Biocatalytic formal regio- and enantioselective Markovnikov hydroamination of aryl alkenes to chiral amines?

Green Chemistry Pub Date: 2023-06-01 DOI: 10.1039/D3GC01030A

Abstract

Enantiomerically pure amines are crucial intermediates for a wide range of pharmaceuticals, natural products, and bioactive compounds. Asymmetric intermolecular hydroamination of alkenes is one of the most atom-economical methods for the synthesis of chiral amines. However, the direct stereoselective hydroamination of alkenes remains a significant challenge. Herein, we developed a novel fully biocatalytic system to enable the direct stereoselective hydroamination of aryl alkenes to produce chiral amines. The process involves sequential alkene asymmetric hydration catalyzed by a hydratase (HD), followed by in situ oxidation of alcohol into ketone by two enantiocomplementary alcohol dehydrogenases (ADHs), and finally, enantioselective transformation of ketone into enantiomerically pure amine by a ω-transaminase (TA). The addition of lactate dehydrogenase (LDH) facilitated the connection between alcohol oxidation and pyruvate reduction, making the cascade reaction redox self-sufficient and driving the process towards the desired target product. In vitro cascade biocatalysis for asymmetric hydroamination of 4-hydroxystyrenes 1a–f was first investigated by using the combined enzymes (HD/ADHs/LDH/TA) with trace amounts of NAD+ (0.05 mM) and pyridoxal-5′-phosphate (PLP) (0.1 mM), affording both enantiomers of amines 4a–f in 30–90% conversions and >99% ee. Furthermore, whole-cell-based cascade biocatalysis was achieved by using the constructed recombinant Escherichia coli cells co-expressing the five enzymes without additional NAD+ cofactor; (R)- and (S)-amines 4a–f could be obtained in 35–93% conversions and >99% ee. Finally, the preparative experiments were demonstrated by using the whole-cell biocatalyst E. coli (RFM-ERR-CB) and E. coli (RFC-ERR-CB) with substrate 1a, affording (S)-4a and (R)-4a in 54.8% and 59.2% yields and >99% ee. This research achievement provides a highly selective, highly atom-economical, green and sustainable method for synthesizing chiral amines from alkenes via formal alkene asymmetric hydroamination.

Graphical abstract: Biocatalytic formal regio- and enantioselective Markovnikov hydroamination of aryl alkenes to chiral amines
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