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

Abstract

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.

Serendipitous Synthesis of 5-Hydroxyuridine from 2′,3′-O-Isopropylidene N4-Acetylcytidine by Hypervalent Iodine(III)-Mediated Reaction

“…Based on the experiments discussed above, we propose a possible reaction mechanism for the formation of cyclouridines 3 and 5 (Scheme 2). In line with the mechanistic proposal made by Suryavanshi and co-workers 15 for the formation of -acyloxyketones from benzylamine, the reaction between 1b and iodobenzene diacetate would generate an ammonium intermediate A, which would trigger the cyclization via an attack of the 5′-hydroxyl group at position C 6 to give the common intermediate B. In path a, intramolecular acetylation at position C 5 generates imine species C by removal of iodobenzene.…”

“…This is not surprising considering the numerous pyrimidine cyclonucleosides that have already been described. 5 Usually prepared by halogenation, dehalogenation or under radical conditions, 5 6 oxidative cyclization of cytidine via hypervalent iodine has, to our knowledge, never been reported. Hypervalent iodine chemistry has become increasingly important for the development of a wide range of organic reactions, 16 but its potential in aqueous media has yet to be fully exploited.…”

“…Such a change in the hybridization of C 5 and C 6 leads to several stereoisomers, and space correlations were used to discriminate between the different possibilities. The R configuration at C 6 would bring H 6 closer to H 1′ , H 2′ and H 3′ , but the corresponding correla-tions were not observed on the ROESY spectrum. Instead, H 6 and H 3′ showed correlation peaks, each engaging a different proton of the methylene (H 6 -H 5′ and H 3′ -H 5′′ ).…”

“…4 It is worth noting that, due to the presence of the 5′-diphosphate group, this proposed mechanism eliminates the possibility of the formation of an O6,5′-cyclouridine intermediate typically generated by anchimeric assistance of the 5′-hydroxyl function. 5,6 These authors also demonstrated that the corresponding 5bromopyrimidine nucleoside was not an intermediate in the reaction and that when performed on a cytidine analogue, deamination occurred to give 5-OHU as the major product, albeit in modest yield (34%). 7 The scope of enzymatic reactions known to modify cytosine by deamination, methylation or oxidation is such that researchers see cytosine as a genomic 'wild card' able to impact coding sequences and genetic expression.…”