Improving Efficiency in Organic Synthesis via Metal and Multimetal Catalysis

我们的目标是在制作具有药用价值的生物活性产品支架时提高合成效率。我们的研究直接影响到多个领域，包括制药、农用化学品和材料化学。这一群体的毕业生受到这些行业的热捧。机器学习和实验算法的设计正在对有机合成产生越来越重要的影响。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集。然而，新反应的发明仍然是人类聪明才智继续发挥核心作用的关键步骤之一。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。我们的研究项目旨在发明新的金属和多金属催化反应。我们应对更高效率挑战的项目包括：多催化：化学家一直在发明金属催化剂，这种催化剂对底物具有广泛的选择性，但仍具有反应特异性。我们创造了我们的方法多组分-多催化剂反应，(MC)2R，作为一种策略，通过由不同金属络合物促进的“时间分辨”合成序列，从简单的构建块构建复杂的产品。我们观察到选择性是由于I)配体与金属之间的优先结合或II)一个金属-配体络合物相对于其他可能的络合物的优先速率的增加。我们之前的工作重点是昂贵的金属，如铑和钯，但我们的下一代(MC)2R将使用贱金属，如镍、铜和钴。此外，我们将建造可以同时结合不止一种金属的配体支架，以创建一条可能显示速度加速的“装配线”配体。最终目标是使用(MC)2R来寻找新的反应。异构化反应：原料(S)的所有原子都出现在产物中的反应的发明。我们寻求增加复杂性但最大限度减少浪费的反应。“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的C-C和C-X成键反应，这是提案中概述的一个关键领域。多米诺反应：我们将在多米诺反应的基础上开发合成有用的碳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，并将在这一新兴领域进行研究。我们还发现了不对称的硼铜化多米诺反应，并将探索该反应在制备杂环支架方面的合成潜力。钴是一种很有吸引力的催化金属，我们发现环化和C-H活化的多米诺骨牌过程是关键步骤。该提案概述了我们将如何探索这一方法的综合潜力。

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.