Metalloprotein catalysts for asymmetric synthesis

用于不对称合成的金属蛋白催化剂

• 批准号: 10210696
• 负责人: Rudi Fasan
• 金额: $ 40.94万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210696
• 关键词: Address; Alkenes; Amines; Biological; Carbon; Catalysis; Chemicals; Chemistry; Complement; Complex; Development; Drug Compounding; Drug Industry; Engineering; Enzymes; Foundations; Generations; Goals; Grant; Heme; Hemeproteins; Hydrogen Bonding; In Situ; Iron; Kinetics; Lead; Libraries; Ligands; Light; Mediating; Metalloproteins; Metals; Methodology; Methods; Modeling; Myoglobin; Natural Products; Optics; Organic Chemistry; Organic Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Preparation; Process; Property; Proteins; Reaction; Reagent; Research; Structure; System; Therapeutic; Transferase; Variant; Work; base; carbene; catalyst; combinatorial; cost effective; density; design; drug discovery; drug synthesis; electronic structure; human disease; insight; interest; non-Native; novel; scaffold; screening; theories; tool; toxic metal

Metalloprotein catalysts for asymmetric synthesis Project Summary The exquisite chemo-, regio-, and stereoselectivity of enzymes make them attractive tools for organic synthesis, in particular for the generation of optically active synthons and intermediates for the synthesis of pharmaceuticals and other biologically active molecules. Reflecting this notion, there have been growing interest and efforts within the pharmaceutical industry toward developing efficient, selective, cost-effective, and sustainable enzyme-catalyzed transformations for drug synthesis and manufacturing. Progress in this direction is critically hampered, however, by the inherently limited range of chemical transformations catalyzed by natural enzymes as compared to those accessible through chemical methods. During the previous grant period, we have demonstrated that myoglobin—a small, robust, and structurally tunable heme-containing protein—, constitutes a highly promising, versatile, and robust scaffold for developing efficient and stereoselective biocatalysts for abiological carbene transfer reactions. Building upon this foundational work and other exciting preliminary results, the proposed research aims at investigating and extending the scope of these hemoprotein catalysts to a range of new, asymmetric carbon-carbon and carbon-heteroatom bond forming transformations useful for the synthesis of optically active building blocks and complex organic scaffolds of direct value for medicinal chemistry and drug discovery. Synergizing with these efforts, complementary strategies based on rational mechanism-guided design and combinatorial/high-throughput approaches will be implemented to expedite the discovery and optimization of myoglobin-based carbene transferases with enhanced catalytic efficiency, expanded reactivity, and fine-tuned stereoselectivity. The studies above will be complemented by detailed mechanistic studies on these reactions and catalysts using a combination of experimental, spectroscopic, computational, and structural methods. These studies will furnish key insights into the kinetic, structural, and electronic properties of reaction intermediates and they will shed light into structural determinants underlying catalyst-controlled reactivity and stereoselectivity, enabling a deeper understanding of these processes and informing further catalyst design. The synthetic value of these methodologies will be further demonstrated through their application to the stereoselective synthesis of drug molecules and in support of focused medicinal chemistry projects. Successful completion of this research is expected to make available new efficient, selective, and sustainable biocatalytic strategies for promoting asymmetric carbene transfer reactions, which will create new opportunities for the synthesis and discovery of biologically active molecules.

用于不对称合成的金属蛋白催化剂 项目概要 酶精致的化学选择性、区域选择性和立体选择性使其成为有机合成的有吸引力的工具。 特别是用于生成光学活性合成子和用于合成药物和其他药物的中间体 反映了这一概念，人们对生物活性分子的兴趣和努力不断增加。 制药工业向高效、选择性、成本效益和可持续的酶催化方向发展 然而，药物合成和制造的转变严重阻碍了这一方向的进展。 与可利用的酶相比，天然酶催化的化学转化范围本质上有限 在之前的资助期间，我们已经通过化学方法证明了肌红蛋白——一种小而坚固的物质。 结构可调节的含血红素蛋白，构成了一个非常有前途、多功能且坚固的支架 在此基础上开发用于非生物卡宾转移反应的高效和立体选择性生物催化剂。 基础工作和其他令人兴奋的初步结果，拟议的研究旨在调查和扩展 这些血红素蛋白催化剂可形成一系列新的不对称碳-碳和碳-杂原子键 可用于合成具有直接价值的光学活性结构单元和复杂有机支架的转换 与这些努力相协同，基于合理的补充策略。 将实施机制引导设计和组合/高通量方法以加快发现速度 基于肌红蛋白的卡宾转移酶的优化，具有增强的催化效率、扩大的反应性和 上述研究将得到对这些反应的详细机理研究的补充。 和催化剂，结合实验、光谱、计算和结构方法。 将为反应中间体的动力学、结构和电子特性提供重要见解，并且它们将摆脱 光进入催化剂控制反应性和立体选择性的结构决定因素，从而实现更深入的研究 了解这些过程并为进一步的催化剂设计提供信息，这些方法的综合价值将是。 通过将其应用于药物分子的立体选择性合成并支持重点研究，进一步证明了这一点 药物化学项目的成功完成预计将提供新的高效、 用于促进不对称卡宾转移反应的选择性和可持续的生物催化策略，这将创造 合成和发现生物活性分子的新机遇。