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Direct access to chiral aliphatic amines by catalytic enantioconvergent redox-neutral amination of alcohols

Nature Synthesis volume 2, pages 572–580 (2023)Cite this article

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Abstract

Chiral aliphatic amines are privileged functionalities in pharmaceutical molecules and play an essential role as ligands and catalysts in organic synthesis. It is therefore important to develop efficient catalytic strategies to access aliphatic amines in an enantiopure form. Despite great advancement in asymmetric amination methods, including reductive amination and C–N cross coupling, direct access to diverse enantioenriched aliphatic amines from readily available feedstocks is still lacking. Herein, we demonstrate direct enantioconvergent amination of racemic secondary alcohols using a variety of aliphatic primary amines, under the cooperative catalysis of a chiral iridium complex with a chiral phosphoric acid. This strategy realizes a challenging catalytic redox-neutral cascade without the need for any stoichiometric reagent, offering a one-step conversion of feedstock substrates to valuable chiral aliphatic secondary amines in high yield and enantioselectivity. The use of this atom-economical carbon–nitrogen bond-forming strategy is illustrated by the enantioselective synthesis of commercial drugs and their analogues. Futhermore, we discovered an intriguing racemization pathway for chiral aliphatic amines, which delivers important guiding principles for redox-related stereoselective control in chiral amine synthesis.

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Fig. 1: Importance and synthesis of aliphatic amines.
Fig. 2: A general amination of alcohols using aliphatic amines with high catalytic efficiency.
Fig. 3: Asymmetric amination of racemic alcohols using aliphatic amines with product functionalization.
Fig. 4: Mechanistic aspects of asymmetric amination with concomitant racemization of the chiral amine product.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

This work was supported by Ministry of Education of Singapore (grant nos. A-0004103-00-00 and A-8000055-00-00) and National University of Singapore (grant no. A-0008372-00-00). X.Q.N. acknowledges the Agency for Science, Technology and Research (A*STAR) for a PhD scholarship.

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Author notes

  1. These authors contributed equally: Xiao Qian Ng, Ching Si Lim.

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Xiao Qian Ng, Ching Si Lim, Ming Wai Liaw, Thanh Truong Quach, Jie Wu & Yu Zhao

  2. Institute of Sustainability for Chemicals, Energy and Environment (ISCE2), Singapore, Singapore

    Xiao Qian Ng & Valerio Isoni

  3. Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore

    Ming Wai Liaw

  4. Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Fuzhou, China

    Bin-Miao Yang & Yu Zhao

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Contributions

X.Q.N. and C.S.L. performed most of the experiments, with support from M.W.L., T.T.Q. and B.-M.Y. on the catalyst and substrate preparation. Y.Z., J.W. and V.I. directed the project. Y.Z., X.Q.N. and C.S.L. cowrote the paper. All authors discussed the results and commented on the paper.

Corresponding authors

Correspondence to Jie Wu or Yu Zhao.

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Nature Synthesis thanks Chao Wang, Xumu Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary Information

Experimental details and Sections I–X.

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Ng, X.Q., Lim, C.S., Liaw, M.W. et al. Direct access to chiral aliphatic amines by catalytic enantioconvergent redox-neutral amination of alcohols. Nat. Synth 2, 572–580 (2023). https://doi.org/10.1038/s44160-023-00264-z

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