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Catalytic asymmetric and stereodivergent oligonucleotide synthesis
Science ( IF 44.7 ) Pub Date : 2021-02-12 , DOI: 10.1126/science.abf4359
Aaron L Featherston 1 , Yongseok Kwon 1 , Matthew M Pompeo 1 , Oliver D Engl 2 , David K Leahy 2 , Scott J Miller 1
Affiliation  

We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA scaffolds have proven to be essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides, which are of broad interest in immuno-oncology as agonists of the stimulator of interferon genes (STING) pathway.



中文翻译:

催化不对称和立体发散寡核苷酸合成

我们报告了二核苷酸的催化立体控制合成。据我们所知,我们首次证明手性磷酸 (CPA) 催化剂在亚磷酰胺转移过程中控制立体磷中心的形成。还证明了前所未有的非对映发散水平,使得能够获得任一亚磷酸酯非对映异构体。两种不同的 CPA 支架已被证明对于实现立体发散至关重要:肽包埋的磷酸苏氨酸衍生的 CPA,它增强和放大了固有的底物偏好,以及 C2 对称 BINOL 衍生的 CPA,它完全颠覆了这种立体化学偏好。目前报道的催化方法不需要化学计量的活化剂或手性助剂,并且可以使用现成的亚磷酰胺进行不对称催化。

更新日期:2021-02-12
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