Novel Reactions of Electrophilic Nitrogen for Preparing Bioactive Molecules

亲电氮制备生物活性分子的新反应

基本信息

批准号：
10650792
负责人：
Donald Allen Watson
金额：
$ 31.76万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650792
关键词：
Alkylation Amines Automobile Driving Biological Catalysis Chemical Structure Chemicals Chemistry Complex Coupling Cyclization Development Dioxanes Disease Drug Compounding Drug Kinetics Felis catus Follow-Up Studies Health Homo Human Letters Ligands Medical Medicine Methods Molecular Narcotics Natural Products Nitrogen Organic Synthesis Pharmaceutical Preparations Pharmacologic Substance Phosphines Positioning Attribute Process Publishing Reaction Research Resistance Route Safety Synthesis Chemistry System Technology Time Transition Elements base cancer cell chemical reaction design drug structure human disease improved inhibitor innovation innovative technologies interest invention nitroalkane nitrogen compounds novel novel therapeutics oxidation programs small molecule stereochemistry strictamine tool tumor necrosis factor-alpha inhibitor

项目摘要

Nitrogen-rich small molecules are critical to human health as they constitute the vast majority of all known pharmaceutical agents. As the requirements for new drugs become stricter, and as the diseases that are targeted become more complex, the chemical structures of those compounds are also becoming more complex. This is driving the need for more efficient means to prepare ever more complex nitrogen-containing small molecules. Typically, in synthetic chemistry, most chemical reactions of nitrogen centers involve low valent, nucleophilic nitrogen atoms. Over the past 100 years, countless synthetic transformations have been developed to prepare nitrogen-containing molecules using this paradigm. In contrast, this proposal seeks to leverage nitrogen compounds in higher oxidation states to seek new reactivity and chemical processes that can prepare complex nitrogen-containing molecules in new ways. Specifically, based upon a strong set of published preliminary results, we will develop new Heck-like reactions of electrophilic nitrogen centers as a means to construct highly substituted stereochemically and topologically complex nitrogen heterocycles. Our studies will discover new nitrogen electrophiles that can participate in these aza-Heck cyclizations, develop novel routes to important classes of biologically active heterocycles, design asymmetric entries into these compounds to control absolute stereochemistry, and dig deeper into the fundamental mechanisms of the reactions to enable further understanding of the processes. To demonstrate the importance of aza-Heck cyclizations, we will also prepare several highly complex natural products with interesting biological profiles in highly expedient ways. Each synthesis will feature aza-Heck technologies as the key enabling reaction. As reflected in our support letters, we are well positioned for follow-up studies at the completion of these synthetic efforts. We will also continue to develop new catalytic methods to prepare complex nitroalkanes and seek to use those compounds in novel transformation for preparing bioactive molecules. Overall, we expect that the development of this chemistry will positively impact human health by providing synthetic, medicinal, and process chemists valuable new tools for the construction of nitrogen-rich bioactive small molecules. At the same time, this study will provide fundamental advances in transition metal-catalyzed cross-coupling chemistry. Modified Specific Aims Nitrogen-rich small molecules are critical to human health as they constitute the vast majority of all known pharmaceutical agents. As targeted diseases are more complex and the requirements for new drugs become stricter to increase safety, the requirements and structures of the drug compounds have also become more complex. In particular, the need for increased selectivity and improved pharmacokinetics is driving a move away from traditional “flat” pharmaceuticals towards those that are chiral and rich in sp3 centers.1 In turn, this has driven the need to develop new methods that can efficiently prepare complex and highly substituted stereogenic nitrogen-containing small molecules. The proposed research will focus on new methods for preparing topologically complex, nitrogen-containing small molecules. We will focus on two strategies that are thematically related in the utilization of high-valent nitrogen precursors. These reactions are a departure from the vast majority of synthetic transformations that rely on low-valent nucleophilic nitrogen centers and will allow rapid access to compounds that traditional methods struggle to prepare. First, we will develop cyclizations of stable, readily prepared nitrogen electrophiles to prepare highly substituted stereogenic aza-heterocycles. These aza-Heck cyclizations will allow facile access to biologically and medicinally relevant heterocycles that other methods struggle to access. Second, we will develop new reactions of nitroalkanes to prepare complex amines. Specific Aims: Specific Aim 1: New Reactions of Electrophilic Nitrogen to Prepare Complex Heterocycles We will develop innovative Heck-type cyclizations of nitrogen electrophiles. This will include developing new routes to highly substituted nitrogen heterocycles of high biological importance, accessing larger heterocycles than are currently possible using aza-Heck reactions, developing asymmetric versions of these cyclizations, and studying the novel mechanisms of these transformations. This will allow rapid entry into heterocyclic systems and enable the synthesis of many bioactive compounds and natural products. Specific Aim 2: Synthesis of Complex, Biologically Active Molecules Using Aza-Heck Strategies We will apply aza-Heck cyclizations to the synthesis of complex natural products of direct interest to human disease. The proposed routes are extremely efficient and will demonstrate the power of aza-Heck technology over traditional synthetic methods. The synthetic efficiency, combined with the bioactivity of the chosen targets, will enable biological follow-up studies. Specific Aim 3: Nitroalkane Alkylation We will develop new reactions of nitroalkanes, including photodependent alkylations of highly substituted nitroalkanes, asymmetric nitroalkane alkylations, and asymmetric reductions of nitroalkanes, enabling innovative entries into biologically important alkyl amines. The unique and complex mechanisms of these transformations will also be elucidated. Overall, this research program will discover and seek to understand new methods for preparing complex, biomedically relevant compounds and enable the synthesis of target molecules of specific interest to the treatment of various human diseases.

富氮小分子对人类健康至关重要，因为它们构成了绝大多数已知的药剂。随着对新药的要求变得更加严格，并且随着针对的疾病变得更加复杂，这些化合物的化学结构也变得更加复杂。这使得需要更有效的方法来制备更复杂的含氮小分子。通常，在合成化学中，大多数氮中心的化学反应都涉及低价亲核氮原子，在过去的 100 年里，已经开发出无数的合成转化来使用这种范例来制备含氮分子。较高氧化态的氮化合物寻求新的反应性和化学过程，以新的方式制备复杂的含氮分子。基于已发表的一系列强有力的初步结果，我们将开发新的亲电子氮中心的类赫克反应，作为构建高度取代的立体化学和拓扑复杂的氮杂环的手段，我们的研究将发现可以在这些氮杂中形成的新的氮亲电子试剂。 -赫克环化，开发重要类别的生物活性杂环的新途径，设计这些化合物的不对称条目以控制绝对立体化学，并更深入地研究反应的基本机制，以便进一步了解为了证明 aza-Heck 环化的重要性，我们还将以非常方便的方式制备几种具有有趣的生物特征的高度复杂的天然产物，正如我们的支持所反映的那样。在完成这些合成工作后，我们已经做好了后续研究的准备，我们还将继续开发新的催化方法来制备复杂的硝基烷烃，并寻求将这些化合物用于制备生物活性分子的新转化。总的来说，我们预计这种化学的发展将为合成、药物和工艺化学家提供构建富氮生物活性小分子的宝贵新工具，从而对人类健康产生积极影响。过渡金属催化的交叉偶联化学。修改后的具体目标富氮小分子对人类健康至关重要，因为它们构成了绝大多数已知的药物制剂。随着目标疾病变得更加复杂，为了提高安全性，对新药的要求变得更加严格，药物化合物的要求和结构也随之变化。特别是，对提高选择性和改进药代动力学的需求正在推动传统“扁平”药物转向手性且富含 sp3 中心的药物。1 反过来，这也推动了开发新方法的需求。可以有效地制备复杂且高度取代的立体异构含氮小分子。拟议的研究将集中于制备拓扑复杂的含氮小分子的新方法，我们将重点关注与高价氮前体的利用主题相关的两种策略，这些反应与绝大多数合成反应不同。依赖于低价高亲核氮中心的转化，将允许快速获得传统方法难以制备的化合物。首先，我们将开发稳定的、易于制备的氮亲电子试剂的环化，以制备取代的立体异构体。这些氮杂赫克环化将能够轻松获得其他方法难以获得的生物学和医学相关的杂环。其次，我们将开发硝基烷烃的新反应来制备复杂的胺。具体目标：具体目标1：亲电氮制备复杂杂环的新反应我们将开发氮亲电子试剂的创新Heck型环化，这将包括开发具有高生物学重要性的取代氮杂环的新路线，获得比目前使用氮杂环更大的杂环。 -赫克反应，开发这些环化的不对称版本，并研究这些转化的新机制，这将允许快速进入杂环系统并能够合成。许多生物活性化合物和天然产物。具体目标 2：使用 Aza-Heck 策略合成复杂的生物活性分子我们将应用 aza-Heck 环化来合成与人类疾病直接相关的复杂天然产物。所提出的路线非常有效，并将展示 aza 的力量。 -超越传统合成方法的技术，合成效率与所选目标的生物活性相结合，将使生物学后续研究成为可能。具体目标3：硝基烷烃烷基化我们将开发硝基烷烃的新反应，包括高度取代的硝基烷烃的光依赖性烷基化、不对称硝基烷烃烷基化和硝基烷烃的不对称还原，从而能够创新地进入具有生物学重要性的烷基胺，这些转化的独特而复杂的机制将成为可能。也予以阐明。总体而言，该研究计划将发现并寻求了解制备复杂的生物医学相关化合物的新方法，并能够合成对治疗各种人类疾病有特殊意义的目标分子。