Abstract
Density functional theory (B3LYP-D3(BJ) and ωB97XD) calculations have been used to assess the stereochemical outcomes of the proposed transannular [4 + 2] cycloaddition pathway for the biosynthesis of mandapamate and isomandapamate from macrocyclic intermediates. Calculations reveal that the topological shift between macrocyclic conformers is vital in controlling the stereoselectivity of the downstream steps toward the isomeric mandapamates. A stepwise 4 + 2 type process is energetically favored over a concerted [4 + 2] pathway at room temperature, and is consistent with the stereochemistries found in the natural products.