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Complex made simple: Enantioselective radical cascades mediated by SmI2

复杂变得简单：SmI2 介导的对映选择性自由基级联

基本信息

批准号：
EP/R029938/1
负责人：
David Procter
金额：
$ 69.28万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR029938%2F1
关键词：
Complex made simple Enantioselective radical

项目摘要

Many of the molecules society needs for the medicines, agrochemicals and materials that will improve the quality of our lives have complicated chemical structures with intricately linked rings of atoms and elaborate 3D forms. For example, in drug discovery it is now recognised that complex 3D drug candidates do better than simple, 'flat' compounds in clinical trials en route to becoming new medicines. Unfortunately, building complex molecules using known chemical processes either takes a lot of time and money, or in some cases, simply can't be done: It is crucial that we build the structures precisely or we will not get the function we desire. Thus, inventing chemical reactions that allow scientists to rapidly and selectively construct complex molecules from simple starting materials is one of the major challenges in science.'Cascade reactions', chemical processes in which a molecule undergoes a number of reactions, one after the other, like toppling dominos, could provide the key to meeting this challenge. In particular, cascade reactions involving radicals hold particular promise. Radicals are highly reactive chemical species and are good at forming bonds in complex molecules when other chemistry fails. However, the high reactivity of radicals comes at a price: radicals are so reactive that they can be hard to control and their reactions often give rise to product mixtures. In fact, generations of chemists have struggled with the problem of how to harness the power of radicals for organic synthesis.Although there are many ways to form radicals for chemical reactions, the commercial reagent, samarium diiodide, is one of the most effective. However, until now, the reagent has a significant limitation. The complex molecules society needs often exist in both left and right-handed forms (enantiomers), however, only one enantiomer will exhibit the properties that we desire. Until a recent breakthrough in our laboratories, controlling chemical reactions using samarium diiodide, so that one enantiomer is obtained rather than a mixture, was thought to be impossible: In the forty years since samarium diiodide was first used in synthesis, and the thousands of publications that followed, no satisfactory enantioselective reactions have been reported until now.Our laboratory has recently invented the first enantiomer-selective reactions using samarium diiodide. The new chemical processes are controlled by a simple, recyclable chiral ligand - a single enantiomer molecule that binds to the samarium atom - and quickly convert simple chemicals to the products we need, possessing complex linked rings of atoms and 3D forms. Crucially, the complex products are formed as single enantiomers. We have also used computational studies to understand how the new chemical reactions work.We will now develop and exploit enantiomer selective radical cascades that allow one-step access to complex molecules that are currently made by laborious multi-step organic synthesis. Thus, we will provide new processes to help national and international scientists build complex molecules in a more streamlined fashion, saving time and money, and minimising the chemical waste generated. Building on our recent studies, we will work out precisely how the new chemical reactions work, so that we can develop even better processes, before showcasing the value of the new reactions by using them to build, in only a few steps, complex biologically-active compounds from Nature. We will also develop better computational methods that allow us to design new chemical reactions prior to testing the findings in the laboratory. Finally, we will look further into the future and explore the feasibility of enantiomer selective cascade reactions that use only a catalytic quantity of samarium diiiodide. Our expertise in the chemistry of samarium diiodide and our recent discovery means that we are the only team in the world who can meet these challenges.

社会需要的许多分子用于改善我们生活质量的药物，农用化学品和材料，具有复杂的化学结构，具有错综复杂的原子环和复杂的3D形式。例如，在药物发现方面，现在人们认识到，复杂的3D候选药物在临床试验中比简单的“平面”化合物更好地成为新药。不幸的是，使用已知的化学过程构建复杂的分子要么需要大量的时间和金钱，要么在某些情况下根本无法完成：我们必须精确地构建结构，否则我们将无法获得我们想要的功能。因此，发明化学反应，使科学家能够快速和选择性地从简单的起始材料构建复杂的分子是科学的主要挑战之一。“级联反应”，即一个分子经历一系列反应的化学过程，一个接一个，就像推倒多米诺骨牌一样，可以提供应对这一挑战的关键。特别是，涉及自由基的级联反应具有特别的前景。自由基是高度反应性的化学物质，当其他化学物质失效时，它们善于在复杂分子中形成键。然而，自由基的高反应性是有代价的：自由基的反应性很强，很难控制，它们的反应往往会产生产物混合物。事实上，几代化学家都在努力解决如何利用自由基的力量进行有机合成的问题。虽然有很多方法可以形成化学反应的自由基，但商业试剂二碘化钐是最有效的方法之一。然而，到目前为止，该试剂具有显著的局限性。社会需要的复杂分子通常以左手和右手形式（对映异构体）存在，然而，只有一种对映异构体会表现出我们想要的特性。直到最近在我们的实验室中取得突破，使用二碘化钐控制化学反应，从而获得一种对映体而不是混合物，被认为是不可能的：在二碘化钐首次用于合成的四十年中，以及随后的数千篇出版物中，迄今为止，还没有令人满意的对映选择性反应的报道。我们实验室最近发明了第一个对映体-使用二碘化钐的选择性反应。新的化学过程由一个简单的，可回收的手性配体控制-一个与钐原子结合的单一对映体分子-并将简单的化学物质快速转化为我们需要的产品，拥有复杂的原子连接环和3D形式。重要的是，复杂的产品作为单一的对映异构体形成。我们还使用计算研究来了解新的化学反应是如何工作的。我们现在将开发和利用对映体选择性自由基级联，使目前通过费力的多步有机合成制备的复杂分子能够一步获得。因此，我们将提供新的工艺，帮助国家和国际科学家以更简化的方式构建复杂的分子，节省时间和金钱，并最大限度地减少所产生的化学废物。在我们最近研究的基础上，我们将精确地研究出新的化学反应是如何工作的，这样我们就可以开发出更好的工艺，然后通过使用它们来展示新反应的价值，只需几个步骤，就可以从自然界中构建出复杂的生物活性化合物。我们还将开发更好的计算方法，使我们能够在实验室测试结果之前设计新的化学反应。最后，我们将进一步展望未来，并探讨对映体选择性级联反应，只使用催化量的钐二碘化的可行性。我们在二碘化钐化学方面的专业知识和我们最近的发现意味着我们是世界上唯一能够应对这些挑战的团队。