Riley A M, Payne R, Potter B V
Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, University of Bath, U.K.
J Med Chem. 1994 Nov 11;37(23):3918-27. doi: 10.1021/jm00049a011.
Syntheses of the enantiomers of myo-inositol 1,3,4-trisphosphate are described. 1,4-Di-O-allyl-myo-inositol was regioselectively p-methoxybenzylated at the 3-position to give 1,4-di-O-allyl-3-O-(p-methoxybenzyl)-myo-inositol followed by benzylation of the remaining free hydroxyl groups to give the key intermediate 1,4-di-O-allyl-2,5,6-tri-O-benzyl-3-O-(p-methoxybenzyl)-myo-inositol. Removal of the p-methoxybenzyl and allyl groups gave 2,4,5-tri-O-benzyl-myo-inositol which was phosphitylated with bis(benzyloxy)(diisopropylamino)phosphine to give the fully protected trisphosphite triester. Oxidation using tert-butyl hydroperoxide gave 2,5,6-tri-O-benzyl-1,3,4-tris(dibenzylphospho)-myo-inositol, and deprotection using sodium in liquid ammonia gave racemic myo-inositol 1,3,4-trisphosphate. Deprotection of the key intermediate 1,4-di-O-allyl-2,5,6-tri-O-benzyl-3-O-(p-methoxybenzyl)-myo-inositol by isomerization of allyl groups followed by mild acid hydrolysis gave 2,4,5-tri-O-benzyl-1-O-(p-methoxybenzyl)-myo-inositol, which was converted to the diastereoisomeric (bis-(-)-camphanates. The diastereoisomers were separated by column chromatography and the camphanates and the p-methoxybenzyl group removed by saponification and acid hydrolysis, respectively, for each diastereoisomer to give the enantiomers of 2,4,5-tri-O-benzyl-myo-inositol. The absolute configurations of the latter were established by conversion of 1L-2,5,6-tri-O-benzyl-3-O-(p-methoxybenyl)-myo-inositol to the known 1L-1,2,4,5,6-penta-O-benzyl-myo-inositol. Phosphorylation and deblocking gave the D- and L-enantiomers of myo-inositol 1,3,4-trisphosphate. Biological evaluation in Limulus photoreceptors showed that 1L-myo-inositol 1,3,4-trisphosphate was much more active than the D-enantiomer, producing repetitive bursts of depolarization due to mobilization of intracellular calcium.
描述了肌醇1,3,4 - 三磷酸对映体的合成。1,4 - 二 - O - 烯丙基 - 肌醇在3位进行区域选择性对甲氧基苄基化反应，得到1,4 - 二 - O - 烯丙基 - 3 - O -（对甲氧基苄基） - 肌醇，随后将其余游离羟基苄基化，得到关键中间体1,4 - 二 - O - 烯丙基 - 2,5,6 - 三 - O - 苄基 - 3 - O -（对甲氧基苄基） - 肌醇。去除对甲氧基苄基和烯丙基得到2,4,5 - 三 - O - 苄基 - 肌醇，其用双（苄氧基）（二异丙基氨基）膦进行亚磷酸酯化反应，得到完全保护的亚磷酸三酯三酯。使用叔丁基过氧化氢进行氧化反应，得到2,5,6 - 三 - O - 苄基 - 1,3,4 - 三（二苄基磷酰基） - 肌醇，在液氨中用钠进行脱保护反应，得到外消旋肌醇1,3,4 - 三磷酸。通过烯丙基异构化反应，随后进行温和酸水解反应，对关键中间体1,4 - 二 - O - 烯丙基 - 2,5,6 - 三 - O - 苄基 - 3 - O -（对甲氧基苄基） - 肌醇进行脱保护反应，得到2,4,5 - 三 - O - 苄基 - 1 - O -（对甲氧基苄基） - 肌醇，将其转化为非对映异构体（双（ - ） - 樟脑酸酯）。通过柱色谱法分离非对映异构体，分别对每个非对映异构体进行皂化反应和酸水解反应，去除樟脑酸酯基和对甲氧基苄基，得到2,4,5 - 三 - O - 苄基 - 肌醇的对映体。通过将1L - 2,5,6 - 三 - O - 苄基 - 3 - O -（对甲氧基苄基） - 肌醇转化为已知的1L - 1,2,4,5,6 - 五 - O - 苄基 - 肌醇，确定了后者的绝对构型。磷酸化反应和脱保护反应得到肌醇1,3,4 - 三磷酸的D - 对映体和L - 对映体。在鲎光感受器中的生物学评价表明，1L - 肌醇1,3,4 - 三磷酸比D - 对映体活性高得多，由于细胞内钙的动员，会产生重复性的去极化脉冲。
