ASYMMETRIC SYNTHESIS OF VANCOMYCIN ANTIBIOTICS

万古霉素类抗生素的不对称合成

• 批准号: 2182271
• 负责人: David A Evans
• 金额: $ 22.55万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2182271
• 关键词: aminoacid; analog; cyclic peptides; cyclization; drug design /synthesis /production; molecular asymmetry; phenolic amine; stereochemistry; vancomycin

The first member of the vancomycin family of peptide antibiotics was isolated in 1956, and the progenitor of the family, vancomycin, has been in clinical use for more than twenty-five years as an antibiotic of last resort. The continuing objective of this research program is to develop an efficient approach to the synthesis of the principal members of the vancomycin family of antibiotics. Accordingly, we will pursue a laboratory synthesis of vancomycin aglycone and the related congeners orienticin C, ristocetin and aridicin A. In conjunction with the execution of these objectives, we will develop new methods for the asymmetric synthesis of complex amino acids and cyclic peptides. In addition, we propose to develop new methodology for the oxidative macrocyclization of phenol-containing peptides to form macrocyclic diphenyl ethers and biphenyls, critical constituents of the vancomycin skeleton. The successful development of this methodology will enable us to pursue a biogenetically modeled synthesis of virtually any member of the vancomycin family. Finally, the full stereochemical assignments of all members of this family of antibiotics rests on NMR spectroscopy, and as such must be considered as tentative. During the course of this project we intend to confirm (correct) the absolute stereochemical assignments of the principal members of this family by total synthesis.

万古霉素家族肽类抗生素的第一个成员是 分离于1956年，并且家族的祖先万古霉素已经被 在临床上作为抗生素使用超过25年， 度假村. 这项研究计划的持续目标是开发 一个有效的方法来合成的主要成员的 万古霉素家族抗生素。 因此，我们将采取 万古霉素苷元及其同系物的实验室合成 orienticin C、ristoclavin和aridicin A。 联同 执行这些目标，我们将开发新的方法， 复杂氨基酸和环肽的不对称合成。 在 此外，我们建议开发新的氧化方法， 含酚肽的大环化以形成大环 二苯醚和联苯，万古霉素的关键成分 骷髅 这种方法的成功发展将使我们能够 进行生物遗传学模拟合成， 万古霉素家族 最后，完整的立体化学分配 该抗生素家族的所有成员都依赖于核磁共振光谱，并且 因此，必须将其视为暂定。 在此过程中， 项目我们打算确认（正确）的绝对立体化学 通过全合成分配这个家族的主要成员。