BENZANNULATION APPROACH TO BIARYL ETHERS

我们的长期研究目标是证明在合成含有联芳醚作为重要结构特征的复杂天然产物时，苯并环化反应的有效使用。万古霉素在临床上用于治疗耐甲氧西林金黄色葡萄球菌和其他革兰氏阳性细菌，说明了联芳醚与健康的相关性。新出现的对万古霉素耐药的细菌菌株证明了对这些分子的联芳醚部分寻找新的有效合成方法的合理性。低聚鞣花单宁，如血素H-6，其体外效价是临床有用的DNA拓扑异构酶II抑制剂依托泊苷（VP-16）的100-200倍，其特点是单体单元之间有一个二烯丙基联芳醚连接体。我们的研究将探索[3+2+1]环加成反应（Dotz反应）在合成功能化联芳醚中的应用。该方法的关键是o -芳基-费舍尔铬羰基配合物与炔烃反应生成不同取代的联芳醚。传统的Dotz反应是利用o -烷基-不饱和碳络合物生成烷基芳醚。邻芳基不饱和碳的使用将导致联芳基醚，这是Dotz反应在有机合成中的前所未有的应用。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电子芳香系统的可用性，目前使用现有技术合成联芳醚很难获得。

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.