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

Nucleosides have important therapeutic
applications that
include
antiviral activities against COVID viruses. It is a common strategy
to convert one or multiple of the hydroxyl (OH) units in nucleosides
to the corresponding ester groups to prepare nucleoside prodrugs for
better performance. Due to the presence of multiple OH units in nucleosides,
current protocols for access to such ester prodrugs involve multiple
steps due to installation and removal of protection groups. Here,
we disclose a catalytic strategy that allows for regioselective functionalization
of a specific OH unit without the need of protecting other OH groups.
The key step in our method is an N-heterocyclic carbene-catalyzed
selective acylation of the pentose unit of nucleosides. We demonstrate
that commercially launched COVID-19 prodrugs such as molnupiravir
can be prepared in concise routes by using our strategy.