Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes
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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.
Robinson , E R T , Frost , A B , Elías-Rodríguez , P & Smith , A D 2017 , ' Enantioselective isothiourea catalysed Michael-Michael-lactonisation cascade; synthesis of δ-lactones and 1,2,3,4-substituted cyclopentanes ' Synthesis , vol 49 , no. 2 , pp. 409-423 . DOI: 10.1055/s-0036-1588636
© Georg Thieme Verlag Stuttgart - New York. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1055/s-0036-1588636
The authors thank the EPSRC (ERTR – grant code EP/J500549/1; ABF - grant code EP/J018139/1), the Spanish government for a FPU Fellowship and the University of Seville (V Plan Propio de Investigación) for financial support (PER). This work was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) ERC grant agreement no. 279850. ADS thanks the Royal Society for a Wolfson Research Merit Award.
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