A Base‐Labile Group for 2′‐OH Protection of Ribonucleosides: A Major Challenge for RNA Synthesis

A novel methodology that disrupts the dogma “RNA synthesis is incompatible with a whole base-labile strategy” has been developed. In this strategy (see scheme), 2′-OH groups are protected by pivaloyloxymethyl groups, compatible with standard base-labile protections for nucleobases and phosphates. Protecting groups are removed in a short two-step all-base procedure to afford RNA efficiently, rapidly, and in high purity without chain rupture or isomerization.