Humilisin E: Strategy for Synthesis and Access to the Functionalized Bicyclic Core

Humilisin E is a diterpenoid possessing a rare epoxidized cyclononene trans-fused with the bicycle[3.2.0]heptane core. Here, we identify a potential biosynthetic precursor, the (P) atropisomer of the corresponding diene, and report two different strategies for the stereocontrolled synthesis of the appropriately functionalized bicyclic core of humilisin E. The first route involves a Stork epoxynitrile cyclization via the corresponding Mg alkoxide, and the second, more stereoselective approach utilizes the Wolff rearrangement as the key step.