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, 6-12, 10.1002/aoc.2929
Several ruthenium and rhodium complexes including 2,2′‐dipyridylamine ligands substituted at the central N atom by an alkyl chain terminated by a maleimide functional group were tested along with a newly synthesized Rh(III) complex of unsubstituted 2,2′‐dipyridylamine as catalysts in the transfer hydrogenation of aryl ketones in neat water with formate as hydrogen donor. All of them except one led to the secondary alcohol products with conversion rates depending on the metal complex. Site‐specific anchoring of the N‐maleimide complexes to the single free cysteine residue of the cysteine endoproteinase papain endowed this protein with transfer hydrogenase properties towards 2,2,2‐trifluoroacetophenone. Quantitative conversions were reached with the Rh‐based biocatalysts, while modest enantioselectivities were obtained in certain reactional conditions.
Max TON: 96ee: 15PDB: ---Notes: ---
Artificial Metalloenzymes Containing an Organometallic Active SiteReview
Bioorganometallic Chemistry: Applications in Drug Discovery, Biocatalysis, and Imaging 2014, 305-338, 10.1002/9783527673438.ch10
Enzymes are the catalysts of the living world. Nature has tailored proteins to catalyze an incredibly wide range of reactions with exquisite selectivity and efficiency under very mild conditions of temperature, pH, pressure, and so on. Protein engineering combined with molecular modeling techniques affords tailor‐made biocatalysts for the industrial production of chiral synthons. Nonetheless, endowing a given protein scaffold with a totally new activity remains a challenging task for the biochemist. Among the current strategies to impart proteins with unnatural activity, those dealing with the construction of artificial metalloenzymes are particularly promising. By definition, artificial metalloenzymes are hybrid catalysts resulting from the incorporation of a transition metal species within a biomacromolecular scaffold. The rationale behind this concept is to combine the wide catalytic scope of transition metal complexes with the high activity and selectivity of biocatalysts. In most of the hybrid catalysts reported so far, the roles devoted to both partners are clearly separated: the metal complex being responsible for reactivity, while the protein environment is used to induce selectivity in the chemical process. In that, artificial metalloenzymes truly resemble enzymes whose efficiency relies on both the active site and the second sphere of coordination (also called the outer coordination sphere). In this chapter, we intend to give an overview of the various anchoring strategies reported over the last decade for the controlled, site‐selective attachment of nonnative metal cofactors within protein matrices together with the activity/selectivity displayed by these hybrid enzymes.
Notes: Book chapter
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, 5482-5489, 10.1039/c3dt53253d
Protein hybrids resulting from the supramolecular anchoring to bovine β-lactoglobulin of fatty acid-derived Rh(iii) diimine complexes catalysed the asymmetric transfer hydrogenation of trifluoroacetophenone with up to 32% ee.
Host protein: ß-lactoglobulinMax TON: 14ee: 32PDB: ---Notes: ---
Chemically Engineered Papain as Artificial Formate Dehydrogenase for NAD(P)H Regeneration
Org. Biomol. Chem. 2011, 9, 5720, 10.1039/c1ob05482a
Organometallic complexes of the general formula [(η6-arene)Ru(N⁁N)Cl]+ and [(η5-Cp*)Rh(N⁁N)Cl]+ where N⁁N is a 2,2′-dipyridylamine (DPA) derivative carrying a thiol-targeted maleimide group, 2,2′-bispyridyl (bpy), 1,10-phenanthroline (phen) or ethylenediamine (en) and arene is benzene, 2-chloro-N-[2-(phenyl)ethyl]acetamide or p-cymene were identified as catalysts for the stereoselective reduction of the enzyme cofactors NAD(P)+ into NAD(P)H with formate as a hydride donor. A thorough comparison of their effectiveness towards NAD+ (expressed as TOF) revealed that the RhIII complexes were much more potent catalysts than the RuII complexes. Within the RuII complex series, both the N⁁N and arene ligands forming the coordination sphere had a noticeable influence on the activity of the complexes. Covalent anchoring of the maleimide-functionalized RuII and RhIII complexes to the cysteine endoproteinase papain yielded hybrid metalloproteins, some of them displaying formate dehydrogenase activity with potentially interesting kinetic parameters.
Max TON: ---ee: ---PDB: ---Notes: TOF = 52.1 h-1 for NAD+
Enantioselective Transfer Hydrogenation of Ketone Catalysed by Artificial Metalloenzymes Derived from Bovine β-Lactoglobulin
Chem. Commun. 2012, 48, 11984, 10.1039/c2cc36980j
Artificial metalloproteins resulting from the embedding of half-sandwich Ru(II)/Rh(III) fatty acid derivatives within β-lactoglobulin catalysed the asymmetric transfer hydrogenation of trifluoroacetophenone with modest to good conversions and fair ee's.
Host protein: ß-lactoglobulinMax TON: 34ee: 26PDB: ---Notes: ---
Piano-Stool d(6)-Rhodium(III) Complexes of Chelating Pyridine-Based Ligands and their Papain Bioconjugates for the Catalysis of Transfer Hydrogenation of Aryl Ketones in Aqueous Medium
J. Mol. Catal. B: Enzym. 2015, 122, 314-322, 10.1016/j.molcatb.2015.10.007
Two half-sandwich d6-rhodium(III) complexes of the general formula [(η5-Cp*)Rh(N^N)Cl]Cl where N^N is a phenanthroline or a bispyridine methane derivative carrying a thiol-targeting maleimide or chloroacetamide function were synthesized and characterized. Both complexes were able to catalyse the transfer hydrogenation of 2,2,2-trifluoroacetophenone in aqueous medium using formate or phosphite as hydrogen donor. Covalent anchoring of these complexes to the cysteine endoproteinase papain yielded hybrid metalloproteins with transfer hydrogenase properties. Under optimized conditions of pH, hydrogen donor concentration and catalyst load, conversion of substrate was nearly quantitative within 24 h at 40 °C and the (S)-enantiomer was obtained preferably albeit with a modest enantiomeric excess of 7–10%. Covalent docking simulations complemented the experimental findings suggesting a molecular rationale for the observed low enantioselectivity. The harmonious use of experimental and theoretical approaches represents an unprecedented starting point for driving the rational design of artificial metalloenzymes built up from papain with higher catalytic efficiency.
Ligand type: Cp*; PhenanthrolineMax TON: 30ee: 9PDB: ---Notes: ---
Ligand type: Cp*; Di(2-pyridyl)Max TON: 20ee: 5PDB: ---Notes: ---
Proteins as Macromolecular Ligands for Metal-Catalysed Asymmetric Transfer Hydrogenation of Ketones in Aqueous Medium
Eur. J. Inorg. Chem. 2018, 2018, 1383-1393, 10.1002/ejic.201701359
Biohybrid catalysts resulting from the dative anchoring of half‐sandwich organometallic complexes [M(arene)(H2O)x(Cl)y]n+ (M = RuII, arene = η6‐benzene, p‐cymene or mesitylene; M = IrIII, RhIII, arene = η5‐Cp*; x = 1–3, y = 0–2, n = 0–2) to bovine beta‐lactoglobulin (βLG) or hen egg white lysozyme showed unprecedented behaviour. These constructs were shown to catalyse the asymmetric transfer hydrogenation of aryl ketones in water with sodium formate as hydrogen donor at a much faster rate than the complexes alone. Full conversion of the benchmark substrate 2,2,2‐trifluoroacetophenone was reached with an ee of 86 % for the most selective biohybrid. Surprisingly, even the crude biohybrid gave a good ee despite the presence of non‐protein‐bound metal species in the reaction medium. Other aryl ketones were reduced in the same way, and the highest ee was obtained for ortho‐substituted acetophenone derivatives. Furthermore, treatment of βLG with dimethyl pyrocarbonate resulted in a noticeable decrease of the activity and selectivity of the biohybrid, indicating that the sole accessible histidine residue (His146) was probably involved in the coordination and activation of Ru(benzene). This work underscores that protein scaffolds are efficient chiral ligands for asymmetric catalysis. The use of sodium formate instead of dihydrogen makes this approach safe, inexpensive and environmentally friendly.
Metal: RuLigand type: Benzene derivativesOptimization: ---Max TON: 43ee: 82PDB: ---Notes: ---
Ligand type: Cp*Optimization: ---Max TON: 16ee: 14PDB: ---Notes: ---
Metal: IrLigand type: Cp*Optimization: ---Max TON: 20ee: 16PDB: ---Notes: ---
Supramolecular Anchoring of NCN-Pincer Palladium Complexes into a β-Barrel Protein Host: Molecular-Docking and Reactivity Insights
Eur. J. Inorg. Chem. 2017, 2017, 3622-3634, 10.1002/ejic.201700365
Several prochiral NCN‐pincer complexes of palladium(II), with hemilabile ligands and a long aliphatic chain, were synthesized and characterized spectroscopically. In some of the complexes, the presence of two different substituents on the N donor atoms made them stereogenic, so that they were isolated as a mixture of diastereoisomers, which could be differentiated by 1H NMR spectroscopy. Binding of some of these complexes to bovine β‐lactoglobin by insertion within its inner cavity was theoretically investigated by molecular‐docking simulations and was experimentally confirmed by CD spectroscopy. Adjunction of H‐bond donor substituents on the ligand framework gave more‐stable supramolecular protein–complex assemblies. These constructs were shown to catalyze aldol condensation reactions in aqueous media, affording, in some cases, the less‐favorable cis product. Since the corresponding complexes exclusively gave the trans product in the absence of β‐lactoglobulin, this unusual diastereoselectivity was ensued by the second sphere of coordination brought by the protein host.
Metal: PdLigand type: NCN-Pincer (amines)Host protein: β-lactoglobulin (βLG)Reaction: Aldol condensationMax TON: 4.9ee: 0PDB: ---Notes: Aldol condensation of methyl isocyanoacetate and benzaldehyde (trans/cis = 38:62)
(η6-Arene) Ruthenium(II) Complexes and Metallo-Papain Hybrid as Lewis Acid Catalysts of Diels–Alder Reaction in Water
Dalton Trans. 2010, 39, 5605, 10.1039/c001630f
Covalent embedding of a (η6-arene) ruthenium(II) complex into the protein papain gives rise to a metalloenzyme displaying a catalytic efficiency for a Lewis acid-mediated catalysed Diels–Alder reaction enhanced by two orders of magnitude in water.
Metal: RuLigand type: Benzene; PhenanthrolineReaction: Diels-Alder reactionMax TON: 440ee: ---PDB: ---Notes: TOF = 220 h-1