Chemoenzymatic Synthesis of Biologically Active Natural products via Lipase TL -Mediated Kinetic Resolution as a Key Step and their Structure Activity Relationship

脂肪酶TL介导的动力学拆分化学酶法合成生物活性天然产物及其构效关系

• 批准号: 14572014
• 负责人: AOYAGI Yutaka
• 金额: $ 1.02万
• 依托单位: Tokyo University of Pharmacy and Life Science
• 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-14572014/
• 关键词: Lipase TL; GE3; Hexadepsipeptides; Asymmetric Synthesis; Glycerols; Antitumor; Piperazic acid; SAR; 光学分割; ジテルペン; 2級アルコール; 速度論的光学分割; グリセロール; 光学活性ピペラジン酸; 低温活性酵素

1)Lipase TL-mediated kinetic resolution of 2-pentanol (C5 unit) and 2-propanol (C3 unit) proceeded in the presence of base at low temperature to give the corresponding optically pure alcohols and acetates in good yields, respectively. The 2-pentanol and its acetate thus obtained were converted both enantiomers of piperazic acid derivatives, which are important segments of hexadepsipeptide GE3. 2)Cytotoxic ent-kaurene diterpenes were isolated from Rabdosia excisa to obtained substrates for Lipase TL-mediated regioselective acetylation of polyhydroxy natural products. 3)Efficient transformation of 7,14-dihydroxy-ent-kaurenes to tetracyclic ent-abietanes under Mitsunobu reaction conditions were developed. The tetracyclyc ent-abietanes have been found to be potent cytotoxic agents. 4)SAR study on ent-kaurenes and tetracyclic ent-abietanes were also examined.

1)在低温碱存在下，脂肪酶TL催化2-戊醇（C5单元）和2-丙醇（C3单元）的动力学拆分，分别以较好的产率得到相应的光学纯醇和乙酸酯。由此获得的2-戊醇及其乙酸酯转化为哌嗪酸衍生物的两种对映异构体，哌嗪酸衍生物是六缩酚酸肽GE 3的重要片段。2)从缺叶香茶菜中分离出具有细胞毒性的对映贝壳杉烯二萜，以获得用于脂肪酶TL介导的多羟基天然产物的区域选择性乙酰化的底物。3)研究了在Mitsunobu反应条件下7，14-二羟基对映贝壳杉烯向四环对映松香烷的高效转化。已发现四环素-松香烷是有效的细胞毒性剂。4)对对映贝壳杉烯和四环对映松香烷的构效关系也进行了研究。

项目成果

Yutaka Aoyagi: "Lipase TL-Mediated Kinetic Resolution of 5-Benzyloxy-1-tert-butyl-dimethylsilyloxy-2-pentanol at low temperature"The Journal of Organic Chemistry. 68. 6899-6904 (2003)

Yutaka Aoyagi：“脂肪酶 TL 介导的低温下 5-苄氧基-1-叔丁基-二甲基硅氧基-2-戊醇的动力学拆分”有机化学杂志。

Ming-yu Gui: "Excisanin H, a Novel Cytotoxic 14,20-Epoxy-ent-Kaurene Diterpenoids from Rabdosia excisa"Journal of Natural Products. 67. 373-376 (2004)

桂明宇：“Excisanin H，一种来自 Rabdosia excisa 的新型细胞毒性 14,20-Epoxy-ent-Kaurene 二萜”天然产物杂志。

Yutaka Aoyagi: "Lipase TL-mediated kinetic resolution of 5 -benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol at low temperature : concise asymmetric synthesis of both enatiomers of a piperazic acid derivative"The Journal of Organic Chemistry. 68. 6899-69

Yutaka Aoyagi：“脂肪酶 TL 介导的低温下 5-苄氧基-1-叔丁基二甲基甲硅烷氧基-2-戊醇的动力学拆分：哌嗪酸衍生物的两种对映体的简明不对称合成”有机化学杂志。

Yutaka Aoyagi: "Lipase XL-Mediated Kinetic Resolution of 5-Benzyl-oxy-1-tert-butyl-dimethylsilyloxy-2-pentanol at low temperature"The Journal o Organic Chemistry. 68. 6899-6904 (2003)

Yutaka Aoyagi：“脂肪酶 XL 介导的低温下 5-苄基-氧基-1-叔丁基-二甲基硅氧基-2-戊醇的动力学拆分”《有机化学杂志》。

Yutaka Aoyagi: "Efficient Synthesis of Novel Cytotoxic cis-Fused alfa-Methylene-gamma-lactones from 7,14-dihydroxy-ent-kaurenes by Transformation under Mitsunobu Reaction Conditions"Tetrahedron Letters. 45. 1421-1425 (2004)

Yutaka Aoyagi：“在 Mitsunobu 反应条件下通过转化从 7,14-二羟基-ent-贝壳杉烯高效合成新型细胞毒性顺式稠合 α-亚甲基-γ-内酯”四面体快报。