Mild and Selective Cooperative-Base Mediated Hydrosilylations for Improved Drug Synthesis

温和选择性合作介导的氢化硅烷化用于改进药物合成

• 批准号: 10436072
• 负责人: Gregory W O'Neil
• 金额: $ 37.6万
• 依托单位: WESTERN WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436072
• 关键词: Boron; Clinical; Complex; Development; Drug Industry; Drug usage; Epoxy Compounds; Equipment; Exposure to; Fostering; Gases; Glycols; Goals; Health; Hydrogen; Hydrogen Bonding; Imidazole; Immunomodulators; Investigation; Mediating; Methodology; Methods; Mission; Modeling; Organic Synthesis; Outcome; Participant; Periodicity; Preparation; Process; Protocols documentation; Public Health; Reaction; Reagent; Reducing Agents; Research; Research Methodology; Safety; Silanes; Silicon; Structure; TMEDA; Testing; United States National Institutes of Health; Universities; Washington; Water; Work; base; burden of illness; cost; design; drug synthesis; functional group; hazard; human disease; improved; novel; novel therapeutics; nucleophilic addition; pressure; success; training opportunity; triethylamine; undergraduate student

Project Summary/Abstract PI: Gregory O’Neil Western Washington University Title: Mild and Selective Cooperative-Base Mediated Hydrosilylations for Improved Drug Synthesis Abstract: Reduction reactions are key transformations in the synthesis of both clinical and experimental drugs used to treat various human diseases. Common reducing agents, however, can present certain hazards (e.g. sensitivity to moisture and the release of flammable H2 gas) and/or require special handling and equipment. Additionally, as the target molecules become more complex, selectivity requirements become more stringent which drives the need for new easily performed and highly selective reduction protocols. This proposal describes the use of organosilanes combined with cooperative-base activation to produce a mild, approachable, and selective reduction method with which to access various biologically active molecules. Both substrate-controlled diastereoselective hydrosilylations and chiral base-mediated enantioselective carbonyl reductions will be investigated. The intramolecularity of these reactions is also expected to render the transformations chemoselective (Aim #1). Regioselective epoxide openings will be accomplished that may feature newly designed silanes and/or Lewis base activators (Aim #2). All of these reactions are expected to generate dioxasilinane products that can then be further functionalized to generate valuable synthetic intermediates that would otherwise be challenging to prepare (Aim #3). This is to be achieved by pursuing the following specific aims: 1. Explore chemo-, regio-, and diastereoselective cooperative base-mediated intramolecular hydrosilylations. 2. Perform mechanism-based optimizations of intramolecular hydrosilylations. 3. Investigate functionalization reactions of dioxasilinane intramolecular hydrosilylation products. This work will have a significant positive impact on providing new and superior access to various important synthetic intermediates through the combination of predictable selectivity, versatility, and mild reaction conditions, as well as presenting significant training opportunities for undergraduate participants in various research methods.

项目总结/摘要 PI：Gregory O'Neil 西华盛顿大学 标题：温和和选择性的合作碱介导的氢化硅烷化用于改进药物合成 摘要：还原反应是临床和实验药物合成中的关键转化 用于治疗各种人类疾病。然而，普通还原剂可能存在某些危害（例如， 对湿气的敏感性和可燃H2气体的释放）和/或需要特殊的处理和设备。 此外，随着靶分子变得更加复杂，选择性要求变得更加严格 这促使需要新的容易执行和高度选择性的还原方案。该提案描述了 使用有机硅烷与合作碱活化相结合，以产生温和的、可接近的， 选择性还原方法，利用该方法获得各种生物活性分子。 底物控制的非对映选择性氢化硅烷化和手性碱介导的对映选择性氢化硅烷化反应都是一种新的反应。 将研究羰基还原。预计这些反应的分子内性也会使 化学选择性转化（目标#1）。将实现区域选择性环氧化物开口， 具有新设计的硅烷和/或刘易斯碱活化剂（目标#2）。预计所有这些反应都将 产生二氧杂环己硅烷产物，然后可以进一步官能化以产生有价值的合成 中间体，否则将具有挑战性的制备（目标#3）。这将通过以下方式实现： 具体目标如下： 1.探索化学，区域和非对映选择性合作碱基介导的分子内 氢化硅烷化。 2.对分子内硅氢加成进行基于机理的优化。 3.研究二氧杂环己硅烷分子内氢化硅烷化产物的官能化反应。 这项工作将对提供新的和上级访问各种重要的 通过可预测的选择性、多功能性和温和反应的组合， 条件，以及为本科参与者提供各种重要的培训机会 研究方法