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)P-4] is produced rapidly from the established second messenger D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P-4] 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)P-3. To assist in the elucidation of the mechanism of action and structural requirements within the Ins-(1,3,4,5)P-4 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)P-4] 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-1,2-0-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-G-deoxy-nlyo-inositol. Both D-6-deoxy-Ins(1,3,4,5)P-4 and its enantiomer will be useful tools to unravel the enigmatic role of Ins(1,3,4,5)P-4 in the polyphosphoinositide pathway of signal transduction.