Abstract
Numerous nucleoside analogs play an important role in acting as anti-viral, anti-tumor and nuclear imaging agents. However, there are a variety of new viruses and various mutants appear, which may results in resistance or inefficiency of anti-viral activity. In this study, as the starting material, uridine was derivatized to afford 4'-α/β-aminomethyl uridine analogs followed by coupling with various acids for construction of libraries via amide-bond formation. 2',3',5'-hydroxyl groups of uridine were first protected with TBDMSCl, followed by restoring 5'-OH group with HOAc. After oxidation with EDC, the aldehyde could be produced. Treatment with aqueous HCHO and NaOH and subsequent reduction with NaBH4, the 4'α-C-branched chain could be generated. Attempt to introduce azido group by nucleophilic substitution of the tosyl group was unsuccessful even under 110 oC. Whereas triflate proved to be an excellent leaving group, only cyclized product 2',4'-BNA was obtained when one free hydroxy moieties were reacted with lithium azide. This was confirmed by comparing with the reported NMR spectra, which showed only singlet for all the three protons (coupling constant was zero) on C1', C2' and C3'. Ditriflates could be prepared when two equivalents of triflic anhydride was used. Repeating the treatment with lithium azide, the desired azido groups could be introduced and no cyclized product was observed. The steric interference raised by the second trifluoromethan -sulfonyl group was proposed to account for the unfavorable nucleophilic attack of 6'-OTf on 2'-TBDMS. Removal of TBDMS group was easily achieved using TBAF, which was followed by transformation of the azido groups to the diamino groups under reduction conditions of hydrogen gas and Pd/C. As the target compound 4',4'-bis-aminomethyl uridine analog was in hand, further coupling with various carboxylic acids to provide the compound libraries through amide linkage are performable. Relevant biological assay studies to find out the potential compound are in progress.