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Ternary catalytic α-deuteration of carboxylic acids

Nature Synthesis volume 1, pages 824–830 (2022)Cite this article

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Abstract

Efficient and practical construction of deuterated molecules has been a long-standing challenge. Although α-deutero carboxylic acids are ubiquitous structural components that serve as a wide array of synthons, and are thus in high demand, α-selective and mild methods for the deuteration of carboxylic acids have remained unexplored. Here we report the development of a ternary catalytic system for the α-deuteration of carboxylic acids in high yields with excellent levels of α-deuteration. The method shows wide functional group tolerance, including the late-stage deuteration of complex molecules, pharmaceuticals and natural products. Mechanistic studies and pKa calculations indicate that the reaction proceeds through the enolization of an acyl pyridinium species. The process was applied to the synthesis of a deuterated EP3 receptor antagonist, with the deutero analogue showing increased metabolic stability in human microsomes compared with the proto compound.

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Fig. 1: Utility of deuterated molecules and activation modes of carboxylic acids.
Fig. 2: Deuteration of carboxylic acid using a ternary catalyst system.
Fig. 3: Divergent transformation of deuterated products.
Fig. 4: Total synthesis of a deuterated bioactive compound and biological analysis through human microsomal metabolic assay.

Data Availability

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

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Acknowledgements

This work was financially supported by MEXT KAKENHI grant numbers JP21A204, JP21H05207 and JP21H05208 for The Grant-in-Aid for Transformative Research Areas (A) Digitalization-driven Transformative Organic Synthesis (Digi-TOS) from MEXT, JSPS KAKENHI grant no. JP15H05846 in Middle Molecular Strategy, no. JP18H04263 in Precisely Designed Catalysts with Customized Scaffolding, a Grant-in-Aid for Scientific Research (B) (no. JP17H03972 and no. JP21H02607), a Grant-in-Aid for Challenging Research (Exploratory) (no. JP19K22501) from JSPS, Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) (no. JP20am0101091 and no. JP22ama121031) and no. JP21ak0101167 from AMED. T.T. thanks the JSPS for a predoctoral fellowship. R.Y. thanks the Qdai-jump Research Program, the Ube Industries Foundation, the Amano Institute of Technology, the ENEOS Tonengeneral Research/Development Encouragement & Scholarship Foundation, the Takeda Science Foundation, the Noguchi Institute and the Astellas Foundation for Research on Metabolic Disorders for financial support. We are grateful to H. Morimoto at Kyushu University for fruitful discussions about the density functional theory calculations.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    T. Tanaka, Y. Koga, Y. Honda, A. Tsuruta, N. Matsunaga, S. Koyanagi, S. Ohdo, R. Yazaki & T. Ohshima

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  1. T. Tanaka
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Contributions

T.T., R.Y. and T.O. conceived the work, analysed the data and discussed the results, and all of the authors co-wrote the manuscript. T.T. designed and carried out the experiments with Y.K. and Y.H. The human microsomal metabolic assay was performed by A.T.

Corresponding authors

Correspondence to R. Yazaki or T. Ohshima.

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A provisional patent application for part of this work has been filed (Kyushu University, application number 2021-147127).

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Nature Synthesis thanks Jin Xie and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Tanaka, T., Koga, Y., Honda, Y. et al. Ternary catalytic α-deuteration of carboxylic acids. Nat. Synth 1, 824–830 (2022). https://doi.org/10.1038/s44160-022-00139-9

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