Study of the Total Synthesis of (−)-Exiguolide

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (−)-exiguolide ((−)-1). Two first types of approaches were set, both relying on the Trost’s domino ene–yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14–C21 and C1–C13) by creating the C13–C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16–C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1–C5 and C6–C21 subunits through Trost’s domino ene–yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (−)-exiguolide.