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

Casamajo, Arnau Rué; Yu, Yuqi; Schnepel, Christian; Morrill, Charlotte; Barker, Rhys; Levy, Colin W.; Finnigan, James; Spelling, Victor; Westerlund, Kristina; Petchey, Mark; Sheppard, Robert J.; Lewis, Richard J.; Falcioni, Francesco; Hayes, Martin A.; Turner, Nicholas J.

Abstract

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

Citation

Casamajo, A. R., Yu, Y., Schnepel, C., Morrill, C., Barker, R., Levy, C. W., Finnigan, J., Spelling, V., Westerlund, K., Petchey, M., Sheppard, R. J., Lewis, R. J., Falcioni, F., Hayes, M. A., & Turner, N. J. (2023). Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters. Journal of the American Chemical Society, 145(40), 22041-22046. https://doi.org/10.1021/jacs.3c07010

• Journal Article Type: Article
• Acceptance Date: Oct 2, 2023
• Online Publication Date: Oct 2, 2023
• Publication Date: Oct 11, 2023
• Deposit Date: Jan 1, 2025
• Journal: Journal of the American Chemical Society
• Print ISSN: 0002-7863
• Electronic ISSN: 1520-5126
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 145
• Issue: 40
• Pages: 22041-22046
• DOI: https://doi.org/10.1021/jacs.3c07010
• Public URL: https://durham-repository.worktribe.com/output/3263141