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Preparation of cyclohexene isotopologues and stereoisotopomers from benzene

机译：来自苯的环己烯同位素和立体异络合物的制备

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摘要

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine(1). Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules(1). Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease(2), was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial(1,3,4). The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound(5), improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug(6,7), these processes are often unselective and the stereoisotopic purity can be difficult to measure(7,8). Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.Cyclohexene isotopologues and stereoisotopomers with varying degrees of deuteration are formed by binding a tungsten complex to benzene, which facilitates the selective incorporation of deuterium into any position on the ring.
机译：氢同位素氘（D）和氚（T）已成为化学，生物学和药物（1）中的基本工具。除了广泛应用于光谱学，质谱和机动学和药代动力学研究之外，对掺入药物分子（1）的掺入药物分子（1）也有相当令人兴趣。德替四巴嗪是一款对亨廷顿疾病（2）的治疗有前途的氘代药物最近被美国食品和药物管理局批准。氘动力学同位素效应，其比较了与其氘代对应物的化合物的化学反应速率，可以是显着的（1,3,4）。用氘的氢替代氢的替代可能影响代谢率和代谢物的分布，用于化合物（5），提高药物的功效和安全性。氘代化合物的药代动力学取决于氘的位置。尽管在药物合成的早期和晚期阶段的方法可用于氘掺入（6,7），但这些方法通常是不可选择的，并且立体异位纯度可能难以测量（7,8）。在这里，我们描述了制备用于制药研究的立体化氘代构件块。作为概念证明，我们通过与钨配合物结合，证明了具有不同程度的氘掺入的环己烯的四步转化。使用氘代和质子酸和氢化物试剂的不同组合，可以精确地控制环己烯环上的氘代位置。总共有52个独特的环己甲酸酯，可以十种不同的同位素的形式提供。可以扩展该概念以准备官能化环己烯的离散立体异位剂。用于制备药物活性化合物作为离散立体母凋亡者的这种系统方法可以改善药物的药理和毒理学性质，并提供与其在体内的分布和代谢相关的机械信息。通过结合A形成具有不同程度的氘的单胞烯同位素和立体异位脱臼。钨络合物至苯，这有利于选择性掺入氘掺入环上的任何位置。

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  • 来源
    《Nature》 |2020年第7808期|288-293|共6页
  • 作者

    Smith Jacob A.; Wilson Katy B.; Sonstrom Reilly E.; Kelleher Patrick J.; Welch Kevin D.; Pert Emmit K.; Westendorff Karl S.; Dickie Diane A.; Wang Xiaoping; Pate Brooks H.; Harman W. Dean;

  • 作者单位

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Oak Ridge Natl Lab Neutron Scattering Div Oak Ridge TN 37830 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

    Univ Virginia Dept Chem Charlottesville VA 22904 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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