Site-Selective Catalysis for Bioactive Scaffold Diversification

生物活性支架多样化的位点选择性催化

• 批准号: 10158499
• 负责人: Scott J Miller
• 金额: $ 83.74万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158499
• 关键词: Address; Alkenes; Amines; Aminoglycoside Antibiotics; Area; Biological; Catalysis; Catalytic Domain; Chemicals; Chemistry; Complex; Development; Environment; Erythromycin; Generations; Goals; Hydrogen Bonding; Investigation; Ketones; Laboratories; Libraries; Medical; Medicine; Modification; Molecular; Natural Products; Oligomycins; Oxidation-Reduction; Pharmaceutical Chemistry; Pharmacologic Substance; Process; Property; Proteins; Reaction; Science; Sirolimus; Site; Structure; Teicoplanin; Therapeutic; Thiostrepton; Vancomycin; analog; bioactive natural products; catalyst; fascinate; functional group; hydroxyl group; polypeptide; scaffold; tool

Project Summary/Abstract We wish to continue our study of a new paradigm for the selective functionalization of complex molecules. Our approach is predicated on the development of fundamental reactions of functional groups that are ubiquitous in bioactive agents. Importantly, bioactive analog generation by this approach spans multiple therapeutic areas, and categorizes these chemical studies as a quintessential “General Medical Science.” The main emphasis of this proposal is the development of simple-to-make catalyst libraries that target functionalization through a vast array of reactions. These will include site-selective reactions of hydroxyl groups, amines, arene C-H bonds, olefins and ketones. In addition, we target a host of redox-active functional groups, as well as an array of C-C bond-forming reactions. Many of these processes have been developed in our laboratory, with our initial studies often focusing on enantioselective catalysis – a field of great importance in its own right, with high significance for the synthesis of pharmaceuticals. Yet, our focus is increasingly on the study of highly complex molecular environments, wherein our enantioselective chemistry serves as a prelude to exploration of substrates for which stereoselectivity represents just a subset of the issues that need to be addressed. We have extensive preliminary results in a number of complex molecular frameworks, including those provided by some venerable natural products, such as erythromycin, vancomycin, teicoplanin and thiostrepton. We wish to continue these studies, but in addition we wish to expand them to analog generation in contexts presented by structures like oligomycin, rapamycin and the aminoglycoside antibiotics. All of these objectives will require the development of new catalysts and new reactions. Foci will include high value catalytic, site-selective deoxygenation chemistry, site- selective amine functionalization, site-selective C-H bond functionalization, site-selective redox reactions, and site-selective C-C, C-O and C-N bond formations – all in complex molecular scaffolds. An important parallel effort in our group includes the development of catalysts for selective control over unusual stereochemical issues, such as atropisomerism, which is an area of growing concern in medicinal chemistry. These projects will expand as well, also as a prelude to mastery of this stereochemical issue in complex molecular environments. The significance of our overall goals may be in new catalysis principles, and in their application to the site-selective modification of complex, bioactive natural products. These investigations thus extend fundamental studies of enantioselectivity to the less well-studied arena of regioselectivity. These efforts will also set the stage for the site-selective chemical alteration of complex polypeptides, and maybe even proteins. Thus, we wish to expand greatly our studies of the selective derivatization of fascinating biologically active agents, with site-selective catalysts as the principal tool. In all cases, we will continue to assess new analogs for their biological properties, hoping to extend further the biological activities we have unveiled in recent years.

项目概要/摘要 我们希望继续研究复杂分子选择性功能化的新范例。 该方法基于普遍存在的官能团基本反应的发展 重要的是，通过这种方法生成的生物活性类似物跨越多个治疗领域， 并将这些化学研究归类为典型的“普通医学科学”的主要重点。 该提案是开发易于制作的催化剂库，其目标是通过大量的功能化 这些反应包括羟基、胺、芳烃 C-H 键的位点选择性反应， 此外，我们还针对大量氧化还原活性官能团以及一系列 C-C 官能团。 通过我们的初步研究，许多这些过程都是在我们的实验室中开发出来的。 通常关注对映选择性催化——一个本身就非常重要的领域，具有很高的意义 然而，我们的注意力越来越集中在高度复杂分子的研究上。 环境，因此我们的对映选择性化学充当了探索底物的前奏 立体选择性只是需要解决的问题的一部分。 结果产生了许多复杂的分子框架，包括由一些古老的天然物质提供的框架 产品，如红霉素、万古霉素、替考拉宁和硫链丝菌素，我们希望继续这些研究， 但此外，我们希望将它们扩展到寡霉素等结构所呈现的背景下的模拟生成， 所有这些目标都需要开发新的雷帕霉素和氨基糖苷类抗生素。 催化剂和新反应将包括高价值催化、位点选择性脱氧化学、位点- 选择性胺官能化、位点选择性C-H键官能化、位点选择性氧化还原反应，以及 位点选择性的 C-C、C-O 和 C-N 键形成——全部在复杂的分子支架中，这是一项重要的并行工作。 我们的团队包括开发用于选择性控制不寻常的立体化学问题的催化剂，例如 作为药物化学日益关注的领域，这些项目将扩大。 好吧，这也是在复杂分子环境中掌握这个立体化学问题的前奏。 我们总体目标的重要性可能在于新的催化原理及其在位点选择性中的应用 因此，这些研究扩展了复杂的、具有生物活性的天然产物的基础研究。 这些努力也将为研究较少的区域选择性领域奠定基础。 因此，我们希望扩展复杂多肽甚至蛋白质的位点选择性化学改变。 我们对令人着迷的生物活性剂的选择性衍生化的研究，具有位点选择性 在所有情况下，我们将继续评估新类似物的生物特性， 希望进一步扩展我们近年来发表的生物活性。