Synthesis and structural analysis of dinucleotides containing 2',3'-trans-bridged nucleic acids with trans-5,6- or 5,7-fused ring skeleton.

Abstract

Artificial nucleic acids in which the conformation of the sugar or phosphate backbone of the oligonucleotide is appropriately fixed can form stable duplexes. In this study, we designed dinucleotides containing 2',3'-trans-bridged nucleic acids (2',3'-trans-BNAs) based on the idea that the sugar conformation and torsions angles δ, ε, ζ, α, and β of the backbone can be controlled by a 5,6- or 5,7-membered trans-fused ring skeleton cyclized between the 2'- and 3'-positions of the sugar moiety. Given that the construction of trans-5,6-fused ring skeletons is synthetically challenging, the synthesis was optimized and a detailed structural analysis of these new bridged 2',3'-trans-BNA systems was conducted. The 2',3'-trans-BNAs could be synthesized from a commercially available D-glucose derivative with the key intramolecular gold-catalyzed cyclization reaction achieved using a cyclization precursor bearing an intramolecular hydroxy group and an internal alkyne. Structural analysis of the 2',3'-trans-BNAs showed an N-type sugar conformation for all the derivatives, which is similar to that in RNA-duplex, and the ζ and α torsion angles for the 2',3'-trans-BNAs were a characteristic feature of the compounds that differ from the corresponding angles of the natural duplexes.