TY - JOUR
T1 - Synthesis of Stereoenriched Piperidines via Chemo- Enzymatic Dearomatization of Activated Pyridines
AU - Grogan, Gideon James
AU - Harawa, Vanessa
AU - Thorpe, Thomas
AU - Marshall, James
AU - Sangster, Jack
AU - Gilio, Amelia
AU - Pirvu, Lucian
AU - Heath, Rachel
AU - Angelastro, Antonio
AU - Finnigan, James
AU - Charnock, Simon J.
AU - Nafie, Jordan
AU - Whitehead, Roger
AU - Turner, Nicholas
PY - 2022/11/9
Y1 - 2022/11/9
N2 - The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature has yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amineoxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of theantipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.
AB - The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature has yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amineoxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of theantipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.
U2 - 10.1021/jacs.2c07143
DO - 10.1021/jacs.2c07143
M3 - Article
SN - 0002-7863
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
ER -