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

Xintong TangYueer ZhouYingjie WangYetong LinShuheng PanQianwei CheJinpeng SangZiming GaoWeiting ZhangYuanyuan WangGuolong LiLongwei GaoZhimei WangXudong YangAo LiuSuyu WangBiao YuPeng XuZhe WangZhaolun ZhangPeng YangWeijia XieHaopeng SunWei Li
Published in: Journal of the American Chemical Society (2024)
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.
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