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

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(J.Med.化学。2016、59、4443)。因此，这种对昂贵、有限、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(NAT)来形成C-C键。化学。2014年，6765)。在这一新兴的化学催化(电子催化)领域中的一个关键挑战是，与催化剂来源明显的传统催化模式不同(例如，在Bronsted酸催化中)，电子催化反应中的电子来源往往是模糊的。本项目将寻求通过采用综合的实验和计算方法来研究弱分子间相互作用在这些反应中被忽视的作用来解决这一模糊性。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。SCI。2021年，12年，14641；ChemRxiv 10.26434/Chemrxiv-2022-915gq)和特鲁希略集团使用计算预测来改进反应设计(WIRES康普特摩尔科学。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，并推动新的电子催化合成方法的发展。伊森将接受使用最先进的电子催化化学进行有机合成的出色培训。除了有机小分子的实验制备、提纯和表征外，他还将发展各种技能，使用计算方法研究反应机理。最后，学生将有机会参加有机问题课，在国内或国际会议上展示他们的研究成果，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。到目前为止，这一领域的进展在很大程度上是由TM催化的新偶联反应的发展推动的。然而，在合成中使用TMS有显著的缺点，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，这也引发了重大的环境和伦理问题。因此，迫切需要开发替代的不含TM的偶联策略来规避这些问题。这项工作将通过提供一种强大的新工具，用于具有成本效益的下一代药物和农用化学品的制造，从而对化学和制药行业(英国第二大制造业)产生重大影响。通过加快这一行业的研究，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。这项工作还将激励催化领域的更广泛发展，因为该领域的创新总是由我们对机械知识的进步推动的。该项目将利用计算建模的全部力量来获得新的机理见解，并极大地减少开发新催化反应所需的时间和资源。除了效率，这种方法还将鼓励合成社区广泛地重新评估我们对看似简单的反应的真正了解。从学术上讲，这个项目将对新任命的讲座迈克尔·詹姆斯博士和克里斯蒂娜·特鲁希略博士的职业轨迹产生重大影响，他们将利用这项工作来推动未来的合作和一个未开发的催化领域的发展

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