Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA.
J Am Chem Soc. 2010 Jan 27;132(3):1159-71. doi: 10.1021/ja909870g.
An account of the total synthesis of celogentin C is presented. A right-to-left synthetic approach to this bicyclic octapeptide was unsuccessful due to an inability to elaborate derivatives of the right-hand ring. In the course of these efforts, it was discovered that the mild Braslau modification of the McFadyen-Stevens reaction offers a useful method of reducing recalcitrant esters to aldehydes. A left-to-right synthetic strategy was then examined. The unusual Leu-Trp side-chain cross-link present in the left-hand macrocycle was fashioned via a three-step sequence comprised of an intermolecular Knoevenagel condensation, a radical conjugate addition, and a SmI(2)-mediated nitro reduction. A subsequent macrolactamization provided the desired ring system. The high yield and concise nature of the left-hand ring synthesis offset the modest diastereoselectivity of the radical conjugate addition. Formation of the Trp-His side-chain linkage characteristic of the right-hand ring was then accomplished by means of an indole-imidazole oxidative coupling. Notably, Pro-OBn was required as an additive in this reaction. Detailed mechanistic investigations indicated that Pro-OBn moderates the concentration of NCS in the reaction mixture, thereby minimizing the production of an undesired dichlorinated byproduct. The natural product was obtained after macrolactamization and deprotection. The chemical shifts of the imidazole hydrogen atoms exhibited significant dependence on temperature, concentration, and pH. Antitumor screening indicated that celogentin C inhibits the growth of some cancer cell lines.
本文介绍了 celogentin C 的全合成。由于无法合成右手环的衍生物,因此采用从右至左的方法合成这种双环八肽的尝试以失败告终。在这些努力过程中,人们发现 Braslau 对 McFadyen-Stevens 反应的温和修饰提供了一种将难还原的酯还原为醛的有用方法。然后检查了从左至右的合成策略。在左手大环中存在的不寻常的 Leu-Trp 侧链交联是通过三步序列形成的,该序列包括分子间 Knoevenagel 缩合、自由基共轭加成和 SmI(2)介导的硝基还原。随后的大环内酯化提供了所需的环系统。左手环合成的高收率和简洁性质弥补了自由基共轭加成的中等非对映选择性。然后通过吲哚-咪唑氧化偶联完成了特征为右手环的 Trp-His 侧链键的形成。值得注意的是,该反应需要 Pro-OBn 作为添加剂。详细的机理研究表明,Pro-OBn 可以调节反应混合物中 NCS 的浓度,从而最大程度地减少了不需要的二氯副产物的生成。大环内酯化和脱保护后得到了天然产物。咪唑氢原子的化学位移表现出对温度、浓度和 pH 的显著依赖性。抗肿瘤筛选表明 celogentin C 抑制某些癌细胞系的生长。