Intramolecular Diels–Alder Approaches to the Decalin Core of Verongidolide: The Origin of the <i>exo</i>-Selectivity, a DFT Analysis

Abstract

Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, Verongidolae. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the 1H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a cis-decalin core and we hypothesize that the relative configuration of the cis-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels–Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels–Alder reactions was exo and an in-depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity.