下一代万科米辛的总合成
Maxwell J Moore1, Shiwei Qu1, Ceheng Tan1
1Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Journal of the American Chemical Society
|September 5, 2020
概括
一种新的19步全合成菌素提供了一个可扩展的途径,以改造类似物. 这种方法克服了抗药性机制,使得新型胺衍生物的产生成为可能.
科学领域:
- 有机化学
- 医学化学
- 合成化学
背景情况:
- 范素是治疗严重的格拉姆阳性细菌感染的关键抗生素.
- 抗万科米辛细菌的出现需要开发新的治疗药物.
- 对于结构-活性关系研究和药物发现来说,菌素及其类型的总合成至关重要.
研究的目的:
- 开发一种下一代高效的菌素全合成剂.
- 建立一个可扩展的合成途径,用于生成口袋修饰的万科米辛类型.
- 促进新型抗生素的开发,
主要方法:
- 由氨基酸子单元合成的17个步骤.
- 动力控制的异构选择性引入形体.
- 用基控制的选性Miyaura化-Suzuki合以形成双轴.
- 可扩展的宏光化和室温SNAr循环化用于环闭.
- 保护无组酶的糖化.
主要成果:
- 达到了17个阶段合成的万科米辛甘氨酸,具有很高的二元选择性 (AB轴的20:1分钟,大分离的30:1分钟).
- 使用SNAr循环进行有效的序列CD (8:1 dr) 和DE (14:1 dr) 环闭.
- 一种19个步骤的菌素总合成,包括两步的酶糖化.
- 证明了大规模合成万科米辛类似物的一种可行的策略.
结论:
- 开发的合成途径是有效和可扩展的,用于生产万科米辛及其类似物.
- 这种方法可以合成修饰的菌素衍生物来对抗抗生素耐药性.
- 这一战略为开发下一代针对抗生素耐药性病原体开辟了道路.
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