Efficient enzymatic synthesis of (S)-1-(3′-bromo-2′-methoxyphenyl)ethanol, the key building block of lusutrombopag

( S )-1-(3′-Bromo-2′-methoxyphenyl)ethanol (( S )- 1b ) is the key precursor for the synthesis of Lusutrombopag. The bioreduction of 1-(3′-bromo-2′-methoxyphenyl)ethanone ( 1a ) offers an attractive method to access this important compound. Through screening the available carbonyl reductases, we obtained a carbonyl reductase from Novosphingobium aromaticivorans (CBR), which could completely convert 100 ​g/L of 1a to ( S )- 1b . Furthermore, a carbonyl reductase from Novosphingobium sp. Leaf2 (NoCR) was identified to completely convert 200 ​g/L of 1a to ( S )- 1b with excellent enantioselectivity (>99% ee ) and 77% isolated yield using FDH/formate system for NADH regeneration. The K m and k cat of recombinant NoCR towards 1a were 0.66 ​mmol/L and 7.5 s -1 , and the catalytic efficiency k cat /K m was 11.3 ​mmol/s . L. Meanwhile, NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring, indicating that NoCR is a valuable biocatalyst with potential practical applications. A carbonyl reductase from Novosphingobium sp. Leaf2 (NoCR) was identified to completely convert 200 ​g/L of 1-(3′-bromo-2′-methoxyphenyl)-ethanone ( 1a ) to ( S )-1-(3′-bromo-2′-methyloxyphenyl)ethaneol (( S )- 1b ), the key precursor for the synthesis of Lusutrombopag, with excellent enantioselectivity (>99% ee ) using FDH/formate system for NADH regeneration.