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

• 批准号: 8119195
• 负责人: Tom G Driver
• 金额: $ 5.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119195
• 关键词: Amination; Azepines; Azides; Aziridines; Biological Factors; Cancer cell line; Carbazoles; Clomipramine; Complex; Development; Electronics; Electrons; Generations; Goals; Health; Human; Hydrogen Bonding; Indoles; Laboratories; Mediating; Metals; Methodology; Methods; Multi-Drug Resistance; Nature; Nitrogen; Organic Synthesis; P-Glycoprotein; P-Glycoproteins; Pharmacologic Substance; Process; Pyrroles; Quality of life; Reaction; Reagent; Resistance; Rhodium; Scheme; Testing; Transition Elements; anthranil; base; carbazole; carboxylate; catalyst; chemotherapeutic agent; cold temperature; coronardine; design; functional group; improved; inhibitor/antagonist; metal complex; perfluorobutyrate; public health relevance; pyrroline; scaffold; telmisartan; zinc iodide

DESCRIPTION (provided by applicant): 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 C H 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 C H 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 1-substituents; (2) heteroaromatic or vinyl 2-substituents; (3) aliphatic 2-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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：氮杂环构成了药物和天然产品的重要子结构，可改善人类的生活质量和健康。从简单，易于使用的起始材料中获取这些化合物的新方法的开发仍然是有机合成的当前挑战。金属试剂（包括硝酸盐）对C H键的功能化，因为它降低了许多N-杂前合成中固有的功能组操作，因此具有巨大的希望。由于叠氮化物很容易获得，因此从它们那里产生了过渡金属硝酸盐的前景非常吸引人。我们的最初结果表明，乙烯基和芳基叠氮化物是过渡金属催化的吲哚，吡咯和甲状腺肿的有价值的前体。在本文中，我们描述的是基于我们最初的结果以允许使用药理学上重要的杂环支架和天然产品的新方法。从基本的角度来看，我们的方法将为过渡金属复合物建立新的反应性，而从合成的角度来看，它们将通过C H氨基化或氮原子转移反应从随时可用的起始物质中快速访问N-杂环。在第一个特定目的中，我们努力通过检查（1）替代电子绘制1-取代的底物来充分研究这种转换的范围和局限性； （2）异芳族或乙烯基2-取代； （3）脂肪族2-杀手； （4）富含电子芳基的亲爱的。这些方法将使访问一系列的N-杂环，包括磺酰基，偶像，二氢吡咯和螺旋形。在特定的目标＃2中，我们试图扩大过渡金属催化的芳基叠氮化物或o-雄性分解的范围和方法，以使杂合的逆逆逆氮，吲哚，官能化的叠氮化氮化物和叠氮化胺能够快速合成。在第三个特定目的中，我们在合成中展示了迅速产生多种耐药性（MDR）逆转剂N-乙酰基甲素，KT-5720和Coronaridine的方法。我们将与贝克实验室合作测试这些化合物的活性以及任何合成中间体，以使MDR耐药性癌细胞系对化学治疗剂敏感。公共卫生相关性：天然产品和制药剂中N-杂环的无处不在的性质继续激发有机化学家设计有助于接触它们的新方法。在此，我们描述了涉及过渡金属催化剂叠氮化物的新方法，这些方法允许使用药理学上重要的杂环支架和天然产物。我们还展示了多种耐药性（MDR）逆转剂简洁合成的新方法。