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

项目概要/摘要 复杂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用性有限是主要障碍 这阻碍了对其在众多生物过程中重要功能的研究。虽然合成方法 组装核酸和蛋白质的方法已经很成熟，强大的工具和技术 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已经 已经开发出来，仍然迫切需要基于新机制的新糖基化方法 快速、立体选择性地组装糖苷键，这对现有技术来说具有挑战性。 我们的长期目标是开发新的立体选择性糖基化技术来解决 基于新机制的挑战糖苷键。拟议研究的目的是 开发了一系列铁催化的一步糖顺式酰胺糖基化方法来组装广泛的 各种 1,2-顺式酰胺糖苷键对现有方法来说具有挑战性。我们的基本理念 这项探索性研究的重点是结构独特的铁氮化合物可能会绕过传统的 基于氧碳鎓离子的糖基化途径，并且它可以立体选择性地转移酰胺基 和一个铁结合的糖基受体，以几乎完全顺式的方式连接到糖基上，大概是通过 2- 酰胺糖基自由基种类。拟议的研究将在两个具体目标的背景下探讨这一想法。 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- 酰胺糖基化方法可有效组装各种顺式酰胺糖苷键。第二， 我们将进一步将这种新方法开发成复杂碳水化合物合成的强大技术。 这种提出的方法是创新的，因为它探索了新的糖基化方法 与众所周知的基于氧碳鎓离子的糖基化策略显着不同的背景 以及金属氮素化合物的已确定的反应性。拟议的研究意义重大，因为它将 提供了组装1,2-顺式酰胺糖苷键的通用解决方案，为组装1,2-顺式酰胺糖苷键奠定了基础 开发一系列尚未开发的、地球上丰富的金属催化方法来应对具有挑战性的问题 糖苷键的形成。完成拟议的研究将提供一系列铁催化方法 有效地提供多种 1,2-顺式酰胺糖苷键。这些坚固且易于适应的 合成方法将补充已知方法并填补现有糖基化的重要空白 技术。这项技术的进一步发展将为自动化碳水化合物添加有价值的工具 合成，这将显着推进生物医学科学。

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.