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Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling
Author(s) -
Tsai ChengChe,
Sandford Christopher,
Wu Tao,
Chen Buyun,
Sigman Matthew S.,
Toste F. Dean
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202006237
Subject(s) - enantioselective synthesis , allylic rearrangement , chemistry , nucleophile , intramolecular force , palladium , asymmetric induction , chirality (physics) , phosphoric acid , nucleophilic substitution , asymmetric carbon , combinatorial chemistry , stereochemistry , catalysis , medicinal chemistry , organic chemistry , chiral anomaly , nambu–jona lasinio model , physics , fermion , quantum mechanics , optically active
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 nucleophilic attack to the π‐allylpalladium intermediate is the enantio‐determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that 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.