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.

来自有机和氨基甲酸酯叠氮化物的催化C2+N1氮杂化 氮杂氨酸官能团在生物学和合成药物化学方面至关重要。 氮杂氨酸是天然产物（例如丝裂霉素和）的生物活性官能团 具有抗肿瘤特性的偶氮霉素。在合成化学中，该紧张的环可以是 由多种亲核者以类似于环氧化物的方式开放。与环氧化物不同， 通常是从烯烃和O-ATOM源（C2 + O1反应），Aziridines合成的 通常不通过C2 + N1方法合成。这些方法效率低下， 广泛适用的Aziridines的C2 + N1合成将是高价的。 在此提案中，我们将有关催化副岛的研究扩展到包括新方向 与药物化学界有关。我们当前催化剂的三个具体局限 将解决对药物化学的不良化的系统。这些限制 包括：相对于叠氮化物的过量烯烃的必要性，缺乏功能群的耐受性， 并且缺乏催化系统的对映选择性版本。首先，我们的铁系统，就像许多人一样 C2 + N1氮化反应需要过量的烯烃与硝酸盐试剂。虽然是 可接受廉价的烷烃（例如1-二次），此缺点可减少其应用 出现在药品中的增值中间体。詹金斯实验室的最新结果 已经证明，不利于金属二苯二烯的形成是减少烯烃的关键 加载到与硝基源的等效性。其次，功能组的公差必须高 为了使Aziridination适用于高度复杂的分子。我们一直在扩展列表 我们系统耐受的功能组，尤其是在适应它 氨基甲酸酯叠氮化物。第三，迄今为止，C2 + N1的手性催化剂非常有限 用脂族烷烃的氮杂化。 D2对称大环配体的发展 系统将使我们能够彻底形成单个对映体催化剂。由于大多数领先的药物 Aziridine Intermediates的候选人具有手性Aziridines，这一突破将 革新用于药物化学的C2 + N1 Aziridation。 一旦克服了这三个障碍，一项额外的任务将展示这种催化 系统的意义和有效性。我们将通过四步合成吡咯兰洛丁。 烯烃和叠氮化物的过程。吡咯洛洛琳是一个包含的双环环系统 对抗生素和抗肿瘤疗法有效的分子。有系统的能力 准备各种各样的物种对于在这种脚手架上的药物开发至关重要。