Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization.
Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization.
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三级C-H键的金属催化器化适用于晚期功能。
DOI：
10.1038/nature14127
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发表时间：
2015-01-29
期刊：
影响因子：
64.8
通讯作者：
Hartwig JF
中科院分区：
文献类型：
--
作者：
Sharma A;Hartwig JF
一些酶能够选择性地氧化未活化的脂肪族C-H键以形成醇;然而，生物系统不具有能够催化C-H键的类似胺化的酶。这种化学的缺乏是有限的，因为含氮基团存在于治疗剂和临床上有用的天然产物中。在一个突出的实例中，红霉素的酮转化为阿奇霉素中的-N（Me）CH 2-基团导致可以以较短的治疗时间每天给药一次的化合物。由于这些原因，合成化学家对识别可以直接将C-H键转化为C-N键的催化剂非常感兴趣。大多数目前使用的用于C-H键胺化的催化剂不适合复杂分子的官能化，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C-H键或在氮原子上含有专门基团的试剂。在C-H键胺化反应中，在叔烷基上形成碳-氮键的那些将是特别有价值的，因为这种键难以从酮或醇前体酶促产生。本文报道了一种温和的、选择性的、铁催化的以底物为限制试剂的叔C-H键叠氮化反应。该反应耐受水性环境，适合复杂结构的“后期”功能化。此外，这种叠氮化产生了安装一系列氮官能团的能力，包括来自生物正交Huisgen“点击”环加成和Staudinger连接的那些。由于这些原因，我们预计这种方法将创造机会，可以轻松地将天然产物，其前体及其衍生物修饰为含有不同极性和含氮基团电荷的类似物。它还可以用于通过直接在复杂的分子结构上产生附着点来帮助鉴定生物活性分子的靶标，例如与荧光标签或亲和色谱的“手柄”的附着点。
Some enzymes are able to selectively oxidize unactivated aliphatic C-H bonds to form alcohols; however biological systems do not possess enzymes that are able to catalyze the analogous amination of a C-H bond. The absence of such chemistry is limiting because nitrogen-containing groups are found in therapeutic agents and clinically useful natural products. In one prominent example, the conversion of the ketone of erythromycin to the –N(Me)CH2– group in azithromycin leads to a compound that can be dosed once daily with a shorter length of treatment. For such reasons, synthetic chemists are very interested in identifying catalysts that can directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited for the 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 carbon-nitrogen bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to generate enzymatically from ketone or alcohol precursors. In this manuscript, we report a mild, selective, iron-catalyzed azidation of tertiary C-H bonds with substrate as limiting reagent. The reaction tolerates aqueous environments and is suitable for “late-stage” functionalization of complex structures. Moreover, this azidation creates the ability to install a range of nitrogen functional groups, including those from bio-orthogonal Huisgen “click” cycloadditions and the Staudinger ligation. For these reasons, we anticipate this methodology will create opportunities to easily modify natural products, their precursors, and their derivatives to analogs that contain distinct polarity and charge from 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 onto complex molecular structures.
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