Metalloenzyme‐Catalyzed Asymmetric Transfer Hydrogenation for the Synthesis of Chiral Amines

A metalloenzyme-catalyzed asymmetric transfer hydrogenation platform has been developed for the stereoselective synthesis of chiral amines. In contrast to natural NAD(P)H-dependent C═N bond reductases, this strategy employs carbonic anhydrase or P450 as a catalyst in combination with a silane-reducing agent, offering a fully orthogonal alternative to conventional NAD(P)H-dependent cellular processes.

Abstract

Chiral amines are prevalent in natural products, pharmaceuticals, and organic catalysts. Their increasing demand has driven the advancement of synthetic methods. In this study, we developed a metalloenzyme-catalyzed asymmetric transfer hydrogenation method for the synthesis of chiral amines. Given the challenges of traditional chemical synthesis, which relies on precious metals and complex synthetic ligands, our approach utilizes base metals derived from natural metalloenzymes for transfer hydrogenation and employs protein scaffolds to achieve stereochemical control. Furthermore, in contrast to natural NAD(P)H-dependent C═N bond reductases, this strategy utilizes silanes as reducing agents and is entirely orthogonal to conventional NAD(P)H-dependent cellular functions. This reactivity highlights the potential to develop new-to-nature enzymatic functions capable of addressing challenges in both organic synthesis and biosynthesis.

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