BENZANNULATION APPROACH TO BIARYL ETHERS

二芳基醚的苯环化方法

• 批准号: 2834133
• 负责人: SHON R PULLEY
• 金额: $ 17.19万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2834133
• 关键词: alkynes; carbene; chemical addition; cyclization; cycloalkene; ethers; etoposide; tannins; vancomycin

Our long-range research objective is to demonstrate the effective use of a benzannulation reaction in the synthesis of complex natural products containing biaryl ethers as an important structural feature. The relevance of biaryl ethers to health is illustrated by vancomycin which, in the clinic, is used to treat methicillin-resistant Staphylococcus aureus and other gram-positive bacteria. The emerging bacterial strains resistant to vancomycin justifies the search for new efficient synthetic methodologies toward the biaryl ether moiety of these molecules. Oligomeric ellagitannins, such as sanguiin H-6 which demonstrates an in vitro potency 100-200 times the clinically useful DNA topoisomerase II inhibitor etoposide (VP-16), are characterized by an digalloyl biaryl ether linker between the monomeric units. Our research will explore the utility of a [3+2+1] cycloaddition reaction (the Dotz reaction) to construct an aromatic ring in the syntheses of functionalized biaryl ethers. Key to this methodology is the reaction of O-aryl- Fischer chromium carbene complexes with alkynes to give diversely substituted biaryl ethers. The traditional Dotz reaction uses O-alkyl- unsaturated carbene complexes to form alkyl-aryl ethers. The use of O-aryl-unsaturated carbenes will lead to biaryl ethers which constitutes an unprecedented application of the Dotz reaction in organic synthesis. This approach is particularly advantageous due to the mild neutral reaction conditions required for cyclization and the availability of highly substituted electron-rich aromatic systems that are currently difficult to obtain using existing technology for the synthesis biaryl ethers.

我们的长期研究目标是证明苯环反应在合成复杂的天然产物中的有效使用，其中含有作为重要结构特征的联芳醚。联芳醚与健康的相关性由万古霉素说明，万古霉素在临床上用于治疗耐甲氧西林的金黄色葡萄球菌和其他革兰氏阳性细菌。新出现的对万古霉素具有抗药性的细菌菌株证明了寻找新的高效合成方法来合成这些分子的联芳醚部分是合理的。齐聚鞣酸，如血根素H-6，其体外效力是临床上使用的DNA拓扑异构酶II抑制剂依托泊苷(VP-16)的100-200倍，其特征是单体单元之间的二烯丙基联芳醚连接物。本研究将探索[3+2+1]环加成反应(Dotz反应)在功能化联芳醚合成中的应用。这一方法的关键是O-芳基-费歇尔铬卡宾络合物与炔烃反应，得到不同取代的联芳醚。传统的Dotz反应使用O-烷基-不饱和卡宾络合物形成烷基-芳基醚。O-芳基不饱和卡宾的使用将导致联芳醚的生成，这是Dotz反应在有机合成中的一种前所未有的应用。这种方法特别有利，因为环化所需的温和中性反应条件和高取代的富含电子的芳香族体系的可用性，这些目前很难使用现有的技术来合成联芳醚。