Kobayashi S, Mori K, Wakabayashi T, Yasuda S, Hanada K
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
J Org Chem. 2001 Aug 10;66(16):5580-4. doi: 10.1021/jo0158128.
A convergent total synthesis of khafrefungin, a novel inhibitor of fungal sphingolipid syntheses isolated from the fermentation culture MF6020, has been developed. Alkenylboronic acid 5 and alkenyliodide 6, key fragments for the total synthesis, were prepared from the corresponding achiral aldehydes using tin(II)-catalyzed and Zr(IV)-catalyzed asymmetric aldol reactions, respectively. The Suzuki coupling reaction of these two fragments was successfully performed to give 17 in good yield. Through the total synthesis, epimerization of the C4 position having a rather highly acidic proton did not occur, indicating that khafrefungin was under strict conformational constraints to prevent the epimerization process. This characteristic stability of khafrefungin has also been discussed using semiempirical calculation and synthesis. Finally, khafrefungin derivatives have also been synthesized, and their antifungal activities have been measured to obtain information on the structure--activity relationships.
从发酵培养物MF6020中分离得到的新型真菌鞘脂合成抑制剂卡弗里芬净的汇聚式全合成方法已被开发出来。全合成的关键片段烯基硼酸5和烯基碘6分别由相应的非手性醛通过锡（II）催化和锆（IV）催化的不对称羟醛反应制备。这两个片段的铃木偶联反应成功进行，以良好的产率得到了17。通过全合成，具有相当高酸性质子的C4位没有发生差向异构化，这表明卡弗里芬净处于严格的构象限制之下，以防止差向异构化过程。还使用半经验计算和合成方法讨论了卡弗里芬净的这种特征稳定性。最后，还合成了卡弗里芬净衍生物，并测定了它们的抗真菌活性，以获得有关构效关系的信息。
