复杂核苷类抗生素ampurimycin及miharamycin的全合成研究

As typical representatives of complex nucleoside antibiotics, amipurimycin and miharamycin show promising bioactivities, and could act as ideal lead compounds as new antibiotics. However, the total synthesis of them has not yet been achieved due to their complex chemical structures, therefore leaving some chiral centers unassigned. Based on careful contemplation of the possible biosynthetic route to generate amipurimycin and miharamycin in nature, we devised a highly efficient and modular route to synthesize all of the possible structures of amipurimycin and miharamycin with cheap and easily available monosaccharide and amino acids as starting materials. Subsequently, comparison of the spectroscopic data of the synthetic samples with those reported in literatures will lead to the final assignment of the two target molecules and the first total syntheses of them. Further more, based on the successful synthesis of amipurimycin and miharamycin, a series of analogues in which different base subunits, higher carbon sugar subunits, and amino acid parts are included could be easily obtained, which will laid foundation for further structure-activity relationship investigation of them.

Amipurimycin及miharamycin是复杂核苷类抗生素的典型代表，具有优异的生物活性，是理想的新型抗生素开发的先导化合物。但由于它们复杂的化学结构，到目前为止尚未完成它们的全合成及最终结构确定。在考察amipurimycin及miharamycin可能生物合成路径的基础上，我们拟以方便易得的单糖、氨基酸为原料，采用'模块式'合成策略来完成所有可能的amipurimycin及miharamycin的结构的合成。将合成化合物的谱图与文献报道数据进行比对，以实现目标分子的最终结构的确定及首次全合成的完成。并在此基础上合成一系列包括含不同碱基、氨基酸及高糖砌块的目标分子的类似物，为进一步研究amipurimycin 及miharamycin 的构效关系奠定基础。

Amipurimycin 是 1977 年 Kishi 等人 从 Streptomyces novoguineensis sp. nov 培养液中分离得到的一种肽核苷类抗生素。该分子表现出优异的抗真菌活性，并且对稻瘟病具有很好的预防和治疗作用。我们采用汇聚式的合成策略，从D/L丝氨酸出发，经过 Weinreb酰胺 共 4步分别得到氨基酮片段；从L-阿拉伯糖出发，共 3步得到糖片段。利用Aldol反应，将糖片段和氨基反应，得到缩合产物，并成功解决了8位异构化的问题。通过对羰基的立体选择性还原，高效构建了7位羟基的手性。采用关五六并环、开五元环的策略，得到了中心高碳糖给体。采用金催化糖基炔酸酯给体与碱基的糖苷化方法构建糖苷键，得到了嘌呤糖苷化产物。通过肽键连接两种顺式环戊氨基酸，得到具有完整骨架的产物。在脱除所有保护基后，最终以总计34步、线性25步分别得到Amipurimycin的四个立体异构体81/82/83/84。接着我们采用同样的策略，从D/L-丝氨酸出发，经过Weinreb酰胺4步得到氨基酮片段；从D-木糖出发，3步得到糖片段。利用Aldol反应，将糖片段和氨基酮片段连接起来，得到缩合产物，并成功解决了8位异构化的问题。通过对羰基的立体选择性还原，高效构建了7位羟基的手性。采用关五六并环、开五元环的策略，得到了中心高碳糖给体。采用金催化糖基炔酸酯给体与碱基的糖苷化方法构建糖苷键，得到了嘌呤糖苷化产物。通过肽键连接两种顺式环戊氨基酸，得到具有完整骨架的产物。在脱除所有保护基后，最终以总计31步、线性22步分别得到C8’-epi -Amipurimycin的四个立体异构体99a/99b/99’a/99’b。