In the Pursuit of the Total Synthesis of Pestalustaine A: Structural Revision and Formation of Original Strained Tricyclic Architectures

We report our quest toward the total synthesis of the reported structure of the sesquiterpene pestalustaine A and its unprecedented tricyclic skeleton. Our retrosynthesis involved an transannular Michael addition of a 1,3-keto-ester and enal-containing bridged-7,7-bicycle obtained from the ring expansion of a chiral disubstituted cyclohexanone and stereoselective Hosomi-Sakurai reaction. Serendipity, allowed us to uncover powerful divergent and unexpexpected cyclizations of this bicycle in ionic or oxidative conditions giving access to complex tricyclic architectures such as tricyclo[5.2.1.12,5]undecane, octahydro-1,5-methanonaphthalene, octahydro-12,6-methanonaphthalene frameworks and the octahydro-1,5-methanoazulene reported skeleton of pestalustaine A. The present synthetic study also led to note a discrepancy between the reported structure of pestalustaine A and the 2D NMR data which led to propose a revised structure of the natural product to a caryophyllene-type framework.