Synthetic study of microtubule-stabilizing agents

微管稳定剂的合成研究

• 批准号: 14572021
• 负责人: YAKURA Takayuki
• 金额: $ 1.86万
• 依托单位: Kyoto Pharmaceutical 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-14572021/
• 关键词: discodermolide; laulimalide; microtubule-stabilizing agents; formal synthesis; パラジウム触媒; ジアゾケトン; 銅触媒; 形式合成; オキソニウムイリド; [3,3]-シグマトロピー転位; 微小管安定化剤; (R)-リンゴ酸; 立体選択的; Baeyer-Villiger反応; 無溶媒反応

Formal syntheses of microtubule-stabilizing agents, discodermolide and laulimalide were achieved.Synthesis of discodermolide was started from dimethyl (R)-malate by using chemo-and stereoselective dirhodium catalyzed C-H insertion reaction and novel acceleration technique of Baeyer-Villiger reaction of sterically hindered ketones as key steps to give (2S)-2-tert-butyldimethylsilyloxy-3-[(2S,3S,4S,5R)-4-tert-butyldimethyl-silyloxy-3, 5-dimethyl-6-oxotrahydropyran-2-yl]propanal, Smiths intermediate of their total synthesis of discodermolide. Formal synthesis of laulimalide was included oxonium ylide formation-[3,3]-sigmatropic rearrangement reaction and SN type cyclization as key steps.

以（R）-苹果酸二甲酯为起始原料，采用化学和立体选择性的铑催化C-H插入反应和空间位阻酮的Baeyer-Villiger反应的新加速技术，合成了（2S）-2-叔丁基二甲基硅氧基-3-[（2S）-2-叔丁基二甲基硅氧基（2S，3S，4S，5 R）-4-叔丁基二甲基-硅氧基-3，5-二甲基-6-氧代四氢吡喃-2-基]丙醛，Smiths全合成discodermolide的中间体。氯环丙内酯的正式合成包括氧鎓叶立德形成-[3，3]-σ迁移重排反应和SN型环合反应为关键步骤。

项目成果

Takayuki Yakura: "Dirhodium(II)-catalysed intramolecular carbon-hydrogen insertion reaction of α-diazoketones : Stereoselective synthesis of 2, 3-cis-2-alkyl-5-oxo-3-silyloxycyclopentanecarboxylates"J.Chem.Soc., Perkin Trans.1. 3643-3649 (1997)

Takayuki Yakura：“二铑(II)催化的α-重氮酮分子内碳氢插入反应：2, 3-顺-2-烷基-5-氧代-3-甲硅烷氧基环戊烷甲酸酯的立体选择性合成”J.Chem.Soc.，Perkin译1。3643-3649（1997）

Takayuki Yakura: "Stereoselective conjugate addition of alkyl groups to (S)-4-(tert-butyldimethylsilyloxy)-2-phenylsulfonyl-2-cyclopentenone by means of trialkyl-aluminum reagents"Synlett. 7461-7470 (1999)

Takayuki Yakura：“通过三烷基铝试剂将烷基立体选择性共轭加成到(S)-4-(叔丁基二甲基甲硅烷氧基)-2-苯磺酰基-2-环戊烯酮”Synlett。

Takayuki Yakura: "Stereoselective conjugate addition of alkyl groups to (S)-4-(tert-butyl-dimethylsilyloxy)-2-cyclopentenone derivatives"Tetrahedron. 56. 7715-7721 (2000)

Takayuki Yakura：“烷基基团与(S)-4-(叔丁基-二甲基甲硅烷氧基)-2-环戊烯酮衍生物的立体选择性共轭加成”四面体。

矢倉 隆之: "Rh(II)触媒分子内C-H挿入反応を用いるシクロペンタノン類の立体選択的合成"薬学雑誌. 120. 1309-1322 (2000)

Takayuki Yagura：“利用 Rh(II) 催化的分子内 C-H 插入反应立体选择性合成环戊酮”，Pharmaceutical Journal 120. 1309-1322 (2000)。

Takayuki Yakura: "Remarkable rate acceleration of the solvent-free Baeyer -Villiger reaction on the surface of NaHCO_3 crystals for sterically congested cyclic and acyclic ketones"Tetrahedron Lett.. 43・39. 6925-6927 (2002)

Takayuki Yakura：“NaHCO_3晶体表面上空间拥挤的环状和无环酮的无溶剂Baeyer-Villiger反应的显着速率加速”Tetrahedron Lett.. 43・39 (2002)。