UNS: New Approaches to Catalyst Screening and Development

PI：Stephen G DiMagnoProposal编号：1500076催化剂是促进化学反应的材料，用于从各种原材料中生产工业化学品、燃料、塑料和药品。一个根本性的科学挑战是设计催化剂，使其对特定类型的反应具有活性。在自然界中，被称为酶的生物催化剂具有非常特殊的催化功能。该项目的总体目标是使用酶来帮助指导新催化剂材料的设计。关键的新奇之处在于，酶筛选过程报告了候选催化剂是否能够进行立体化学，这是制造许多有价值的化合物和药物的基础。在这一持续的努力中，将开发和研究涉及立体化学的复杂化学反应。一个可能的目标是一种更有效的方法来合成商业药物，如普瑞巴林。该项目的教育活动包括在生物和化学的交界处对研究生和博士后研究助理进行培训，以及通过化学日对高中生进行推广。这项由NSF支持的研究计划的继续重点是使用酶通过一种名为原位酶筛选(ISES)的过程来帮助识别合成有机化学中感兴趣的催化剂。ISES中使用的报告酶是手性传感器，可提供候选催化剂的相对速率、立体选择性和底物范围的信息。这项更新提案将使用ISES工具和ISES筛查结果之前的发现来推进三个目标。第一个目标是扩展Rh和Pd介导的(伪)卤化/碳环化转化，改变环的大小，探索后环化/交叉复分解和闭环复分解之间的竞争，检查其他亲核试剂，并测试机械假设，特别是关于碳环化步骤的立体化学过程。第二个目标是扩大ISES方法的范围，特别关注通过三种酶对开发磷酸二乙酯离开基团和乙酸乙酯离开基团的活酶对。为此，产气假单胞菌将表达候选的二烷基磷酸酶报告酶，该酶将与酒精脱氢酶一起用于筛选直接涉及磷酸二乙酯置换的金属配体介导的烯丙基取代。第三个目标是寻找可行的催化组合，用于3-取代氧杂环己烷和N-保护氮杂环丁烷的亲核开环去对称化反应。如果成功，这种化学将为β(2)-氨基酸(AAs)和伽马(3)-AAs的不对称合成提供一个全新的领域。

PI: Stephen G DiMagnoProposal Number: 1500076Catalysts are materials that promote chemical reactions for production of industrial chemicals, fuels, plastics, and pharmaceuticals from a wide variety of raw materials. A fundamental scientific challenge is to design the catalyst to be active for a specific type of reaction. In Nature, biological catalysts called enzymes have very specific catalyst functions. The overall goal of this project is to use enzymes to help guide the design of new catalyst materials. The key novelty is that the enzyme screening process reports if the catalyst candidate is capable of performing stereochemistry, which is fundamental to making many valuable compounds and pharmaceuticals. In this continuing effort, complex chemical reactions involving stereochemistry will be developed and studied. One possible target is a more efficient approach to synthesis of commercial drugs like Pregabalin. The educational activities of the project include training of graduate students and post-doctoral research associates at the interface of biology and chemistry, as well as high school student outreach through Chemistry Day.This proposed continuation of NSF-supported research focuses on the use enzymes to help identify catalysts of interest for synthetic organic chemistry through a process called In Situ Enzymatic Screening (ISES). The reporting enzymes used in ISES are chiral sensors that provide information the relative rate, stereoselectivity, and substrate scope of catalyst candidates. This renewal proposal will use ISES tools and previous discoveries from ISES screening outcomes to advance three Aims. The first Aim is to extend both the Rh- and Pd-mediated (pseudo) halometalation/carbocyclization transformations various ring sizes, explore competition between post-cyclization/cross-metathesis and ring-closing metathesis, examine other nucleophiles, and test mechanistic postulates, particularly regarding the stereochemical course of the carbocyclization step. The second Aim is develop the scope of the ISES method, with specific focus on developing viable enzyme couples for both the diethyl phosphate leaving group and for the acetate leaving group through a three enzyme couple. Towards this end, candidate dialkyl phosphatase reporting enzymes will be expressed from E. aerogenes, and this enzyme will be used, in tandem with an alcohol dehydrogenase, to screen for metal-ligand mediated allylic substitution directly that involves displacement of the diethyl phosphate. The third Aim seeks to identify viable catalytic combinations for the desymmetrization of 3-substituted oxetanes and N-protected azetidines via nucleophilic-opening. If successful, this chemistry would provide a fundamentally new entry into the asymmetric synthesis of beta(2)-amino acids (AAs) and of gamma(3)-AAs.