Synthesis of 4,8-anhydro- d- glycero- d- ido-nonanitol 1,6,7-trisphosphate as a novel IP 3 receptor ligand using a stereoselective radical cyclization reaction based on a conformational restriction strategy

Abstract

4,8-Anhydro- d- glycero- d- ido-nonanitol 1,6,7-trisphosphate ( 9 ), designed as a novel IP 3 receptor ligand having an α- C-glycosidic structure, was synthesized via a radical cyclization reaction with a temporary connecting allylsilyl group as the key-step. Phenyl 2- O-allyldimethylsilyl-3,4-bis- O-TBS-1-seleno-β- d-glucopyranoside ( 10a ), conformationally restricted in the unusual 1C 4-conformation, was treated with Bu 3SnH/AIBN to form the desired α-cyclization product 16a almost quantitatively. On the other hand, when a conformationally unrestricted O-benzyl-protected 2- O-allyldimethylsilyl -1-selenoglucoside 15 was used as the substrate, the radical reaction was not stereoselective and gave a mixture of the α-and β-products. From 16a , the target C-glucoside trisphosphate 9 was synthesized via phosphorylation of the hydroxyls by the phosphoramidite method. During the synthetic study, an efficient procedure for the oxidative C–Si bond cleavage, via a nucleophilic substitution at the silicon with p-MeOPhLi followed by Fleming oxidation, was developed. The C-glycoside 9 was found to be a full agonist for Ca 2+ mobilization, although its activity was weaker than that of the natural ligand IP 3. Thus, the α- C-glucosidic structure was shown to be a useful mimic of the myo-inositol backbone of IP 3.