Medium-Ring Effects on the Endo/Exo Selectivity of the Organocatalytic Intramolecular Diels–Alder Reaction

The intramolecular Diels–Alder reaction has been used as a powerful method to access the tricyclic core of the eunicellin natural products from a number of 9-membered-ring precursors. The endo/exo selectivity of this reaction can be controlled through a remarkable organocatalytic approach, employing MacMillan’s imidazolidinone catalysts, although the mechanistic origin of this selectivity remains unclear. We present a combined experimental and density functional theory investigation, providing insight into the effects of medium-ring constraints on the organocatalyzed intramolecular Diels–Alder reaction to form the isobenzofuran core of the eunicellins.