A bio-inspired synthesis of xishacorenes A, B, and C, and a new congener, xishacorene D, from fuscol is reported. The xishacorenes are unique apolar diterpenoids derived from fuscol via an acid-mediated polyene cyclization. The synthesis of xishacorenes and xishacorene D was achieved through a series of reactions, including glycosylation and cyclization. The physical properties of the xishacorenes were re-evaluated, revealing discrepancies from previously reported values, likely due to solubility issues in methanol. Biological assays showed that fuscol and its derivative, xishacorene B, inhibit the IRF pathway, suggesting their hydrophilic nature contributes to their bioactivity. The study supports the proposed biosynthesis of xishacorenes from geranylgeranyl pyrophosphate (GGPP) and highlights the importance of hydrophilic substituents in their biological activity. The findings provide insights into the biosynthesis and bioactivity of these natural products. The authors also note potential conflicts of interest and acknowledge contributions from various institutions and individuals.A bio-inspired synthesis of xishacorenes A, B, and C, and a new congener, xishacorene D, from fuscol is reported. The xishacorenes are unique apolar diterpenoids derived from fuscol via an acid-mediated polyene cyclization. The synthesis of xishacorenes and xishacorene D was achieved through a series of reactions, including glycosylation and cyclization. The physical properties of the xishacorenes were re-evaluated, revealing discrepancies from previously reported values, likely due to solubility issues in methanol. Biological assays showed that fuscol and its derivative, xishacorene B, inhibit the IRF pathway, suggesting their hydrophilic nature contributes to their bioactivity. The study supports the proposed biosynthesis of xishacorenes from geranylgeranyl pyrophosphate (GGPP) and highlights the importance of hydrophilic substituents in their biological activity. The findings provide insights into the biosynthesis and bioactivity of these natural products. The authors also note potential conflicts of interest and acknowledge contributions from various institutions and individuals.