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Study of the Total Synthesis of (−)-Exiguolide

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journal contribution
posted on 2012-08-17, 00:00 authored by Cyril Cook, Frédéric Liron, Xavier Guinchard, Emmanuel Roulland
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.

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