Mechanistic Investigation into Modern Catalytic Reactions

项目总结：对新兴催化方法的机械理解是一个重要因素 在将新的转化方法成功地应用于药物和其他高活性物质的合成中。 重视化学品。尽管如此，新的反应发现和它的 机械性的描述。该研究计划在以下两个重要领域解决了这一挑战 当代催化--工程酶的光氧化还原催化和生物催化。 光催化剂利用可见光产生高活性的自由基中间体 可以从战略上引导这些资金参与各种有价值的债券形成。有一种 检测和表征这些开放壳层的各种光物理方法 中间体。然而，过渡态几何结构的实验探索，关键成键和 在光氧化还原催化中，几乎不存在键断裂事件。在此背景下，本研究 该计划建立了13C动力学同位素效应作为过渡态的难以捉摸的实验探测器 光氧化还原反应的几何学。除了阐明这些复杂的反应机制外， 这一测量是校准理论方法的重要实验基准 准确评估这些反应中决定速率和选择性的步骤。 细胞色素P450的定向进化导致了卡宾和硝烯转移的发现 这些含血红素的酶的活性。对这些系统的机械研究在很大程度上 由于与执行标准相关的内在挑战，一直局限于理论研究 酶系统的物理有机实验。这一计划利用了一种新开发的 分子内13C动力学同位素效应技术与经典KH/KD实验一起获得洞察力 这些反应中C-C和C-N键形成步骤的过渡态几何构型。高水平 QM/MM计算和MD模拟也被用来解释实验结果和 了解这些生物催化反应中选择性的来源。

Project Summary: Mechanistic understanding of emerging catalytic methodologies is an important factor in the successful application of novel transformations to the synthesis of pharmaceuticals and other high- value chemicals. Despite this, there is a significant lag between new reaction discovery and its mechanistic description. This research program addresses this challenge in two important areas of contemporary catalysis – photoredox catalysis and biocatalysis by engineered enzymes. Photocatalysts harness the power of visible light to generate highly reactive radical intermediates that can be strategically channeled to participate in a variety of valuable bond-formations. There are a variety of photophysical approaches for the detection and characterization of these open-shell intermediates. However, experimental probes of the transition state geometry, of key bond-forming and bond-breaking events in photoredox catalysis, are virtually non-existent. In this context, this research program establishes 13C kinetic isotope effects as the elusive experimental probe of the transition state geometry of photoredox reactions. In addition to shedding light on these complex reaction mechanisms, this measurement serves as an important experimental benchmark to calibrate theoretical methods to accurately evaluate the rate- and selectivity-determining steps in these reactions. Directed evolution of cytochromes P450 has led to the discovery of carbene- and nitrene-transfer activity of these heme-containing enzymes. Mechanistic investigations of these systems have largely been limited to theoretical studies due to the inherent challenges associated with conducting standard physical organic experiments in enzymatic systems. This program utilizes a newly developed intramolecular 13C kinetic isotope effect technique along with classical kH/kD experiments to gain insight into the transition state geometry of C–C and C–N bond-forming steps in these reactions. High-level QM/MM calculations and MD simulations are also utilized to interpret experimental findings and understand the origin of selectivity in these biocatalytic reactions.