (pΠ_d(Ac), 3 ). Its 6.4% hyperchromicity and an analysis of the ¹H-NMR. spectra indicate that the conformation and the base-base interactions in 4 are similar to those in natural pyrimidine dinucleoside phosphates.     

Stereoselective synthesis of pyrrolo[2,3-d]pyrimidine α- and β-D-ribonucleosides from anomerically pure D-ribofuranosyl chlorides: Solid-Liquid Phase-Transfer Glycosylation and 15N-NMR Spectra

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethye]amine ( = TDA-1), MeCN) of pyrrolo[2,3-d]pyrimidines such as 3a and 3b with an equimolar amount of 5-O-[(1,1 -dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribofuranosyl chloride (1) [6] gave the protected β-D -nucleosides 4a and 4b , respectively, stereoselectively (Scheme). The β-D -anomer 2 [6] yielded the corresponding α-D -nucleosides 5a and 5b with traces of the β-D -compounds. The 6-substituted 7-deazapurine nucleosides 6a , 7a , and 8 were converted into tubercidin (10) or its α-D -anomer (11) . Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T₁ values of H? C(8) in the α-D -series are significantly increased compared to H? C(8) in the β-D -series while the opposite is true for T₁ of H? C(1′). ¹⁵N-NMR data of 6-substituted 7-deazapurine D -ribofuranosides were assigned and compared with those of 2′-deoxy compounds. Furthermore, it was shown that 7-deaza-2′deoxyadenosine ( = 2′-deoxytubercidin; 12 ) is protonated at N(1), whereas the protonation site of 7-deaza-2′-deoxyguanosine ( 20 ) is N(3).     

Synthesis of 5-Methyluridine and Its 5′-Mercapto-, 2-Amino-, and 4′,5′-Unsaturated Analogues

The stereospecific cis-hydroxylation of 1-(2,3-dideoxy-β-D -glyceropent-2-enofuranosyl)thymine (1) into 1-β-D -ribofuranosylthymine (2) by osmium tetroxide is described. Treatment of 2′,3′-O, O-isopropylidene-5-methyl-2,5′-anhydrouridine (8) with hydrogen sulfide or methanolic ammonia afforded 5′-deoxy-2′,3′-O, O-isopropylidene-5′-mercapto-5-methyluridine (9) and 2′,3′-O, O-isopropylidene-5-methyl-isocytidine (10) , respectively. The action of ethanolic potassium hydroxide on 5′-deoxy-5′-iodo-2′,3′-O, O-isopropylidene-5-methyluridine (7) gave rise to the corresponding 1-(5-deoxy-β-D -erythropent-4-enofuranosyl)5-methyluracil (13) and 2-O-ethyl-5-methyluridine (14) . The hydrogenation of 2 and its 2′,3′-O, O-isopropylidene derivative 4 over 5% Rh/Al₂O₃ as catalyst generated diastereoisomers of the corresponding 5-methyl-5,6-dihydrouridine ( 17 and 18 ).     

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 .