Copper carbenes alkylate guanine chemoselectively through a substrate directed reaction

Cu(i) carbenes derived from α-diazocarbonyl compounds lead to selective alkylation of the O(6) position in guanine (O(6)-G) in mono- and oligonucleotides. Only purine-type lactam oxygens are targeted – other types of amides or lactams are poorly reactive under conditions that give smooth alkylation of guanine. Mechanistic studies point to N7G as a directing group that controls selectivity. Given the importance of O(6)-G adducts in biology and biotechnology we expect that Cu(i)-catalyzed O(6)-G alkylation will be a broadly used synthetic tool. While the propensity for transition metals to increase redox damage is well-appreciated, our results suggest that transition metals might also increase the vulnerability of nucleic acids to alkylation damage.