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Electrochemical deutero-(di)carboxylations for the preparation of deuterium-labeled medicinal building blocks

Author

Listed:
  • Subhojit Mondal

    (University of Alberta)

  • Sahil

    (University of Alberta)

  • Alex Brown

    (University of Alberta)

  • Michael W. Meanwell

    (University of Alberta)

Abstract

Sacrificial anodes have been broadly deployed in electro-synthesis for the development of reductive electrosynthetic reactions. The metal cations released from sacrificial anodes during these processes are widely believed to not affect reaction outcomes. Here, we disclose an electrochemical deutero-(di)carboxylation of acetylenes and cinnamic acids that in fact relies on anodically generated Mg2+ cations to achieve regioselective α-carboxylation to afford deuterated malonic acids with precise control over both the site and amount of deuteration. The unusual, beneficial role of Mg2+ cations on product selectivity is supported by mechanistic studies and density functional theory [ZORA-B3LYP-D3BJ/def2-TZVP/DMF(SMD)] calculations, and is believed to mimic enzymatic α-carboxylation mechanisms. The deuteration patterns in the malonic acid products can be precisely controlled, providing a platform for the concise synthesis of high-value β-d₂- and β-d₁-α-amino acid analogs, as well as other precisely deuterated frameworks.

Suggested Citation

  • Subhojit Mondal & Sahil & Alex Brown & Michael W. Meanwell, 2025. "Electrochemical deutero-(di)carboxylations for the preparation of deuterium-labeled medicinal building blocks," Nature Communications, Nature, vol. 16(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64818-9
    DOI: 10.1038/s41467-025-64818-9
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    References listed on IDEAS

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    1. Qiang Liu & Lipeng Wu & Ralf Jackstell & Matthias Beller, 2015. "Using carbon dioxide as a building block in organic synthesis," Nature Communications, Nature, vol. 6(1), pages 1-15, May.
    2. Pengfei Li & Chengcheng Guo & Siyi Wang & Dengke Ma & Tian Feng & Yanwei Wang & Youai Qiu, 2022. "Facile and general electrochemical deuteration of unactivated alkyl halides," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Jonathan D. Dabbs & Caleb C. Taylor & Martin S. Holdren & Sarah E. Brewster & Brian T. Quillin & Alvin Q. Meng & Diane A. Dickie & Brooks H. Pate & W. Dean Harman, 2024. "Designing chemical systems for precision deuteration of medicinal building blocks," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Zhiwei Zhao & Ranran Zhang & Yaowen Liu & Zile Zhu & Qiuyan Wang & Youai Qiu, 2024. "Electrochemical C−H deuteration of pyridine derivatives with D2O," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
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