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Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

preprint
submitted on 10.03.2020 and posted on 11.03.2020 by Cheng-Che Tsai, Christopher Sandford, Tao Wu, Buyun Chen, Matthew S. Sigman, F. Dean Toste
The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we identified that the presence of multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C−O bonds at fully-substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.

Funding

National Institutes of Health (R35 GM118190)

National Institutes of Health (GM121383)

Ministry of Science and Technology, Taiwan (106-2917-I-564-056)

Horizon 2020 Marie Skłodowska-Curie Fellowship (789399)

Extreme Science and Engineering Discovery Environment (XSEDE, supported by the NSF (ACI-1548562) and provided through allocation TG-CHE190060)

History

Email Address of Submitting Author

fdtoste@berkeley.edu

Institution

University of California, Berkeley

Country

United States

ORCID For Submitting Author

0000-0001-8018-2198

Declaration of Conflict of Interest

There are no conflicts of interest to declare

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