Total Synthesis of (+)-Melonine and (+)-N₄-Oxy Melonine Enabled by an Intramolecular Alkene Diamination Reaction

Among more than four thousand monoterpene indole alkaloids (MIAs) isolated to date, only a few feature a 2,2,3-trisubstituted indoline moiety. (+)-Melonine and (+)-N₄-oxy melonine possess a highly rearranged carbon framework, presumably arising from cyclization of a rearranged iminium ion of quebrachamine precursor. We report herein the first enantioselective total synthesis of (+)-melonine and (+)-N₄-oxy melonine featuring: a) a highly enantioselective CBS reduction followed by a stereospecific Johnson-Claisen rearrangement for the synthesis of enantioenriched β-substituted γ,δ-unsaturated ester; b) Bower's bis-cyclizative diamination of alkene, enabling the conversion of a functionalized cycloheptene to the tetracyclic core of the natural products; and c) an AlMe₃-mediated lactamization that concurrently achieves desymmetrization at the C20 prochiral center.