Stereocomplementary Synthesis of β‐Aryl Propanamines by Enzymatic Dynamic Kinetic Resolution‐Reductive Amination

Abstract

Chiral β-aryl propanamine is an important structure unit of bioactive molecules or drugs. But its efficient synthesis remains a challenging task. In this study, several enantiocomplementary imine reductases capable of dynamic kinetic resolution-reductive amination of sixteen 2-phenylpropanal derivatives of diverse structural characteristics with four different amines were identified through screening 196 imine reductases. Further-more, (S)-IR60, (R)-IR74 and (R)-IR207 were applied to access a series of different β-aryl propanamines with excellent ee values (90 to 99 %) and high isolated yields (36 to 79 %), and two of them were further transformed into 3-methylindolines through intramolecular Buchwald-Hartwig cross-coupling and deallylation, providing an effective method to construct this class of pharmaceutically important compounds.

Application of Imine Reductase in Bioactive Chiral Amine Synthesis

“…In 2023, Zhu's group used IRED-catalyzed DKR of 2phenylpropionaldehyde derivatives to obtain a series of (R)and (S)-β-arylpropylamines with excellent conversion and enantioselectivity (90% to 99% ee). 93 This strategy provides an effective method for constructing such drug-active compounds. For example, this type of IRED catalyzes the highly stereoselective construction of 3-methylindoline, 94 a key intermediate for the treatment of phosphatase and spondylin homologo-deficient cancers; or another key intermediate of Akt/PBK phosphorylation inhibitors, a phase II clinical trial drug for the treatment of phosphatase and spondylin homologo-deficient cancers (Scheme 25a).…”

“…In 2023, Zhu’s group used IRED-catalyzed DKR of 2-phenylpropionaldehyde derivatives to obtain a series of ( R )- and ( S )-β-arylpropylamines with excellent conversion and enantioselectivity (90% to 99% ee) . This strategy provides an effective method for constructing such drug-active compounds.…”

Engineered Imine Reductase for Asymmetric Synthesis of Dextromethorphan Key Intermediate

“…Imine reductases (IREDs) have been applied to catalyze reduction of various imines such as pyrrolines, piperidines, azepines, sulfur-containing cyclic imines, 3 H -indoles, tetrahydro-β-carbolines, and dihydroisoquinolines. − IREDs and reductive aminases also catalyze asymmetric reductive amination of carbonyl compounds to form the corresponding chiral α- or β-amines. − One-pot biocatalytic cascade of ene reductases and IREDs and a multifunctional biocatalyst EneIRED have been applied for the synthesis of chiral amines from α,β-unsaturated ketones, aldehydes, or imines; however, IREDs can only catalyze the reduction of imines or reductive amination of ketones and aldehydes instead of α,β-unsaturated compounds in most cases. − In 2019, we identified a group of highly hindrance-tolerant IREDs that could efficiently convert 1-benzyl-HHIQs derivatives into the corresponding 1-benzyl-OHIQs including ( S )- 2a in 98% ee values . However, the low specific activity (0.035 U/mg) and low substrate concentration (10 mM) limit its practical application.…”