Collective Total Synthesis of Isocoumarin Natural Products via Copper-Catalyzed Annulations of Diaryliodonium Salts

The development of general and modular synthetic platforms for the collective synthesis of natural product families remains a significant challenge. For isocoumarins─biologically significant aromatic lactones─existing strategies are typically substrate-specific. Herein, we report a unified approach based on a copper-catalyzed, highly regioselective intermolecular (4 + 2) cycloadditions between readily available and modular diaryliodonium salts and alkynes. This method exhibited broad generality across terminal and internal, alkyl and aryl alkynes, overcoming long-standing regioselectivity issues with unsymmetrical variants. Leveraging the two modular building block libraries, we achieved the total synthesis of 12 structurally diverse isocoumarin natural products and analogues, including ( S )-Diaporthin, Thunberginols A/B, Legioliulin, Arnottin I, and the alkaloid Oxynitidine. The syntheses were consistently shorter, higher-yielding, and practically scalable (e.g., gram-scale preparation of Legioliulin), establishing a robust platform for collective synthesis and medicinal chemistry exploration. Moreover, the isocoumarin scaffold functioned as a versatile linchpin for accessing more complex molecular architectures.