Chemical Synthetic Approach towards Clarifying Mechanism of Action for Cytotoxicity of Squalene-Derived Polyethers

近年来，从海洋和陆地植物中分离出了具有生物活性和结构独特的三萜聚醚，被认为是生物来源于角鲨烯的天然产物（角鲨烯）.其中有<50>Itokawa等人从长叶桉（Eurycoma longifolia）木材中分离得到的具有细胞毒性（对KB细胞的IC = 5.3 μg/mL）的longilene peroxide（1），尽管1的相对立体结构和构象已用X射线晶体学分析和光谱学方法阐明，但其绝对构型迄今尚未确定，尽管该化合物以及相关的聚醚具有生物遗传学意义。本研究首次从光学活性的C_2对称双环氧化物出发，利用其分子的对称性，通过双向合成的概念，实现了（-）-longilene peroxide（1）的不对称全合成。因此，已确定了longilene过氧化物的未知绝对构型。 ...更多信息 Glabrescol（3）和环氧三四氢呋喃（THF）二醇（2）是Jacobs等人从牙买加特有植物Spatkelia glabrescens（芸香科）中分离出来的，它们在生物遗传学上彼此相关。虽然没有关于这两种化合物生物活性的报道，但这些含有五个或三个THF环的聚醚可能显示出离子转运功能以及细胞毒性。许多类型的oxasqualcine已被分离;然而，它往往是难以确定其立体结构，仅通过光谱分析，特别是在系统中，包括非环状季碳中心。在这种情况下，预测和合成可能的立体异构体是有效的。虽然2的平面结构和部分相对构型也通过NMR方法阐明，但尚未达到确定化合物2的整个立体化学。在本研究中，我们通过首次不对称全合成完成了角鲨烯衍生的环氧三THF二醇（2）的立体结构的完全归属。少

Recently, biologically active and structurally unique triterpene polyethers, which are thought to be biogenetically squalene- derived natural products (oxasqualenoids), have been isolated from both marine and terrestrial plants. Among them is cytotoxic (IC_<50> = 5.3 μg/mL against KB cells) longilene peroxide (1), isolated from the wood of Eurycoma longifolia by Itokawa et al. Although the relative stereostracture and conformation of 1 have been elucidated by X-ray crystallographic analysis and spectroscopic methods, the absolute configuration had not hitherto been determined in spite of the biogenetic interest in the compound as well as the relevant polyethers. In this research, the first asymmetric total synthesis of (-)-longilene peroxide (1) has been achieved starting from the optically active C_2-symmetric diepoxide through the concept of two-directional synthesis utilizing its intrinsic molecular symmetry. Thus, the unknown absolute configuration of longilene peroxide has been de … More termined by this synthesis.Glabrescol (3) and an epoxy tri-tetrahydrofuran (THF) diol (2) biogenetically related to each other were isolated from the endemic Jamaican plant Spatkelia glabrescens (Rutaceae) by Jacobs et al. Although there is no report on the biological activities of both compounds, these polyethers containing five or three THF rings may be expected to exhibit ionophoric functions as well as cytotoxicities. Many types of oxasqualenoids have been isolated; however, it is often difficult to determine their stereostructures only by spectroscopic analysis, especially in systems including acyclic quaternary carbon centers. In such cases, it is effective to predict and synthesize the possible stereoisomers. Although the planar structure and partial relative configuration of 2 were also elucidated by NMR methods, determination of the entire stereochemistry of compound 2 has not been reached. In this research, we have accomplished complete assignment of the stereostmcture of the new squalene-derived epoxy tri-THF diol (2) through its first asymmetric total synthesis. Less