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N-Heterocycles from Azides through Rhodium-Catalyzed Nitrenoid Transfer

通过铑催化的氮烯基转移从叠氮化物生成 N-杂环

基本信息

批准号：
8288720
负责人：
Tom G Driver
金额：
$ 28.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-12-30
项目状态：
已结题

项目摘要

Abstract Nitrogen heterocycles constitute an important substructure in pharmaceuticals and natural products that improve the quality of life and health of humans. The development of new methods that access these compounds from simple, readily available starting materials remains a current challenge of organic synthesis. The functionalization of CH bonds by metal reagents, including nitrenoids, holds great promise as it reduces the functional group manipulation inherent in many N-heterocycle syntheses. Since azides are readily available, the prospect of transition metal nitrenoid generation from them is highly appealing. Our initial results demonstrate that vinyl- and aryl azides are valuable precursors for the transition metal-catalyzed synthesis of indoles, pyrroles, and carbazoles. Herein, we describe new methods that build upon our initial results to permit access to pharmacologically important heterocyclic scaffolds and natural products. From a fundamental point of view, our methods will establish new reactivity for transition metal complexes, while from a synthetic standpoint, they will enable rapid access to N-heterocycles from readily available starting materials via CH amination or nitrogen atom transfer reactions. In the first specific aim, we strive to fully investigate the scope and limitations this transformation through the examination of substrates with (1) alternative electron-withdrawing ¿-substituents; (2) heteroaromatic or vinyl ¿-substituents; (3) aliphatic ¿-substituents; (4) dearomatization of electron rich aryl groups. These methods will enable access to a range of N-heterocycles, including sulfonylindoles, azaindoles, dihydropyrroles, and spirocycles. Within specific aim #2, we seek to expand the scope and methodology of transition metal- catalyzed aryl azide or o-anthranil decomposition to enable the rapid synthesis of heteroaromatic carbazoles, indoles, functionalized azepines, and aziridines. In the third specific aim, we showcase our methods in syntheses that rapidly generate multiple drug resistance (MDR) reversal agents, N-acetylardeemin, KT-5720, and coronaridine. We will collaborate with the Beck laboratory to test the activity of these compounds as well as any synthetic intermediates towards sensitizing MDR resistant cancer cell lines to chemotherapeutic agents. The ubiquitous nature of N-heterocycles in natural products and pharmaceutical agents continues to inspire organic chemists to design new methods that facilitate access to them. Herein, we describe new methods that involve transition metal catalysts azides, which permit access to pharmacologically important heterocyclic scaffolds and natural products. We also showcase our new methods in succinct syntheses of multiple drug resistance (MDR) reversal agents.

摘要氮杂环构成了药物和天然产品中的重要亚结构，提高人类的生活质量和健康水平。开发新的方法来访问这些以简单易得的原料合成化合物仍然是目前有机合成的一个挑战。金属试剂对CH键的官能化，包括类硝基化合物，由于它的还原而具有很大的前景许多N-杂环合成中固有的官能团操纵。因为叠氮化物很容易在可获得的情况下，从它们产生过渡金属类硝基化合物的前景是非常有吸引力的。我们的初步结果证明了乙烯基叠氮化物和芳基叠氮化合物是过渡金属催化合成的有价值的前驱体吲哚、吡咯和咔唑。在此，我们描述了建立在初步结果基础上的新方法，以允许获得具有重要药理作用的杂环支架和天然产物。从根本上讲从观点来看，我们的方法将为过渡金属络合物建立新的反应性，而从合成的从观点来看，它们将使人们能够通过CH从容易获得的原料中快速获得N-杂环胺化或氮原子转移反应。在第一个具体目标中，我们努力通过具有(1)替代吸电子取代基的底物的检查；(2)杂芳烃或乙烯基取代基；(3)脂肪族取代基；(4)富电子芳基的脱芳构化。这些方法将能够获得一系列N-杂环，包括磺基吲哚、氮杂环、二氢吡咯和螺旋循环。在具体目标2中，我们寻求扩大过渡金属的范围和方法- 催化芳基叠氮或邻菲咯烷分解以实现杂芳咔唑的快速合成，吲哚、官能化氮杂环丙烷和氮杂环丙烷。在第三个具体目标中，我们展示了我们的方法快速产生多药耐药(MDR)逆转剂的合成N-乙酰地敏，KT-5720，和冠冕花碱。我们还将与贝克实验室合作测试这些化合物的活性。作为任何使耐多药癌细胞对化疗药物增敏的合成中间体。天然产物和药物制剂中N-杂环的普遍存在继续激励有机化学家设计便于获取它们的新方法。在这里，我们描述了涉及过渡金属催化剂叠氮化物的新方法，这允许获得具有重要药理作用的杂环支架和天然产物。我们也展示我们简明合成多药耐药(MDR)逆转的新方法探员们。