Application of N-Oxides for the Synthesis of Nitrogen Heterocycles

项目摘要： 氮杂环是生物活性天然产物的普遍存在的关键结构基序， 具有针对癌症、精神疾病、抗微生物剂和镇痛剂的经证实的功效的药物。 然而，将新的氮杂环引入药物框架中的合成策略是可行的。 非平凡的和昂贵的，特别是当考虑复杂的三维（3D）目标。我们打算 扩展我们最近的工作，已确定N-氧化物化学作为一个有前途的，创新的， 解决这个难题的合适方案。为了产生药理学上感兴趣的氮杂环，我们将使用 N-氧化物，容易制备和稳定的化合物，作为[3+2]环加成的前体。n-氧化物化合 在20世纪80年代首次用于有限数量的环加成反应。然而，尽管坚实和合乎逻辑的 推理在那个时候，缺乏对这些反应如何发生的机械理解预测 亲电中间体会导致副反应、低收率和差的立体化学控制。 因此，合成社区低估了这种反应歧管，并避免了这种方法。 然而，重新评估原始实验数据的角度与高质量的密度泛函 理论，导致我们发现了定义溶剂在这种离子体系中的关键作用的机械细节， 消除了以前设想的有效利用的合成障碍。我们打算复活并建立这个 由简单前体形成氮杂环的未开发的合成途径，而没有繁重的开销 作为药物化学中实用且重要的方案。除了我们提出的工作之外， 镇痛剂（氮杂双环），新型抗菌剂（咪唑啉）和对映体富集系统，N- 氧化物化学具有许多新的方向和发现的潜力，包括环状N-氧化物，甲硅烷基， 亚胺和N-手性化合物。与NIH/R15目标一致，该项目旨在 平易近人的学生在实验和/或计算化学经验的各个层次，适应 通用设计的教育理念。最初的实验项目范围从表演和 在监督下优化已建立的反应（初学者），以运行新的反应并分析 复杂反应混合物（高级/研究生）。同样，在计算方面，学生可以学习 建立Z矩阵并识别新类似物的基态（初学者），继续寻找过渡结构， 进行能源分解分析和发展关键分析技能（高级/研究生）。最后， 我们的计划是优化这种氮氧化物化学，以创造氮杂环作为核心成分， 镇痛剂（Aim I）、抗菌剂（Aim II）和立体定向的3D结构（Aim III）。该提案提供了一个 创新的，适应性强的策略，通过共同的反应来创造各种各样的化合物 这一途径将使制药界能够在其努力的基础上， 在抗菌药物和止痛药的战略领域发现新药。

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.