American Chemical Society
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Cinchona Urea-Catalyzed Asymmetric Sulfa-Michael Reactions: The Brønsted Acid−Hydrogen Bonding Model

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journal contribution
posted on 2016-07-09, 00:00 authored by Matthew N. Grayson, K. N. Houk
The cinchona alkaloid-derived urea-catalyzed asymmetric conjugate addition of aromatic thiols to cycloalkenones was studied using density functional theory (DFT). Deprotonation of the thiol gives a protonated amine that activates the electrophile by Brønsted acid catalysis, while the urea group binds the nucleophilic thiolate by hydrogen bonding. These results demonstrate the generality of the Brønsted acid−hydrogen bonding transition state (TS) model for cinchona alkaloid catalysis that we recently showed to be favored over Wynberg’s widely accepted ion pair−hydrogen bonding model and represent the first detailed mechanistic study of a cinchona urea-catalyzed reaction. The conformation of the catalyst methoxy group has a strong effect on the TS, an effect overlooked in previous mechanistic studies of reactions catalyzed by cinchona alkaloids.