SusChEM: Cytochrome P450 based catalysts for C(sp3)-H amination

通过这个奖项，化学学部的生命过程化学项目将资助罗切斯特大学的鲁迪·法桑教授开发和研究将碳氢键转化为碳氮键的酶（生物催化剂）。碳-氮键在人造和自然产生的有机分子中都很常见。目前可用的从碳氢键生成碳氮键的方法很大程度上依赖于使用稀有和昂贵的金属和浪费的试剂。构建C-N化学键的催化方法对商品化学品和药品的制造具有潜在的极高价值。该项目正在开发一种酶，这种酶可以从容易获得的、低浪费或零浪费的原料开始，提高新的C-N键形成的速度。由于这些化学反应在自然界中并不存在，因此本研究对于扩大具有合成价值的化学反应范围具有广泛而深远的意义。参与该项目的研究生和本科生正在接受跨学科的培训。少数民族学生积极参与研究。Fasan博士为罗彻斯特市学区的高中生提供了一门动手化学课程。Fasan研究小组最近发现，工程细胞色素P450酶构成了利用叠氮基底物促进分子内C(sp3)-H胺化的有前途的系统。有机叠氮化物由于其易于合成，优异的原子经济性以及作为反应副产物释放惰性氮气而成为碳氢胺化的特别有吸引力的底物。在这些有希望的结果的基础上，本项目探索了p450催化的C-H胺化反应在不同含叠氮化物底物背景下的范围，并实施了提高这些催化剂的C-H胺化活性和选择性的策略。此外，p450介导的C-H胺化反应的机制和催化中间体通过互补方法的组合来确定。最终，这项研究有望产生关于工程P450酶作为介导非活化脂肪族C-H键氨基功能化的催化平台的范围的知识，并对这些新型酶转化的机制有基本的了解。参与该项目的研究生和本科生正在接受化学、酶学、蛋白质工程和光谱学的跨学科培训。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Rudi Fasan of the University of Rochester to develop and investigate enzymes (biological catalysts) that convert carbon-hydrogen (C-H) bonds into carbon-nitrogen (C-N) bonds. Carbon-nitrogen bonds are common in both man-made and naturally occurring organic molecules. Currently available methods for making C-N bonds from C-H bonds largely rely on the use of rare and expensive metals and wasteful reagents. Catalytic methods for the construction of C-N chemical bonds are potentially extremely valuable for the manufacture of commodity chemicals and pharmaceuticals. This project is developing enzymes that increase the rate of new C-N bond formation starting from easily accessible, low or zero waste raw materials. Since these chemical reactions do not occur in nature, this research has broad and far-reaching implications toward expanding the range of synthetically-valuable chemical reactions. Graduate and undergraduate students involved in the project are receiving cross-disciplinary training. Minority students actively participate in the research. Dr. Fasan offers of a hands-on chemistry course to high school students of the Rochester City School District. The Fasan research group has recently discovered that engineered cytochrome P450 enzymes constitute promising systems for promoting intramolecular C(sp3)-H amination using azide-based substrates. Organic azides are particularly attractive substrates for C-H amination due to their ready synthetic accessibility, excellent atom economy, and the release of inert nitrogen gas as the reaction by-product. Building on these promising results, this project explores the scope of P450-catalyzed C-H amination reactions in the context of different azide-containing substrates and implements strategies to enhance the C-H amination activity and selectivity of these catalysts. In addition, the mechanism and catalytic intermediates involved in the P450-mediated C-H amination reactions are determined via a combination of complementary approaches. Ultimately, this research is expected to generate knowledge about the scope of engineered P450 enzymes as catalytic platforms for mediating the aminofunctionalization of unactivated aliphatic C-H bonds and fundamental understanding of the mechanism of these novel enzymatic transformations. Graduate and undergraduate students involved in the project are receiving cross-disciplinary training in chemistry, enzymology, protein engineering, and spectroscopy.