Novel Strategies for the Assembly of Carbon-Boron Bonds via the Photoinduced Generation of Boryl-Radicals

通过光诱导产生硼基自由基组装碳硼键的新策略

• 批准号: EP/V015982/2
• 负责人: Meera Mehta
• 金额: $ 10.17万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV015982%2F2
• 关键词: Novel; Strategies; Assembly; Carbon; Boron

Boron-containing small organic molecules are one of the most important class of compounds in modern synthetic chemistry due to their use in the Nobel Prize-winning hydroboration-oxidation and Suzuki cross-coupling. Borylated building-blocks are routinely used in the preparation of high-value materials both in academia and industry. Therefore, the invention of novel chemical reactions that form C-B bonds in unprecedented ways is of strategic importance to facilitate the discovery, evolution and manufacture of molecules that impact our society.In general, boron-based functionalities are introduced into organic molecules using two-electron processes like the reaction of Grignards with B-electrophiles or the aromatic C-H borylation using transition metal catalysis. The overarching aim of this project is to explore a complementary approach where C-B bonds are assembled through the reactivity of B-centred radicals (boryl radicals). The use and application of these reactive intermediates is considerably underdeveloped but can provide many orthogonal and complementary solutions to current ionic and metal-mediated borylation strategies.The project is divided in three Aims that will target specific challenges relevant to the preparation of borylated materials.Aim 1. We develop a photochemical approach for the generation of boryl radicals from amine-boranes, a class of stable and abundant materials. These open-shell intermediates will be used to achieve direct and selective C-H borylation of N-heterocycles, one of the most important motifs in pharmaceutical and agrochemical materials. This reactivity will provide a novel approach to functionalise these high-value molecules with a selectivity orthogonal to the one displayed by current metal-catalysed methodologies. We will also benchmark the applicability of the chemistry by applying it to a series of "real-world" substrates of industrial interest that will be provided through a collaboration with Janssen Pharmaceutical. Furthermore, we will evaluate the use of these novel borylated materials in main-stream cross-coupling reactions. Aim 2. Here we will develop divergent multicomponent reactions based on the intramolecular cyclization of boryl radicals. We will use our knowledge in radical cascades to provide unprecedented borylation-functionalization processes. This chemistry involves the generation of homo-allylic amine-boryl radicals that will undergo an intramolecular cyclization followed by a diversification through a final reaction with a broad range of trapping agents. We will evaluate the full scope and limitation of this reactivity and also apply it to the preparation of blockbuster drug analogues. Aim 3. This strategy for olefin borylation-functionalization will be expanded by merging it with nickel catalysis. This will enable the development of an innovative dual photoredox-nickel platform for tandem radical borylation and cross-coupling that will generate in a divergent manner complex and densely functionalised materials.A relevant aspect will be investigating the scalability of the various processes that we will develop. This part of the project will be executed through a collaboration with Janssen Pharmaceutical that will allow to use their state-of-the-art flow-chemistry facilities.Overall, this project will provide novel reactivity modes for the formation of C-B bonds exploring the reactivity of boryl radicals in photoredox catalysis. Given the importance of borylated building blocks in a synthetic, bio-organic, medicinal and material chemistry, this project will facilitate the discovery, development and manufacture of high-value materials with overall impact to the well-being of UK society.

含硼有机小分子是现代合成化学中最重要的化合物之一，因为它们在获得诺贝尔奖的硼氢化-氧化和铃木交叉偶联中得到了应用。硼化结构单元在学术界和工业界通常用于制备高价值材料。因此，以前所未有的方式形成 C-B 键的新型化学反应的发明对于促进影响我们社会的分子的发现、进化和制造具有重要的战略意义。 一般来说，使用双电子将基于硼的功能引入有机分子中诸如格氏试剂与 B-亲电子试剂的反应或使用过渡金属催化的芳香族 C-H 硼化反应等过程。该项目的总体目标是探索一种补充方法，通过以 B 为中心的自由基（硼基自由基）的反应性组装 C-B 键。这些反应中间体的使用和应用还相当不发达，但可以为当前的离子和金属介导的硼化策略提供许多正交和补充的解决方案。该项目分为三个目标，将针对与硼化材料的制备相关的特定挑战。 1. 我们开发了一种光化学方法，用于从胺硼烷（一类稳定且丰富的材料）中产生硼基自由基。这些开壳中间体将用于实现 N-杂环的直接和选择性 C-H 硼基化，这是药物和农化材料中最重要的基序之一。这种反应性将提供一种新颖的方法来功能化这些高价值分子，其选择性与当前金属催化方法所显示的选择性正交。我们还将通过将其应用于一系列具有工业利益的“现实世界”基质来对化学的适用性进行基准测试，这些基质将通过与杨森制药公司合作提供。此外，我们将评估这些新型硼化材料在主流交叉偶联反应中的使用。目标 2. 在这里，我们将开发基于硼基自由基分子内环化的不同多组分反应。我们将利用我们的知识进行彻底的级联，以提供前所未有的硼化功能化过程。这种化学涉及产生同烯丙基胺-硼基自由基，该自由基将经历分子内环化，然后通过与多种捕获剂的最终反应而多样化。我们将评估这种反应性的全部范围和局限性，并将其应用于重磅药物类似物的制备。目标 3. 该烯烃硼基化官能化策略将通过与镍催化相结合来扩展。这将使开发用于串联自由基硼化和交叉偶联的创新双光氧化还原镍平台成为可能，该平台将以不同的方式生成复杂且密集的功能化材料。相关方面将研究我们将开发的各种工艺的可扩展性。该项目的这一部分将通过与杨森制药公司合作执行，杨森制药公司将使用其最先进的流动化学设施。总的来说，该项目将为 C-B 键的形成提供新颖的反应模式，探索反应性光氧化还原催化中的硼基自由基。鉴于硼化结构单元在合成、生物有机、医药和材料化学中的重要性，该项目将促进高价值材料的发现、开发和制造，对英国社会的福祉产生整体影响。