Synthesis of d- and l-myo-Inositol 1,4,6-Trisphosphate, Regioisomers of a Ubiquitous Second Messenger

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Abstract
A regioisomer of the second messenger d-myo-inositol 1,4,5-trisphosphate [d-Ins(1,4,5)P3, 1], dl-myo-inositol 1,4,6-trisphosphate [dl-Ins(1,4,6)P3, 4ab], together with the chiral antipodes d-Ins(1,4,6)P3(4a) and l-Ins(1,4,6)P3(4b), was synthesized from myo-inositol. The racemic 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 benzylation 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 group gave the triol 13ab. Phosphorylation of 13ab followed by deprotection 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 diastereoisomers, 18 and 19, which were separated by flash chromatography. Further transformations provided the corresponding d- and l-1,4,6 triols, 13a and 13b, respectively, and phosphorylation, followed by deprotection of the fully blocked products as for the racemic 4ab, gave 4a and 4b, respectively. The absolute configuration of fully protected 11a was determined by transformation to the known compound l-1,2,4,5-tetra-O-benzyl-myo-inositol (22). Compound 4a was a full agonist at the platelet Ins(1,4,5)P3 receptor for Ca2+ release, but 4b was devoid of activity.