采用 Ugi 多组分反应改进 15-去氧精胍醇类似物的合成。
Improved synthesis of 15-deoxyspergualin analogs using the Ugi multi-component reaction.
机构信息
Department of Pathology and The Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA.
出版信息
Bioorg Med Chem Lett. 2011 May 1;21(9):2587-90. doi: 10.1016/j.bmcl.2011.02.079. Epub 2011 Mar 1.
Spergualin is a natural product that exhibits immunosuppressive, anti-tumor and anti-bacterial activities. Its derivatives, such as 15-deoxyspergualin (15-DSG), have been clinically approved for acute allograft rejection. However, the reported syntheses are cumbersome (>10 steps) and they suffer from low overall yields (∼0.3% to 18%). Moreover, spergualin and its derivatives are chemically unstable and rapidly hydrolyzed in aqueous buffer. Here, we have re-explored these issues and report a modified synthetic route with significantly improved overall yield (∼31% to 47%). The key transformation is a microwave-accelerated Ugi multi-component reaction that is used to generate the peptoid core in a single step. Using the products of this route, we found that modifications of the hemiaminal significantly increased chemical stability. Thus, we anticipate that this synthetic route will improve access to biologically active 15-DSG derivatives.
Spergualin 是一种具有免疫抑制、抗肿瘤和抗菌活性的天然产物。其衍生物，如 15-去氧精胍菌素（15-DSG），已被临床批准用于急性同种异体移植排斥反应。然而，已报道的合成方法繁琐（＞10 步），总收率低（约 0.3%至 18%）。此外，Spergualin 及其衍生物化学性质不稳定，在水性缓冲液中迅速水解。在这里，我们重新探讨了这些问题，并报告了一种改进的合成路线，总收率显著提高（约 31%至 47%）。关键的转化是微波加速的 Ugi 多组分反应，可一步生成肽类似物核心。使用该路线的产物，我们发现对半缩醛亚胺的修饰显著提高了化学稳定性。因此，我们预计这条合成路线将有助于获得具有生物活性的 15-DSG 衍生物。
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