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synthesis of biologically active compounds for the conrol of signal transduction by using phosphorus functional group

利用磷官能团合成用于控制信号转导的生物活性化合物

基本信息

批准号：
09672162
负责人：
SHIBUYA Shiroshi
金额：
$ 1.98万
依托单位：
Tokyo University of Pharmacy and Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

Biologically active compounds for the conrol of signal transduction were synthesized by an application of phosphorus functional group.1. Asymmetric dihydroxylation of 1(E)-alkenylphosphonates afforded the corresponding threo-alpha, beta-dihydroxyphosphonates. Good enantioselectivty was obadserved in the AD reaction of 1(E)-alkenylphosphonates with conjugated aromatic substituents. In the asymmetric dihydroxylation of racemic mixture of 1-acyloxy-2(E)-alkenylphosphonates with AD-mix-alpha- or beta-reagents, the kinetic rate of dihydroxylation was highly dependent upon the configuration of the 1-acyloxy functional group as well as the nature of the substitutent at the 3-position.2. (Phosphonomethyl)phenylalanine and (phosphonodifluoromethyl)phenylalanine and their beta-amino acid congeneres, stable analogues of phosphotyrosine, were prepared from 2-benzyl-1, 3-propanediols possessing either a dithylphosphonomethyl- or diethylphosphonodifluoromethyl functionality at the para position via the lipase-catalyzed desymmetrization.3. Methylene phosphonate analogues of thymidine 3'-phosphate and 2'-deoxyuridine 3'-phosphate were prepared in a stereocontrolled manner through intramolecular N-glycosilation of phenyl 2,3-dideoxy-3-diethylphosphonomethyl-5-O-(2-pyrimydinyl)- 1 -thioglycosides, followed by acid hydrolysis. N-glycolylation of 3-(diethoxyphosorothioyl)methyl-5-O-benzoyl-O-ethyl-2,3 -dideoxy-riboses with silylated thymidine in the presence of TiCI_4 proceeded highly diastereoselectivly to give the corresponding beta-nucleotide analogues in good yield. A remarkable neighboring group participation of the methylenephosphonothioate functionality was obaserved in the course of the beta-N-glycosylation.

利用含磷官能团合成了具有信号转导调控活性的化合物. 1（E）-烯基膦酸酯的不对称二羟基化得到相应的苏型-α，β-二羟基膦酸酯。在1（E）-烯基膦酸酯与共轭芳香取代基的AD反应中观察到了良好的对映选择性。在1-酰氧基-2（E）-烯基膦酸酯的外消旋混合物与AD-mix-α-或β-试剂的不对称双羟基化反应中，双羟基化反应的动力学速率高度依赖于1-酰氧基官能团的构型以及3-位取代基的性质.（膦酰基甲基）苯丙氨酸和（膦酰基二氟甲基）苯丙氨酸及其β-氨基酸同系物，即稳定的磷酸酪氨酸类似物，是由在帕拉具有二乙基膦酰基甲基或二乙基膦酰基二氟甲基官能团的2-苄基-1，3-丙二醇通过脂肪酶催化的去对称化反应制备的.通过苯基2，3-二脱氧-3-二乙基膦酰基甲基-5-O-（2-嘧啶基）-1-硫代糖苷的分子内N-糖基化，然后酸水解，以立体控制的方式制备了胸苷3 '-磷酸和2'-脱氧尿苷3 '-磷酸的亚甲基膦酸酯类似物。3-（二乙氧基硫代磷酰）甲基-5-O-苯甲酰基-O-乙基-2，3-双脱氧核糖与硅烷基化胸苷在TiCl_4存在下进行N-羟乙基化反应，以高的非对映选择性得到相应的β-核苷酸类似物。在β-N-糖基化过程中，观察到硫代亚甲基膦酸酯官能团的显著相邻基团参与。