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 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.

Enantioselective remote C–H activation directed by a chiral cation

“…In both cases the chiral information is covalently incorporated into the ligand scaffold in the conventional manner and a directing group guides borylation to the ortho position. In contrast, the creation of chirality over long ranges, where the enantiotopic site is far from the new stereocenter, is an outstanding challenge in which catalyst designs that incorporate non-covalent interactions 30 offer unique opportunities (36)(37)(38). We have recently developed anionic bipyridine ligands that bear a remote sulfonate group in order to impart control of regioselectivity in iridium-catalyzed C-H borylation via non-covalent interactions with the substrate (39)(40)(41).…”

Catalytic Enantioselective Synthesis of Pyridyl Sulfoximines

“…Our exploration of this intriguing reaction began with the evaluation of aspartic acid-containing catalysts for the oxidation of NH-unsubstituted substrate 1a using the conditions proved to be successful in the desymmetrization of chiral pyridine derivatives. , Excitingly, with the employment of P1 , previously identified as an excellent catalyst in our prior studies, the reaction proceeded smoothly; however, poor enantioselectivity was obtained (59:41 er; Table , entry 1). Our initial attempts at optimization, modifying the i +1, i +2 and i +3 positions of the peptide, gave similar or worse results (Table , entries 2–7).…”

“…In the successful asymmetric oxidation of loratadine and varenicline derivatives, a urea-directing group played a critical role in the enantiocontrol (Figure c). , With this inspiration, urea-protected substrate 1b was synthesized through the reaction of 1a with 3,5-bis­(trifluoromethyl)­phenyl isocyanate (Table ). Indeed, with 1b , the enantiomeric ratio increased to 69:31 er (Table , entry 1).…”

“…Therefore, the construction of enantioenriched pyridine derivatives has gained increased attention in the past year. , We recently reported that bis­(pyridine)­s connected to a prochiral carbon center could undergo desymmetrization through selective mono-oxidation using an aspartic acid (Asp)-peptide catalyst with excellent enantiocontrol (up to 99:1 er) . This strategy was also successfully applied to the asymmetric synthesis of helically chiral analogs of loratadine, the active ingredient of Claritin (Scheme c). , Given this result, we were curious about the performance of prochiral bis­(pyridyl)- S -centered substrates with our versatile Asp-peptide catalysts. − We decided to explore the catalytic asymmetric synthesis of sulfoximines due to the lack of successful examples in this field. − 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) . Furthermore, the electron-withdrawing sulfoximine substituent could reduce the nucleophilicity of the pyridine nitrogen, resulting in lower reactivity.…”

Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls

“…Challengingly, the new arena of alkyl aldehydes, especially α-branched alkyl aldehydes, as aldol donors is expected to be explored with catalytic peptides. β-Turn tetrapeptides constitute a range of successful artificial enzymes in organic transformations . X-ray analysis of a novel β-turn tetrapeptide, designed and synthesized by us based on our previous work, shows that the catalytic terminal NH 2 and COOH groups both locate on the same side of the turn plane (Figure ).…”