Synthesis of N,O-homonucleosides with high
conformational freedom
Giovanni Romeo, a,* Salvatore V. Giofré,a Anna Piperno, a Roberto Romeo,a
and Maria Assunta Chiacchiob
aDipartimento Farmaco-Chimico, Università di Messina, Viale SS.Annunziata, 98168, Messina, Italy
bDipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria,6, 95125, Catania, Italy
E-mail:
[email protected]
Dedicated to Prof Nicolò Vivona on his 70th birthday
Abstract
The 1,3-dipolar cycloaddition of vinyloxymethyl thymine with different nitrones has been exploited for the preparation of N,O-homonucleosides where the oxymethylene tether replaces the aminal linkage between the sugar moiety and the nucleobase
Keywords: Homonucleosides, 1,3-dipolar cycloaddition, nitrones, vinyloxymethyl thymine, antiviral agents
Introduction
During the past two decades, great strides have been made in the design of modified nucleoside drugs for the treatment of viral infections despite the stigma of toxicity and the development of drug resistance.1,2 In particular, isoxazolidine homonucleosides 3, synthesized by cycloaddition reaction between nitrones and allyl nucleobases in a diastereoselective or enantioselective way, have emerged as an important class of carbanucleoside analogues.3,4 The introduction of a carbon bridge between the nucleobase and the ribose unit or the isoxazolidine mimic leads to an increased resistance to hydrolytic or enzymatic cleavage and a more conformational flexibility and rotational freedom with respect to the natural nucleosides.5 Moreover, nucleoside mimics, characterized by higher flexibility, seem to be beneficial for the interaction with receptors; recently, it has been demonstrated that the binding sites of many enzymes are more flexible than previously thought and, as a direct consequence, more flexible inhibitors could show better features.6
