最后阶段的氧化C-H甲基化
Kaibo Feng1, Raundi E Quevedo1, Jeffrey T Kohrt2
1Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL, USA.
Nature
|March 18, 2020
概括
这项研究引入了一种新方法,用于将甲基组添加到复杂分子中,从而提高药物的效力. 这种晚期C(sp3) -H甲基化技术是高效的,在药物化学中广泛适用.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 催化剂是一种催化剂.
背景情况:
- "神奇的甲基效应"通过添加甲基组,特别是与异构原子相邻的甲基组,显著提高了生物活性分子的效力.
- 现有的甲基化方法在复杂分子结构的范围和适用性方面存在局限性,阻碍了药物开发.
研究的目的:
- 开发一种区域选择性和化学选择性氧化C(sp3) -H甲基化方法,用于药物支架和天然产品的后期功能化.
- 为了使复杂分子的有效和有针对性的甲基化,促进"神奇的甲基效应"的探索.
主要方法:
- 一种新的方法,结合了选择性C-H氧化与使用催化剂 (Mn(CF3PDP)) 的温和,功能组耐受性甲基化.
- 使用或易斯酸辅助的活性中间体形成,用于用有机试剂进行甲基化.
- 将该方法应用于41种不同的基质,包括医学上重要的核心,药物和自然产品.
主要成果:
- 在18种药理学上相关的分子上实现了选择性C ((sp3) -H末期甲基化,包括Tedizolid和天然产品等药物.
- 通过晚期甲基化证明了两种"神奇甲基"候选药物的成功合成.
- 在abiraterone类似物上展示了远程甲基化,强调了该方法的多功能性.
结论:
- 开发的方法为晚期C(sp3) -H甲基化提供了一个强大的工具,与复杂的药物架构和天然产品兼容.
- 这种技术显著减少了合成的努力,加速了新疗法和化学探针的发现和开发.
- 扩大了"神奇甲基效应"在药物化学研究中的应用.
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