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

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.