Eugenol-based meroterpenoids with neural differentiation activity from Eugenia caryophyllata

Phytochemical investigation of Eugenia caryophyllata buds led to the discovery of nine previously undescribed eugenol-based meroterpenoids, named eugenianols A-I (1-9). Among them, compound 1 is the first reported meroterpenoid featuring a eugenol moiety fused with a sesquiterpenoid unit via two C-C bonds, forming an unprecedented tricyclo[9.4.0.0^4,7]pentadecane core skeleton. Compounds 2-5 represent a class of meroterpenoids with unprecedented architectures characterized by distinct C-C bond linkage patterns between the eugenol and sesquiterpenoid moieties. Notably, the unusual linkage of 4 resulted in a rare configurationally stable Csp²-Csp³ chiral axis combining both axial and point chirality. Compounds 6-9 constitute a class of undescribed ether bridged eugenol-based meroterpenoids. Their structures were elucidated through comprehensive spectroscopic techniques, single-crystal X-ray diffraction, and quantum-chemical calculations. A plausible biosynthetic pathway for these eugenol-based meroterpenoids was proposed. Furthermore, biological evaluations revealed that compound 7 significantly promoted neural differentiation-promoting activity, indicating potential neuroprotective properties.