ASYMMETRIC SYNTHESIS OF VANCOMYCIN ANTIBIOTICS

万古霉素类抗生素的不对称合成

• 批准号: 2182270
• 负责人: David A Evans
• 金额: $ 21.7万
• 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/2182270
• 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.

万古霉素家族的肽抗生素家族的第一个成员是 1956年孤立，家族的祖先万古霉素一直是 在临床用途超过25年中，作为最后的抗生素 采取。 该研究计划的持续目标是开发 一种有效的方法来合成主要成员 万古霉素抗生素家族。 因此，我们将追求 实验室合成万古霉素aglycone及相关同类物 东方蛋白C，ristocetin和aridicin A.结合 执行这些目标，我们将为 复杂氨基酸和环状肽的不对称合成。 在 此外，我们建议开发氧化的新方法 含苯酚的肽的大环化形成大环 二苯基醚和双苯基，万古霉素的关键成分 骨骼。 这种方法的成功发展将使我们 追求几乎任何成员的生物基因建模的合成 万古霉素家族。 最后，完整的立体化学作业 该抗生素家族的所有成员都取决于NMR光谱， 因此，必须将其视为暂定。 在此过程中 我们打算确认（正确）绝对立体化学化学的项目 该家族的主要成员的分配是通过完全合成的。