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Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

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Science  01 Dec 2017:
Vol. 358, Issue 6367, pp. 1182-1187
DOI: 10.1126/science.aap9674
  • Fig. 1 Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds.

    (A) The merger of photoredox and hydrogen atom transfer (HAT) catalysis enables α-amino C(sp3)–H selective hydrogen isotope exchange (HIE) of alkyl amine–based drugs. Light and dark blue circles represent the positions of isotopically labeled C(sp2)–H and C(sp3)–H bonds, respectively. (B) Hypothesis for the proposed photoredox-catalyzed deuteration and tritiation. Me, methyl; Et, ethyl; R, alkyl or aryl group; DMSO, dimethyl sulfoxide; BDE, bond dissociation energy.

  • Fig. 2 Reaction development.

    (A) Proposed catalytic cycle for the photoredox-catalyzed HAT protocol. SET, single-electron transfer; LED, light-emitting diode. (B) Procedures and requirements for program-scale deuteration and high-specific-activity tritiation. The colored circles (maroon or green) and numbers denote the positions of the C–H bonds that are labeled and the percent incorporation of the hydrogen isotope, respectively. NMP, N-methyl-2-pyrrolidone; t-Bu, tert-butyl group; rt, room temperature; h, hours. (C) High-specific-activity T2O is accessible from T2 and PtO2 at a micromolar scale and can be used for photoredox-catalyzed tritiation in a one-pot procedure.

  • Fig. 3 Scope of program-scale deuteration.

    Reaction conditions: photoredox catalyst 1 or 12 (2 mol %), triisopropylsilanethiol 13 (30 mol %), D2O (50 equivalents), Li2CO3 (1.2 equivalents, added when substrate is used as its acid salt), NMP, rt, 34-W blue LED or integrated photoreactor. The products were isolated as the appropriate acid salts shown in parentheses. Ac, acetyl group. *The two protons at the α-amino methylene position are diastereotopic and are labeled to different extents.

  • Fig. 4 Scope of high-specific-activity tritiation.

    Reaction conditions: substrate (2 μmol), photoredox catalyst 1 or 12 (4 mol %), thiol catalyst 13 or 14 (60 mol %), T2O (preformed from 1 Ci T2 and PtO2), NMP, rt, 34-W blue LED or integrated photoreactor. ‡Incorporation depicted is for the 2 Ci reaction with [3H]22.

Supplementary Materials

  • Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

    Yong Yao Loh, Kazunori Nagao, Andrew J. Hoover, David Hesk, Nelo R. Rivera, Steven L. Colletti, Ian W. Davies, David W. C. MacMillan

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Supplementary Text
    • Figs. S1 to S5
    • Tables S1 and S2
    • NMR Spectra
    • References

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