Stereoselective Assembly of Challenging Glycosidic Linkages with Earth-Abundant Metal Catalysts

项目摘要/摘要 复合碳水化合物在多种生物功能和疾病过程中发挥着重要作用； 然而，它们的结构复杂性和同质形式的可获得性有限是一个主要障碍 这阻碍了对它们在众多生物过程中的重要作用的研究。虽然综合方法 组装核酸和蛋白质的工具和技术已经建立得很好， 复合碳水化合物的合成仍然有限。尽管一系列有效的糖基化方法 虽然已经开发出了基于新机制的新的糖基化方法，但仍然迫切需要能够 快速和立体选择性地组装糖苷键，事实证明，这对现有技术具有挑战性。 我们的长期目标是开发新的立体选择性糖基化技术，以解决 挑战基于新机制的糖苷连接。拟议研究的目标是 开发一系列铁催化的一步糖基顺式-氨基糖基化方法来组装广谱的 1，2-顺-氨基糖苷键的种类繁多，对现有方法具有挑战性。我们的基本理念 这项探索性研究的一个特点是，一种结构独特的类铁氮化物可能会绕过常规的 氧碳正离子的糖基化途径，并且它可以立体选择性地转移两个氨基 和铁结合的糖基受体，以几乎排他的顺式方式与甘氨酸结合，推测是通过2- 氨基糖基物种。这项拟议的研究将在两个具体目标的背景下探索这一想法。 首先，我们计划发现新的铁催化剂和胺化试剂，并开发一系列铁催化的顺式- 有效组装各种顺-氨基糖苷键的氨基糖基化方法。第二, 我们将进一步将这一新方法发展成稳健的复杂碳水化合物合成技术。 这一提议的方法是创新的，因为它探索了新的糖基化方法 这与众所周知的氧卡宾正离子糖基化策略有很大不同 以及从金属-硝基化合物的既定反应性。这项拟议的研究意义重大，因为它将 提供组装1，2-顺-氨基糖苷键的一般解决方案，并为 开发一系列未被探索的、富含地球的金属催化的挑战方法 糖苷键的形成。拟议研究的完成将提供一系列铁催化方法 这有效地提供了各种各样的1，2-顺-氨基糖苷键。这些健壮且易于适应的 合成方法将补充已知的方法，填补现有糖基化的一个重要空白 技术。这项技术的进一步发展将为自动化碳水化合物增加有价值的工具 合成，这将大大促进生物医学科学的发展。

Project Summary/Abstract Complex carbohydrates play important roles in a variety of biological functions and disease processes; however, their structural complexity and limited availability in homogeneous forms represent a major roadblock that hampers study of their important functions in numerous biological processes. While synthetic approaches that assemble nucleic acids and proteins have been well-established, the robust tools and technologies for complex-carbohydrate synthesis are still limited. Although a range of effective glycosylation approaches have been developed, new glycosylation methods based on novel mechanisms are still urgently needed which can rapidly and stereoselectively assemble glycosidic linkages that prove challenging with existing technologies. Our long-term goal is to develop new stereoselective glycosylation technologies that address challenging glycosidic linkages based on novel mechanisms. The objective of the proposed research is to develop a series of iron-catalyzed one-step glycal cis-amidoglycosylation approaches to assemble a wide variety of 1,2-cis-amido glycosidic linkages that prove challenging with existing methods. Our underlying idea of this exploratory research is that a structurally unique iron-nitrenoid may bypass the conventional oxocarbenium ion-based glycosylation pathways, and that it can stereoselectively transfer both an amido group and an iron-bound glycosyl acceptor in nearly exclusive cis-fashion to a glycal, presumably through a 2- amidoglycosyl radical species. The proposed research will explore this idea in the context of two Specific Aims. First, we plan to discover new iron catalysts and amination reagents and develop a range of iron-catalyzed cis- amidoglycosylation approaches that effectively assemble a variety of cis-amido glycosidic linkages. Second, we will further develop this new approach into robust technology for complex-carbohydrate synthesis. This proposed approach is innovative because it explores the new glycosylation approaches in a context that significantly departs both from the well-known oxocarbenium ion-based glycosylation strategies and from the established reactivity of metal-nitrenoids. The proposed research is significant because it will provide a general solution to assemble 1,2-cis-amido glycosidic linkages and lay the foundation for the development of an array of under-explored, earth-abundant metal-catalyzed approaches for challenging glycosidic-bond formation. Completion of the proposed research will provide a range of iron-catalyzed methods that effectively afford a wide variety of 1,2-cis-amido glycosidic linkages. These robust and easily adaptable synthetic approaches will complement the known methods and fill an important gap of existing glycosylation technologies. Further development of this technology will add valuable tools for the automated carbohydrate synthesis, which will significantly advance biomedical sciences.