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

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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