ASYMMETRIC SYNTHESIS OF VANCOMYCIN ANTIBIOTICS

万古霉素多肽抗生素家族的第一个成员是 1956年被隔离，家族的祖先万古霉素一直在 作为“最后的抗生素”临床使用超过23年 在其间的几年里，人们发现有 没有自然产生的细菌菌株对 万古霉素及三十余种万古霉素的杀菌效果 在过去的二十年里被分离和鉴定的变种。 这项提案的第一个目标是开发一种有效的方法来 主要的万古霉素和瑞斯托菌素亚基的合成， 万古霉素、放线菌酸和里士霉酸。通过这件事 练习我们打算确认两个分子的立体化学结构 万古霉素和瑞斯托星。然后我们将进行实验室合成 万古霉素及其相关同系物冬凌草素C、瑞斯托菌素和艾迪菌素 A.在执行这些目标的同时，我们将制定 复杂氨基酸和环的不对称合成新方法 多肽。此外，我们建议发展新的方法，以 含酚多肽的氧化大环化反应 大环二苯醚和联苯，其关键成分 万古霉素骨架。这一方法的成功发展将 使我们能够利用生物遗传模型合成几乎所有 万古霉素家族的成员。最后，全立体化学 这一抗体家族的所有成员的归属取决于核磁共振 光谱学，因此必须被认为是试验性的。在.期间 在这个项目的过程中，我们打算确认(更正)绝对 这个家庭的主要成员的立体化学分配总数 综合。

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.