Novel Reactions of Electrophilic Nitrogen for Preparing Bioactive Molecules

亲电氮制备生物活性分子的新反应

• 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
• 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

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.

富含氮的小分子对人类健康至关重要，因为它们构成了所有已知药剂的绝大多数。随着对新药的要求变得更加严格，以及目标疾病变得更加复杂，这些化合物的化学结构也变得更加复杂。这推动了对制备更复杂的含氮小分子的更有效手段的需求。 通常，在合成化学中，氮中心的大多数化学反应都涉及低价、亲核的氮原子。在过去的100年里，无数的合成转化被开发出来，以使用这种范式来制备含氮分子。相比之下，这一提议寻求利用更高氧化态的氮化合物来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。 具体地说，在一系列已发表的初步结果的基础上，我们将开发新的亲电氮中心的类Heck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一种手段。我们的研究将发现可以参与这些氮杂-海克环化反应的新的亲氮化合物，开发新的路线来获得重要的生物活性杂环，设计不对称进入这些化合物以控制绝对立体化学，并深入挖掘反应的基本机制以使人们能够进一步了解这些过程。为了证明氮杂环化反应的重要性，我们还将以非常方便的方式制备几种具有有趣生物学特性的高度复杂的天然产品。每一次合成都将以aza-Heck技术为关键的使能反应。正如我们的支持信所反映的那样，在完成这些综合努力后，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。 总体而言，我们预计这种化学的发展将为合成、药物和过程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。同时，本研究也将为过渡金属催化的交叉偶联化学提供基础性的进展。 修改后的特定目标 富含氮的小分子对人类健康至关重要，因为它们构成了所有已知药剂的绝大多数。由于靶向疾病更加复杂，对新药的要求越来越严格，以增加安全性，药物化合物的要求和结构也变得更加复杂。特别是，对提高选择性和改进药代动力学的需要正在推动从传统的“扁平”药物转向手性和富含SP3中心的药物1，这反过来又推动了开发能够有效地制备复杂和高度取代的立体致氮小分子的新方法的需要。 拟议的研究将集中在制备拓扑复杂的含氮小分子的新方法上。我们将重点介绍在利用高价氮前体方面的两个主题相关的战略。这些反应不同于绝大多数依赖于低价亲核氮中心的合成转化，这些反应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、容易制备的氮亲电体的环化反应，以制备高取代的立体生成氮杂杂环。这些氮杂-海克环化反应将使人们能够方便地获得其他方法难以获得的生物和药物相关的杂环化合物。第二，我们将开发硝基烷烃的新反应来制备复合胺。 具体目标： 具体目标1：亲电性氮的新反应合成复杂杂环我们将开发创新的Heck型氮亲电环化反应。这将包括开发具有高度生物学意义的高取代氮杂环的新路线，获得比目前使用aza-Heck反应可能的更大的杂环，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：利用aza-Heck策略合成复杂的生物活性分子我们将把aza-Heck环化反应应用于合成与人类疾病直接相关的复杂天然产物。建议的路线非常有效，将展示氮杂-海克技术相对于传统合成方法的力量。合成效率与所选目标的生物活性相结合，将使生物后续研究成为可能。 具体目标3：硝烷烷基化我们将开发硝基烷烃的新反应，包括高取代硝基烷烃的光依赖烷基化反应、不对称硝基烷基化反应和不对称还原硝基烷烃反应，使创新进入具有重要生物意义的烷基胺。这些转变的独特而复杂的机制也将被阐明。 总体而言，这项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，并使合成对治疗各种人类疾病特别感兴趣的目标分子成为可能。