Ribonucleosides phosphonates

Phosphonylation. This reagent is useful for preparation of protected deoxy-ribonucleoside-3-hydrogen phosphonates (2), which can be used for synthesis of deoxyribonucleotides. 

The synthesis of nucleoside diphosphates is best achieved using the Poulter reaction,9 which involves reaction of the tris(tetra-n-butylammonium) salt of pyrophosphate with a nucleoside 5 -tosylate in acetonitrile. A general procedure for the synthesis of nucleoside tosylates of thymidine and 2 -deoxyadenosine is included (Protocol 15), whilst the syntheses of the other tosylates (including ribonucleosides) have been described using related procedures. Simple modification of the protocol, whereby the tetra-n-butylammonium salt of pyrophosphoric acid is replaced by methylene or difluomethylene bis phosphonate, allows the synthesis of hydrolytically stable dNTP analogues.10... 

Stereodefined oligo(ribonucleoside phosphorothioate)s were available only by the enzymatic method [51 -54] or by partially stereocontrolled H-phosphonate procedure [55,56]. However, both procedures could provide only products with RP configuration. Alternatively, compounds containing the single phosphorothioate modification were synthesized by nonstereospecific phosphoramidite or H-phosphonate methods and then separated into diastereomers by tedious HPLC procedure with various degree of success [57-59]. Such constructs became important tools for investigation of the mechanism of action of ri-bozymes. 

Tris(hexafluoroisopropyl) phosphite (105) has been used to prepare ribonucleoside H-phosphonates (106), and deoxyribo-nucleoside phosphites (107) ° both were used as monomers to prepare oligonucleoside H-phosphonates on a solid support, with W-methylimidazole as catalyst for the coupling of (107). Several new alkyl phosphorodiamidites (108) and (109) have been used... 

The nucleotide analogue (38) has been prepared from the difluoromethylene phosphonate precursor (39). The presence of orthogonal protecting groups at positions 2 and 3 allows the synthesis of the difluoromethylene phosphonates of both ribonucleosides and deoxyribonucleosides. The difluoromethylene phosphonate (40) of the anti-HIV agent FTC has been prepared by glycosylation of Z>w(trimethylsilyl)-5-fluorocytosine with (41) in the presence of tin (IV)chloride. ... 

Nucleoside 3 -H-phosphonates 1 (ribonucleosides) and 2 (deoxyribonucleosides) seem to be the most attractive as starting materials in the chemical synthesis of DNA and RNA fragments. They entirely dominate the field of oligonucleotide synthesis. Nucleoside... 

Ribonucleoside 3 -H-phosphonates 1 were synthesized from protecting ribonucleosides 2 in 75-90% yield using the PClj-imidazole procedure [172],... 

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. 

The formation of mixed anhydrides 2 is critical for overall yield of the conversion of H-phosphonate monoesters 1 into H-phosphonothioate 4. The transformation of an H-phos-phonate into an H-phosphonothioate function in the ribo series proved to be a stereoselective process. In contradistinction to (his transformation, synthesis of the ribonucleoside 3 -H-phosphonothioate via phosphinate intermediates [202] hardly showed any stereoselectivity. 

In the area of 3, 5 -cyclic nucleotides, it has been found that attempted 5 -phosphorylation of the 3 -epimers of thymidine and deoxyadenosine with phosphoryl chloride gave the cyclic phosphates 195 (B = Ad, T) the 5 -phosphates could be obtained by phosphorylation of the 3 -0-benzoyl derivatives.245 Two groups have reported the synthesis of base-modified derivatives of c AMP (e.g. benzimidazoles, benzotriazoles, indazoles), for evaluation as activators of cAMP-dependcnt protein kinase 1.246,247 There have been syntheses described of ribonucleoside 3 ,5 -cyclic methyl- and phenyl-phosphonates248,249 and -phosphonothioates, one of the procedures giving both the cyclic phosphonates and phosphonothioates as the 5p-epimer only.249 a paper... 

Diethyl pyrocarbonate has been used to convert uridine 2 - or 3 -phosphate into the 2, 3 -cyclic phosphate in high yield, and an adamantyl 2, 3 -cyclic phosphonate (421) was obtained when uridine reacted with I-adamantylphos-phonyl chloride. Phosphorylation of ribonucleosides with pyrophosphoryl chloride followed by hydrolysis in neutral solution afforded a simple synthesis of ribonucleoside 2, 3 -cyclic phosphate 5 -phosphates. Two phosphorylating agents mentioned earlier in this section can also yield 3, 5 -cyclic phosphates either by treatment of nucleoside 5 -(2-iV7V-dimethylamino-4-nitrophenyl phosphates) with acetic acid in pyridine (Scheme I4i) i, 83 qj. treatment of nucleoside 5 -(5 -methyl phosphorothioates) with iodine in pyridine. Another route to 3, 5 -cyclic phosphates involved cyclization of the nucleoside 5 -trichIoro-methylphosphonates (422) (obtained by the action of trichloromethylphosphonyl... 

Ribonucleoside H-phosphonates were introduced by Todd in 1957 to prepare diribonucleotide phosphate diesters (1). The H-phosphonates were activated for condensation with diphenyl chlorophosphate, and this activator was later extended to the synthesis of deoxyribonucle-otide dimers (2). Activation of deoxynucleoside H-phosphonates with acyl chlorides allows for the synthesis of oligodeoxynucleotides greater than 100 bases in length (3,4). Since these initial results, a number of laboratories have used acyl chlorides and nucleoside H-phosphonates in the synthesis of oligodeoxynucleotides (5-9). This chemistry has also been extended to the synthesis of phosphate analogs of oligodeoxynucleotides (10-16). 

The AMP analogue 143 has been described, along with the similar analogues of thynoidine 5 - and 3 -monophosphates. Another paper describes a range of S -O-phosphonates of ribonucleosides and deoxyribonucleosides, and also the S -O-phosphonomethyl con unds 145 (B=Thy, Ade), prepared from 144 by treatment with The carbocyclic phosphonate... 

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