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, Fen‐Er Chen
Abstract
We report the discovery of a new imine reductase (IRED), named At IRED, by genome mining. Site-saturation mutagenesis on At IRED 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).
Topics & Concepts
Steric effectsImineChemistrySaturated mutagenesisMutagenesisProtein engineeringMutantStereochemistryEnzymeCombinatorial chemistryReductaseBiochemistryCatalysisGeneChemical Synthesis and AnalysisSynthesis and bioactivity of alkaloidsSynthesis and Biological Activity