Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189

A general and efficient method for the synthesis of pronucleotide (ProTide) 5′-phosphoramidate monoesters is reported. This method consists of a highly stereoselective 5′-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3′-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.