Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric Reduction: Design, Synthesis, Scope, and Mechanistic Studies

Abstract

The coenzyme NAD(P)H plays an important role in electron as well as proton transmission in the cell. Thus, a variety of NAD(P)H models have been involved in biomimetic reduction, such as stoichiometric Hantzsch esters and achiral regenerable dihydrophenantheridine. However, the development of a general and new-generation biomimetic asymmetric reduction is still a long-term challenge. Herein, a series of chiral and regenerable NAD(P)H models with central, axial, and planar chiralities have been designed and applied in biomimetic asymmetric reduction using hydrogen gas as a terminal reductant. Combining chiral NAD(P)H models with achiral transfer catalysts such as Brønsted acids and Lewis acids, the substrate scope could be also expanded to imines, heteroaromatics, and electron-deficient tetrasubstituted alkenes with up to 99% yield and 99% enantiomeric excess (ee). The mechanism of chiral regenerable NAD(P)H models was investigated as well. Isotope-labeling reactions indicated that chiral NAD(P)H models were regenerated by the ruthenium complex under hydrogen gas first, and then the hydride of NAD(P)H models was transferred to unsaturated bonds in the presence of transfer catalysts. In addition, density functional theory calculations were also carried out to give further insight into the transition states for the corresponding transfer catalysts.

Synthesis and Applications of Ferrocene‐Fused Nitrogen Heterocycles

“…This strategy was suitable for the reduction of a number of electrondeficient tetrasubstituted alkenes, challenging substrates in asymmetric hydrogenation, with excellent yields and levels of enantioselectivity (Scheme 14). [38,39] This methodology proved also highly efficient for the asymmetric reduction of hetero-cyclic compounds featuring iminic substructures such as benzoxazinones, quinoxalinones and quinazolinones. [38][39][40][41] The mechanism of these biomimetic reductions has been elucidated by a combination of experimental and theoretical studies.…”

“…[38,39] This methodology proved also highly efficient for the asymmetric reduction of hetero-cyclic compounds featuring iminic substructures such as benzoxazinones, quinoxalinones and quinazolinones. [38][39][40][41] The mechanism of these biomimetic reductions has been elucidated by a combination of experimental and theoretical studies.…”

Enantioselective Synthesis of Tetrahydroquinolines viaOne‐Pot Cascade Biomimetic Reduction†

“…Recently, biomimetic asymmetric hydrogenation of imines and heteroaromatics with catalytic amount of NAD(P)H models such Scheme 1 Catalytic enantioselective synthesis of tetrahydroquinolines as phenanthridine (PD) has been successfully reported. [12,13] Hence, we envisaged chiral tetrahydroquinolines could be obtained by one-pot cascade reaction from readily available 2-aminochalcones using the PD instead of HEH in the catalytic amount (Scheme 1). It was noted that there might be many challenges in this reaction.…”

Biomimetic Asymmetric Reduction of Quinazolinones with Chiral and Regenerable NAD(P)H Models

“…[14] Recently, our group reported the synthesis of chiral and regenerable NAD(P)H models based on the planar-chiral ferrocene and their application in biomimetic asymmetric reduction of tetrasubstituted olefins and imines. [15] Inspired by this work, we envisaged that biomimetic asymmetric reduction of quinazolinones with regenerable and chiral NAD(P)H models would be another straightforward approach for synthesis of chiral dihydroquinazolinones. Herein, we present biomimetic asymmetric reduction of quinazolinones, giving the chiral products with high yields and up to 98% ee.…”