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BENZANNULATION APPROACH TO BIARYL ETHERS

二芳基醚的苯环化方法

基本信息

批准号：
6386476
负责人：
MICHAEL HARMATA
金额：
$ 17.18万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-05-01 至 2003-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6386476
关键词：
alkynes carbene chemical addition cyclization cycloalkene ethers etoposide tannins vancomycin

项目摘要

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有效地使用benzannulation反应在合成复杂的天然产物含有联芳醚作为一个重要的结构特征。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金黄色葡萄球菌和其他革兰氏阳性菌。新出现的耐万古霉素的细菌菌株证明了寻找新的有效的合成方法对这些分子的联芳醚部分。低聚鞣花单宁，如血根素H-6，其体外效力是临床上有用的DNA拓扑异构酶II抑制剂依托泊苷（VP-16）的100-200倍，其特征在于单体单元之间的二别戊酰基联芳基醚接头。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构建芳环的实用性。该方法的关键是O-芳基- Fischer铬卡宾配合物与炔反应得到二取代的联芳醚。传统的Dotz反应使用O-烷基-不饱和卡宾络合物来形成烷基-芳基醚。O-芳基不饱和卡宾的使用将导致联芳醚，这构成了Dotz反应在有机合成中前所未有的应用。由于环化所需的温和中性反应条件以及高度取代的富电子芳香族体系的可用性，这种方法特别有利，而目前使用现有的联芳醚合成技术难以获得这些体系。