New Approaches to Catalyst Screening and Development

催化剂筛选和开发的新方法

基本信息

批准号：
2102705
负责人：
David Hage
金额：
$ 57.5万
依托单位：
University of Nebraska-Lincoln
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102705&HistoricalAwards=false
关键词：
New Approaches Catalyst Screening Development

项目摘要

This research project builds on a platform being developed by the University of Nebraska research team to exploit enzymes as catalytic reporters to facilitate reaction discovery and catalyst optimization. This approach is termed In Situ Enzymatic Screening. The method utilizes ‘reporting enzymes’ to provide real-time information on the relative rates for a set of parallel organic/organometallic reactions of interest. Parallel screening methods are of interest to chemists in academia and industry as they enable the identification of fundamentally new transformations of novel catalysts for targeted reactions. There is a particular need for focused screening in process chemistry groups in the pharmaceutical industry, where reaction optimization is critical. This project seeks to develop new enzymatic screening tools that are applicable across a range of temperatures and that take advantage of phosphate ester functionality for which enzymatic screens are not yet available. The project will also help build the future STEM (science, technology, engineering, and mathematics) workforce by training a diverse group of undergraduate and graduate students in an interdisciplinary research environment at the chemistry/biology interface, including elements of organic, organometallic, analytical, and enzymatic chemistry. This project will further explore and develop an information-rich parallel screening method, termed In Situ Enzymatic Screening (ISES), that uses enzymes as biomacromolecular sensors to provide read-out directly to the experimentalist. This research builds upon the team's earlier proof-of-concept studies that led to the first examples of catalytic asymmetric allylic amination chemistry with nickel, an earth-abundant metal, and that uncovered a useful new transformation for diversity-oriented synthesis known as thiocyanopalladation/carbocyclization. This proposal seeks to fully launch the ‘phosphate-ISES’ and ‘thermal-ISES’ screening platforms. The former goal is motivated by the emergence and importance of substrates bearing dialkyl phosphate functionalities, an important functional group both for transition metal coordination and for specific chemistry. These new enzymatic screening platforms have been built by expressing and testing candidates for screening enzymes that recognize dialkyl phosphates and/or that operate at elevated temperatures. Preliminary results point to enzymes that produce a UV/vis signal under such conditions, enabling the screening of candidate metal-ligand combinations at elevated temperatures or in reactions where dialkyl phosphate functionalities are critical. These methods are being developed with specific targeted chemistry in mind, particularly the catalytic asymmetric synthesis of alpha-halovinyl amino acids as potential mechanism-based inhibitors for PLP (pyridoxal phosphate) enzymes. This synthetic goal builds on recent developments in this laboratory in which quaternary, alpha-(1’-fluoro) vinyl amino acids were synthesized for the first time. The scientific broader impacts of this work include opening new avenues for the catalyst discovery process and for green and sustainable chemistry.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.

该研究项目建立在由内布拉斯加大学研究小组开发的平台上，利用酶作为催化生产者来促进反应发现和催化剂优化。该方法利用“报告酶”来提供真实的酶。一组感兴趣的平行有机/有机金属反应的相对速率的时间信息平行筛选方法引起了学术界和工业界的化学家的兴趣，因为它们能够识别新型催化剂的全新转化。制药行业的过程化学组特别需要集中筛选，其中反应优化至关重要，该项目旨在开发适用于各种温度并利用磷酸酯的新酶筛选工具。该项目还将通过在化学/生物学的跨学科研究环境中培训多元化的本科生和研究生群体，帮助培养未来的 STEM（科学、技术、工程和数学）劳动力。界面，包括有机元素，该项目将进一步探索和开发一种信息丰富的平行筛选方法，称为原位酶筛选（ISES），该方法使用酶作为生物大分子传感器直接向实验人员提供读数。建立在该团队早期的概念验证研究的基础上，该研究产生了与镍（一种地球上储量丰富的金属）催化不对称烯丙基胺化化学的第一个例子，并且发现一种用于多样性导向合成的有用的新转化，称为硫氰基钯化/碳环化。该提案旨在全面启动“磷酸盐-ISES”和“热-ISES”筛选平台，前一个目标是由带有二烷基的底物的出现和重要性推动的。磷酸官能团是过渡金属配位和特定化学的重要官能团，这些新的酶平台筛选是通过表达和测试用于筛选识别二烷基磷酸酯和/或操作的酶的候选物而构建的。初步结果表明，在这种条件下，酶可以产生紫外/可见光信号，从而能够在高温下或在磷酸二烷基酯功能至关重要的反应中筛选候选金属-配体组合。考虑到化学，特别是α-卤代乙烯基氨基酸的催化不对称合成作为PLP（磷酸吡哆醛）酶的潜在基于机制的抑制剂，该合成目标建立在该实验室的最新进展之上，其中首次合成了四元 α-(1'-氟) 乙烯基氨基酸。这项工作在科学上产生了更广泛的影响，包括为催化剂发现过程以及绿色和可持续化学开辟了新途径。该奖项反映了 NSF 的法定使命和使命。通过使用基金会的智力优点和更广泛的影响审查标准进行评估，该项目被认为值得支持。