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品的前体是重要的一步 许多药物过程。在许多情况下，只有一个天然产品的对映异构体或 药物化合物具有预期的生物学活性。其他对映异构体可能是 无效，因此浪费了物质，或引起危险的不良副作用。但是， 对映体生物活性分子的合成可能很困难且昂贵。对映选择性变体 在某些最重要的分子复杂性构建反应中，例如Diels-alder 环加成和加水功能化反应在底物范围内受到限制 能力。极性反转的自由基阳离子反应大大扩展了底物范围和 可见光光催化的出现提供了一种具有成本效益的方法来催化这些反应。 很少有不对称的光催化方法有限 天然产物和药物合成。拟议的研究将发展不对称 聚催化自由基阳离子反应的共催化方法论。这种方法 将利用自由基阳离子和溶液中的反拮抗之间的离子形成。 手性氢键供体共同催化剂结合反敌人将提供一种手段 优化独立于光催化剂的不对称反应，获得无与伦比的对照 超过反应率和选择性。该方法最初将针对 光学自由基阳离子Diels-Alder Cyclotition。光催化剂的单独优化 氢键捐赠共催化剂将提供合成有用的不对称 转型。将此方法应用于对映射吲哚的合成 提供明确的证据表明其适用于生物学上重要化合物的合成和 脚手架。所提出的方法将转化为非对称光催化的 烯烃的水功能化以提供对映射增值产品。成功 这种不对称的共催化方法的发展将为化学家提供用于 快速合成对映体化合物文库，以快速筛查和发育。 我通过Tehshik教授的拟议研究和指导获得的培训 Yoon将为我提供有机合成和方法论广泛的背景 发展。通过与我的光谱和光化学背景结合使用 将发展独立职业，作为R1大学教授，专注于使用 机械研究以开发新型药物有用的有机转化。