Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using F-19 NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst substrate adduct has been observed, and its constitution elucidated unambiguously by C-13 and N-15 isotopic labeling. Isotopic entrainment has shown the observed catalyst-substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S center dot center dot center dot O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation-pi interactions over C-H center dot center dot center dot-pi is responsible for diastereoselectivity.