4.6 Article

Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation

Journal

NATURE CATALYSIS
Volume 5, Issue 11, Pages 982-992

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41929-022-00857-5

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Funding

  1. Pfizer
  2. University of Liverpool
  3. Innovate UK Knowledge Transfer Partnership [KTP11214]

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A rhodium-catalysed reductive transamination reaction is reported for the synthesis of chiral piperidines and fluoropiperidines from simple pyridinium salts. The reaction demonstrates excellent diastereo- and enantio-selectivities and functional group tolerance, overcoming the limitations of asymmetric hydrogenation and traditional multistep synthesis.
Chiral piperidines are widespread in natural products and drug molecules. However, effective methods for their synthesis from simple starting materials are scarce. Herein, we report a rhodium-catalysed reductive transamination reaction for the rapid preparation of a variety of chiral piperidines and fluoropiperidines from simple pyridinium salts, with excellent diastereo- and enantio-selectivities and functional group tolerance. Thus, key to this reaction is the introduction of a chiral primary amine under reducing conditions, which, in the presence of water, undergoes transamination with the pyridinium nitrogen moiety while inducing chirality on the ring. The method overcomes some notable shortcomings of asymmetric hydrogenation and traditional multistep synthesis, affording various highly valuable chiral piperidines, including those bearing reducible and coordinating functional groups, heterocycles and, importantly, fluorine. The transamination mechanism also allows for alkylated and N-15-labelled piperidines to be easily accessed. The reaction is easily scalable, with multi-hundred-gram scale demonstrated.

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