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.

项目总结/摘要 我们希望继续研究复杂分子选择性功能化的新范例。我们 这种方法是基于功能基团的基本反应的发展，这些功能基团在生物化学中普遍存在。 生物活性剂。重要的是，通过这种方法产生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 该建议是开发简单制造的催化剂库，其目标是通过大量的 一系列的反应。这些将包括羟基、胺、芳烃C-H键的位点选择性反应， 烯烃和酮。此外，我们针对一系列氧化还原活性官能团，以及一系列C-C 成键反应。这些过程中有许多是在我们的实验室中开发的， 通常专注于对映选择性催化-一个非常重要的领域，具有很高的意义 用于合成药物。然而，我们的重点越来越多地放在研究高度复杂的分子 环境，其中我们的对映选择性化学作为探索底物的前奏， 立体选择性只是需要解决的问题的一个子集。我们有大量的初步证据 导致了许多复杂的分子框架，包括那些由一些古老的自然 红霉素、万古霉素、替考拉宁和硫链丝菌素等。我们希望继续进行这些研究， 但是另外我们希望将它们扩展到类似物的产生， 雷帕霉素和氨基糖苷类抗生素。所有这些目标都需要开发新的 催化剂和新反应。重点将包括高价值的催化，选址脱氧化学， 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，和 位点选择性的C-C、C-O和C-N键形成-所有这些都在复杂的分子支架中。一个重要的平行努力 在我们的小组包括催化剂的发展，选择性控制不寻常的立体化学问题，如 作为阻转异构体，这是药物化学中日益关注的领域。这些项目将扩大， 也是掌握复杂分子环境中立体化学问题的前奏。的 我们的总体目标的意义可能是在新的催化原理，并在他们的应用程序的网站选择性 对复杂的、具有生物活性的天然产物进行改性。因此，这些研究扩展了 对映体选择性研究较少的区域选择性竞技场。这些努力也将为 复杂多肽甚至蛋白质的位点选择性化学改变。因此，我们希望扩大 极大地促进了我们对迷人的生物活性剂的选择性衍生化的研究， 催化剂作为主要工具。在所有情况下，我们将继续评估新类似物的生物学特性， 希望能进一步扩展我们近年来所揭示的生物活性。