Synthesis of Niraparib via Chemoenzymatic Dearomatization of Substituted Pyridines

A chemoenzymatic dearomatization strategy, involving initial reduction of a pyridinium with sodium borohydride followed by a biocatalytic amine oxidase/ene imine reductase (AmOx/EneIRED) cascade, has enabled the synthesis of the PARP inhibitor Niraparib. A variety of tetrahydropyridines with different N ‐alkyl and 3‐(4′‐aryl) substituents were screened, leading to the selection of N ‐ethyl 3‐(4′‐aminophenyl)‐1,2,5,6‐tetrahydropyridine as the preferred substrate for the synthesis of Niraparib. Using AmOx 6‐HDNO E350L_E352D and EneIRED361 yielded the ( S )‐3‐(4′‐aminophenyl)piperidine product in 66% yield and 93% enantiomeric excesses (ee) on 50 mL scale. Subsequent modifications and a final N ‐dealkylation step allowed for the isolation of Niraparib.