Palladium-Catalyzed Tsuji-Trost Reaction in Complex Mixtures

在这个由化学系化学结构、动力学和机制B计划资助的项目中，匹兹堡大学化学系的Kazunori Koide教授将研究用于痕量金属分析的新型化学试剂，并开发能够使非细胞渗透分子细胞渗透的化学技术。这两个目标对人类健康都很重要，因为它们可以导致新药物的开发。该项目位于有机化学、无机化学和生物化学的交界处，因此非常适合各级科学家的教育。这一群体也处于有利地位，可以为本科生和研究生以及博士后研究人员提供最高水平的教育和培训。该研究小组积极开展外联活动，包括招募不具代表性的少数族裔学生进行暑期研究和参加本科生研究专题讨论会。钯催化的脱烯丙基反应(Tsuji-Trost反应)是一种在有机合成中广泛应用的反应，曾被尝试用于化学传感和化学生物学。虽然取得了可喜的成果，但仍有必要进一步改进。作为使用荧光Tsuji-Trost反应进行Pd定量的平台，其动态范围还不够宽。作为化学生物学的一种手段，虽然在中性磷酸盐缓冲液中反应是有效的，但在细胞培养液中反应要慢一个数量级以上。在这个项目中，有两个具体的目标：(1)建立一种高通量定量钯的荧光或比色方法；(2)在培养的人类细胞中建立一种生物相容的Tsuji-Trost反应来检测生物活性分子。针对具体目标1，课题组将利用艾林图和测量活化能来合理调整动力学曲线。对于特定的目标2，研究小组将利用他们最近的发现，在细胞培养介质中，三(2-呋喃)膦的羟甲基化类似物优于商业膦。这两个目标将把钯催化的应用扩展到它还没有被广泛使用的研究领域。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。

In this project funded by the Chemical Structure, Dynamics, and Mechanisms B Program of the Chemistry Division, Professor Kazunori Koide of the Department of Chemistry at University of Pittsburgh will investigate new classes of chemical reagents for trace metal analysis and for developing a chemical technology that can make non-cell-permeable molecules cell permeable. Both objectives are important in human health, as they can lead to the development of new pharmaceuticals. The project lies at the interface of organic, inorganic, and biological chemistry, and is therefore well suited to the education of scientists at all levels. This group is also well-positioned to provide the highest level of education and training for undergraduate and graduate students and post-doctoral researchers. The research group is active in outreach activities that involve recruiting under-representative minority students for summer research and participation in undergraduate research symposium. Palladium catalyzed deallylation (Tsuji-Trost reaction), a widely used reaction in organic synthesis, had been attempted for chemosensing and chemical biology. Although promising results were obtained, further improvements are essential. As a platform for Pd quantification using a fluorogenic Tsuji-Trost reaction, the dynamic range is not yet sufficiently broad. As a means in chemical biology, although the reaction is efficient in neutral phosphate buffer, it is more than one order of magnitude slower in cell culture media. In this project, two specific aims will be pursued: (1) to develop a fluorometric or colorimetric method to quantify palladium in a high throughput manner, and (2) to develop a biocompatible Tsuji-Trost reaction to uncage bioactive molecules in cultured human cells. For specific aim 1, the research group will use Eyring plots and measure the activation energy of enthalpy to rationally adjust the kinetic profile. For specific aim 2, the research group will leverage their recent finding that hydroxymethylated analogs of tris(2-furyl)phosphine are superior to commercial phosphines in cell culture media. These two aims will expand the applications of Palladium catalysis into research areas in which it has not been used extensively.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.