Asymmetric Synthesis of Sterically Hindered 1-Substituted Tetrahydro-β-carbolines Enabled by Imine Reductase: Enzyme Discovery, Protein Engineering, and Reaction Development

Yitong Li; Xiaoping Yue; Zhining Li; Zedu Huang; Fener Chen

doi:10.1021/acs.orglett.3c00147

Asymmetric Synthesis of Sterically Hindered 1-Substituted Tetrahydro-β-carbolines Enabled by Imine Reductase: Enzyme Discovery, Protein Engineering, and Reaction Development

Org Lett. 2023 Mar 3;25(8):1285-1289. doi: 10.1021/acs.orglett.3c00147. Epub 2023 Feb 19.

Authors

Yitong Li¹, Xiaoping Yue¹, Zhining Li², Zedu Huang², Fener Chen^{1

2}

Affiliations

¹ Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, P.R. China.
² Department of Chemistry, Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai Engineering Research Center of Industrial Asymmetric Cataly sis of Chiral Drugs, 220 Handan Road, Shanghai 200433, P.R. China.

PMID: 36802632
DOI: 10.1021/acs.orglett.3c00147

Abstract

We report the discovery of a new imine reductase (IRED), named AtIRED, by genome mining. Site-saturation mutagenesis on AtIRED generated two single mutants M118'L and P120'G and the double mutant M118'L/P120'G with improved specific activity toward sterically hindered 1-substituted dihydro-β-carbolines. The synthetic potential of these engineered IREDs was showcased by the preparative-scale synthesis of nine chiral 1-substituted tetrahydro-β-carbolines (THβCs), including (S)-1-t-butyl-THβC and (S)-1-t-pentyl-THβC, in 30-87% isolated yields with excellent optical purities (98-99% ee).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbolines
Imines* / metabolism
Oxidoreductases* / genetics
Oxidoreductases* / metabolism
Protein Engineering

Substances

Oxidoreductases
tryptoline
Imines
Carbolines