A multifunctional catalyst that stereoselectively assembles prodrugs
A multifunctional catalyst that stereoselectively assembles prodrugs
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DOI：
10.1126/science.aam7936
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发表时间：
2017-04-28
期刊：
影响因子：
56.9
通讯作者：
Davies, Ian W.
中科院分区：
文献类型：
--
作者：
DiRocco, Daniel A.;Ji, Yining;Davies, Ian W.
手性磷化合物的催化立体选择性合成是一个尚未解决的问题。最先进的方法依赖于拆分或化学计量的手性助剂。氨基磷酸酯前药是用于治疗病毒性疾病和癌症的原核苷酸（磷酰胺酯前药）疗法的关键组分。在这里，我们描述了一种催化立体选择性方法的发展，通过一个动态的立体选择性过程安装磷立体氨基磷酸酯核苷。详细的机理研究和计算建模导致了多功能催化剂的合理设计，使立体选择性高达99：1。
The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.