C−H Activation Initiated Skeletal Recasting of Cyclopropane Carboxylic Acid

The selective activation and transformation of carbon–carbon (C–C) single bonds remains a formidable challenge in synthetic organic chemistry, particularly when involving unstrained frameworks. Herein, we report a modular and mechanistically distinct strategy that merges Pd(II)-catalyzed C(sp³)–H activation with strain-release-driven C–C bond cleavage to achieve skeletal reorganization of cyclopropane carboxylic acid derivatives. This tandem transformation delivers 3-oxabicyclo[3.1.0]hexan-2-one scaffolds, valuable motifs found in numerous bioactive compounds, with high efficiency and stereocontrol from readily available precursors. Key to the success of this process is the sequential use of mono-protected amino acid (MPAA) ligands for directed site-selective C–H activation, followed by transition-metal-mediated cyclopropane ring opening. This dual-activation sequence consti-tutes a novel application of skeletal recasting, extending the paradigm beyond aromatic systems and leveraging non-aromatic strain-driven pathways. The methodology exhibits broad substrate scope, functional group tolerance, and significant potential for late-stage diversification. Detailed experimental and computational studies were conducted to elucidate the mechanistic underpinnings of the transformation, highlighting the pivotal roles of ligand coordination, ring strain, and transition state organization in governing reactivity and selectivity. This work provides a blueprint for strain-enabled molecular editing and demonstrates the untapped po-tential of integrating orthogonal bond activation modes for scaffold remodeling in complex molecule synthesis.