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Intramolecular Michael Additions in Uridine Derivatives: Isolation of the Labile 5′O-C6 Cyclonucleoside

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posted on 16.09.2020 by Arnaud Gissot, Stéphane Massip, Philippe Barthélémy
Uridine derivatives undergo a diastereospecific intramolecular hetero Michael addition onto uracil C6 to give cyclo-adducts. In contrast to the potent amine and thiol nucleophiles at the 5′ position of ribose, which readily give the N- and S-cyclonucleosides in good yields, the cyclization reaction from the “natural” 5′-hydroxyl is tedious and has so far been overlooked most probably because of the thermodynamic instability of the O-cyclo-adduct. Here, we show that the O-cyclonucleoside 1 can be isolated, although in low isolated yields, in acidic conditions following an original mechanism. Whether such cyclization reactions occur from biologically relevant pyrimidine-based nucleosides is an open question of interest. Given the structures of thymidine-based antiviral drugs, our results suggest a new hypothetical mode of action for these drugs.