Preparation of Highly Functionalized ortho-Naphthoquinone Methides and Their Subsequent Intermolecular [4 + 2]-Cycloadditions with Olefins.

Many natural products isolated from Rubiaceae plants, such as mollugin and rubioncolin B, contain 1-hydroxy-2-methoxycarbonylnaphthohydropyran skeletons. To access this framework, we developed a novel method for the preparation of highly functionalized ortho-naphthoquinone methides (o-NQMs) and subsequent intermolecular [4 + 2]-cycloaddition reactions with olefins. o-NQM precursors were prepared via Hauser-Kraus annulation of cyanophthalides with an α,β-unsaturated ester. Treatment of these precursors with a Lewis acid generated the corresponding o-NQMs, which underwent intermolecular [4 + 2]-cycloaddition with olefins to afford polycyclic compounds bearing the 1-hydroxy-2-methoxycarbonylnaphthohydropyran skeleton. This approach provides efficient access to the frameworks found in natural products and facilitates structural derivatization. The present methodology was further applied to synthetic studies toward rubioncolin B.