THE SYNTHESIS OF LACTONAMYCIN AND ANALOGS

本项目的目的是开发一种有效的合成新发现的内霉素分子，并制备优化其生物活性的内霉素类似物。内霉素的六环结构不同于任何其他化合物。它对包括耐甲氧西林（MSRA）和耐万古霉素（VRE）菌株在内的现有抗生素耐药细菌具有强效活性。内乳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，以实现立体，区域和对映体选择性转化。具体目的是：开发一种短而高效的内霉素合成方法。利用这一努力，探索实现立体、区域和对映体控制合成转化的新一般策略，包括(i)扩展Diels-Alder反应中分子内氢键和/或硼酸盐络合的作用，（ii）发展动态热力学（而不是动力学）分辨率，（iii）在sharpless型不对称二羟基化预计会失败的情况下，研究新的配体来控制OsO4的分子内递送。采用合成途径制备内酯霉素类似物，目的是：(1)制备可获得的内酯霉素水溶性衍生物，(2)分离并优化其抗生素和抗肿瘤活性，(3)鉴定药效团，(4)开始SAR研究。与辉瑞公司合作，测试抗生素、抗癌和其他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.