Synthesis of 4,8-anhydro-d-glycero-d-ido-nonanitol 1,6,7-trisphosphate as a novel IP<inf>3</inf>receptor ligand using a stereoselective radical cyclization reaction based on a conformational restriction strategy
Terauchi M., Yahiro Y., Abe H., Ichikawa S., Tovey SC., Dedos SG., Taylor CW., Potter BVL., Matsuda A., Shuto S.
4,8-Anhydro-d-glycero-d-ido-nonanitol 1,6,7-trisphosphate (9), designed as a novel IP3receptor 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 unusual1C4-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. © 2005 Elsevier Ltd. All rights reserved.