Total Synthesis of (-)-Illisimonin A Enabled by Pattern Recognition and Olefin Transposition.

We report an asymmetric total synthesis of (-)-illisimonin A, a sesquiterpene natural product with neurotrophic activity. Illisimonin A possesses a unique cage-like 5/5/5/5/5 pentacyclic scaffold containing a -pentalene and a norbornane, two highly strained and challenging structural motifs. It also contains seven contiguous fully substituted stereocenters, including three all-carbon quaternary centers, two of which are adjacent. Our synthesis exploits a pattern recognition strategy to identify a 5,6-fused bicyclic intermediate derived from ()-carvone in two steps as the starting point and leverages five sequential olefin transposition reactions to decorate the bicyclic carbocycle. Other key steps include a tandem Mukaiyama hydration-translactonization to form the γ-butyrolactone and an intramolecular aldol cyclization to close the cage and finally deliver (-)-illisimonin A in 16 steps.