Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring

first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity

Reiko Yokoyama, Satoshi Matsumoto, Satoshi Nomura, Takafumi Higaki, Takeshi Yokoyama, Syun ichi Kiyooka

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring was performed with respect to the asymmetric synthesis of anesthetic (S)-ketamine 1. Diastereoselective nucleophilic 1,2-addition reaction of phenyllithium to α-ketoxime-ether acetal 9 bearing chiral auxiliary on the α-carbonyl function gave benzyloxyamine 11 major in 83% yield with 82% de, which was converted to the corresponding amino ketone 12. However, the reaction of 2-chlorophenyllithium did not work in which this route was unavailable for the synthesis of 1. Then, an alternative strategy directed toward 1, starting with a compound having 2-chlorophenyl groups in advance, was designed in which the chiral quaternary carbon center bearing a nitrogen atom in the ring is created by the enantioselective reduction of the atropisomeric intermediate ketone 18, and the sequential allyl cyanate-to-isocyanate rearrangement with complete 1,3-chirality transfer. The first asymmetric synthesis of 1 with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy.

Original languageEnglish
Pages (from-to)5181-5191
Number of pages11
JournalTetrahedron
Volume65
Issue number27
DOIs
Publication statusPublished - Jul 4 2009

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Ketamine
Bearings (structural)
Ketones
Anesthetics
Nitrogen
Carbon
Cyanates
Isocyanates
Acetals
Oximes
Ether
Addition reactions
Chirality
Atoms
Cyclohexane
phenyllithium
benzyloxyamine

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Enantioselective construction of nitrogen-substituted quaternary carbon centers adjacent to the carbonyl group in the cyclohexane ring : first asymmetric synthesis of anesthetic (S)-ketamine with high selectivity. / Yokoyama, Reiko; Matsumoto, Satoshi; Nomura, Satoshi; Higaki, Takafumi; Yokoyama, Takeshi; Kiyooka, Syun ichi.

In: Tetrahedron, Vol. 65, No. 27, 04.07.2009, p. 5181-5191.

Research output: Contribution to journalArticle

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