Total Synthesis of Isoxeniolide A**

Abstract

Isoxeniolide A is a 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.