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Acquisition of Supercritical Fluid Chromatography System

购置超临界流体色谱系统

基本信息

批准号：
10797957
负责人：
Rudi Fasan
金额：
$ 11.56万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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

项目摘要

Metalloprotein Catalysts for Asymmetric Synthesis 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中间体，用于合成药物和其他生物制品活性分子。制药行业内越来越多的兴趣和努力反映了这一理念致力于开发高效、选择性、成本效益高且可持续的酶催化药物合成转化和制造。然而，由于化学物质范围固有的有限性，这一方向的进展受到严重阻碍。与通过化学方法实现的转化相比，由天然酶催化的转化。期间在之前的资助期间，我们已经证明了肌红蛋白——一种小的、强大的、结构可调的含血红素蛋白质——构成了一种非常有前途、多功能且坚固的支架，用于开发高效和立体选择性的用于非生物卡宾转移反应的生物催化剂。在此基础工作和其他令人兴奋的初步工作的基础上结果，拟议的研究旨在调查这些血红蛋白催化剂并将其范围扩展到一系列新的不对称碳-碳和碳-杂原子键形成变换可用于光学合成对药物化学和药物发现具有直接价值的活性构件和复杂有机支架。与这些努力相协同，基于合理机制引导设计的补充策略和将实施组合/高通量方法以加快肌红蛋白的发现和优化基于卡宾转移酶，具有增强的催化效率、扩大的反应性和微调的立体选择性。这上述研究将通过使用组合对这些反应和催化剂进行详细的机理研究来补充实验、光谱、计算和结构方法。这些研究将为以下问题提供重要见解：反应中间体的动力学、结构和电子特性，它们将揭示结构决定因素潜在的催化剂控制反应性和立体选择性，使人们能够更深入地了解这些过程和为进一步的催化剂设计提供信息。这些方法的综合价值将通过它们得到进一步证明应用到药物分子的立体选择性合成并支持重点药物化学项目。这项研究的成功完成预计将提供新的高效、选择性和可持续的生物催化促进不对称卡宾转移反应的策略，这将为合成和合成创造新的机会生物活性分子的发现。