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

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全世界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”，是几乎所有合成努力的核心，对未来的药品、农用化学品和先进材料的发现至关重要。一套使用金属催化剂的碳-碳键形成交叉偶联反应已经被开发出来，这些方法在世界上每个化学实验室都被常规使用。由此产生的交叉耦合技术对科学和社会的积极影响是显著的。不幸的是，大多数交叉偶联是由铂族金属（如铑、钯、铱和铂）介导的，这些昂贵金属的供应面临风险，因此它们的使用不可持续。在不确定的未来背景下，寻找不使用金属或使用低成本金属催化剂的新型交叉偶联方法吸引了全球合成界的关注。世界领先的科学家们现在有一个共同的愿景，那就是建立一个不那么依赖铂族金属的化学社区。当前交叉耦合的方法还有一个额外的问题。分子制造者传统上使用已经“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，就可以开发出产生更少废物的更短、更便宜的化学过程。随着未来更可持续化学的发展，全球合成界渴望从“功能化”原料转向更简单的起始材料，这些材料可以作为单一过程的一部分进行功能化和化学转化。最后，无金属交叉耦合还有一个额外的关键好处。金属催化过程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工业，其中产品供人类消费或用于设备，其性能可能因“无法检测”的金属污染物水平而受到损害。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工艺，最终可能取代普遍使用昂贵的铂族金属的金属催化技术。我们应对这一挑战的方法是独一无二的，它基于硫可以取代金属的建议；(i)通过原位功能化底物来激活底物，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，我们将使用易于获得和可调的有机硫物种，称为亚砜，作为活性简单原料的试剂和催化剂，直接用于提供高价值产品的新型交叉偶联。至关重要的是，我们的方法不需要预先功能化的原料进行交叉偶联，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。我们的建议的核心是所谓的中断脉冲反应，这是一个鲜为人知且很少被利用的化学过程，在这个过程中，亲核试剂与亚砜的硫结合，产生磺酸盐。我们的突破性策略要么是不含金属，要么是使用廉价的贱金属催化剂，从而避免了对昂贵、供应风险和污染铂族金属的需求。在材料和药物的合成和修饰方面的应用将贯穿整个项目，向分子制造商和最终用户展示我们的新技术的实用性，从而为未来的影响绘制路线。我们在使用亚砜的创新交叉耦合工艺方面的记录使我们能够独特地应对这一挑战。

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.