Proposed Biosynthesis of the Complex Ring-Fused Diterpene Rameswaralide. Mechanistic Insights Using Density Functional Theory

isomerization and enolization to the key polyene macrocycle, then leading to rameswaralide via a 4 + 3 cycloaddition. Alternatively, protonation on the oxygen center of the enol ether cyclic hemiketal intermediate is shown to facilitate its ring opening, and the following topological shift between the conformers of the key macrocyclic polyene intermediate is a critical step in the overall sequence leading to the thermodynamically favored isomer of rameswaralide.