Bisnucleophilic Ambident Reactivity of Bicyclo[1.1.0]butanes via Lewis Acid Catalyzed Aldol-Ene Cascade: Diastereoselective Synthesis of Fused Oxabicyclic Scaffolds

The substantial strain embedded within the compact framework of bicyclo[1.1.0]butanes (BCBs) has established them as versatile 1,3-dipolar synthons for strain-release transformations. However, these advances have exclusively relied on the ambiphilic reactivity of BCBs. In contrast, their ambident reaction modality has remained unexplored, despite its potential to fundamentally expand the reactivity landscape of BCBs and provide access to previously inaccessible chemical space. Herein, we report the first bisnucleophilic reaction of BCBs via a Sc(OTf) 3 -catalyzed annulative coupling with succinaldehyde, enabling direct access to cyclobutene-fused oxabicycloheptanes in high yields with complete diastereocontrol. Distinct from the conventional 1,3-functionalization of BCBs, this transformation features formal 1,2-functionalization and reveals a previously unrecognized aldolene-type reactivity of this highly strained scaffold. This cascade protocol is operationally simple, scalable, and broadly tolerant of functional groups, while the resulting products provide streamlined access to densely functionalized fused cis -[2]-ladderane and angularly fused isoxazolidine scaffolds in diastereomerically pure form.