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.

项目总结 将烯烃转化为天然产品的前体是#年的重要一步。 许多制药工艺。在许多情况下，只有一种天然产品或 药物化合物具有预期的生物活性。其他对映体可能是 不活动，从而浪费材料，或造成危险的不良副作用。然而， 合成对映体生物活性分子可能是困难和昂贵的。对映选择性变异体 一些最重要的构建分子复杂性的反应，如Diels-Alder反应 环加成反应和加氢功能化反应在底物范围和放大方面受到限制。 才能。极性反转自由基阳离子反应极大地扩大了底物的范围，提高了反应的稳定性。 可见光催化的出现为催化这些反应提供了一种经济有效的方法。 很少有不对称光催化方法被开发出来，但应用有限 天然产物和药物合成。拟议的研究将发展一种不对称的 光催化自由基阳离子反应的共催化方法学。这种方法论 将利用溶液中自由基阳离子和反阴离子之间的离子对形成。 结合反阴离子的手性氢键供体共催化剂将提供一种方法 优化不对称反应，实现无与伦比的光催化剂产率控制 超过了反应速度和选择性。此方法最初将针对 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 而氢键供体共催化剂将提供一种合成上有用的不对称 转型。该方法学在对映体吲哚类化合物合成中的应用 提供清楚的证据证明其在生物重要化合物的合成中的适用性 脚手架。所提出的方法将被转化为不对称光催化 烯烃加氢功能化提供对映体增值产品。成功者 这种不对称共催化方法的发展将为化学家提供 用于药物快速筛选和开发的快速合成对映体化合物文库。 我通过拟议的研究和特赫希克教授的指导接受的培训 Yoon将为我提供在有机合成和方法学方面的广泛背景 发展。通过结合我在光谱学和光化学方面的背景 将作为一名R1大学教授发展独立的职业生涯，专注于使用 机制研究，以开发新颖的、药用有用的有机转化。