The Journal of Organic Chemistry ARTICLE Scheme 7. Transformation of Azomycin Nucleoside α-15 into Precursor α-7 Scheme 10. Conversion of Tribenzoate α-20 to the Silylated Diacetate α-18 Scheme 8. Preparation of 3,5-O,O-(1,1,3,3-Tetra- isopropyldisiloxanylidene)-Protected D-Riboses 24 and Their Coupling with NI-TES by the Vorbru€ggen Method Scheme 9. Preparation of Putative Precursors α- and β-27 obtained by debenzoylation of D-ribose derivative β-20.21d,27 The hydroxyl groups at C-50 and C-30 were protected with the 30,50-O,O-(1,1,3,3-tetraisopropyldisiloxanylidene) group, and the conﬁguration of the free hydroxyl at C-20 was inverted by substituting the triﬂate with tetrabutylammonium acetate.27 Then the disiloxanylidene group was removed, and the diol was monotosylated and acetylated to give β-7. We thought that we could shorten the lengthy synthesis by starting from a β-D- ribose derivative already containing the disiloxanylidene group (Scheme 8). Thus, D-ribose was silylated and acetylated in a one- pot reaction in the same way as the TBDPS-protected analogue 17 was prepared. The crude anomeric mixture containing impurities (47% yield) of α- and β-24 (74:19) was coupled with NI-TES in CH3CN with 1 equiv of TfOTES at 0 C for 45 min to give separable nucleosides (β-25, 30%; α-25, 32%). Unfortu- nately, lowering the reaction temperature to 10 C favored the α-anomer even more (β-25, 16%; α-25, 32%). However, the yield of the desired β-anomer was too low to pursue this approach any further. The putative precursor derived from β- D-ribose was accessed from silyl-protected β-18 (Scheme 9). It was selectively deblocked at C-50 and tosylated to furnish precursor β-27. Analogously, the α-anomer was prepared from α-18, which was either directly accessible by coupling by the Vorbr€uggen method or accessible from tribenzoate α-20 (Scheme 10). Transesteriﬁcation with MeOH/MeONa gave triol nucleoside α-28 in an admixture with an unknown impurity, possibly of structure 29, already reported19 by Prisbe et al. The two compounds could not be separated by ﬂash chromatography, but easily after monosilylation with TBDPSCl. The silylated diol α-30 formed was acetylated to give nucleoside α-18. The seemingly obvious direct conversion of α-28 to the precursor α-27 by monotosylation followed by acetylation did not work as tosylation could not be conducted selectively, but produced a ditosylate preferentially. ’ CONCLUSIONS Our results unambiguously establish that 1-O-acetyl-D-pen- toses and D-galactose pentaacetate and triethylsilylated 2-nitro- imidazole can be coupled in acetonitrile using TESOTf (Vorbr€uggen method) to give 2-nitroimidazole nucleosides. The anomeric ratio of the products is delicately inﬂuenced by the substrate structure and the reaction temperature. This approach is an attractive alternative to protocols based on excess Hg(CN)2 alone or in combination with SnCl4 for coupling. 50-O- TBDPS nucleosides can be desilylated and tosylated easily to furnish precursors for tracers to image hypoxia. 8162 dx.doi.org/10.1021/jo200727k |J. Org. Chem. 2011, 76, 8159–8167