Metalloprotein catalysts for asymmetric synthesis

用于不对称合成的金属蛋白催化剂

• 批准号: 10382445
• 负责人: Rudi Fasan
• 金额: $ 38.96万
• 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/10382445
• 关键词: Address; Alkenes; Amines; 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; human disease; insight; interest; non-Native; novel; rational design; 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 项目摘要 酶的精细的化学选择性、区域选择性和立体选择性使它们成为有机合成的诱人工具 特别是用于产生光学活性合成子和中间体，用于合成药物和其他 生物活性分子。反映这一概念的是，在 制药工业朝着高效、选择性、低成本、可持续的酶催化方向发展 药物合成和制造的转型。然而，这方面的进展受到严重阻碍，因为 与可获得的酶相比，天然酶催化的化学转化的固有范围有限 通过化学方法。在之前的资助期间，我们已经证明了肌红蛋白-一种小的、健壮的和 结构可调的含血红素的蛋白质-，构成了一种非常有前途的、多功能的和坚固的支架 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。以此为基础 基础工作和其他令人振奋的初步成果，拟议的研究旨在调查和推广 这些血红蛋白催化剂的范围包括一系列新的不对称碳-碳和碳-杂原子键的形成 用于合成光学活性构建块和具有直接价值的复杂有机支架的转化 用于药物化学和药物发现。与这些努力协同，基于Rational的补充战略 将实施机制导向设计和组合/高通量方法，以加快发现 并优化了基于肌红蛋白的卡宾转移酶，提高了催化效率，扩大了反应活性，并 微调的立体选择性。上述研究将通过对这些反应的详细机理研究来补充。 以及使用实验、光谱、计算和结构方法相结合的催化剂。这些研究 将提供对反应中间体的动力学、结构和电子性质的关键见解，它们将 光转化为潜在的催化剂控制的反应性和立体选择性的结构决定因素，使更深层次的 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 进一步展示了它们在药物分子立体选择性合成中的应用，并支持Focus 药物化学项目。这项研究的成功完成有望使新的、高效的、 促进不对称卡宾转移反应的选择性和可持续的生物催化战略，这将创造 合成和发现生物活性分子的新机遇。