Traversing the Regioselectivity of Intermolecular Pericyclic Aryne Reactions: Total Syntheses of Laetevirenol A and Isoampelopsin D

Abstract Resveratrol-derived natural products feature a diverse group of stilbenoids, characterized by extensive structural variation and pharmacological potential. Herein, we document our innovation in the synthesis of laetevirenol A, a biologically captivating resveratrol dimer, and isoampelopsin D enabled by operating an aryne-based synthetic program. The synthetic strategy involves the incorporation of aryne building blocks into methylene indane/indene nuclei by harnessing their innate reactivity. A dehydro Diels–Alder cycloaddition and an aryne-ene reaction were developed to construct the carbon framework of laetevirenol A and isoampelopsin D. Attempts were made to rationalize the unexpected regioselectivity behavior of crucial benzyne reactions from both empirical and computational perspectives. Ultimately, laetevirenol A and its analogs were also biologically investigated to uncover their potential antioxidant activities. This work offers valuable insights into the regioselectivity of intermolecular pericyclic aryne reactions and serves as an example of controlling aryne regioselectivities in the synthesis of molecular targets.