Phenonium ions as control elements for the synthesis of chiral small molecules

铷离子作为手性小分子合成的控制元素

• 批准号: 10027148
• 负责人: Nicholas James Race
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10027148
• 关键词: Address; Architecture; Carbon; Chemicals; Chemistry; Complex; Elements; Goals; Ions; Methods; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Public Health; Structure; Synthesis Chemistry; drug candidate; drug discovery; laboratory development; programs; rapid technique; small molecule

Project Summary The goal of this proposal is to develop new synthetic methods for the rapid and precise construction of chiral small molecule building blocks. The focal point of the chemistry described is the use of the phenonium ion as a control element to surmount current synthetic limitations associated with stereo- and regiocontrol. Consequently, this reactive intermediate enables the synthesis of benzylic and homobenzylic stereocenters, which are important motifs found in many pharmaceutical agents. Various phases of this proposal concern expanding upon preliminary results from our laboratory for the development of new methods to generate phenonium ions from unconventional starting materials. In each case, new methods for addressing fundamental synthetic limitations will be obtained as well as a deeper fundamental understanding of phenonium ion formation and reactivity. Execution of the chemistry described will enable modular access to small molecule building blocks of relevance to drug discovery programs, e.g., chiral heterocycles. Relevance to public health: The vast majority of pharmaceutical candidates that make it to market are structurally complex, as defined by the presence of sp3 carbons and stereocenters. Many drug molecules contain common architectures such as benzylic and/or homobenzylic stereocenters. New methods that enable streamlined and modular access to these motifs are, therefore, very important. Supporting this program would result in new synthetic approaches to chiral small molecules containing benzylic and/or homobenzylic stereocenters from simple, readily-available starting materials. In so doing, unsolved challenges related to stereo- and regiocontrol will also be addressed.

项目概要 该提案的目标是开发新的合成方法来快速、精确地构建 手性小分子构建块。所描述化学的重点是苯鎓离子的使用 作为控制元素来克服当前与立体和区域控制相关的合成限制。 因此，这种反应中间体能够合成苯甲基和同苯甲基立体中心， 这是在许多药剂中发现的重要基序。 该提案的各个阶段涉及扩展我们实验室的初步结果 开发从非常规起始材料生成苯鎓离子的新方法。在每种情况下， 将获得解决基本合成局限性的新方法以及更深层次的基本原理 了解苯鎓离子的形成和反应性。执行所描述的化学反应将能够 模块化访问与药物发现项目相关的小分子构建块，例如手性 杂环。 与公共卫生的相关性： 根据定义，绝大多数进入市场的候选药物结构复杂 通过 sp3 碳和立构中心的存在。许多药物分子包含常见的结构，例如 苯甲基和/或同苯甲基立体中心。新方法可实现对这些内容的简化和模块化访问 因此，主题非常重要。支持该计划将带来新的手性合成方法 含有苄基和/或均苄基立构中心的小分子，起始原料简单、易于获得 材料。在此过程中，与立体和区域控制相关的未解决的挑战也将得到解决。