Total Synthesis of Isoxeniolide A

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 nine-membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, 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 analogs for structure-activity relationship studies. The total synthesis of the xenicane-type marine natural product isoxeniolide A has been accomplished through a ring-opening/ring-closing metathesis sequence and an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction to forge the nine-membered ring as the key enabling steps. The NHK cyclization was highly diastereoselective and provided the oxabicyclo[7.4.0]tridecene core of isoxeniolide A as a single stereoisomer.**image