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

从 C(sp3)–H 键直接生成碳正离子中间体的温和策略。

• 批准号: 10802699
• 负责人: Patricia Zhang Musacchio
• 金额: $ 9.63万
• 依托单位: WORCESTER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10802699
• 关键词: Address; Area; Bypass; Carbon; Chemicals; Conceptions; Disease; Drug Compounding; Electrons; Generations; Goals; Health; Hydrogen; Hydrogen Bonding; Libraries; Life; Medicine; Metals; Methods; Modification; Motivation; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Process; Quality of life; Reaction; Reagent; Research; Societies; Technology; Therapeutic; Visible Radiation; Work; arm; chemical reaction; design; disability; drug development; functional group; innovation; oxidation; small molecule

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.

项目概要/摘要 拟议研究的总体目标是开发高度可行且快速的 我们的重点是合成改变生命的药物化合物的化学技术。 C-H 官能化领域，这是一种成熟的合成策略，可以加速 自从其构思以来，大多数 Csp3-H 的发现。 功能化方法依赖于通过烷基或自由基的开壳机械途径 烷基金属中间体，继续推进C-H改性技术， 我们迫切需要新的机械设计。 电子）机制可以在 C-H 功能化上下文中访问以提供 为此，我们的核心是与当前最先进的方法进行正交反应。 假设是设计可以访问碳正离子中间体的反应平台 直接来自 Csp3-H 键 该设计将无需预先安装功能。 通常需要产生碳正离子的基团，从而简化了直接 修饰后期药物先导物并导致化合物的快速合成 用于高通量药物开发的创新方法。 Csp3–H 键合成反应性高碳阳离子是通过逐步分解过程：首先 在所需的键上夺取氢原子，然后进行自由基-极性交叉，或 通过机理的设计将碳自由基氧化成其阳离子当量。 通过光催化平台执行，我们预计反应是温和且有效的 五年目标是利用拟议的战略来实现目标。 苄基、脂肪族和 a-卤代 C-H 键，并利用产生的碳阳离子来促进 该提案是与丰富的亲核伙伴形成高价值的债券。 重要的是我们将研究一个尚未探索且成熟的反应空间 有了新的合成机会，有可能提供模块化的方法， 试剂的简单性和产品的复杂性。