SYNTHESIS OF D-MYO-INOSITOL AND L-MYO-INOSITOL 1,4,6-TRISPHOSPHATE, REGIOISOMERS OF A UBIQUITOUS 2ND-MESSENGER

A regioisomer of the second messenger D-myo-inositol 1,4,5-trisphospha te [D-Ins(1,4,5)P-3,1], DL-myo-inositol 1,4,6-trisphosphate [DL-Ins(1, 4,6)P-3, 4ab], together with the chiral antipodes D-Ins(1,4,6)P-3(4a) and L-Ins(1,4,6)P-3(4b), was synthesized from myo-inositol. The racemi c diol 6, after removal of the trans-ketal of fully protected 5 was p- methoxybenzylated to give the 6-O-alkylated derivative 9, as the major product in 52% yield. Gentle acidic hydrolysis of 9, followed by benz ylation of the resulting triol, gave the fully protected compound 11ab . Isomerization of the two allyl groups followed by acidic hydrolysis of the resulting cis-prop-1-enyl moieties and the p-methoxybenzyl grou p ga ve the triol 13ab. Phosphorylation of 13ab followed by deprotecti on of the resulting compound. 14ab, with sodium in liquid ammonia and purification by ion exchange chromatography provided 4ab in 60% yield. The intermediate 9 was converted into the cis-diol 16ab in two steps. Selective acylation at the equatorial hydroxyl group using (S)-(+)-O- acetylmandelic acid in the presence of DCC and DMAP provided two diast ereoisomers, 18 and 19, which were separated by flash chromatography. Further transformations provided the corresponding D- and L-1,4,6 trio ls, 13a and 13b, respectively, and phosphorylation, followed by deprot ection of the fully blocked products as for the racemic 4ab, gave 4a a nd 4b, respectively. The absolute configuration of fully protected 11a was determined by transformation to the known compound L-1,2,4,5-tetr a-O-benzyl-myo-inositol (22). Compound 4a was a full agonist at the pl atelet Ins(1,4,5)P-3 receptor for Ca2+ release, but 4b was devoid of a ctivity.