Developing Synthetic Methods for Bioactive Phosphorus Compounds Using H-Phosphonate Chemistry: A Progress Report

Abstract

In this paper a short account of our recent research concerning the development of new synthetic methods and reagents for the preparation of nucleotides and their analogues, is given.     

DEVELOPING SYNTHETIC METHODS FOR BIOACTIVE PHOSPHORUS COMPOUNDS USING H-PHOSPHONATE CHEMISTRY: A PROGRESS REPORT

In this paper a short account of our recent basic studies aiming toward development of new synthetic methods for the preparation of nucleotide analogues using H-phosphonate chemistry is presented.     

Stereochemistry of Internucleotide Bond Formation by the H-Phosphonate Method. 5. The Role of Brønsted and H-Bonding Base Catalysis in Ribonucleoside H-Phosphonate Condensation—Chemical and Stereochemical Consequences

Efficiency and stereoselectivity of condensations of ribonucleoside 3′-H-phosphonates with ethanol promoted by pivaloyl chloride were investigated as a function of tertiary amines used. Side reactions leading to an increased demand for the condensing agent were identified as derived from an attack of the pivalate anion at carbonyl centers of reactive pivaloyl derivatives. The conditions that secured quantitative yields of H-phosphonate diester condensations were assessed. Several tertiary amines promoted condensations with stereoselectivity higher than that observed for pyridine derivatives. A correlation between diastereoselectivity of the product formation and Brønsted and H-bonding basicities of the amine used was found.     

Synthesis of phosphopeptides via global phosphorylation on the solid phase: Resolution of H-phosphonate formation

The formation of the H-phosphonate by-products from the global phosphorylation of a Thr-containing peptide resin using both di-t-butyl and dibenzyl N,N-diethylphosphoramidite was identified to result from 1H-tetrazole-mediated cleavage of the t-butyl or benzyl from the intermediate dialkyl phosphite triester and re-arrangement of the resultant hydroxy phosphite diester to the H-phosphonate form. This side reaction was rectified by the use of aqueous iodine for the oxidation step in which the H-phosphonate is oxidised to the benzyl phosphorodiester which, on acidolytic treatment, gives the desired dihydrogen phosphate.     

Synthesis of β-H-Phosphono-α-phosphonomethyl Analogues of Nucleoside 5"-Diphosphates

Novel -H-phosphono--phosphonomethyl analogues of nucleoside 5"-diphosphates were synthesized by phosphonylation of 5"-O-phosphonomethylthymidine and 9-[2-phosphonomethyloxy)ethyl]adenine with sodium pyrophoshite. The structures of the resulting individual compounds were confirmed by NMR and UV spectroscopy.     

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.     

Synthesis of phosphopeptides via global phosphorylation on the solid phase: Resolution of H-phosphonate formation

Summary The formation of the H-phosphonate by-products from the ‘global’ phosphorylation of a Thr-containing peptide resin using both di-t-butyl and dibenzylN,N-diethylphosphoramidite was identified to result from 1H-tetrazolemediated cleavage of thet-butyl or benzyl from the intermediate dialkyl phosphite triester and re-arrangement of the resultant hydroxy phosphite diester to the H-phosphonate form. This side reaction was rectified by the use of aqueous iodine for the oxidation step in which the H-phosphonate is oxidised to the benzyl phosphorodiester which, on acidolytic treatment, gives the desired dihydrogen phosphate.