Synthesis of Nucleobase‐Modified Oligonucleotides by Post‐Synthetic Modification in Solution

Abstract Oligonucleotides containing modified nucleobases have applications in various technologies. In general, to synthesize oligonucleotides with different nucleobase structures, each modified phosphoramidite monomer needs to be prepared over multiple steps and then introduced onto the oligonucleotides, which is time‐consuming and inefficient. Post‐synthetic modification is a powerful strategy for preparing many types of modified oligonucleotides, especially nucleobase‐modified ones. Depending on the stage of modification, post‐synthetic modification can be divided into two stages: “solid‐phase modification,” wherein an oligonucleotide attaches to the resin, and “solution‐phase modification,” wherein an oligonucleotide detaches itself from the resin. In this review, we focus on post‐synthetic modification in solution for the synthesis of nucleobase‐modified oligonucleotides, except the modifications to linkers for conjugation. Moreover, the reactions are summarized for each modified position of the nucleobases.