Bioinspired Total Synthesis of Myltayloriones A‐B and Mylnudones A–D

ABSTRACT Herein, we report the first asymmetric synthesis of the dimeric sesquiterpenoid myltayloriones A and B. The synthesis features a stereodivergent Echavarren Au‐catalyzed reaction that enables the synthesis of two subunits from a common dienyne precursor, followed by an endo ‐Diels–Alder heterodimerization. Additional key transformations include a ligand‐controlled Pd‐catalyzed reductive hydrogenolysis for C1 isomerization, and a metal‐catalyzed hydrogen atom transfer (MHAT)‐initiated Baran–Giese cyclization to forge a highly congested penta‐substituted cyclopropane. The selectivity of Pd‐catalyzed hydrogenolysis originates from two different oxidative addition pathways, as further elucidated by density functional theory (DFT) calculations. This synthetic work has enabled further investigation of the potent growth differentiation factor 15 (GDF15) inhibitory and insect antifeedant activity exhibited by myltaylorione A. Furthermore, the developed strategy enabled the concise synthesis of mylnudones A–D and revised the structures of mylnudones A and B.