A semi-empirical and density functional study on the origin of regioselective epoxy-ring opening of 2′3′-lyxoanhydrothymidine

Abstract

The importance of antisense oligonucleotides is well recognized due to its application in therapeutic purposes, to inhibit and to activate gene expression and for many mechanistic studies. With the advancement of antisense technology, attempts have been made to synthesize the oligoarabinonucleotides as oligoribonucleotides mimics. Synthetic strategies adopted for synthesizing such nucleotides are the regioselective phosphorylation of 2′,3′-epoxynucleosides of lyxo configuration. Regioselectivities observed in such reactions are excellent, however, the reason for the preferential approach of a nucleophile (phosphate dianion) on a particular reactive site of epoxy ring remains obscure. In this study, we have unraveled the factors responsible for the regioselective epoxy ring opening of 2′3′-lyxoanhydrothymidine 1 with phosphate dianion at semi-empirical AM1 and at DFT level. The relative importance of hydrogen bonding of the leaving oxyion with axial hydroxymethyl group in the transition states of lyxouridine epoxide was analyzed and suggested that this was not an important factor, which control the regioselectivity as speculated. The intrinsic electrophilicity, however, is important for the regioselective epoxy ring opening of lyxouridine epoxide 1. The influence of solvent on regioselectivities has also been examined.