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

项目概要/摘要 功能化二氮丙啶是一种特殊的支架，因为其具有多种反应性特征，可以导致 复杂的含 N,N 杂环药效基团的生产。其中，二氮杂卓类药物和苯二氮卓类药物最为突出 被认为是药理学上最相关的药物家族之一。因此，化学合成领域已将其重点放在 关注开发合成此类高度复杂杂环的新方法。该提案旨在 研究二乙烯基二氮丙啶在一系列反应条件下的对映选择性重排反应 光学纯二氮杂卓类和苯二氮卓类药物的系统合成。该提案包含 3 个目标。目标 1： 通过立体选择性重排反应对映选择性合成 1,2-、1,3- 和 1,4-二氮杂卓类药物 取代的二氮丙啶。目标 2：取代二氮丙啶的对映选择性重排反应 苯二氮卓类药物的合成。目标 3：Diaza-Claisen 重排用于合成相关药物支架和 复杂杂环。 Moura-Letts 实验室开发了一个强大的研究平台，用于开发合成方法 杂环支架。技能和训练有素的学生的结合将有助于成功实施 本提案中描述的目标。 二乙烯基二氮丙啶的克莱森重排反应从未有报道。然而，所获得的知识 二氮丙啶合成及其环加成反应已成为设计和合理化的基石 提议的反应。这项工作将允许高效、系统地访问各种前所未有的复杂信息 二氮杂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学特征。 GML集团高度 有兴趣开发有机方法来合成小杂环并将其转化为更多 复杂的药理学相关支架。该项目的成功将有助于发现潜在的 通过易于接近的反应实现前所未有的二氮杂-[3,3]-克莱森重排和扩环途径 乙烯基和二乙烯基二氮丙啶。该项目的影响力还因其开发最先进的有机产品的能力而扩大 本科生、高中生和退伍军人的化学技能。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