Development of an Enzymatic Process for the Synthesis of the Key Intermediate of Telotristat Ethyl

Abstract ( R )‐1‐(4‐chloro‐2‐(3‐methyl‐1H‐pyrazol‐1‐yl)phenyl)‐2,2,2‐trifluoroethan‐1‐ol [( R )‐ 2 ] is a key chiral intermediate in the synthesis of telotristat ethyl, an anti‐carcinoid syndrome drug. However, the synthetic methods for ( R )‐ 2 mainly include chemical reductions, rarely involving biocatalysis or bioreduction until now. Here, we report a method for obtaining ( R )‐ 2 by biocatalytic reduction of corresponding prochiral acetophenone ( 1 ) with bulky o ‐substitution using recombinant Lactobacillus fermentum short‐chain dehydrogenase/reductase 1 ( Lf SDR1) as a biocatalyst. Further engineering of Lf SDR1 variants could access asymmetric reduction of 1 and yield ( R )‐ 2 with a >99% ee and a >99% conversion. In addition, through the test of different co‐solvents and a series of initial substrate concentrations, substrate 1 with the concentration of 60 g/L can be completely converted into ( R )‐ 2 on a preparative scale (1.13 g, 3.93 mmol, 75.6% isolated yield) in 24 hours. This study presents an efficient enzymatic process for the biocatalytic synthesis of key chiral intermediate ( R )‐ 2 in the synthesis of telotristat ethyl. magnified image