Stereoselective Synthesis and Evaluation of C6"-Substituted 5a-Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2
Stereoselective Synthesis and Evaluation of C6"-Substituted 5a-Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2
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DOI：
10.1021/acs.orglett.7b00945
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发表时间：
2017-05-05
期刊：
影响因子：
5.2
通讯作者：
O'Doherty, George A.
中科院分区：
文献类型：
--
作者：
Li, Mingzong;Li, Yu;O'Doherty, George A.
描述了SL 0101的n-Pr-变体的5 α-卡巴糖类似物的收敛合成。合成类似物是为了寻找在抑制p90核糖体s6激酶（RSK 1/2）中具有有效体内功效的化合物。该合成从奎尼酸得到所需的C-4 L-鼠李糖立体化学，并使用高度选择性的铜酸盐加成、NaBH 4还原、Mitsunobu转化和烯烃二羟基化来安装剩余的立体化学。Pd催化的环化立体选择性地将糖苷配基安装在异头位置。类似物作为RSK 1/2抑制剂进行了评价，发现其活性提高了3至6倍。
A convergent synthesis of 5a-carbasugar analogues of the n-Pr-variant of SL0101 is described. The analogues were synthesized in an effort to find compounds with potent in vivo efficacy in the inhibition of p90 ribosomal s6 kinase (RSK1/2). The synthesis derived the desired C-4 L-rhamnose stereochemistry from quinic acid and used a highly selective cuprate addition, NaBH4 reduction, Mitsunobu inversion, and alkene dihydroxylation to install the remaining stereochemistry. A Pd-catalyzed cyclitolization stereoselectively installed the aglycon at the anomeric position. The analogues were evaluated as RSK1/2 inhibitors and found to have 3- to 6-fold improved activity.