Enzymatic Cascades for Stereoselective and Regioselective Amide Bond Assembly

Amide bond formation is fundamental in nature and is widely used in the synthesis of pharmaceuticals and other valuable products. Current methods for amide synthesis are often step and atom inefficient, requiring the use of protecting groups, deleterious reagents and organic solvents that create significant waste. The development of cleaner and more efficient catalytic methods for amide synthesis remains an urgent unmet need. Herein, we present novel biocatalytic cascade reactions for synthesising various amides under mild aqueous conditions from readily available organic nitriles combining nitrile hydrolysing enzymes and amide bond synthetase enzymes. These cooperative biocatalytic cascades enable kinetic resolution of racemic nitriles and provide a highly enantioselective biocatalytic extension of the Strecker reaction. The regioselective non-directed C-H bond amidation of simple arenes was demonstrated through the incorporation of photoredox catalysis to the front end of the cascade. C-H bond amidation of simple aromatic precursors was also achieved via a CO₂ fixation cascade combining enzymatic carboxylation and amide bond synthesis in one-pot.