Bicyclo[2.2.2]octane-2,3-diol as an universal linker for the solid-phase synthesis of oligonucleotides

Abstract

In solid-phase synthesis, a universal linker modified on a solid support is generally used for the synthesis of oligonucleotides bearing a non-natural nucleoside at the 3′-terminus. Herein, we have developed three new universal linkers using bicyclo[2.2.2]octane-2,3-diol group. Saturated, unsaturated, and dibenzo-fused type linkers containing bicyclo[2.2.2]octane-2,3-diol, bicyclo[2.2.2]oct-5-ene-2,3-diol, and 9,10-dihydro-9,10-ethanoanthracene-11,12-diol, respectively, were synthesized and loaded onto a solid support. Upon releasing the oligonucleotides from the solid supports under basic conditions, it was found that the desired oligonucleotides and the impurities derived from the universal linker were well-separable on the HPLC chart using the dibenzo-fused type linker. In the synthesis of the phosphorothioate-modified oligonucleotide, the dibenzo-fused type also showed that the desired oligonucleotide and the impurities were well-separable. These results demonstrated that the dibenzo-fused type linker has great potential to become a new universal linker used for the solid-phase synthesis of oligonucleotides.