Nucleoside H-phosphonate

The thermal synthesis of nucleoside-5 -phosphite monoester using (NH HPCb was carried out under relatively mild conditions (60°C, reaction time about 24 h) by A. W. Schwartz s group in Nijmegen, Holland in the case of uridine, the yield was 20%. Ammonium phosphate, however, cannot be used it gave yields of only 0.15% after very long reaction times (46 days). This confirms earlier suggestions that nucleoside-H-phosphonates, and condensation products possibly derived from them, would have been formed more readily on the primeval Earth than nucleotides (de Graaf and Schwartz, 2005). 

Formation of the nucleoside phosphorodichloridite at -30 °C by PCI3 in CH2CI2 solution (step a) is followed by reaction with ethanol (step b). Subsequently dealkylation occurs with the assistance of hydrogen chloride formed in reaction (a) to give the desired 5 -nucleoside H-phosphonate (step c). It was found that a mixture of ethanol and tcrt-butanol (1 1) as alcoholysis agent prevented side reactions and gave a higher yield than when ethanol alone was used. 

A facile method for the oxidation of nucleoside H-phosphonates to phosphates has been developed with BTSP and N,0-bis(trhnethylsilyl)acetamide, MeC(NSiMe3)OSiMe3, in the presence of Me3Si0S02CF3 as a catalyst (equations 67 and 68) °. 

Methodologies to create functional and topological diversity in libraries of nucleoside phosphoramidates have been improved by the use of parallel solid-phase synthesis. A representative 600-member library of dinucleoside phosphoramidates (16) and tri-nucleoside phosphoramidates (17) was synthesised from CGP-support-bound di- and tri-nucleoside H-phosphonates (5 -DMT protected) and selected amines. The library was screened for antiviral activity against HBV and some of its members showed potent activity. ... 

The preparation of nucleosidephosphorofluoridate (15), phosphorofluori-dothioate (16), and phosphorofluoridodithioate (17) monoesters in high yield from the corresponding nucleoside H-phosphonates has been described." The... 

Transformations of nucleoside H-phosphonate monoesters into their corresponding if-phosphonothioate and H-phosphonodithioate derivatives and the nature of the side-reactions that may accompany these processes have been... 

Todd uncovered the potential of nucleoside H-phosphonates for oligonucleotide synthesis in the very early days of nucleic acid chemistry [15], However, this knowledge laid dormant for almost three decades, while other methods flourished. 

The methodology has been resurrected very recently in the H-phosphonate variant. An attempt by Adamo et al. [326] to use a chlorosulfonated polystyrene resin for activation of the nucleoside H-phosphonate monoesters was not particularly impressive, but the corresponding chlorocarbonylated polystyrene performed well, permitting the synthesis of up to a hexanucleotide. Similar results were reported by Mohe et al. [327] for the dinucleoside H-phosphonate synthesis promoted by a phosphorochloridate supported on polystyrene. 

The use of the Michaelis-Arbuzov reaction has been made in the synthesis of dinucleoside-3 -5-phosphorothiolates using disulphides (73) and nucleoside 5 -dialkylphosphite derivatives. Particularly efficient reactions were achieved using a 5 -Wj(trimethylsilyl)phosphite (74) which afforded the phosphorothiolate directly after aqueous work up. Derivative (74) was obtained by treating the corresponding nucleoside H-phosphonate with chlorotrimethylsilane in pyridine in the presence of triethylamine. 

Triethylammonium salts of aryl H-phosphonates have been coupled to the 3 -OH of deoxynucleosides using pivaloyl chloride as condensing agent subsequent hydrolysis by aqueous pyridine gives nucleoside H-phosphonate building blocks... 

Romanowska J, Szymanska-Michalak A, Boryski J, Stawinski J, Kraszewski A, Loddo R, Sauna G, Colin G, Secci B, La Colla P (2009) Aryl nucleoside H-phosphonates. part 16 synthesis and anti-HlV-1 activity of di-aryl nucleoside phosphotriesteis. Bioorg Med Chem 17 3489-3498... 

A new method is provided for the synthesis of nucleoside H-phosphonate monomers. The method comprises contacting a mononucleoside having a 3 -hydroxyl moiety with triphosgene and an excess of phosphorous acid [174]. 

Formation of the undesired symmetrical product (R2 = ribonucleoside) can be completely eliminated by using three molar excess of diphenyl phosphonate and the reaction went to completion in 15 min under these conditions. Lower reactivity of the ribonucleoside phenyl H-phosphonates (R2 = phenyl) has been manifested in their slower hydrolysis to the nucleoside H-phosphonates upon addition of water. The hydrolysis was found to be substantially faster in the presence of a base. 

Dinucleoside-a-hydroxybenzylphosphonates 2 in up to 90% yield were synthesized by reacting the symmetric dinucleoside H-phosphonates 1 with benzaldehyde derivative in the presence of catalytic amounts of a tertiary base like diisopropylethylamine (DIPEA), or tri-ethylamine (TEA). Dinucleoside-a-hydroxybenzylphosphonates 2 are consideied uncharged prodrugs of 5 -nucleoside H-phosphonates 3 and 5 -nucleoside monophosphates 4. These two compounds are released by controlled hydrolysis via two different pathways the phospho-nate-phosphate rearrangement and the direct cleavage mechanism [188]. 

Todd et al. used nucleoside 3 -H phosphonates to prepare 3 -5 -intemucleotidic bonds for the first time [189], Diphenyl chlorophosphale was used to activate nucleoside H-phosphonate. 

Dinucleoside H-phosphonates were obtained when deoxyribonucleoside H-phosphonate reacted with 3 -benzoylthymidine in the presence of l,3-dimethyl-2-chloroimida-zolinium chloride-coupling reagent [177]. The P H] NMR spectrum of the reaction mixture showed that the signal of the nucleoside H-phosphonate at 5 = 2.81 ppm completely disappeared and new signals were observed at 5 = 8.21 and 7.20 ppm. The chemical shift suggested that nucleoside H-phosphonate was converted into the corresponding dinucleoside H-phosphonate. 

Transesterification of nucleoside H-phosphonates with various diols in pyridine in the presence of 2-chloro-5,5-dimethyl-l,3,2-dioxaphosphorinane (a mild condensing agent) furnished rapid and clean formation of the corresponding hydroxyalkyl nucleoside H-phosphonate [193]. With ethylene glycol (n = 2), the desired hydroxyethyl H-phosphonate was formed as a minor product, only 10% (5p = 8.6 ppm), while the main phosphorus-containing species was a compound resonating at 5p = 23.1 ppm. The presence... 

Various approaches for the preparation of nucleoside H-phosphonamidates are known, but the most efficient and versatile route to nucleoside V-alkyl H-phosphonamidates was found to be aminolysis of the in xifM-produced aryl nucleoside H-phosphonates with appropriate amines. 

Aryl nucleoside H-phosphonates 1 react with primary amines 2 or aminonucleoside 3 to give the desired nucleoside phosphonamidates 4 or 5 in >90% yield [182b,182c, 191,197]. 

Kraszewski et al. [208] have developed a new, efficient method for the synthesis of phosphorothioate diester, based on the H-phosphonate chemistry. The reaction of aryl nucleoside H-phosphonate with elemental sulfur furnished the corresponding aryl nucleoside phosphorothioate. The synthesis of phosphorothioates can be carried out as a four-components-one-pot reaction, by allowing nucleoside H-phosphonate to react with phenols in the presence of diphenyl phosphorochloridate to furnish aryl nucleoside H-phosphonates, which react with elemental sulfur. 

Nucleoside H-phosphorothioates of type 2 were synthesized by reacting unprotected nucleoside H-phosphonates 1 with elemental sulfur, suspended in pyridine containing tri-ethylamine and trimethylsilyl chloride [209]. After 5 min, the starling compounds were completely converted into nucleoside phosphorothioate. 

Unfortunately, charged phosphorylated or phosphonylated nucleosides are unable to penetrate the cell membranes or the blood-brain barrier because of their low lipophiUci-ty. Meier et al. [66] have described the synthesis of a new prodrug system for antiviral nucleosides AZT and ddT based on a-hydroxybenzylphosphonates 1, which present uncharged prodrugs of 5 -nucleoside H-phosphonates and 5 -nucleoside monophosphates. All compounds 1 exhibited pronounced activity against HIV-l- and HlV-2-infected cells without toxicity. Compounds 3 can be considerd as potential prodrugs of the 3 -azido-3 -deoxythimidine and 2, 3 -deoxythimidine, their H-phosphonate monoesters as well as their monophosphates. 

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