Catalytic Regioselective Acylation of Unprotected Nucleosides for Quick Access to COVID and Other Nucleoside Prodrugs

Nucleosides have important therapeuticapplications thatincludeantiviral activities against COVID viruses. It is a common strategyto convert one or multiple of the hydroxyl (OH) units in nucleosidesto the corresponding ester groups to prepare nucleoside prodrugs forbetter performance. Due to the presence of multiple OH units in nucleosides,current protocols for access to such ester prodrugs involve multiplesteps due to installation and removal of protection groups. Here,we disclose a catalytic strategy that allows for regioselective functionalizationof a specific OH unit without the need of protecting other OH groups.The key step in our method is an N-heterocyclic carbene-catalyzedselective acylation of the pentose unit of nucleosides. We demonstratethat commercially launched COVID-19 prodrugs such as molnupiravircan be prepared in concise routes by using our strategy.

Automated summary

Nucleosides have therapeutic applications against COVID viruses. Converting hydroxyl units in nucleosides to ester groups is a common strategy for preparing nucleoside prodrugs. However, this process usually involves multiple steps. A new catalytic strategy allows for selective acylation of a specific OH unit in nucleosides, simplifying the preparation of prodrugs such as molnupiravir.