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: 10491122
• 负责人: Guangbin Dong
• 金额: $ 20.5万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491122
• 关键词: Address; Adopted; Aromatic Compounds; Attention; Biological; Biological Availability; Boron; Chemicals; 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：作为新兴的芳香化合物生物膜剂，1,2-氮杂素具有 在药物发现中受到了越来越多的关注。但是，当前合成1,2- Azaborines遇到了很大的困难，包括如何访问多取代的1,2-- Azaborines和BN核酸，如何避免使用昂贵的催化剂和处理 敏感中间体，如何提高模块化和可伸缩性等。在这里，我们建议 制定硼介导的应变缓释还原环化（BSRC）策略以解决这些策略 可及性和实用性挑战。我们的目标是在拟议的资金期间，是 建立BSRC方法，用于制备多取代的1,2-氮杂线和4,9-BN- Quinolines分别来自可用的环丙基酮和副丙烯基吡啶​​（AZP）。 具体而言，我们将进行反应发现，方法优化，范围探索以及 机理研究。预计拟议的研究将为精简提供一种新的方法 1,2-氮杂碱的合成，反过来应加速新型的准备 药物类似物并扩大了药物发现的化学空间。