Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution. Issue 20 (23rd April 2018)

• Record Type: Journal Article
• Authors: Cini, Elena; Barreca, Giuseppe; Carcone, Luca; Manetti, Fabrizio; Rasparini, Marcello; Taddei, Maurizio
• Is Part Of: European journal of organic chemistry. Issue 20/21(2018)
• Page Start: 2622
• Page End: 2628
• Publication Date: 2018-04-23
• Subjects: Antiviral agents -- Kinetic resolution -- Nucleotides -- Prodrugs -- Protecting groups; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201800158
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : 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]‐amino}propanoate (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. Abstract : A new method for the introduction of a P‐stereogenic centre is described. The method involves dynamic kinetic resolution of a stereochemically labile phosphoryl chloride, using a nucleoside protected at the 3′‐position with a benzyl group as the chiral selector. Only this convenient pocedure is required to obtain high stereoselectivity in an eight‐step synthesis of the anti‐HCV drug Sofosbuvir.