Total Synthesis of Euonymine and Euonyminol Octaacetate
Total Synthesis of Euonymine and Euonyminol Octaacetate
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卫矛碱和卫矛醇八乙酸酯的全合成
DOI：
10.1021/jacs.1c11038
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发表时间：
2021
影响因子：
15
通讯作者：
Inoue Masayuki
中科院分区：
文献类型：
--
作者：
Wang Yinghua;Nagai Toshiya;Watanabe Itsuki;Hagiwara Koichi;Inoue Masayuki
Euonymine（1）和Euonyminol八乙酸酯（2）共享Euonyminol（3）的核心结构，Euonyminol（3）是二氢-β-沉香呋喃家族中羟基化程度最高的成员。在2中，3的9个羟基中有8个被乙酰化，1有6个乙酰基和一个14元双内酯，包括一个吡啶二羧酸和两个甲基。不同的酰化模式提供了不同的生物活性：1和2分别显示抗HIV和P-糖蛋白抑制作用。11个连续的立体中心和9个氧官能团的ABC环系统的1和2代表了一个艰巨的挑战，这是进一步提高了大环结构的1。在这里，我们公开了一种有效的合成策略，对映选择性全合成1和2。从（R）-甘油丙酮化合物开始，我们通过Et 3 N加速的Diels-Alder反应构建了B环，通过分子内碘醚化构建了C环，并且通过闭环烯烃复分解构建了A环。10个立构中心通过一系列基板控制的立体选择性C-C和C-O键的形成，通过利用明智设计的基板的三维结构安装。这些新开发的反应序列导致受保护的eumoniminol 5，作为组装1和2的共同中间体。5的整体脱保护和随后的乙酰化产生2。或者，5的区别性保护基团允许位点选择性双酯化以产生双内酯。结合[3 + 2]-环加成和还原脱硫引入了大环上两个甲基的最后剩余的立体中心。最后，通过脱保护和乙酰化反应，首次完全合成了1。
Euonymine (1) and euonyminol octaacetate (2) share the core structure of euonyminol (3), the most hydroxylated member of the dihydro-β-agarofuran family. In2, eight of the nine hydroxy groups of3are acetylated, and1has six acetyl groups and a 14-membered bislactone comprising a pyridine dicarboxylic acid with two methyl groups. The different acylation patterns provide distinct biological activities:1and2display anti-HIV and P-glycoprotein inhibitory effects, respectively. The 11 contiguous stereocenters and 9 oxygen functionalities of the ABC-ring system of1and2represent a formidable challenge, which is further heightened by the macrocyclic structure of1. Here we disclose an efficient synthetic strategy for enantioselective total synthesis of1and2. Starting from (R)-glycerol acetonide, we constructed the B-ring by an Et3N-accelerated Diels–Alder reaction, the C-ring by intramolecular iodoetherification, and the A-ring by ring-closing olefin metathesis. The 10 stereocenters were installed through a series of substrate-controlled stereoselective C–C and C–O bond formations by exploiting the three-dimensional structures of judiciously designed substrates. These newly developed reaction sequences led to protected euonyminol5, which served as a common intermediate for assembling1and2. Global deprotection of5and subsequent acetylation produced2. Alternatively, the discriminative protective groups of5allowed for site-selective bis-esterification to generate bislactone. Combining [3 + 2]-cycloaddition and reductive desulfurization introduced the last remaining stereocenters of the two methyl groups on the macrocycle. Finally, deprotection and acetylation gave rise to fully synthetic1for the first time.