Enantioselective Syntheses of (S)-Ketamine and (S)-Norketamine.

An efficient asymmetric synthesis of (S)-ketamine (esketamine) based on catalytic enantioselective transfer hydrogenation of cyclic enone and [3,3]-sigmatropic rearrangement of allylic cyanate to isocyanate is described. The catalytic asymmetric route afforded esketamine (99.9% ee) in 50% overall yield over four steps and forms the basis for the future development of the drug substance. Furthermore, the route was applicable to the synthesis of (S)-norketamine via simple hydrolysis of isocyanate penultimate.