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 substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents 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.
Hsieh S.-Y., Tang Y., Crotti S., Stone E.A., Miller S.J. (2019). Catalytic Enantioselective Pyridine N-Oxidation. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 141(46), 18624-18629 [10.1021/jacs.9b10414].
Catalytic Enantioselective Pyridine N-Oxidation
Crotti S.;
2019
Abstract
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 substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
