Total synthesis of phosphatidylinositol 3,5-bisphosphate

磷酸化肌醇作为第二信使在细胞内信号转导中起关键作用。磷脂酰肌醇3，5-二磷酸（PI 3，5-P2）是近年来发现的一种新的第二信使。本课题采用两种不同的合成策略合成了3，5-二磷酸磷脂酰肌醇酯。第一个是从D-葡萄糖的非对映选择性合成，第二个是meso-肌醇衍生物的不对称去对称化1。由D-葡萄糖不对称全合成磷脂酰肌醇3，5-二磷酸酯通过乙烯基铜试剂与D-葡萄糖的手性醛衍生物的1，2-加成反应，得到所需的烯丙醇非对映体。经羟基保护、酸水解、Wittig亚甲基化和关环复分解（RCM）反应得到Conduritol B衍生物。通过OsO_4催化氧化非C_2对称的Conduritol B衍生物，合成了磷脂酰肌醇3，5-二磷酸的关键中间体二醇。最后，这种二醇被成功地转化为磷脂酰肌醇3，5-二磷酸通过建立amidite程序2。meso-1，2，3-三醇的对映选择性去对称化反应我们开发了肌醇的meso-1，2，3-三醇衍生物的高对映选择性的一锅法去对称化反应，先进行不对称酰化反应，然后用CuCl_2-手性二胺络合物催化不对称苯甲酰化反应进行动力学拆分。将meso-肌醇衍生物的不对称选择性去对称化反应成功地应用于关键中间体磷脂酰肌醇3，5-二磷酸酯的不对称全合成

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