UNS: New Approaches to Catalyst Screening and Development

催化剂是一种促进化学反应的材料，用于从各种各样的原材料生产工业化学品，燃料，塑料和药品。一个基本的科学挑战是设计对特定类型的反应具有活性的催化剂。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利用酶来帮助指导新催化剂材料的设计。关键的新颖之处在于，酶筛选过程报告了候选催化剂是否能够进行立体化学反应，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，涉及立体化学的复杂化学反应将得到发展和研究。一个可能的目标是更有效地合成像普瑞巴林这样的商业药物。该项目的教育活动包括培养生物学和化学领域的研究生和博士后研究助理，以及通过化学日向高中生进行宣传。这项由美国国家科学基金会（nsf）支持的研究计划的延续，重点是通过原位酶筛选（ISES）的过程，利用酶来帮助识别合成有机化学感兴趣的催化剂。在ISES中使用的报告酶是手性传感器，提供有关催化剂候选物的相对速率、立体选择性和底物范围的信息。该更新建议将使用ISES工具和先前从ISES筛选结果中发现的发现来推进三个目标。第一个目标是将Rh-和pd介导的（伪）卤金属化/碳环化转化扩展到不同的环尺寸，探索环化后/交叉复分解和闭合环复分解之间的竞争，检查其他亲核试剂，并测试机制假设，特别是关于碳环化步骤的立体化学过程。第二个目标是发展ISES方法的范围，特别关注通过三酶对为磷酸二乙酯离去基和乙酸离去基开发可行的酶偶。为此，候选二烷基磷酸酶报告酶将从产气大肠杆菌中表达，该酶将与醇脱氢酶串联使用，以筛选金属配体介导的烯丙基取代，直接涉及磷酸二乙酯的置换。第三个目标旨在通过亲核开孔确定可行的催化组合，用于3-取代的氧乙烷和n -保护的氮杂苷的去对称化。如果成功的话，这种化学反应将为不对称合成β(2)-氨基酸（AAs）和γ(3)-氨基酸（AAs）提供一个全新的途径。

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.