Construction of Morphan Derivatives by Nitroso-Ene Cyclization: Mechanistic Insight and Total Synthesis of (±)-Kopsone.

A type II nitroso-ene cyclization was developed for the construction of morphan derivatives with good functional-group tolerance. DFT calculations revealed that the nitroso-ene reaction proceeds in a stepwise manner involving diradical or zwitterionic intermediates. The rate-determining step is C-N bond formation, followed 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.