Acquisition of Supercritical Fluid Chromatography System

用于不对称合成的金属蛋白催化剂 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。 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，制药业内部的兴趣和努力越来越大 开发用于药物合成的高效、选择性、成本效益和可持续的酶催化转化 和制造业。然而，这方面的进展受到化学物质固有的有限范围的严重阻碍。 与通过化学方法获得的转化相比，由天然酶催化的转化。在.期间 在之前的赠款期间，我们已经证明了肌红蛋白-一种小的、健壮的、结构可调的血红素-含有 蛋白质-，构成了一种非常有前途的、多功能的、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。在这项基础性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和扩大这些血红蛋白催化剂的范围到一系列 用于光学合成的新的不对称碳-碳和碳-杂原子键形成转化 对药物化学和药物发现有直接价值的活性积木和复合有机支架。 协同这些努力，以合理的机制指导设计和 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、扩大的反应活性和微调的立体选择性。这个 上述研究将得到对这些反应和催化剂的详细机理研究的补充。 实验方法、光谱方法、计算方法和结构方法。这些研究将为我们提供对 反应中间体的动力学、结构和电子性质，它们将有助于揭示结构决定因素 潜在的催化剂控制的反应性和立体选择性，使我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的 应用于药物分子的立体选择性合成和支持重点药物化学项目。 这项研究的成功完成有望提供新的高效、选择性和可持续的生物催化剂 促进不对称卡宾转移反应的策略，这将为合成和 生物活性分子的发现。

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.