Improving Efficiency in Organic Synthesis via Catalytic Reactions

通过催化反应提高有机合成效率

• 批准号: RGPIN-2015-05553
• 负责人: Lautens, Mark
• 金额: $ 9.11万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613620
• 关键词: Improving; Efficiency; Organic; Synthesis; via

The future of organic synthesis requires chemists to discover and develop new reactions and new strategies in order to address the pressing issues of identifying new medicinal agents, agrochemicals and materials while at the same time producing less waste and finding more efficient ways of making the end products. Our research addresses two significant and enduring problems associated with improving efficiency in organic synthesis. We seek to identify new chemical transformations that have the potential to change how we make a product of interest by expanding the repertoire of chemical reactions that are available to the community. Ideally new reactions are simple combinations of the reacting partners so as to minimize waste. Reactions need to be scalable, simple and practical if they are to be widely adopted. In addition we are identifying new strategies to streamline the ways synthesis is conducted in the laboratory so as to reduce the waste associated with operations in a synthetic sequence. We have had success in both these areas for the past decade and have recently made several discoveries that have propelled our work in new and exciting directions. A typical synthetic sequence involves mixing all reagents in a solvent, an extractive work-up and purification of the products (chromatography, distillation, crystallization). This sequence is repeated over and over. At each step there is a considerable amount of waste, often far exceeding the amount of actual product isolated. In contrast Nature has all of the necessary reaction components, catalysts and other ingredients present at the outset and each reaction is conducted in the presence of the all other agents. Typically the catalysts are highly evolved to be very selective for a single substrate and so a clearly defined pathway is observed. Chemists seek a broad substrate scope yet have the high selectivity that Nature achieves. Our studies are designed to show that metal catalyzed reactions developed over the past 40 years can co-exist within a single flask and thereby achieve a sequence of chemical reactions with all the catalysts and substrates present at the outset. Success is measured by avoiding work-up and purification after each step and instead a single work-up and purification is done at the end of the entire sequence. Rather than synergistic catalysis we seek "independent sequential catalysis" where each metal (and its associated ligand) preforms the desired reaction while leaving other reagents and products untouched. These studies tackle fundamental questions including metal-ligand binding when multiple metals and ligands are present (thermodynamic stability) as well as the reactivity of each metal-ligand complex (kinetic reactivity) if more than one species is formed. Our goal is to make molecules of interest to the broader chemical community and show that there are simpler ways to make a desired target of interest.

有机合成的未来需要化学家发现和开发新的反应和新的策略，以解决识别新的药剂，农用化学品和材料的紧迫问题，同时产生更少的废物，并找到更有效的方法来制造最终产品。我们的研究解决了与提高有机合成效率相关的两个重要而持久的问题。我们寻求确定新的化学转化，这些化学转化有可能通过扩大社区可用的化学反应库来改变我们制造感兴趣产品的方式。理想的新反应是反应伙伴的简单组合，以减少浪费。如果要广泛采用，反应需要可扩展、简单和实用。此外，我们正在确定新的战略，以简化在实验室中进行合成的方式，从而减少与合成序列中的操作相关的浪费。 在过去的十年里，我们在这两个领域都取得了成功，最近又有了几项发现，这些发现将我们的工作推向了新的令人兴奋的方向。典型的合成顺序包括在溶剂中混合所有试剂、萃取后处理和产物纯化（色谱法、蒸馏、结晶）。这一过程不断重复。在每一步都有相当数量的废物，往往远远超过实际分离的产品量。相比之下，自然界在一开始就有所有必要的反应组分、催化剂和其他成分，每个反应都是在所有其他试剂的存在下进行的。通常，催化剂高度进化为对单一底物具有非常高的选择性，因此观察到明确定义的途径。化学家寻求一个广泛的底物范围，但具有高选择性，自然实现。我们的研究旨在表明，过去40年来开发的金属催化反应可以在一个烧瓶中共存，从而实现一系列化学反应，其中所有催化剂和底物都存在于一开始。通过在每个步骤后避免后处理和纯化，而是在整个序列结束时进行单个后处理和纯化来衡量成功。而不是协同催化，我们寻求“独立的顺序催化”，其中每种金属（及其相关配体）进行所需的反应，而不影响其他试剂和产物。这些研究解决了一些基本问题，包括当存在多种金属和配体时的金属-配体结合（热力学稳定性）以及如果形成多于一种物质时每个金属-配体络合物的反应性（动力学反应性）。我们的目标是使更广泛的化学界感兴趣的分子，并表明有更简单的方法来制造感兴趣的目标。