2025/04/10 by Natalia Antos, Aleksandra Rudzka, Anna A. Hoser +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · Chemistry · Engineering · #Enzyme Catalysis and Immobilization #Radical Photochemical Reactions #Innovative Microfluidic and Catalytic Techniques Innovation
paper · doi:10.1002/adsc.202500250
openalex publication_date 2025/04/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/06/23
Abstract α‐Chiral amines are versatile building blocks for the asymmetric synthesis of optically pure high‐added‐value chemicals, including pharmaceuticals, agrochemicals, and natural products. Herein, we report a one‐pot, two‐step sequential deracemization of racemic sec ‐alcohols to optically enriched primary amines throught a photo‐biocatalytic oxidation‐reductive amination linear cascade. In the first step, near‐to‐quantitative oxidation of a set of racemic (hetero)benzylic alcohols into prochiral ketones was accomplished using visible light photoredox catalysis relying on 440 nm blue LEDs irradiation, 9‐fluorenone as a transition‐metal‐free photocatalyst, and O 2 ‐saturated dimethyl sulfoxide (DMSO) as the reaction medium and a quencher of the in situ generated hydrogen peroxide (H 2 O 2 ). The intermediary ketones were further converted into the corresponding non‐racemic amines with up to 99% conversion, high‐to‐excellent optical purity (90–99.9% ee), and complementary absolute configuration via a stereoselective reductive amination catalyzed by lyophilized E. coli cells containing the respective ( R )‐ or ( S )‐selective recombinant transaminases ( E. coli /TAs) in an aqueous KPi buffer in the presence of pyridoxal‐5′‐phosphate (PLP) as cofactor and isopropylamine ( i PrNH 2 ) as an amino group donor. The developed photo‐biocatalytic system was scaled up for racemic 1‐phenylethanol (1.0 mmol), furnishing ( S )‐(−)‐1‐phenylethylamine with 91% conv., 82% isolated yield and 99% ee. An exemplary functionalization of the obtained ( S )‐α‐methylbenzylamine with 6‐chloro‐3‐isopropylpyrimidine‐2,4(1 H ,3 H )‐dione led to afford an enantiomerically enriched newly launched cardiac‐specific myosin inhibitor mavacamten in 76% yield and 99% ee. In addition, a single‐crystal X‐ray diffraction (XRD) analysis was performed, furnishing the first crystal structure for the titled API.