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Designing chemical systems for precision deuteration of medicinal building blocks

Author

Listed:
  • Jonathan D. Dabbs

    (University of Virginia)

  • Caleb C. Taylor

    (University of Virginia)

  • Martin S. Holdren

    (University of Virginia)

  • Sarah E. Brewster

    (University of Virginia)

  • Brian T. Quillin

    (University of Virginia)

  • Alvin Q. Meng

    (University of Virginia)

  • Diane A. Dickie

    (University of Virginia)

  • Brooks H. Pate

    (University of Virginia)

  • W. Dean Harman

    (University of Virginia)

Abstract

Methods are lacking that can prepare deuterium-enriched building blocks, in the full range of deuterium substitution patterns at the isotopic purity levels demanded by pharmaceutical use. To that end, this work explores the regio- and stereoselective deuteration of tetrahydropyridine (THP), which is an attractive target for study due to the wide prevalence of piperidines in drugs. A series of d0–d8 tetrahydropyridine isotopomers were synthesized by the stepwise treatment of a tungsten-complexed pyridinium salt with H−/D− and H+/D+. The resulting decomplexed THP isotopomers and isotopologues were analyzed via molecular rotational resonance (MRR) spectroscopy, a highly sensitive technique that distinguishes isotopomers and isotopologues by their unique moments of inertia. In order to demonstrate the medicinal relevance of this approach, eight unique deuterated isotopologues of erythro-methylphenidate were also prepared.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52127-6
    DOI: 10.1038/s41467-024-52127-6
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    References listed on IDEAS

    as
    1. Renyuan Pony Yu & David Hesk & Nelo Rivera & István Pelczer & Paul J. Chirik, 2016. "Iron-catalysed tritiation of pharmaceuticals," Nature, Nature, vol. 529(7585), pages 195-199, January.
    2. Jacob A. Smith & Katy B. Wilson & Reilly E. Sonstrom & Patrick J. Kelleher & Kevin D. Welch & Emmit K. Pert & Karl S. Westendorff & Diane A. Dickie & Xiaoping Wang & Brooks H. Pate & W. Dean Harman, 2020. "Preparation of cyclohexene isotopologues and stereoisotopomers from benzene," Nature, Nature, vol. 581(7808), pages 288-293, May.
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