Mild Strategies in the Direct Generation of Carbocation Intermediates from C(sp3)–H Bonds

项目总结/摘要 拟议研究的广泛目标是开发高度使能和快速的 用于合成改变生命的药物化合物的化学技术。我们的重点是 C-H官能化领域，这是一种成熟的合成策略， 生物活性小分子的发现。自其概念形成以来，大多数Csp 3-H 官能化方法依赖于经由烷基的开壳机理途径， 金属烷基中间体。为了继续推进C-H改性技术， 迫切需要新的机械设计。我们假设极性（两个- 电子）机制可以在C-H官能化背景下访问，以提供 与当前最先进方法的正交反应性。为此，中央 一个假设是设计一个反应平台， 直接从Csp 3-H键上。该设计将绕过预先安装功能的需要 通常需要产生碳阳离子的基团，从而简化了直接 对晚期药物先导物进行修饰，从而快速合成化合物， 用于高通量药物开发的文库。转换的创新方法 Csp 3-H键转化为高活性碳阳离子是通过一个逐步的分解过程： 在所需键处夺取氢原子，然后进行自由基-极性交叉，或 将碳自由基氧化成其阳离子等价物。随着机制的设计 用光催化平台执行，我们设想反应是温和的， 参与一个广泛的范围。五年目标是利用拟议战略， 苄基、脂肪族和α-卤代C-H键，并利用所得碳阳离子促进 与丰富的亲核伙伴形成高价值的键。该提案 重要的是，我们将研究一个尚未开发的反应空间， 随着新的合成机会有可能提供模块化的方法， 试剂的简单性和产物的复杂性。

Project Summary/Abstract The broad goal of the proposed research is to develop highly enabling and rapid chemical technologies for the synthesis of life-altering drug compounds. Our focus is in the area of C–H functionalization, a synthetic strategy that is well-established to expedite the discovery of bioactive small molecules. Since its conception, the majority of Csp3–H functionalization methods rely on open-shell mechanistic pathways via alkyl radicals or metal alkyl intermediates. To continue the advancement of C–H modification technologies, there is a critical need for new mechanistic designs. We hypothesize that polar (two- electron) mechanisms can be accessed in a C–H functionalization context to offer orthogonal reactivity to the current state-of-the-art methods. To this end, our central hypothesis is to design reaction platforms that can access carbocation intermediates directly from a Csp3–H bond. The design will bypass the need for pre-installed functional groups that are usually required to generate carbocations, thus streamlining the direct modification of late-stage drug leads and resulting in the rapid synthesis of compound libraries for high-throughput drug development. The innovative approach to convert Csp3–H bonds into highly reactive carbocations is via a stepwise dismantling process: first hydrogen atom abstraction at the desired bond followed by a radical-polar crossover, or oxidation of a carbon radical to its cationic equivalent. With the design of the mechanism executed with a photocatalytic platform, we envision the reaction to be mild and capable of engaging a broad scope. The five-year goal is to utilize the proposed strategy to target benzylic, aliphatic and a-halo C–H bonds and utilize the resulting carbocations to facilitate high value bond formations with abundant nucleophilic partners. The proposal is significant in that we will be investigating an underexplored reaction space that is ripe with new synthetic opportunities that have the potential to offer modularity in approach, simplicity of reagents, and complexity of products.