Medium-Controlled Intramolecular Catalysis in the Direct Synthesis of 5′-O-Protected Ribonucleoside 2′- and 3′-Dialkylphosphates

Reexamination of the Evidence for Solvent-Induced Intramolecular Electrophilic Catalysis by acis Vicinal Hydroxyl Group in Ribonucleoside Phosphorylation Reactions

“…Importantly the substrates with a free 2'-hydroxyl group showed much greater reactivity in the second stage, which is the alcoholysis of the intermediate chlorophosphates. [6] In our hands, when 5'-O-trityl uridine 1 was treated with excess POCl 3 in dichloromethane in the presence of pyridine the 1 H-decoupled 31 P NMR spectrum was closely similar to that reported by Roussev et al [3] Two resonance signals were observed at d 22.20 and d 21.00 in a ratio of approximately 60:40, apparently corresponding to the two resonances previously reported. Crucial to this rationalization was the identification of the intermediate as a mixture of the regioisomeric phosphorodichloridates 2 and 3.…”

“…This was rationalized in terms of the cis vicinal hydroxyl group hydrogen bonding to the PO group of the ribonucleoside phosphorodichloridate 2 or 3, thereby assisting the subsequent nucleophilic displacements of chlorine by electrophilic catalysis. [3] The downfield signal at d P 22.20 appeared as a doublet of doublets with J values of 3.5 and 12.4 Hz (Figure 1). This assignment was based on the 31 P NMR spectrum of the reaction mixture.…”

“…Early demonstration of a dramatically enhanced hydrolytic reactivity of RNA compared to DNA established a crucial mechanistic role for the 2'-hydroxyl group. Thus, the report by Roussev et al [3] of the electrophilic catalysis of displacement reactions at a neighboring phosphoryl center by the cis vicinal hydroxyl group, if it is correct, offers a potentially novel mechanism that could be of significance to ribozymes. The comparatively recent discovery of RNA catalysis (ribozymes) [2] has stimulated renewed interest in the potential role(s) of the 2'-hydroxyl group in an increasingly diverse range of reactions.…”

“…[1] Hitherto, it has been accepted that the major role of the 2'-hydroxyl group is nucleophilic catalysis and the 2',3'-cyclic phosphate intermediate is well established. [3] In the case of the ribonucleosides the two-stage sequence led to a mixture of the corresponding 2'-and 3'phosphate triesters (Scheme 1) while in the case of the 2'deoxyribonucleosides the 3'-phosphate triester was produced. Thus, the report by Roussev et al [3] of the electrophilic catalysis of displacement reactions at a neighboring phosphoryl center by the cis vicinal hydroxyl group, if it is correct, offers a potentially novel mechanism that could be of significance to ribozymes.…”

“…[3] In the case of the ribonucleosides the two-stage sequence led to a mixture of the corresponding 2'-and 3'phosphate triesters (Scheme 1) while in the case of the 2'deoxyribonucleosides the 3'-phosphate triester was produced. [3] In the case of the ribonucleosides the two-stage sequence led to a mixture of the corresponding 2'-and 3'phosphate triesters (Scheme 1) while in the case of the 2'deoxyribonucleosides the 3'-phosphate triester was produced.…”