Theoretical Study\non\nthe Biosynthesis of the Mandapamates:\nMechanistic Insights Using Density Functional Theory

Density functional\ntheory (B3LYP-D3(BJ) and ωB97XD) calculations\nhave been used to assess the stereochemical outcomes of the proposed\ntransannular [4 + 2] cycloaddition pathway for the biosynthesis of\nmandapamate and isomandapamate from macrocyclic intermediates. Calculations\nreveal that the topological shift between macrocyclic conformers is\nvital in controlling the stereoselectivity of the downstream steps\ntoward the isomeric mandapamates. A stepwise 4 + 2 type process is\nenergetically favored over a concerted [4 + 2] pathway at room temperature,\nand is consistent with the stereochemistries found in the natural\nproducts.