Solid-state and solution conformations of isotiazofurin: crystallographic, computational and 1H NMR studies

Isotiazofurin (C9H12N2O5S, NSC363223) is a thiazole nucleoside analogue of the antitumour agent tiazofurin. The conformation of this analogue has been studied using a variety of experimental and computational techniques. The crystal and molecular structure of isotiazofurin has been determined using single-crystal X-ray diffraction techniques and refined to a conventional R value of 0.030 for all data. Conformational features conserved in other thiazole nucleoside structures are also observed in the solid-state structure of isotiazofurin. The C-glycosidic torsion angle remains in the anti conformation and the carboxamide amino group remains cis-planar to the ring nitrogen. Ab initio calculations at the RHF/321G*@321G* level and natural bond orbital analysis of the results suggest that the carboxamide cis-planar conformation observed in the solid state is maintained in solution. However, semiempirical calculations suggest that a syn conformation about the C-glycosidic bond is energetically favored. This is supported by 1H nuclear Overhauser enhancement (NOE) studies. Analyses of NOE results using both slow- and rapid-exchange models indicate a preference for the syn conformation in solution. Thus, the anti conformation observed in the crystal structures of isotiazofurin is not maintained by isotiazofurin in solution.