Mechanistic Studies of Halenium-Alkene Additions for Chemical Catalysis

在化学系化学催化计划的支持下，密歇根州立大学的Babak Borhan教授和James E.Jackson教授正在研究新的方法，以控制在同一操作中产生碳-卤键和碳-亲核键的反应中产物的三维结构和“利手性”。这些反应的产物是许多应用的重要的手性构件，例如，用于合成药物活性物质或农用化学品。博尔汉-杰克逊团队正在努力扩大和改进方法，以从简单得多的起始物质中催化形成一系列特定的所需利手的化合物。先进的分析技术将应用于研究领域，这样就可以合理地设计出更好的催化剂，而不是过去基本上反复试验的方法。最终，预计这项工作将导致对科学、工程、医学和商业具有重要意义的手性分子的更有效的制造过程。该资助项目的更广泛影响将扩展到允许两名PI及其同事通过SEED项目等计划在实验室招聘、培训和科学激励高中生和本科生。这些早期理科学生中的许多人属于在物理科学中代表性较低的群体，他们参与到一个充满活力的国际实验室和学习社区中，有可能帮助多样化的学生池考虑未来的STEM(科学，技术，工程和数学)为基础的学习和职业。最近，烯烃的卤代官能化已经加入了广泛应用和真正有用的化学转化的名单，可以通过使用手性催化的对映选择性的方式实现。然而，到目前为止，用于不对称卤烯加成过程的最有效的催化剂，例如众所周知的金鸡纳生物碱二聚体(DHQD)2PHAL，主要是在经验的基础上确定的。这一合作项目侧重于对重要类别的卤代官能化反应进行详细的机理分析，目的是使合理设计既负担得起又具有高度选择性的简化和实用的新型催化剂。所采取的方法是多方面的，涉及反应动力学、同位素标记示踪、动力学同位素效应、量子化学模型以及光谱分析和结构分析，特别注意底物烯烃、卤化剂和催化剂反应中心之间的相互作用。以烯丙基酰胺为重点，研究小组将调查分子内卤代环化和分子间卤代官能化，推导每类反应的速率定律，并确定控制机理途径的因素。感兴趣的烯烃加成一步形成两个新的立体中心，潜在地产生四个结构不同的手性产物，或者当两种区域化学可能性都可能获得时，甚至八个。从简单的烯烃原料出发，这种复杂的、富含官能团的产品的多样性是有价值的，但前提是选择性可以控制。这项研究旨在提供实现通用催化剂和工艺设计所需的智力基础，在机理理解的基础上加速发现。如果成功，这些合作的实验/机理研究将为立体选择性催化剂的设计和开发提供一个有用的模型，远远超出这里研究的卤代-烯烃加成反应。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemical Catalysis Program in the Division of Chemistry, Professors Babak Borhan and James E. Jackson of Michigan State University are studying new methods to control the three-dimensional structure and "handedness" of products in reactions that generate carbon-halogen and carbon-nucleophile bonds in the same operation. The products of these reactions serve as important chiral building blocks for many applications, for example, for the synthesis of pharmaceutically active agents or of agrochemicals. The Borhan-Jackson teams are working to expand and refine methods to catalyze the formation of a wide range of compounds of a specific desired handedness from much simpler starting substances. Sophisticated analysis techniques will be brought to bear on the areas of study such that superior catalysts can be rationally designed, in contrast to the essentially trial-and-error approaches used in the past. Ultimately, it is anticipated that this work will lead to more efficient processes for the manufacture of chiral molecules of importance to science, engineering, medicine, and commerce. The broader impacts of the funded project will extend to allowing the two PIs and their coworkers to recruit, train, and scientifically stimulate high school and undergraduate students in the laboratory via programs such as Project SEED. The involvement of these early stage science students many of whom belong to groups underrepresented in the physical sciences, in a dynamic, international lab and learning community, has the potential to help diversify the pool of students considering future STEM (science, technology, engineering and mathematics)-based study and careers.Halofunctionalizations of alkenes have recently joined the list of broadly applicable and genuinely useful chemical transformations that can be achieved in an enantioselective manner using chiral catalysis. However, to date, the most effective catalysts for asymmetric halenium-alkene addition processes, for example the well-known cinchona alkaloid dimer (DHQD)2PHAL, have been identified largely on an empirical basis. This collaborative project focuses on detailed mechanistic analyses of important classes of halofunctionalization reactions with the goal of enabling the rational design of simplified and practical new catalysts that are both affordable and highly selective. The approach taken is multi-faceted and involves examination of reaction kinetics, isotopic label tracing, kinetic isotope effects, quantum chemical models, and spectroscopic and structural analyses, with particular attention to the interactions among substrate alkenes, halogenation agents, and catalyst reactive sites. With an emphasis on allylamides, the investigative team will survey intramolecular halocyclizations and intermolecular halofunctionalizations, derive rate laws for each class of reaction, and determine the factors that control the mechanistic pathways. The alkene additions of interest form two new stereocenters in one step, potentially giving rise to four structurally distinct chiral products, or even eight when both regiochemical possibilities may be accessed. Coming from simple olefinic starting materials, this diversity of complex, functional group rich products is valuable, but only if the selectivity can be controlled. This research aims to provide the intellectual foundation needed to achieve generalized catalyst and process design, accelerating discovery based upon mechanistic understanding. If successful, these collaborative experimental/mechanistic studies will provide a useful model for the design and development of stereoselective catalysts well beyond the halenium-alkene addition reactions under study here.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.