Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences

选择性氮原子转移在生物医学科学中的应用

• 批准号: 10200095
• 负责人: Hao Xu
• 金额: $ 40.63万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10200095
• 关键词: Alkenes; Amination; Biological; Biology; Biomedical Research; Carbohydrates; Catalysis; Chemicals; Clinical Research; Complex; Glycosides; Goals; Ions; Iron; Label; Metals; Methods; Molecular; Nitrogen; Organic Synthesis; Pharmaceutical Chemistry; Reaction; Research; Science; Series; Synthesis Chemistry; Temperature; Therapeutic; base; drug discovery; functional group; glycosylation; novel; programs; public health relevance; small molecule; tool

Project Summary/Abstract The long-term goal of our research program is to develop general and selective nitrogen atom transfer methods that can generate new molecular entities through precise functionalization of both complex molecules and simple commodity chemicals. A large number of therapeutic molecules and small-molecule biological probes have at least one nitrogen atom; therefore, synthetic methods based on direct nitrogen atom transfer to organic molecules are important synthetic tools. Although a variety of valuable olefin amination methods have been established, new selective nitrogen atom transfer methods based on novel reaction mechanisms are still urgently needed which can be effective and exquisitely selective across a broad range of substrates and thereby fill important gaps of existing synthetic approaches. Inspired by these outstanding synthetic challenges, we intend to discover new reactivity in three directions of selective nitrogen atom transfer and we will develop new synthetic methods that hold the promise to become unique and enabling tools for organic synthesis and medicinal chemistry. First, we will explore uncharted territory in iron catalysis and discover the iron-catalyzed olefin amination that does not involve radical intermediates and would thereby be compatible with a range of functional groups which are problematic with the alternative amination methods. Completion of this project will provide effective methods for selective olefin amination in complex molecules. Next, we will discover a fundamentally new cis-glycosylation reaction that does not proceed through an oxocarbenium ion and develop a series of iron-catalyzed one-step glycal amidoglycosylation methods that efficiently connect glycals and glycosyl acceptors to selectively afford 1,2-cis-amido glycosidic linkages that are known to be difficult to form reliably in high stereoselectivity using traditional glycosylation methods. Completion of this project will provide an array of unique methods that fill an important gap in complex-carbohydrate synthesis. Furthermore, we will explore an entirely new HN3 activation mechanism and develop a range of metal-free methods that enable direct addition of HN3 at ambient temperature across a wide variety of unactivated olefins for azido-group labeling of complex molecules. Completion of this project will provide a valuable tool of azido-group labeling for applications in synthetic chemistry and chemical biology.

项目概要/摘要 我们研究计划的长期目标是开发通用和选择性氮原子转移 通过精确功能化两个复杂分子来生成新分子实体的方法 和简单的商品化学品。大量的治疗分子和小分子生物 探针具有至少一个氮原子；因此，基于直接氮原子转移的合成方法 有机分子是重要的合成工具。尽管多种有价值的烯烃胺化方法已经 已建立，基于新反应机制的新选择性氮原子转移方法仍在研究中 迫切需要它可以在广泛的底物中有效且具有精确的选择性 从而填补现有合成方法的重要空白。受到这些突出的合成挑战的启发， 我们打算在选择性氮原子转移的三个方向上发现新的反应性，我们将开发 新的合成方法有望成为有机合成的独特且有效的工具 药物化学。 首先，我们将探索铁催化的未知领域，发现铁催化烯烃 胺化不涉及自由基中间体，因此与一系列相容 替代胺化方法存在问题的官能团。该项目的完成将 为复杂分子中选择性烯烃胺化提供有效的方法。接下来我们会发现一个 全新的顺式糖基化反应，不通过氧碳鎓离子进行并发展 一系列铁催化的一步糖醛酰胺糖基化方法，可有效连接糖醛和 糖基受体选择性地提供已知难以形成的 1,2-顺式酰胺糖苷键 使用传统的糖基化方法可以可靠地实现高立体选择性。该项目的完成将提供 一系列独特的方法填补了复杂碳水化合物合成的重要空白。此外，我们将 探索全新的 HN3 活化机制并开发一系列无金属方法，使 在环境温度下将 HN3 直接加成到各种未活化的叠氮基烯烃中 复杂分子的标记。该项目的完成将为叠氮基标记提供有价值的工具 在合成化学和化学生物学中的应用。