Chemical Synthesis of Heterocyclic-Sugar Nucleoside Analogues Giovanni Romeo,* ,† Ugo Chiacchio,* ,‡ Antonino Corsaro, ‡ and Pedro Merino* ,§ Dipartimento Farmaco-Chimico, Universita ` di Messina, Via SS Annunziata, 98168 Messina, Italy, Dipartimento di Scienze Chimiche, Universita ` di Catania, Viale Andrea Doria 6, 95125 Catania, Italy, and Laboratorio de Sintesis Asimetrica, Departamento de Quimica Organica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, CSIC, E-50009 Zaragoza, Aragon, Spain, Pedro Merino: pmerino@unizar.es Received September 5, 2008 Contents 1. Introduction 3337 2. Heterocyclic Nucleosides with One Heteroatom 3338 2.1. Pyrrolidinyl Nucleosides 3338 2.2. Thionucleosides 3345 3. Heterocyclic Nucleosides with Two Heteroatoms 3351 3.1. Dioxolanyl Nucleosides 3351 3.2. Dithiolanyl Nucleosides 3354 3.3. Oxathiolanyl Nucleosides 3355 3.4. Oxazolidinyl Nucleosides 3358 3.5. Thiazolidinyl Nucleosides 3359 3.6. Isoxazolidinyl Nucleosides 3360 3.7. Isoxazoline Nucleosides 3366 3.8. Pyrazolinyl Nucleosides 3367 4. Concluding Remarks 3367 5. Acknowledgments 3367 6. References 3367 1. Introduction A variety of nucleoside analogues have now been discov- ered which expand the antiviral and anticancer spectrum and/ or modify the pharmacological and/or pharmacokinetic properties of the parent compounds. 1 In terms of their structure nucleosides can be considered to be constituted by three key elements: (i) the hydroxymethyl group, which is necessary for the phosphorylation of the molecule by kinases in order to achieve biological activity, (ii) the heterocyclic base moiety, which is implied in the recognition process of the nucleoside through specific hydrogen bonds, and (iii) the furanose ring, which in several instances seems to act as a spacer presenting the hydroxymethyl group and the base in the correct orientation (Figure 1). A lot of structural modifications have been described, many of them having been successfully developed as therapeutic agents in medicine. 2 Indeed, several compounds modified in the sugar have been developed as antiviral agents. 3 Most of them have several common features. For instance, they do not have the 3′ hydroxyl group. An exception is fialuridine, which has that group but inhibits reverse transcription (it has a potent anti-HBV activity). Some variations of the base moiety are also present, and only variations on the substituents of the furanose ring were studied extensively; in this way substances like the well- known AZT or other 2′,3′-deoxynucleosides have appeared (Figure 2). 4 However, it has also been found that nucleoside analogues with modified substituents in the furanose ring have several disadvantages, including chemical instability and clinical toxicity. 5 With the aim of overcoming these drawbacks, several studies have been directed to analogues in which the furanose ring has been replaced by a different five-membered ring system including carbocycles. Pioneering examples of this new generation of compounds are carbovir, 6 lobucavir, 7 dioxolane T, 8 or lamivudine 9 (Figure 3). It is also worth noting, in the case of lamivudine, that if we consider the sulfur atom as an additional one within the furanose ring, lamivudine can be seen as a nucleoside of L-series. 10 Accordingly, both series of enantiomers in nucleo- side analogues synthesis should be taken into consideration. 11 The main theme of this section deals with the synthesis of nucleoside analogues in which the spacer is a heterocyclic system different from tetrahydrofuran, which are referred to as heterocyclic nucleosides 12 by analogy to carbocyclic nucleosides. The latter compounds are not considered, and the reader should refer to other reviews that have previously been reported. 13 * To whom correspondence should be addressed. E-mail: pmerino@ unizar.es. † Universita ` di Messina. ‡ Universita ` di Catania. § Universidad de Zaragoza. Giovanni Romeo was born in Giarre (CT), Italy. He received his Doctoral degree in Chemistry from the University of Messina. After a postdoctoral position at the University of Messina, he was appointed as Associate Professor of Chemistry at the Department Farmaco-Chimico of the University of Messina in 1982 and in 1990 was promoted to Full Professor of Organic Chemistry. He has held visiting positions at University Chemical Laboratory, Cambridge (U.K.), at the Department of Organic Chemistry of the University of Zaragoza (Spain), and at the Department of Chemistry University of Bergen (Norway). He is coauthor of more than 180 publications. His research interests focus on heterocyclic chemistry, asymmetric dipolar cycloaddition, and synthesis of bioactive heterocycles. Currently, his activity is focused on topics related to the synthesis of potential antiviral drugs and carrier models for their intracellular delivery. Chem. Rev. 2010, 110, 3337–3370 3337 10.1021/cr800464r  2010 American Chemical Society Published on Web 03/16/2010