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Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization

机译：适用于后期功能化的叔C-H键的金属催化叠氮化

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摘要

Many enzymes oxidize unactivated aliphatic C-H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C-H bonds. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the -N(Me)CH_(2~-) group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time. For such reasons, synthetic chemists have sought catalysts that directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom. Among C-H bond amination reactions, those forming a C-N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation. Here we report a mild, selective, iron-catalysed azidation of tertiary C-H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen 'click' cycloadditions and the Staudinger ligation. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment-for example, to fluorescent tags or 'handles' for affinity chromatography-directly on complex molecular structures.
机译：许多酶选择性地氧化未活化的脂族C-H键以形成醇。然而，生物系统不具有催化C-H键类似胺化的酶。由于含氮基团对于治疗剂和临床有用的天然产物的生物学活性至关重要，因此不存在此类酶限制了潜在的候选药物的发现。在说明结合氮基功能的重要性的一个突出例子中，红霉素的酮在阿奇霉素中转化为-N（Me）CH_（2〜-）基团导致可以每天用一次较短的剂量给药的化合物治疗时间。由于这些原因，合成化学家已经寻求了将C-H键直接转化为C-N键的催化剂。目前大多数用于C-H键胺化的催化剂不适用于复杂分子的分子间功能化，因为它们需要过量的底物或导向基团，苛刻的反应条件，弱或酸性的C-H键或在氮原子上包含特殊基团的试剂。在C-H键胺化反应中，在叔烷基上形成C-N键的那些反应特别有价值，因为这种连接很难由可能通过氧化在生物合成途径中产生的酮或醇形成。在这里我们报告温和的，选择性的铁催化的三次C-H键叠氮化，而不会过量的有价值的底物发生。该反应可耐受水性环境，并且适合在多步合成的后期阶段对复杂结构进行功能化。此外，这种叠氮化使安装一系列基于氮的官能团成为可能，包括来自惠斯根“ click”环加成反应和Staudinger连接的官能团。我们预计，这些反应将为改性天然产物，其前体及其衍生物提供机会，以产生含氮基团而导致极性和电荷不同的类似物。通过在复杂分子结构上直接建立附着点（例如，用于亲和色谱的荧光标签或“手柄”），它还可用于帮助识别生物活性分子的靶标。

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  • 来源
    《Nature》 |2015年第7536期|600-604|共5页
  • 作者

    Ankit Sharma; John F. Hartwig;

  • 作者单位

    Department of Chemistry, University of California, Berkeley, California 94720, USA;

    Department of Chemistry, University of California, Berkeley, California 94720, 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);
  • 原文格式 PDF
  • 正文语种 eng
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