An Intramolecular Nucleophile-Catalyzed Aldol-Lactonization (NCAL) Reaction of S-Aryl-(E)-6-oxohex-2-enethioate with N,N-4-Dimethylaminopyridine N-Oxide

Meng

et al. 2021

ACS Catal.

An efficient chiral 4-aryl-pyridine-N-oxide (ArPNO) nucleophilic organocatalyst was rationally designed, synthesized, and applied to the acylative dynamic kinetic resolution of azoles, aldehydes, and anhydride. The restriction of the pyridine's C-4 position, where the dialkylamino group should be always present when using chiral pyridine-N-oxide as an acyl transfer catalyst, was overcome, thereby allowing structural diversity at this position. In the presence of 5 mol % 3,5-dimethylphenyl-derived ArPNO catalyst, the corresponding 2,5-disubstituted tetrazole hemiaminal esters were obtained in up to 93% yields, >20:1 rr, and 99% ee. Other N-heteroaromatics, including substituted pyrazole, imidazole, purine, benzimidazole, and benzotriazole, were also suitable substrates. Mechanistic studies by control experiments and density functional theory calculations indicated that an acyloxypyridinium cation was formed, and the nucleophilic substitution of azole hemiaminal with the acyloxypyridinium cation was the rate-determining step. Furthermore, the nucleophilic ability of oxygen in pyridine-N-oxide was higher than that of nitrogen in pyridine. This work provides an effective method for the utilization of the C-4 position of the pyridine ring, allowing the development of more varied chiral 4-substituted pyridine-N-oxides as efficient nucleophilic organocatalysts.

Section: Introductionmentioning

confidence: 99%

Chiral 4-Aryl-pyridine-N-oxide Nucleophilic Catalysts: Design, Synthesis, and Application in Acylative Dynamic Kinetic Resolution

Meng

et al. 2021

ACS Catal.

“…However, the nucleophilic sites in the aforementioned reported catalysts ( C1 – C8 ) were mainly focused on nitrogen or carbon atoms, and the application of oxygen atoms as the nucleophilic sites has not been applied to such reactions. Recently, chiral DMAP N -oxides, in which the oxygen atom acts as the nucleophilic site, were found to be efficient nucleophilic catalysts. − In 2017, Spivey and co-workers first developed an atropoisomeric DMAP N -oxide organocatalyst in N -sulfonylation for KR of 2-substituted indolines . Thereafter, our group reported l -prolinamide-derived PPY N -oxides as efficient acyl transfer catalysts .…”

Section: Introductionmentioning

confidence: 99%

Dynamic Kinetic Resolution of Carboxylic Esters Catalyzed by Chiral PPY N-Oxides: Synthesis of Nonsteroidal Anti-Inflammatory Drugs and Mechanistic Insights

Yin

et al. 2021

ACS Catal.

Bifunctional chiral 4-pyrrolidinopyridine (PPY) N-oxides catalyzing the dynamic kinetic resolution of racemic carboxylic esters was reported to construct chiral α-aryl α-alkyl carboxylic esters in up to 93% yield and 99% ee. Several esters of nonsteroidal anti-inflammatory drugs (NSAIDs), including (S)-ibuprofen ester, (S)-ketoprofen ester, (S)-fenaprofen ester, and (S)-flurbinprofen ester, were obtained. Additionally, the drug molecule (S)-naproxen could be achieved by hydrogenation of (S)-naproxen ester. The (S)-naproxen ester was prepared on a gram scale in 87% yield and 94% ee. The catalyst was recyclable and reusable. Mechanistic studies were conducted by control experiments, HRMS analysis, 1H NMR spectral detection, stereochemical experiments, racemization studies, competitive experiments, a linearity relationship determination, a kinetic order analysis, and a DFT computational study. The obtained results suggested that in PPY N-oxides the oxygen atom served as the nucleophilic site and N–H bond acted as the H-bond donor, resulting in a synergistic effect. In comparison with previous works using nitrogen or carbon as the nucleophilic sites, we found that chiral PPY N-oxides with oxygen as the nucleophilic site could also catalyze such reactions.

“…Therefore, the development of a chiral acyl transfer catalyst to achieve excellent enantioselectivities of alcoholysis products, using simple MeOH as the nucleophile, is desirable. Herein, we described the DKR of azlactones with MeOH as the nucleophile using chiral 2-substituted DMAP- N -oxides as the acyl transfer catalysts. − …”

Section: Introductionmentioning

confidence: 99%

Rational Design of 2-Substituted DMAP-N-oxides as Acyl Transfer Catalysts: Dynamic Kinetic Resolution of Azlactones

Huang

et al. 2020

J. Am. Chem. Soc.

A novel concept that conversion of chiral 2substituted DMAP into its DMAP-N-oxide could significantly enhance the catalytic activity and still be used as an acyl transfer catalyst is presented. A new type of chiral 2-substituted DMAP-Noxides, derived from L-prolinamides, has been rationally designed, facilely synthesized, and applied in the dynamic kinetic resolution of azlactones. Using simple MeOH as the nucleophile, various Lamino acid derivatives were produced in high yields (up to 98% yield) and enantioselectivities (up to 96% ee). Furthermore, αdeuterium labeled L-phenylalanine derivative was also obtained. Experiments and DFT calculations revealed that in 2-substituted DMAP-N-oxide, the oxygen atom acted as the nucleophilic site and the N−H bond functioned as the H-bond donor. High enantioselectivity of the reaction was governed by steric factors, and the addition of benzoic acid reduced the activation energy by participating in the construction of a H-bond bridge. The theoretical chemical study indicated that only when attack directions of the chiral catalyst were fully considered could the correct calculation results be obtained. This work paves the way for the utilization of the C2 position of the pyridine ring and the development of chiral 2-substituted DMAP-N-oxides as efficient acyl transfer catalysts.