Electron-catalysed C-C coupling: an integrated experimental and computational approach

电子催化 C-C 耦合：一种集成的实验和计算方法

• 批准号: 2752686
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2752686
• 关键词: Electron; catalysed; coupling; integrated; experimental

It has been estimated that more than 75% all C-C bonds in the pharmaceutical industry are made using transition-metal (TM) catalysis (J. Med. Chem. 2016, 59, 4443). This reliance on costly, finite, precious-metal resources has therefore raised serious concerns about the long-term sustainability of this life-changing industry. This project aims to address this crucial problem by developing a general, sustainable, TM-free approach to C-C bond formation using electron-catalysed radical-nucleophilic substitution (Nat. Chem. 2014, 6, 765). A key challenge in this emerging area of chemocatalysis (electron catalysis) is that, unlike conventional modes of catalysis where the source of the catalyst is obvious (e.g. as in Bronsted acid catalysis), the source of electrons in electron-catalysed reactions is often ambiguous. This project will seek to resolve this ambiguity by employing an integrated experimental and computational approach to study the overlooked role of weak intermolecular interactions in these reactions. This approach will merge the multidisciplinary expertise in the James Group on electron-catalysed reactions (Chem. Sci. 2021, 12, 14641; ChemRxiv 10.26434/chemrxiv-2022-9l5gq) and Trujillo Group using computational predictions to improve reaction design (WIREs Comput Mol Sci. 2022, e1616). This synergistic collaboration will ultimately enable longstanding mechanistic questions to be answered and empower the development of new electron-catalysed synthetic methodologies.Ethan will receive excellent training in organic synthesis using state-of-theart electron-catalysed chemistry. In addition to the experimental preparation, purification, and characterization of small organic molecules, he will also develop a diverse skillset using computational methods to study reaction mechanisms. Finally, the student will have the opportunity to attend organic problem classes, present their research at national or international meetings and interactwith industrial project partners.Methods for the formation of new C-C bonds are fundamental to the discovery of new bioactive molecules. To date, advances in this area have largely been driven by the development of new TM-catalysed coupling reactions. However, there are notable disadvantages associated with the use of TMs in synthesis, such as their cost, sustainability, and toxicity. Additionally, the supply of TMs can fluctuate dramatically as they must be imported from international mines, which also raises significant environmental and ethical concerns. There is therefore an urgent need to develop alternative TM-free coupling strategies that can circumvent these issues.This work will have a significant impact on the chemical and pharmaceutical industry (the second largest manufacturing sector in the UK) by providing a powerful new tool to be utilised in the cost-effective manufacture of next generation medicines and agrochemicals. By expediting research in this industry, untreated patients, or communities facing famine, who are waiting for new drugs or plant protection products to be developed will be indirect beneficiaries of this work.This work will also inspire wider developments in catalysis as innovation in this field is invariably driven by advances in our mechanistic understanding. This project will harness the full power of computational modelling to obtain new mechanistic insight and dramatically reduce the amount of time and resources that go into developing a new catalytic reaction. In addition to efficiency, this approach will encourage the synthetic community to widely re-evaluate what we truly know about seemingly "simple" reactions.Academically, this project will have a major impact on the career trajectories of newly appointed lectures Dr Michael James and Dr Cristina Trujillo, who will use this work to fuel future collaborations and the growth of an undeveloped field of catalysis

据估计，制药行业中超过75%的C-C键是使用过渡金属（TM）催化制成的（J. Med. Chem. 2016, 59, 4443）。因此，这种对昂贵、有限的贵金属资源的依赖，引发了人们对这个改变生活的行业的长期可持续性的严重担忧。该项目旨在通过开发一种通用的、可持续的、无tm的方法来解决这一关键问题，该方法使用电子催化的自由基-亲核取代来形成C-C键（Nat. Chem. 2014, 6,765）。化学催化（电子催化）这一新兴领域面临的一个关键挑战是，与催化剂来源明显的传统催化模式（例如，在Bronsted酸催化中）不同，电子催化反应中的电子来源往往是模糊的。该项目将通过采用综合实验和计算方法来研究这些反应中被忽视的弱分子间相互作用来解决这种模糊性。这种方法将融合詹姆斯小组在电子催化反应（化学）方面的多学科专业知识。科学学报，2021,12,14641；ChemRxiv 10.26434/ ChemRxiv 2022-9l5gq)和Trujillo Group使用计算预测改进反应设计（WIREs Comput Mol Sci. 2022, e1616）。这种协同合作最终将使长期存在的机械问题得到解答，并使新的电子催化合成方法得到发展。伊森将接受先进的电子催化化学有机合成方面的培训。除了小有机分子的实验制备，纯化和表征外，他还将开发使用计算方法研究反应机制的多种技能。最后，学生将有机会参加有机问题课程，在国内或国际会议上展示他们的研究，并与工业项目合作伙伴互动。形成新的C-C键的方法是发现新的生物活性分子的基础。迄今为止，这一领域的进展主要是由新的tm催化偶联反应的发展所推动的。然而，在合成中使用TMs有明显的缺点，例如它们的成本、可持续性和毒性。此外，TMs的供应可能波动很大，因为它们必须从国际矿山进口，这也引起了重大的环境和道德问题。因此，迫切需要开发替代的无tm耦合策略，以规避这些问题。这项工作将对化学和制药工业（英国第二大制造业）产生重大影响，为下一代药物和农用化学品的成本效益制造提供了一种强大的新工具。通过加速该行业的研究，等待新药或植物保护产品开发的未经治疗的患者或面临饥荒的社区将成为这项工作的间接受益者。这项工作也将激发催化领域更广泛的发展，因为这一领域的创新总是由我们对机械理解的进步所驱动的。该项目将利用计算建模的全部力量来获得新的机理见解，并大大减少开发新的催化反应所需的时间和资源。除了效率之外，这种方法还将鼓励合成界广泛地重新评估我们对看似“简单”的反应的真正了解。在学术上，该项目将对新任命的讲师Michael James博士和Cristina Trujillo博士的职业轨迹产生重大影响，他们将利用这项工作推动未来的合作和催化未开发领域的发展