Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Chem Rec. 2010 Apr;10(2):101-18. doi: 10.1002/tcr.201090001.
Vinblastine has been widely known as a prominent agent in cancer chemotherapy, and in order to search for more potent drugs, various analogs have been derived from natural products. However, because modifications of natural products have limited classes of derivatives, an efficient synthetic route toward vinblastine has been required.Herein a stereocontrolled total synthesis of (+)-vinblastine is described. The synthesis of the upper half features a stereoselective construction of the tertiary alcohol through a 1,3-dipolar cycloaddition of nitrile oxide and a Baeyer-Villiger oxidation, a facile indole formation utilizing a radical cyclization of o-alkenylthioanilide, and a macrocyclization of 2-nitrobenzenesulfonamide. The crucial coupling of the upper half with synthetic vindoline was successfully performed to furnish the coupling product in nearly quantitative yield, and subsequent transformations provided (+)-vinblastine.
长春碱作为一种广泛应用于癌症化疗的重要药物，为了寻找更有效的药物，人们从天然产物中衍生出各种类似物。然而，由于天然产物的修饰具有有限的衍生物类别，因此需要一种有效的长春碱合成途径。本文描述了（+）-长春碱的立体控制全合成。上半部分的合成通过腈氧化物的 1,3-偶极环加成和 Baeyer-Villiger 氧化反应，立体选择性地构建叔醇，利用邻烯基硫代苯胺的自由基环化反应，以及 2-硝基苯磺酰胺的大环化反应，轻松地形成吲哚，完成了上半部分的合成。上半部分与合成 vindoline 的关键偶联反应以近乎定量的收率成功进行，随后的转化提供了（+）-长春碱。
