Aryl Nucleoside H-Phosphonates—Novel Derivatives of Controlled Reactivity

Abstract

The most essential factors influencing the formation of aryl nucleoside H-phosphonates are discussed.

Recently, aryl nucleoside H-phosphonates (1) (Scheme 1) emerged as a new type of intermediates in the synthesis of phosphate derivatives¹. In contradistinction to other reactive species derived from H-phosphonate monoesters, these compounds bear only one electrophilic centre (located on phosphorus) and their reactivity can be modulated by substituents on the aromatic ring².     

Studies on Aryl H-Phosphonates. Synthesis of Nucleoside N-Alkylphosphonamidates

Abstract

The aminolysis of aryl nucleoside H-phosphonate diesters with various amines was studied. The new simple and efficient method of synthesis of nucleoside phosphonamidates is described.     

Studies on the Oxidation of Nucleoside Hydrogenphosphonates

Abstract

Oxidation of nucleoside H-phosphonate diesters has been investigated using dipyridyl disulphide, hexachloroacetone and iodine, under various reaction conditions.     

31P NMR Studies on Oxidative Transformations of Aryl Nucleoside H-Phosphonate Diesters

Abstract

Various aspects of oxidative coupling of nucleoside aryl H-phosphonate diesters with nucleosides to produce important synthetic intermediates in the phosphotriester approach to oligonucleotide synthesis, dinucleoside aryl phosphotriesters, was investigated.     

Recent Studies in Nucleoside Phosphonate Chemistry

Abstract

New activation pathways have been found for H-phosphonate monoesters subjected to a reaction with alkyl chlorophosphates or sterically hindered aromatic acyl chlorides. Studies on synthesis of nucleoside methylphosphnate diesters using a new condensing system are also discussed.     

Nucleosides Having Quinolone Derivatives as Nitrogenated Base: Regiospecific and Stereospecific Ribosylation of 3-Carbethoxy-1,4-dihydro-4-oxoquinolines

Abstract

Ribosylation reactions of previously silylated 3-carbethoxy-8-methyl-1,4-dihydro-4-oxoquinoline (6a) and 3-carbethoxy-6-methyl-1,4-dihydro-4-oxoquinoline (6b) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (7), under Lewis acid catalysis, were studied. The method using hexamethyldisilazane (HMDS)/trimethylchlorosilane (TMCS) mixture for silylation and anhydrous stannic chloride as catalyst for ribosylation failed to give any nucleoside product. On the other hand, the protected nucleoside 3-carbethoxy-6-methyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,4-dihydro-4-oxoquinoline (8b) was obtained in good yields using bis(trimethylsilyl)trifluoroacetamide (BSTFA) containing 1% of TMCS and the same catalyst. Compound 8b was more easily isolated in higher yields with an improvement of the later method by replacing stannic chloride with trimethylsilyl trifluoromethanesulfonate (TMSOTf).

De-O-benzoylation of 8b with methanolic sodium hydroxide solution afforded the free riboside 3-carbomethoxy-6-methyl-1-β-D-ribofuranosyl-1,4-dihydro-4-oxoquinoline (9b). The structures of the obtained products were confirmed by their LTV, MS, IR, ¹H and ¹³C-NMR data.     

SYNTHESIS OF OLIGONUCLEOSIDE BORANOPHOSPHATES VIA AN H-PHOSPHONATE METHOD WITHOUT NUCLEOBASE PROTECTION

Short oligonucleoside boranophosphates containing all four nucleosides were synthesized on solid support using base-unprotected nucleoside H-phosphonate monomers. This strategy avoided irreversible base modifications during the boronation procedure. Structures of the boranophosphate oligomers were confirmed by ¹H, ³¹P, ¹⁰B NMR and MS analysis as well as by enzymatic hydrolysis.     

Boranophosphate Oligonucleotides: New Synthetic Approaches

Abstract

Recently our laboratory reported a new backbone-modified class of oligonucleotides, with a borane (B₃3?) group replacing one of the non-bridging oxygen atoms. Here we present two new approaches to synthesize the boranophosphate oligonucleotides. All-stereoregular boranophosphate oligonucleotides can be prepared by enzymatic template extension reactions using nucleoside a-boranotriphosphates, which are good substrates for a number of polymerases. Larger scale synthesis of boranophosphate oligonucleotides can be carried out by effective chemical synthesis using the H-phosphonate approach, instead of previously used phosphoramidite methodology. The main advantage of H-phosphonate methodology is the ability to carry out one boronation reaction, after oligonucleotide chain elongation has been completed, using mild conditions without base damage and producing the desired boranophosphate oligonucleotides in high yield.     

Homo Dinucleoside-α-hydroxyphosphonate Diesters as Prodrugs of the Antiviral Nucleoside Analogues 2′,3′-Dideoxythymidine and 3′-Azido-2′,3′-dideoxythymidine

Abstract

The synthesis of a new prodrug system for antiviral nucleosides AZT (1) and ddT (2) based on α-hydroxybenzylphosphonates 3 is described. 3 hydrolyze via different mechanisms yielding the H-phosphonate monoesters 4 or nucleoside monophosphates 5, respectively. 3 were more lipophilic than 1, 2 and showed marked activity against HIV-1/2.     

Oligonucleotides Incorporating N7-(2′-Deoxy-β-d-erythro-pentofuranosyl)isoguanine

Abstract

The H-phosphonate and the phosphoramidite of N⁷-2′-deoxyisoguanosine (2) were prepared and incorporated into oligonucleotide duplexes. Their base pairing properties were investigated and compared with those of the parent purine nucleosides.     

SYNTHESIS OF CYCLIC DINUCLEOTIDES BY AN H-PHOSPHONATE METHOD IN SOLUTION

Abstract

We report synthesis of each of the ten cyclic 2′-deoxyribodinucleotides by a solution-phase H-phosphonate method. The cyclic dimers have been characterized by ³¹P NMR, MS, UV, and enzymatic degradation.     

An Efficient Method for the Synthesis of β-d-Ribonucleosides Catalyzed by Metal Iodides

Abstract

Several β-d-ribonucleosides were synthesized in high yields under mild conditions by N-glycosylations of methyl 2,3,5-tri-O-benzoyl-β-d-ribofuranosyl carbonate (1) with trimethylsilylated nucleoside bases in acetonitrile using a catalytic amount of metal iodide such as SnI₂, SbI₃ or TeI₄. A deprotection of N⁶ -benzoyl group of coupling product took place to a considerable extent when N⁶ -benzoyl-N⁶ , N⁹ -bis(trimethylsilyl)adenine was employed as a nucleoside base using SnI₂ or SnCI₂ as a catalyst while it was minimized when SbI₃ or TeI₄ was used. Further, the N-glycosylation of 1 with 7-trimethylsilyltheophylline in the presence of a catalytic amount of metal iodide was more effectively achieved in nitrile solvents other than acetonitrile.

     

Reactions of Nucleoside Hydrogenphosphonates with Diphenyl Chlorophosphate and Sterically Hindered Aromatic Acyl Chlorides

Abstract

The final product of the reaction of H-phosphonate monoesters with diphenylchlorophosphate was found to be the corresponding dichlorophosphite. Stericalty hindered aromatic acyl chlorides react with H-phosphonate diesters affording C-phosphonate derivatives.     

Synthesis of Nucleoside <Emphasis Type="Italic">N</Emphasis>-Phosphoamino Acids and Peptide Formation

Nucleoside N-phosphoamino acids were synthesized through Atherton-Todd reaction of nucleoside H-phosphonate with amino acids, and their structures were confirmed by NMR and ESI-MS. After nucleoside N-phosphoamino acid was incubated in anhydrous methanol at 40 °C for 72 h, di- to tetra-peptide derivatives were detected by ESI-MS, and their structures were further identified by multistage mass spectrometry. These and previously published studies in aqueous solution suggest that nucleoside N-phosphoamino acids could have been prebiotic precursors of oligopeptides.     

Asymmetrically Substituted myo-Inositols. XXXIX. The Synthesis of Conjugate of 2',3'-Didehydro-3'-deoxythymidine with Phosphatidylinositol: A New Nucleoside Phospholipid with Potential Anti-HIV Activity

A partially protected phosphatidylinositol with a free hydroxyl group in the cyclitol moiety was synthesized by phosphorylation of a tetrasubstituted myo-inositol using the H-phosphonate and phosphoamidite methods. The H-phosphonate method was advantageous for the synthesis of selectively protected monophosphoinositide due to a lesser number of stages. Two schemes for the conjugation of 2',3'-didehydro-3'-de oxythymidine with phosphatidylinositol using succinic acid as a linker were tested in the synthesis of the target nucleoside phospholipid.     

Studies on Ribonucleoside Hydrogenphosphonates. Effect of a Vicinal Hydroxyl Function on the Stability of H-Phosphonate Diester Bond

Abstract

Stability of hydrogenphosphonate diester bond in the presence of a free vicinal hydroxyl function has been investigated on the example of ribonucleoside H-phosphonates. It was found that H-phosphonate diesters undergo immediate intramolecular cyclization, both with or without a base, affording 2′, 3′-cyclic H-phosphonate diesters.     

5′-Phosphorylation of Oligonucleotides with Phosphorous Acid in Automated DNA Synthesis

Abstract

Coupling of phosphorous acid in automated DNA synthesis using H-phosphonate methodology leads to 5′-5′ linked dimers and 5′-H-phosphonates. The yield is dependent on the phosphorous acid concentration, chain length of the oligomer, and pore size of the support. 5′-Phosphate oligomers are obtained from the H-phosphonate oligomers by silylation and oxidation.     

Aryl nucleoside H-phosphonates. Part 16: Synthesis and anti-HIV-1 activity of di-aryl nucleoside phosphotriesters

Di-aryl nucleoside phosphotriesters have been explored as a new type of pronucleotides for the purpose of anti-HIV-1 therapy and efficient synthetic protocols, based on H-phosphonate chemistry, have been developed for the preparation of this class of compounds. It was found that anti-HIV-1 activity of the phosphotriesters bearing an antiviral nucleoside moiety (AZT, ddA) and also ddU was due, at least partially, to intracellular conversion into the corresponding nucleoside 5′-monophosphates, and their efficiency correlated well with the pK_a values of the aryloxy groups present.     

Facile Synthesis of N-(1-Alkenyl) Derivatives of 2,4-Pyrimidinediones

Abstract

N-(1-alkenyl) derivatives of 2,4-pyrimidinediones (6–9) were prepared in a one pot synthesis from aldehydes and the nucleobases using trimethylsilyl trifluoromethanesulfonate (TfOTMS) as coupling reagent. Presilylation of the above nucleobases, and N ⁶-benzoyladenine, with excess N,O-bis(trimethylsilyl)acetamide (BSA) followed by addition of one mol eq. TfOTMS yielded the N-(1-trimethylsilyloxyalkyl) derivatives 1–5.     

Use of New Phosphonylating and Condensing Agents in The Synthesis of Oligonucleotides Via The H-Phosphonate Approach

Abstract

Bis (1, 1, 1, 3, 3, 3-hexafluoro-2-propyl) phosphonate was most promising as a phosphonylating agent for the preparation of nucleoside-3′-phosphonate units. 1, 3-Dimethyl-2-chloro-imida-zolinium chloride (UWC) as a coupling agent has successfully been used for the internucleotidic H-phosphonate bonds formation via the H-phosphonate approach on a solid support.