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: 8466983
• 负责人: HISASHI None YAMAMOTO
• 金额: $ 21.98万
• 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/8466983
• 关键词: 3-hydroxybutanal; Academia; Alder plant; Alkenes; Area; Benign; Catalysis; Complex; Cyclization; Development; Development Plans; Drug Industry; Enzymes; Equilibrium; Funding; Future; Goals; Hafnia; Hafnium; Halogens; Human; Investigation; Iron; Laboratories; Lead; Learning; Libraries; Ligands; Metals; Methodology; Methods; Molecular; Nature; Nitrogen; Organic Synthesis; Oxygen; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Production; Public Health; Reaction; Research; Route; Solutions; Structure; Students; Sulfur; System; Techniques; Thermodynamics; Training; Transition Elements; United States National Institutes of Health; Vanadium; Work; Zirconium; base; carbonyl compound; career; catalyst; chemical synthesis; chiral molecule; computer studies; design; drug market; experience; functional group; graduate student; innovation; interest; next generation; oxidation; programs; success; undergraduate student; 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.

现代药物是高度功能化的分子，这些分子通常是手性的。在 制药行业，单手性药物占药物总市场的一半以上，关键 前十种药物中有9种是手性的。手性化合物的生物医学重要性具有 领先的实验室刺激了激烈的研究工作。生产最有希望的解决方案 这些分子依赖于不对称的催化过程，尤其是催化不对称氧化， 可以将多功能组引入分子。该项目的长期目标是 开发催化不对称氧化过程，可以在A处产生高度功能化的药物 有用的选择性和可伸缩性水平。开发这些催化剂的目的是提供可靠的 并容易访问以简单的方式制作以前无法实现的分子。 在此续签建议中，我们概述了开发和使用新氧化催化剂的计划 多功能分子的对映选择性合成。与传统过渡金属不同 催化剂，在该程序中开发和研究的催化剂是有机分子或包含 非损害金属。这些无金属催化剂不仅具有基本利益，而且还具有 工业重要性，因为有害过渡金属在药物中是不可取的。 许多子项目都得到了有希望的初步结果的支持，而其他则代表了新的。 催化剂或方法论开发的方向。机械，晶体学和 计算研究将提供对催化过程的理解并引导开发 更有效的催化剂。催化选择性氧化可以将氧，氮或卤素引入 底物催化和有选择性。 我们的具体主要目的是不对称的环氧化。对此反应的调查有望领导 开发广泛有用的不对称氧化催化方法，这将影响许多 化学合成的方面。此外，这项努力将提供出色的合成培训 方法论开发本科，毕业生和博士后学生对 制药行业或学术界的研究职业 修改的特定目标 催化对映选择性氧化是制药行业极为重要的过程。这很清楚 因为最生物活性分子具有高度功能化的结构。简单的烯烃和羰基 化合物是合成化学家可用的最具吸引力的起始材料，易于使用 大量和许多品种。大自然实现了复杂的高度特异性合成 通过这些简单的酶催化剂通过酶催化剂通过独特选择性氧化的物质 化合物。虽然目前有许多广泛有用的催化不对称还原方法，但 这些用于氧化的催化不对称技术中的较少。应该指出的是选择性 氧化催化代表比选择性还原催化更大的挑战，而不是 其中至少是配体在氧化条件下的热力学不稳定。虽然最近 在这个重要领域已经取得了进展，还不够。我们在此提出催化 可以将氧气和硫引入底物的氧化化学，区域和对映体的氧化 简单地输入了迄今为止已有高度功能化的复杂分子的合成 已知。因此，我们在这里的贡献有望提供一组新的和一般的手性氧化 制药实验室和药品行业的催化剂。 下一个资金期的具体目的是不对称的环氧化。目标分为两个部分： （1）用于环氧化的钒，hafnium和锆催化剂，并将其应用于环氧化 - 环化级联； （2）基于铁的催化剂，用于不对称的环氧化和C-H氧化和 激活。这些催化剂在其表现方面是重要的，是简单，良性的促进方式 对映选择性环氧反应。总体而言，拟议的工作不仅会导致高效 选择性氧化的合成途径，但更重要的是，将导致发展 应该证明对药物化学具有一般价值的方法。 拟议的项目将包括几种简单生物活性分子的合成，以证明如何 我们的催化剂起作用。当然，这些方法的实际效用要广泛得多。还期望 所学的知识将同样适用于其他系统的新氧化催化剂的开发。 提出的方法是创新的，因为它们每个都是一个未知的过程，可大写 在我们小组使用以前的NIH支持开发的全新催化剂设计概念上。他们也是 利用许多没有其他实验室可用的配体库。提议 研究很重要，因为预计它将提供催化剂的精细工具箱，这将使 可能需要提供以前无法实现的复杂分子来发展全新 未来的药理学策略。