Yi-Xiang
Geng, Teng-Fei
Xiao, Dong Xie, Ming-MingLi, Pan-Pan
Zhou, Guo-Qiang Xu*, Peng-Fei Xu*
http://10.1038/s41467-025-64399-7
Abstract
Bicyclo[2.1.1]hexanes (BCHs), three-dimensional benzene bioisosteres char acterized by high sp3-carbon content, hold great promise for diverse appli cations in medicinal chemistry. Although significantadvanceshavebeenmade in the synthesis of racemic BCHs, highly enantioselective approaches remain comparatively rare. Here we report a mild, secondary amine–catalyzed asymmetric [2π+2σ] cycloaddition of bicyclo[1.1.0]butanes (BCBs) with α,β-unsaturated aldehydes, whichovercomeskeylimitationsofexistingmetal catalyzed and photochemical methods. The protocol operates under ambient air and tolerates a wide range of BCB and aldehyde substrates bearing diverse functional groups, affording BCH scaffolds in yields of up to 84% under Supramolecular Iminium Catalysis with excellent enantioselectivity (up to 99% ee) and high diastereoselectivity (>20:1 dr). The mild conditions and opera tional simplicity underscore the potential of this transformation for stereo selective manufacturing of BCHs at scale. Mechanistic experiments and DFT studies support an acid-promoted dual activation of both substrates, followed by an enamine–iminium tandem catalytic process that delivers the enan tioenriched products.