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

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.