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.

项目摘要/摘要 PI：Gregory O'Neil 西华盛顿大学 标题：轻度和选择性的合作基碱介导的氢硅烷赖以改进的药物合成 摘要：减少反应是临床和实验药物合成的关键转化 用于治疗各种人类疾病。但是，常见的还原剂可能会出现某些危害（例如 对水分的敏感性以及可燃烧的H2气体的释放）和/或需要特殊的处理和设备。 此外，随着目标分子变得更加复杂，选择性要求变得更加严格 这驱动了对新的需要进行的新需求和高度选择性的减少协议。该提案描述了 使用有机硅与合作基碱激活相结合，产生轻度，平易近人的 选择性还原方法可以访问各种生物活性分子。 底物控制的钻石选择性水硅烷和手性碱介导的对映选择性 将研究羰基减少。这些反应的分子内性也有望使 转换化学选择性（AIM＃1）。将实现区域选择性环氧化物开口 具有新设计的Silanes和/或Lewis碱基激活剂（AIM＃2）。所有这些反应预计 生成二氧化碳产品，然后可以进一步功能化以产生有价值的合成 否则将是准备挑战的中间人（AIM＃3）。这是通过追求 遵循特定目的： 1。探索化学，区域和映射合作碱基介导的分子内分子 氢硅烷基。 2。进行基于机理的分子内氢硅烷的优化。 3。研究二氧化物分子内氢硅烷化产物的功能化反应。 这项工作将对提供各种重要重要的新的和卓越的机会产生重大的积极影响 合成中间通过可预测的选择性，多功能性和轻度反应的组合 条件，并为各种本科参与者提供了重要的培训机会 研究方法。