Cobalt-catalyzed stereoselective synthesis of chiral gem-difluorocyclopropanes with vicinal stereocenters

Abstract

The introduction of fluorine atoms into a cyclopropane ring has been demonstrated to augment both biological activity and bioavailability. Chiral gem-difluorocyclopropanes, especially those incorporating vicinal stereocenters, are prevalent in the structural motifs of diverse biologically active compounds. Despite their significance, the synthesis of chiral gem-difluorocyclopropanes bearing vicinal stereocenters remains constrained. In this context, we present a cobalt-catalyzed regio-, diastereo-, and enantioselective hydroalkylation of gem-difluorocyclopropenes, obviating the necessity for any chelation-directing group, thus facilitating the access to chiral gem-difluorocyclopropanes with vicinal stereocenters. The devised protocol demonstrates compatibility with readily available reactants, exhibits a broad substrate scope, and affords high stereoselectivities. Mechanistic study indicates that the hydrometallation of alkenes with Co(I)–H species governs the stereochemistry of this transformation, with reductive elimination constituting the turnover-limiting step. Notably, the identification of various crucial alkylcobalt intermediates via in situ high-resolution mass spectrometry furnishes compelling evidence supporting the proposed reaction mechanism.