Total Synthesis of Isoxeniolide A

Isoxeniolide A is highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the 9-membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Here, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E-configured cyclononene ring was a diastereoselective intramolecular Nozaki-Hiyama-Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and of analogs for structure-activity relationship studies.