Total Synthesis and Complete Structural Assignment of Yaku'amide A
Total Synthesis and Complete Structural Assignment of Yaku'amide A
复制标题
DOI：
10.1021/ja401457h
复制
发表时间：
2013-04-10
影响因子：
15
通讯作者：
Inoue, Masayuki
中科院分区：
文献类型：
--
作者：
Kuranaga, Takefumi;Sesoko, Yusuke;Inoue, Masayuki
本文首次报道了雅库酰胺A的全合成和全立体化学归属。雅库酰胺A(1)是从海绵Ceratopsion sp.中分离得到。作为一种极强的细胞毒素。除N-端酰基(NTA)上的C4立体化学外，其余结构均已确定。该十三肽由2个蛋白原性氨基酸残基和11个非蛋白原性氨基酸残基组成，由NTA和一个C端胺(CTA)组成。α，β-脱氢异亮氨酸，E-和Z-α，β-脱氢异亮氨酸是1的最不常见的非蛋白生成残基，需要开发新的方法来组装它们。因此，铜介导的交叉偶联反应被有效地用于三种二肽与脱氢异亮氨酸的E/Z选择性合成以及与脱氢缬氨酸的四肽的构建。然后将该四肽逐步延长，以提供两个可能的C4-同分异构体1。广泛的核磁共振研究表明，天然的I具有C4S-立体化学，并且用P388小鼠白血病细胞进行的生物测定表明，这两个C4-同分异构体具有类似的毒性。目前构建1的高度不饱和多肽序列的合成方法将使研究脱氢氨基酸残基的构象性质与细胞毒性之间的关系成为可能。
Here we report the first total synthesis and the complete stereochemical assignment of yaku'amide A. Yaku'amide A (1) was isolated from a sponge Ceratopsion sp. as an extremely potent cytotoxin. Its structure was determined except for the C4-stereochemistry in the N-terminal acyl group (NTA). This tridecapeptide consists of 2 proteinogenic and 11 nonproteinogenic amino acid residues and is capped with NTA and a C-terminal amine (CTA). alpha,beta-Dehydrovaline, E- and Z-alpha,beta-dehydroisoleucines are the most unusual nonproteinogenic residues of 1 and necessitated development of new methodologies for their assembly. Consequently, Cu-mediated cross-coupling reactions were efficiently employed for E/Z-selective syntheses of the three dipeptides with the dehydroisoleucines and for construction of the tetrapeptide with the dehydrovaline. The peptide was then elongated from the tetrapeptide in a stepwise fashion to deliver the two possible C4-epimers of 1. Extensive NMR studies revealed that the natural I possessed the C4S-stereochemistry, and biological assays using P388 mouse leukemia cells demonstrated that both C4-epimers possessed comparable toxicities. The present synthetic methodologies for construction of the highly unsaturated peptide sequence of 1 will allow studies of the relationships between the conformational properties of dehydro amino acid residues and cytotoxicity.