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

2 '-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on beta-2 '-deoxynucleosides with the natural beta-configuration. In fact, their isomeric alpha-2 '-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both alpha- and beta-2 '-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare alpha-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 alpha-2 '-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its beta-anomer exhibited no inhibition at 100 mu M. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.