Research ArticleORGANIC CHEMISTRY

Bioinspired design of a robust d3-methylating agent

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Science Advances  08 May 2020:
Vol. 6, no. 19, eaba0946
DOI: 10.1126/sciadv.aba0946
  • Fig. 1 Bioinspired invention of DMTT as a robust d3-methylating agent.

    (A) SAM methyl transferase mediated nucleophilic reactions. (B) Deuterium-labeled drugs and candidates. (C) Invention of d3-methylating reagent DMTT. Reaction conditions: (1) HCOOH (3.0 equiv, 88 wt % aqueous solution), CD3OD (10.0 equiv, >99% D), H2SO4 (11.0 equiv, 98 wt %), reflux at 60°C for 4 hours to afford methyl-d3 formate; (2) dibenzothiophene (1.0 equiv), and above methyl-d3 formate, heat up to 60°C until the mixture became a clear solution. Photo credit: Yunfei Zhao, Nanjing University. EC50, half median effective concentration.

  • Fig. 2 Investigations of compound 2a with DMTT agent.

    Reaction conditions: 2a (0.2 mmol), DMTT (0.2 mmol), and base (0.4 mmol) in 2 ml of MeCN for 12 hours, 1H NMR yields were presented using CH2Br2 as an internal standard. rt, room temperature.

  • Fig. 3 Pd-catalyzed C─H bond methylation-d3.

    Reaction conditions: substrates 34 (1.0 equiv), DMTT (3.0 to 1.2 equiv), Pd(OAc)2 (10 mol %), Cu(OAc)2 (1.2 equiv), and trifluoroacetate (TFA) (5.0 equiv) in 2 ml of dichloroethane (DCE) for 12 hours at 60°C. Isolated yields were presented. *3.0 equivalents of DMTT were used. nd, not detected.

  • Fig. 4 Methyleneation of trifluoromethyl-substituted alkenes.

    Reaction conditions: substrates 36 (1.0 equiv), DMTT (2.0 equiv), and KHMDS (2.0 equiv) in 2 ml of tetrahydrofuran (THF) for 12 hours at room temperature. Isolated yields were presented.

  • Table 1 Reaction development.

    Reaction conditions: 1a (0.2 mmol), DMTT (0.2 mmol), and base (0.4 mmol) in 2 ml of MeCN for 12 hours.


    Embedded Image
    EntryVariation from
    the standard conditions
    1b/1c/1d/1e*
    1None90 (99% D)
    †/0/0/0
    2Without K2CO30/0/0/0
    3Using KOH35 (99% D)/0/0/0
    4Using DBU50 (99% D)/16/0/0
    51.5 equiv of DMTT62 (99% D)/20/0/0
    6CD3I (1.0 equiv.) instead of DMTT2/0/0/8
    7CD3I (5.0 equiv) instead of DMTT7/0/43/10
    8(CD3)2SO4 (1.0 equiv) instead of
    DMTT
    31/27/0/0
    9DMSO-d6 instead of DMTT0/0/0/0
    10[CD3Ph2S]+OTf instead of DMTT64/0/0/0

    *1H NMR yields were presented using CH2Br2 as an internal standard.

    †Isolated yield.

    ‡At 80°C.

    • Table 2 Substrate scope, late-stage modification, and deuterated drug synthesis.

      Reaction conditions: substrates a (1.0 equiv), DMTT (1 to 2 equiv), and K2CO3 (2 to 4 equiv) in 2 ml of MeCN for 12 hours. Isolated yields were presented.


      Embedded Image

      *Reaction conditions: substrates a (1.0 equiv), DMTT (1.0 equiv), and KOH (2.0 equiv) in 2 ml of MeCN/H2O (v:v = 1/1) for 12 hours. Isolated yields were presented.

      • Table 3 Dimethylation-d6 of primary amines.

        Reaction conditions: substrates 32 (1.0 equiv), DMTT (2 equiv), Ni(OAc)2·4H2O (10 mol%), and KF (2 equiv) in 2 ml of DCM/H2O (v:v = 20/1) for 12 hours. Isolated yields were presented.


        Embedded Image

        *1.0 equiv of DMTT was used.

        Supplementary Materials

        • Supplementary Materials

          Bioinspired design of a robust d3-methylating agent

          Minyan Wang, Yunfei Zhao, Yue Zhao, Zhuangzhi Shi

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