ASYMMETRIC SYNTHESIS OF VANCOMYCIN ANTIBIOTICS

万古霉素类抗生素的不对称合成

• 批准号: 3303031
• 负责人: David A Evans
• 金额: $ 13.66万
• 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 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3303031
• 关键词: drug design /synthesis /production; glycine; glycopeptides; molecular asymmetry; phenolic amine; 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-three years as an "antibiotic of last resort." Over the intervening years it has been discovered that there are no naturally occuring strains of bacteria which are immune to the bacterocidal effects of vancomycin and the more than thirty vancomycin variants which have been isolated and identified over the last two decades. The first objective in this proposal is to develop an efficient approach to the synthesis of the principal vancomycin and ristocetin subunits, vancomycinic acid, actinoidinic acid and ristomycinic acid. Through this exercise we intend to confirm the stereochemical assignments of both vancomycin and ristocetin. We then will pursue a laboratory synthesis of vancomycin 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 diphenylethers 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 antibodies 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 assignment 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在 临床用途超过23年，作为“最后的抗生素 度假胜地。“在随后的几年中，人们发现有 没有自然发生的细菌菌株免疫 万古霉素和三十多个万古霉素的杀菌作用 在过去的二十年中，已被隔离和确定的变体。 该提案的第一个目标是开发一种有效的方法 主要万古霉素和ristocetin亚基的合成， 万古霉素，放星素酸和霉菌酸。 通过这个 锻炼我们打算确认两者的立体化学作业 万古霉素和ristocetin。 然后，我们将追求实验室的合成 万古霉素和相关的同类物质CRIENTICIN C，RISTOCETIN和ARIDICIN 答：结合这些目标的执行，我们将开发 复杂氨基酸和环状的不对称合成的新方法 肽。 此外，我们建议为 含苯酚的肽形成的氧化大环化 大环二苯基和双苯基，临界成分 万古霉素骨骼。 这种方法的成功发展将 使我们能够追求几乎所有的生物基因建模的合成 万古霉素家族的成员。 最后，完整的立体化学化学 该抗体家族的所有成员的任务都取决于NMR 光谱法，因此必须将其视为试探性。 在 我们打算确认（纠正）绝对的过程的过程 总共对该家族的主要成员的立体化学分配 合成。