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.

有机和氨基甲酸酯叠氮化合物催化C2+N1氮杂环化反应 氮杂环丙烷官能团在生物学和合成药物化学中具有重要意义。 氮杂环丙烷是天然产物中具有生物活性的官能团，如丝裂霉素和 有抗肿瘤特性的氮菌素。在合成化学中，这种紧张的环可以是 由多种亲核试剂以类似于环氧化物的方式开启。与环氧化物不同， 通常由烯烃和O原子来源(C2+O1反应)、氮杂环丙烷合成 通常不是通过C2+N1方法合成的。这些方法效率低下，而且 广泛应用的C2+N1合成氮杂环丙烷具有很高的应用价值。 在这项建议中，我们扩展了我们对催化氮杂环化反应的研究，包括新的方向 与药物化学界相关。我们当前催化剂的三个具体限制 将解决使其不便于药物化学的系统。这些限制 包括：相对于叠氮化物需要过多的烯烃，没有官能团容差， 我们的催化系统缺乏对映选择性版本。首先，像许多人一样，我们的铁制 C2+N1氮杂化反应，需要过量的烯烃而不是氮试剂。虽然这是 对于廉价的烯烃(如1-癸烯)来说是可以接受的，这一缺点限制了它的应用 医药中出现的增值中间体。詹金斯实验室的最新结果 已经证明，不利于金属四氮的形成是减少烯烃的关键 装载到与氮气源相当的程度。第二，功能组的容忍度必须很高 使氮杂环化反应适用于高度复杂的分子。我们一直在扩大名单 我们的系统可以容忍的官能团的数量，特别是正在调整它以适应 氨基甲酸酯叠氮化物。第三，到目前为止，C2+N1的手性催化剂极其有限 与脂肪族烯烃的氮杂环化反应。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的对映体催化剂。因为大多数主要药物 具有氮杂环丙烷中间体的候选化合物以手性氮杂环丙烷为特征，这一突破将 革命性地将C2+N1氮杂环丙烷用于药物化学。 一旦这三个障碍被克服，另一项任务将展示这种催化作用 制度的重要性和有效性。我们将通过四步反应合成吡咯吲哚 从烯烃和叠氮化物中提取的过程。吡咯吲哚是一种双环体系，它包含 对抗生素和抗肿瘤治疗有效的分子。有系统地 制备种类繁多的这些物种将是在这种支架上开发药物的关键。