Catalytic Enantioselective Pyridine N-Oxidation

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 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. <br><br>

Catalytic Enantioselective Synthesis of Pyridyl Sulfoximines

“…1−7 However, the long C−S bond would make it more difficult for the catalyst to differentiate the two pyridine rings, which makes the enantiocontrol a great challenge (C−S length: 1.759 Å vs C−C length: 1.520 Å; see Supporting Information, page 66). 10 drawing sulfoximine substituent could reduce the nucleophilicity of the pyridine nitrogen, resulting in lower reactivity. Moreover, the sulfoximine N atom might provide a competitive site for chemoselective oxidation.…”

“…8 Therefore, the construction of enantioenriched pyridine derivatives has gained increased attention in the past year. 9, 10 We recently reported that bis(pyridine)s connected to a prochiral carbon center could undergo desymmetrization through selective monooxidation using an aspartic acid (Asp)-peptide catalyst with excellent enantiocontrol (up to 99:1 er). 10 This strategy was also successfully applied to the asymmetric synthesis of helically chiral analogs of loratadine, the active ingredient of Claritin (Scheme 1c).…”

“…9, 10 We recently reported that bis(pyridine)s connected to a prochiral carbon center could undergo desymmetrization through selective monooxidation using an aspartic acid (Asp)-peptide catalyst with excellent enantiocontrol (up to 99:1 er). 10 This strategy was also successfully applied to the asymmetric synthesis of helically chiral analogs of loratadine, the active ingredient of Claritin (Scheme 1c). 10,11 Given this result, we were curious about the performance of prochiral bis(pyridyl)-S-centered substrates with our versatile Asp-peptide catalysts.…”

“…10 This strategy was also successfully applied to the asymmetric synthesis of helically chiral analogs of loratadine, the active ingredient of Claritin (Scheme 1c). 10,11 Given this result, we were curious about the performance of prochiral bis(pyridyl)-S-centered substrates with our versatile Asp-peptide catalysts. 10−12 We decided to explore the catalytic asymmetric synthesis of sulfoximines due to the lack of successful examples in this field.…”

Catalytic Kinetic Resolution and Desymmetrization of Amines

“…Besides the enantioselective remote desymmetrization of diarylmethylamines enabled by chiral TM catalysts, the Miller group disclosed the remote desymmetrization of bis(pyridine)methylamines via asymmetric organocatalyzed pyridine N-oxidation in 2019 (Scheme 58 ). 92 A series of methylamines bearing bis(3-pyridyl) moieties ( 172 ) were examined under the asymmetric N-oxidation reaction with H 2 O 2 enabled by an aspartic acid containing peptide catalyst cat-58 , which gave access to the chiral monopyridine- N -oxide products 173 with good to high enantioselectivities. It is worth mentioning that the bulky N -pivaloyl group is critical to the high enantioselectivities of these reactions ( 173e ).…”