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）：氮杂环化合物构成了药物和天然产物中的重要亚结构，可改善人类的生活质量和健康。开发从简单、易得的起始材料获得这些化合物的新方法仍然是有机合成的当前挑战。C H键的功能化的金属试剂，包括nitrenoids，具有很大的希望，因为它减少了许多N-杂环合成中固有的官能团操作。由于叠氮化物是容易获得的，由它们产生过渡金属类氮杂环戊烯的前景是非常吸引人的。我们的初步研究结果表明，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。在这里，我们描述了新的方法，建立在我们的初步结果，以允许访问至关重要的杂环支架和天然产物。从基本的角度来看，我们的方法将建立新的过渡金属配合物的反应性，而从合成的角度来看，它们将使快速获得N-杂环从容易获得的起始材料通过CH胺化或氮原子转移反应。在第一个具体的目标，我们努力充分调查的范围和限制，这种转变，通过检查基板（1）替代吸电子1-取代基;（2）杂芳族或乙烯基2-取代基;（3）脂肪族2-取代基;（4）脱芳构化的富电子芳基。这些方法将使得能够获得一系列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内，我们寻求扩展过渡金属催化的芳基叠氮化物或邻氨基苯甲酸分解的范围和方法，以使得能够快速合成杂芳族咔唑、吲哚、官能化氮杂环庚三烯和氮杂环丙烷。在第三个具体目标中，我们展示了我们的合成方法，快速产生多药耐药（MDR）逆转剂，N-乙酰亚胺，KT-5720，和coronaridine。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对化疗药物敏感的MDR耐药癌细胞系的活性。公共卫生相关性：N-杂环化合物在天然产物和药物制剂中无处不在的性质继续激励有机化学家设计新的方法，以促进获得它们。在这里，我们描述了新的方法，涉及过渡金属催化剂叠氮化物，这允许访问至关重要的杂环支架和天然产物。我们还展示了我们在多药耐药（MDR）逆转剂的简洁合成方面的新方法。