Visible Light-Enabled Synthesis of Heterocycles through Energy Transfer

通过能量转移可见光合成杂环

• 批准号: 10636772
• 负责人: Corinna Stefanie Schindler
• 金额: $ 30.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636772
• 关键词: Acids; Alkenes; Alkynes; Area; Catalysis; Characteristics; Chemicals; Chemistry; Complex; Cyclization; Development; Drug Kinetics; Energy Transfer; Exhibits; Genomics; Health; Human; Imines; Investigation; Knowledge; Label; Lead; Libraries; Mediating; Medicine; Methods; Michigan; Mission; Modification; Molecular; Natural Products; Pathway interactions; Pharmaceutical Chemistry; Pharmacologic Substance; Property; Protocols documentation; Public Health; RNA; Reaction; Reagent; Research; Structure; Toxic effect; Triplet Multiple Birth; Ultraviolet Rays; United States National Institutes of Health; Universities; Variant; Visible Radiation; azetidine; biological research; cycloaddition; drug development; drug discovery; functional group; high throughput screening; improved; member; novel strategies; novel therapeutics; nucleobase; oxetane; programs; scaffold; three dimensional structure; tool; triplet state

Project Summary/Abstract Azetidines, azetines, and oxetanes are four-membered heterocycles that exhibit desirable pharmacokinetic effects and represent important building blocks in current medicinal chemistry. Cycloaddition reactions between alkenes and imines or carbonyls, also referred to as (aza) Paternò-Büchi reactions, represent the most direct synthetic approach to access these compounds, however the current utility of these transformations is highly restricted due to the stringent requirement of UV-light and competing reaction paths accessible upon photochemical excitation. Thus, the ability to incorporate functionalized azetidines, azetines, and oxetanes into pharmaceutical lead structures is currently severely limited due to a lack of efficient synthetic methods. To date, no visible light-based platform of general synthetic utility for cycloadditions between alkenes and imines or carbonyls exists. The objective of the proposed research program is to identify and develop chemical strategies that enable efficient cycloadditions between these functional groups to access azetidines, azetines, and oxetanes based on energy transfer catalysis facilitated by visible light. These new synthetic methods will provide general and modular protocols for the synthesis of a large variety of heterocyclic motifs that are highly desirable in current medicinal chemistry. Additionally, the strategies described will enable cycloaddition reactions between alkenes and imines or carbonyls under mild reaction conditions with high functional group tolerance as they forego the requirement of UV-light. The utility of the accessible 4-membered heterocycles as building blocks will be demonstrated in secondary modifications and by enabling the synthesis of biologically active target structures from commercially available starting materials. The compounds prepared within this research program will be incorporated into the compound library maintained by the Center for Chemical Genomics (CCG) at the University of Michigan and become part of high-throughput screening (HTS) approaches for biological research and new drug discovery projects. In summary, the research described will enable general, catalytic strategies for aza Paternò-Büchi and Paternò-Büchi reactions relying on energy transfer upon excitation with visible light. These new transformations represent desirable synthetic tools that will enable direct access to functionalized azetidines, azetines, and oxetanes, and are expected to have broad implications in the area of medicinal chemistry.

项目总结/摘要 氮杂环丁烷、氮杂环丁烷和氧杂环丁烷是四元杂环化合物，其表现出理想的药代动力学 影响，并代表了当前药物化学的重要组成部分。环加成反应 烯烃与亚胺或羰基之间的反应，也称为（氮杂）Paternand-Büchi反应，代表了 获得这些化合物的最直接的合成方法，然而，这些化合物的当前效用并不明显。 由于对紫外光和竞争反应途径的严格要求， 光化学激发时可接近。因此，引入官能化氮杂环丁烷，氮杂环丁烷， 由于缺乏有效的合成方法， 方法.迄今为止，还没有用于烯烃之间的环加成的通用合成效用的基于可见光的平台。 并且存在亚胺或羰基。该研究计划的目的是确定和开发 能够使这些官能团之间有效环加成以获得氮杂环丁烷的化学策略， 氮杂环丁烷和基于可见光促进的能量转移催化的氧杂环丁烷。 这些新的合成方法将为合成多种化合物提供通用和模块化的方案 杂环基序是当前药物化学中非常需要的。此外，战略 所描述的将使得烯烃和亚胺或羰基之间的环加成反应在温和的反应下进行 具有高官能团耐受性的条件，因为它们放弃了UV光的要求。的效用 作为结构单元的可接近的4元杂环将在二级修饰中得到证明， 通过使得能够从市售的起始材料合成生物活性目标结构。 本研究计划中制备的化合物将被纳入化合物库 由密歇根大学化学基因组学中心（CCG）维护，并成为 高通量筛选（HTS）方法用于生物研究和新药发现项目。 总之，所描述的研究将使氮杂Paternal-Büchi和 依赖于可见光激发时的能量转移的Paternel-Büchi反应。这些新 转化代表了能够直接获得官能化氮杂环丁烷的理想合成工具， 氮杂环丁烷和氧杂环丁烷，并且预期在药物化学领域具有广泛的应用。