Molecular Scientific Research on Cytotoxic Oxasqualenoids Based on Chemical Synthesis

最近，从海洋生物和陆地生物中都分离出了高度氧化和结构多样化的三萜聚醚，它们被认为是生物生成的角鲨烯衍生的天然产物(氧杂奎烯)。然而，即使用目前非常先进的光谱方法，也很难确定它们的立体结构，特别是在包括立体生成的季碳中心的非环体系中，如氧杂奎烯中的那些。在这种情况下，预测和合成可能的刻板结构是有效的。在这里，我们报道了通过化学合成方法很难用其他方法确定其构型的天然产物的全部归属。Intricatetraol和enShuol分别于1993年和1995年由铃木和他的同事从红藻Laurencia tricata和omaezakiana Masuda中分离得到，并且Th…包括杂环四醇在内的更多的粗提物对P388具有细胞毒作用，IC&lt；50&gt；为12.5μg/m L。虽然平面结构和部分构型已经通过光谱分析和化学分析来确定，但到目前为止还没有确定整个构型。通过首次不对称全合成，我们完成了(+)-杂环四醇和(+)-恩舒醇的不完全立体结构的全归属。对HeLa S_3细胞表现出明显的细胞毒作用，IC_(50)和GT_(50)为4.3μg/mL。虽然平面结构和部分立体化学也通过光谱分析和化学分析得到了阐明，但还没有达到对整个立体化学的确定。我们首次完成了(+)-Auililol的不对称全合成，其特征是具有高度区域和立体控制的类生物生成A-D醚环。在合成过程中，我们发现在硝基甲烷中用三异丙基三氟硅酯(TIPSOTf)处理双同环氧醇时，通常的环氧化物底物的5-exo环化反应转变为6-endo环化反应，这与Baldwin规则相悖。这种方法与以前报道的方法不同，在这些方法中，需要对环氧化物底物进行精细的修饰才能实现6-内环化。6-内环化反应成功地应用于恩舒尔和奥尼洛尔中B环的形成。较少

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