Click-like ortho-quinone methide trapping using rare 3-methylene isochromanones for a series of multifunctional pseudo-natural products

Abstract

3-Methylene isochromanones represent a unique subclass of isocoumarins with very limited synthetic accessibility. Effectively utilizing a highly reactive precursor as a reactive linchpin could provide a practical and flexible pathway to access this valuable scaffold and facilitate its diversification. Here, we demonstrate that the fermentation-accessible precursor hydroxyophioisocoumarin (HOI) serves as a uniquely reactive linchpin. We developed a novel click-like ortho-quinone methide platform that utilizes reactive HOI and various nucleophiles, allowing for a wide substrate scope in the synthesis of a series of multifunctional 3-methylene isocoumarins under mild and convenient conditions. The synthesized compounds exhibited notable biological activity, providing new chemical space for research in related fields.