Total synthesis of phosphatidylinositol 3,5-bisphosphate

磷脂酰肌醇3,5-二磷酸全合成

• 批准号: 13672215
• 负责人: SHIRAI Ryuichi
• 金额: $ 2.56万
• 依托单位: NARA INSTITUTE OF SCIENCE AND TECHNOLOGY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672215/
• 关键词: PI 3,5-P2; phosphatidylinositol; second messenger; intracellular signal transduction; asymmetric synthesis; total synthesis; stereoselective synthesis; glucose; PI 3,5-P2; PI3, 5-P2

Phosphorylated phoshoinositides play pivotal roles as second messengers in intracellular signal transduction. Phosphatidylinositol 3,5-bisphosphate (PI 3,5-P2) was recently identified as novel second messenger. In this research project, phosphatidylinositol 3,5-bisphospate was synthesized by two different synthetic tactics. The first was diastereoselective synthesis from D-glucose, and the second was asymmetric desymmetrization of meso-myo-inositol derivative1. Asymmetric total synthesis of phosphatidylinositol 3,5-bisphosphate from D-glucoseThe 1,2-addition of vinyl copper reagent to the chiral aldehyde derivative fron D-glucose gave the desired diastereomer of allyl alcohol. Protection of hydroxyl group, acid hydrolysis, Wittig methylenation and ring-closing metathesis (RCM) gave the conduritol B derivatives. By catalytic OsO_4 oxidation of non-C_2 symmetric conduritol B derivatives, we could synthesize the desired diol as key intermediate of phosphatidylinositol 3,5-bisphosphate. Finally, this diol was successfully converted to phosphatidylinositol 3,5-bisphosphate by established amidite procedure2. Enantioselective desymmetrization of meso-1,2,3-TriolWe could developed the highly enatioselective one-pot desymmetrization of meso-1,2,3-triol derivatives of myo-inositol by asymmetric acylation followed by successive kinetic resolution by CuCl_2-chirat diamine complex catalyzed asymmetric benzoylation. Enantioselective desymmetrization of meso-myo-inositol derivative was successfully applied to the asymmetric total synthesis of the key intermediate of phosphatidylinositol 3,5-bisphosphate

磷酸化的磷肌苷作为第二信使在细胞内信号转导中起着关键作用。磷脂酰肌醇3,5-二磷酸（pi3,5 - p2）最近被确定为新的第二信使。本课题采用两种不同的合成策略合成了磷脂酰肌醇3,5-二磷酸。第一个是d -葡萄糖的非对映选择性合成，第二个是中肌醇衍生物的不对称去对称化。从d -葡萄糖中不对称全合成3,5-二磷酸磷脂酰肌醇乙烯基铜试剂在d -葡萄糖的手性醛衍生物上加成1,2得到所需的烯丙醇非对映体。羟基保护、酸水解、Wittig甲基化和合环复合反应（RCM）得到了孔杜糖醇B衍生物。通过OsO_4催化氧化非c_2对称孔枝糖醇B衍生物，合成了所需的二醇作为磷脂酰肌醇3,5-二磷酸的关键中间体。最后，该二醇通过建立的酰胺法成功转化为磷脂酰肌醇3,5-二磷酸2。通过不对称酰化，再通过CuCl_2-chirat二胺配合物催化不对称苯甲酰化，建立了肌醇中位1,2,3-三醇衍生物的高对映选择性一锅脱对称反应。将中肌肌醇衍生物的对映选择性去对称反应成功地应用于磷脂酰肌醇3,5-二磷酸关键中间体的不对称全合成

项目成果

Asuka Nishikawa: "Synthesis of L-α-Phosphatidyl-D-myo-inositol 3, 5-Bisphosphate from D-Glucose"Tetrahedron Letters. 42・52. 9195-9198 (2001)

Asuka Nishikawa：“从D-葡萄糖合成L-α-磷脂酰-D-肌醇3, 5-二磷酸”四面体快报42・52（2001）。

Asuka Nishikawa: "Synthesis of L-α-Phosphatigyl-D-myo-inositol 3,5-Bisphosphate from D-Glucose"Tetrahedron Letters. 42. 9195-9198 (2001)

Asuka Nishikawa：“从 D-葡萄糖合成 L-α-磷酸基-D-肌醇 3,5-二磷酸”Tetrahedron Letters 42. 9195-9198 (2001)

Asuka Nishikawa: "Synthesis of L-α-Phosphatidyl-D-myo-inositol 3,5-Bisphosphate from D-Glucose"Tetrahedron Letters. 42. 9195-9198 (2001)

Asuka Nishikawa：“从 D-葡萄糖合成 L-α-磷脂酰-D-肌醇 3,5-二磷酸”Tetrahedron Letters 42. 9195-9198 (2001)