Metalloprotein Catalysts for Asymmetric Synthesis

用于不对称合成的金属蛋白催化剂

基本信息

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
项目类别：
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

项目摘要

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概要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。特别是用于生成手性合成子和用于合成药物和其他药物的中间体生物活性分子反映了这一概念，引起了制药界的极大兴趣。行业整合高效、选择性、成本效益和可持续的酶催化药物转化然而，这一方向的进展受到固有的有限范围的严重阻碍。与通过化学方法进行的化学转化相比，由天然酶催化的化学转化。我们之前 NIH 资助的研究结果发现，肌红蛋白是一种小而强健的物质。结构可调的含血红素蛋白，构成了一种非常有前途且用途广泛的支架，用于开发基于这些令人兴奋的结果，提出了用于卡宾转移反应的高效和立体选择性生物催化剂。研究旨在调查和扩展这些血红蛋白催化剂的范围，涵盖广泛的卡宾- 用于构建碳-碳、碳-氮和碳-硫键的介导转化。将研究并利用互补策略来增强和调节催化活性、化学和此外，对这些反应的机理和深入了解也很有价值。催化剂结构和反应性/选择性之间的相关性将通过实验、这些努力将有助于指导原则和光谱研究的定义。设计和开发具有高活性和高活性的肌红蛋白基催化剂的一般合理驱动策略微调化学、区域和立体选择性，用于执行各种不对称卡宾插入反应。系统将为药物化学和药物发现提供具有直接价值的手性构建模块这类新型金属蛋白催化剂的合成效用将通过其最终，这项研究有望在合成具有挑战性的药物分子的制备中得到应用。对提供新的高效、选择性和可持续的生物催化策略产生重大影响，以促进不对称卡宾转移反应，从而克服了该领域的突出挑战。