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.

非对称合成的金属蛋白催化剂酶的独家化学，区域和立体选择性使它们成为有机合成的吸引人工具，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学活性分子。反映这一观念，制药行业的兴趣和努力越来越大致力于发展有效，选择性，成本效益和可持续的酶催化转化用于药物合成和制造业。但是，在这个方向上的进展受到了严重的限制化学范围的阻碍与通过化学方法获取的转化相比，天然酶催化的转化。在以前的赠款期，我们已经证明了肌红蛋白 - 小型，健壮且结构可调的血红素蛋白质 - 建立一个高度有希望，多才多艺且可靠的脚手架，以发展有效和立体选择性生物催化剂用于碳纤维转移反应的生物催化剂。基于这项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将这些血蛋白催化剂的范围扩展到一系列新的，不对称的碳碳和碳杂原键形成的转化有用于光学上的合成积极的构建块和复杂的有机脚手架，具有医学化学和药物发现的直接价值。与这些努力协同作用，基于理性机制引导设计的完整策略和将实施组合/高通量方法，以加快肌红蛋白的发现和优化基于催化效率，反应性扩大和微调的立体选择性的基于卡宾转移。这上述研究将通过使用组合对这些反应和催化剂的详细机械研究完成实验，光谱，计算和结构方法。这些研究将提供有关的关键见解反应中间体的动力学，结构和电子特性，它们会将光脱落到结构决定器中潜在的催化剂控制的反应性和立体选择性，使得对这些过程有更深入的了解告知进一步的催化剂设计。这些方法的合成价值将通过它们的合成价值进一步证明适用于药物分子的立体选择性合成并支持重点的医学化学项目。预计这项研究的成功完成将提供新的高效，选择性和可持续的生物催化促进不对称碳转移反应的策略，这将为合成和发现生物活性分子。