Chemoenzymatic synthesis of both enantiomers of 2-tert-butyl-2-methyl-1,3- benzodioxole-4-carboxylic (TBMB) acid

Toshinori Higashi, Chika Abe, Keiko Ninomiya, Takuya MacHida, Nobuyuki Chishima, Shohei Taketomi, Miyu Furuta, Yoko Komaki, Yoshihiko Senba, Taeko Tokuda, Mitsuru Shoji, Takeshi Sugai

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Abstract

Both enantiomers of 2-tert-butyl-2-methyl-1,3-benzodioxole-4-carboxylic (TBMB) acid, which has a unique quaternary chiral center located on the acetal carbon, were prepared from a racemic ketone in which the carboxy group was replaced by a trifluoroacetyl group. First, reduction with fungi, Geotrichum candidum provided (2S,1′S)- and (2R,1′S)- 1′-(2-tert-butyl-2- methyl-1,3-benzodioxol-4-yl)-2′,2′,2′-trifluoroethanol in a highly enantiofacially selective manner. After acetylation, the resulting diastereomeric mixture was submitted to Candida antarctica lipase B-catalyzed transesterification. The reaction proceeded in a stereoselective manner under the influence of the chiral center at the acetal carbon, even though it was six atoms removed from the ester carbonyl carbon. Although the two substrates had the same absolute configuration at the secondary alcohol, the reaction rate of one stereoisomer was 72 times greater than that of the other isomer. The reason for this differential reactivity was attributed mainly to a large difference in Vmax(app) between the stereoisomers. The products, acetate and alcohol, were easily separated by chromatography, and each was then derivatized to (R)- and (S)-TBMB acid, with >99.2% ee, respectively.

Original languageEnglish
Pages (from-to)2549-2558
Number of pages10
JournalAdvanced Synthesis and Catalysis
Volume352
Issue number14-15
DOIs
Publication statusPublished - 2010 Oct 4
Externally publishedYes

Keywords

  • asymmetric synthesis
  • enzyme catalysis
  • kinetic resolution
  • transesterification

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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    Higashi, T., Abe, C., Ninomiya, K., MacHida, T., Chishima, N., Taketomi, S., Furuta, M., Komaki, Y., Senba, Y., Tokuda, T., Shoji, M., & Sugai, T. (2010). Chemoenzymatic synthesis of both enantiomers of 2-tert-butyl-2-methyl-1,3- benzodioxole-4-carboxylic (TBMB) acid. Advanced Synthesis and Catalysis, 352(14-15), 2549-2558. https://doi.org/10.1002/adsc.201000446