Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution

The preparation of Sofosbuvir, the potent key component of recent Hepatitis C (HCV) infection therapies, is reported. The process is based on the dynamic kinetic resolution of the stereochemically unstable isopropyl-2-([chloro(phenoxy)phosphoryl]-aminopropanoate (8). A high stereoselectivity was obtained when the right protective group for 3'-OH was chosen. Ester and carbonate-based protective groups gave lower stereoselectivities, but benzyl protection allowed the phosphorylation to occur with a 92:8 ratio in favour of the product with the right configuration at the P-stereogenic centre. Starting from the γ-lactone of 2-deoxy-2-fluoro-2-methylpentonic acid, the synthesis was accomplished in eight steps in 40% overall yield using commercially available reagents, and without any enzymatic or chemical resolution technique.