CHIRAL CYCLOPENTANE-BASED MIMICS OF D-MYO-INOSITOL 1,4,5-TRISPHOSPHATE FROM D-GLUCOSE

Two routes from D-glucose to chiral, ring-contracted analogs of the se cond messenger D-myo-inositol 1,4,5-trisphosphate are described. Methy l alpha-D-glucopyranoside was converted by an improved procedure into methyl 6-O-(p-methoxybenzylidene)-alpha-D-glucopyranoside (6) and then ce into methyl -methoxybenzyl)-alpha-D-gluco-hexodialdopyranoside (1,5 ) (14) in four steps. In the first ring-contraction method 14 was conv erted into methyl -methoxybenzyl)-alpha-D-gluco-hept-6-enopyranoside ( 1,5) (15), which on sequential treatment with Cp(2)Zr(n-Bu)(2) followe d by BF3 . Et(2)O afforded a mixture of -1,2-bis[(p-methoxybenzyl)oxy] -5-vinylcyclopentane (16) and its 4S,5R diastereoisomer 17. Removal of the p-methoxybenzyl groups of 16 and subsequent phosphorylation and d eprotection afforded the first target compound, droxy-1,2,4-tris(phosp honooxy)-5-vinylcyclopentane (3). In the second route, intermediate 14 was subjected to SmI2-mediated ring contraction to give xymethyl)-1,2 -bis[(p-methoxybenzy)oxy]cyclopentane (20). Benzylation of 20 provided -hydroxy-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (22) and 2S,3S,4R, 5S)-3,4-bis(benzyloxy)-5-(hydroxymethyl)- 1,2-bis[(p-methoxybenzyl)oxy ]cyclopentane (21), which were elaborated to the target trisphosphates ydroxymethyl)-1,2,4-tris(phosphonooxy)cyclopentane (4) and phosphonoo xy)-5-[(phosphonooxy)methyl]cyclopentane (5), respectively. Both 3 and 4 mobilized intracellular Ca2+, but 4 was only a few fold less potent than D-myo-inositol 1,4,5-trisphosphate, demonstrating that effective mimics can be designed that do not bear a six-membered ring.