SYNTHESIS OF THE ENANTIOMERS OF MYOINOSITOL 1,2,4,5-TETRAKISPHOSPHATE, A REGIOISOMER OF MYOINOSITOL 1,3,4,5-TETRAKISPHOSPHATE

Routes for the synthesis of racemic myo-inositol 1,2,4,5-tetrakisphosp hate DL-Ins(1,2,4,5)P-4 5ab and the chiral antipodes D- and L-myo-inos itol 1,2,4,5-tetrakisphosphate 5a and 5b, respectively, are described. For the synthesis of racemate 5ab, 3,6-di- O-benzoyl-1,2:4,5-di-O-iso propylidene-myo-inositol 7ab is prepared in two steps from myo-inosito l. The ketals are hydrolysed under acidic conditions to give DL-1,4-di -O-benzoyl-myo-inositol 8ab. Phosphitylation of compounds 8ab using ch loro(diethoxy)phosphine in the presence of base, followed by oxidation and a three-step deprotection strategy, gives DL-Ins(1,2,4,5)P-4 5ab. The chiral tetrakisphosphates 5a and 5b are synthesized using a diffe rent route. The 4,5-isopropylidene group of -O-benzyl-1,2:4,5-di-O-iso propylidene-myo-inositol 13ab are selectively removed under mild acidi c conditions to give diol 14ab. p-Methoxybenzylation at the 4,5-positi ons followed by acid hydrolysis of the cis-isopropylidene ketal afford s cis-diol 16ab. Selective coupling of (S)-(+)-O-acetylmandelic acid w ith diol 16ab at the equatorial hydroxy group provides two diastereois omers 18 and 19, which are separated by chromatography. Basic hydrolys is of the individual diastereoisomers provides the enantiomers 16a and 16b. Acidic hydrolysis gives D- and L-3,6-di-O-benzyl-myo-inositol 20 a and 20b, respectively. Phosphitylation and oxidation of tetraols 20a and 20b gives the fully blocked derivatives, which are deprotected to give tetrakisphosphates 5a and 5b, respectively. The absolute configu ration of compound 20a is established by a chemical method. DL-1,2:4,5 -Di-O-isopropylidene-myo-inositol 12ab is coupled to (S)-(+)-O-acetylm andelic acid to give a mixture of bis-esters 26 and 27 and crystallisa tion of the mixture of diastereoisomers affords pure isomer 27. Basic hydrolysis gives the pure enantiomer 12a (for which the absolute confi guration is known) and benzylation followed by acid hydrolysis gives t etraol 20a with the same physical properties as compound 20a prepared by a different route described previously. D-Ins(1,2,4,5)P, 5a is a po tent mobiliser of intracellular Ca2+ ions in permeabilised platelets, while L-Ins(1,2,4,5)P-4 5b is inactive.