The synthesis of spirocyclopropane skeletons enabled by Rh(III)-catalyzed enantioselective C–H activation/[4 + 2] annulation

Considering the prevalence of spirocyclopropane motifs in bioactive compounds, the development of efficient methods for the synthesis of various chiral spirocyclopropane motifs would be highly desirable but challenging. Herein, we report an asymmetric synthesis of spirocyclopropane skeletons enabled by a chiral CpmRh-catalyzed C–H activation/[4 + 2] annulation of aromatic substrates (e.g., indole, pyrrole, benzene, naphthalene, thiophene) and acrylamides with methylenecyclopropanes (MCPs). Notably, we realized an asymmetric C(sp2)–H activation/annulation cascade with multi-substituted non-cyclic alkenes catalyzed by a chiral 1,1'-Bi-2-naphthol (BINOL)-derived CpmRh(III) catalyst, in which diverse spirocyclopropane scaffolds were prepared with good to excellent yields and enantioselectivities (up to 98% yield, up to 99.7:0.3 er). Density functional theory (DFT) studies prove that the energy barrier of the product configuration is low in the whole reaction process. Furthermore, the spirocyclopropane product (S)-3aj exhibited a better antiproliferation activity against the pancreatic cancer cell line BxPC-3 and could be a good lead compound for further anti-pancreatic-tumor drug development.