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

二乙烯基二氮丙啶的重排反应用于对映选择性合成二氮杂卓类和苯二氮卓类药物

• 批准号: 10730814
• 负责人: Gustavo Moura-Letts
• 金额: $ 44.98万
• 依托单位: ROWAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730814
• 关键词: Analgesics; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antifungal Agents; Antipsychotic Agents; Attention; Benzodiazepines; Claisen rearrangement; Complex; Development; Diazepam; Drug Targeting; Environment; Family; Flumazenil; High School Student; Imines; Industrialization; Knowledge acquisition; Laboratories; Mental disorders; Methodology; Methods; Molecular; Muscle relaxants; Optics; Organic Chemistry; Pathway interactions; Pharmaceutical Preparations; Production; Property; Qualifying; Rationalization; Reaction; Recurrence; Reporting; Research; Route; Scheme; Series; Students; Talampanel; Veterans; Viral; Work; antimicrobial; chemical synthesis; cycloaddition; design; drug synthesis; hypnotic; interest; method development; novel; pharmacologic; pharmacophore; scaffold; sedative; skills; student training; success; undergraduate student

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

项目总结/摘要 官能化的二氮杂环丙烷是特权支架，这是由于可以导致二氮杂环丙烷的多个反应性特征。 制备复合的含N，N-杂环药效团。其中，二氮杂卓类和苯二氮杂卓类 是最具争议性的毒品家族之一因此，化学合成领域已经将其重点放在 因此，需要关注用于合成这种高度复杂的杂环的新方法的开发。这项建议旨在 研究了二乙烯基二氮杂环丙烷在一系列反应条件下的不对称重排反应， 光学纯二氮杂卓和苯并二氮杂卓的系统合成。该提案包括三个目标。目标1： 1，2-、1，3-和1，4-二氮杂卓的立体选择性重排反应合成 取代的二氮丙啶。目的2：取代二氮杂环丙烷的对映选择性重排反应 苯并二氮杂卓的合成。目的3：二氮-克莱森重排用于合成相关药物支架和 复杂杂环。 Moura-Lounge实验室已经开发了一个强大的研究平台，用于开发合成 杂环支架。这种技能和受过培训的学生的结合将有助于成功实施 本提案中描述的目标。 二乙烯基二氮杂环丙烷的Claisen重排反应未见报道。然而，获得的知识 从二氮杂环丙烷合成和它们的环加成已经作为设计和合理化的基石， 建议的反应。这项工作将允许有效和系统地访问大量各种前所未有的复杂 二氮杂和苯并二氮杂，从而有助于进一步阐明它们的药理学特征。GML集团高度重视 有兴趣开发有机方法的合成和转化小杂环到更多的 复杂的药理学相关支架。该项目的成功将允许潜在的发现一个 前所未有的二氮杂-[3，3]-Claisen重排和扩环途径，通过反应容易获得 乙烯基和二乙烯基二氮杂环丙烷。该项目的影响也扩大了其发展国家的最先进的有机 化学技能在本科生，高中生和返回退伍军人。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的学术和工业水平上竞争。 1