Vicinal Bis(methylene) Heterocyclic Diene in Natural Product Synthesis: A Convergent Biomimetic Total Synthesis of Prunolactone A.

The first total syntheses of the natural isocoumarin prunolactone A with a 6/6/6/6/6 spiropentacyclic skeleton and its unnatural (3')-epimer in 10 and 8 steps, respectively, are reported. The syntheses feature generation of a reactive 3,4-bis(methylene)isocoumarin intermediate, its biomimetic Diels-Alder reactions with the shikimic-acid-derived scytolide and (8)-scytolide, and a Mitsunobu reaction allowing access to scytolide in a stereochemically pure form. Computational support for the selectivity of the Diels-Alder reaction is provided.