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Catalytic Enantioselective Pyridine N-Oxidation

preprint
submitted on 14.09.2019 and posted on 17.09.2019 by Sheng-Ying Hsieh, Yu Tang, Simone Crotti, Elizabeth Stone, Scott Miller
The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic acid containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro stereogenic center are demonstrated, presenting a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.

Funding

NIH R35 GM132092

History

Email Address of Submitting Author

scott.miller@yale.edu

Institution

Yale University

Country

USA

ORCID For Submitting Author

0000-0001-7817-1318

Declaration of Conflict of Interest

No conflict of interest

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in Journal of the American Chemical Society

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