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.

项目摘要/摘要 复杂的碳水化合物在多种生物学功能和疾病过程中起着重要作用。 但是，它们的结构复杂性和均匀形式的有限可用性代表了主要的障碍 这阻碍了他们在众多生物过程中对其重要功能的研究。而合成方法 组装核酸和蛋白质已经建立了良好的，可靠的工具和技术 复杂的碳水化合物合成仍然有限。尽管一系列有效的糖基化方法具有 已经开发了，仍然需要基于新机制的新糖基化方法 迅速和立体选择性地组装糖苷链接，这些糖苷链接证明了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 基于新颖机制的挑战性糖苷连接。拟议研究的目的是 开发一系列铁催化的一步甘氨酸顺式 - 氨基糖基化方法，以组装宽阔的方法 通过现有方法证明具有挑战性的1,2-CIS-Amido糖苷链接。我们的基本想法 这项探索性研究是，结构上独特的亚硝酸铁可以绕过常规 基于氧化核离子的糖基化途径，并且可以立体选择性地转移两个amido组 以及一个几乎独家顺式时尚的铁结合糖基受体，大概是通过2-- 胺糖基自由基物种。拟议的研究将以两个具体目标的背景来探讨这一想法。 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。 有效地组装各种顺式氨基糖苷链接的胺化方法。第二， 我们将进一步将这种新方法开发为用于复杂碳水化合物合成的强大技术。 这种提出的方​​法具有创新性，因为它探讨了一种新的糖基化方法 这两种情况都与众所周知的基于氧化核离子的糖基化策略不同 以及从金属硝酸盐的既定反应性。拟议的研究很重要，因为它将 提供一个一般解决方案，以组装1,2-CIS-氨基糖苷连接，并为 开发一系列爆发较少的，丰富的金属催化方法，以挑战 糖苷键形成。拟议研究的完成将提供一系列铁催化的方法 这实际上提供了各种各样的1,2-CIS-Amido糖苷连接。这些坚固且容易适应 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。该技术的进一步开发将为自动碳水化合物添加宝贵的工具 合成，这将显着提高生物医学科学。