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 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 功能化领域，这是一种成熟的合成策略，可以加速 生物活性小分子的发现。自诞生以来，大多数 Csp3–H 功能化方法依赖于通过烷基或自由基的开壳机制途径 烷基金属中间体。为了继续推进C-H修饰技术， 迫切需要新的机械设计。我们假设极地（二 电子）机制可以在 C-H 功能化上下文中访问以提供 与当前最先进方法的正交反应。为此，我们中央 假设是设计可以访问碳正离子中间体的反应平台 直接由 Csp3–H 键形成。该设计将绕过预装功能的需要 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库。创新的转换方法 Csp3–H 键合成高活性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 碳自由基氧化为其等价阳离子。随着机制的设计 通过光催化平台执行，我们预计反应是温和且有效的 涉及广泛的范围。五年目标是利用拟议的战略来实现 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 与丰富的亲核伙伴形成高价值的键。该提案是 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。