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Sulfoxides as substrate activators: New cross-couplings for making materials and medicines

亚砜作为底物活化剂：用于制造材料和药物的新交叉偶联

基本信息

批准号：
EP/T013419/1
负责人：
David Procter
金额：
$ 93.07万
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：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FT013419%2F1
关键词：
Sulfoxides substrate activators New cross

项目摘要

Synthetic chemistry is the engine that drives the advance of science and technology as man-made molecules and materials are vital to the work of millions of scientists around the world. In particular, the selective formation of carbon-carbon bonds, so-called 'cross-coupling', lies at the heart of almost any synthetic endeavour and is crucial for the discovery of tomorrow's pharmaceuticals, agrochemicals and advanced materials.A suite of cross-coupling reactions using metal catalysts has been developed for carbon-carbon bond formation and these methods are routinely used in every chemistry laboratory in the world. The resulting, positive impact of cross-coupling technology on science and on society has been remarkable. Unfortunately, the majority of cross-coupling is mediated by platinum group metals (e.g. rhodium, palladium, iridium and platinum) and the supply of these costly metals is at risk, thus making their use unsustainable. It is against the backdrop of an uncertain future that the search for new cross-coupling methods that do not use a metal or use a low-cost metal catalyst has gripped the global synthetic community. The world's leading scientists now share a vision of a chemical community less reliant on platinum group metals.There is an additional problem with the current methods for cross-coupling. Molecule-makers traditionally use starting, chemical feedstocks that are already 'functionalised'; i.e. they contain a 'handle' that facilitates chemical manipulation. If simpler, non-functionalised feedstocks could be used instead, shorter, less expensive chemical processes that generate less waste could be developed. With the promise of more sustainable chemistry in the future, the global synthetic community are eager to move away from 'functionalised' feedstocks to simpler starting materials that are functionalised and chemically transformed as part of a single process. Finally, metal-free cross-coupling has an additional key benefit. Trace metal contamination in products arising from metal-catalysed processes is a major problem in industry, particularly the pharmaceutical and organic electronic industries, where products are for human consumption or for use in devices where performance can be compromised by 'undetectable' levels of metal contaminant.In this project we will develop metal-free and low-cost metal catalysed cross-coupling processes that could eventually replace ubiquitous metal-catalysed technologies that use expensive platinum group metals. Our approach to this challenge is unique and is based on the proposal that sulfur can replace metals in; (i) activating substrates by functionalising them in situ, and (ii) providing a center around which coupling partners can be assembled prior to carbon-carbon bond-formation. More specifically, we will use readily-available and tuneable, organosulfur species, called sulfoxides, as reagents and catalysts to active simple feedstocks for direct use in new cross-couplings that deliver high value products. Crucially, our approach does not require pre-functionalised feedstocks for cross-coupling as activated substrates will be formed in situ and used directly in the same reaction vessel. At the heart of our proposal lies the so-called Interrupted Pummerer reaction, a little-known and seldom exploited chemical process in which a nucleophile adds to the sulfur of a sulfoxide to give a sulfonium salt. Our groundbreaking strategies will either be metal-free or will use inexpensive base-metal catalysts, thus avoiding the need for expensive, supply-risk, and contaminating platinum group metals.Applications in the synthesis and modification of materials and pharmaceuticals will be used throughout the project to showcase the utility of our new technology to molecule makers and end-users, thus plotting a course to future impact. Our track record in innovative cross-coupling processes using sulfoxides leaves us uniquely placed to meet this challenge.

合成化学是推动科学技术进步的引擎，因为人造分子和材料对世界各地数百万科学家的工作至关重要。特别是，选择性地形成碳-碳键，即所谓的“交叉偶联”，是几乎任何合成努力的核心，对发现明天的制药、农用化学品和先进材料至关重要。人们已经开发了一套使用金属催化剂的交叉偶联反应来形成碳-碳键，这些方法经常被世界上每个化学实验室使用。由此产生的交叉耦合技术对科学和社会产生了显著的积极影响。不幸的是，大多数交叉耦合是由铂族金属(例如，Rh、Pd、Ir和Plum)调节的，这些昂贵金属的供应面临风险，因此它们的使用不可持续。正是在未来不确定的背景下，寻找不使用金属或使用低成本金属催化剂的新的交叉偶联方法吸引了全球合成界的注意力。世界顶尖的科学家现在都有一个共同的愿景，那就是一个化学界对铂族金属的依赖程度降低。目前的交叉偶联方法还有一个额外的问题。传统上，分子制造商使用的是已经“功能化”的起始化学原料；也就是说，它们包含一个便于化学操作的“手柄”。如果可以使用更简单、非功能化的原料，就可以开发出更短、成本更低、产生更少废物的化学工艺。由于未来有望实现更可持续的化学，全球合成界迫切希望从‘功能化’原料转向更简单的起始材料，这些材料作为单一工艺的一部分进行功能化和化学转化。最后，无金属交叉耦合还有一个额外的关键好处。金属催化过程中产生的产品中的微量金属污染是工业中的一个主要问题，特别是制药和有机电子行业，这些行业的产品供人类消费或用于设备中，这些设备的性能可能会受到无法检测到的金属污染物的影响。在这个项目中，我们将开发无金属和低成本的金属催化交叉耦合过程，最终可能取代使用昂贵的铂族金属的无处不在的金属催化技术。我们应对这一挑战的方法是独一无二的，基于以下建议：硫可以取代金属；(I)通过原位功能化来激活衬底，以及(Ii)提供一个中心，在碳-碳键形成之前，偶联伙伴可以围绕这个中心组装。更具体地说，我们将使用容易获得和可调节的有机硫物种，称为亚硫醚，作为试剂和催化剂，激活简单的原料，直接用于提供高价值产品的新的交叉联结。重要的是，我们的方法不需要用于交叉偶联的预先功能化的原料，因为活化的底物将在原位形成并直接在同一反应容器中使用。我们提议的核心是所谓的中断的Pummerer反应，这是一种鲜为人知、很少被利用的化学过程，在这个过程中，亲核试剂与亚硫醚的硫相加得到硫盐。我们的突破性战略将是不含金属的，或者将使用廉价的贱金属催化剂，从而避免昂贵、供应风险和污染铂族金属的需要。材料和药物的合成和修改中的应用将在整个项目中使用，向分子制造商和最终用户展示我们新技术的实用性，从而规划出未来影响的道路。我们在使用亚硫醚的创新交叉偶联工艺方面的记录使我们在迎接这一挑战方面处于独特的地位。