Discovery and bioinspired total syntheses of unprecedented sesquiterpenoid dimers unveiled bifurcating [4 + 2] cycloaddition and target differentiation of enantiomers†
Abstract
[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.
![Graphical abstract: Discovery and bioinspired total syntheses of unprecedented sesquiterpenoid dimers unveiled bifurcating [4 + 2] cycloaddition and target differentiation of enantiomers](/en/Image/Get?imageInfo.ImageType=GA&imageInfo.ImageIdentifier.ManuscriptID=D3SC05233H&imageInfo.ImageIdentifier.Year=2024)
- This article is part of the themed collection: 2024 Chemical Science Covers
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