Harawa V,
Thorpe TW,
Marshall JR,
Sangster JJ,
Gilio AK,
Pirvu L,
Heath RS,
Angelastro A,
Finnigan JD,
Charnock SJ,
Nafie JW,
Grogan G,
Whitehead RC,
Turner NJ.
*
University of Manchester, UK
Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines.
J. Am. Chem. Soc. 2022;
144: 21088-21095
DOI:
10.1021/jacs.2c07143
Key words
biocatalysis - piperidines - amine oxidase - ene-imine reductase
Significance
Saturated heterocycles such as piperidines are prevalent structural motifs in pharmaceuticals. However, the synthesis of chiral piperidines with various substitution patterns remains challenging, especially the access to 3- and 3,4-disubstituted derivatives. Turner et al. developed a chemo-enzymatic approach to synthesize 3-substituted piperidines via the dearomatization of pyridinium salts. The new methodology enables the synthesis of pharmaceutically relevant building blocks in high enantioselectivity, such as a 3-arylpiperidine en route to PARP-inhibitor niraparib.
Comment
The key step of the piperidine synthesis by Turner et al. is an amine oxidase/ene-imine reductase (EneIRED) biocatalytic cascade. The first step of the cascade involves the oxidation of the chemically generated tetrahydropyridine A using amine oxidase 6-HDNO to generate pyridinium ion B. The latter undergoes reduction to enamine intermediate C via an EneIRED-mediated conjugate addition of a hydride. Enamine C is in equilibrium with iminium intermediate D from which an EneIRED-mediated reduction to the desired piperidine enantiomer via dynamic kinetic resolution takes place. Screening of various EneIRED panels resulted in the identification of complementary EneIRED series A and B which allow the synthesis of either enantiomer of a desired substrate. This article has also been highlighted with a different focus in the section "Organo- and Biocatalysis" of this issue: Synfacts
2023, 19, 293.
