Synthesis and Anti-HIV Activity of 6-Substituted Purine 2′-Deoxy-2′-fluororibosides

Abstract

3′,5′-Di-O-protected 6-chloropurine arabinoside 4b was treated with diethylaminosulfur trifluoride (DAST) and subsequently deprotected with pyridinium p-toluenesulfonate to give 6-chloropurine 2′-deoxy-2′-fluororiboside 6a. The displacement with nucleophile afforded the 6-substituted congener 6b-e. Treatment of 5′-O-protected 6-chloropurine arabinoside 3c with DAST gave lyxoepoxide 7.     

Utilization Of Tetrabutylammonium Triphenyldifluorosilicate (TBAT) In The Synthesis of 6-Fluoropurine Nucleosides

Abstract

Tetrabutylammonium triphenydifluorosilicate (TBAT) has been found to be a useful reagent for the conversion of 6-chloropurine nucleosides to 6-fluoropurine derivatives. The 6-chloropurine nucleosides were reacted with trimethylamine to form quaternary trimethylammonium salts which were treated in situ with TBAT in DMF to effect conversion to the 6-fluoro derivatives in yields of 59–72%.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

Expeditious and Stereoselective Synthesis of α-Guanosine

Abstract

The preparation of the unnatural nucleoside α-guanosine (1) has been achieved from readily available, literature precursors in ca. 6–9% overall yield. The key step, construction of the α-anomeric bond between the purine and the sugar, was accomplished by S_N2 displacement of protected β-chlororibose derivative 2 with 2-amino-6-chloropurine. The optimal conditions for this reaction involved cesium carbonate in N-methylpyrrolidinone (α/β ratio: 7.7:1).     

AN IMPROVED SYNTHESIS OF 9-[2-(DIETHOXYPHOSPHONOMETHOXY)ETHYL]ADENINE AND ITS ANALOGUES WITH OTHER PURINE BASES UTILIZING THE MITSUNOBU REACTION

Abstract

Unprotected adenine, 6-chloropurine, 2.6-diaminopurine. and 2-amino-6-chluropurine have been directly coupled with 2-(diethoxyphosphonomethoxy)ethanol under Mitsunobu reaction conditions to provide acyclic phosphonate nucleotide analogues which are intermediates for antiviral agents such as PMEA.     

Unsaturated Nucleoside Analogues: Synthesis and Antitumor Activity

Abstract

Five classes of unsaturated nucleoside analogues were investigated as inhibitors of growth of murine leukemia L 1210 culture. The structural types include E ole-fins 1, Z-olefins 2, acetylene derivatives 3, allenes 4 and oxacyclopentenes 5. Compounds of the type 1-3 (X = Cl) were obtained by alkylation of the respective nucleic acid bases or 2-amino-6-chloropurine with E and Z-1,4-dichloro-2-butene or 1,4-di-chloro-2-butyne. Acid hydrolysis of intermediates 1, 2 and 3 (X = CI) led to the corresponding alcohols 1, 2 and 3 (X = OH). Chloroallene 4 (B = Ade, X = CI) was obtained by chlorination of adenallene (B = Ade, X = OH). Compounds of the type 5 were obtained by base-catalyzed cyclization of the respective 2-butynes. A prolonged hydrolysis of compound 2 (B = 2-amino-6-chloropurine, X = CI) gave tricyclic derivative 7. Similar cyclization of 2 (B = Ade, X = CI) afforded a 3, g-bridged adenine 8. Alcohol 2 (B = Ade, X = OH) is a poor substrate for adenosine deaminase as contrasted with compounds 1, 3 and 4 (B = Ade. X = OH). 4-Hydroxybutyl derivative 6 (B = Ade, X = CI) was completely inert.     

Synthesis of trans-4-Amino-1-hydroxy-2-methyl-2-butene from Isoprene

A novel synthetic pathway to trans-4-amino-1-hydroxy-2-methyl-2-butene (7), a useful synthetic intermediate of zeatin, is presented here. On selective monophthalimide formation, the trans-1, 4-dibromo-2-methyl-2-butene (10) prepared from isoprene (1) predominantly gives trans-1-bromo-2-methyl-4-phthalimido-2-butene (11). The compound (11) is converted to 7 via trans-1-acetoxy-2-methyl-4-phthalimido-2-butene (6). The overall yield of 7 from 1 is 33.6%. Base-catalyzed hydrolysis of 11 also gives 7 directly. Zeatin can be prepared by the condensation of 7 with 6-chloropurine.     

Conformationally Locked Nucleoside Analogs. Synthesis of 2′-Deoxy-2′-C, 4′-C-Bridged Bicyclic Nucleosides

Abstract

1-α-Methylarabinose was converted, in three steps, to 2-deoxy-2-methyleneribose derivative 3, which was subjected to hydroboration to give 2-α-hydroxymethyl derivative 4 exclusively. 4 was converted to 2,4-bis(hydroxymethyl)ribose derivative 6 in four steps. Mesylation, detritylation, and ring closure, followed by hydrolysis of the mesyl group at O5, gave 3,6-dioxabicyclo[3,2,1]octane derivative 8. After acetylation, 8 was coupled with silylated 6-chloropurine to give desired α- and β-bicyclic-sugar nucleosides.     

Synthesis of New Nucleoside Analogues Comprising a Geminal Difluorocyclopropane Moiety as Potential Antiviral/Antitumor Agents

Abstract

Geminal difluorocyclopropane analogues of nucleosides 7a–7e were synthesized. Compounds 7a and 7c–7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a–7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.     

Synthesis of 3′-Fluoro-3′-deoxy-N6-cyclopentyladenosine

Abstract

Starting from 9-(β-D-xylofuranosyl)-6-chloropurine, the title compound was prepared in four steps. Reaction with cyclopentylamine followed by treatment of the 2′-O,5′-O-ditritylated material with diethylaminosulfur trifluoride (DAST), yielded after deprotection the desired compound.     

Lithiation-Stannylation Chemistry of Nucleosides

Abstract

Two examples of anionic stannyl migration practically useful for nucleoside synthesis are presented. One involves the migration from the 8- to 2-position of 6-chloropurine derivatives, which provided a new entry to 2-substituted purine nucleosides. The other is that from the 6- to 2′-position of 1′,2′-unsaturated uridine. The latter enabled the preparation of a hitheroto unknown class of nucleoside analogues, 2′-substituted 1′,2′-unsaturated uridines.     

Synthesis and Biological Activity of 4′-Thio-2′-deoxy Purine Nucleosides

Abstract

Coupling of 1-O-acetyl-2-deoxy-3,5-di-O-toluoyl-4-thio-_d-ribofuranose with 6-chloropurine and 2,6-dichloropurine gave a mixture of 9α and 9β anomers as major products. These anomers were separated and converted to 2′-deoxy-4′-thio analogues of adenosine, inosine, guanosine, 2-amino-adenosine, and 2-chloro adenosine as well as their α-anomers.     

A New Method for the Synthesis of 2′-O-Benzyladenosine Using Mitsunobu Reaction

Abstract

A new method to introduce a benzyl group onto the 2′-OH of purine ribonucleoside is described. Thus, 6-chloropurine 3′-O-benzoylriboside and its 5′-O-trityl congener were condensed with benzyl alcohol using the Mitsunobu reaction to give the 2′-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depending on the solvent used. The product was converted to adenosine, indicating that the stereochemistry at C-2′ is retained.     

Synthesis of 6-Arylthio Analogs of 2′,3′-Dideoxy-3′-Fluoroguanosine and Their Effect against Hepatitis B Virus Replication

A key compound, 2-amino-6-chloro-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)purine, was prepared from 2-amino-6-chloropurine riboside in 5 steps, then subjected to the nucleophilic displacement with benzenethiols to afford 6-arylthio congeners. These compounds showed a similar anti-HBV effect to that of 2′,3′-dideoxy-3′-fluoroguanosine.     

Introduction of a Benzyl Group onto the 2′-OH of 6-Chloropurine 3′-O-Benzoylriboside

Abstract

A new method to introduce a benzyl group onto the 2′-OH of purine ribonucleoside is described. Thus, 6-chloropurine 3′-O-benzoylriboside and its 5′-O-trityl congener were condensed with benzyl alcohol using the Mitsunobu reaction to give the 2′-O-benzyl derivative. The yields were varied from 4.6 to 62.9% depending on the solvent. The product was converted to adenosine, indicating that the stereochemistry at C-2′ is retained.     

Convenient Syntheses of 6-Methylpurine and Related Nucleosides

Abstract

Efficient methods for the synthesis of 6-methylpurine (3), 9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-methylpurine (8), and 6-methyl-9-β-D-ribofuranosylpurine (5) are described. Methodology involving the (Ph₃P)₄Pd catalyzed cross-coupling reaction of CH₃ZnBr with several different 6-chloropurine derivatives is described in high yield. This methodology now provides a facile and high-yielding synthesis of 8, which is needed in significant amounts for studies in cancer gene therapy.     

The search of novel inhibitors of HIV-1 integrase among 5-(4-halogenophenyl)-5-oxopentyl derivatives of nucleic bases

New nucleic base derivatives were obtained by alkylation of uracil, thymine, cytosine, adenine, 6-chloropurine, and 2-amino-6-chloropurine with 5-chloro-1-(4-halogenophenyl)-1-pentanones, and their physical and chemical properties were studied. The influence of the compounds synthesized on the HIV-1 integrase activity was studied.     

SYNTHESIS of 2′-DEOXY-2′-FLUOROGUANYL-(3′,5′)-GUANOSINE

ABSTRACT

The protected analogue of 2-amnio-6-chloropurine arabinoside (3b) was subjected to reaction with diethylaminosulfur trifluoride (DAST) and subsequently treated with NaOAc in Ac₂O/AcOH to give N ²,O ^3′,O ^5′-triacetyl-2′-deoxy-2′-fluoroguanosine (5a). After deacetylation of the sugar moiety and protection of 5′-OH by a 4,4′-dimethoxytrityl group, this nucleoside component was converted to 2′-deoxy-2′-fluoroguanyl-(3′,5′)-guanosine (6c, GfpG).     

Synthesis of 2-Alkynylcordycepins and Evaluation of Their Vasodilating Activity

Abstract

Based on the recently developed lithiation-mediated stannyl migration of 6-chloropurine derivatives, 2-iodocordycepin was prepared from cordycepin. The reaction of this compound with terminal alkynes was carried out to synthesize a series of 2-alkynyl derivatives. The vasodilating effect of these compounds was evaluated.     

Synthesis of the Fluoromethyl Derivatives of Carbocyclic Oxetanocin A

Abstract

Treatment of the 2,3-di-O-benzoate 1 with sodium boronhydride mainly afforded the 3-O-benzoate 2 accompanied with isomers 3a,b and fully deprotected product 4. Compound 2 was converted to 5, from which 8 was obtained. The 1-cyclobutanols 8 and 5 were successfully condensed with 6-chloropurine by Mitsunobu reaction to give 9 and 11, respectively. After partial deprotection, the cyclobutyl nucleosides 10 and 15 were subjected to fluorination using DAST to afford the fluoromethyl analogs 12 and 16 from which target compounds 14 and 17 were obtained in good yields, respectively.