FULL PAPER DOI: 10.1002/ejoc.200900793 Synthesis of the First Selenium-Containing Acyclic Nucleosides and Anomeric Spironucleosides from Carbohydrate Precursors Susana Maza, [a] Óscar López, [a] Sergio Martos, [a] Inés Maya, [a] and José G. Fernández-Bolaños* [a] Keywords: Selenium / Carbohydrates / Spiro compounds / Nucleosides / Heterocycles We report the synthesis of acyclic and spiranic imidazole-de- rived C-selenonucleosides. 5-Hydroxy-4-tetrahydroxybutyl imidazolidine-2-selones, a novel class of acyclic selenonu- cleosides, were transformed into (tetrahydroxybutylimidazol- 2-yl)diselenide, by acetylation and chemoselective N-de- acetylation with methanolic imidazole. Furthermore, the syn- thesis of a new class of conformationally restricted arabino- configured spironucleosides containing an imidazolidine-2- Introduction Nucleoside analogues have proved to exhibit important pharmacological properties, especially as antiviral, [1] antitu- mor, [2] and antifungal agents. [3] Recent modifications of the nucleoside structure consist of the introduction of a sele- nium atom, an essential trace element, [4] either by replacing the endocyclic oxygen atom of the carbohydrate residue [5] or as part of the nucleobase. [6–8] The incorporation of 6- selenoguanosine [9] and 4-selenothymidine [10] into DNA to study nucleic acid base pairing by X-ray and for DNA visu- alization, respectively, has also been described. Further- more, a series of selenium-containing nucleosides and oligo- nucleotides have been used for convenient phasing of X-ray crystallographic data. [11–13] Some methylseleno nucleosides were found to inhibit prostatic cancer cells growth. [14] Sele- nium has not been found in DNA, although its presence in natural uridines from tRNAs has been documented. [15] Although the synthesis of acyclic nucleosides [1b,16] has generated much interest due to their potent biological ac- tivities, no selenium-containing acyclic nucleosides have been reported up to now. The chemistry of organoselenium compounds has been developed to a significant small extent because of the intrinsic instability [17] of some of these com- pounds. We have devoted our efforts in developing strate- gies to reach, from carbohydrates, stable and versatile or- ganoselenium templates. [18] In this communication we have [a] Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, 41071 Seville, Spain Fax: +34-95-4624960 E-mail: bolanos@us.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.200900793. Eur. J. Org. Chem. 2009, 5239–5246 © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5239 selone unit around the glycosidic bond was achieved, start- ing from N-fructosamines, via 4-hydroxy-4-tetrahydoxy- butyl-imidazolidine-2-selones as the key intermediates. Acetylation–deacetylation of these intermediates gave access to stable aromatic imidazoline-2-selones. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) explored the access to chiral 2-seleno-1,3-N-heterocyclic templates, an attractive challenge from both synthetic and biological points of view. Results and Discussion Reaction of phenyl isoselenocyanate [18] with -glucosa- mine hydrochloride in aqueous ethanol in the presence of NaHCO 3 afforded 5-hydroxy-4-polyhydroxyalkylimid- azolidine-2-selone 3 in a high yield of 99 % after column chromatography (Scheme 1). This reaction must be carried out in the dark, as many selenium-containing compounds undergo UV-induced decomposition. [19] The reaction might proceed via nondetected selenourea 2, which could undergo spontaneous cyclization through the carbonyl group of the open chain form to give imid- azolidine-2-selone by a 5-exo-trig cyclization, according to Baldwin’s [20] rules. NMR spectroscopic data showed 3 to exist as a nonresolved mixture of 5R/5S diastereoisomers, in a 90:10 ratio, measured by 1 H NMR spectroscopy. The assignment of the 5R configuration for the major dia- stereoisomer was based on the J 4,5 coupling constant (3.1 Hz), indicating that both protons are in a trans ar- rangement, whereas for the 5S derivatives the J value was 7.4 Hz, with 4-H and 5-H in a cis relationship. Acid-catalyzed dehydration of 3 with AcOH in a re- fluxing EtOH/water mixture afforded bicyclic glucofuran- osoimidazolidine-2-selone 4 in 89 % yield (Scheme 1). The synthesis of 4 was previously reported, [21] but without the isolation of parent selone 3. Attempts to convert bicyclic derivative 4 into corresponding aromatic imidazoline-2- selone 5 by dehydration under strong acid conditions were