Journal
TETRAHEDRON
Volume 65, Issue 27, Pages 5181-5191Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2009.05.004
Keywords
Asymmetric synthesis of (S)-ketamine; Nitrogen-substituted quaternary carbon centers
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Funding
- Japan Society for the Promotion of Science
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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 alpha-ketoxime-ether acetal 9 bearing chiral auxiliary on the alpha-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 I with excellent selectivity (>99% ee) was accomplished by a short path according to the strategy. (C) 2009 Elsevier Ltd. All rights reserved.
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