THE SYNTHESIS OF LACTONAMYCIN AND ANALOGS

本项目的目标是开发一种新发现的分子拉通霉素的有效合成方法，并制备其类似物，以优化其生物活性。拉克托霉素的六环结构不同于任何其他化合物。它对包括甲氧西林耐药(MSRA)和万古霉素耐药(VRE)在内的现有抗生素耐药的细菌显示出强大的活性。拉克托霉素也具有显著的抗癌活性。在我们的工作过程中，我们打算探索实现立体、区域和对映选择性转换的新的一般策略。本课题的具体目标是：开发一种短而高效的拉他霉素合成方法。以这一努力为契机，探索实现立体、区域和对映体控制的合成转化的新的一般策略，包括(I)扩大分子内氢键和/或硼酸盐络合在Diels-Alder反应中的作用，(Ii)开发动态热力学(而不是动力学)拆分，以及(Iii)研究在夏普莱斯类型的不对称双羟基化预计失败的情况下控制OsO4分子内传递的新配体。目的：利用合成路线制备拉他霉素类似物，目的是(I)获得拉他霉素的水溶性衍生物，(Ii)分离和优化抗生素和抗肿瘤活性，(Iii)鉴定药效团，以及(Iv)开始SAR研究。与辉瑞公司合作，测试类似物和合成中间体的抗生素、抗癌和其他生物活性。

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.