Asymmetric Total Synthesis of Octalactins A, B and Their Analogues

八乳素A、B及其类似物的不对称全合成

• 批准号: 12554023
• 负责人: SHIINA Isamu
• 金额: $ 6.98万
• 依托单位: Tokyo University of Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12554023/
• 关键词: Octalactins; Cytotoxic Activity; 8-Membered Ring Lactone; Asymmetric Total Synthesis; Asymmetric Aldol Reaction; Lactonization; Mixed-anhydride; MNBA; 抗がん剤; 8員環ラクトン; アンチユニット; MNBA; 高速ラクトン化; オクタラクチンA; ラクトン化; 鎖状ポリオキシ化合物; 光学活性ジアミン; 二価スズのトリフラ

Octalactins A and B were isolated from the marine bacterium Streptomyces sp. in 1991.The structure of these compounds includes an unusual saturated medium-sized lactone moiety, and octalactin A exhibits a potent cytotoxic activity against some tumor cell lines.A method for the synthesis of octalactins A and B is established via a new and quite effective mixedanh ydride lactonization for, the synthesis of an eight-membered ring moiety using 2-methyl-6-nitrobenzoic anhydride (MNBA) with DMAP.Both an optically active linear precursor of the lactone and a side chain of octalactins are prepared by the enantioselective aldol reaction of ketene silyl acetals with aldehydes.The desired 8-membered ring lactone was first synthesized by S-Py ester method after 96 h ; however, the lactonization sluggishly proceeded in refiuxed toluene with the silver salt catalyst.Furthermore, the target cyclized molecule was not produced at all when the reaction was carried out at room temperature.On the other hand, the cyclization reaction of the seco acid was efficiently accelerated by MNBA with DMAP to afford the desired 8-membered ring lactone in 84% yield at room temperature, and the corresponding diolide was not produced.Thus, an efficient method for the preparation of the synthetic precursor of octalactins was established via the effective, construction of the medium-sized ring lactone moiety.

Octalactins A和B是1991年从海洋细菌Streptomycessp.中分离得到的两个化合物，它们的结构中含有一个不寻常的中等大小的饱和内酯部分，并且Octalactin A对某些肿瘤细胞具有较强的细胞毒活性。使用2-甲基-6-硝基苯甲酸酐（MNBA）和DMAP合成八元环部分。通过乙烯酮甲硅烷基缩醛与醛的对映选择性羟醛缩合反应制备了内酯的光学活性线性前体和八角体的侧链。所需的8- 96 h后，首次采用S-Py酯法合成了六元环内酯;然而，在用银盐催化剂回流的甲苯中，内酯化反应进行缓慢。此外，当反应在室温下进行时，根本不产生目标环化分子。另一方面，在室温下，用MNBA和DMAP有效地促进了开环酸的环化反应，以84%的产率得到了所需的八元环内酯，并且没有产生相应的二萜。中等大小的环内酯部分的构建。

项目成果

Akifumi Kagayama: "Diastereoselective Aldol and Reformatsky Reactions of α-Halo Carbonyl Compounds and Aldehydes Mediated by Titanium(II) Chloride"Bulletin of the Chemical Society of Japan. 73. 2579-2585 (2000)

Akifumi Kagayama：“由氯化钛(II)介导的α-卤代羰基化合物和醛的非对映选择性羟醛和重整反应”日本化学学会公报73. 2579-2585 (2000)。

Isamu Shiina: "An Efficient Method for the Preparation of Carboxylic Esters from Nearly Equimolar Amounts of Carboxylic Acids and Alcohols Using 2-Methyl-6-nitrobenzoic Anhydride with Trielhylamine in the Presence of a Catalytic Amount of 4-(Dimethylamino

Isamu Shiina：“在催化量的 4-(二甲氨基) 存在下，使用 2-甲基-6-硝基苯甲酸酐和三乙胺，从近等摩尔量的羧酸和醇制备羧酸酯的有效方法

Isamu Shiina: "An Effective Use of Benzole Anhydride and Its Derivatives for the Synthesis of Carboxylic Esters and Lactones : A Powerful and Convenient Mixed-anhydride Method Promoted by Basic Catalysts"The Journal of Organic Chemistry. 69. 1822-1830 (20

Isamu Shiina：“有效使用苯酐及其衍生物合成羧酸酯和内酯：碱性催化剂促进的强大而方便的混合酸酐方法”有机化学杂志。

Hidehiro ARAI, Isamu SHIINA, Teruaki MUKAIYAMA: "A Convenient Method for the Preparation of Unsymmetrical Bis-Aldols by Way of Sequential Two Aldol Reactions"Chemistry Letters. 118-119 (2001)

Hidehiro ARAI、Isamu SHIINA、Teruaki MUKAIYAMA：“通过连续两个羟醛反应制备不对称双羟醛的便捷方法”化学快报。

Isamu SHIINA, Katsuhiko KONISHI, Yu-suke KURAMOTO: "Enantioselective Alkylation of Aldehydes with Diethylzinc Using a New Catalyst System, ((R) -Thiolan-2-yl)diphenylmethanol and Metal Alkoxides"Chemistry Letters. 164-165 (2002)

Isamu SHIINA、Katsuhiko KONISHI、Yu-suke KURAMOTO：“使用新的催化剂体系、((R)-硫杂兰-2-基)二苯甲醇和金属醇盐对醛与二乙基锌进行对映选择性烷基化”化学快报。