An Environmentally Benign Method for the Synthesis of C-aryl Glycosides

一种环境友好的 C-芳基糖苷合成方法

• 批准号: 7678360
• 负责人: Thomas Gerard Minehan
• 金额: $ 7.15万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678360
• 关键词: Acids; Adopted; Antifungal Agents; Benign; Biological; Biological Factors; C-glycoside; Carbohydrates; Carbon; Chemical Industry; Chemicals; Communicable Diseases; Complex; Corrosives; Development; Ecosystem; Evaluation; Family; Future; Glycosides; Goals; Health; Human; Isomerism; Metals; Methodology; Methods; Mind; Modeling; NMR Spectroscopy; Pharmacologic Substance; Preparation; Procedures; Process; Property; Protocols documentation; Reaction; Reagent; Research; Scientist; Solvents; Staging; Temperature; Testing; Transition Elements; Variant; Zinc; analog; antineoplastic antibiotics; aryl halide; catalyst; fighting; improved; liquid chromatography mass spectrometry; novel; programs; research study; stereochemistry; tool; toxic metal

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop an environmentally friendly method for the preparation of 2-deoxy-C-aryl glycosides, a family of natural products which demonstrate important biological properties such as antitumor, antibiotic and antifungal activities. Previous approaches to the synthesis of this class of compounds have involved the use of corrosive Lewis acids or toxic metals for the preparation of the carbon-carbon linkage between carbohydrate and aromatic moieties. Although we have previously shown that benign organoindium reagents may be employed in fashioning the glycosidic carbon-carbon bond efficiently, we wish to explore a new method that will allow the construction of this bond with the stereochemical configuration found in the natural products. With this goal in mind, we will investigate the preparation and reactivity of benign glycosyl zinc reagents as key intermediates in the synthesis of C-aryl glycosides. It is anticipated that temperature will be a key factor in determining the orientation of the carbon-zinc bond, which ultimately will determine the stereochemistry of the glycosidic carbon-carbon bond. Optimal conditions for the transition-metal catalyzed cross-coupling reaction between the glycosyl zinc reagent and aryl halides or triflates for the formation of the C-glycosides will also be explored. Finally, to assess the broad utility of this method, the preparation of the glycosidic core of the angucycline natural product Sch 47555 will be undertaken, and the mildness of the reaction conditions will be gauged by attempting a late-stage joining of fully functionalized carbohydrate and aromatic units bearing a sensitive O-glycosidic linkage. Because of the pronounced biological activities of the C-aryl glycosides, it is likely that even structural variants and simplified analogs of these natural products will have intriguing properties; as a result, a further aim of our synthetic efforts is to produce sufficient quantities of these substances for pharmacological evaluation. If successful, this research will provide scientists with an additional tool for the assembly of medicinally relevant compounds to fight sickness and infectious disease. Furthermore, if such environmentally benign protocols are widely adopted in the chemical industries, the negative impacts of large-scale chemical processes on fragile ecosystems and the biosphere will be diminished, which in the long term will result in improved human health.

描述（由申请人提供）：该项目的长期目标是开发一种环境友好的方法来制备2-脱氧-C-芳基糖苷，这是一类天然产物，具有抗肿瘤、抗生素等重要的生物特性。和抗真菌活性。以前合成此类化合物的方法涉及使用腐蚀性路易斯酸或有毒金属来制备碳水化合物和芳香族部分之间的碳-碳键。尽管我们之前已经证明良性有机铟试剂可用于有效地形成糖苷碳-碳键，但我们希望探索一种新方法，允许利用天然产物中发现的立体化学构型构建这种键。考虑到这一目标，我们将研究作为 C-芳基糖苷合成中关键中间体的良性糖基锌试剂的制备和反应性。预计温度将是决定碳-锌键方向的关键因素，最终将决定糖苷碳-碳键的立体化学。还将探索糖基锌试剂和芳基卤化物或三氟甲磺酸酯之间过渡金属催化交叉偶联反应形成 C-糖苷的最佳条件。最后，为了评估该方法的广泛实用性，将制备安古环素天然产物 Sch 47555 的糖苷核心，并通过尝试后期连接完全功能化的碳水化合物和带有敏感O-糖苷键的芳香单元。由于 C-芳基糖苷具有显着的生物活性，因此即使是这些天然产物的结构变体和简化类似物也可能具有有趣的特性；因此，我们合成工作的另一个目标是生产足够数量的这些物质用于药理学评估。如果成功，这项研究将为科学家提供一种额外的工具，用于组装医学相关化合物以对抗疾病和传染病。此外，如果这种环境友好的协议在化学工业中得到广泛采用，大规模化学过程对脆弱生态系统和生物圈的负面影响将减少，从长远来看，这将改善人类健康。