New Synthetic Methods Utilizing Radical Cation Intermediates Enabled by Visible Light Photocatalysis

项目摘要/摘要：催化反应选择性转化无处不在的 将官能团添加到增值产品中，可以有效地合成与药物相关的分子。 通过光氧化还原生成经典的活性中间体，如自由基、阳离子和阴离子 催化和质子耦合电子转移(PCET)已经改变了化学家构建络合物的方式 分子，并实现了新的成键逻辑。然而，这些温和的光催化歧管的应用 烯烃基阳离子中间体的生成仍依赖于强氧化条件 以促进烯烃氧化。烯烃基阳离子中间体的双亲性质使这些物种 能够快速构建分子复杂性和简化开发的有价值的合成关键字 与药物相关的分子。拟议研究的目标是开发一部小说 非正则合成烯烃自由基阳离子中间体的合成平台 酒精原料。这项提议寻求利用从细胞内收集的机械性见解 与激发态氧化还原化学能力相一致的烯烃自由基阳离子中间体的形成， 在综合有利的条件下生成自由基阳离子。这一方法论的发展 将解决自由基阳离子化学的三个基本限制：1)使用严酷的氧化条件 烯烃氧化2)烯烃作为自由基阳离子前体的限制和3)氧化不稳定的用途 反应伙伴。研究战略概述了一种严格的方法，以建立一个机械上不同的 从非正则前驱体中获取经典烯烃基阳离子的方法及新的研究进展 不属于传统自由基阳离子化学范围的合成方法。在目标1中，我们将利用 建立光氧化还原催化原理为开发催化还原平台奠定基础 经典烯烃自由基阳离子非正则中间体的生成及其官能化 卤代氢前体。烯烃自由基阳离子的还原生成将首先应用于 环状碳官能化反应的进展。这个还原平台随后将扩展到 使非经典邻位阳离子反应性能够正式获得，这是通过常规烯烃无法获得的 自由基阳离子化学。在目标2中，将应用C-H PCET来选择性地激活强C- 用于直接生成烯烃自由基阳离子中间体的简单醇的氢键。生成的PCET 然后将烯基阳离子应用于核苷酸衍生的直接生成和官能化 用于核苷酸类似物库的便捷合成的自由基阳离子。这项工作将提供一种新颖的 合成经典和非经典活性中间体的综合有利途径 产生了新的合成方法，可以简化生物相关分子的合成，并 促进改善人类健康的努力，符合美国国立卫生研究院的核心价值观。

Project Summary/Abstract: The development of catalytic reactions to selectively transform ubiquitous functional groups to value-added products can enable the efficient synthesis of medicinally relevant molecules. The facile generation of classical reactive intermediates such as radicals, cations, and anions via photoredox catalysis and proton-coupled electron transfer (PCET) have shifted the way chemists construct complex molecules and enabled novel bond-forming logic. However, the application of these mild photocatalytic manifolds towards the generation of alkene-derived radical cation intermediates still relies on strongly oxidative conditions to facilitate alkene oxidation. The ambiphilic nature of alkene radical cation intermediates renders these species valuable synthetic linchpins capable of rapidly building molecular complexity and streamlining the development of pharmaceutically relevant molecules. The goal of the proposed research is the development of a novel synthetic platform for the photocatalytic formation of alkene radical cation intermediates from non-canonical alcohol starting materials. This proposal seeks to leverage the mechanistic insights gleaned from the intracellular formation of alkene radical cation intermediates in concert with the capabilities of excited state redox chemistry, to generate radical cations under synthetically advantageous conditions. The development of this methodology will address three fundamental limitations of radical cation chemistry: 1) the use of harsh oxidative conditions for alkene oxidation 2) the constraint of alkenes as radical cation progenitors and 3) the use of oxidatively labile reaction partners. The research strategy outlines a rigorous approach for establishing a mechanistically distinct method to access classical alkene-radical cations from non-canonical precursors, and the development of new synthetic methods outside the scope of conventional radical cation chemistries. In aim 1, we will leverage established principles of photoredox catalysis for the development of a reductive platform for the catalytic generation and subsequent functionalization of classical alkene radical cations intermediates from non-canonical halohydrin precursors. The reductive generation of alkene radical cations will initially be applied to the development of annulative carbofunctionalizations reactions. This reductive platform will then be expanded to enable formal access to non-classical vicinal di-cation reactivity which is inaccessible via conventional alkene radical cation chemistries. In aim 2, C–H PCET will be applied for the selective homolytic activation of strong C– H bonds of simple alcohols for the direct generation of alkene radical cation intermediates. PCET generated alkene radical cations will then be applied to the direct generation and functionalization of nucleotide-derived radical cations for the expedient synthesis of nucleotide analog libraries. This work will provide a novel and synthetically advantageous approach to the generation of both classical and non-classical reactive intermediates and result in new synthetic methods that can streamline the synthesis of biologically relevant molecules and facilitate efforts to improve human health, in line with the NIH’s core values.