RNA 2'-OH modification with stable reagents enabled by nucleophilic catalysis

RNA modification at 2'-OH has typically required highly reactive acylating species that exhibit short half-lives in water, challenging purification, and limited shelf lives. Here, we investigate the use of more stable species as electrophilic reagents, employing nucleophilic catalysis to promote reactions. Results show that multiple previously unreported electrophiles can react in high stoichiometric yields with RNA under appropriate catalysis. Most notably, aryl esters can transfer acyl groups to RNA in one hour, but are stable for months even in pure water. The results expand the functional chemotypes of RNA-reactive species, and identify reagent classes with improved stability and selectivity.