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: 7504661
• 负责人: Tom G Driver
• 金额: $ 29.65万
• 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/7504661
• 关键词: Amination; Azepines; Azides; Aziridines; Biological Factors; Cancer cell line; Carbazoles; Clomipramine; Complex; Condition; Development; Drug resistance; Electronics; Electrons; Facility Construction Funding Category; Generations; Goals; Health; Human; Indoles; Laboratories; Mediating; Metals; Methodology; Methods; Multi-Drug Resistance; Nature; Nitrogen; Object Attachment; Organic Synthesis; P-Glycoprotein; P-Glycoproteins; Pharmacologic Substance; Process; Public Health; Pyrroles; Quality of life; Range; Reaction; Reagent; Resistance; Rhodium; Scheme; Testing; Transition Elements; anthranil; aziridine; base; carbazole; carboxylate; catalyst; chemotherapeutic agent; cold temperature; coronardine; design; functional group; improved; indole; inhibitor/antagonist; metal complex; perfluorobutyrate; 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）：氮杂环是改善人类生活质量和健康的药物和天然产物中的重要子结构。从简单易得的起始材料中获取这些化合物的新方法的发展仍然是当前有机合成的一个挑战。金属试剂（包括类氮杂环）对碳氢键的功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纵。由于叠氮化物很容易获得，因此从叠氮化物中生成过渡金属类氮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，我们描述了建立在我们的初步结果之上的新方法，以允许获得药理学上重要的杂环支架和天然产物。从基本的角度来看，我们的方法将为过渡金属配合物建立新的反应性，而从合成的角度来看，它们将使易于获得的起始材料通过碳氢胺化或氮原子转移反应快速获得n -杂环。在第一个具体目标中，我们努力通过检查具有(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)杂芳香或乙烯基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，包括磺酰基多、偶氮多、二氢吡咯和螺环。在特定的目标#2中，我们寻求扩大过渡金属催化芳基叠氮化物或邻蒽酮分解的范围和方法，以实现杂芳香咔唑、吲哚、功能化氮卓和氮嘧啶的快速合成。在第三个具体目标中，我们展示了我们的合成方法，快速生成多重耐药（MDR）逆转剂，n -乙酰二胺，KT-5720和冠状苯胺。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，以使耐多药耐药的癌细胞系对化疗药物敏感。公共卫生相关性：n -杂环在天然产物和药物制剂中的普遍存在的性质继续激励有机化学家设计新的方法，以方便获取它们。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，它允许获得药理学上重要的杂环支架和天然产物。我们还展示了我们的新方法，以简洁的合成多重耐药（MDR）逆转剂。