Designing Olefin Metathesis Catalysts for Frontier Opportunities in Chemical Biology and Beyond

我们研究的一个主要目标是设计坚固的、选择性的催化剂，通过烯烃歧化反应促进碳-碳键的形成。烯烃复分解是目前用于催化形成C-C键的最通用、最强大的工具之一。2005年诺贝尔奖认可了它的范围，以及它在改善对人类健康和福祉至关重要的分子可持续生产方面的潜力。然而，到目前为止，这些变革性的机会受到促成反应的催化剂分解的限制。虽然易操作的催化剂在有机合成中扩大了烯烃歧化反应的吸收起到了重要作用，但近年来随着人们将注意力转向在具有挑战性的环境中进行歧化反应，它们的局限性已经开始被认识到。事实上，短的使用寿命使得这些催化剂在生产过程中不足以产生足够的生产力。在其他要求苛刻的环境中，如化学生物学，它们的性能是不可预测的，尽管过度使用(即，作为反应物而不是催化剂)。克服这些挑战的关键是了解基本的无机化学：催化剂在反应条件下的意外行为。我们通过系统地揭示潜在的分解途径，并将这些途径与特定的设计弱点联系起来，在这一领域做出了独特的、世界领先的贡献。在短期内，基础无机化学的知识为如何最好地实施化合过程提供了指导方针。从长远来看，它能够设计出新的、寿命更长、生产效率更高的催化剂。这一提议旨在开发能够实现复分解的巨大前景的高性能催化剂。我们将在现有理解的基础上，消除代表当前技术水平的催化剂中的一个关键弱点。我们还将追求新的能力。目前，还没有在水中保持高活性的复分解催化剂，这也是因为水会引发分解。这一点很重要，因为水无处不在，而且它的负面影响被广泛忽视。我们已经确定了与最大耐水性相关的关键结构特征，我们将利用这些特征开发用于化学生物学的催化剂，包括在DNA存在的情况下。这将为生物分子在其天然介质中的高效转化打开大门。因此，对富含水分的环境，或许还有活细胞进行分子标记的长期目标可能会实现。我们还将探索新的设计范式，包括基于富含地球的金属镍的复分解催化剂。后者是一个艰巨但诱人的目标。廉价的镍催化剂可以提高复分解过程的经济可行性，而镍相对于铂开采的副产品钚(Ru)的环境足迹要小得多，也非常有吸引力。

A major goal of our research is the design of robust, selective catalysts that promote the formation of carbon-carbon bonds via the olefin metathesis reaction. Olefin metathesis is one of the most versatile, powerful tools now in use for the catalytic formation of C-C bonds. Its scope, and its potential to improve the sustainable production of molecules essential to human health and well-being, were recognized with the 2005 Nobel Prize. To date, however, these transformative opportunities are limited by decomposition of the catalysts that enable reaction. While easily-handled catalysts played a major role in expanding the uptake of olefin metathesis in organic synthesis, their limitations have begun to be acknowledged in recent years, as attention turned to carrying out metathesis reactions in challenging contexts. In fact, short lifetimes makes these catalysts insufficiently productive for use in manufacturing processes. In other demanding contexts, such as chemical biology, their performance is unpredictable despite use in excess (that is, as reactants instead of catalysts). Essential to overcome these challenges is an understanding of the underlying inorganic chemistry: the unintended behaviour of the catalyst under the conditions of reaction. We have made unique, world-leading contributions to this area by systematically uncovering the underlying decomposition pathways, and tying these to specific design weaknesses. in the short term, knowledge of the underlying inorganic chemistry provides guidelines for how best to implement metathesis processes. In the longer term, it enables design of new, longer-lived, more productive catalysts. This proposal is aimed at developing high-performing catalysts capable of realizing the great promise of metathesis. We will build on our present understanding to eliminate a key weakness in the catalysts that represent the current state of the art. We will also pursue new capabilities. At present, there are no metathesis catalysts that retain high activity in water, again because water triggers decomposition. This is important, because water is ubiquitous, and because its negative impact has been widely overlooked. We have identified key structural features associated with maximum water-tolerance, which we will use to develop catalysts for use in chemical biology, including in the presence of DNA. These would open the door to efficient transformations of biological molecules in their native media. Long-standing goals for the facile tagging of molecules water-rich environments, and perhaps living cells, may thus be realized. We will also explore new design paradigms, including metathesis catalysts based on the earth-abundant metal nickel. The latter is an ambitous but enticing goal. Cheap Ni catalysts could improve the economic feasibility of metathesis processes, while the much smaller environmental footprint of nickel relative to ruthenium (a byproduct of platinum mining) is also immensely attractive.