Direct Synthesis of α- and β-2′-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation

作者：Xintong Tang, Yueer Zhou, Yingjie Wang, Yetong Lin, S. Pan, Qianwei Che, Jinpeng Sang, Ziming Gao, Weiting Zhang, Yuanyuan Wang, Guolong Li, Longwei Gao, Zhimei Wang, X H Yang, Ao Liu, Suyu Wang, Biao Yu, Peng Xu, Zhe Wang, Zhaolun Zhang, Peng Yang, Weijia Xie, Haopeng Sun, Wei Li · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c01780 · 被引用次数：20 · 研究领域：Carbohydrate Chemistry and Synthesis、HIV/AIDS drug development and treatment、Biochemical and Molecular Research

2′-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on β-2′-deoxynucleosides with the natural β-configuration. In fact, their isomeric α-2′-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and β-2′-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2′-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O -glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N -glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P -heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2′-deoxynucleoside with IC 50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its β-anomer exhibited no inhibition at 100 μM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.