Molecular Scientific Research on Cytotoxic Oxasqualenoids Based on Chemical Synthesis

最近，从海洋和陆地生物中分离出高度氧化且结构多样的三萜聚醚，这种聚醚被认为是角鲨烯衍生的生物遗传学天然产物（oxasqualenoids）。然而，即使采用目前非常先进的光谱方法，也很难确定它们的立体结构，特别是在含立体性季碳中心的无环体系中，如类草烯类化合物。在这种情况下，预测和合成可能的立体结构是有效的。在此，我们报告了通过化学合成的天然产物，其构型难以通过其他方法确定的oxasqualoids成员intricatetraol， enshuol和aurilol的先前不完整的立体结构的全部分配。1993年和1995年，Suzuki等分别从赤藻中分离出了intricattraol和enshuol，其中含有intricattraol的粗馏分对P388具有细胞毒性，IC<50>为12.5 μg/mL。虽然通过光谱和化学分析已经确定了其平面结构和部分构型，但迄今为止尚未确定其整体构型。我们通过首次不对称全合成完成了(+)-错综醇和(+)-enshuol先前不完全立体结构的总赋值。Aurilol由Yamada等人于1998年从海兔（Dolabella auricularia）中分离得到，对HeLa S_3细胞具有细胞毒性，IC_<50>，为4.3 μg/mL。虽然通过光谱分析和化学分析也阐明了其平面结构和部分立体化学性质，但尚未确定其整体立体化学性质。我们首次完成了(+)-aurilol的不对称全合成，具有高度区域和立体控制的生物遗传学样A-D醚环结构。全合成实现了aurilol不完全立体结构的全配准。在这些合成过程中，我们发现在硝基甲烷中用三氟化三异丙基硅基酯（TIPSOTf）处理双聚环氧醇时，环氧化合物底物通常的5-外环模式转变为6-内环模式，这违背了Baldwin规则。这种方法不同于以前报道的那些需要对环氧化物底物进行精细修饰以获得6-内环化的方法。6-内环成功地应用于enshuol和aurilol的B环形成。少

Recently, highly oxidized and structurally diverse triterpene polyethers, which are thought to be biogenetically squalene-derived natural products (oxasqualenoids), have been isolated from both marine and terrestrial organisms. However, it is often difficult to determine their stereostructures even by the current, highly advanced spectroscopic methods, especially in acyclic systems including stereogenic quaternary carbon centers such as those in oxasqualenoids. In such cases, it is effective to predict and synthesize the possible stereostructures. Herein, we report total assignments of the previously incomplete stereostructures of intricatetraol, enshuol, and aurilol, members of the oxasqualenoids, through the chemical syntheses of the natural products, the configurations of which are difficult to determine by other means.Intricatetraol and enshuol were isolated from the red algae Laurencia intricata and omaezakiana Masuda by Suzuki and co-workers in 1993 and 1995, respectively, and th … More e crude fraction including intricatetraol exhibited cytotoxicity against P388 with IC<50> of 12.5 μg/mL. Although the planar structures and partial configurations were elucidated by spectroscopic and chemical analyses, until now the entire configurations had not been determined. We have accomplished the total assignments of the previously incomplete stereostructures of (+)-intricatetraol and (+)-enshuol through the first asymmetric total syntheses.Aurilol was isolated from the sea hare, Dolabella auricularia, by Yamada et al. in 1998 and exhibited cytotoxicity against HeLa S_3 cells with IC_<50> of 4.3 μg/mL. Although the plane structure and partial stereochemistry were also elucidated by spectroscopic and chemical analyses, determination of the entire stereochemistry has not been reached. We have accomplished the first asymmetric total synthesis of (+)-aurilol featuring the highly regio- and stereocontrolled biogenetic-like A-D ether ring formations. The total synthesis has realized the total assignment of the incomplete stereostructure of aurilol.During these syntheses, we found that the switching of the usual 5-exo cyclizations of epoxide substrates to the 6-endo mode, which goes against Baldwin rule, is demonstrated by treating bishomoepoxy alcohols with triisopropylsilyl triflate (TIPSOTf) in nitromethane. This method is diffarent to those previously reported in which elaborate modifications of the epoxide substrate are required to attain 6-endo cyclization. The 6-endo cyclization was successfully applied to the B ring formation in enshuol and aurilol. Less