A practical large-scale synthesis of enantiomerically pure 3-[bis(methoxycarbonyl)methyl]cyclohexanone via catalytic asymmetric Michael reaction

Youjun Xu, Ken Ohori, Takashi Ohshima, Masakatsu Shibasaki

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

A highly practical and efficient procedure for the large-scale (up to 6 mol) synthesis of enantiomerically pure (R)-3-[bis(methoxycarbonyl)methyl]cyclohexanone using an (R)-AlLibis(binaphthoxide) complex ((R)-ALB)-catalyzed asymmetric Michael reaction was developed. The reaction was successfully accelerated under highly concentrated conditions without lowering chemical yield or the high enantiomeric excess. Under these conditions, only 0.05 mol% of the catalyst forced the reaction to completion in 48 h. The work-up procedure was also improved and the enantiomerically pure compound was obtained as a white crystal in up to 95% yield without chromatographic separation. Finally, pre-manufacturing scale synthesis was performed. Using 0.1 mol% of the catalyst with 0.09 mol% of KO-t-Bu and MS 4 Å, the Michael reaction of 2-cyclohexenone (6.0 mol, 581 mL) with dimethyl malonate (6.0 mol, 686 mL) was completed in 24 h at ambient temperature to afford more than a kilogram of the enantiomerically pure product in 91% yield after three successive crystallizations. The described method renders the enantiomerically pure Michael adduct readily available on greater than kilo scale.

Original languageEnglish
Pages (from-to)2585-2588
Number of pages4
JournalTetrahedron
Volume58
Issue number13
DOIs
Publication statusPublished - Mar 25 2002
Externally publishedYes

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Catalysts
Crystallization
Crystals
Temperature
cyclohexanone
2-cyclohexen-1-one
methyl malonate

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

A practical large-scale synthesis of enantiomerically pure 3-[bis(methoxycarbonyl)methyl]cyclohexanone via catalytic asymmetric Michael reaction. / Xu, Youjun; Ohori, Ken; Ohshima, Takashi; Shibasaki, Masakatsu.

In: Tetrahedron, Vol. 58, No. 13, 25.03.2002, p. 2585-2588.

Research output: Contribution to journalArticle

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