Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes

Emily R. T. Robinson, Aileen B. Frost, Pilar Elías-Rodríguez, Andrew D. Smith

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

This manuscript describes the application of α,β-unsaturated acyl ammonium intermediates in a Michael-Michael-lactonisation cascade process to furnish δ-lactones. Generation of α,β-unsaturated acyl ammonium intermediates was achieved upon addition of isothiourea catalyst HyperBTM into α,β-unsaturated acid chlorides. Subsequent reaction with enonemalonates gave access to δ-lactones in 20-64% yield, 72.5:27.5 to 95:5 er and 81:19 to >95:5 dr. Additionally, application of a ring-opening protocol yielded1,2,3,4-substituted cyclopentanes in 28-77% yield, 76:24 to 98:2 er and 86:14 to >95:5 dr. Interestingly, highest er was observed at high reaction temperatures, with 70˚C proving optimal. This effect was investigated by conducting an Eyring analysis, which indicated that differential activation entropy rather than differential activation enthalpy is responsible for enantiodiscrimination in this process.
Original languageEnglish
Pages (from-to)409-423
Number of pages15
JournalSynthesis
Volume49
Issue number2
Early online date23 Nov 2016
DOIs
Publication statusPublished - Jan 2017

Keywords

  • Lewis base catalysis
  • α,β-unsaturated acyl ammonium intermediates
  • Isothiourea catalysis
  • Cascades
  • Enantioselective catalysis

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