Mechanistic Studies of Halenium-Alkene Additions for Chemical Catalysis

在化学系化学催化项目的支持下，Babak Borhan教授和James E。密歇根州立大学的杰克逊正在研究新的方法，以控制在同一操作中产生碳-卤素键和碳-亲核键的反应中产物的三维结构和“手性”。这些反应的产物作为重要的手性结构单元用于许多应用，例如用于合成药物活性剂或农用化学品。Borhan-Jackson团队正在努力扩展和改进方法，以催化从更简单的起始物质形成各种特定所需手性的化合物。与过去使用的基本上是试错法的方法相比，先进的分析技术将对研究领域产生影响，从而可以合理地设计出上级催化剂。最终，预计这项工作将导致更有效的工艺，用于制造对科学，工程，医学和商业具有重要意义的手性分子。资助项目的更广泛影响将扩展到允许两个PI及其同事通过项目SEED等项目在实验室招募，培训和科学地刺激高中和本科生。这些早期科学学生中的许多人属于物理科学中代表性不足的群体，在一个充满活力的国际实验室和学习社区中的参与，有可能有助于使考虑未来STEM的学生群体多样化（科学、技术、工程和数学）-烯烃的卤代官能化最近加入了广泛适用和真正有用的化学品的名单，在一些实施方案中，手性催化剂可以是可以使用手性催化以对映选择性方式实现的非对映异构体转化。然而，迄今为止，用于不对称卤-烯烃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）2 PHAL，已经在很大程度上在经验基础上被鉴定。这个合作项目的重点是详细的卤官能化反应的重要类别的机理分析，使简化和实用的新催化剂，既负担得起的和高选择性的合理设计的目标。所采取的方法是多方面的，包括检查反应动力学，同位素标记示踪，动力学同位素效应，量子化学模型，光谱和结构分析，特别注意底物烯烃，卤化剂和催化剂反应位点之间的相互作用。以烯丙基酰胺为重点，调查小组将调查分子内卤环化和分子间卤官能化，推导出每类反应的速率定律，并确定控制机械途径的因素。感兴趣的烯烃加成在一个步骤中形成两个新的立体中心，潜在地产生四种结构上不同的手性产物，或者当可以访问两种区域化学可能性时甚至八种。从简单的烯烃起始原料出发，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。这项研究的目的是提供所需的知识基础，实现广义催化剂和工艺设计，加速发现的基础上的机械理解。如果成功的话，这些合作实验/机理研究将为设计和开发立体选择性催化剂提供一个有用的模型，远远超出了本文所研究的卤-烯烃加成反应。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.