Metalloprotein catalysts for asymmetric synthesis

不对称合成中的金属蛋白催化剂 项目摘要 酶的精确的化学选择性、区域选择性和立体选择性使它们成为有机合成的有吸引力的工具， 特别是用于产生光学活性的二聚体和用于合成药物和其他药物的中间体， 生物活性分子。为反映这一概念， 制药行业朝着开发高效，选择性，成本效益和可持续的酶催化 用于药物合成和制造的转化。然而，这方面的进展受到严重阻碍， 与可获得的那些相比，天然酶催化的化学转化的范围固有地有限 通过化学方法。在上一个资助期，我们已经证明肌红蛋白-一个小的，强大的， 结构可调的含血红素的蛋白-，构成了一个非常有前途的，通用的，和强大的支架， 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。在此基础上 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的范围涉及一系列新的、不对称的碳-碳和碳-杂原子键形成 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化 用于药物化学和药物发现。与这些努力协同，基于合理的 将实施机制引导设计和组合/高通量方法以加快发现 和优化肌红蛋白基碳烯转移酶，其具有增强的催化效率、扩大的反应性， 微调立体选择性。上述研究将通过对这些反应的详细机理研究来补充 和催化剂，使用实验、光谱、计算和结构方法的组合。这些研究 将提供关键的洞察动力学，结构，和电子性质的反应中间体，他们将摆脱 光进入催化剂控制的反应性和立体选择性的基础结构决定因素，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 通过它们在药物分子的立体选择性合成中的应用， 药物化学项目。这项研究的成功完成，预计将提供新的高效， 选择性的，可持续的生物催化策略，促进不对称卡宾转移反应，这将创造 为合成和发现生物活性分子提供了新的机会。

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.