Efficient Solid‐Phase Synthesis of pppRNA by Using Product‐Specific Labeling

A novel solid-phase synthesis and purification strategy for 5′-triphosphate oligonucleotides by using lipophilic tagging of the triphosphate moiety is reported. This is based on triphosphate synthesis with 5′-O-cyclotriphosphate intermediates, whereby a lipophilic tag, such as decylamine, is introduced during the ring-opening reaction to give a linear gamma-phosphate-tagged species. This method enables the highly efficient synthesis of 5′-triphosphorylated RNA derivatives and their gamma-phosphate-substituted analogues and will especially facilitate the advancement of therapeutic approaches that make use of 5′-triphosphate oligonucleotides as potent activators of the cytosolic immune sensor RIG-I.