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 E350LE352D 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.
Gerlach et al. (Mon,) studied this question.