Rearrangement Reactions of Divinyldiaziridines for the Enantioselective Synthesis of Diazepines and Benzodiazepines

项目摘要/摘要 功能化的二氮杂环丙烷是一种特权支架，因为它具有大量的反应性特征，可以导致 含氮杂环药物载体的生产。其中，二氮卓类药物和苯二氮卓类药物 作为药理上最相关的药物家族之一。因此，化学合成领域已经集中了它的 关注合成这种高度复杂的杂环的新方法的发展。这项提议旨在 研究了一系列反应条件下二乙烯基重氮杂环丙烷的对映选择性重排反应。 光学纯二氮卓类和苯二氮卓类药物的系统合成。这项建议包括三个目标。目标1： 1，2-，1，3-和1，4-二氮卓类化合物的立体选择性重排合成 取代的二氮杂环丙烷。目的2：取代二氮杂环丙烷的不对称重排反应 苯二氮卓类药物的合成。目的3：Diaza-Claisen重排反应合成相关药物支架和 复杂的杂环。 Moura-Letts实验室为开发合成方法开发了一个强大的研究平台 杂环支架。这种技能和训练有素的学生的结合将有助于成功实施 本提案中所描述的目标。 二乙烯基二氮杂环丙烷的Claisen重排反应尚未见报道。然而，所获得的知识 从二氮杂啶合成和它们的环加成反应已经成为设计和合理化 建议的反应。这项工作将允许高效和系统地访问各种前所未有的复杂 二氮卓类药物和苯二氮卓类药物，从而有助于进一步阐明它们的药理特性。GML小组高度重视 有兴趣开发有机方法来合成和转化小杂环到更多 复杂的药理相关支架。该项目的成功将允许潜在地发现一种 史无前例的二氮-[3，3]-Claisen重排和扩环反应途径 乙烯基和二乙烯基二氮杂环丙烷。这个项目的影响也因其开发最先进的有机产品的能力而扩大 本科生、高中生和归国老兵的化学技能。这些学生有潜力 获得一定水平的有机专业知识，使他们有资格在最高学术和工业水平上竞争。 1

Project Summary/Abstract Functionalized diaziridines are privileged scaffolds due to the multitude of reactivity profiles that can lead to the production of complex N,N-containing heterocyclic pharmacophores. Among these, diazepines and benzodiazepines stand out as one of the most pharmacologically relevant drug families. Thus, the chemical synthesis field has focused its attention on the development of novel methods for the synthesis of such highly complex heterocycles. This proposal aims to study the enantioselective rearrangement reactions of divinyldiaziridines under a series of reaction conditions for the systematic synthesis of optically pure diazepines and benzodiazepines. This proposal consists of 3 Aims. Aim 1: Enantioselective Synthesis of 1,2-, 1,3- and 1,4-Diazepines via the Stereoselective Rearrangement Reactions of Substituted Diaziridines. Aim 2: Enantioselective Rearrangement Reactions of Substituted Diaziridines for the Synthesis of Benzodiazepines. Aim 3: Diaza-Claisen Rearrangement for the Synthesis of Relevant Drug Scaffolds and Complex Heterocycles. The Moura-Letts laboratory has developed a strong research platform for the development of methods for the synthesis of heterocyclic scaffolds. This combination of skills and trained students would facilitate the successful implementation of the aims described in this proposal. The Claisen rearrangement reactions of divinyldiaziridines have never been reported. However, the knowledge acquired from diaziridine synthesis and their cycloadditions has served as a cornerstone for the design and rationalization of the proposed reactions. This work will allow efficient and systematic access to a large variety of unprecedented complex diazepines and benzodiazepines and thus help further elucidate their pharmacological profiles. The GML group is highly interested in developing organic methodologies for the synthesis and transformation of small heterocycles into more complex pharmacologically-relevant scaffolds. The success of this project would allow for the potential discovery of an unprecedented diaza-[3,3]-Claisen rearrangement and ring expansion pathways through the reaction of easily accessible vinyl and divinyldiaziridines. The impact of this project is also expanded by its ability to develop state-of-the-art organic chemistry skills in undergraduate students, high school students and returning veterans. These students have the potential to acquire a level of organic expertise that will qualify them to compete at the highest academic and industrial levels. 1