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 I, 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)Cu2(μ-NO3)(NO3)](NO3)2 (1), [(L)Cu2(μ-CO3)(CH3OH)](BF4)2 (2),
and [(L)Cu2(μ-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,
kcat = 2 × 10-4 s-1 at 55 °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)Cu2(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
α-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)Cu3(μ3-OH)(μ-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.