Toward the 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 a transannular Michael addition of a 1,3‐keto‐ester and enal‐containing bicyclo[4.4.1]undec‐3‐ene obtained from the ring expansion of a chiral γ,γ−disubstituted cyclohexanone and stereoselective Hosomi‐Sakurai reaction. Serendipity allowed us to uncover powerful divergent and unexpected cyclizations of this bicycle in ionic or oxidative conditions, giving access to complex tricyclic architectures such as tricyclo[5.2.1.1 2,5 ]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 us to note a discrepancy between the reported structure of pestalustaine A and the 2D NMR data, which led us to propose a revised structure of the natural product to a caryophyllene‐type framework, a reassignment supported by computational prediction of NMR chemical shifts.