A Switchable Platform for Divergent Skeletal Editing of Bicyclo[1.1.0]butanes Enabled by Monoatomic O/N Insertion

Skeletal editing enables modular restructuring of molecular frameworks, but switchable, divergent transformations from a single precursor remain underexplored. Herein, we report a switchable skeletal editing platform for bicyclo[1.1.0]butanes, enabled by monoatomic oxygen or nitrogen insertion. Four distinct molecular scaffolds are accessed via condition-dependent strain-release and rearrangement cascades: oxygen insertion affords β-methylene carbonyls via oxa-bicyclo[1.1.1]pentane-mediated ring opening and decarbonylation, itaconate derivatives via Grob-type ring opening, and cis-cyclopropanes via ring contraction; nitrogen insertion, in contrast, triggers ring expansion to form 2,4-disubstituted pyrroles. This strategy rapidly delivers bioactive-like frameworks with broad functional group tolerance. Synthetic utility is demonstrated by modular synthesis of bioactive molecules such as Esonarimod, Ralfuranone, and Rubrolide E. Mechanistic studies reveal that the position of the leaving group, whether on the heteroatom itself, the β-carbon, or the γ-carbon, within heteroatom-substituted cyclobutane intermediates dictates the divergent outcomes. These results establish a conceptually novel heteroatom-mediated strategy for programmable skeletal editing, significantly expanding the reactivity profile of bicyclo[1.1.0]butanes.