Improving Efficiency in Organic Synthesis via Metal and Multimetal Catalysis

通过金属和多金属催化提高有机合成效率

• 批准号: RGPIN-2020-04168
• 负责人: Lautens, Mark
• 金额: $ 8.81万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748355
• 关键词: Improving; Efficiency; Organic; Synthesis; via

Our objectives are to improve synthetic efficiency when making medicinally interesting scaffolds of bioactive products. Our research directly impacts diverse fields including pharmaceuticals, agrochemicals and materials chemistry. Graduates of the group are highly sought by these industries. Machine learning and design of experiments algorithms are making an increasing and valuable impact on organic synthesis. So too is automation, using rapid screening to reach the optimal set of conditions in a multivariable setting. Yet the invention of new reactions remains one of the essential steps where human ingenuity continues to play a central role.  Doing so can allow exploration of previously unknown chemical space. The drugs of tomorrow will need novel molecular architectures and new methods are needed to access these structures. Our research program aims to invent new metal and multi-metal catalyzed reactions. Our projects to address the challenges of higher efficiency include: Multicatalysis: Chemists have been inventing metal catalysts that are broadly substrate-selective yet still reaction-specific. We have coined our approach multicomponent-multicatalyst reactions, (MC)2R, as a strategy to build up complex products from simple building blocks through "time-resolved" synthetic sequences each promoted by a different metal complex. We observe selectivity due to i) preferential binding between ligand and metal or ii) preferential rate increases of one metal-ligand complex over other possible complexes. Our prior work focused on expensive metals such as rhodium and palladium but our next generation (MC)2R will use base metals such as nickel, copper and cobalt. Furthermore, we will be building ligand scaffolds that can simultaneously bind more than one metal to create an "assembly line" ligand that could show rate acceleration. The ultimate goal is to use (MC)2R to find new reactions. Isomerization Reactions: The invention of reactions wherein all the atoms of the starting material(s) appear in the product are needed. We seek reactions that increase complexity but minimize waste. "Atom efficiency" is an important objective, particularly catalytic reactions that use less solvent. We recently found base metals including nickel catalyzes novel C-C & C-X bond-forming reactions and this is a key area outlined in the proposal. Domino Reactions: We will be developing enantioselective routes to useful carbo- and heterocyclic compounds based on domino reactions. We have recently reported copper catalyzed domino "click"-cyclization reactions and will be building on this emerging area. We have also found asymmetric borylcupration domino reactions and will explore the synthetic potential of this reaction in making heterocyclic scaffolds. Cobalt is an attractive metal for catalysis and we identified a domino process involving cyclization and C-H activation as key steps. The proposal outlines how we will explore the synthetic potential of this methodology.

我们的目标是提高合成效率时，使医学感兴趣的生物活性产品的支架。我们的研究直接影响到各个领域，包括制药，农用化学品和材料化学。该集团的毕业生受到这些行业的高度追捧。机器学习和实验设计算法正在对有机合成产生越来越大的影响。自动化也是如此，使用快速筛选在多变量设置中达到最佳条件。然而，新反应的发明仍然是人类创造力继续发挥核心作用的重要步骤之一，这样做可以探索以前未知的化学空间。未来的药物将需要新的分子结构，需要新的方法来获得这些结构。我们的研究计划旨在发明新的金属和多金属催化反应。我们致力于解决更高效率的挑战的项目包括：多催化：化学家们一直在发明具有广泛底物选择性但仍具有反应特异性的金属催化剂。我们创造了我们的方法多组分多催化剂反应，（MC）2 R，作为一种策略，建立复杂的产品从简单的积木通过“时间分辨”的合成序列，每个由不同的金属络合物促进。我们观察到选择性是由于i）配体和金属之间的优先结合或ii）一种金属-配体络合物相对于其他可能的络合物的优先速率增加。我们之前的工作主要集中在昂贵的金属，如铑和钯，但我们的下一代（MC）2 R将使用贱金属，如镍，铜和钴。此外，我们将构建配体支架，可以同时结合一种以上的金属，以创建一个“装配线”配体，可以显示速率加速。最终目标是利用（MC）2 R发现新的反应。异构化反应：发明的反应，其中所有的原子的起始材料（S）出现在产品是必要的。我们寻求增加复杂性但减少浪费的反应。“原子效率”是一个重要的目标，特别是使用较少溶剂的催化反应。我们最近发现，包括镍在内的贱金属催化新型C-C和C-X键形成反应，这是提案中概述的一个关键领域。多米诺反应：我们将开发基于多米诺反应的有用的碳和杂环化合物的对映选择性路线。我们最近报道了铜催化的多米诺骨牌“点击”环化反应，并将建立在这一新兴领域。我们还发现了不对称硼铜化多米诺反应，并将探索该反应在制备杂环支架中的合成潜力。钴是一种有吸引力的金属催化剂，我们确定了一个多米诺骨牌过程，包括环化和C-H活化的关键步骤。该提案概述了我们将如何探索这种方法的合成潜力。