Selective deuteration and tritiation of pharmaceutically relevant sulfoximines

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Smith, Blair I. P. and Knight, Nathan M. L. and Knox, Gary J. and Lindsay, David M. and Paterson, Laura C. and Bergare, Jonas and Elmore, Charles S. and Bragg, Ryan A. and Kerr, William J. (2024) Selective deuteration and tritiation of pharmaceutically relevant sulfoximines. Angewandte Chemie International Edition. e202417179. ISSN 1521-3773 (https://doi.org/10.1002/anie.202417179)

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Abstract

Pharmaceutical-aligned research endeavors continue to diversify, including via the installation of new chemical functionality and non-classical bioisosteres within drug design. With this, an equally high demand emerges for the direct installation of isotopic substituents into these scaffolds within drug discovery programmes, as isotopologues are essential for the elucidation of the biological efficacy and metabolic fate of the active pharmaceutical ingredient (API). The sulfoximine functional group has recently become established as a high-value unit in this context; however, general and effective methods for the synthesis of deuterium (2H, D) and tritium (3H, T) labelled analogues have remained elusive. Herein, we disclose the design and development of the first iridium-catalyzed sulfoximine-directed hydrogen isotope exchange (HIE) systems that permit the site-selective integration of a distinguishing atomic label at aromatic C(sp2)–H and more challenging C(sp3)–H moieties. Moreover, we exemplify the broad applicability of these methods within a spectrum of molecular settings, as well as in the late-stage generation of isotopically-enriched complex bioactive architectures.

ORCID iDs

Smith, Blair I. P., Knight, Nathan M. L., Knox, Gary J. ORCID logoORCID: https://orcid.org/0000-0003-2674-9338, Lindsay, David M. ORCID logoORCID: https://orcid.org/0000-0003-4498-5094, Paterson, Laura C., Bergare, Jonas, Elmore, Charles S., Bragg, Ryan A. and Kerr, William J. ORCID logoORCID: https://orcid.org/0000-0002-1332-785X;
CORE (COnnecting REpositories)