Jadwiga Jankowska

Studies on aryl H-phosphonates. I: An efficient method for the preparation of deoxyribo- and ribonucleoside 3'-H-phosphonate monoesters by transesterification of diphenyl H-phosphonate

Abstract A convenient method for the preparation of deoxyribonucleoside and ribonucleoside 3′-H-phosphonate monoesters via transesterification of diphenyl H-phosphonate with suitable protected nucleosides in pyridine is described.

9-Fluorenemethyl H-phosphonothioate, a versatile reagent for the preparation of H-phosphonothioate, phosphorothioate, and phosphorodithioate monoesters

Abstract Simple and efficient synthesis of a new H-phosphonothionylating reagent, 9-fluorenemethyl H-phosphonothioate, was developed. The synthetic utility of the reagent has been demonstrated in the preparations of nucleoside H-phosphonothioate, nucleoside phosphorothioate, and nucleoside phosphorodithioate monoesters.

A new, efficient entry to nucleoside 2′,3′-O,O-cyclophosphorothioates

Abstract The reaction of 5′-protected ribonucleosides with diphenyl H-phosphonate in pyridine furnished rapid formation of the corresponding 2′,3′-cyclic H-phosphonates 3, which upon sulfurisation and the subsequent removal of the 5′-protecting group, afforded nucleoside 2′,3′-O,O-cyclophosphorothioates 5 in high yields.

A new method for the synthesis of nucleoside 2′,3′-O,O-cyclic phosphorodithioates via aryl cyclic phosphites as intermediates

Abstract The reaction of 5′- O -protected ribonucleosides with tri(4-nitrophenyl) phosphite in the presence of pyridine furnished rapid formation of the corresponding 4-nitrophenyl 2′,3′- O , O -cyclic phosphites which upon sulfhydrolysis, followed by sulfurization of the resultant cyclic H-phosphonothioate and removal of the 5′- O -protecting groups, afforded nucleoside 2′,3′- O , O -cyclic phosphorodithioates in high yields.

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.

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 arising from R P and S P diastereomers were reversed.

Interaction of thymidylate synthase with the 5'-thiophosphates, 5'-dithiophosphates, 5'-H-phosphonates and 5'-S-thiosulfates of 2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine.

Abstract New analogs of dUMP, dTMP and 5-fluorodUMP, including the corresponding 5thiophosphates (dUMPS, dTMPS and FdUMPS), 5dithiophosphates (dUMPS2, dTMPS2 and FdUMPS2), 5Hphospho nates (dUMPH, dTMPH and FdUMPH) and 5S thiosulfates (dUSSO3, dTSSO3 and FdUSSO3), have been synthesized and their interactions studied with highly purified mammalian thymidylate synthase. dUMPS and dUMPS2 proved to be good substrates, and dTMPS and dTMPS2 classic competitive inhibitors, only slightly weaker than dTMP. Their 5-fluoro congeners behaved as potent, slowbinding inhibitors. By contrast, the corresponding 5Hphosphonates and 5Sthiosulfates displayed weak activities, only FdUMPH and FdUSSO3 exhibiting significant interactions with the enzyme, as weak competitive slowbinding inhibitors versus dUMP. The pHdependence of enzyme timeindependent inhibition by FdUMP and FdUMPS was found to correlate with the difference in pKa values of the phosphate and thiophosphate groups, the profile of FdUMPS being shifted (~1 pH unit) toward lower pH values, so that binding of dUMP and its analogs is limited by the phosphate secondary hydroxyl ionization. Hence, together with the effects of 5Hphosphonate and 5Sthiosulfate substituents, the much weaker interactions of the nucleotide analogs (35 orders of magnitude lower than for the parent 5phosphates) with the enzyme is further evidence that the enzymes active center prefers the dianionic phosphate group for optimum binding.

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 H-phosphonates. Part 13. A new, general entry to aryl nucleoside phosphate and aryl nucleoside phosphorothioate diesters

The reaction of nucleoside H-phosphonate monoesters with phenols in the presence of a condensing agent, followed by oxidation of the in-situ-generated aryl nucleoside H-phosphonate diesters with iodine–water or with elemental sulfur, provides a new, ‘one-pot’, efficient entry to nucleoside phosphate or nucleoside phosphorothioate diesters bearing diverse aryl moieties.

New Methods for Multiple Modifications of a Phosphorus Centre. Their Relevance to Nucleotide and Oligonucleotide Analogues Synthesis

Abstract Nucleoside phosphoramidates and their analogues with the P‒N bond in bridging positions of the phosphoramidate linkage were prepared by a new method utilizing the corresponding pyridine adducts of metaphosphates. Also, a new procedure was developed for the synthesis of unprotected nucleoside phosphoromono- and phosphorodithioates.