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

SusChEM：基于细胞色素 P450 的 C(sp3)-H 胺化催化剂

• 批准号: 1609550
• 负责人: Rudi Fasan
• 金额: $ 49.95万
• 依托单位: University of Rochester
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1609550&HistoricalAwards=false
• 关键词: SusChEM; Cytochrome; P450; based; catalysts

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.

有了这个奖项，化学系的生命过程化学计划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-氮键在人造和天然存在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于商品化学品和药物的制造具有潜在的极高价值。该项目正在开发酶，从容易获得的，低或零废物的原材料开始，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不会发生，因此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酶构成了使用叠氮化物基底物促进分子内C（sp3）-H胺化的有前途的系统。有机叠氮化合物是C-H胺化反应中特别有吸引力的底物，这是由于它们易于合成、优异的原子经济性以及作为反应副产物的惰性氮气的释放。基于这些有希望的结果，该项目探索了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，参与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，这项研究预计将产生有关工程P450酶作为催化平台的范围的知识，用于介导未活化的脂肪族C-H键的氨基官能化，以及对这些新型酶促转化机制的基本理解。 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。

项目成果

Selective Functionalization of Aliphatic Amines via Myoglobin-Catalyzed Carbene N–H Insertion

通过肌红蛋白催化的卡宾 N-H 插入选择性官能化脂肪胺

• DOI: 10.1055/s-0039-1690007
• 发表时间: 2020
• 期刊: Synlett
• 影响因子: 2
• 作者: Steck, Viktoria;Sreenilayam, Gopeekrishnan;Fasan, Rudi
• 通讯作者: Fasan, Rudi

Effect of proximal ligand substitutions on the carbene and nitrene transferase activity of myoglobin

• DOI: 10.1016/j.tet.2019.03.009
• 发表时间: 2019-04-19
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Moore, Eric J.;Fasan, Rudi
• 通讯作者: Fasan, Rudi

A Continuing Career in Biocatalysis: Frances H. Arnold

• DOI: 10.1021/acscatal.9b02737
• 发表时间: 2019-11-01
• 期刊: ACS CATALYSIS
• 影响因子: 12.9
• 作者: Fasan, Rudi;Kan, S. B. Jennifer;Zhao, Huimin
• 通讯作者: Zhao, Huimin