Novel enantioselective synthesis of (S)-ketamine using chiral auxiliary and precursor Mannich base

Abstract

Ketamine has been extensively used as an anesthetic drug. Chiral auxiliaries such as tert-butanesulfinamide (TBSA) can be used for the asymmetric synthesis of (S)-ketamine. Condensation of TBSA with ketones provides tert-butanesulfinylimines in consistently high yields. The tert-butanesulfinyl group actuates the imine for nucleophilic addition, is a potent chiral directing group, and after nucleophilic addition is easily dissociated by intervention with acid solution. To prepare 2-(N-piperidinomethyl)-1-phenylcyclohexylamine (1), we started with the cyclohexanone and using Mannich reaction achieved an aminoketone. Then, we made the sulfiniylamin (2) by the condensation of TBSA with aminoketone. By using salts such as Ti(OEt)4, we obtained N-tert-butanesulfinylketimine in 85% yield. Next, we provided a new chiral center (3) using Grignard reagent as nucleophile at −78 °C (80% yield). Finally, after many steps, the (S)-ketamine synthesized under ozonolysis conditions, with good yield and enantioselectivity (75% yield and 75% ee).