Michal Sobkowski

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.

Studies on aryl H-phosphonates. 3. Mechanistic investigations related to the disproportionation of diphenyl H-phosphonate under anhydrous basic conditions

Abstract Diphenyl H-phosphonate undergoes under anhydrous reaction conditions a base-promoted disproportionation to triphenyl phosphite and phenyl H-phosphonate. On the basis of 31P NMR data the most likely mechanism for this transformation was proposed. In order to substantiate these findings and to get a deeper insight into the chemistry of aryl H-phosphonate esters, we carried out also some studies on activation of phenyl and diphenyl H-phosphonates with various condensing agents. We found that aryl vs alkyl esters of phosphonic acid often follow different reaction pathways during the activation, and this can most likely be traced back to higher electrophilicity of the phosphorus centre and to higher reactivity of the P-H bonds in aryl H-phosphonate derivatives.

Nucleoside Phosphonates. Development of Synthetic Methods and Reagents

Abstract In this paper a short account of our recent research concerning development of new synthetic methods and new reagents for the preparation of DNA and RNA fragments and their analogues is given. #Dedicated to Professor Yoshihisa Mizuno on the occasion of his 75th birthday. ¶Present address: Astra Production Chemicals, S-151 85 Sodertalje, Sweden.

The chemical synthesis of biochemically active oligoribonucleotides using dimethylaminomethylene protected purine H-phosphonates

Abstract Dimethylaminomethylene was applied as the protecting group for the exocyclic amino groups of adenosine and guanosine in the automated chemical synthesis of oligoribonucleotides on a polymer bound support. The dimethyl-aminomethylene protecting group can be removed at room temperature under conditions where the concomitant loss of the 2′-protection group can be excluded. The transformation of 2′-O-(t-butyldimethylsilyl)-5′-O-(4,4′-dimethoxytrityl) protected nucleosides to 3′-H-phosphonates yields synthons, well suited for the automated chemical synthesis of oligoribonucleotides. Using these H-phosphonate monomers, a coupling time of two minute: is sufficient to obtain average coupling yields of more than 98 %. Synthesized RNA is recognized as a substrate in an enzymatic reaction, forms the expected secondary structures and is suitable for NMR structural investigations.

A proposal for a convenient notation for P-chiral nucleotide analogues. Part 3. Compounds with one nucleoside residue and nonnucleosidic derivatives.

Recently, we have proposed a new DP/LP stereochemical notation for P-chiral dinucleoside monophosphate analogues that permits simple correlation between spatial arrangement of the substituents and the configuration at the phosphorus center. As an extension of this work, we present here applications of the DP/LP notation to derivatives containing only one nucleoside unit (e.g., alkyl nucleoside phosphodiesters, nucleoside phosphomonoesters, cyclic phosphate derivatives, nucleoside di-, and triphosphates) and to nonnucleosidic phosphorus compounds.

The Reactions of H-Phosphonates with Bifunctional Reagents. V. Functionalization of Support-Bound Oligonucleotides and Synthesis of Nonradioactive Hybridization Probes a

Three methods for the functionalization of oligonucleotides with aminoalkyl moieties have been developed and their efficiencies were evaluated in the preparation of non-radioactive hybridization probes.

Studies on reactions of nucleoside H-phosphonates with bifunctional reagents. Part 2. Stability of nucleoside H-phosphonate diesters in the presence of amino alcohols

H-Phosphonate diesters undergo transesterification with amino alcohols to afford as primary products the mixed and the symmetrical H-phosphonate esters. Alcohols react similarly but only in the presence of an external base or in a basic solvent. The rate and the course of transesterification strongly depend on the reaction conditions, the reactivity of the H-phosphonate diester used, and the nature of the amino alcohol.

A proposal for a convenient notation for P-chiral nucleotide analogues. Part 2. Dinucleoside monophosphate analogues

A configuration of ligands around a phosphorus atom in P-chiral dinucleoside monophosphate analogues can be described using DP/LP stereochemical notation, which allows immediate correlation between the notation of configuration and the actual spatial arrangement of the phosphorus ligands. The area of applications of this new stereochemical nomenclature covers dinucleoside units bridged by virtually any type of tri-and tetra-coordinated phosphorus moieties, that is, phosphorothioates, phosphoramidates, phosphoramidites, boranephosphates, methanephosphonates, H-phosphonates, and many others.

A proposal for a new stereochemical notation for P-chiral nucleotide analogues and related compounds

A new stereochemical notation for P-chiral nucleotide analogues and related compounds is proposed. In this notation, the names of configurations, designated as D P and L P, are derived from a geometrical relationship, rather than from priority rules, of substituents at the phosphorus centre. This new stereochemical description offers clear advantages over the CIP R/S nomenclature, particularly when used for comparing the influence of absolute configuration at the phosphorus centre on physicochemical and biological properties of oligonucleotide analogues or in stereochemical correlation analysis of P-chiral nucleotide derivatives.

Aryl H-phosphonates. Part IV. A new method for internucleotide bond formation based on transesterification of aryl nucleoside H-phosphonate diesters

Abstract Under mild reaction conditions nucleoside aryl H-phosphonate diesters undergo fast and efficient transesterification with suitably protected nucleosides, affording dinucleoside (3′–5′) H-phosphonate diesters.