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: 10369700
• 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/10369700
• 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; Yang; azetidine; base; biological research; cycloaddition; drug development; drug discovery; functional group; high throughput screening; improved; 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.

项目摘要/摘要 氮杂丁碱，偶氮和氧烷是四元的杂环，暴露了理想的药代动力学 效果并代表当前药物化学中的重要组成部分。环加成反应 在烷烃和亚胺或羰基之间，也称为（Aza）Patanò-Büchi反应，代表 最直接的合成方法可以访问这些化合物，但是当前的实用程序 由于紫外线和竞争反应路径的严格要求，转换受到了高度限制 光化学兴奋时可以使用。这是合并功能化的千替丁的能力，偶氮， 由于缺乏有效的合成，目前进入药物铅结构的氧烷目前受到严重限制 方法。迄今为止，尚无可见的基于光的一般合成效用平台，用于烷烃之间的环加成。 以及亚胺或羰基存在。拟议的研究计划的目的是识别和开发 这些官能团之间可以有效的环加成的化学策略，以访问千替丁， 基于可见光制备的能量转移催化剂的烷丁烷和氧烷。 这些新的合成方法将为综合多种多样的一般和模块化方案提供 在当前药物化学中非常需要的杂环基序。此外，策略 所描述的将在轻度反应下实现烯烃和亚胺或羰基之间的环加成反应 具有高功能群耐受性的条件，因为它们放弃了紫外线的要求。效用 可访问的4元杂环作为构建块，将以次要修改和 通过从市售起始材料中启用生物活性目标结构的合成。 该研究计划中准备的化合物将纳入化合物库 由密歇根大学化学基因组学中心（CCG）维护，成为 用于生物学研究和新药物发现项目的高通量筛查（HTS）方法。 总之，所描述的研究将使AzaPaternò-Büchi和 Patanò-Büchi的反应依赖能量转移，并以可见光兴奋。这些新 转换代表理想的合成工具，可以直接访问官能化的Azetidines， 烷丁烷和氧烷，预计将对医学化学领域具有广泛的影响。