Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zürich, HCI H405, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
Chemistry. 2011 Nov 11;17(46):13017-31. doi: 10.1002/chem.201101799. Epub 2011 Oct 4.
The total synthesis of the mycobacterial toxins mycolactones A/B (1 a/b) has been accomplished based on a strategy built around the construction of the mycolactone core through ring-closing metathesis. By employing the Grubbs second-generation catalyst, the 12-membered core macrocycle of mycolactones, with a functionalized C2 handle attached to C11, was obtained in 60-80 % yield. The C-linked upper side chain (comprising C12-C20) was completed by a highly efficient modified Suzuki coupling between C13 and C14, while the attachment of the C5-O-linked polyunsaturated acyl side chain was achieved by Yamaguchi esterification. Surprisingly, a diene containing a simple isopropyl group attached to C11 could not be induced to undergo ring-closing metathesis. By employing fluorescence microscopy and flow cytometry techniques, the synthetic mycolactones A/B (1 a/b) were demonstrated to display similar apoptosis-inducing and cytopathic effects as mycolactones A/B extracted from Mycobacterium ulcerans. In contrast, a simplified analogue with truncated upper and lower side chains was found to be inactive.
基于通过闭环复分解构建茂内内酯核心的策略，已经完成了分枝杆菌毒素茂内内酯 A/B（1a/b）的全合成。通过使用第二代 Grubbs 催化剂，获得了具有功能化 C2 手柄连接到 C11 的茂内内酯的 12 元环核心大环，产率为 60-80%。C 连接的上侧链（包含 C12-C20）通过 C13 和 C14 之间的高效改良 Suzuki 偶联完成，而 C5-O 连接的多不饱和酰基侧链的连接则通过 Yamaguchi 酯化完成。令人惊讶的是，不能诱导连接到 C11 的含有简单异丙基的二烯进行闭环复分解。通过荧光显微镜和流式细胞术技术，证明合成的茂内内酯 A/B（1a/b）与从溃疡分枝杆菌中提取的茂内内酯 A/B 具有相似的诱导细胞凋亡和细胞病变作用。相比之下，具有缩短的上下侧链的简化类似物被发现没有活性。
