Synthesis of 4′-thionucleosides by 1,3-dipolar cycloadditions of the simplest thiocarbonyl ylide with alkenes bearing electron-withdrawing groups

Abstract

Reactions of the simplest thiocarbonyl ylide with a variety of appropriate alkenes bearing electron-withdrawing substituents afforded the corresponding tetrahydrothiophenes, which could be easily elaborated into hydroxy and hydroxymethyl derivatives and then coupled with nucleobases to produce different 4′-thionucleosides. Particularly, α- and β-anomers of 1-[3,4-bis(hydroxymethyl)tetrahydro-2-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with dimethyl fumarate and maleate, while 1-[4-(hydroxymethyl)tetrahydro-2-thienyl]- and 1-[4-(hydroxymethyl)tetrahydro-3-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with a chiral α,β-unsaturated amide. These processes, simple in the experimental conditions and large availability of the starting materials, affording moderate to good yields of 4′-thionucleosides, represent an optimum alternative to those, already known, based on sugars, which often have the drawbacks of a higher number of steps and lower yields.