Σύνθεση φωσφορυλιωμένων παραγώγων της myo-ινοσιτόλης

Abstract

Target of the present work is the development of a new synthetic methodology towards the synthesis of phosphorylated myo-inositol derivatives, by using myoinositol as starting material. The introduction includes a brief discussion on the history of myo-inositol and the biological role of myo-inositol phosphates and phosphoinositides. Also, protecting groups of the hydroxyl moiety are presented, in order to help the reader understand the strategy that is used in our synthetic plans. The chapter of the introduction ends with a short discussion of former synthetic methods of myo-inositol phosphates and phosphoinositides. In the main section we present our experimental results and their discussion. First, a retrosynthetic approach is followed for three target molecules [phosphorylated intermediates for the synthesis of PI-(3)P, PI2-(4,5)P and PI3-(3,4,5)]. Then, a synthetic plan is designed with three key features: selective reactions, high yields and compatibility with solid phase chemistry. The first synthetic plan employs camphor in order to form a ketal protective group and to simultaneously achieve resolution. Forward steps could not follow the three key features we set at the beginning, therefore this plan was abandoned. The second synthetic plan adopts the cyclohexylidene ketal approach. The (2,3):(4,5)-di-O-cyclohexylidene ketal of myo-inositol is combined with a new resolution method, where camphanoyl chloride is used as the chiral agent. The camphanic esters are separated by column chromatography. The protective groups employed in the second synthetic plan (apart from the cyclohexylidene ketals) are the TBDPS group, the MOM group and the Bz group. TBDPS is used as the blocking group of position 1 whereas Bz groups are used to block positions which are meant to be phosphorylated. Finally, MOM groups have the role of blocking positions meant to be free hydroxyls in the final molecules. All reactions after the third step are highly selective, with no other regioisomers detected, and yields are generally very good. The TBDPS group resembles a diphenylsilyloxy linker, allowing the comparison between the present synthesis and future work concerning a solid phase approach. Specifically, MOM groups allow the use of arachidonic acid on the glycerol moiety (easily introduced on position 1), which could subsequently lead to natural phosphoinositides.