Development of Asymmetric Sulfoxidation Catalysts Based on Functional Models for Vanadium-Dependent Haloperoxidases.

Abstract

Vanadium dependent haloperoxidases (VHPO) are a novel class of peroxidase enzymes that utilize H2O2 to perform the two electron oxidation of nucleophilic substrates. Two important questions remained regarding the mechanism of VHPO and its functional models: 1) the role of protonation in activation of the complex for oxidation and 2) the identity of the transition state. Density functional theory was used to identify seven energetically accessible protonation states of the established functional model, peroxo-oxovanadium(V)-N,N-hydroxyethyliminodiacetate ([VO(O2)Hheida]2-), with a hydroperoxo species being the most stable by 0.6-6.6 kcal/mol. The gas-phase calculations overestimate the energetic differences between protonation states. The small distribution of energies results in multiple protonation states being present in solution. X-ray absorption (XAS) and vibrational spectroscopy were employed to identify the protonated intermediates in solution. The intensity of the pre-edge transition of the XAS spectrum at 5470 eV does not change upon protonation of the complex. Accounting for the uncertainty, the quantity of a V-OH species present must be less 20% of the total protonated complex in solution. Isotope labeling and normal mode analysis were used to assign the C=O, V-O2, O-O, and V-O vibrational bands. FTIR and Raman spectroscopies show that upon protonation of [VO(O2)Hheida]- a shift occurs in the νC=O, νV-O2(asym), νO-O, and νv-O of 5, 9, 3 and 3cm-1, respectively. The vibrational spectroscopy is consistent with the calculated energetic differences, demonstrating that multiple protonated species exist. A linear SN2-like transition states (S-O-O=175°) were located for halide and sulfide oxidation for both an anionic peroxo species and a hydroperoxo species. The latter species lowers the barrier to activation by 9 kcal/mol. No transition states were located for oxo-transfer involving the V=O bond. Based on the transition state geometry, a chiral ligand was designed, synthesized, and structurally characterized as peroxo-oxovanadium(V)-N,N-norephedrinediacetate. This complex carries out asymmetric sulfoxidations with enantiomeric excess as high as 26%. The use of H2O2 as the terminal oxidant generates non-stereoselective diperoxovandates, which eliminates the enantioselectivity. These results demonstrate the potential for rational design of asymmetric catalysts through the use of modern computational methods and the important role of diperoxovandates as competitive oxidants in peroxo-vanadium catalysis.