Building Morphan Derivatives by Nitroso-Ene Cyclization: Mechanistic Insights and Total Synthesis of (±)-Kopsone

A type II nitroso-ene cyclization was developed for the construction of morphan derivatives with a good functional group tolerance. DFT calculations revealed the nitroso-ene reaction is stepwise involving diradical or zwitterionic intermediates. The rate-determining step is the C-N bond formation, following by a rapid hydrogen transfer step with a chair-conformation transition state. The current approach was also successfully applied in the first total synthesis of (±)-kopsone, a highly strained yet simple morphan-type alkaloid isolated from Kopsia macrophylla.