Enzyme-assisted total synthesis of the optical antipodes D-myo-inositol 3,4,5-trisphosphate and D-myo-inositol 1,5,6-trisphosphate:: Aspects of their structure -: Activity relationship to biologically active inositol phosphates

Unambiguous total syntheses of bath optical antipodes of the enantiomeric pair D-myo-inositol 3,4,5-trisphosphate (Ins(3,4,5)P-3) and D-myo-inositol 1,5,6-trisphosphate (Ins(1,5,6)P-3) are described. The ring system characteristic of myo-inositol was constructed de novo from p-benzoquinone. X-ray data for the enzymatically resolved (1S,2R,3R,4S)-1,4-diacetoxy-2,3-dibromocyclohex-5-ene enabled the unequivocal assignment of the absolute configuration. Subsequent transformations under stereocontrolled conditions led to enantiopure C-2-symmetrical 1,4-(di-O-benzyldiphospho)conduritol B derivatives. Their synthetic potential was exploited to prepare Ins(3,4,5,6)P-4 and Ins(1,4,5,6)P-4 in three steps. With a recently identified and partially purified InsP(5)/InsP(4) phosphohydrolase from Dictyostelium discoideum, these enantiomers could be converted to the target compounds, Ins(3,4,5)P-3 and Ins(1,5,6)P-3, on a preparative scale. An HPLC system employed for both purification of the inositol phosphates and analytical runs ensured that the products were isomerically homogeneous. The sensitivity of detection achieved by a complexometric postcolumn derivatization method indicates that the complexation properties of Ins(3,4,5)P-3/Ins(1,5,6)P-3 resemble those of Ins(1,2,3)P-3, a compound with antioxidantpotential. The set of inositol phosphates synthesized was used to clarify structural motifs important for molecular recognition by p42(IP4) , high-affinity Ins(1,3,4,5)P-4/PtdIns(3,4,5)P-3-specific binding protein from pig cerebellum.