权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Site-Selective Catalysis for Bioactive Scaffold Diversification

生物活性支架多样化的位点选择性催化

基本信息

批准号：
10619591
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
项目类别：
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

项目摘要

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.

项目摘要/摘要我们希望继续研究复杂分子选择性官能化的新范式。我们的该方法是基于普遍存在的官能团的基本反应的发展生物活性物质。重要的是，通过这种方法产生的生物活性类似物跨越了多个治疗领域，并将这些化学研究归类为典型的“普通医学科学”。主要强调的是这项提议是开发易于制作的触媒程序库，通过大量的一系列的反应。这些反应将包括羟基、胺、芳烃C-H键、烯烃和酮。此外，我们的目标是许多氧化还原活性官能团，以及一系列C-C 成键反应。其中许多工艺都是在我们的实验室开发的，我们进行了初步的研究经常专注于对映选择性催化--一个本身就非常重要的领域，具有很高的意义用于合成药物。然而，我们的重点越来越集中在高度复杂的分子的研究上。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。我们有大量的初步资料结果产生了许多复杂的分子框架，包括由一些古老的天然产品，如红霉素、万古霉素、替考拉宁和硫链菌素。我们希望继续这些研究，但除此之外，我们还希望将其扩展到类似寡霉素的结构所呈现的上下文中的模拟产生，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。重点将包括高价值催化、现场选择性脱氧化学、现场- 选择性胺官能化、位选择性C-H键官能化、位选择性氧化还原反应以及位置选择性的C-C、C-O和C-N键的形成--都在复杂的分子支架中。一项重要的并行努力在我们的团队中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，如如阿托品异构症，这是药物化学中一个日益受到关注的领域。这些项目将扩大为嗯，也是在复杂的分子环境中掌握这个立体化学问题的前奏。这个我们总体目标的意义可能在于新的催化原理，以及它们对位点的选择性应用对复杂的生物活性天然产物进行改性。因此，这些调查扩展了对对研究较少的区域选择性领域的对映体选择性。这些努力也将为复杂多肽，甚至蛋白质的位置选择性化学变化。因此，我们希望扩大我们对具有选择性的生物活性物质的选择性衍生化进行了大量的研究以催化剂为主要工具。在所有情况下，我们都将继续评估新的类似物的生物学特性，希望进一步扩大我们近年来揭开的生物活性。