Stereoselective Synthesis of Nucleotide Analog Prodrugs (ProTides) via an Oxazaphospholidine Method

This paper describes the stereocontrolled synthesis of <i>O-</i>aryl phosphoramidate nucleotide prodrugs (ProTides), namely Remdesivir, Sofosbuvir, and NUC-1031, using an oxazaphospholidine method. The 5'-phosphoramidate derivatives were synthesized via a one-pot process involving the condensation of nucleoside 5'-oxazaphospholidine derivatives with phenol, bromination of the resulting phosphite using <i>N</i>-bromosuccinimide, and subsequent reaction with an amine. The target compounds were obtained with high stereoselectivity (dr >99:1). This one-pot strategy substantially reduced the reaction time from those of traditional phosphorylation methods using P(V) derivatives, providing an efficient and streamlined route to ProTides.