Yokoyama T,
Yokoyama R,
Nomura S,
Matsumoto S,
Fujiyama R,
Kiyooka S.-i.
*
Kochi University, Japan
Synthesis of (
S)-Ketamine via [1,3]-Chirality Transfer of a Stereocenter Created by Enantioselective
Aldol Reaction.
Bull. Chem. Soc. Jpn. 2009;
82: 1528-1532
DOI:
10.1246/bcsj.82.1528
Key words
Kiyooka aldol - Ichikawa rearrangement - psychoactive molecules
Significance
Ketamine is an anesthetic and analgesic that has been used in both human and veterinary
medicine since 1963. While commercially available as a racemic mixture, the S-enantiomer has more potent anesthetic effects while also avoiding the side effects
of the R-enantiomer such as restlessness, agitation, and hallucinations. In order to access
enantioenriched (S)-ketamine, the Kiyooka group developed a short synthesis that provides the desired
product in 36% yield.
Comment
The synthesis begins with a highly selective Kiyooka aldol reaction which affords
the desired enantiomer in 86% ee as a 3:2 mixture of atropisomers. After reduction
and benzyl protection of the primary alcohol, the secondary alcohol reacts with trichloroacetyl
isocyanate and hydrolyzes to give a carbamate. Exposure to dehydrating conditions
affords an allyl cyanate which undergoes an Ichikawa rearrangement with stereochemical
retention. Reduction and HCl salt formation sets the stage for the final ozonolysis
which provides (S)-ketamine.
