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Synthesis of secondary difluoromethylphosphonate-contaning amino acid and its biological examination

二氟甲基膦酸仲氨基酸的合成及其生物学检测

基本信息

批准号：
10671988
负责人：
OTAKA Akira
金额：
$ 1.92万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Phosphorylation and dephosphorylation of proteins serve as post-translational modifications that are critical for intracellular signal transudation. Therefore, nonhydrolyzable phosphoamino acid mimetic-containing peptides have gained much attention as useful agents for exploring signaling events. Among various nonhydrolyzable phosphoamino acid analogs, those employing the difluoromethylene unit (CF2) as a replacement for the phosphoryl ester oxygen have shown particular utility. We have already achieved the synthesis of CF2-substituted pTyr and pSer mimetics; however, synthesis of 2-amino-4, 4-difluoro-3-methy1-4-phosphonobutanoic acid (F2Pmab) as a CF2-substituted pThr mimetic was lacing. In this study, we accomplished the preparation of racemic protected F2Pmab by CeCl3-mediated conjugate addition of diethyl difluoromethylphosphonate anion onto a nitroalkene. Furthermore, we accomplished the stereoselective synthesis of all four F2Pmab isomers by applying Cu-mediated coupling reaction of (diethylphosphonodifluoromethyl) -zinc bromide with β-iodo-α, β- unsatureted carboxylic acid derivatives, followed by diastereoselective hydrogenation and amination with the aid of a chiral auxiliary. The protected amino acid derivative was successfully incorporated into peptides using a two-step deprotection methodology consisting of high acidic-and low acidic reagents. For high acidic reagents, 1 M TMSOTf-thioanisole in TFA system was used, and 0.3 M

蛋白质的磷酸化和去磷酸化是翻译后修饰，对细胞内信号传导至关重要。因此，非水解性磷酸氨基酸模拟多肽作为探索信号事件的有用试剂受到了人们的广泛关注。在各种非水解性磷酸氨基酸类似物中，那些使用二氟亚甲基单元(CF2)来替代磷酸酯氧的类似物显示出特别的用途。我们已经实现了CF2取代的pTyr和pSer模拟物的合成，但作为CF2取代的pThr模拟物的2-氨基-4，4-二氟-3-甲基-4-膦酸丁酸(F2Pmab)的合成尚处于起步阶段。在本研究中，我们通过CeCl3介导的二乙基二氟甲基膦酸阴离子与硝基烯烃的共轭加成反应，完成了外消旋保护的F2Pmab的制备。此外，我们还通过铜催化的二乙基膦-二氟甲基-溴化锌与β-碘-α，β不饱和羧酸衍生物的偶联反应，然后在手性辅助下进行非对映选择性氢化和胺化，完成了F2Pmab四个异构体的立体选择性合成。采用由高酸性试剂和低酸性试剂组成的两步去保护方法，将受保护的氨基酸衍生物成功地结合到多肽中。对于强酸性试剂，在TFA体系中使用1M TMSOTf-硫代苯甲醚，0.3M