Abstract
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 1 H-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.
Published Version
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