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.
|Titolo:||Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution|
TADDEI, MAURIZIO (Corresponding)
|Citazione:||Cini, E., Barreca, G., Carcone, L., Manetti, F., Rasparini, M., & Taddei, M. (2018). Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2018(20-21), 2622-2628.|
|Appare nelle tipologie:||1.1 Articolo in rivista|