Development of Efficient Synthetic Method of Antitamor Annonaceous Acetogenins and Investigation of Highly Potent Derivatives

抗炎番荔枝苷高效合成方法的开发及高效衍生物的研究

• 批准号: 14572006
• 负责人: MAEZAKI Naoyoshi
• 金额: $ 1.09万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572006/
• 关键词: Annonaceous Acetogenin; Asymmetric Synthesis; Antitumor Natural Product; Asymmetric Alkynylation; Reiterative Synthesis; Stereodivergent Synthesis; Systematic Synthesis; Annonaceous Plant; 抗腫瘍活性天然物

Annonaceous acetogenins are class of natural product which exhibit potent cyctotoxicity against human antitumor cell lines. Development of efficient synthetic method of these compounds is required for finding of highly potent derivatives, structure determination of the natural acetogenins, and research of the mode of action. We investigated a novel systematic synthesis of THF cores of acetogenins based on reiterative process, which will be a powerful tool to synthesize various congeners. As a result of the research, we obtained results as follows.1)Asymmetric Alkynylation of α-Oxyaldehydes with a C_4-unitInvestigation for an appropriate C_4-unit to realize high yield and excellent diastereoselectivity revealed that 3-butyne-1,2-diol benzylideneacetal was the best C_4-unit among those we tested. Diastereoselectivity was completely controlled by changing a chiral ligand of alkynylating reagent.2)Stereodivergent Synthesis of THF Ring SegmentFour kinds of diastereomers of mono-THF segment are stereodivergently synthesized by changing the method of THF ring closure.3)Highly Stereocontrolled Synthesis of Poly-THF Ring Segment by Reiterative ProcessSynthesis of poly-THF segment based on reiterative strategy was examined. Eight kinds of bis-THF cores were synthesized in good yield with excellent diastereoselectivity.4)Synthesis of Acetogenin by Assembly with γ-Lactone SegmentTo confirm that our method can be applied to a synthesis of acetogenins, murisolin (mono-THF acetogenin) was synthesized by employing asymmetric alkynylation with diyne as a key step. Thus, the methodology for synthesis of annonaceous acetogenins was established.

番荔枝内酯类化合物是一类对人抗肿瘤细胞株具有较强细胞毒性的天然产物。开发高效的合成方法是寻找高效的衍生物、确定天然乙酸配基的结构和研究其作用机制的需要。本论文研究了一种新的基于叠代反应的四氢呋喃环乙酸内酯的系统合成方法，该方法为合成各种同类物提供了有力的工具。1）α-羟基醛与C_4-单元的不对称炔基化反应研究了合适的C_4-单元以实现高产率和良好的非对映选择性，结果表明3-丁炔-1，2-二醇亚苄基缩醛是最好的C_4-单元。通过改变炔基化试剂的手性配体，完全控制了非对映选择性; 2）THF环段的立体分散合成通过改变THF环的闭合方法，立体分散地合成了四种单THF环段的非对映异构体; 3）重复法高度立体控制合成多THF环段研究了重复法合成多THF环段的方法。4）γ-内酯片段组装法合成乙配基为了证实本方法可用于乙配基的合成，我们采用二炔的不对称炔基化反应作为关键步骤合成了murisolin（单-THF乙配基）。建立了番荔枝内酯类化合物的合成方法。

项目成果

Naoyoshi Maezaki: "Highly Stereoselective and Stereodlvergent Synthesis of Four Types of THF Cores in Acetogenins Using a C4-Chiral Building Block"Organic Letters. 4・17. 2977-2980 (2002)

Naoyoshi Maezaki：“使用 C4 手性构件对 Acetogenins 中四种类型的 THF 核心进行高度立体选择性和立体聚合”有机快报 4・17（2002 年）。

Naoto Kojima: "Systematic Construction of a Monotetrahydrofuran-Ring Library in Annonaceous Acetogenins by Asymmeric Alkynytation and Stereodivergent Tetrahydrofuran-Ring Formation"Chemistry-A European Journal. 9・20. 4980-4990 (2003)

Naoto Kojima：“通过不对称炔基化和立体发散四氢呋喃环形成在番荔枝苷中系统构建单四氢呋喃环文库”化学-A 欧洲杂志 9・20（2003 年）。

Naoyoshi Maezaki: "Total Synthesus of the Antitumor Acetogenin MosinB : Desymmetrization Approach to the Stereodivergent Synthesis of threo/trans/erythro-Type Acetogenins"Chemistry A European Journal. 9・2. 389-399 (2003)

Naoyoshi Maezaki：“抗肿瘤Acetogenin MosinB的全合成：苏式/反式/赤式Acetogenins的立体发散合成方法”Chemistry A 欧洲杂志9·2（2003）。

Naoyoshi Maezaki: "Highly Stereoselective and Stereodivergent Synthesis of Four Types of THF Cores in Acetogenins Using a C4-Chiral Building Block"Organic Letters. 4(17). 2977-2980 (2002)

Naoyoshi Maezaki：“使用 C4 手性构件在 Acetogenins 中高度立体选择性和立体发散合成四种类型的 THF 核心”有机信件。

Naoyoshi Maezaki: "Systematic Synthesis of Bis-THF Ring Cores in Annonaceous Acetogenins"Organic Letters. 5・9. 1411-1414 (2003)

Naoyoshi Maezaki：“Annonaceous Acetogenins 中双 THF 环核心的系统合成”有机快报 5・9（2003 年）。