Chemical Synthesis of a Locked Nucleic Acid-Substituted Dinucleotide Cap Analog

This article describes a reliable and efficient method for synthesis of the dinucleotide cap analog m^7(LNA) G[5']ppp[5']G containing a locked nucleic acid moiety. The required LNA intermediate for the final coupling reaction, m^7(LNA) GDP, is prepared in six steps starting from 5'-DMTr-N-DMF LNA guanosine. The overall reaction involves removal of DMTr and DMF groups, 5' monophosphorylation, imidazolide formation, diphosphorylation, and regioselective m⁷ methylation. The final coupling reaction of m^7(LNA) GDP with ImGMP in the presence of zinc chloride as a catalyst affords m^7(LNA) G[5']ppp[5']G in 59% yield. © 2021 Wiley Periodicals LLC. Basic Protocol: Synthesis of an LNA-substituted dinucleotide cap analog Support Protocol: Preparation of the tris(tributylammonium) phosphate linker.