Discovering Modular Catalysts for Asymmetric Synthesis with Computation

科罗拉多州立大学化学系的Robert Paton博士获得了化学系化学催化项目的奖励，为发现手性催化剂开发了新的计算方法。手性分子的制备在药物、农用化学品和材料的发现中起着至关重要的作用。新批准的药物以单对映体、手性化合物为主。Paton博士的团队开发了新的理论和模拟方法，以加速发现用于高选择性构建手性分子的新催化剂和新反应。这将与新的机械发现和与实验家的合作携手并进，拓宽参与科学家的视野。该研究团队将包括本科生和研究生研究人员，他们将学习与现代STEM工作场所相匹配的各种技能，并将通过科罗拉多州的外展活动吸引公众。人们普遍认为，在发现新的催化剂结构时，需要用合理的方法来代替经验筛选。在这个项目中，Robert Paton博士正在开发计算协议，将小分子片段结合到已知偶联反应的合成逻辑中，以构建和优化不对称转化的催化剂结构。虚拟催化剂库正在使用空间和电子性质的计算化学描述以自动化的方式组装和映射。目前正在开发一种分类方法，将深入的量子化学努力引向催化剂空间中最有利可图的领域，以促进对映选择性氢键相转移催化、双功能有机催化和涉及金属-磷酰胺配合物的转化。在每一种情况下，新的机理发现都揭示了给定底物的催化活性和高对映体选择性的结构先决条件。大型催化剂库的自动化构建，以及空间和电子参数的计算为更广泛的社区提供了使用的大型数据集。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Dr. Robert Paton of the Department of Chemistry at Colorado State University is supported by an award from the Chemical Catalysis program in the Division of Chemistry to develop new computational approaches for chiral catalyst discovery. The preparation of chiral molecules plays a vital and enabling role in the discovery of medicines, agrochemicals, and materials. Newly approved drugs are dominated by single enantiomer, chiral compounds. Dr. Paton’s group develops new methods of theory and simulation to accelerate the discovery of new catalysts and new reactions for the highly-selective construction of chiral molecules. This will go hand-in-hand with new mechanistic discoveries and collaborations with experimentalists that broaden the horizons of participating scientists. The research team, which will include undergraduate and postgraduate researchers, will learn a diverse array of skills well-aligned with the modern STEM workplace and will engage the public through outreach events in Colorado.There is a widely recognized need for rational approaches to replace empirical screening in the discovery of new catalyst structures. In this project, Dr. Robert Paton is developing computational protocols that combine small-molecule fragments adhering to the synthetic logic of known coupling reactions to construct and optimize catalyst architectures for asymmetric transformations. Virtual catalyst libraries are being assembled and mapped in an automated fashion using computational chemistry descriptions of steric and electronic properties. A triaged approach is being developed that directs in-depth quantum chemical efforts towards the most profitable areas of catalyst space to promote enantioselective hydrogen-bonding phase-transfer catalysis, bifunctional organocatalysis, and transformations involving metal-phosphoramidite complexes. In each case, new mechanistic discoveries are revealing the structural pre-requisites for catalytic activity and high enantioselectivity for a given substrate. The automated construction of large catalyst libraries, and the computation of steric and electronic parameters are providing that large datasets of use to the broader community.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.