Discovery and bioinspired total syntheses of unprecedented sesquiterpenoid dimers unveiled bifurcating [4 + 2] cycloaddition and target differentiation of enantiomers

[4 + 2] cycloaddition has led to diverse polycyclic chiral architectures, serving as novel sources for organic synthesis and biological exploration. Here, an unprecedented class of cadinane sesquiterpene [4 + 2] dimers, henryinins A-E ( 1-5 ), with a unique 6/6/6/6/6-fused pentacyclic system, were isolated from Schisandra henryi . The divergent total syntheses of compounds 1-5 and their enantiomers ( 6-10 ) were concisely accomplished in eight linear steps using a protection-free approach. Mechanistic studies illustrated the origin of selectivity in the key [4 + 2] cycloaddition as well as the inhibition of reaction pathway bifurcation via desymmetrization. The chemical proteomics results showed that a pair of enantiomers shared common targets (PRDX5 C100 and BLMH C73) and had unique targets (USP45 C588 for 4 and COG7 C419 for 9 ). This work provides experimental evidence for the discovery of unprecedented cadinane dimers from selective Diels-Alder reaction and a powerful strategy to explore the biological properties of natural products. The [4 + 2] cycloaddition has led to diverse polycyclic chiral architectures, serving as novel sources for organic synthesis and biological exploration.