Metalloprotein Catalysts for Asymmetric Synthesis

用于不对称合成的金属蛋白催化剂

• 批准号: 9896830
• 负责人: Rudi Fasan
• 金额: $ 35.89万
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896830
• 关键词: Active Sites; Address; Alkenes; Alkynes; Biological; Carbon; Catalysis; Cells; Chemicals; Development; Drug Industry; Engineering; Enzymes; Funding; Generations; Goals; Heme; Hemeproteins; Hydrogen Bonding; In Situ; Isotopes; Kinetics; Lead; Ligands; Mediating; Metalloporphyrins; Metalloproteins; Metals; Methodology; Methods; Modification; Mutagenesis; Myoglobin; Natural Products; Nature; Nitrogen; Organic Synthesis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Porphyrins; Post-Translational Protein Processing; Preparation; Process; Property; Proteins; Reaction; Reagent; Research; Structure; Sulfur; System; Therapeutic; Time; United States National Institutes of Health; Variant; X-Ray Crystallography; base; carbene; catalyst; cofactor; computer studies; cost effective; density; design; drug development; drug discovery; drug synthesis; experimental study; human disease; insight; interest; novel; scaffold; spectroscopic survey; 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 chiral synthons and intermediates for the synthesis of pharmaceuticals and other biologically active molecules. Reflecting this notion, there have been significant interest within the pharmaceutical industry toward integrating 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. Ramifications of our prior NIH-funded research have led to the discovery that myoglobin—a small, robust, and structurally tunable heme-containing protein—, constitutes a very promising and versatile scaffold for developing efficient and stereoselective biocatalysts for carbene transfer reactions. Building upon these exciting results, the proposed research aims at investigating and extending the scope of these hemoprotein catalysts across a broad range of carbene- mediated transformations useful for the construction of carbon−carbon, carbon−nitrogen, and carbon−sulfur bonds. A set of complementary strategies will be investigated and leveraged to enhance and modulate the catalytic activity, chemo- and stereoselectivity of these catalysts. Furthermore, valuable insights into the mechanism of these reactions and into correlations between catalyst structure and reactivity/selectivity will be gained through a combination of experimental, computational, and spectroscopic studies. These efforts will contribute to the definition of guiding principles and a general, rationally driven strategy for the design and development of myoglobin-based catalysts with high activity and fine-tuned chemo-, regio- and stereoselectivity for executing a variety of asymmetric carbene insertion reactions. These systems will provide access to chiral building blocks of immediate value for medicinal chemistry and drug discovery efforts. The synthetic utility of this new class of metalloprotein catalysts will be further demonstrated through their application for the preparation of synthetically challenging drug molecules. Ultimately, this research is expected to have a major impact toward making available new efficient, selective, and sustainable biocatalytic strategies for promoting asymmetric carbene transfer reactions, thereby overcoming outstanding challenges in this field.

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 特别用于手性合成子和中间体的生成，用于合成药物和其他 生物活性分子。反映这一概念的是，制药行业内部一直有很大的兴趣 行业朝着整合高效、选择性、成本效益和可持续的酶催化药物转化的方向发展 合成和制造。然而，这一方向的进展受到固有的有限范围的严重阻碍 由天然酶催化的化学转化，与通过化学方法获得的转化相比。 我们之前由美国国立卫生研究院资助的研究的结果导致发现肌红蛋白-一种小的，强壮的，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和多功能的开发支架 卡宾转移反应的高效和立体选择性生物催化剂。在这些令人振奋的成果的基础上，拟议的 研究的目的是研究和扩大这些血红蛋白催化剂的范围，覆盖广泛的卡宾- 对构建碳−碳、碳−氮和碳−硫键有用的介导性转化。一套 将研究和利用互补策略来增强和调节催化活性、化学和 这些催化剂的立体选择性。此外，对这些反应的机制和 催化剂结构和反应性/选择性之间的关联将通过结合实验、 计算和光谱研究。这些努力将有助于确定指导原则和 用于设计和开发基于肌红蛋白的高活性和高活性催化剂的通用、合理驱动的策略 微调的化学、区域和立体选择性，用于执行各种不对称卡宾插入反应。这些 系统将提供对药物化学和药物发现具有直接价值的手性构建块的访问 努力。这类新型金属蛋白催化剂的合成用途将通过它们的 应用于合成具有挑战性的药物分子的制备。最终，这项研究预计将有一个 对提供新的高效、选择性和可持续的生物催化战略以促进 不对称卡宾转移反应，从而克服了这一领域的突出挑战。