A General Co-Catalytic Methodology for Enantioselective Photoredox Radical Cation Reactions

对映选择性光氧化还原自由基阳离子反应的通用助催化方法

• 批准号: 10001979
• 负责人: Wesley Bryan Swords
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001979
• 关键词: Affect; Alder plant; Alkenes; Anions; Binding; Biological; Carbon; Catalysis; Cations; DDX26 gene; Dangerousness; Development; Diels Alder reaction; Disease; Drug Screening; Hydrogen Bonding; Ions; Laboratories; Libraries; Medicine; Mentorship; Methodology; Methods; Molecular; Natural Products; Nature; Organic Synthesis; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Photochemistry; Process; Public Health; Reaction; Research; Spectrum Analysis; Structure; Training; Translating; Universities; Variant; Visible Radiation; Work; career; catalyst; cost; cost effective; cycloaddition; diene; drug development; enantiomer; indoline; novel; oxidation; prevent; professor; reaction rate; scaffold; scale up; screening; side effect; wasting

PROJECT SUMMARY The transformation of alkenes into precursors for natural products is an important step in many pharmaceutical processes. In many cases, only one enantiomer of a natural product or pharmaceutical compound has the intended biological activity. Other enantiomers may be inactive, and thus a waste of material, or cause dangerous unwanted side-effects. However, the synthesis of enantiopure bioactive molecules can be difficult and costly. Enantioselective variants of some of the most important molecular complexity-building reactions, like the Diels-Alder cycloaddition and hydrofunctionalization reaction, are limited in substrate scope and scale-up ability. The polarity inverted radical cation reaction greatly expanded the substrate scope and the advent of visible light photocatalysis provided a cost-effective method to catalyze these reactions. Few asymmetric photocatalytic methodologies have been developed with limited application to natural product and pharmaceutical synthesis. The proposed research will develop an asymmetric co-catalytic methodology general to photocatalyzed radical cation reactions. This methodology will take advantage of ion-pair formation between the radical cation and a counteranion in solution. Chiral hydrogen bond donor co-catalysts that bind the counteranions will provide a means to optimize the asymmetric reaction independent of the photocatalyst yielding unparalleled control over the reaction rate and selectivity. This methodology will be initially optimized for the photoinitiated radical cation Diels-Alder cycloaddition. Separate optimization of the photocatalyst and the hydrogen bond donating co-catalysts will provide a synthetically useful asymmetric transformation. Application of this methodology to the synthesis of enantiopure indolines will provide clear evidence of its applicability in the synthesis of biologically important compounds and scaffolds. The proposed methodology will be translated to the asymmetric photocatalysis of alkene hydrofunctionalization to provide enantiopure value-added products. The successful development of this asymmetric co-catalytic methodology will provide chemists with the means to rapidly synthesize enantiopure compound libraries for rapid drug screening and development. The training I receive through the proposed research and mentorship from Professor Tehshik Yoon will provide me with an extensive background in organic synthesis and methodology development. Through combination with my background in spectroscopy and photochemistry I will develop an independent career as an R1 university professor focused on the use of mechanistic study to develop novel, pharmaceutically useful organic transformation.

项目摘要 将烯烃转化为天然产物的前体是合成天然产物的重要步骤。 许多制药工艺。在许多情况下，天然产物的仅一种对映体或 药物化合物具有预期的生物活性。其它对映异构体可以是 无活性，因此浪费材料，或引起危险的不希望的副作用。但 对映体纯的生物活性分子的合成可能是困难和昂贵的。对映选择性变体 一些最重要的分子复杂性构建反应，如狄尔斯-阿尔德反应， 环加成和氢官能化反应，在底物范围和放大方面受到限制 能力极性反转自由基阳离子反应大大扩展了底物范围， 可见光催化剂的出现为催化这些反应提供了一种经济有效的方法。 已经开发了很少的不对称光催化方法，其应用有限， 天然产物和药物合成。这项研究将开发一种不对称的 光催化自由基阳离子反应的一般共催化方法。这种方法 将利用溶液中自由基阳离子和抗衡阴离子之间的离子对形成。 结合抗衡阴离子的手性氢键供体助催化剂将提供一种手段， 优化不依赖于光催化剂的不对称反应，产生无与伦比的控制 反应速率和选择性。这种方法最初将针对 光引发自由基阳离子Diels-Alder环加成反应。光催化剂的单独优化 并且氢键供给助催化剂将提供合成上有用的不对称 转型将该方法应用于对映体纯吲哚啉的合成， 提供了其在合成生物学上重要的化合物中的适用性的明确证据， 脚手架所提出的方法将转化为非对称的 烯烃加氢官能化以提供对映体纯的增值产物。成功 这种不对称共催化方法的发展将为化学家提供一种手段， 快速合成对映体纯化合物库，用于快速药物筛选和开发。 我通过Tehshik教授提议的研究和指导接受的培训 Yoon将为我提供有机合成和方法学方面的广泛背景知识 发展通过结合我在光谱学和光化学方面的背景， 将发展一个独立的职业生涯作为一个R1大学教授专注于使用 机制研究，以开发新的，药学上有用的有机转化。