Nucleophilic Activation of Cyclopropanes for Enantioselective Catalytic Transformations

ConspectusActivation of cyclopropanes remained a challenging process until the 1980s, when pioneering reports by Wenkert and Reissig showed that cyclopropanes could be activated by introducing donors and acceptors at vicinal positions via push-pull systems, thereby giving rise to the field of donor-acceptor cyclopropanes. This ushered in their first golden age, characterized by the studies of their reactivity and synthetic potential as well as the elucidation of the main reaction mechanisms. Interestingly, this field underwent an unforeseen resurgence in the 2000s, largely driven by Lewis acid-catalyzed reactions, whereas nucleophilic activation trailed behind. This approach leverages an electrophilic activation of cyclopropanes, promoting the ring opening and subsequent transformations─a trend that extends into the present day. Furthermore, the use of chiral bisoxazoline or bis(oxazolinyl)pyridine ligands with Lewis acids enabled the first enantioselective transformations of donor-acceptor cyclopropanes.Over the past years, this area evolved even more rapidly with the emergence of novel organocatalytic activation strategies, complemented by significant progress in enantioselective activation of cyclopropanes, providing access to chiral scaffolds with a high degree of stereocontrol. Beyond the continued dominance of metal catalysis, organocatalytic electrophilic activation strategies also emerged, such as iminium-ion and chiral Brønsted acid catalysis. Concurrently, nucleophilic activation approaches of cyclopropanes have steadily flourished, driven by pioneering examples in enamine-, Brønsted base-, and N-heterocyclic carbene-catalyzed ring opening reactions of donor-acceptor cyclopropanes.Electrophilic activation methodologies of cyclopropanes typically involve coordination of the catalyst to the acceptor(s), generally carbonyl(s), facilitating their ring opening, while nucleophilic activation proceeds through covalent or non-covalent interactions of the catalyst activating the donor, thereby enhancing its nucleophilicity and promoting the ring opening. N-Heterocyclic carbenes can activate formylcyclopropanes through the Breslow intermediate, generating nucleophilic enaminol moieties that enable their ring opening. On the other hand, β-cyclopropyl aldehydes can generate enamine species through condensation with aminocatalysts, which can then undergo ring opening, providing a reactive α,β-unsaturated iminium-ion species, also capable of reacting as its corresponding dienamine. Finally, Brønsted base-catalyzed activation of cyclopropanes proceeds through deprotonation of β-cyclopropyl carbonyls or sulfones, allowing for their ring opening and 1,3-dipole-like reactivity.This Account seeks to showcase nucleophilic activation of cyclopropane strategies as an alternative approach to conventional electrophilic approaches, highlighting the initial discoveries and charting the developments and applications of these approaches. Herein, key challenges and applications of these strategies are outlined, providing an instructive guide for future experimental design and the exploration of novel methodologies within this field.