Engineering new enzymatic platforms for atroposelective C–N bond formation

The control of a molecule’s three-dimensional shape has important implications for both its physical and biological properties. Atropisomers—stereoisomers resulting from hindered rotation around a single bond—exhibit axial chirality that can profoundly impact pharmacological properties, making their selective synthesis increasingly important in drug development. Although the number of single-atropisomer pharmaceuticals has significantly grown over the past decade, methods for their stereoselective preparation remain limited, with inefficient and costly chromatographic separations still widely used. This project addresses this challenge by engineering enzymes capable of novel atroposelective C–N bond-forming reactions, providing direct access to medicinally relevant axially chiral scaffolds. The approach will combine enzymatic desymmetrisation to access electron-rich biaryl atropisomers with atroposelective SNAr reactions to generate electron-poor counterparts. Directed evolution will be applied to enhance activity and selectivity, supported by machine learning to accelerate optimisation and computational protein design to improve enzyme function. Together, these studies will establish a biocatalytic platform for the efficient, sustainable synthesis of drug-like atropisomeric compounds.