Theoretical Studies on Construction of Tricyclic Ketal Core of Bullataketals Through a Biomimetic Intermolecular (3+3) Type Cycloaddition

Abstract The tricyclic ketal scaffold, found in bioactive natural products such as bullataketals A / B , represents a synthetically challenging yet pharmacologically important structural motif. The detailed mechanism to construct the tricyclic ketal core and mechanistic basis for its regioselectivity are unresolved. Here, we employ density functional theory (DFT) calculations to elucidate the plausible reaction pathways and rationalize the observed product distribution. Potential energy surface (PES) analysis reveals the critical intermediates and transition states governing the cycloaddition, and evaluation of the competing transition states demonstrates the regioselectivity of the reaction. Our computational study validates the proposed biosynthetic hypothesis, offering valuable insights for the synthesis design of complex tricyclic ketal core‐containing natural products.