Catalytic transesterification of dialkyl phosphates by a bioinspired dicopper(II) macrocyclic complex

For a number of phosphoryltransfer enzymes, including the exonuclease subunit of DNA polymerase 1, a mechanism involving two-metal ions and double Lewis-acid activation of the substrate, combined with leaving group stabilization, has been proposed. Inspired by the active site structure of this enzyme, we have designed as a synthetic phosphoryl transfer catalyst the dicopper(II) macrocyclic complex LCu2. Crystal structures of complexes [(L)Cu-2(mu-NO3)(NO3)](NO3)(2) (1), [(L)Cu-2(mu-CO3)(CH3OH)](BF4)(2) (2), and [(L)Cu-2(mu-O2P(OCH3)(2))(NO3)](NO3)(2) (3) illustrate various possibilities for the interaction of oxoanions with the dicopper(II) site. 1 efficiently promotes the transesterification of dimethyl phosphate (DMP) in CD3OD, k(cat) = 2 x 10(-4) s(-1) at 55 degrees C. 1 is the only available catalyst for the smooth transesterification of highly inert simple dialkyl phosphates. From photometric titrations and the pH dependence of reactivity, we conclude that a complex [(L)Cu-2(DMP)(OCH3)](2+) is the reactive species. Steric bulk at the -OR substituents of phosphodiester substrates O2P(OR)(2)(-) drastically reduces the reactivity of 1. This is explained with -OR leaving group stabilization by Cu coordination, an interaction which is sensitive to steric crowding at the alpha-C-atom of substituent R. A proposed reaction mechanism related to that of the exonuclease unit of DNA polymerase I is supported by DFT calculations on reaction intermediates. The complex [(L)Cu-3(mu(3)-OH)-(mu-CH3O)(2)(CH3CN)(2)](ClO4)(3) (4) incorporates a [Cu(OH)(OCH3)(2)(CH3CN)(2)]- complex anion, which might be considered as an analogue of the [PO2(OCH3)(2)(OCD3)](2-) transition state (or intermediate) of DMP transesterification catalyzed by LCu2.