Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones
The Journal of Organic Chemistry
American Chemical Society
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Grayson, M. (2017). Mechanism and Origins of Stereoselectivity in the Cinchona Thiourea- and Squaramide-Catalyzed Asymmetric Michael Addition of Nitroalkanes to Enones. The Journal of Organic Chemistry, 82 (8), 4396-4401. https://doi.org/10.1021/acs.joc.7b00521
We report density functional theory calculations that examine the mechanism and origins of stereoselectivity of Soós' landmark discovery from 2005 that cinchona thioureas catalyze the asymmetric Michael addition of nitroalkanes to enones. We show that the electrophile is activated by the catalyst's protonated amine and that the nucleophile binds to the thiourea moiety by hydrogen bonding. These results lead to the correction of published mechanistic work which did not consider this activation mode. We have also investigated the corresponding cinchona squaramide-catalyzed reaction and found that it proceeds by the same mechanism despite the differences in the geometry of the two catalysts' hydrogen-bond-donating groups, which demonstrates the generality of this mechanistic model.
M.N.G. thanks Girton College, Cambridge (Research Fellowship) for financial support. Part of this work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/), 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.
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External DOI: https://doi.org/10.1021/acs.joc.7b00521
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264650
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