Nucleosides. Part 3.1 Synthesis of 2-N-Substituted 1-β-D-Arabinofuranosylisocytosine Derivatives by The Reaction of 2′,5′-Dichloro-2′,5′-Dideoxyuridine with Amines

Abstract

Reaction of 2′,5′-dichloro-2′,5′-dideoxyuridine (1) with ammonia and benzylamine afforded the corresponding 2-N-substituted 1-(5-chloro-5-deoxy-β-D-arabinofuranosyl)-isocytosine derivatives (2 and 10). Reaction of 1 with ammonia, methylamine, cyclohexylamine, and benzylamine followed by treatment with methanolic sodium methoxide gave the corresponding 2-N-substituted 1-(2,5-anhydro-β-D-arabino-furanosyl)isocytosine derivatives (6, 11, and 12).     

Synthesis and Antiviral Activity of 1,5-and 1,3-Dialkyl-1,2,4-triazole C-Nucleosides Derived from 1-(Chloroalkyl)-1-aza-2-azoniaallene Salts

Abstract

Reactions of α, α′-dichloroazo compounds 2 with SbCl₅ gave 1-(chloroalkyl)-1-aza-2-azoniaallene salts 3 as reactive intermediates. Cycloadditions of 3 with the ribofuranosyl cyanide 4 afforded the β-D-ribofuranosyl-1,2,4-triazolium salts 5, which rearranged spontaneously to salts 6. Hydrolysis of 6 gave the 1,2,4-triazole C-nucleosides 7, which yielded the free nucleosides 8 after deblocking. Analogously, 12 was prepared from the cycloaddition of 4 with the α-chloroazo compound 10 in the presence of SbCl₅. Deblocking of 12 with sodium methoxide afforded 13. Compounds 8a,b,e,f and 13 were tested against HIV-1, HIV-2, HSV-1 and HSV-2 and were found to be inactive.     

Synthesis and evaluation of the anti-hepatitis B virus activity of 4′-Azido-thymidine analogs and 4′-Azido-2′-deoxy-5-methylcytidine analogs: structural insights for the development of a novel anti-HBV agent

Abstract

Hepatitis B virus (HBV) infection is a major worldwide health problem that requires the development of improved antiviral therapies. Here, a series of 4′-Azido-thymidine/4′-Azido-2′-deoxy-5-methylcytidine derivatives (6, 10–15) were synthesized, and their anti-HBV activities evaluated. Compounds 10–15 were synthesized via an S_NAr reaction of 18, in which the 4-position of the thymine moiety was activated as the 2,4,6-triisopropylbenzenesulfonate. Compounds 11–15 showed no antiviral activity. However, 4′-Azido thymidine (6) and 4′-Azido-2′-deoxy-5-methylcytidine (10) displayed significant anti-HBV activity (EC₅₀ = 0.63 and 5.99?µM, respectively) with no detectable cytotoxicity against MT-2 cells up to 100?µM.     

A novel entecavir analogue constructing with a spiro[2.4]heptane core structure in the aglycon moiety: Its synthesis and evaluation for anti-hepatitis B virus activity

Synthesis of a novel 2′-deoxy-guanine carbocyclic nucleoside 4 constructed with spiro[2.4]heptane core structure in the aglycon moiety was carried out. Radical-mediated 5-exo-dig mode cyclization and following cyclopropanation proceeded efficiently to furnish the spiro alcohol 10. Subsequent Mitsunobu-type glycosylation between 13 and 14, deoxygenation of the 2′-hydroxyl group of 16 and deprotection of 17 gave the title compound 4. Compound 4 demonstrated moderate anti-HBV activity (EC₅₀ value of 0.12 ± 0.02 µM) and no cytotoxicity against HepG2 cells was observed up to 100 µM.     

Synthesis of Homologated Halovinyl Derivatives from Aristeromycin and Their Inhibition of Human Placental S-Adenosyl-L-homocysteine Hydrolase¶

Abstract

Moffatt oxidation of 2′,3′-O-isopropylidenearisteromycin (1a) and treatment of the 5′-carboxaldehyde with [(p-tolylsulfonyl)methylene]triphenylphosphorane gave the homologated vinylsulfone 2. Treatment of 2 with tributylstannane/AIBN gave the (E/Z)-vinylstannanes which were converted into the E and Z fluoro- and iodovinyl analogs. Chain extension via the 5′-cyano-5′-deoxy derivative 10a gave the 6′-carboxaldehyde of homoaristeromycin. S-Adenosyl-L-homocysteine hydrolase was strongly inhibited by the fluorovinyl, 5b, and iodovinyl, 4b and 7b, compounds, and time-dependent kinetics were observed [1–2 μM (K_i) and 0.1–0.2 min^?1 (k _inact)]. The mechanism of inactivation was shown to involve addition of water at the vinyl 5′ or 6′ carbons with elimination of halide.

     

Synthesis of sucrose epoxides,partial de-esterification of 1′,2:4,6-di-O-isopropylidenesucrose tetra-acetate,and selective tosylation of 3,6′-di-O-acetyl-1′,2:4,6-di-O-isopropylidenesucrose

Selective de-esterification of 1′,2:4,6-di-O-isopropylidenesucrose tetra-acetate² (1) with methanolic ammonia at ?10° gave an inseparable mixture (2+3) of the 3,4′,6′- and 3,3′,6′-triacetates and also the 4,6′-diacetate 4. When the reaction was performed at 5°, it gave 4, the 4-acetate 8, and the parent diacetal 9. These derivatives allow selective reaction at hydroxyl groups in sucrose, in particular at HO-3′ and, HO-4′, not hitherto possible. Mesylation of 4 gave the 3′,4′-dimesylate 7, which, on treatment with aqueous acetic acid followed by acetylation, afforded 3′,4′-di-O-mesylsucrose hexa-acetate (11). Treatment of 11 with sodium methoxide in methanol at 70° for 1 min gave the ribo-3′,4′-epoxide 12 as the minor, and the lyxo-3′,4′-epoxide 13 as the major, product. Selective tosylation of 4 gave the 3',4'-ditosylate 14 (3.7%), 4′-tosylate 15 (3.1%), and 3'-tosylate 16 (31%), indicating the order of reactivity HO-3′>HO-4′ in 4. De acetalation of 15 and 16 followed by acetylation gave the hepta-acetates of 4′- and 3′-O-tosylsucrose, respectively, which were converted into the respective epoxides, 13 and 12, by methanolic sodium methoxide.     

Branched-chain sucroses: Synthesis and Wittig reaction of the 1′-aldehydo derivative of sucrose

The reaction of 2,3,4,3′,4′-penta-O-acetylsucrose (1) with 3.3 mol. equiv. of tert-butyldiphenylsilyl chloride in pyridine in the presence of 4-dimethylamino-pyridine gave the 6,1′,6′-tris(tert-butyldiphenylsilyl) derivative 2 (27%) and the 6,6′-bis(tert-butyldiphenylsilyl) derivative (67%). Oxidation of the HO-1′ in 3 with methyl sulphoxide and trifluoroacetic anhydride gave the 1′-aldehydo derivative 5, which reacted with the stabilised Wittig reagent (Ph₃PCHCO₂Et) to give the 1′-ethoxycarbonylmethylene derivative 6. Deacetylation of the hepta-acetate 7 of 6 with methanolic sodium methoxide was accompanied by a Michael addition reaction to give 2,1′-anhydro-1′-methoxycarbonylmethylsucrose.     

Reaction of methanesulphonyl chloride-N,N-dimethylformamide with partially esterified derivatives of sucrose

Treatment of sucrose 2,3,3′,4′,6-penta-acetate (1) with methanesulphonyl chloride-N,N-dimethylformamide (reagent A) gave the 1′,4,6′-trichloride 2, the 1′-O-formyl-4,6′-dichloride 3, the 4,6′-dichloride 4, and the 1′,4-di-O-formyl-6′-chloride 5. De-esterification of 3 afforded the unsubstituted 4,6′-dichloride 6 which, on acetylation, gave the corresponding hexa-acetate 7, also prepared by acetylation of 4. In compounds 2, 3, and 4, substitution at C-4 by chloride ion occurred with inversion of configuration. The structure of 5 was confirmed by conversion into the known 6′chloro-6′-deoxysucrose hepta-acetate by de-esterification followed by acetylation. Treatment of sucrose 1′,2,3,3′,4′,6′-hexa-acetate (10) with the reagent gave the 4,6-dichloride 11 and 4-O-formyl-6-chloride 12. The formyl group in 12 was selectively removed by using an anion-exchange resin to give 16. De-esterification of 12 with methanolic sodium methoxide gave 6-chloro-6-deoxysucrose (13) which, on acetylation and benzoylation, afforded the hepta-acetate 14 and the hepta-benzoate 15, respectively. Alternatively, 15 was prepared by the reaction of 1′,2,3,3′,4,4′,6′-hepta-O-benzoylsucrose with reagent A. Treatment of 14 with sodium methoxide in methanol followed by acetylation gave 3,6-anhydrosucrose hexa-acetate (24). Reaction of sucrose 2,3,3′,4,4′-pentabenzoate (17) with reagent A gave the known 1′,6,6′-trichloro-1′,6,6′-trideoxysucrose pentabenzoate (18) and 1′-O-formyl-6,6′-dichloride 19. Treatment of 19 with anion-exchange resins selectively removed the formyl group to give 20. The structure of 20 was confirmed by conversion into the 1′-chlorosulphate-6,6′-dichloride (21). Treatment of sucrose 1′,2,3,3′,4,4′-hexabenzoate (22) with reagent A gave the expected 6,6′-dichloride (23).     

Synthesis of Novel 3′-Hydroxymethyl 5′-Deoxythreosyl Phosphonic Acid Nucleoside Analogues as Potent Antiviral Agents

A very efficient synthetic route to novel 3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleosides was described. The discovery of threosyl phosphonate nucleoside (PMDTA, EC₅₀ = 2.53 μM) as a potent antihuman immunodeficiency virus (anti-HIV) agent has led to the synthesis and biological evaluation of 3′-modified 5′-deoxy versions of the threosyl phosphonate nucleosides. 3′-Hydroxymethyl 5 ′-deoxythreosyl phosphonic acid nucleoside analogues 15, 19, 24, and 28 were synthesized from 1,3-dihydroxyacetone and tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 19 exhibits moderate in vitro anti-HIV-1 activity (EC₅₀ = 10.2 μM).     

Synthesis and Absolute Configuration of Pyriculol

A total synthesis of optically active pyriculol is described. The Wittig reaction between an aldehyde 19 and a triphenylphosphonium ylide 12 gave an intermediate 20. Successive treatment of 20 with p-toluenesulfonic acid, active manganese dioxide, and potassium carbonate gave (3′R,4′S)-pyriculol (23), which was identical with natural pyriculol (1) in all respects. From this synthesis, the absolute stereochemistry of pyriculol (1) was determined to be 2-[(3′R,4′S)-3′,4′-dihydroxy- (1′E,5′E)-1′,5′-heptadienyl]-6-hydroxybenzaldehyde     

Design and Synthesis of Novel Carbocyclic Versions of 2′-spirocyclopropyl Ribonucleosides as Potent Anti-HCV Agents

The discovery of 2′-spirocyclopropyl-ribocytidine as a potent inhibitor of RNA synthesis by NS5B (IC₅₀ = 7.3 μM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of carbocyclic versions of 2′-spiropropyl-nucleosides from cyclopentenol 6. Spirocyclopropylation of enone 7 was completed by using (2-chloroethyl)-dimethylsulfonium iodide and potassium t-butoxide to form the desired intermediate 9a. The synthesized nucleoside analogues, 18, 19, 26, and 27, were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. The synthesized cytosine nucleoside 19 showed moderate anti-HCV activity (IC₅₀ = 14.4 μM).     

Nucleosides. II. Synthesis and Properties of 3,4-Diaryl-4,5-dihydro-1-(β-D-ribofuranosyl)-1,2,4-triazole-5-thiones

Abstract

3,4-Diaryl-4,5-dihydro-1,2,4-triazole-5-thiones (1a-c) were silylated to give compounds (2a-c) which were condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (3) in the presence of trimethylsilyl trifluoromethane sulfonate to afford the corresponding nucleosides 4a-c. Treatment of 4a-c with sodium methoxide in methanol at room temperature afforded the debenzoylated nucleosides 5a-c. The reaction of 5a with acetone in the presence of p-toluenesulfonic acid gave the 2′, 3′-isopropylidene derivative (6a). Phosphorylation of 6a with phosphoryl chloride and triethylphosphate followed by treatment with barium hydroxide afforded barium 3,4-diphenyl-4,5-dihydro(β-D-ribofuranosyl)-1,2,4-triazole-5-thione-5′- monophosphate, which gave after lyophilization the free acid (7a)     

Synthesis of Triazole Nucleoside Derivatives

Abstract

5′-O-Mesyl-2′,3′-O-isopropylidene ribonucleosides (4 and 12) were converted to their 5′-substituted nucleosides in good yields by reacted with NaN₃ or KI. 2′,3′-O-Isopropylidene ribonucleosides (3 and 11) were prepared in good yields from ribonucleosides 1 and 2 with a reaction mixture of acetone and triethyl orthoformate instead of using acetone diethyl acetal. Compound 1 or 2 was treated with 2-acetoxyisobutyryl halide (Cl or Br) to give 1-[2-O-acetyl-3-halo-3-deoxy-5-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-β-D-xylofuranosyl]-1,2,4-triazole-3-carboxamide (19, 22, and 23) in high yields. Instead of using 2-acetoxyisobutyryl bromide, the mixture of 2-acetoxyisobutyryl chloride and NaBr was employed in the synthesis of 22 and 23. Treatment of 19 with an activated Zn/Cu couple and deprotection gave 2′,3′-anhydro nucleoside (21), and treatment of 22 and 23 with an activated Zn/Cu couple and a little of HOAc and deprotection gave corresponding 2′,3′-unsaturated triazole nucleosides (24 and 25), respectively. The biological activity of the compounds (7 ～ 10, 15 ～ 18, and 24) was examined in human liver cancer cells (A-549), lung cancer cells (BEL-7402), and Flu-A cells.

Synthesis of Triazole Nucleoside Derivatives

All authors

Zicheng Li, Shuhua Chen, Ning Jiang & Gang Cui

https://doi.org/10.1081/NCN-120022032

Published online:

07 February 2007

Compound 1.     

14.

Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside     

Rakesh Kumar  Edward E. Knaus  Leonard I. Wiebe 《Nucleosides, nucleotides & nucleic acids》2013,32(9):895-904

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

15.

Novel Synthesis of 4′C-Aryl-Branched Acyclic Nucleoside Using [3,3]-Sigmatropic Rearrangement     

《Nucleosides, nucleotides & nucleic acids》2013,32(9):1781-1788

Abstract

A very efficient synthetic route for preparing a novel 4′-C-aryl branched-1′,2′-seco-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is described. Mesylate 7 was successfully synthesized via a Horner-Wadsworth-Emmons reaction and a [3,3]-sigmatropic rearrangement, with which an adenine base was coupled by nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) to give the target nucleoside 9.     

16.

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring     

Yuji Sumita  Michiyo Shirato  Yoshihito Ueno  Akira Matsuda  Satoshi Shuto 《Nucleosides, nucleotides & nucleic acids》2013,32(1-2):175-187

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

17.

Synthesis and Anti-HIV Activity of Novel 4′-Trifluoromethylated 5′-Deoxycarbocyclic Nucleoside Phosphonic Acids     

Jun-Pil Jee  Seyeon Kim 《Nucleosides, nucleotides & nucleic acids》2015,34(9):620-638

Efficient synthetic route to novel 4′-trifluoromethylated 5′-deoxycarbocyclic nucleoside phosphonic acids was described from α-trifluoromethyl-α,β-unsaturated ester. Coupling of purine nucleosidic bases with cyclopentanol using a Mitsunobu reaction gave the nucleoside intermediates which were further phosphonated and hydrolyzed to reach desired nucleoside analogs. Synthesized nucleoside analogs were tested for anti-HIV activity as well as cytotoxicity. Adenine analog 22 shows significant anti-HIV activity (EC₅₀ = 8.3 μM) up to 100 μM.     

18.

The Synthesis of Some 5-Substituted-6-aza-2′-deoxyuridines     

I. Basnak  P. L. Coe  R. T. Walker 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):163-175

Abstract

5-(2-Thienyl)-1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-6-azauracil [VIII] and 5-cyclopropyl-1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-6-azauracil [X] were obtained in high yields (93.5% and 81.3% respectively) exclusively as β anomers, by condensation of the corresponding silylated triazine bases with 2-deoxyu-3,5-di-O-p-toluoyl-D-erythro-pentosyl chloride in chloroform. After deblocking both nucleosides with sodium methoxide in methanol, 5-(2-thienyl)-6-aza-2′-deoxyuridine [IX] and 5-cyclopropyl-6-aza-2′-deoxyuridine [XI] were obtained. The nucleoside IX was further acetylated, brominated with Br₂/CCl₄ and deblocked with methanolic ammonia to give 6-aza-5[2-(5-bromothienyl)]-2′-deoxyuridine[XIV].     

19.

Nucleic Acid Related Compounds. LXXXI. Efficient General Synthesis of Purine (Amino,Azido, and Triflate)-Sugar Nucleosides     

Morris J. Robins  S. D. Hawrelak  Amelia E. Hernández  Stanislaw F. Wnuk 《Nucleosides, nucleotides & nucleic acids》2013,32(2-4):821-834

Abstract

Treatment of 3′,5′-O-(tetraisopropyldisiloxanyl)adenosine and its arabino epimer with trifluoromethanesulfonyl chloride/DMAP gave the 2′-triflates in high yields. Displacements (LiN₃/DMF) and deprotection gave 2′-azido-2′-deoxyadenosine and its arabino epimer which were reduced with Bu₃SnH/AIBN/DMAC/benzene (or Staudinger reduction) to give 2′-amino-2′-deoxyadenosine and its epimer. Oxidation of 2′,5′-bis-O-(tert-butyldimethylsilyl)adenosine, stereoselective reduction, triflation, azide displacement, deprotection, and reduction gave 3′-amino-3′-deoxyadenosine.     

20.

Synthesis of Branched-Chain and Bicyclic Thiosugar Nucleosides     

Stephen H. Kawai  Jik Chin  George Just 《Nucleosides, nucleotides & nucleic acids》2013,32(8):1045-1060

Abstract

The synthesis of strategically protected nucleosides bearing β-mercaptoethyl chains at the α-C-3′ position from 1,2-di-O-acetyl-2′-S-acetyl-5-t?butyldiphenylsilyl-3-deoxy-3-C-(2′-mercaptoethyl)-α-D-ribofuranose 1 is described. It was found that treatment of the 5-O-methanesulfonyl sugar 19 or nucleoside 5 with either benzylmercaptan or methoxide resulted in rapid cleavage of the thiolester followed by intramolecular cyclization. This was used to prepare the novel trans?fused oxathiahydrindane nucleosides 7 and 27 as well as the cAMP analogue 29.     

Synthesis of (E)-5-(2-cIOdovinyl)-3′-0-(1-Methyl-1,4-Dihydropyridyl-3 -Carbonyl)-2′-Fluoro-2′-Deoxyuridine (Ivfru-Cds) for Brain Targetted Delivery of Ivfru,an Antiviral Nucleoside

Abstract

(E)-5-(2-lodovinyl)-2′-fluoro-3′-0-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11) was synthesized for future evaluation as a lipophilic, brain-selective, pyrimidine phosphorylase-resistant, antiviral agent for the treatment of Herpes simplex encephalitis (HSE). Treatment of (E)-5-(2-iodovinyl)-2′-fluoro-2′-deoxyuridine (6) with TBDMSCI in the presence of imidazole in DMF yielded the protected 5′-O-t-butyldimethylsilyl derivative (7). Subsequent reaction with nicotinoyl chloride hydrochloride in pyridine afforded (E)-5-(-2-iodovinyl)-2′-fluoro-3′-O-(3-pyridylcarbonyl)-5′-O-t-butyldimethylsily-2′-deoxyuridine (8). Deprotection of the silyl ether moiety of 8 with n-Bu₄N⁺F^? and quaternization of the resulting 3′-O-(3-pyridylcarbonyl) derivative 9 using iodomethane afforded the corresponding 1-methylpyridinium salt 10. The latter was reduced with sodium dithionite to yield (E)-5-(2-iodovinyl)-2′-fluoro-3′-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2′-deoxyuridine (11).     

Novel Synthesis of 4′C-Aryl-Branched Acyclic Nucleoside Using [3,3]-Sigmatropic Rearrangement

Abstract

A very efficient synthetic route for preparing a novel 4′-C-aryl branched-1′,2′-seco-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is described. Mesylate 7 was successfully synthesized via a Horner-Wadsworth-Emmons reaction and a [3,3]-sigmatropic rearrangement, with which an adenine base was coupled by nucleophilic substitution conditions (K₂CO₃, 18-Crown-6, DMF) to give the target nucleoside 9.     

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Synthesis and Anti-HIV Activity of Novel 4′-Trifluoromethylated 5′-Deoxycarbocyclic Nucleoside Phosphonic Acids

Efficient synthetic route to novel 4′-trifluoromethylated 5′-deoxycarbocyclic nucleoside phosphonic acids was described from α-trifluoromethyl-α,β-unsaturated ester. Coupling of purine nucleosidic bases with cyclopentanol using a Mitsunobu reaction gave the nucleoside intermediates which were further phosphonated and hydrolyzed to reach desired nucleoside analogs. Synthesized nucleoside analogs were tested for anti-HIV activity as well as cytotoxicity. Adenine analog 22 shows significant anti-HIV activity (EC₅₀ = 8.3 μM) up to 100 μM.     

The Synthesis of Some 5-Substituted-6-aza-2′-deoxyuridines

Abstract

5-(2-Thienyl)-1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-6-azauracil [VIII] and 5-cyclopropyl-1-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-6-azauracil [X] were obtained in high yields (93.5% and 81.3% respectively) exclusively as β anomers, by condensation of the corresponding silylated triazine bases with 2-deoxyu-3,5-di-O-p-toluoyl-D-erythro-pentosyl chloride in chloroform. After deblocking both nucleosides with sodium methoxide in methanol, 5-(2-thienyl)-6-aza-2′-deoxyuridine [IX] and 5-cyclopropyl-6-aza-2′-deoxyuridine [XI] were obtained. The nucleoside IX was further acetylated, brominated with Br₂/CCl₄ and deblocked with methanolic ammonia to give 6-aza-5[2-(5-bromothienyl)]-2′-deoxyuridine[XIV].     

Nucleic Acid Related Compounds. LXXXI. Efficient General Synthesis of Purine (Amino,Azido, and Triflate)-Sugar Nucleosides

Abstract

Treatment of 3′,5′-O-(tetraisopropyldisiloxanyl)adenosine and its arabino epimer with trifluoromethanesulfonyl chloride/DMAP gave the 2′-triflates in high yields. Displacements (LiN₃/DMF) and deprotection gave 2′-azido-2′-deoxyadenosine and its arabino epimer which were reduced with Bu₃SnH/AIBN/DMAC/benzene (or Staudinger reduction) to give 2′-amino-2′-deoxyadenosine and its epimer. Oxidation of 2′,5′-bis-O-(tert-butyldimethylsilyl)adenosine, stereoselective reduction, triflation, azide displacement, deprotection, and reduction gave 3′-amino-3′-deoxyadenosine.     

Synthesis of Branched-Chain and Bicyclic Thiosugar Nucleosides

Abstract

The synthesis of strategically protected nucleosides bearing β-mercaptoethyl chains at the α-C-3′ position from 1,2-di-O-acetyl-2′-S-acetyl-5-t?butyldiphenylsilyl-3-deoxy-3-C-(2′-mercaptoethyl)-α-D-ribofuranose 1 is described. It was found that treatment of the 5-O-methanesulfonyl sugar 19 or nucleoside 5 with either benzylmercaptan or methoxide resulted in rapid cleavage of the thiolester followed by intramolecular cyclization. This was used to prepare the novel trans?fused oxathiahydrindane nucleosides 7 and 27 as well as the cAMP analogue 29.