N-Heterocycles from Azides through Rhodium-Catalyzed Nitrenoid Transfer

摘要 氮杂环构成药物和天然产物中的重要亚结构， 改善人类的生活质量和健康。开发新的方法， 从简单、容易获得的起始材料制备化合物仍然是有机合成的当前挑战。 C的功能化通过金属试剂，包括类氮烯，形成H键， 许多N-杂环合成中固有的官能团操作。由于叠氮化物易于 因此，由它们制备过渡金属类氮杂环戊烯的前景非常诱人。我们的初步结果 表明乙烯基叠氮化物和芳基叠氮化物是过渡金属催化合成 吲哚、吡咯和咔唑。在这里，我们描述了新的方法，建立在我们的初步结果， 获得重要的杂环支架和天然产物。从基本面上 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 从这个角度来看，它们将能够从容易获得的起始材料通过CH 胺化或氮原子转移反应。 在第一个具体目标中，我们努力通过以下方式充分调查这种转变的范围和局限性： 检查具有（1）替代吸电子<$-取代基的底物;（2）杂芳族或乙烯基 â-取代基;（3）脂肪族â-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，包括磺酰基吲哚、氮杂吲哚、二氢吡咯和 螺环在具体目标#2中，我们寻求扩大过渡金属的范围和方法， 催化的芳基叠氮化物或邻氨基苯甲酸的分解能够快速合成杂芳族咔唑， 吲哚、官能化氮杂卓和氮杂环丙烷。在第三个具体目标中，我们展示了我们的方法， 快速产生多药耐药性（MDR）逆转剂N-乙酰亚胺，KT-5720， 和冠孢定。我们将与贝克实验室合作，测试这些化合物的活性，以及 作为使MDR抗性癌细胞系对化疗剂敏感的任何合成中间体。N-杂环化合物在天然产物和药物中的普遍存在 继续激励有机化学家设计新的方法，以促进获得它们。 在此，我们描述了涉及过渡金属催化剂叠氮化物的新方法，其允许 获得重要的杂环支架和天然产物。我们也 展示了我们在多药耐药（MDR）逆转的简洁合成方面的新方法 剂.

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.