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Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues
Angewandte Chemie International Edition ( IF 16.6 ) Pub Date : 2018-03-22 , DOI: 10.1002/anie.201801659
Masahito Yoshida 1 , Koya Saito 1 , Hikaru Kato 2 , Sachiko Tsukamoto 2 , Takayuki Doi 1
Affiliation  

The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl3‐catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid‐labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction.

中文翻译:

Siladenoserinol A及其类似物的全合成,生物学评价

现已实现了p53–Hdm2相互作用抑制剂矽亚丝氨酸A的总合成。反不正当竞争法3炔烃衍生物的催化加氢烷氧基化反应平稳且区域选择性进行,从而以优异的收率得到了双环缩酮。使用最初开发的膦酰基乙酸酯衍生物,通过Horner-Wadsworth-Emmons反应成功引入了甘油磷酸胆碱部分。最后,除去对酸不稳定的保护基,然后在区域上选择性地形成丝氨醇部分的氨基磺酸盐,得到了所需的硅腺苷丝氨醇A,并且苯甲酰基和脱氨化的类似物也被成功合成。生物学评估表明,氨基磺酸盐对于生物活性至关重要,双环缩酮上的酰基修饰可以提高对p53–Hdm2相互作用的抑制活性。
更新日期:2018-03-22
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