First derivatives of myo-inositol 1,4,6-trisphosphate modified at positions 2 and 3: structural analogues of d-myo-inositol 1,4,5-trisphosphate Original Research Article

Novel, structurally modified potential mimics of the second messenger d-myo-inositol 1,4,5-trisphosphate, based on the biologically active regioisomer d-myo-inositol 1,4,6-trisphosphate, were synthesised. dl-5-O-Benzyl-1,4,6-tri-O-p-methoxybenzyl-myo-inositol was the key intermediate for the preparation of the following compounds: dl-3-deoxy-, dl-3-deoxy-2-O-methyl-, dl-3-O-(2-hydroxyethyl)-, dl-3-O-(3-hydroxypropyl)- and dl-3-O-(4-hydroxybutyl)-myo-inositol 1,4,6-trisphosphate. dl-1,4,6-Tri-O -allyl-5-O-benzyl-myo-inositol was used to prepare dl-2-O-methyl-myo-inositol 1,4,6-trisphosphate. Deoxy-compounds were prepared by reduction of the corresponding tosylated intermediate using Super Hydride. The hydroxyalkyl groups were introduced at the C-3 of myo-inositol using the corresponding benzyl protected hydroxy alkyl bromide via the cis-2,3-O-dibutylstannylene acetal. Methylation and benzylation at C-2 was accomplished using methyl iodide and benzyl bromide, respectively, in the presence of sodium hydride. Deblocking of p-methoxybenzyl groups was accomplished with TFA in dichloromethane and the allyl groups were removed by isomerisation to the cis-prop-1-enyl derivative, which was hydrolysed under acidic conditions to give the corresponding 1,4,6-triol. The 1,4,6-triols were phosphitylated with the P(III) reagent bis(benzyloxy)(diisopropylamino)phosphine in the presence of 1H-tetrazole then oxidised with 3-chloroperoxybenzoic acid followed by deblocking by hydrogenolysis to give dl-2-O-methyl-, dl-3-O-deoxy-, dl-3-O-deoxy-2-O-methyl-, dl-3-O-(2-hydroxyethyl)-, dl-3-O-(3-hydroxypropyl)- and dl-3-O-(4-hydroxybutyl)-myo-inositol 1,4,6-trisphosphate, respectively.