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.

万古霉素家族肽类抗生素的第一个成员是 分离于1956年，该家族的祖先万古霉素已在 临床使用超过23年，作为“最后的抗生素” 度假村.“在过去的几年里，人们发现， 没有天然存在的细菌菌株， 万古霉素和30多种万古霉素的杀菌作用 在过去的二十年中已经分离和鉴定的变体。 本建议的第一个目标是制定一个有效的办法， 主要万古霉素和瑞斯托霉素亚基的合成， 万古霉素酸、放线菌素酸和瑞斯托霉素酸。 通过这个 练习我们打算确认两者的立体化学分配 万古霉素和利托那韦。 然后，我们将进行实验室合成， 万古霉素及相关同系物东方霉素C、瑞斯托霉素和阿里霉素 A. 在实现这些目标的同时，我们将制定 复杂氨基酸和环状氨基酸不对称合成的新方法 缩氨酸 此外，我们还建议制定新的方法， 含酚肽的氧化大环化， 大环二苯醚和联苯， 万古霉素骨架 这种方法的成功发展将 使我们能够追求生物遗传学模拟合成几乎任何 万古霉素家族的成员。 最后，完整的立体化学 该抗体家族的所有成员的分配依赖于NMR 光谱，因此必须被视为暂定。 期间 在这个项目的过程中，我们打算确认（纠正）绝对 总的来说，这个家族的主要成员的立体化学分配 合成.