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Organocatalytic Enamine-Activation of Cyclopropanes for Highly Stereoselective Formation of Cyclobutanes

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journal contribution
posted on 04.02.2015, 00:00 authored by Kim Søholm Halskov, Florian Kniep, Vibeke Henriette Lauridsen, Eva Høgh Iversen, Bjarke Skyum Donslund, Karl Anker Jørgensen
A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor–acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π–orbital of the enamine and the σ*C–C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor–acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.