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

微管蛋白结合天然产物的全合成及比吸收率研究

基本信息

批准号：
17590020
负责人：
NAKADA Masahisa
金额：
$ 2.45万
依托单位：
Waseda University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17590020/
关键词：
tubluin natural products asymmetric total synthesis chiral building blocks intramolecular Diels-Alder reaction intramolecular hetero Diels-Alder reaction S_N2' reduction intramolecular Heck reaction 有機化学合成化学生体関連物質

项目摘要

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.

与微管蛋白结合的天然产物分为两类，抑制微管蛋白聚合的化合物和抑制解聚的化合物。这些化合物最终会抑制有丝分裂，从而表现出细胞毒性。长春花碱和紫杉醇类化合物已被用于临床抗肿瘤药物，埃博西酮类化合物被认为是很有前途的抗肿瘤药物。因此，与微管蛋白结合的天然产物是潜在的抗肿瘤药物的先导化合物。因此，在本项目中，我们旨在开发具有抑制微管蛋白聚合活性的(+)-灯盏花素的改进合成路线，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(+)-鱼腥草素的研究中，我们通过具有倒C11立体中心的13元大环内酯与TIPS保护的羟基的高立体选择性的TADA反应，成功地建立了改进的合成方法。在不对称全合成FR182876的研究中，我们通过IMDA反应和HIMDA反应发展了FR182876的ABCD环的立体选择性结构，并成功地通过分子内Heck反应构建了高应变的七元环部分，完成了FR182877的不对称全合成。在紫杉醇的不对称全合成研究中，我们发展了2-苄氧甲基-2-甲基环烷-1，3-二酮的通用合成方法，发现它们的面包酵母还原和CBS还原都具有很高的非对映选择性和对映选择性。此外，我们还通过烯丙基膦盐的S_N_2‘还原或氰化物与含有紫杉醇A环和C环部分的烯酮的共轭加成，完成了紫杉醇C3立体中心的高立体选择性构建。