Isothiourea-mediated asymmetric Michael-lactonisation of trifluoromethylenones: a synthetic and mechanistic study

Louis C. Morrill, James Douglas, Tomas Lebl, Alexandra M. Z. Slawin, David J. Fox*, Andrew D. Smith

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)

Abstract

HBTM-2.1 promotes the catalytic asymmetric intermolecular Michael-lactonisation of arylacetic acids and trifluoromethylenones in the presence of pivaloyl chloride, giving C(6)-trifluoromethyldihydropyranones with high diastereo- and enantiocontrol (up to 95 : 5 dr and >99% ee) that are readily derivatised to diverse synthetic building blocks containing trifluoromethyl-stereogenicity. Kinetic studies indicate the reaction is first order with respect to both in situ formed mixed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using a, alpha,alpha-di-deuterio 4-fluorophenylacetic acid, consistent with rate determining deprotonation of an intermediate acyl isothiouronium ion.

Original languageEnglish
Pages (from-to)4146-4155
Number of pages10
JournalChemical Science
Volume4
Issue number11
DOIs
Publication statusPublished - 2013

Keywords

  • ACYL-TRANSFER CATALYST
  • BICYCLIC-BETA-LACTONES
  • SECONDARY BENZYLIC ALCOHOLS
  • MILD ELECTROPHILIC TRIFLUOROMETHYLATION
  • C-CARBOXYL TRANSFER
  • ENANTIOSELECTIVE ALPHA-TRIFLUOROMETHYLATION
  • KINETIC RESOLUTION CATALYSTS
  • PROMOTED BIS-CYCLIZATIONS
  • AMIDINE-BASED CATALYSTS
  • SILYL KETENE ACETALS

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