Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences

项目概要/摘要 我们的研究计划的长期目标是发展一般的和选择性的氮原子转移 可以通过两种复杂分子的精确官能化产生新分子实体的方法 和简单的日用化学品大量的治疗性分子和小分子生物学 探针具有至少一个氮原子;因此，基于直接氮原子转移到 有机分子是重要的合成工具。尽管已经有多种有价值的烯烃胺化方法， 尽管已经建立了一些新的基于新反应机理的选择性氮原子转移方法， 迫切需要在广泛的底物范围内有效和精确选择性的， 从而填补现有合成方法的重要空白。受到这些杰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， 新的合成方法，有望成为有机合成的独特工具， 药物化学 首先，我们将探索铁催化的未知领域，并发现铁催化的烯烃 胺化不涉及自由基中间体，因此与一系列的 这些官能团对于替代的胺化方法是有问题的。该项目的完成将 提供了在复杂分子中选择性烯烃胺化的有效方法。接下来，我们将发现一个 根本上新的顺式糖基化反应，不通过氧碳正离子进行， 一系列铁催化的一步糖酰胺基化方法， 糖基受体选择性地提供已知难以形成的1，2-顺式-酰胺基糖苷键 使用传统的糖基化方法以高立体选择性可靠地进行。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 探索一种全新的HN 3活化机制，并开发一系列无金属方法， 在环境温度下直接将HN 3加成到各种各样的叠氮基未活化烯烃上 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。

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.