Modular Synthesis of 1,2-Azaborines via Boron-mediated Strain-release Reductive Cyclization

通过硼介导的应变释放还原环化模块化合成 1,2-氮杂硼烷

• 批准号: 10329269
• 负责人: Guangbin Dong
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329269
• 关键词: Address; Adopted; Aromatic Compounds; Attention; Biological; Biological Availability; Boron; Chemicals; Cleaved cell; Coupling; Cyclization; Drug Design; Funding; Goals; Investigation; Ketones; Knowledge; Libraries; Literature; Mediating; Metals; Methods; Nature; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Planet Earth; Preparation; Reaction; Reagent; Research; Solubility; Source; Structure; Structure-Activity Relationship; Technology; Thermodynamics; Work; analog; aqueous; base; catalyst; dehydrogenation; driving force; drug discovery; flexibility; functional group; improved; novel; novel strategies; physical property; public health relevance; pyridine; quinoline; small molecule; success

Abstract: As an emerging class of bioisosteres of aromatic compounds, 1,2-azaborines have received increasing attention in drug discovery. However, the current synthesis of 1,2- azaborines encounters substantial difficulties, including how to access poly-substituted 1,2- azaborines and BN-heteroarenes, how to avoid using expensive catalysts and handling sensitive intermediates, how to increase modularity and scalability, etc. Here, we propose to develop a boron-mediated strain-release reductive cyclization (BSRC) strategy to address these accessibility and practicality challenges. Our objective, in the proposed funding period, is to establish the BSRC method for preparing multi-substituted 1,2-azaborines and 4,9-BN- quinolines from readily available cyclopropyl ketones and aziridyl pyridines (AZPs), respectively. Specifically, we will conduct the reaction discovery, method optimization, scope exploration, and mechanism studies. The proposed research is expected to offer a new approach for streamlined synthesis of 1,2-azaborines, which, in turn, should accelerate preparation of novel pharmaceutical analogues and expand the chemical space for drug discovery.

摘要：作为一类新兴的芳香族化合物生物电子等排体，1，2-氮杂硼杂环己烯具有 在药物发现中受到越来越多的关注。然而，目前的1，2- 氮杂硼杂环遇到了很大的困难，包括如何获得多取代的1，2- 氮杂硼和BN-杂芳烃，如何避免使用昂贵的催化剂和处理 敏感的中间体，如何提高模块化和可扩展性等。在这里，我们建议 开发硼介导的应变释放还原环化（BSRC）策略来解决这些问题 可访问性和实用性的挑战。在建议的拨款期内，我们的目标是 建立了制备多取代1，2-氮杂硼杂环和4，9-BN-的BSRC方法， 喹啉分别来自容易获得的环丙基酮和氮丙啶基吡啶（AZPs）。 具体而言，我们将进行反应发现，方法优化，范围探索， 机理研究拟议的研究预计将提供一种新的方法， 1，2-氮杂硼杂环的合成，这反过来又会加速新的 药物类似物和扩大药物发现的化学空间。