Synthesis of Stereoenriched Piperidines via Chemo- Enzymatic Dearomatization of Activated Pyridines

Gideon James Grogan; Vanessa Harawa; Thomas Thorpe; James Marshall; Jack Sangster; Amelia Gilio; Lucian Pirvu; Rachel Heath; Antonio Angelastro; James Finnigan; Simon J. Charnock; Jordan Nafie; Roger Whitehead; Nicholas Turner

doi:10.1021/jacs.2c07143

Synthesis of Stereoenriched Piperidines via Chemo- Enzymatic Dearomatization of Activated Pyridines

Gideon James Grogan, Vanessa Harawa, Thomas Thorpe, James Marshall, Jack Sangster, Amelia Gilio, Lucian Pirvu, Rachel Heath, Antonio Angelastro, James Finnigan, Simon J. Charnock, Jordan Nafie, Roger Whitehead, Nicholas Turner

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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 amine
oxidase/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 the
antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

Original language	English
Number of pages	8
Journal	Journal of the American Chemical Society
DOIs	https://doi.org/10.1021/jacs.2c07143
Publication status	Published - 9 Nov 2022

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10.1021/jacs.2c07143Licence: CC BY

jacs.2c07143Final published version, 3.04 MBLicence: CC BY

X-ray Diffraction Equipment for Macromolecular Crystallography at York
Davies, G. J. (Principal investigator), Antson, A. A. (Co-investigator), Brzozowski, A. M. (Co-investigator), Cowtan, K. (Co-investigator), Fascione, M. A. (Co-investigator), Grogan, G. J. (Co-investigator), Plevin, M. J. (Co-investigator), Thomas, G. H. (Co-investigator), Wilkinson, A. J. (Co-investigator), Willems, L. I. (Co-investigator) & Wilson, K. S. (Co-investigator)
BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL)
18/09/20 → 17/09/22
Project: Research project (funded) › Research

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Grogan, G. J., Harawa, V., Thorpe, T., Marshall, J., Sangster, J., Gilio, A., Pirvu, L., Heath, R., Angelastro, A., Finnigan, J., Charnock, S. J., Nafie, J., Whitehead, R., & Turner, N. (2022). Synthesis of Stereoenriched Piperidines via Chemo- Enzymatic Dearomatization of Activated Pyridines. Journal of the American Chemical Society. https://doi.org/10.1021/jacs.2c07143

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title = "Synthesis of Stereoenriched Piperidines via Chemo- Enzymatic Dearomatization of Activated Pyridines",

abstract = "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.",

author = "Grogan, {Gideon James} and Vanessa Harawa and Thomas Thorpe and James Marshall and Jack Sangster and Amelia Gilio and Lucian Pirvu and Rachel Heath and Antonio Angelastro and James Finnigan and Charnock, {Simon J.} and Jordan Nafie and Roger Whitehead and Nicholas Turner",

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doi = "10.1021/jacs.2c07143",

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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 -

Synthesis of Stereoenriched Piperidines via Chemo- Enzymatic Dearomatization of Activated Pyridines

Abstract

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Projects

X-ray Diffraction Equipment for Macromolecular Crystallography at York

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