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

Author:

Gohari Seyed Jamaladdin1,Javidan Abdollah2,Moghimi Abolghasem3,Taghizadeh Mohammad Javad1,Iman Maryam4

Affiliation:

1. Department of Chemistry, Faculty of Science, Imam Hossein Comprehensive University, Tehran, Iran.

2. Department of Medicine Chemistry, Faculty of Science, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran, and University of Eyvanekey, Eyvanekey, Iran.

3. Department of Chemistry, Faculty of Science, Islamic Azad University, Tehran North Branch, Tehran, Iran.

4. Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.

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).

Publisher

Canadian Science Publishing

Subject

Organic Chemistry,General Chemistry,Catalysis

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