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

Density functional theory (M06-2X and ωB97X-D) calculations show that the most likely biosynthesis pathway to the complex ring-fused system in the coral metabolite rameswaralide proceeds by way of a [4 + 3] transannular cyclization pathway from a macrocycle polyene intermediate as the key step. Alternative pathways implicating a [4 + 2] transannular cyclization sequence and a late-stage α-ketol rearrangement step were found to be untenable. The polyene macrocyclic intermediate is derived from a furanocembranoid precursor following initial oxidation and dearomatization of the furan ring in the latter. Proton-assisted ring opening of the resulting enol ether cyclic hemiketal next leads to an enedione intermediate, which undergoes Z/E 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.