Sorbonne Université, France
Artificial Metalloenzymes Design for Asymmetric Catalysis in Aqueous Media
Artificial metalloenzymes are hybrid species resulting from the controlled assembling of synthetic metal cofactors to biomolecular scaffolds such as peptides, proteins or DNA. In this way, reactivity is provided by the metal centre and its immediate environment, i.e. the first coordination sphere, while selectivity is imparted by the biopolymer scaffold providing the second coordination sphere. Incorporation of metal ions / complexes into native protein scaffolds is typically carried out following covalent, supramolecular or dative anchoring strategies with variable success in terms of reactivity and selectivity .
During the last six years, we concentrated our efforts in the design of artificial metalloenzymes to catalyse asymmetric transfer hydrogenation reactions in aqueous medium. To this aim, we focussed on two protein scaffolds, namely papain and bovine -lactoglobulin (figure 1) on which we successively applied the three assembling strategies mentioned above.
A large range of half-sandwich ruthenium(II)- and rhodium(III) cofactors were designed, synthesized and their catalytic activity assessed on a benchmark reaction. Then these cofactors assembled to the selected protein hosts . The resulting hybrid metalloproteins were fully characterized by a range of appropriate analytical techniques, including X-ray crystallography . Eventually, the catalytic activity of the metalloprotein hybrids was investigated on the ATH of various aryl ketones. The most effective construct afforded full conversion and enantiomeric excess up to 95% .
 Schwizer, F.; Okamoto, Y.; Heinisch, T.; Gu, Y.; Pellizzoni, M. M.; Lebrun, V.; Reuter, R.; Kohler, V.; Lewis, J. C.; Ward, T. R., Artificial Metalloenzymes: Reaction Scope and Optimization Strategies. Chem. Rev. 2017, 118 (1), 142-231.
 Chevalley, A.; Salmain, M., Enantioselective transfer hydrogenation of ketone catalysed by artificial metalloenzymes derived from bovine b-lactoglobulin. Chem. Commun. 2012, 48, 11984-11986; Chevalley, A.; Cherrier, M. V.; Fontecilla-Camps, J. C.; Ghasemi, M.; Salmain, M., Artificial metalloenzymes derived from bovine β-lactoglobulin for the asymmetric transfer hydrogenation of an aryl ketone – synthesis, characterization and catalytic activity. Dalton Trans. 2014, 43 (14), 5482 – 5489; Madern, N.; Talbi, B.; Salmain, M., Aqueous phase transfer hydrogenation of aryl ketones catalysed by achiral ruthenium(II) and rhodium(III) complexes and their papain conjugates. Appl. Organomet. Chem. 2013, 27 (1), 6-12; Cázares-Marinero, J. d. J.; Przybylski, C.; Salmain, M., Hybrid biocatalysts from the dative assembling of half-sandwich RuII, RhIII or IrIII complexes with bovine β-lactoglobulin (βLG): Application to the asymmetric transfer hydrogenation of ketones in water. Eur. J. Inorg. Chem. 2018, 1383-1393.
 Cherrier, M. V.; Engilberge, S.; Amara, P.; Chevalley, A.; Salmain, M.; Fontecilla-Camps, J. C., Structural basis for enantioselectivity in the transfer hydrogenation of a ketone catalyzed by an artificial metalloenzyme. Eur. J. Inorg. Chem. 2013, (21), 3596-3600 ; Cherrier, M. V.; Amara, P.; Talbi, B.; Salmain, M.; Fontecilla-Camps, J. C., Crystallographic evidence for unexpected selective tyrosine hydroxylations in an areated Ru-papain conjugate. Submitted to Metallomics.
 Vologdin, N.; Mangiatordi, G.; Pocquet, L.; Thorimbert, S. Salmain, M. Manuscript under preparation