An 8-Step Approach for the Total Synthesis of (-)-Pleocarpanone

Pleocarpanone is a natural norsesquiterpene with a guaiane carbon skeleton. This class of natural products present diverse biological activities and have attracted the interest of many synthetic chemists. The isolation of this natural product from the plant Pleocarphus revolutus was first reported in 1977 by Sammes and co-workers.1 The stereochemistry was confirmed after its first total synthesis in 2007 by Snapper and coworkers, 2 however, their synthesis required 18 steps from an expensive starting material (Scheme 1A). Our group has been interested in the pursuit of concise and efficient approaches toward the synthesis of natural products, as privileged scaffolds, which could be applied in our medicinal chemistry program. Since pleocarpanone has no biological activity reported so far, and only one synthesis has been reported, we designed an 8-step approach from the cheap monoterpene (-)-perillyl alcohol, in order to obtain reasonable quantities of pleocarpanone, enabling its biological evaluation (Scheme 18). Our synthesis started with the conversion of alcohol 1 into phosphonate 2, taking advantage of its allylic position (Scheme 1 C). Next, the more electron-rich alkene was selectively cleaved during an ozonolysis, following an intramolecular Horner-Wadsworth-Emmons olefination. After that, an al lyl group was installed in two steps: a-iodination of enone 3, and a Stille cross-coupling with allyltributylstannane. The remaining carbons were attached via copper-catalyzed 1,4-addition, which provided a mixture of four possible isomers. The second ring was forged by a ring-closing metathesis reaction of the isomeric mixture, and the synthesis was finished after a Mukaiyama hydration. Despite this initial success reported herein, this synthesis is currently under optimization, especially concerning the selectivity in the conjugate addition.