Enantio-Complementary Synthesis of Atropisomeric C–N Biaryl Amines via Imine Reductase-Mediated Dynamic Kinetic Resolution
Year: 2026
Type: preprint
Abstract: C–N axially chiral biaryl amines constitute privileged scaffolds in drug discovery and asymmetric catalysis, yet they remain synthetically challenging due to low rotational barriers and inherent conformational flexibility. While biocatalysis presents an attractive avenue for constructing chiral amines, the lack of mirror-image enzymes has historically limited access to all stereoisomers. Here, we develop an unconventional biocatalytic platform leveraging dynamic kinetic reductive amination to synthesize C–N axially chiral biaryl amines in both enantiomeric forms. Through systematic screening and enzyme engineering, we achieved the synthesis of diverse aryl indole atropisomers with exceptional yields and enantioselectivities (up to 99% yield and 99% ee). Strikingly, we uncovered a unique stereo-divergent behavior wherein a single biocatalyst switches its stereochemical outcome solely by toggling the amine partner between alkylamines and arylamines. Mechanistic investigations using molecular dynamics (MD) simulations unveiled the origins of the high enantioselectivity, the substrate-dependent stereochemical reversal, and the catalytic enhancement imparted by a single point mutation. This study not only provides a robust platform for accessing elusive C–N axial chirality but also exemplifies the synergy between enzyme engineering and computational modeling in achieving stereo-divergent synthesis.
Source: ChemRxiv
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G3338197758, G453260783, G885406935
OpenAlex ID: W7225104203