Palladium-Catalyzed Tsuji-Trost Reaction in Complex Mixtures

本研究课题由匹兹堡大学化学系化学结构·动力学·机理B研究计划资助，研究用于微量金属分析的新型化学试剂，并开发使非细胞渗透性分子具有细胞渗透性的化学技术。 这两个目标对人类健康都很重要，因为它们可以导致新药的开发。 该项目位于有机，无机和生物化学的界面，因此非常适合各级科学家的教育。 该集团也有能力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，包括招募代表性不足的少数民族学生参加夏季研究和参加本科生研究研讨会。 钯催化的脱烯丙基反应（Tsuji-Trost反应）是一种广泛应用于有机合成的反应，在化学传感和化学生物学方面有着广泛的应用。 虽然取得了令人鼓舞的成果，但仍需进一步改进。 作为使用荧光Tsuji-Trost反应进行Pd定量的平台，动态范围还不够宽。 作为化学生物学中的一种手段，虽然反应在中性磷酸盐缓冲液中是有效的，但在细胞培养基中慢一个数量级以上。在这个项目中，将追求两个具体目标：（1）开发一种荧光或比色方法，以高通量的方式定量钯，和（2）开发一种生物相容的Tsuji-Trost反应，以释放培养的人类细胞中的生物活性分子。对于具体目标1，研究小组将使用Eyring图并测量焓的活化能，以合理调整动力学曲线。 对于具体目标2，研究小组将利用他们最近的发现，即三（2-呋喃基）膦的羟甲基化类似物在细胞培养基中上级商业膦。 这两个目标将扩大钯催化的应用到研究领域，它还没有被广泛使用。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.