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: 7872761
• 负责人: Tom G Driver
• 金额: $ 29.25万
• 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/7872761
• 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）：氮杂环构成药物和天然产物中的重要子结构，可改善人类的生活质量和健康。开发从简单易得的起始原料中获取这些化合物的新方法仍然是有机合成当前的挑战。通过金属试剂（包括氮烯类化合物）对 C H 键进行官能化具有很大的前景，因为它减少了许多 N-杂环合成中固有的官能团操作。由于叠氮化物很容易获得，因此从它们生成过渡金属氮烯化合物的前景非常有吸引力。我们的初步结果表明，乙烯基和芳基叠氮化物是过渡金属催化合成吲哚、吡咯和咔唑的有价值的前体。在此，我们描述了基于我们初步结果的新方法，以允许获得药理学上重要的杂环支架和天然产物。从基本角度来看，我们的方法将为过渡金属络合物建立新的反应性，而从合成角度来看，它们将能够通过 C H 胺化或氮原子转移反应从容易获得的起始材料快速获得 N-杂环。在第一个具体目标中，我们力求通过检查具有（1）替代吸电子1-取代基的底物来充分研究这种转变的范围和局限性； (2)杂芳族或乙烯基2-取代基； (3)脂肪族2-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催化芳基叠氮化物或邻邻氨基苯甲酰分解的范围和方法，以实现杂芳族咔唑、吲哚、功能化氮杂卓和氮丙啶的快速合成。在第三个具体目标中，我们展示了快速生成多重耐药性 (MDR) 逆转剂、N-乙酰醛明、KT-5720 和 Coronaridine 的合成方法。我们将与贝克实验室合作，测试这些化合物以及任何合成中间体的活性，以提高耐多药癌细胞系对化疗药物的敏感性。公共健康相关性：N-杂环在天然产物和药剂中普遍存在，不断激发有机化学家设计新方法以方便获取它们。在此，我们描述了涉及过渡金属催化剂叠氮化物的新方法，该方法允许获得药理学上重要的杂环支架和天然产物。我们还展示了多重耐药（MDR）逆转剂的简洁合成新方法。