A Stereoelectronic Effect in Prebiotic Nucleotide Synthesis

A plausible route for the spontaneous synthesis of an activated ribonucleotide that is poised for polymerization has been put forth (Powner et al. (2009) Nature, 459, 239-242). A key step in this route necessitates the regioselective phosphorylation of the secondary alcohol on C-3', of an anhydroarabinonucleoside in the presence of the primary alcohol on C-5'. Here, we propose that this regioselectivity relies on electron delocalization between a lone pair (n) of O-5' and an antibonding orbital (pi*) of C-2=N-3. This n ->pi* interaction modulates reactivity without the use of a protecting group. Thus, a stereoelectronic effect could have opened a gateway to the RNA world, the chemical milieu from which the first forms of life are thought to have emerged on Earth some 4 billion years ago.