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

描述(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，2-脱氧-C-芳基糖苷是一类具有重要生物学特性的天然产物，如抗肿瘤、抗生素和抗真菌活性。以前合成这类化合物的方法包括使用腐蚀性Lewis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。虽然我们以前已经证明，良性的有机铟试剂可以有效地形成糖苷碳-碳键，但我们希望探索一种新的方法，使其能够以天然产物中发现的立体化学构型来构建这种键。本着这一目标，我们将研究作为合成C-芳基糖苷的关键中间体的良性糖基锌试剂的制备和反应活性。预计温度将是决定碳-锌键取向的关键因素，这最终将决定糖苷碳-碳键的立体化学。还将探索过渡金属催化的糖基锌试剂与芳基卤化物或三氟化物之间的交叉偶联反应生成C-糖苷的最佳条件。最后，为了评估这种方法的广泛实用性，将进行安古环素天然产物SCH 47555的糖苷核心的制备，并将通过尝试将具有敏感的O-糖苷键的全功能化碳水化合物和芳香族单元在后期加入来衡量反应条件的温和程度。由于C-芳基糖苷具有显著的生物活性，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耐人寻味的性质；因此，我们合成努力的进一步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另一种工具，用于组装与药物相关的化合物，以抗击疾病和传染病。此外，如果在化学工业中广泛采用这种对环境无害的协议，大规模化学过程对脆弱的生态系统和生物圈的负面影响将会减少，从长远来看，这将改善人类健康。

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.