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



Wu, Jianjun, Chen, Zhenyu ORCID: 0000-0001-7714-9936, Barnard, Jonathan H, Gunasekar, Ramachandran ORCID: 0000-0002-8060-9291, Pu, Chunyang, Wu, Xiaofeng ORCID: 0000-0001-5549-8836, Zhang, Shiyu, Ruan, Jiwu and Xiao, Jianliang ORCID: 0000-0003-2010-247X
(2022) Synthesis of chiral piperidines from pyridinium salts via rhodium-catalysed transfer hydrogenation. Nature Catalysis, 5 (11). pp. 982-992.

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Abstract

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 15N-labelled piperidines to be easily accessed. The reaction is easily scalable, with multi-hundred-gram scale demonstrated. [Figure not available: see fulltext.].

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 21 Oct 2022 08:31
Last Modified: 20 Apr 2023 01:30
DOI: 10.1038/s41929-022-00857-5
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3165687