Synthesis of 2′,3′-Didehydro-2′,3′-Dideoxy-3′-C-Methyl Substituted Nucleosides

Abstract

1-(2,3-Dideoxy-3-C-hydroxmethyl-β-D-threo-pentofuranosyl) -,1- (2,3-didehydro-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl) -and 1-(3-C-azidomethyl-2,3-dideoxy-3-C-hydroxymethyl-β-D-glycero- pentofuranosyl)uracil, thymine and cytosine were synthesized and evaluated for anti-HIV activity. The synthetic strategy was based on an allylic alcohol transposition of the corresponding 3′-C-methylene-nucleoside analogues.     

The Crystal and Molecular Structure of the Complex of 2′3′-Didehydro-2′3′-Dideoxyguanosine with Pyridine

Abstract

The structure of 2′,3′-didehydro-2′,3′-dideoxyguanosine was determined by X-ray crystallographic analysis of the complex with pyridine. The two independent nucleoside molecules have similar, commonly observed glycosyl link (x = -102.3° and -94.2°) and 5′-hydroxyl (y = 54.0° and 47.6°) conformations. The five-membered rings are very planar with r.m.s. deviations from planarity of less than 0.015 A. 2′,3′-Didehydro-2′,3′-dideoxyadenosine has a similar glycosyl link conformation but a different 5′-hydroxyl group orientation and a slightly less planar 5-membered ring.     

Concise and Efficient Synthesis of 3′-O-Tetraphosphates of 2′-Deoxyadenosine and 2′-Deoxycytidine

We describe concise and efficient synthesis of biologically very important 3′-O-tetraphosphates namely 2′-deoxyadenosine-3′-O-tetraphosphate (2′-d-3′-A4P) and 2′-deoxycytidine-3′-O-tetra-phosphate (2′-d-3′-C4P). N⁶-benzoyl-5′-O-levulinoyl-2′-deoxyadenosine was converted into N⁶-benzoyl-5′-O-levulinoyl-2′-deoxyadenosine-3′-O-tetraphosphate in 87% yield using a one-pot synthetic methodology. One-step concurrent deprotection of N⁶-benzoyl and 5′-O-levulinoyl groups using concentrated aqueous ammonia resulted 2′-d-3′-A4P in 74% yield. The same synthetic strategy was successfully employed to convert N⁴-benzoyl-5′-O-levulinoyl-2′-deoxycytidine into 2′-d-3′-C4P in 68% yield.     

Phosphonates Derivatives of 2′,3′-Dideoxy-2′,3′-didehydro-pentopyranosyl Nucleosides

Abstract

Adenine and thymine derivatives of 2′,3′-dideoxy-2′,3′-didehydropento-pyranosyl nucleosides carrying a phosphonomethyl moiety at their 4′-O-position and in a cis relationship with the heterocyclic base have been synthesized.     

Synthesis of 2′,3′-Dideoxyribavirin

Abstract

A synthesis of 1-(2,3-dideoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′,3′-dideoxyribavirin, ddR) is described. Glycosylation of the sodium salt of 1,2,4-triazole-3-carbonitrile (5) with 1-chloro-2-deoxy-3,5-di-0-p-toluoyl-α-D-erythro-pentofuranose (1) gave exclusively the corresponding N-1 glycosyl derivative with β-anomeric configuration (6), which on ammonolysis provided a convenient synthesis of 2′-deoxyribavirin (7). Similar glycosylation of the sodium salt of methyl 1,2,4-triazole-3-carboxylate (2) with 1 gave a mixture of corresponding N-1 and N-2 glycosyl derivatives (3) and (4), respectively. Ammonolysis of 3 furnished yet another route to 7. A four-step deoxygenation procedure using imidazolylthiocarbonylation of the 3′-hydroxy group of 5′-0-toluoyl derivative (9a) gave ddR (11). The structure of 11 was proven by single crystal X-ray studies. In a preliminary in vitro study ddR was found to be inactive against HIV retrovirus.     

Synthesis of Some 2′,3′-Dideoxy-3′-C-Fluoromethyl and 3′-C-Azidomethyl Nucleosides

Abstract

The synthesis of 3′-C-fluoromethyl and 3′-C-azidomethyl nucleosides is reported. The 3′-C-fluoromethyl furanoside 4 was synthesized via fluoride ion induced displacement of the corresponding trifluoromethanesulfonate. The 3′-C-hydroxymethyl furanoside 3 was converted to the corresponding 3′-C-azidomethyl furanoside 6 using triphenylphosphine-carbon tetrabromide-lithium azide. The 3′-C-fluoromethyl furanoside derivative 5 and the 3′-C-azidomethyl furanoside derivative 7 were subsequently condensed with silylated purine and pyrimidine bases. Deblocking and separation of the anomers by chromatography afforded the α- and β-nucleoside analogues. The nucleosides were tested for inhibition of HIV multiplication in vitro and were found to be inactive in the assay.     

Synthesis of the 2′-,3′-Didehydro-2′-,3′-dideoxy and 2′-,3′-Dideoxy Derivatives of 6-Azauridine and a New Route to 2′-,3′-Didehydro-2′-,3′-dideoxy-5-chlorouridine

Abstract

The 5′-O-(4,4′-dimethoxytrityl) and 5′-O-(tert-butyldimethylsilyl) derivatives of 2′-,3′-O-thiocarbonyl-6-azauridine and 2′,3′-O-thiocarbonyl-5-chlorouridine were synthesized from the parent nucleosides by reaction with 4, 4′-dimethoxytrityl chloride and tert-butyldimethylsilyl chloride, respectively, followed by treatment with 1,1′-thiocarbonyldiimidazole. Introduction of a 2′-,3′-double bond into the sugar ring by reaction of the 5′-protected 2′-,3′-O-thionocarbonates with 1, 3-dimethyl-2-phenyl-1, 3, 2-diazaphospholidiine was unsuccessful, but could be accomplished satisfactorily with trimethyl phosphite. Reactions were generally more successful with the 5′-silylated than with the 5′-tritylated nucleosides. Formation of 2′-,3′-O-thiocarbonyl derivatives proceeded in higher yield with 5′-protected 6-azauridines than with the corresponding 5-chlorouridines because of the propensity of the latter to form 2,2′-anhydro derivatives. In the reaction of 5′-O-(tert-butyldimethylsilyl)-2′-,3′-O-thiocarbonyl-6-azauridine with trimethyl phosphite, introduction of the double bond was accompanied by N³-methylation. However this side reaction was not a problem with 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-O-thioarbonyl-5-chlorouridine. Treatment of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-6-azauridine with tetrabutylammonium fluoride followed by hydrogenation afforded 2′-,3′-dideoxy-6-azauridine. Deprotection of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-5-chlorouridine yielded 2′-,3′-didehydro-2′-,3′-dide-oxy-5-chlorouridine.     

Synthesis of Some 2′,3′-Dideoxy-2′-C-Methyl-Substituted Nucleosides

Abstract

Nucleoside analogues analogues1-(2′,3′-dideoxy-2′-C-hydroxymethyl-β-D-erythro-pentofuranos-yl)thymine (1), 2′,3′-dideoxy-2′-C-hydroxymethylcytidine (2), 2′,3′-dideoxy-2′-C-hydroxymethyladenosine (3), 1-(2′-C-azidomethyl-2′,3′-dideoxy-β-D-erythro-pento-furanosyl)thymine (4), 2′-C-azidomethyl-2′,3′-dideoxycytidine (5), and 2′3′-dideoxy-2′-C-methylcytidine (6) have been synthesized from (S)-4-hydroxymethyl-y-butyro-lactone (7)     

Synthesis of 2′-C-α-Methyl-2′,3′-dideoxynucleosides

Abstract

A general method for the synthesis of 2′-C-α-methyl-2′,3′-dideoxynucleosides is presented. Stereofacial selectivity of the 2-C-methylation reaction of γ-lactone has been investigated, in which the presence of a bulky group at the 5-hydroxymethyl produced the α-isomer as a major product. During glycosylation, the α-methyl group directed the formation of nucleosides in favor of the ß-isomer. This methodology is applied to the synthesis of some new pyrimidine and purine nucleosides.

     

Intramolecular Radical Reactions of 5′-O-Modified 2′,3′-Didehydro-2′,3′-Dideoxyuridine Derivatives

Abstract

Radical reactions of 5′-O-(2-bromo-1-methoxy)ethyl- and 5′-O-(2-propynyl)-2′,3′-dideoxy-2′,3′-didehydrouridines were investigated. Both reactions proceeded in a 6-exo-trig manner to give products cyclized regio- and stereospecifically at the 3′-position. The structures of these products were analyzed by X-ray crystallography.

     

A New Synthesis of 2′,3′-Didehydro-3′-deoxy-3-Alkylthymidine

Abstract

The preparation of 3-alkyl D4T derivatives has been carried out starting from the corresponding 5′-O-t-butyldimethylsilyl-3′-O-methanesulfonylthymidine 2 by way of deprotection-elimination and succesive alkylation reactions.     

Synthesis of 2′,3′-Didehydro-2′,3′-dideoxy-2′-C-methylsubstituted Nucleosides Using a Novel SN2′ Type Reaction

Abstract

1-(2,3-Dideoxy-2-C-hydroxymethyl-β-D-threo-pentofuranosyl)-, 1-(2,3-didehydro-2,3-dideoxy-2-C-hydroxymethyl-β-D-glycero-pentofuranosyl)- and 1-(2-C-azidomethyl-2,3-didehydro-2,3-dideoxy-β-D-glycero-pentofuranosyl)uracuracil, thymine and cytosine were synthesized and evaluated for their anti-HIV activities. A key step of the synthesis involves a novel alcohol transposition of2-methylene-nucleoside analogues.     

Synthesis of 2′-Deuterio and 3′-Deuterio Cytidine 5′-Diphosphate

Abstract

2′-²H- and 3′-²H-CDP were synthesized from 5′-MMT-3′-O-TBDMS and 2′,5′- O-diTBDMS cytidine derivatives, respectively, by oxidation followed by acidic removal of 5′-protection, reduction with [NaBD(OAc)₃] and finally displacement of a tosyl group by pyrophosphate.     

Synthesis of 3′-Amino and 5′-Amino Hydantoin 2′-Deoxynucleosides

Abstract

3′-Amino and 5′-amino derivatives of hydantoin 2′-deoxynucleosides have been prepared from the corresponding 3′-phthalimido and 5′-azido nucleosides, respectively, which in turn were prepared by condensation of appropriate sugars with 5-benzylidenehydantoin. The amino nucleosides were tested for their potential activity against HIV and HSV.     

Synthesis of 2′,3′-Dideoxy- and 3′-Azido-2′,3′-dideoxy-pyridazine Nucleosides as Potential Antiviral Agents

Abstract

The synthesis of 4-methoxy-, 4-amino-3-chloro-, and 4-amino-1-(2,3-dideoxy-B-D-glycero-pentofuranosyl)pyridazin-6-one nucleosides, 6,19 and 20 is described. The synthesis of 3,4-dichloropyridazin-6-one (10) was accomplished in 44% overall yield using bromomaleic anhydride (17) as the starting material. The condensation of the silylated base of 10 with the halogenose 12 in the presence of trimethylsilyl triflate as a catalyst afforded a mixture of3,4-dichloro-1-(3,5-di-O-p-toluoyl-2-deoxy-B-D-erythro-pentofuranosyl)pyrridazin-6-one (13) in 67% and its α-anomer 14 in 12% yield, respectively. A series of 3′-sulfonate esters were prepared to explore the synthesis of 3-chloro-4-hydroxy-1-(3-azido-2,3-dideoxy-B-D-erythro-pentofuranosyl) pyridazin-6-one (32) via 6,3-anhydronucleoside analogues. Compounds 15, 19 and 20 were evaluated against human immunodeficiency virus, human cytomegalovirus, and herpes simplex virus type 1 but were inactive.     

Synthesis of 3′-N-Substituted 3′-Amino-3′-Deoxythymidine Derivatives

Abstract

A series of 3′-N-substituted 3′-amino-3′-deoxythymidine derivatives with alkyl, alkenyl and alkylaryl substituents was synthesized by two methods. The first method involved the reaction of 1-(2,3-dideoxy-3-0-mesyl-5-0-trityl-β-D-threo-pentofuranosyl)thymine with an appropriate amine. In the second method, 3′-amino-5′-0-trityl-3′-deoxy-thymidine served as a synthetic precursor which was reacted with an appropiate aldehyde or ketone followed by sodium borohydride reduction. An improved synthesis of 3′-amino-3′-deoxythymidine from 3′ -azido-5′-0-trityl-3′-deoxythymidine using sodium borohydride was also described.     

Synthesis and antiviral evaluation of α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides

We have identified a selective S_N2′ reaction triggered by iodide ion that leads to the ring-opening of 2,2′-anhydro-α-nucleosides. By applying the method, we have synthesized α-d-2′,3′-didehydro-2′,3′-dideoxy-3′-C-hydroxymethyl nucleosides, designed as potential antiviral agents.     

Synthesis and Evaluation of Anti-HIV-1 and Antitumor Activity of 2′,3′-didehydro-2′,3′-dideoxy-3-deazaadenosine, 2′,3′-dideoxy-3-Deazaadenosine and Some 2′,3′-dideoxy-3-deaza-adenosine 5′-dialkyl Phosphates1

Abstract

- The 4-amino-1-(2.3-dideoxy-β-D-glycero-pent-2-enofurano-syl)-1H-irnidazo[4,5-c]pyridine (1) and 4-amino-1-(2,3-dideoxy-β-D-gfycero-pentofuranosyl)-1H-imidazo[4,5-c]pyridine (2), 3-deaza analogues of the anti-HIV agents 2′.3′-didehydro-2′,3′-dideoxyadenosine (d4A) and 2′,3′-dideoxy-adenosine (ddA), have been synthesized. The reaction of 3-deazaadenosine (3) with 2-acetoxyisobutyryl bromide yielded a mixture of cis and trans 2′,3′-ha-lo acetates which was convertcd into olefinic nucleoside (1) on treatment with a Zn/Cu couplc and then with methanolic ammonia. The 2′,3′-dideoxy-3-deazaadenosine (2) was obtained by catalytic reduction of 1. A number of phosphate triester derivatives of 2 have also been prepared. The diethyl-, dipropyl- and dibutylpliospliates 7a-c and 3-deazaadenosine have shown anti-HIV activity at non-cytotoxic doses. Compounds 7a-c have also shown significant cytostatic activity against murine colon adenocarcinoma cells.     

Acyclic 2′, 3′-Dideoxy-2′,3′-didehydronucleoside 5′-Triphosphates as Termination Substrates of Broad Set of DNA Polymerases

Abstract

O4′-Nor-2′,3′-dideoxy-2′,3′-didehydronucleoside 5′-triphosphates (acyclo-d₄NTP) have been shown to have the properties of effective termination substrates for DNA biosynthesis, catalyzed by several different DNA polymerases.     

Synthesis and Structure of 2′,3′-Dideoxy-3′-fluoro-5-cyanouridine

Abstract

The title compound was prepared by reaction of the 5-bromo congener with potassium cyanide in DMF. X-ray analysis revealed its solid state structure and the obtained conformation was compared to the con-formation of 3′-azido-3′-deoxythymidine (AZT) and of 2′,3′-dideoxy-3′-fluoro-5-chlorouridine, respectively, two very selective anti-HIV agents. They both show two separate molecules in their asymmetric unit, one of each fairly resembling the conformation of the title compound 4. The latter, however, displayed only very moderate activity.