Palladium-catalysed transannular C-H functionalization of alicyclic amines.
Palladium-catalysed transannular C-H functionalization of alicyclic amines.
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DOI：
10.1038/nature16957
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发表时间：
2016-03-10
期刊：
影响因子：
64.8
通讯作者：
Sanford, Melanie S.
中科院分区：
文献类型：
--
作者：
Topczewski, Joseph J.;Cabrera, Pablo J.;Saper, Noam I.;Sanford, Melanie S.
候选药物的发现是一项资源密集型工作，经常需要并行合成数百甚至数千个分子。碳氢键几乎存在于所有药剂中。因此，开发选择性、快速且有效的方法将碳氢键转化为新的化学实体有可能极大地简化药物开发。饱和含氮杂环（脂环胺）在药物中占有重要地位，包括治疗抑郁症（帕罗西汀、阿米替发）、糖尿病（格列齐特）、白血病（阿沃西迪）、精神分裂症（利培酮、贝拉哌酮）和尼古丁成瘾（金雀花碱和伐尼克兰）。然而，现有的饱和氮杂环的C-H官能化方法，特别是在远离氮的位点，仍然极其有限。在这里，我们报告了一种在远离氮的位点选择性操纵脂环胺碳氢键的新方法。我们的反应利用底物的船形构象，在各种脂环胺支架上实现钯催化的胺引导的C-H键向C-C键的转化。该方法适用于合成多种生物活性分子的新型衍生物，包括最畅销的戒烟药物伐尼克兰 (Chantix®)。我们预计这种方法应该在药物化学中广泛有用。
The discovery of pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. Carbon-hydrogen bonds are present in almost all pharmaceutical agents. As such, the development of selective, rapid, and efficient methods for converting carbon-hydrogen bonds into new chemical entities has the potential to dramatically streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, including treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukemia (alvocidib), schizophrenia (risperidone, belaperidone), and nicotine addiction (cytisine and varenicline). However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited . Here we report a new approach to selectively manipulate the carbon–hydrogen bonds of alicyclic amines at sites remote to nitrogen. Our reaction leverages the boat conformation of the substrates to achieve the palladium-catalyzed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. This approach is applied to the synthesis of novel derivatives of several bioactive molecules, including the top-selling smoking cessation drug varenicline (Chantix®). We anticipate that this method should prove broadly useful in medicinal chemistry.
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影响因子：
16.6
作者：
Chen, Xiao;Engle, Keary M.;Wang, Dong-Hui;Yu, Jin-Quan
通讯作者：
Yu, Jin-Quan
DOI：
10.1021/jo4013628
发表时间：
2013-10-04
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Nadres ET;Santos GI;Shabashov D;Daugulis O
通讯作者：
Daugulis O
影响因子：
21.8
作者：
Wencel-Delord, Joanna;Glorius, Frank
通讯作者：
Glorius, Frank
影响因子：
15
作者：
Lee M;Sanford MS
通讯作者：
Sanford MS
影响因子：
2.8
作者：
Bercaw, John E.;Day, Michael W.;Virgil, Scott
通讯作者：
Virgil, Scott