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

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.