Mainly due to their diverse reactivity as metal homoenolate equivalents in the presence of various electrophiles, 1-substituted cyclopropanol derivatives constitute precious synthetic intermediates in organic chemistry for the elaboration of complex molecules. Different approaches including the Simmons-Smith cyclopropanation and titanium-mediated cyclopropanation between Grignard reagents and esters (Kulinkovich cyclopropanation) have been developed for their formation. Despite these advances, the direct nucleophilic addition of carbon nucleophiles to the parent ketone, which constitutes a distinct and valuable synthetic disconnection, remains underexplored. The poor reactivity of classical hemiketals as cyclopropanone precursors is a consequence of the limited leaving group ability of alkoxides and has hampered the use of such an approach for the synthesis of cyclopropanols. In this work, we report the use of 1-sulfonylcyclopropanols as stable cyclopropanone precursors, acting as privileged substrates in the addition of organometallic reagents such as Grignards, organolithium and organozinc reagents, producing a wide variety of 1-substituted cyclopropanol derivatives in high yields. The use of enantiopure 2-substituted substrates led to the formation of highly enantioenriched cyclopropanols difficult to access otherwise. When alkenyl Grignard reagents are used as nucleophiles, the olefin of the resulting 1-vinylcyclopropanol can be activated with electrophilic reagents such as NBS, triggering a regio- and stereospecific 1,2 migration to afford alkylidenecyclobutanones in enantioenriched form. These strained molecules are difficult to access by other methods and are highly valuable as compact Michael acceptors to afford 2,3-substituted cyclobutanones.

General synthesis of cyclopropanols via organometallic addition to cyclopropanone equivalents: Application to the formation of enantioenriched alkylidenecyclobutanones

ACS Spring 2022

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