Catalytic Asymmetric Oxidation: Easy Entry to Highly Functionalized Molecules

催化不对称氧化：轻松进入高功能化分子

• 批准号: 8283752
• 负责人: HISASHI None YAMAMOTO
• 金额: $ 22.78万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283752
• 关键词: 3-hydroxybutanal; Academia; Agreement; Alcohols; Alder plant; Alkenes; Amines; Area; Benign; Budgets; Calendar; Catalysis; Complex; Cost Allocation; Cost Sharing; Cyclization; Development; Development Plans; Direct Costs; Doctor of Philosophy; Drug Industry; Enzymes; Equilibrium; Facilities and Administrative Costs; Funding; Future; Goals; Hafnia; Hafnium; Halogens; Homo; Human; Human Resources; Investigation; Iron; Laboratories; Lead; Learning; Libraries; Ligands; Metals; Methodology; Methods; Molecular; Names; Nature; Nitrogen; Organic Synthesis; Oxygen; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Principal Investigator; Process; Production; Public Health; Publications; Reaction; Research; Route; Solutions; Structure; Students; Sulfur; System; Techniques; Telephone; Thermodynamics; Training; Transition Elements; United States National Institutes of Health; Vanadium; Work; Writing; Zirconium; base; carbonyl compound; career; catalyst; chemical synthesis; chiral molecule; computer studies; cost; design; drug market; experience; functional group; innovation; interest; next generation; oxidation; programs; success; zirconium oxide

Modern drugs are highly functionalized molecules, and often these molecules are chiral. In the pharmaceutical industry, single chiral drugs constitute over half the total drug market, and the key components in 9 of the top 10 drugs are chiral. The biomedical importance of chiral compounds has spurred intense research efforts by leading laboratories. The most promising solution for production of these molecules has relied on asymmetric catalytic processes, especially catalytic asymmetric oxidation, which can introduce multi-functional groups into the molecule. The long term goal of the project is to develop catalytic asymmetric oxidation processes, which can create highly functionalized drugs at a useful level of selectivity and scalability. The objective of developing these catalysts is to provide reliable and easy access to make molecules previously unattainable in a simple manner. In this renewal proposal, we outline plans for the development and use of new oxidation catalysts for enantioselective synthesis of multi-functional molecules. Unlike traditional transition metal-based catalysts, the catalysts being developed and studied in this program are organic molecules or contain non-harmful metals. These transition metal-free catalysts are not only of a fundamental interest, but also of industrial importance, since harmful transition metals are undesirable in pharmaceutical drugs. Many of the subprojects are supported by promising preliminary results, whereas others represent new directions in either catalyst or methodology development. Mechanistic, crystallographic, and computational studies will provide an understanding of the catalytic processes and steer the development of more effective catalysts. Catalytic selective oxidation can introduce oxygen, nitrogen, or a halogen to the substrate catalytically and selectively. Our specific major aim is asymmetric epoxidation. The investigations of this reaction are expected to lead to the development of broadly useful asymmetric oxidation catalysis methodologies that will impact many facets of chemical synthesis. Additionally, the effort will provide excellent training in synthetic methodology development to undergraduate, graduate, and postdoctoral students interested in a research career in the pharmaceutical industry or academia Modified Specific Aim Catalytic enantioselective oxidation is an extremely important process for the drug industry. This is clear because the most bioactive molecules have highly functionalized structures. Simple olefins and carbonyl compounds are the most attractive starting materials available to the synthetic chemist, easily accessible in large quantities and in many varieties. Nature achieves highly specific syntheses of complex substances through the uniquely selective oxidation by enzyme catalysts starting from these simple compounds. While there are currently many broadly useful methods for catalytic asymmetric reduction, there are far fewer of these catalytic asymmetric techniques for oxidation. It should be noted that selective oxidation catalysis represents more formidable challenges than does for selective reduction catalysis, not the least of which is the thermodynamic instability of ligands under oxidative conditions. Although recently there has been progress in this important area, it is not yet sufficient. We propose herein catalytic oxidation which can introduce oxygen and sulfur into substrates chemo-, regio-, and enantioselectively to provide simple entry to the synthesis of highly functionalize complex molecules that have heretofore been known. Thus, our contribution here is expected to provide a set of new and general chiral oxidation catalysts for pharmaceutical laboratories and drug industries. The specific aim of the next funding period is asymmetric epoxidation. The aim is divided into two parts: (1) vanadium, hafnium, and zirconium catalysts for epoxidation and their application to epoxidation- cyclization cascades; and (2) iron-based catalysts for asymmetric epoxidation and C-H oxidation and activation. These catalysts are significant in their representation as simple, benign ways to promote enantioselective epoxidation reactions. Overall, the proposed work will not only lead to an efficient synthetic route for selective oxidations, but, more importantly, will result in the development of methodology that should prove to be of general value to medicinal chemistry. The proposed project will include syntheses of several simple bioactive molecules to demonstrate how our catalysts work. The actual utility of the methods, of course, is much broader. It is also expected that what is learned will be equally applicable to the development of new oxidation catalysts of other systems. The proposed approaches are innovative because each of them is an unknown process which capitalizes on a totally new concept of catalyst design developed by our group using previous NIH support. They also take advantage of a number of ligand libraries which are available in no other laboratory. The proposed research is significant, because it is expected to provide a fine toolbox of catalysts, which will make possible the provision of previously unattainable complex molecules needed to develop entirely new pharmacologic strategies in the future.

现代药物是高度官能化的分子，通常这些分子是手性的。在 医药行业，单手性药物占整个药品市场的一半以上，而关键 排名前十的药物中有九种成分是手性的。手性化合物在生物医学上的重要性 刺激了领先实验室的紧张研究努力。最有希望的生产解决方案 这些分子依赖于不对称催化过程，特别是催化不对称氧化， 它可以将多官能团引入到分子中。该项目的长期目标是 开发催化不对称氧化工艺，可以一次生产出高度功能化的药物 有用的选择性和可扩展性水平。开发这些催化剂的目的是提供可靠的 以及以一种简单的方式容易地获得以前无法获得的分子。 在这份更新建议中，我们概述了开发和使用新型氧化催化剂的计划，以 多官能团的对映选择性合成。与传统的过渡金属基不同 催化剂，本项目正在开发和研究的催化剂为有机分子或含有 无害金属。这些不含过渡金属的催化剂不仅具有根本意义，而且 对工业具有重要意义，因为有害的过渡金属在药物中是不受欢迎的。 许多次级项目得到了有希望的初步成果的支持，而另一些则代表了新的 催化剂或方法开发方面的指导。机械学、结晶学和 计算研究将提供对催化过程的理解，并指导发展 更有效的催化剂。催化选择性氧化可将氧、氮或卤素引入 该底物具有催化和选择性。 我们的主要目标是不对称环氧化反应。对这一反应的调查有望导致 对广泛使用的不对称氧化催化方法的发展，这将影响许多 化学合成的各个方面。此外，这项努力将提供极好的合成培训 面向本科生、研究生和博士后学生的方法开发 制药行业或学术界的研究生涯 修改后的特定目标 催化对映体选择性氧化是医药工业中一个极其重要的过程。这一点很清楚 因为最具生物活性的分子具有高度官能化的结构。单烯烃和羰基 化合物是合成化学家可用的最有吸引力的起始材料，很容易获得 数量大，品种多。自然界实现了对络合物的高度特异的合成 通过独特的酶催化剂选择性氧化物质，从这些简单的 化合物。虽然目前有许多广泛有用的方法用于催化不对称还原， 用于氧化的这种催化不对称技术要少得多。应该指出的是，选择性地 氧化催化比选择性还原催化更具挑战性，而不是 其中最小的是配体在氧化条件下的热力学不稳定性。尽管最近 在这一重要领域已经取得了进展，但还不够。我们在此建议催化 一种氧化作用，可以将氧和硫化学地、区域地和对映体选择性地引入到底物中 为合成迄今已被用于合成高官能化复杂分子提供了简单途径 为人所知。因此，我们的贡献有望提供一套新的和普遍的手性氧化 用于制药实验室和制药工业的催化剂。 下一个资金期的具体目标是不对称环氧化。目标分为两个部分： (1)用于环氧化的钒、汞和锆催化剂及其在环氧化中的应用- 环化级联；和(2)不对称环氧化和C-H氧化铁基催化剂以及 激活。这些催化剂具有重要的意义，因为它们是一种简单、良性的促进方式 对映选择性环氧化反应。总体而言，拟议的工作不仅将导致高效的 选择性氧化的合成路线，但更重要的是，将导致 应证明对药物化学具有普遍价值的方法学。 拟议的项目将包括几个简单的生物活性分子的合成，以演示如何 我们的催化剂起作用了。当然，这些方法的实际用途要广泛得多。还预计， 所得结果将同样适用于开发其他体系的新型氧化催化剂。 提议的方法是创新的，因为它们每一个都是一个未知的过程，它将 基于我们团队利用以前的NIH支持开发的全新的催化剂设计概念。他们也 利用许多其他实验室无法获得的配位体库。建议数 研究意义重大，因为预计它将提供一个很好的催化剂工具箱，这将使 可能提供以前无法获得的复杂分子，需要开发出全新的 未来的药理策略。