Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences

项目摘要/摘要 我们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 可以通过两个复杂分子的精确官能化来产生新的分子实体的方法 和简单的商品化学品。大量的治疗分子和小分子生物 探针至少有一个氮原子，因此，基于直接氮原子的合成方法转移到 有机分子是重要的合成工具。尽管各种有价值的烯烃胺化方法有 基于新的反应机理的新的选择性氮原子转移方法已经建立，但仍在进行中 迫切需要的，可以是有效的和精致的选择在广泛的衬底和 从而填补现有综合方法的重要空白。受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，我们将开发 新的合成方法有望成为有机合成的独特和使能工具 药物化学。 首先，我们将探索铁催化的未知领域，发现铁催化的烯烃。 不涉及自由基中间体的胺化反应，因此将与一系列 对替代胺化方法有问题的官能团。该项目的完成将 为复杂分子中的选择性烯烃胺化提供了有效的方法。接下来，我们将发现一个 从根本上说，新的顺式糖基化反应不通过氧卡宾离子进行并发展 一系列铁催化的一步糖氨基糖基化方法，有效地连接糖链和 糖基受体选择性地提供已知难以形成的1，2-顺式-氨基糖苷键 在使用传统糖基化方法的高立体选择性中可靠。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中的一个重要空白。此外，我们还将 探索全新的HN3激活机制，并开发一系列不含金属的方法，以实现 在常温下通过各种叠氮基的未活化烯烃直接加成HN3 复杂分子的标记。该项目的完成将为叠氮基团的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.