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物催化 C2+N1 氮丙啶化 氮丙啶官能团在生物学和合成药物化学中至关重要。 氮丙啶是天然产物中具有生物活性的官能团，例如丝裂霉素和 阿齐霉素，具有抗肿瘤特性。在合成化学中，这个应变环可以是 由多种亲核试剂以类似于环氧化物的方式打开。与环氧化物不同， 通常由烯烃和 O 原子源（C2 + O1 反应）合成，氮丙啶 通常不通过 C2 + N1 方法合成。这些方法效率低下并且 广泛应用的氮丙啶C2+N1合成将具有很高的价值。 在本提案中，我们扩展了催化氮丙啶化的研究以包括新的方向 与药物化学界相关。我们当前催化剂的三个具体限制 将解决使其不利于药物化学的系统。这些限制 包括：相对于叠氮化物需要过量的烯烃、缺乏官能团耐受性、 我们的催化系统缺乏对映选择性版本。首先，我们的熨斗系统，像许多系统一样 C2 + N1 氮丙啶化反应，需要相对于氮烯试剂过量的烯烃。虽然这是 对于廉价的烯烃（例如 1-癸烯）来说是可以接受的，但这个缺点限制了其在高 药品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烯的形成是减少烯烃的关键 负载量与氮宾源相当。二、官能团耐受性必须高 使氮丙啶化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功能组，特别是正在对其进行调整 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 与脂肪族烯烃进行氮丙啶化。 D2-对称大环配体的研究进展 系统将使我们能够轻松地形成单一对映体催化剂。由于大多数主导药物 具有氮丙啶中间体的候选药物具有手性氮丙啶特征，这一突破将 彻底改变药物化学的 C2 + N1 氮丙啶化反应。 一旦克服了这三个障碍，一项额外的任务将展示这种催化作用 系统的意义和有效性。我们将通过四步合成吡咯并吲哚啉 由烯烃和叠氮化物加工而成。吡咯并吲哚啉是一个双环系统，包含 对抗生素和抗肿瘤治疗有效的分子。系统地进行能力 准备各种各样的这些物种对于在该支架上开发药物至关重要。