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: 10416714
• 负责人: Donald Allen Watson
• 金额: $ 36.26万
• 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/10416714
• 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; Methods; Molecular; Narcotics; Natural Products; Nitrogen; Nitrogen Oxides; Organic Synthesis; Pharmacologic Substance; Phosphines; Positioning Attribute; Process; Publishing; Reaction; Research; Resistance; Route; Safety; Synthesis Chemistry; System; Technology; Time Study; Transition Elements; base; cancer cell; chemical reaction; design; drug structure; human disease; improved; inhibitor; innovation; innovative technologies; interest; 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.

富氮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。随着对新药的要求越来越严格，以及靶向疾病变得越来越复杂，这些化合物的化学结构也变得越来越复杂。这促使人们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，氮中心的大多数化学反应涉及低价亲核氮原子。在过去的100年里，无数的合成转化已经被开发出来，以使用这种范式制备含氮分子。相比之下，该提案试图利用处于较高氧化态的氮化合物来寻求新的反应性和化学过程，从而可以以新的方式制备复杂的含氮分子。 具体而言，基于一组强有力的已发表的初步结果，我们将开发新的赫克样反应的亲电氮中心作为一种手段来构建高度取代的立体化学和拓扑结构复杂的氮杂环。我们的研究将发现新的氮亲电试剂，可以参与这些氮杂-赫克环化，开发新的路线，以重要类别的生物活性杂环，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，使进一步了解的过程。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生物特征的高度复杂的天然产物。每一种合成都将以aza-Heck技术作为关键的实现反应。正如我们的支持信中所反映的那样，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。 总的来说，我们预计这种化学的发展将通过为合成，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，对人类健康产生积极影响。同时，本研究将为过渡金属催化的交叉偶联化学提供基础性进展。 修改后的具体目标 富氮小分子对人类健康至关重要，因为它们构成了所有已知药剂的绝大多数。随着靶向疾病越来越复杂，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越来越复杂。特别是，对增加选择性和改善药代动力学的需求正在推动从传统的“扁平”药物转向那些手性和富含sp3中心的药物。1反过来，这又推动了开发新方法的需求，这些方法可以有效地制备复杂和高度取代的立体含氮小分子。 拟议的研究将重点关注制备拓扑复杂的含氮小分子的新方法。我们将集中在两个战略，是主题相关的高价氮前体的利用。这些反应与依赖低价亲核氮中心的绝大多数合成转化不同，并且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，容易制备的氮亲电试剂的环化反应，以制备高度取代的立体氮杂杂环。这些氮杂-赫克环化将允许容易地获得其他方法难以获得的生物学和医学相关杂环。第二，我们将开发新的硝基烷烃反应来制备复杂的胺。 具体目标： 具体目标1：制备复杂杂环的亲电氮新反应我们将开发氮亲电试剂的创新Heck型环化反应。这将包括开发具有高生物重要性的高度取代的氮杂环的新路线，使用氮杂-赫克反应获得比目前可能的更大的杂环，开发这些环化的不对称版本，以及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。 具体目标二：使用氮杂-赫克策略合成复杂的生物活性分子我们将应用氮杂-赫克环化来合成与人类疾病直接相关的复杂天然产物。所提出的路线是非常有效的，并将证明氮杂赫克技术的力量超过传统的合成方法。合成效率与所选靶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：硝基烷烷基化我们将开发硝基烷的新反应，包括高度取代的硝基烷的光依赖性烷基化、不对称硝基烷烷基化和硝基烷的不对称还原，从而实现对生物重要的烷基胺的创新进入。这些转变的独特而复杂的机制也将得到阐明。 总的来说，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，并能够合成治疗各种人类疾病的特定目标分子。