Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters

• DOI: 10.1021/jacs.3c07010
• Publication Date: 2023-10-02T19:57:50Z
• Authors: Arnau Rué Casamajo; Yuqi Yu; Christian Schnepel; Charlotte Morrill; Rhys Barker; Colin W. Levy; James Finnigan; Victor Spelling; Kristina Westerlund; Mark Petchey; Robert J. Sheppard; Richard J. Lewis; Francesco Falcioni; Martin A. Hayes; Nicholas J. Turner
• Keywords: Stereocenter; Biocatalysis; Diastereomer

Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling construction of structure-activity-property-toxicology relationships. Complex chiral molecules containing multiple stereocenters an important component compound library expansion but can be difficult to access traditional organic synthesis. Herein, we report a biocatalytic process specific diastereomer amine block used drug discovery. A reductive aminase (RedAm) was engineered following structure-guided mutagenesis strategy produce desired isomer. The RedAm (IR-09 W204R) able generate (S,S,S)-isomer 3 45% conversion and 95% ee from racemic ketone 2. Subsequent palladium-catalyzed deallylation yielded target primary 4 73% yield. This biocatalyst at preparative scale represents potential starting point further engineering development.