摘要/Abstract

耐格霉素是具有抗革兰氏阴性菌活性的天然产物.以廉价易得的3-羰基-4-氯丁酸乙酯为原料，以八步29%的总收率实现了耐格霉素的形式合成.该工作改进了文献的合成路线，利用生物催化不对称还原高立体选择性引入C-5位的手性羟基，并将危险的叠氮引入反应放在合成后期，降低合成路线的操作风险.分子中C-3位的仲碳胺基手性中心通过Ellamn试剂介导的不对称Mannich反应构建.该路线易于放大，有望为构建耐格霉素类似物分子库以及高通量药物筛选奠定基础.
关键词: 耐格霉素, Mannich反应, 革兰氏阴性菌, 形式合成
Negamycin is a potent gram-negative antibiotic. By using commercial available ethyl 4-chlorobutyrate as starting material, the formal synthesis of negamycin was achieved within 8 steps and 29% overall yield. This modified synthetic route features in-situ enzymatic promoted asmmetric reduction reaction to introduce chiral hydroxy group at C-5, a late-stage azidination at C-6 to avoid the introduction of explosive azide group in the early stage in previous syntheses. The C-3 aza-chiral center was constructed via Ellman reagent-based asymmetric Mannich reaction. This efficient route is scalable and suitable to establish a library of negamycin analogues for future high-throughput screening.
Key words: negamycin, Mannich reaction, gram-negative pathogens, formal synthesis


PDF全文下载地址:

点我下载PDF