Stereodivergent total synthesis of rocaglaol initiated by synergistic dual-metal-catalyzed asymmetric allylation of benzofuran-3(2H)-one
Stereodivergent total synthesis of rocaglaol initiated by synergistic dual-metal-catalyzed asymmetric allylation of benzofuran-3(2H)-one
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DOI：
10.1016/j.chempr.2022.04.006
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发表时间：
2022-05
期刊：
影响因子：
23.5
通讯作者：
Yang Xu;Hongkai Wang;Zhuang Yang;Yuqiao Zhou;Yangbin Liu;Xiaoming Feng
中科院分区：
文献类型：
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作者：
Yang Xu;Hongkai Wang;Zhuang Yang;Yuqiao Zhou;Yangbin Liu;Xiaoming Feng
立体发散全合成生物活性天然化合物的所有立体异构体，以实现对立体化学结构-活性关系的完整评价是非常具有挑战性和价值的。天然黄素类化合物含有紧凑的官能化环戊烷[b]苯并呋喃支架，具有广泛的生物活性。在这里，我们公开了一种新的苯并呋喃-3(2H)的立体发散烯丙基烷基化反应，它依赖于手性N，N‘-二氧化钴(或镍)络合物和亚磷酰胺-Ir催化剂的协同催化。通过两种手性催化剂的适当排列，α-烯丙化产物的所有四种可能的立体异构体都具有良好的非对映选择性和对映体选择性。目标分子Rocaglaol的简明合成是以立体发散的方式提供的，遵循统一的合成路线，使用相同的一套起始材料。随后，对八种罗卡洛尔立体异构体的抗癌活性进行了初步研究，揭示了立体化学变化对生物活性的显著影响。
The stereodivergent total synthesis of all stereoisomers of bioactive natural compounds to enable complete evaluation of stereochemical structure-activity relationships is highly challenging and valuable. Naturally occurring flavaglines, containing a compact functionalized cyclopenta[b]benzofuran scaffold, display a wide range of biological activities. Herein, we disclose a novel stereodivergent allylic alkylation of benzofuran-3(2H)-one that relies on the synergistic catalysis of a chiralN,N′-dioxide-Co(or Ni) complex and a phosphoramidite-Ir catalyst. All four possible stereoisomers of the α-allylated product are provided with excellent diastereo- and enantioselectivities by appropriate permutations of the two chiral catalysts. The concise synthesis of the targeted molecule rocaglaol is furnished in a stereodivergent manner, following a uniform synthetic route and using the same set of starting materials. Subsequently, a preliminary study on the anticancer activity for eight stereoisomers of rocaglaol reveals the pronounced influence of stereochemistry variations on biological activity.