Cinchona Urea-Catalyzed Asymmetric Sulfa-Michael Reactions: The Brønsted Acid-Hydrogen Bonding Model.

Grayson, Matthew N 
Houk, KN 

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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.

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0306 Physical Chemistry (incl. Structural)
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J Am Chem Soc
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American Chemical Society (ACS)
We are grateful to The English-Speaking Union (Lindemann Trust Fellowship to M.N.G.), Girton College, Cambridge (Research Fellowship to M.N.G.) and the NSF (CHE- 1361104 to K.N.H.) for financial support. Computational resources were provided by the UCLA Institute for Digital Research and Education (IDRE) and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575). Part of this work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www., provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and funding from the Science and Technology Facilities Council.