Abstract
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.
Highlights
We have investigated an asymmetric conjugate addition reaction catalyzed by a cinchona alkaloid-derived urea reported by Singh and co-workers in 2010 (Scheme 1).[2]
The only study of cinchona ureas is by Csaḿ pai and coworkers, who used density functional theory (DFT) to calculate ΔE⧧ for various cinchonaurea catalysts in the enantioselective Michael addition of nitromethane to 1,3-diphenylpropenone.[36]
Mode B was considered in their computational work, and transition states (TSs) leading to the minor product were not calculated
Summary
We have investigated an asymmetric conjugate addition reaction catalyzed by a cinchona alkaloid-derived urea (cinchona urea) reported by Singh and co-workers in 2010 (Scheme 1).[2]. We have investigated an asymmetric conjugate addition reaction catalyzed by a cinchona alkaloid-derived urea (cinchona urea) reported by Singh and co-workers in 2010 (Scheme 1).[2] They proposed that their reaction proceeded via a Wynberg ion pair−hydrogen bonding type mechanism (Mode A, Figure 1).
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