THE SYNTHESIS OF LACTONAMYCIN AND ANALOGS

该项目的目标是开发一种新发现的分子lactonamycin的有效合成方法，并制备优化其生物活性的类似物。内酯霉素的六环结构不同于任何其他化合物。 它对现有抗生素耐药的细菌具有强效活性，包括耐甲氧西林（MSRA）和耐万古霉素（VRE）菌株。 内酯霉素还具有显著的抗癌活性。 在我们的工作过程中，我们打算探索新的一般策略，实现立体，区域，和对映选择性转换。具体目标是：开发一种短而高效的内酯霉素合成方法。 利用这一努力作为一个机会，探索新的通用策略，实现立体，区域和对映体控制的合成转化，包括（i）扩展分子内氢键和/或硼酸盐络合在Diels-Alder反应中的作用，（ii）发展动态热力学（与动力学相反）分辨率，和（iii）在Sharpless-型不对称二羟基化预期失败。 采用合成路线制备内酯霉素类似物，目的是（i）制备水溶性内酯霉素衍生物，（ii）分离和优化抗生素和抗肿瘤活性，（iii）鉴定药效团，（iv）开始SAR研究。 与辉瑞公司合作，用于抗生素、抗癌和其它生物活性的类似物和合成中间体。

The objectives of this project are to develop an efficient synthesis of the recently discovered molecule lactonamycin and to prepare analogs of it that optimize its biological activity. Lactonamycin's hexacyclic structure is unlike that of any other compound. It exhibits potent activity against bacteria resistant to existing antibiotics including methicillin-resistant (MSRA) and vancomycin-resistant (VRE) strains. Lactonamycin also possesses significant anticancer activity. In the course of our work we intend to explore new general strategies for achieving stereo-, regio-, and enantioselective transformations. The specific aims are: To develop a short and efficient synthesis of lactonamycin. To use that effort as an opportunity to explore new general strategies for accomplishing stereo-, regio-, and enantiocontrolled synthetic transformations including (i) extending the role of intramolecular hydrogen bonding and/or borate complexation in Diels-Alder reactions, (ii) developing a dynamic thermodynamic (as opposed to kinetic) resolution, and (iii) examining new ligands for controlling intramolecular delivery of OsO4 under circumstances where Sharpless-type asymmetric dihydroxylation is expected to fail. To employ the synthetic route to prepare analogs of lactonamycin with the aim of (i) making available water-soluble derivatives of lactonamycin, (ii) separating and optimizing the antibiotic and antitumor activities, (iii) identifying the pharmacophores, and (iv) beginning SAR studies. To test, in collaboration with Pfizer Inc., analogs and synthetic intermediates for antibiotic, anticancer and other biological activities.