Synthesis of the enantiomers of 6-deoxy-myo-inositol 1,3,4,5-tetrakisphosphate, structural analogues of myo-inositol 1,3,4,5-tetrakisphosphate

D-myo-Inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] is produced rapidly from the established second messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P4] in stimulated cells. Despite extensive investigations, in particular concerning its potential role in mediating cellular Ca2+ influx, no exact cellular function has been described for this inositol phosphate; however, binding sites have been identified in a number of tissues and it has been shown to act synergistically with Ins(1,4,5)P3. To assist in the elucidation of the mechanism of action and structural requirements within the Ins(1,3,4,5)P4 moiety that are necessary for recognition and activation of the receptor, structural analogues of this tetrakisphosphate are required. Routes for the synthesis of racemic 6-deoxy-myo-inositol 1,3,4,5-tetrakisphosphate [6-deoxy-DL-Ins(1,3,4,5)P4] and the chiral antipodes D- and L-6-deoxy-myo-inositol 1,3,4,5-tetrakisphosphate are described here. The racemic tetrakisphosphate was synthesised from DL-1,2-O-isopropylidene-myo-inositol in eight steps. Deoxygenation at C-6 was achieved following the Barton-McCombie procedure. Both chiral tetrakisphosphates were synthesised through resolution of racemic cis-diol 6-deoxy-1,4,5-tri-O-p-methoxybenzyl-myo-inositol with the chiral auxiliary (S)-(+)-O-acetylmandelic acid. Absolute configuration was confirmed by synthesis of the known D-6-deoxy-myo-inositol. Both D-6-deoxy-Ins(1,3,4,5)P4 and its enantiomer will be useful tools to unravel the enigmatic role of Ins(1,3,4,5)P4 in the polyphosphoinositide pathway of signal transduction.