Studies on the total synthesis and SAR of natural products that bind to tublin

与tublin结合的天然产物分为两类，一类是抑制tublin聚合的化合物，另一类是抑制tublin解聚的化合物。这些化合物抑制有丝分裂从而表现出细胞毒性。长春花碱和紫杉醇衍生物已被临床用作抗肿瘤药物，而艾替隆衍生物已被认为是有前景的抗肿瘤药物。因此，与tublin结合的天然产物是抗肿瘤药物的潜在先导化合物。因此，在本项目中，我们旨在开发具有微管蛋白聚合抑制活性的(+)- phoomopsidin的改进合成路线，并旨在开发FR182876和紫杉醇的不对称合成路线，用于其SAR研究。在高效合成(+)- phoomopsidin的研究中，我们通过具有倒转C11立体中心的13元大环内酯与TIPS保护羟基进行高立体选择性的TADA反应，成功建立了改进的合成方法。在FR182876的不对称全合成研究中，我们通过IMDA反应和HIMDA反应建立了FR182876的ABCD环的立体选择性构建，并通过分子内Heck反应成功构建了高应变的七元环片段，完成了FR182876前体FR182877的不对称全合成。在紫杉醇的不对称全合成研究中，我们建立了2-苄基氧甲基-2-甲基环烷- 1,3 -二酮的一般合成方法，发现它们的面包酵母还原和CBS还原都具有很高的非映体选择性和对映体选择性。此外，我们还通过S_N2还原烯丙基磷盐或在含有紫杉醇a环和c环的烯酮上共轭加成氰化物，完成了紫杉醇C3立体中心的高度立体选择性构建。

Natural products that bind to tublin are classified to two groups, the compounds inhibit polymerization of tublin and the ones inhibit de-polymerization. These compounds resultantly inhibit mitosis to exhibit cytotoxicity. Vinblastine and taxol derivatives have been clinically used as antitumor drugs and epothilone derivatives have been conceived to be promising antitumor drugs. Thus, natural products that bind to tublin are the potential lead compounds for antitumor drugs. Hence, in this project we aimed at developing the improved synthetic route to(+)-phomopsidin, which shows tubulin polymerization inhibitory activity, as well as aimed at developing the asymmetric synthetic route of FR182876 and taxol for their SAR studies. In the studies of the efficient synthesis of (+)-phomopsidin, we successfully established the improved synthetic method through the highly stereoselective TADA reaction of the 13-membered macrocyclic lactone possessing the inverted C11 stereogenic center with the TIPS protected hydroxyl group. In the studies on the asymmetric total synthesis of FR182876, we have developed the stereoselective construction of the ABCD rings of FR182876 by the IMDA reaction and the HIMDA reaction, and we have succeeded in constructing the highly strained seven-membered ring moiety by the intramolecular Heck reaction to accomplish the asymmetric total synthesis of FR182877, which is a precursor of FR182876. In the studies on the asymmetric total synthesis of taxol, we have developed the general synthetic method for 2-benzyloxymethyl-2-methylcycloalkane-1, 3-diones and found that both their baker's yeast reduction and their CBS reduction proceeded with high diastereo-and enantioselectivity. Moreover, we have accomplished the highly stereoselective construction of the taxol C3 stereogenic center by the S_N2' reduction of the allylic phosphonium salt or the conjugate addition of a cyanide to the enone possessing the taxol A-ring and, C-ring moieties.