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. © 2010 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.