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

合成化学是推动科学和技术进步的引擎，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，碳-碳键的选择性形成，即所谓的“交叉偶联”，几乎是所有合成工作的核心，对于发现未来的药物、农用化学品和先进材料至关重要。已经开发了一套使用金属催化剂的交叉偶联反应用于碳-碳键的形成，这些方法在世界上每个化学实验室都是常规使用的。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，大多数交叉偶联是由铂族金属（例如铑、钯、铱和铂）介导的，并且这些昂贵金属的供应存在风险，从而使得它们的使用不可持续。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交叉偶联方法已经吸引了全球合成界。世界顶尖的科学家们现在都有一个共同的愿景，那就是减少对铂族金属的依赖。分子制造商传统上使用已经“功能化”的起始化学原料;即它们含有促进化学操作的“手柄”。如果可以使用更简单的非功能化原料，则可以开发更短，更便宜的化学工艺，产生更少的废物。随着未来可持续化学的发展，全球合成界都渴望从“功能化”原料转向更简单的起始材料，这些材料作为单一过程的一部分进行功能化和化学转化。最后，无金属交叉耦合具有额外的关键优势。由金属催化过程产生的产品中的痕量金属污染是工业中的主要问题，特别是制药和有机电子工业，其中产品是供人类消费或用于设备中的性能可能会受到“无法检测”的金属污染物水平的影响。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偶联工艺，最终可以取代无处不在的金属-使用昂贵的铂族金属的催化技术。我们应对这一挑战的方法是独特的，并且基于硫可以取代金属的提议：（i）通过原位官能化活化底物，以及（ii）提供一个中心，在碳-碳键形成之前可以围绕该中心组装偶联伙伴。更具体地说，我们将使用容易获得和可调的有机硫物质，称为亚砜，作为试剂和催化剂，以活化简单的原料，直接用于提供高价值产品的新交叉偶联。至关重要的是，我们的方法不需要用于交叉偶联的预官能化原料，因为活化的底物将原位形成并直接在同一反应容器中使用。我们建议的核心是所谓的中断Pummerer反应，这是一个鲜为人知且很少开发的化学过程，其中亲核试剂添加到亚砜的硫中以产生锍盐。我们的突破性策略将是无金属或使用廉价的贱金属催化剂，从而避免对昂贵、供应风险和污染的铂族金属的需求。在整个项目中，材料和药物的合成和改性应用将被用于向分子制造商和最终用户展示我们的新技术的实用性，从而绘制未来影响的路线。我们在使用亚砜的创新交叉偶联工艺方面的记录使我们在应对这一挑战方面处于独特的地位。

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.