Synthesis of 3-Position-Modified Analogues of myo-Inositol 1,4,5-Trisphosphate, Tools for Investigation of the Polyphosphoinositide Pathway of Cellular Signaling.

Methods for the synthesis of 3-O-(carboxymethyl)- and 3-O-alkylated myo-inositol 1,4,5-trisphosphates in racemic form from myo-inositol have been devised. For DL-3-O-(carboxymethyl)-myo-inositol 1,4,5-trisphosphate, an analogue of myo-inositol 1,3,4,5-tetrakisphosphate, DL-3-O-allyl-2,6-di-O-benzyl-1-O-(p-methoxybenzyl)-4,5-O-isopropylidene-myo-inositol (14) was prepared from myo-inositol in seven steps. The triol DL-3-O-allyl-2,6-di-O-benzyl-myo-inositol (26), which was obtained after treatment of 14 with acid, was phosphitylated and the product oxidized to give the fully protected trisphosphate 27. The efficient oxidative cleavage of the 3-O-allyl ether of 27 in the presence of the cyanoethyl-protected phosphate triesters was achieved by treatment of 27 with NaIO(4)/RuCl(3).hydrate to afford the fully protected 3-O-(carboxymethyl) trisphosphate 28. After deblocking, DL-3-O-(carboxymethyl) trisphosphate 6 was obtained. For DL-3-O-alkylated myo-inositol 1,4,5-trisphosphate analogues, the fully protected 14 was isomerized to the cis-prop-1-enyl derivative 15. The propenyl group was removed to give DL-2,6-di-O-benzyl-1-O-(p-methoxybenzyl)-4,5-isopropylidene-myo-inositol (16). The 3-O-methyl ether 17, 3-O-ethyl ether 18, and 3-O-n-propyl ether 19 derivatives were synthesized by treatment of the anion of 16 with methyl iodide, ethyl iodide, or n-propyl iodide, respectively. Removal of the isopropylidene and p-methoxybenzyl groups afforded 3-O-alkylated triols 20, 21, or 22, which were phosphitylated and the products oxidized to give the respective fully protected 3-O-alkylated trisphosphates 23-25. Deprotection furnished 3-O-methyl- (3), 3-O-ethyl- (4), or 3-O-n-propyl-myo-inositol 1,4,5-trisphosphate (5). These compounds will be useful pharmacological tools to explore the interaction of myo-inositol 1,4,5-trisphosphate with its receptor and metabolic enzymes.