Ironmonger A.
*
Shipton M.
Slater F.
Szeto P.
Unthank MG.
Alexandre F.-R.
Caillet C.
Dousson CB.
GlaxoSmithKline Medicines Research Centre, Stevenage and Northumbria University, Newcastle upon Tyne, UK; Merck & Co., Inc., Rahway, USA
A Highly Diastereoselective Chloride-Mediated Dynamic Kinetic Resolution at Phosphorus On-Route To A Key Intermediate In the Synthesis Of GSK2248761A.
Tetrahedron Lett. 2018;
59: 2154-2156
Key words
Fosdevirine - GSK2248761A - non-nucleoside reverse transcrip-tase inhibitor - dynamic kinetic resolution - phosphinate esters
Significance
Fosdevirine (GSK2248761A) is a non-nucleoside reverse transcriptase inhibitor that was of interest for the treatment of HIV. A recent process-scale synthesis of the (R)-enantiomer was achieved by a late-stage classical resolution of racemic phosphinate G using cinchonidine as the resolving agent (Org. Process Res. Dev. 2018, 22, 200). A new route to key intermediate (R
P)-G in the synthesis of (R)-fosdevirine features a highly diastereoselective dynamic kinetic resolution in the reaction of the phosphinyl chloride rac-C with methyl (S)-phenylglycinate (D).
Comment
The key step in the dynamic kinetic resolution is the rapid racemization of phosphinyl chloride rac-C by nucleophilic attack at the phosphorus atom by chloride ions followed by diastereoselective reaction of one of the phosphinyl chloride enantiomers with the methyl (S)-phenylglycinate. Fifteen chiral amines were screened in the DKR reaction with best results (dr = 21:1) being obtained with methyl (S)-phenylglycinate. The overall yield of (R
P)-H from A was 50% (10 g scale).
