Development of Photo-Biocatalytic Redox System for Asymmetric Synthesis of Optically Active Amines Using Blue Light and Transaminases. A Case Study Toward Mavacamten

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 O2-saturated dimethyl sulfoxide (DMSO) as the reaction medium and a quencher of the in situ generated hydrogen peroxide (H2O2). 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 (iPrNH2) 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(1H,3H)-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.