Jiao Mengjie, Zhang Jie, Wang Minyan, Lu Hongjian, Shi Zhuangzhi
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210093, China.
Nat Commun. 2024 Jun 13;15(1):5067. doi: 10.1038/s41467-024-48590-w.
Deuterium labeling compounds play a crucial role in organic and pharmaceutical chemistry. The synthesis of such compounds typically involves deuterated building blocks, allowing for the incorporation of deuterium atoms and functional groups into a target molecule in a single step. Unfortunately, the limited availability of synthetic approaches to deuterated synthons has impeded progress in this field. Here, we present an approach utilizing alkyl-substituted thianthrenium salts that efficiently and selectively introduce deuterium at the α position of alkyl chains through a pH-dependent HIE process, using DO as the deuterium source. The resulting α-deuterated alkyl thianthrenium salts, which bear two deuterium atoms, exhibit excellent selectivity and deuterium incorporation in electrophilic substitution reactions. Through in situ formation of isotopically labelled alkyl halides, these thianthrenium salts demonstrate excellent compatibility in a series of metallaphotoredox cross-electrophile coupling with (hetero)aryl, alkenyl, alkyl bromides, and other alkyl thianthrenium salts. Our technique allows for a wide range of substrates, high deuterium incorporation, and precise control over the site of deuterium insertion within a molecule such as the benzyl position, allylic position, or any alkyl chain in between, as well as neighboring heteroatoms. This makes it invaluable for synthesizing various deuterium-labeled compounds, especially those with pharmaceutical significance.
氘标记化合物在有机化学和药物化学中起着至关重要的作用。此类化合物的合成通常涉及氘代构建单元，可在一步反应中将氘原子和官能团引入目标分子中。不幸的是，氘代合成子的合成方法有限，阻碍了该领域的发展。在此，我们提出一种利用烷基取代的噻蒽鎓盐的方法，该方法通过pH依赖的氢同位素交换（HIE）过程，以DO作为氘源，在烷基链的α位高效且选择性地引入氘。所得的带有两个氘原子的α-氘代烷基噻蒽鎓盐在亲电取代反应中表现出优异的选择性和氘掺入率。通过原位形成同位素标记的烷基卤化物，这些噻蒽鎓盐在一系列与（杂）芳基、烯基、烷基溴以及其他烷基噻蒽鎓盐的金属光氧化还原交叉亲电偶联反应中表现出优异的兼容性。我们的技术适用于多种底物，具有高氘掺入率，并能精确控制分子内氘插入的位置，如苄基位置、烯丙基位置或其间的任何烷基链以及相邻的杂原子。这使得它对于合成各种氘标记化合物，尤其是具有药物意义的化合物非常宝贵。
