Creation of Asymmetric Catalysts Based on New Concept, and Their Application to Efficient Synthesis of Pharmaceutical Lead Compounds

基于新概念的不对称催化剂的制备及其在药物先导化合物高效合成中的应用

• 批准号: 13307062
• 负责人: KANAI Motomu
• 金额: $ 29.95万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13307062/
• 关键词: asymmetric catalyst; bifunctional catalysis; pharmaceutical lead; asymmetric synthesis; biologically active natural products; asymmetric cyanosil lation; asymmetric aldol reaction; asymmetric Mannich reaction; フッ化銅; アルドール反応; シアノアルキル化反応; 直接的触媒的ア

We developed a chiral heteropolymetallic complex containing a lanthanide metal, alkali metal, and BINOL. This new catalyst promotes the direct enantioselective aldol reaction from unmodified ketones and aldehydes with high enantioselectivity. We also developed a novel chiral ligand, linked BINOL, and found that the zinc complex can promote very efficient C-C bond formation between a hydroxyl ketone and aldehydes or imines. The maximum catalyst turnover was reached up to 20000 with maintaining an excellent enantioselectivity. Moreover, we developed a new sugar-derived catalyst that can promote enantioselective cyanosilylation of ketones and ketoimines with high efficiency. Using these catalyses, we established efficient synthetic route of camptothecin (anticancer drug), oxybutynin (muscarinic receptor antagonist), and sorbinil (aldose reductase inhibitor). These synthetic route have a potential of being applied to industrial synthesis.

我们开发了一种含有镧系金属、碱金属和BINOL的手性异多金属配合物。这种新的催化剂促进了未修饰的酮和醛的直接对映选择性羟醛缩合反应，具有高的对映选择性。我们还开发了一种新的手性配体，连接BINOL，并发现锌配合物可以促进非常有效的羟基酮和醛或亚胺之间的C-C键的形成。催化剂的最大周转率高达20000，同时保持了优异的对映选择性。此外，我们开发了一种新的糖衍生的催化剂，可以促进酮和酮亚胺的对映选择性氰硅烷化，具有高效率。利用这些催化剂，我们建立了抗癌药物喜树碱、毒蕈碱受体拮抗剂奥昔布宁和醛糖还原酶抑制剂索比尼的高效合成路线。这些合成路线具有工业化应用潜力。

项目成果

Oisaki, K., Suto, Y., Kanai, M., Shibasaki, M.: "A New Method for the Catalytic Aldol Reaction to Ketones"J.Am.Chem.Soc.. 125. 5644-5645 (2003)

Oisaki, K.、Suto, Y.、Kanai, M.、Shibasaki, M.：“催化酮醛醇反应的新方法”J.Am.Chem.Soc.. 125. 5644-5645 (2003)

Funabashi K., Jachmann, M., Kanai, M., Shibasaki M.: "Multicenter Strategy for the Development of Catalytic Enantioselective Nucleophilic Alkylation of Ketones Me_2Zn Addition to α-Ketoesters"Angew.Chem.Int.Ed.. 42. 5489-5492 (2003)

Funabashi K.、Jachmann, M.、Kanai, M.、Shibasaki M.：“开发酮 Me_2Zn 加成到 α-酮酯的催化对映选择性亲核烷基化的多中心策略”Angew.Chem.Int.Ed.. 42. 5489 -5492 (2003)

Shibuguchi, T., Fukuta, Y., Akachi, Y., Sekine, A., Ohshima T., Shibasaki, M.: "Development of new asymmetric two-center catalysts in phase-transfer reactions"Tetrahedoron Lett.. 43. 9539-9543 (2002)

Shibuguchi, T.、Fukuta, Y.、Akachi, Y.、Sekine, A.、Ohshima T.、Shibasaki, M.：“相转移反应中新型不对称双中心催化剂的开发”Tetrahedoron Lett.. 43。

Takamura, M., Yanagisawa, H., Kanai, M., Shibasaki, M.: "Efficient synthesis of Antihyperglycemic (S)-α-Aryloxy-β-phenylpropionic Acid Using a functional Asymmetric Catalyst"Chem.Pharm.Bull.. 50. 1118-1121 (2002)

Takamura, M.、Yanagisawa, H.、Kanai, M.、Shibasaki, M.：“使用功能性不对称催化剂有效合成抗高血糖 (S)-α-芳氧基-β-苯基丙酸”Chem.Pharm.Bull.. 50. 1118-1121 (2002)

Yoshikawa, N., Shibasaki, M.: "Catalytic asymmetric synthesis of β-hydroxy-α-amino acid esters by direct aldol reaction of glycinate Schiff bases"Tetrahedron. 58. 8289-8298 (2002)

Yoshikawa, N., Shibasaki, M.：“通过甘氨酸希夫碱的直接羟醛反应催化不对称合成 β-羟基-α-氨基酸酯”Tetrahedron，58。8289-8298 (2002)