Application of N-Oxides for the Synthesis of Nitrogen Heterocycles

N-氧化物在氮杂环合成中的应用

基本信息

批准号：
10579651
负责人：
THOMAS MONTGOMERY
金额：
$ 40.65万
依托单位：
DUQUESNE UNIVERSITY
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：
2022-09-16 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579651
关键词：
3-Dimensional Address Alkaloids Analgesics Area Attention Bicycling Bicyclo Compounds Biological Chemicals Chemistry Communities Complex Computer Models Data Education Ensure Environment Equipment Evaluation Family Future Generations Goals Human Resources Imidazolidines Imidazolines Imines Investigation Investments Laboratories Learning Literature Lithium Malignant Neoplasms Mental disorders Methods Modeling Modernization Molecular Target Natural Products Nitrogen Organic Chemistry Oxides Pathway interactions Pennsylvania Periodicity Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Philosophy Property Protocols documentation Reaction Reporting Reproducibility Research Research Personnel Resources Role Running Science Side Solid Solvents Structure Students Supervision System Techniques Time Training United States National Institutes of Health Universities Work analog antimicrobial bioactive natural products computational chemistry cost cycloaddition density design epibatidine experience experimental study health science research innovation interest laboratory experiment non-opioid analgesic novel novel therapeutics predictive modeling programs restraint scaffold skills small molecule student training theories three dimensional structure tool trend two-dimensional undergraduate student ylide

项目摘要

Project Summary: Nitrogen heterocycles are a ubiquitous and key structural motif of bioactive natural products and pharmaceuticals with proven efficacy targeting cancer, psychiatric disorders, antimicrobials, and analgesics. However, the synthetic strategy of introducing new nitrogen heterocycles into a pharmaceutical framework is nontrivial and costly, especially when considering complex three-dimensional (3D) targets. We intend to expand upon our recent body of work that has identified N-oxide chemistry as a promising, innovative, adaptable solution for this conundrum. To create nitrogen heterocycles of pharmacological interest, we will use N-oxides, easily prepared and stable compounds, as precursors for [3+2] cycloadditions. N-oxide compounds were first used in a limited number of cycloaddition reactions in the 1980s. However, despite solid and logical reasoning at that time, the lack of mechanistic understanding on how these reactions occurred predicted electrophilic intermediates that would cause side reactions, low yields, and poor stereochemical control. Consequently, the synthetic community undervalued this reaction manifold and avoided such an approach. However, re-evaluation of the original experimental data with the perspective of high-quality density functional theory, led to us uncovering mechanistic details defining the critical role of solvent in such ionic systems, and eradicated the previously conceived synthetic barriers to efficient use. We intend to resurrect and establish this unexplored synthetic avenue forming nitrogen heterocycles from simple precursors without onerous overhead as a practical and significant protocol in medicinal chemistry. Beyond our proposed work delivering key analgesics (aza-bicycles), novel antimicrobials (imidazolines), and enantio-enriched systems, the impact of N- oxide chemistry has the potential for many new directions and discoveries including cyclic N-oxides, silyl imines, and N-chiral compounds. Aligned with NIH/R15 goals, this project has been designed to be approachable for students of all levels of experience in experimental and/or computational chemistry, adapting the educational philosophy of Universal Design. Initial experimental projects range from performing and optimizing established reactions under supervision (beginner) to running novel reactions and analyzing complex reaction mixtures (advanced/graduate). Likewise, on the computational side students can learn to build Z-matrixes and identify ground states for new analogs (beginner), progress to finding transition structures, performing energy decomposition analyses and develop critical analysis skills (advanced/graduate). Ultimately, our plan is to optimize this N-oxide chemistry to create nitrogen heterocycles as the core component for analgesics (Aim I), antimicrobials (Aim II), and stereo-defined 3D structures (Aim III). This proposal offers an innovative, adaptable strategy for creating a wide range of such compounds through a shared reaction pathway that will empower the pharmaceutical community to expand upon its efforts significantly in the discovery of novel drugs in the strategic areas of antimicrobials and analgesics.

项目摘要：氮杂环是生物活性天然产物的普遍存在和关键的结构序具有靶向癌症，精神疾病，抗菌和镇痛药的疗效的药物。但是，将新的氮杂环引入药物框架的合成策略是非平地和昂贵，尤其是在考虑复杂的三维（3D）目标时。我们打算扩展我们最近的工作体系，该工作已经确定N-氧化物化学是一种有希望的，创新的，这个难题的适应性解决方案。为了产生药理学兴趣的氮杂环，我们将使用 N-氧化物，易于制备且稳定的化合物，作为[3+2]环加成的前体。 N氧化物化合物首先在1980年代有限数量的环加成反应中使用。但是，尽管稳定且逻辑当时的推理，缺乏对这些反应如何发生的机械理解的预测亲电中间体会导致侧面反应，低产量和立体化学对照不良。因此，综合界低估了这种反应歧管，并避免了这种方法。但是，重新评估原始的实验数据，以高质量密度功能的角度进行重新评估理论，导致我们发现了定义溶剂在这种离子系统的关键作用的机理细节，并消除了先前构想的合成障碍，以有效使用。我们打算复活并建立这个未开发的合成大道从简单的前体形成氮杂环，而没有繁重的开销作为药物化学方面的实用和重要方案。除了我们提议的工作提供密钥之外镇痛药（Aza-bicycles），新型抗菌剂（咪唑啉）和富含对映的系统，N-的影响氧化物化学具有许多新的方向和发现的潜力亚胺和N-手续化合物。与NIH/R15目标保持一致，该项目被设计为适用于实验和/或计算化学方面的各个经验的学生，适应普遍设计的教育哲学。最初的实验项目范围从表演和在监督下（初学者）优化对运行新反应和分析的既定反应复杂的反应混合物（高级/研究生）。同样，在计算方面，学生可以学会构建Z-矩阵并确定新类似物（初学者）的基态，进展到寻找过渡结构，进行能量分解分析并发展关键分析技能（高级/研究生）。最终，我们的计划是优化这种N-氧化化学，以创建氮异环作为作为核心成分镇痛药（AIM I），抗菌剂（AIM II）和立体定义的3D结构（AIM III）。该建议提供了创新的，适应性的策略，通过共同的反应来创建各种此类化合物将使制药界有能力大大扩展其努力的途径在抗菌和镇痛药的战略领域发现新药。