Synthetic Studies on Taxane Diterpenoids and their Analogous Compounds

紫杉烷二萜类化合物及其类似化合物的合成研究

• 批准号: 07558088
• 负责人: KUWAJIMA Isao
• 金额: $ 10.88万
• 依托单位: Tokyo Institute of Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07558088/
• 关键词: Taxane Diterpenoids; Total Synthesis; (+) -Taxusin; (-) -Taxol; Enantioselective; Biological Acticity; Taxinine; 不斉合成; 制癌活性; 抗癌剤; 活性類縁体

Based on the methodology for construction of taxane tricarbocycles previously develop, total syntheses of taxane diterpenoids have been studied. Enantioselective total synthesis of (+)-taxusin has been performed by using the following transformations : (1)enantioselective conjugate addition isobutyric ester enolate to the enone, (2)construction of tricarbocycle, (3)cyclopropanation on DELTA^<3.8>-double bond, (4) reductive cleavage of cyclopropyl ketone to introduce 19-Me, (5)Introduction of 5-OH and methylenation of C-4 carbonyl group.Enantioselective total synthesis of taxol, a more interesting and important target, has also been achieved as follows, By using 3-bromo-cyclohexadiene-2-carbacetal was used as a C fragment, and its coupling with optically pure A fragment afforded a tricarbocycle precursor. After B ring cyclization, diene moiety of C fragment was converted to the 4,7-diol via singlet oxygen oxygenation followed by cleavage of the 0-0 bond. After appropriate protection of 1,2-and 7,9-diol moieties, 19-methyl group was introduced via a similar way with taxusin synthesis, the resulting enol was converted to the desire ketone under basic conditions. Appropriate functional group manipulation including D ring construction led us to an efficient synthesis of (-)-taxol in enantioselective manner.On the other hand, total synthesis of taxinine has been planed by using an anisole C fragment, and the tricarbocycle containing C enone fragment was synthesized. Conversion of this intermediate to taxinine is now in progress.

在前人研究的紫杉烷三环化合物的合成方法基础上，对紫杉烷二萜类化合物的全合成进行了研究。采用异丁酸酯烯醇化物与烯酮的共轭加成反应、三碳环的构建、DELTA^ -双键的环丙烷化反应、环丙基酮的还原裂解反应、19-Me的引入等方法，对（+）-红豆杉素进行了对映选择性全合成<3.8>，（5）5-羟基的引入和C-4羰基的亚甲基化。紫杉醇的对映选择性全合成也得到了实现。以3-溴-环己二烯-2-甲缩醛为C片段，并将其与光学纯A片段偶联得到三环前体。在B环化后，C片段的二烯部分通过单线态氧合随后裂解0-0键转化为4，7-二醇。在对1，2-和7，9-二醇部分进行适当保护后，通过与紫杉醇合成类似的方法引入19-甲基，所得烯醇在碱性条件下转化为所需的酮。通过适当的官能团操作，包括D环的构建，我们成功地实现了（-）-紫杉醇的对映选择性合成，并利用苯甲醚C片段进行了紫杉碱的全合成，合成了含苯甲醚C烯酮片段的三环化合物。目前正在将该中间体转化为紫杉碱。

项目成果

I.Kuwajima: "Control of Stereochemistry by sigma-Participation of a Silyl Group. Novel Ring Expansion Reactions of a 1-Oxa-2-Silacyclopentane Derivative" J.Org.Chem.62, No.13. 4206-4207 (1997)

I.Kuwajima：“通过甲硅烷基的 σ 参与控制立体化学。1-Oxa-2-Silacyclopentane 衍生物的新型扩环反应”J.Org.Chem.62，No.13。

I.Kuwajima: "Diastereo-and Enantioselective Synthesis of Allylsilanes. A Useful C Ring Fragment of Taxol" Tetrahedron Lett.38, No.23. 4129-4132 (1997)

I.Kuwajima：“烯丙基硅烷的非对映和对映选择性合成。有用的紫杉醇 C 环片段”Tetrahedron Lett.38，No.23。

I.Kuwajima: "A New Approach for Ingenol Synthesis" J.Org.Chem:. 62・No.10. 3032-3233 (1997)

I.桑岛：“巨大戟二萜醇合成的新方法”J.Org.Chem：62·No.10（1997）。

I.Kuwajima: "Enantioselective Total Synthesis of (±)-Taxusin" J.Am.Chem.Soc.in press.

I. Kuwajima：“(±)-紫杉素的对映选择性全合成”J.Am.Chem.Soc.in press。

I.Kuwajima: "Highty Efficient Method for Coriolin Synthesis" Tetrahedron Lett.38・No.3. 465-468 (1997)

I.桑岛：“科里林合成的高效方法”Tetrahedron Lett.38·No.3（1997）