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

用地球上丰富的金属催化剂立体选择性组装具有挑战性的糖苷键

• 批准号: 10173059
• 负责人: Xuefei Huang
• 金额: $ 14.3万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173059
• 关键词: Stereoselective; Assembly; Challenging; Glycosidic; Linkages

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.

项目总结/摘要 复合碳水化合物在多种生物功能和疾病过程中发挥重要作用; 然而，它们的结构复杂性和同质形式的有限可用性是一个主要障碍 这阻碍了对它们在许多生物过程中的重要功能的研究。虽然综合办法 组装核酸和蛋白质的技术已经很成熟， 复合碳水化合物的合成仍然有限。虽然一系列有效的糖基化方法已经被证明是有效的， 尽管已经开发了新的糖基化方法，但是仍然迫切需要基于新机制的新的糖基化方法，其可以 快速和立体选择性地组装糖苷键，这证明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， 具有挑战性的糖苷键基于新的机制。拟议研究的目的是 开发了一系列铁催化的一步糖基顺式-酰胺基糖基化方法， 各种1，2-顺式-酰胺基糖苷键，其证明对现有方法具有挑战性。我们的基本想法 这一探索性研究的一个重要方面是，一种结构独特的铁氮类化合物可以绕过传统的 氧碳正离子为基础的糖基化途径，它可以立体选择性地转移酰胺基 和铁结合的糖基受体以几乎排他的顺式方式连接到糖基，推测是通过2- 氨基糖基自由基种类。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- 酰胺基糖基化方法有效地组装各种顺式-酰胺基糖苷键。第二、 我们将进一步发展这种新方法，使其成为合成复合碳水化合物的可靠技术。 这种方法是创新的，因为它探索了新的糖基化方法， 这与众所周知的基于氧碳正离子的糖基化策略 以及来自于金属-类氮戊环的已建立的反应性。这项研究意义重大，因为它将 为1，2-顺式氨基糖苷键的组装提供了一种通用的解决方案，为进一步研究1，2-顺式氨基糖苷键的结构奠定了基础。 开发一系列未开发的、地球上丰富的金属催化方法， 糖苷键形成。完成拟议的研究将提供一系列铁催化方法 其有效地提供多种1，2-顺式-酰胺基糖苷键。这些强大且易于适应的 合成方法将补充已知的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，这将大大推进生物医学科学。