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 p air 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 character istic of myo-inositol was constructed de novo from p-benzoquinone. X-ray da ta for the enzymatically resolved (1S,2R,3R,4S)-1,4-diacetoxy-2,3-dibromocy clohex-5-ene enabled the unequivocal assignment of the absolute configurati on. Subsequent transformations under stereocontrolled conditions led to ena ntiopure 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 In s(1,4,5,6)P-4 in three steps. With a recently identified and partially puri fied InsP(5)/InsP(4) phosphohydrolase from Dictyostelium discoideum, these enantiomers could be converted to the target compounds, Ins(3,4,5)P-3 and I ns(1,5,6)P-3, on a preparative scale. An HPLC system employed for both puri fication of the inositol phosphates and analytical runs ensured that the pr oducts were isomerically homogeneous. The sensitivity of detection achieved by a complexometric postcolumn derivatization method indicates that the co mplexation 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 phosph ates synthesized was used to clarify structural motifs important for molecu lar 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.