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

化学系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(C-H)键转化为碳-氮(C-N)键的酶(生物催化剂)。碳-氮键在人工合成和自然生成的有机分子中都很常见。目前可用的从C-H键制备C-N键的方法主要依赖于稀有和昂贵的金属的使用和浪费的试剂。构建C-N化学键的催化方法对于商品化学品和药品的制造具有潜在的极其重要的价值。该项目正在开发酶，以提高新的C-N键的形成速度，从容易获得、低或零浪费的原材料开始。由于这些化学反应在自然界中不会发生，这项研究对扩大具有合成价值的化学反应的范围具有广泛而深远的影响。参与该项目的研究生和本科生正在接受跨学科培训。少数民族学生积极参与研究。法桑博士为罗切斯特市学区的高中生开设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。有机叠氮化合物是C-H胺化反应特别有吸引力的底物，因为它们易于合成，具有极好的原子经济性，而且反应副产物会释放惰性氮气。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底物的背景下的范围，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，通过互补方法的组合，确定了P450介导的C-H胺化反应所涉及的机理和催化中间体。最终，这项研究有望产生关于工程P450酶作为催化平台介导未激活的脂肪族C-H键的氨基功能化的范围的知识，并从根本上理解这些新的酶转化的机制。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方面的跨学科培训。

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.