Catalytic C2+N1 Aziridination from Organic and Carbamate Azides

有机和氨基甲酸酯叠氮化物催化 C2 N1 氮丙啶化

• 批准号: 9232309
• 负责人: David M. Jenkins
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232309
• 关键词: Address; Alkaloids; Alkenes; Amino Alcohols; Antibiotics; Azides; Aziridines; Carbamates; Chromium; Communities; Complex; Cyclization; Development; Effectiveness; Epoxy Compounds; Family; Flowcharts; Imines; Iron; Ligands; Mitomycins; Natural Products; Oxygen; Pharmaceutical Chemistry; Pharmacologic Substance; Process; Property; Reaction; Reagent; Research; Shapes; Source; Synthesis Chemistry; System; Testing; Therapeutic; analog; catalyst; diazo compound; drug candidate; drug development; drug discovery; enantiomer; functional group; metal complex; nitrene; scaffold; synthetic biology

Catalytic C2+N1 Aziridination from Organic and Carbamate Azides The aziridine functional group is critical in biology and synthetic medicinal chemistry. Aziridines are biologically active functional groups in natural products, such as mitomycins and azinomycins, that have antitumor properties. In synthetic chemistry, this strained ring can be opened by a wide variety of nucleophiles in a manner analogous to epoxides. Unlike epoxides, which are often synthesized from an alkene and an O-atom source (a C2 + O1 reaction), aziridines are not typically synthesized by a C2 + N1 approach. These approaches are inefficient and a broadly applicable C2 + N1 synthesis of aziridines would be highly valuable. In this proposal, we extend our research on catalytic aziridination to include new directions relevant to the medicinal chemistry community. Three specific limitations of our current catalyst system that render it inexpedient for medicinal chemistry will be addressed. These limitations include: the necessity for excess alkene relative to azide, absence of functional group tolerance, and lack of an enantioselective version of our catalytic system. First, our iron system, like many C2 + N1 aziridination reactions, required excess alkene versus nitrene reagent. While this is acceptable for inexpensive alkenes (e.g. 1-decene), this drawback curtails its application with high value-added intermediates that appear in pharmaceuticals. Recent results from the Jenkins labs have demonstrated that disfavoring formation of a metallotetrazene is key to reducing alkene loading to equivalency with the nitrene source. Second, functional group tolerance must be high for aziridination to be applicable for highly complex molecules. We have been expanding the list of functional groups that are tolerated by our system and, in particular, are adapting it for carbamate azides. Third, to date, there are extremely limited chiral catalysts for C2 + N1 aziridination with aliphatic alkenes. The development of D2-symmetric macrocyclic ligand systems will allow us to facilely form single enantiomer catalysts. Since most leading drug candidates with aziridine intermediates feature chiral aziridines, this breakthrough will revolutionize C2 + N1 aziridination for medicinal chemistry. Once these three barriers have been overcome, an additional task will showcase this catalytic system's significance and effectiveness. We will synthesize pyrroloindolines through a four step process from alkenes and azides. Pyrroloindolines are a bicyclic ring system that contains molecules that are effective for antibiotic and antitumor therapeutics. The ability to systematically prepare a wide variety of these species will be critical for development of drugs on this scaffold.

有机叠氮化合物和氨基甲酸酯叠氮化合物的C2+N1氮杂环丙烷化反应 氮丙啶官能团在生物学和合成药物化学中至关重要。 氮杂环丙烷是天然产物中的生物活性官能团，例如丝裂霉素和 azinomycins，具有抗肿瘤特性。在合成化学中，这种应变环可以是 以类似于环氧化物的方式被各种亲核试剂打开。与环氧化物不同， 其通常由烯烃和O原子源（C2 + O 1反应）合成， 通常不通过C2 + N1方法合成。这些方法效率低下， 广泛适用的氮杂环丙烷的C2 + N1合成将是非常有价值的。 在这个建议中，我们扩展了我们对催化氮丙啶化的研究，包括新的方向 与药物化学界相关。我们目前催化剂的三个具体限制 使其不适合药物化学系统将被处理。这些限制 包括：烯烃相对于叠氮化物过量的必要性，官能团耐受性的缺乏， 以及我们的催化系统缺乏对映选择性。首先，我们的铁系统，像许多 C2 + N1氮杂环丙烷化反应，需要过量的烯烃相对于氮烯试剂。虽然这是 对于便宜的烯烃（例如1-癸烯）是可接受的，但是该缺点限制了其应用， 药品中的增值中间体。Jenkins实验室的最新结果 已经证明，不利于金属四氮烯的形成是减少烯烃的关键 加载至与氮烯源相当。第二，功能群容忍度必须高 使氮丙啶化反应适用于高度复杂的分子。我们一直在扩大名单 我们的系统所能容忍的官能团，特别是， 氨基甲酸酯叠氮化物。第三，迄今为止，C2 + N1的手性催化剂极其有限 与脂族烯烃的氮丙啶化。D2-对称大环配体的研究进展 系统将允许我们容易地形成单一对映体催化剂。自从大多数领先药物以来 具有氮丙啶中间体的候选物具有手性氮丙啶，这一突破将 彻底改变了药物化学中的C2 + N1氮丙啶化反应。 一旦克服了这三个障碍，另一项任务将展示这种催化作用， 制度的意义和作用。我们将通过四步反应合成吡咯并吲哚啉 从烯烃和叠氮化物的方法。吡咯并吲哚啉是双环系统，其含有 对抗生素和抗肿瘤治疗有效的分子。有系统地 制备各种各样的这些物种将是至关重要的开发药物的这种支架。