Chemistry and stereochemistry of internucleotide bond formation by the H-phosphonate method

Abstract

The appropriately protected ribonucleoside 3′-H-phosphonates react with nucleosides and alcohols in the presence of condensing agents under mild conditions, with notable stereoselectivity. The chemistry and stereochemistry of this reaction were investigated using ³¹P NMR spectroscopy. A plausible mechanism for the asymmetric induction observed was identified as Dynamic Kinetic Asymmetric Transformation (DYKAT), operating due to different esterification rates of rapidly equilibrating P-epimers of the reactive intermediates. This diverse reactivity was tentatively attributed to steric demands of the H-phosphonic moiety located in the vicinity of the bulky protecting group in the 2′-position. The role of nucleophilic and base catalysis was analysed and the absolute configuration of the intermediates involved in the reaction pathways was tentatively assigned using ³¹P NMR stereochemical correlation analysis. Under optimal reaction conditions, the diastereomers of dinucleoside H-phosphonate diesters could be obtained usually in >90 : 10 ratio.