Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.
J Am Chem Soc
; 146(12): 8768-8779, 2024 03 27.
Article
in En
| MEDLINE
| ID: mdl-38483318
ABSTRACT
2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-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 IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.
Full text:
1
Database:
MEDLINE
Main subject:
Phosphines
/
Neuroblastoma
Limits:
Humans
Language:
En
Year:
2024
Type:
Article