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

摘要

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-(2-hydroxyethyl)-,DL-3-(3-hydroxyethyl)-and DL-3-(4-hydroxyethyl)-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 sing 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 ad 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-deoxy-,DL-3-deoxy-2-O-methyl-,DL-3-(2-hydroxyethyl)-,DL-3-(3-hydroxyethyl)-and DL-3-(4-hydroxyethyl)-myo-inositol 1,4,6-trisphosphate,respectively.