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.     

New and one pot chemoselective synthesis of nucleoside 5'-H-phosphonate diesters

Arbuzov reaction of phenyl phosphorodichloridite with two equiv of alcohol, or mixture of one equiv of alcohol and one equiv of tert-butyl alcohol led to the corresponding aryl H-phosphonate diesters. Following displacement of the H-phosphonate diesters with unprotected nucleosides chemoselectively produced nucleoside 5-H-phosphonate diesters in good yields, respectively.     

Chemical Synthesis of RNA-Fragment Analogues That Have Phosphorothioate Linkages of Identical Configuration

Abstract

Oligouridine all-Rp-phosphorothioates were synthesized using the H-phosphonate approach followed by sulfurisation with S₈ and treatment with nuclease P1. The degree of stereoselection in the couplings is reported for different 2′-O-silyl protecting groups. The influence of the heterocyclic base was also investigated.     

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.     

A cautionary note on the use of the 31P NMR spectroscopy in stereochemical correlation analysis

Stereoselectivity in condensation of protected ribonucleoside 3'-H-phosphonates with hydroxylic components was investigated using 31P NMR spectroscopy. The correlation between absolute configuration at the phosphorus center and the chemical shifts of the produced H-phosphonate diesters and the corresponding phosphorothioates, was studied.     

Studies on reactions of nucleoside H-phosphonates with bifunctional reagents. Part VI. Reaction with diols

Reactions of nucleoside H-phosphonates with various diols using different types of condensing agents have been studied. Depending on the coupling procedure and the length of a polymethylene chain of the diol, acyclic H-phosphonate diesters or cyclic phosphite triesters were formed. The course of oxidation with iodine to produce cyclic nucleoside alkyl phosphotriesters or hydroxyalkyl nucleoside phosphodiesters can be controlled by the amount of water present in the reaction medium.     

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.     

A CAUTIONARY NOTE ON THE USE OF THE 31P NMR SPECTROSCOPY IN STEREOCHEMICAL CORRELATION ANALYSIS

Stereoselectivity in condensation of protected ribonucleoside 3′-H-phosphonates with hydroxylic components was investigated using ³¹P NMR spectroscopy. The correlation between absolute configuration at the phosphorus center and the chemical shifts of the produced H-phosphonate diesters and the corresponding phosphorothioates, was studied.     

Aryl nucleoside H-phosphonates as a tool for investigation of stereospecificity during coupling

It was found that in stereoselective condensations of ribonucleoside 3'-H-phosphonates with alcohols, the major diastereomer of the produced H-phosphonate diesters is formed from the minor diastereomer of the intermediate phosphonic-pivalic anhydride.     

ARYL NUCLEOSIDE H-PHOSPHONATES AS A TOOL FOR INVESTIGATION OF STEREOSPECIFICITY DURING COUPLING

It was found that in stereoselective condensations of ribonucleoside 3′-H-phosphonates with alcohols, the major diastereomer of the produced H-phosphonate diesters is formed from the minor diastereomer of the intermediate phosphonic-pivalic anhydride.     

The Prooligonucleotide Approach: Synthesis of Mixed SATE-Phosphotriester Phosphodiester Oligonucleotides

Abstract

Synthesis of mixed SATE phosphotriester-phosphodiester prooligos was done following two ways. Phosphodiesters were generated by selective β-elimination of cyanoethyl using DBU or were introduced with H-phosphonate chemistry.     

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.     

Stereochemistry of internucleotide bond formation by the H-phosphonate method. 1. Synthesis and 31P NMR analysis of 16 diribonulceoside (3'-5')-H-phosphonates and the corresponding phosphorothioates

Sixteen diribonucleoside (3'-5')-H-phosphonates were synthesized via condensation of the protected ribonucleoside 3'-H-phosphonates with nucleosides, and the influence of a nucleoside sequence on the observed stereoselectivity was analyzed. 31P NMR spectroscopy was used to evaluate a relationship between chemical shift and absolute configuration at the phosphorous center of the H-phosphonate diesters as well as of the corresponding phosphorothioate diesters. Although for the most cases such correlation was found, there was however several exceptions to the rule where the relative positions of resonances arisingfrom Rp and Sp diastereomers were reversed.     

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.     

An efficient oxidizing reagent for the synthesis of mixed backbone oligonucleotides via the H-phosphonate approach

The mixture of carbon tetrachloride, N-methyl morpholine (NMM), pyridine and water in acetonitrile has been exploited for the oxidation of dinucleoside H-phosphonate diesters to the corresponding phosphates. The system is found to be inert to the phosphoramidate (P-N) and the phosphorothioate (P-S) linkages and has successfully been applied to the solid phase synthesis of mixed-backbone oligonucleotides (MBOs).     

Modification of H-phosphonate method of oligonucleotide synthesis on polymer support

The mechanism of the internucleotide condensation and side-reactions in H-phosphonate approach has been investigated with the help of NMR-spectroscopy. On the basis of the results obtained a modification minimizing side-reactions in the course of the nucleotide component preactivation has been developed. It includes the use of acetonitrile--quinoline (4:1) mixture as the solvent in coupling reactions. The efficiency of the method is illustrated by the synthesis of oligodeoxynucleotides.     

Use of new phosphonylating and coupling agents in the synthesis of oligodeoxyribonucleotides via the H-phosphonate approach.

New phosphonylating and coupling agents for the synthesis of oligodeoxyribonucleotides via H-phosphonate approach have been developed. Tris(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite, prepared by the reaction of lithium salt of 1,1,1,3,3,3-hexafluoro-2-propoxide with PCl3, reacts with deoxyribonucleosides in the presence of a catalytic amount of triethylamine to produce in the high yield the corresponding deoxyribonucleoside 3'-H-phosphonate units. The use of a new coupling reagent, 1,3-dimethyl-2-chloro-imidazolinium chloride (DMCI) for the internucleotidic H-phosphonate bond formation via the H-phosphonate approach is also discussed in detail.     

Interaction of vanadate with monosaccharides and nucleosides: a multinuclear NMR study

Proton, 13C and 51V nuclear magnetic resonance spectroscopy has been used to study the interaction of vanadate with several molecules containing more than one hydroxyl group, including various aldoses and nucleosides. The aldoses D-mannose and D-ribose mainly form tridentate complexes, of trigonal bipyramidal geometry, with vanadate at pH 7. These sugars use three consecutive hydroxyl groups, cis to each other, of their pyranose forms to bind vanadate in those cyclic triesters. Other aldoses, like D-glucose, which do not have this unique structural characteristic, do not form tridentate complexes, but can form weaker bidentate cyclic diesters using two consecutive pyranose cis hydroxyl groups. Of course, the pyranose forms of D-mannose and D-ribose, as well as the furanose form of D-ribose, also yield cyclic diesters of vanadate. All these aldoses form weak monodentate noncyclic monoesters of tetrahedral geometry using a single hydroxyl group. The nucleosides uridine, cytidine and adenosine form two complexes of trigonal bipyramidal geometry with vanadate. In these complexes, having 1:1 and 2:1 ligand-to-metal stoichiometries, the nucleosides form cyclic diesters with vanadate using their C2, and C3, hydroxyl groups.     

Synthesis of Deoxyribonucleoside Phosphorodithioate Dimers by a Triester Method

Abstract

Modified oligodeoxynucleotides have recently received much attention due to their therapeutic applications. Among the more promising are phosphorodithioates where both nonbridging oxygen atoms in the phosphate diesters are replced by sulfur. Deoxynucleoside phosphorodithioate dimers have been prepared in several ways, using H-phosphonate, phosphordiamidite, phosphoramidite, and thiophosphoramidite methods. Reports have also appeared on the synthesis of oligonucleotides with alternating phosphodiester and dithiophosphodiester linkages, as well as one on ribonucleoside dimers. Of the above methods, the thiophosphoramidite method has been applied successfully for the preparation of mixed base oligonucleotides containing contiguous phosphorodithioate linkages. However, this method gives products which contain varying amounts of phosphorothioate linkages (2 ? 10%) due to factors associated with the involvement of trivalent thiophosphorus compounds. In addition, the thiophosphoramidite synthons are difficult to purify on silica gel column, and have a tendency to dismutate in presence of acidic catalysts such as tetrazole. The thiophosphite intermediate which is formed is also unstable to tetrazole. Similarly in the thio- and dithio-H-phosphonate method, the primary coupling products are unstable to catalysts, pivaloyl chloride and iodine. Recently, Dahl et al reported^1–2 synthesis of dimers and oligomers upto octamer which also leads to formation of small amounts of phosphorothioate linkages. In additon, about 1.2% per phosphorodithioate linkage of the oligomer is cleaved during