Total synthesis of the second messenger analogue D-myo-inositol 1-phosphorothioate 4,5-bisphosphate: optical resolution of DL-1-O-allyl-2,3,6-tri-O-benzyl-myo-inositol and fluorescent labelling of myo-inositol 1,4,5-trisphosphate

Abstract

Two routes for the synthesis of the myo-inositol 1,4,5-triphosphate analogue myo-inositol 1-phosphorothioate 4,5-bisphosphate have been devised. DL-2,3,6-Tri-O-benzyl-1-O-(cis-prop-1-enyl)-myo-inositol was prepared from DL-1-O-allyl-2,3,6-tri-O-benzyl-myo-inositol and phosphorylated to the protected 4,5-biphosphate. Removal of the propenyl group generated DL-1,2,4-tri-O-benzyl-5,6-bis[bis(2-cyanoethoxy)phospho]-myo-inositol which was thiophosphorylated to give DL-2,3,6-tri-O-benzyl-1-O-[bis(2-cyanoethoxy)thiophospho]-4,5-bis[bis(2-cyanoethoxy)phospho]-myo-inositol. Deblocking afforded racemic myo-inositol 1-phosphorothioate 4,5-bisphosphate, which was reacted with the iodoketone of a fluorescent label to generate a fluorescently labelled inositol 1,4,5-trisphosphate analogue. DL-1-O-Allyl-2,3,6-tri-O-benzyl-myo-inositol was resolved into its enantiomers by means of the crystalline 4,5-biscamphanate ester. 1 D-(+)-1-O-Allyl-2,3,6-tri-O-benzyl-myo-inositol was used to prepare D-myo-inositol 1-phosphorothioate 4,5-bisphosphate in a fashion analogous to the racemic modification via1 D-(+)-2,3,6-tri-O-benzyl-1-O-(cis-prop-1-enyl)-4,5-bis[bis(2-cyanoethoxy)phospho]-myo-inositol.