UNAMBIGUOUS TOTAL SYNTHESIS OF THE ENANTIOMERS OF MYOINOSITOL 1,3,4-TRISPHOSPHATE - 1L-MYO-INOSITOL 1,3,4-TRISPHOSPHATE MOBILIZES INTRACELLULAR CA2+ IN LIMULUS PHOTORECEPTORS

Syntheses of the enantiomers of myo-inositol 1,3,4-trisphosphate are d escribed. 1,4-Di-O-allyl-myo-inositol was regioselectively p-methoxybe nzylated at the 3-position to give 1,4-di-O-allyl-3-O-(p-methoxybenzyl )-myo-inositol followed by benzylation of the remaining free hydroxyl groups to give the key intermediate ,6-tri-O-benzyl-3-O-(p-methoxybenz yl)myo-inositol. Removal of the p-methoxybenzyl and allyl groups gave 2,4,5-tri-O-benzyl-myo-inositol which was phosphitylated with bis(benz yloxy)(diisopropylamino)phosphin to give the fully protected trisphosp hite triester. Oxidation using tert-butyl hydroperoxide gave O-benzyl- 1,3,4-tris(dibenzylphospho)-myo-inositol, and deprotection using sodiu m in liquid ammonia gave racemic myo-inositol 1,3,4-trisphosphate, Dep rotection of the key intermediate ,6-tri-O-benzyl-3-O-(p-methoxybenzyl )-myo-inositol by isomerization of allyl groups followed by mild acid hydrolysis gave 2,4,5-tri-O-benzyl-1-O-(p-methoxybenzyl)-myo- inositol , which was converted to the diastereoisomeric bis-(-)-camphanates. Th e diastereoisomers were separated by column chromatography and the cam phanates and the p-methoxybenzyl group removed by saponification and a cid hydrolysis, respectively, for each diastereoisomer to give the ena ntiomers of 2,4,5-tri-O-benzyl-myo-inositol. The absolute configuratio ns of the latter were established by conversion of ,6-tri-O-benzyl-3-O -(p-methoxybenzyl)-myo-inositol to the known 1L-1,2,4,5,6-penta-O-benz yl-myo-inositol. Phosphorylation and deblocking gave the D- and L-enan tiomers of myo-inositol 1,3,4-trisphosphate. Biological evaluation in Limulus photoreceptors showed that 1L-myo-inositol 1,3,4-trisphosphate was much more active than the D-enantiomer, producing repetitive burs ts of depolarization due to mobilization of intracellular calcium.