Synthesis of 4,8-anhydro-d-glycero-d-ido-nonanitol 1,6,7-trisphosphate as a novel IP3 receptor ligand using a stereoselective radical cyclization reaction based on a conformational restriction strategy

• DOI: 10.1016/j.tet.2005.02.025
• Publication Date: 2005-03-05T12:11:39Z
• Authors: Masaru Terauchi; Yumi Yahiro; Hiroshi Abe; Satoshi Ichikawa; Stephen C. Tovey; Skarlatos G. Dedos; Colin W. Taylor; Barry V.L. Potter; Akira Matsuda; Satoshi Shuto
• Keywords: 01 natural sciences; 0104 chemical sciences

Abstract 4,8-Anhydro- d -glycero- d -ido-nonanitol 1,6,7-trisphosphate ( 9 ), designed as a novel IP3 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 1C4-conformation, was treated with Bu3SnH/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 Ca2+ mobilization, although its activity was weaker than that of the natural ligand IP3. Thus, the α-C-glucosidic structure was shown to be a useful mimic of the myo-inositol backbone of IP3.