Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution

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.

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

“…[53,54] The synthesis of 129 is summarized in Schemes 14 and 15 [55] andr elies upon two key sequences:c onstruction of chiral lactone 135 (Scheme 14) and introductiono ft he chiral phosphate moiety (Scheme 15). The preparation of chiral lactone 135 startedw ith the acylation of (R)-4-isopropyloxazolidin-2-one (130) with ethyl 2-fluoropropanoate,w hich was conducted at 120 8Cw ith the aid of ClSO 3 H. An aldol reactiono ft he obtained amide 131 with acrolein in the presenceo fT iCl 4 [56]…”

“…After removal of the TBS group, alcohol 141 was treated with (2 S )‐isopropyl 2‐{[chloro(phenoxy)phosphoryl]amino}propanoate ( 142 ) to give chiral phosphoramidate 143 with excellent diastereoselectivity (92:8 diastereomeric ratio (d.r.)). Finally, compound 129 was obtained through the Pd‐catalyzed deprotection of the 3′‐alcohol in MeOH (Scheme ) …”

Thoughts on What Chemists Can Contribute to Fighting SARS‐CoV‐2 – A Short Note on Hand Sanitizers, Drug Candidates and Outreach

“…Thes ynthesis of compounds like remdesivir is far from trivial, though, not least because the amino acid ester and aryloxy group make the phosphorus of the phosphoramidate astereogenic center.Synthesizing chiral phosphoramidates of this level of complexity is as ynthetic challenge, [37] and so is the synthesis of other drug candidates for treating the virus that will be identified by homology modeling and targetbased virtual ligand screening or conventional medicinal chemistry approaches.Developing efficient syntheses for such compounds and making them available to laboratories that test them is as econd opportunity for chemists who wish to contribute to fighting SARS-CoV-2.…”

Thoughts on What Chemists Can Contribute to Fighting SARS‐CoV‐2 – A Short Note on Hand Sanitizers, Drug Candidates and Outreach

“…The synthesis of compounds like remdesivir is far from trivial, though, not least because the amino acid ester and aryloxy group make the phosphorus of the phosphoramidate a stereogenic center. Synthesizing chiral phosphoramidates of this level of complexity is a synthetic challenge, and so is the synthesis of other drug candidates for treating the virus that will be identified by homology modeling and target‐based virtual ligand screening or conventional medicinal chemistry approaches. Developing efficient syntheses for such compounds and making them available to laboratories that test them is a second opportunity for chemists who wish to contribute to fighting SARS‐CoV‐2.…”