Bio-hybrid catalysts in
asymmetric catalysis
Kasper van den Hurk
Van ’t Hoff Institute for Molecular Sciences
Supervisor: Joost N.H. Reek
Daily supervisor: Frédéric Terrade
Abstract
Bio-hybrid catalysts result from combining a catalytically active transition metal complex with a biomolecular host and lie at the interface between transition metal catalysis and biocatalysis. Until recently, transition metal catalysis and biocatalysis have developed in parallel as separate approaches towards achieving enantioselective transformations. The field of Bio-hybrid catalysis aims at
harnessing second coordination sphere interactions to create transition metal complexes that display enzyme-like activities and selectivities.
In this review, the design strategies and the catalytic scope of the reported bio-hybrid catalysts are discussed. Many examples of enantioselective catalysis with bio-hybrid catalysts have been reported, showing promising results. However, for all reactions reported to date, good alternatives using conventional approaches are available. The main advantage that bio-hybrid catalysts have is that they allow for asymmetric catalysis in water. In the long term, it is imperative that the field starts to address some of the challenges in enantioselective catalysis, for which there are no alternatives available in conventional methods.
Introduction
The catalytic activity and selectivity of conventional transition metal catalysts are almost exclusively controlled by the first coordination sphere provided by the ligands. The dominant strategy towards obtaining enantiomerically pure compounds involves forcing an incoming reagent to approach from one prochiral face of a substrate, by sterically blocking the other side. The growing insight in
organometallic chemistry and the development of optimisation techniques has provided us with very effective transition metal catalysts. However, transition metal catalysts remain inadequate for numerous chemical conversions for which high activity and selectivity cannot be reached. In contrast, enzymes often outperform synthetic catalysts by employing highly efficient second-sphere substrate interactions provided by the biomolecular scaffold, such as hydrogen bonding and hydrophobic interactions. The second coordination sphere of an enzyme is an important contributor to the activity and selectivity by recognising and positioning substrates and by stabilizing
intermediates. Enzymes are increasingly applied in synthetic processes and have proven to be very effective. Natural enzymes, however, evolved to catalyse very specific reactions with specific
substrates and their scope could not always be expanded to the desired conversions. It is not always possible to produce sufficient amount of enzyme to use them for synthesis purpose and they are not always stable outside of their original organism.
Until recently, transition metal catalysis and biocatalysis have developed in parallel as separate approaches towards achieving enantioselective transformations. Over the last decade, however, significant efforts have been made to merge the attractive properties of natural and synthetic catalysts by designing transition metal catalyst systems based on the building blocks of nature. This field seeks to create transition metal catalysts with an enzyme-like second coordination sphere for reactions not found in nature.
In this review, various bio-hybrid transition metal catalysts and their applications in asymmetric catalysis are highlighted and the role of the second coordination sphere in the activity and the
selectivity is discussed. There will be special attention for proteins acting as the biomolecular scaffold and supramolecular anchoring strategies. In addition, the potential of this field of research is
evaluated.
Biomolecular scaffold
Catalysis in nature relies primarily on proteins. Nevertheless, oligonucleotides may offer an attractive scaffold for the incorporation of catalytically competent organometallic moieties. The chemical compositions of RNA and DNA lack the functional groups needed for catalysis and instead fully depend upon a catalytically active moiety to act as a cofactor. Various functional ligands can be rationally incorporated into the matrices of nucleic acids and the phosphate backbone provides a source of chirality. This field was first explored by Roelfes et al. by introducing a [Cu(diimine)]2+
complex within double stranded salmon testes DNA.1)
The concept of DNA-based asymmetric catalysis has mainly found applications in enantioselective Lewis acid-catalysed C-C bond forming reactions, including Diels-Alder cycloaddition, Friedel-Crafts alkylation and Michael addition.2) High enantiomeric excess (ee) values (>80%) were reported for
these reactions using a 2,2’-bipyridine ligand, in which the DNA and metal binding is at the same position in the molecule, meaning that the substrates are in closer proximity of the DNA (Scheme 1). These and other approaches were reviewed by Roelfes and co-workers in 2010.2)
Scheme 1: Scope of DNA/Cu-dmbipy catalyzed C–C bond forming reactions.3)
Another, perhaps more obvious approach to combining transition metal catalysts with natural moieties is the incorporation of amino acids, for they constitute an easily accessible chiral pool. Furthermore, amino acids are the source of chirality in most chemical conversions performed by nature. After the modification of a diphosphane moiety with leucine by Hayashi et al. in 1982 to
obtain a chiral diphosphane ligand4), many examples of connecting ligands to small peptide
structures were reported.5)
Longer oligopeptide ligands were first synthesised by Gilbertson and co-workers.6) Various
phosphane-modified amino acids were introduced at different positions in synthetic oligopeptides containing β-turn and helical structures. Inspired by this work, several other groups have created phosphane-containing oligopeptides as ligands for various transition metal catalysed reactions.5)
The purest and most challenging form of mimicking enzymes is de novo design of the polypeptide scaffold from the 20 natural amino acids. This involves constructing a polypeptide sequence which is not directly related to any natural protein and folds precisely into a well-defined three-dimensional structure capable of binding a metal ion. In theory, this would allow all the structural features required for highly selective catalysis to be present from the start. α helical bundles were among the first de novo designed proteins, for they are known to be common scaffolds for heme containing proteins in nature.7) Unfortunately, our current knowledge of protein folding limits the number of de
novo designed polypeptides to only a few types.8) For this reason, the design of bio-hybrid catalyst
using proteins as the biomolecular scaffold has focused on native proteins.
When using a native protein, either an existing active site and/or binding pocket can be reengineered or a new active site can be created. Pioneering work in this field of research was reported by Wilson and Whitesides and makes use of an existing binding pocket in avidin.9) The binding pocket of the
protein must be large enough to accommodate both the transition metal catalyst and the substrates in order to be suitable for catalysis. Examples of proteins that have either been used or investigated include, apart from avidin and streptavidin, the oxygen transport protein Myoglobin10)11), bovine
serum albumin12) and papain13), a cysteine protease present in papaya. More recently, bovine
β-lactoglobulin was applied in this way.14)
Avidin and streptavidin are the most successful hosts for artificial metalloproteins used in catalysis to date. The strategy used to incorporate metals into the binding pocket is based on the exceptional affinity of the protein for biotin and biotinylated catalysts.15) This strategy will be discussed in more
detail later. The thermal stability, tolerance to high concentrations of organic solvents, well-defined structure and coordination site and the suitability for optimization techniques make avidin and streptavidin attractive candidates for the biomolecular scaffold.16)
Another Class of possible scaffolds consists of proteins like ferritin, containing a large vacant space that allows for the incorporation of unnatural metal cofactors.17) These proteins have proven to be
very useful in the selection of substrates based on their shape and size and have been successfully applied as a reactor for nanoparticles. The catalysis, however, did not yield any significant
enantioselectivity.
An alternative is creating an active site in a polypeptide that does not yet have a binding pocket. This method can be applied to a greater number of proteins, but it is less clear how the structure and stability will be affected, for it may disrupt some important intramolecular interactions. An example of this approach is the binding of a CuII ion in the peptide hormone bovine pancreatic polypeptide.18)
In a recent study, a protein dimer was used as the biomolecular scaffold. Protein dimerization is the result of a combination of intermolecular, mostly hydrophobic, interactions. The chirality of the
dimer interface, acting as the second coordination sphere, provides enantioselectivity while the hydrophobic nature facilitates the binding of the organic substrates and thus may improve the catalytic activity. Although the introduction of the transition metal catalyst into the scaffold may cause disruption of the structure and loss of dimerization affinity, a suitable dimeric protein was found and this might expand the number of scaffolds that can be used in catalysis.19)
Anchoring strategies
There are different strategies for the incorporation of the catalytic transition metal centres into the polypeptide scaffolds: dative, supramolecular and covalent anchoring (Figure 1).
Figure 1: Representation of the different anchoring strategies for biohybrid catalysts: (a) supramolecular, (b)
dative and (c) covalent. M denotes the catalytically active transition metal centre.3)
Dative anchoring involves direct coordination of the transition metal to the protein in existing cavities or on the outer sphere. Kaiser and co-workers were the first to modify the active site of an enzyme datively by substitution of zinc by copper in carboxypeptidase A, affording novel catalytic properties. More recently, zinc has been replaced by manganese20) and rhodium21) in the active site of carbonic
anhydrase (Figure 2).
Figure 2: Application of dative anchoring by replacing zinc atoms in carbonic anhydrase.5)
Since proteins can have multiple residues present which can act as a metal binding site (His, Asp, Glu, Lys, etc.), it can be difficult to create a well-defined transition metal centre in the catalyst. Site-directed mutagenesis and chemical modification can lead to more precise positioning of the transition metal in the protein. For example, Reetz et al. have been able to increase the
enantioselectivity of a copper-coordinated protein, by removing several native histidines, which could act as alternative copper binding sites.22)
The covalent anchoring approach involves the covalent incorporation of a transition metal complex via the ligand to a predetermined position in the target protein. Kaiser and co-workers were the first to create an artificial metalloprotein by covalent modification of an amino acid.23) Like in this seminal
report, a cysteine residue is often used as the anchoring site. Many different metal complexes have been incorporated using the same covalent attachment procedure.5) Disappointingly however, the
catalytic potential of the resulting artificial metalloproteins remains very modest and the optimization techniques are not straightforward.
The supramolecular approach makes use of the strong and highly specific non-covalent interactions between proteins and small molecules, like inhibitors. By exploiting the high affinity of an inhibitor for a protein, an organometallic moiety can be introduced within a protein environment, resulting in the formation of stable supramolecular complexes. The interaction between avidin and biotin is one of the strongest protein-substrate interactions known and it was used by Wilson and Whitesides to incorporate a rhodium-diphosphane complex into the protein.9) Moreover, this affinity is only
moderately affected by derivatization of the valeric acid side chain of biotin, which functions as a spacer to connect the chelating ligand (Figure 3).24)
Figure 3: Schematic representation of artificial metalloproteins based on biotin-(strept)avidin technology.25)
Whitesides’ work has inspired several groups to exploit the biotin-avidin system for the creation of artificial metalloproteins . A great advantage of this technology is that both the protein host and the transition metal catalyst can be optimized separately and joined together afterwards. This allows one to improve the performance of the catalyst either by varying the spacer and the ligand, or by
mutating the gene of the host protein.25) Ward and co-workers found that changing the host protein
to streptavidin, which has a less cationic character and a deeper binding pocket, but similar affinity to biotin, improved the performance of the catalyst drastically.26)
The variety of possibilities to modify the catalyst both chemically and biologically allows for profound testing of combinations of different biotinylated metal complexes with (strept)avidin proteins, which have been modified at strategic positions. At these positions saturation mutagenesis was applied, which means that all possible mutations at a specific site were generated. Many streptavidin
isoforms, resulting from saturation mutagenesis, were screened with a library of biotinylated ligands, either differing in the chelating bisphenylphosphino moiety or in the spacer.25) This so-called
chemogenetic approach resulted in successful improvement of the catalyst. The biotin binding site of streptavidin later proved to be large enough to accommodate small M=O containing coordination compounds, such as vanadyl salts.27)
Additional supramolecular anchoring strategies have been applied. The transport proteins serum albumin display the ability to bind a variety of hydrophobic guests tightly. The crystal structure of human serum albumin indicates that it is capable of storing five substrates using several hydrophobic cavities at a time.17) Different serum albumins have been tested as hosts for organometallic
moieties.28) Although the exact position of anchoring in the proteins was not elucidated with absolute
certainty in all cases, X-ray crystal structures showed that binding probably occurs in the IB
subdomain. Another example is myoglobin, which can include a metal complex or a modified heme instead of native heme in the active site. Myoglobin was successfully modified by the group of Watanabe to host chromium-salphen complexes.10)
Catalytic scope
From the early stage of development of artificial metalloproteins, catalytic enantioselective
hydrogenations have been extensively investigated. In the seminal report of Wilson and Whitesides, in which the biotin-(strept)avidin technology was introduced, the rhodium-catalysed reduction of acetamidoacrylic acid was reported.9) Only modest enantioselectivity was achieved (41% ee), but
optimization of the technology by Ward and co-workers resulted in >95% ee for this reaction and further chemogenetic improvements led to >95% ee for both enantiomers and a threefold rate increase.25) These so-called second generation hybrid catalysts showed improved tolerance towards
organic solvents.
De Vries and co-workers attached a rhodium complex covalently to papain for the same kind of hydrogenation reaction.13) This resulted in full conversion, but no enantiomeric discrimination. It was
suggested that papain is an unsuitable host for application in asymmetric catalysis due to its conformational flexibility.
The biotin-(strept)avidin concept has also been successfully applied in the enantioselective transfer hydrogenation of ketones by the group of Ward, using a biotinylated aminosulfonamide as a ligand for the ruthenium η6-arenes.29) Based on the X-ray crystal structure of the catalyst, optimizations by
designed evolution and mutagenesis were applied and excellent enantioselectivities were obtained for a broad range of substrates, including p-methylbenzophenone with 98% ee.30)
Artificial metalloproteins have also been successful in stereoselective sulfoxidation reactions, which are challenging with organometallic catalysis. Mn-salen complexes were incorporated into apo-Myoglobin by Watanabe and co-workers and 32% ee was obtained using H2O2 as oxidant.31) The
importance of conformational rigidity was once again shown by the group of Lu, who improved the enantioselectivity of the catalyst by applying a dual anchoring technique resulting in up to 51% ee.11)
Changing one of the attachment sites resulted in further increase of enantioselectivity to 60% ee.32)
Moreover, the relatively apolar nature of the active site does not favour binding of the formed sulfoxide and therefore overoxidation does not occur (Scheme 2).
Scheme 2: a) Enantioselective and chemoselective sulfoxidation reactions catalyzed by
apo-Myoglobin/Mn-salen. b) Schematic representation of the protein-bound metal complex.3)
Serum albumins are another class of hosts for sulfoxidation catalysts. Gross et al. incorporated iron and manganese corroles into various serum albumins and up to 74% ee was obtained with Mn-corrole catalysts and H2O2 as the oxidant.33) More recently, vanadyl-loaded streptavidin was used by
the group of Ward in asymmetric sulfoxidation reactions, with [VO(H2O)5]2+ ions believed to be bound
in the biotin binding pocket.27) The bio-hybrid catalyst displayed increased activity (and selectivity)
compared to the protein-free salt.
Carbonic anhydrases, in which the active site zinc was replaced by manganese, was used as a catalyst for epoxidation reactions by the group of Kazlauskas, leading to enantioselectivities up to 67% ee.20)
Recently, incorporation of manganese complexes into xylanase gave rise to 80% ee in the epoxidation of 4-methoxystyrene using KHSO5 as oxidant.34)
Most bio-hybrid catalysts for C-C bond forming reactions are based on DNA as the biomolecular scaffold. This has been extensively reviewed by Roelfes2) and will not be covered in this report. Using
both dative and supramolecular anchoring, Reetz and co-workers introduced a copper complex into bovine serum albumin, producing an enantioselective catalyst for the Diels-Alder cycloaddition of aza-chalcone with cyclopentadiene that gave rise to ee values up to 98%.28) The binding of a CuII ion
in the peptide hormone bovine pancreatic polypeptide resulted in a catalyst capable of asymmetric Diels-Alder and Michael additions.18)
Asymmetric alkylations have been achieved using the biotin-(strept)avidin system, using a
biotinylated palladium complex.35) This reaction has, in contrast to other reactions catalysed by
bio-hybrid catalysts, no equivalent in enzymatic catalysis. Using a chiral o-aminobenzoate spacer, up to 93% ee was achieved. The low to moderate ee values reported for the reaction in the absence of streptavidin, underlines the importance of the scaffold, although the ligand is chiral in this case. Recently, a biotinylated rhodium complex anchored to engineered streptavidin enabled asymmetric C-H activation, allowing for the coupling of benzamides and alkenes to access
dihydroisoquinolones.36) The bio-hybrid catalyst gave rise to ee values up to 86% and the reaction
Conclusion
In the past years, the field of bio-hybrid catalysis has been explored intensively, aiming to provide transition metal catalysis with enzyme-like properties and thus to increase activity and selectivity of synthetic homogeneous catalysts.
Many examples of enantioselective catalysis with bio-hybrid catalysts have been reported in which the biomolecular host is responsible for the induced chirality in the product. Especially the biotin-(strept)avidin concept and the DNA-based catalysts have been very successful in complementary reaction types, obtaining enantioselectivities of greater than 90% ee. For all the enantioselective reactions catalysed by bio-hybrid catalysts reported to date, good alternatives using conventional approaches are available in terms of enantioselectivity. The main advantage that bio-hybrid catalysts have is that they allow for asymmetric catalysis in water. Indeed, many of the reactions with ee values greater than 90% represent the best results that have been reported for asymmetric catalysis in aqueous solution (Roelfes, ChemCatChem 2010).
The rate of the reaction is also affected by the biomolecular scaffold. In some cases the reaction becomes slower (Watanabe Coord 2007, Reetz Angew 2006), but an increasing number of reported bio-hybrid catalysts show a positive effect of the host on the reaction rate (Lu Jacs 2004, Ward JACS 2008, Roelfes Angew 2009, Ward Angew 2008, Ward Science 2012). The rate increase in some cases is up to 2 orders of magnitude and most of them are substrate dependent, which is consistent with an enzyme active site that prefers binding of specific substrates over others.
This substrate selectivity is an important feature of biomolecules that bio-hybrid catalysts can benefit from. The second coordination sphere, provided by the biomolecular host, determines the chemical properties, such as the polarity of the microenvironment around the transition metal complex. In this way the host can attract specific substrates to the reactive site of the bio-hybrid catalyst, increasing the rate of the reaction, and exclude other molecules, increasing the chemoselectivity of the reaction. The accessibility of the catalytic centre for specific substrates indicates the importance of the second coordination sphere as a whole. Not only the direct surrounding of the transition metal complex, which is responsible for the enantioselectivity of the reaction and the stabilization of the intermediates, but the whole microenvironment around the transition metal is responsible for the outcome of a catalysed reaction.
Another attractive feature of the bio-hybrid catalysts is the possibility to optimize the catalyst in different ways. Chemical and biological optimization can be independently applied to the first coordination sphere (ligands) and the second coordination sphere (biomolecular host), respectively. Despite all the promising features of bio-hybrid catalysts, no new possibilities have been revealed to date. Although bio-hybrid catalysts showed slightly improved results for some reactions in aqueous solution, the high cost of their development will deter most synthetic chemists from using bio-hybrid catalysts in their reactions. Therefore, the field of bio-hybrid catalysis should concentrate on
improving our knowledge of complex catalytic systems. In the long term, however, it is imperative that the field starts to address some of the challenges in enantioselective catalysis, for which there are no alternatives available in conventional methods.
Future prospect
At this stage, the practical use of bio-hybrid catalysts is limited due to high cost of their development and the good alternatives that are available. Their general scope and the rapid optimization
techniques makes them attractive candidates for reactions that are not possible with biocatalysts or for challenging substrates for conventional homogeneous catalysis. The number of examples in which excellent enantioselectivities are combined with attractive influence of the second coordination sphere, such as rate acceleration and chemoselectivity, is increasing, as well as the number of possible biomolecular scaffolds and optimization techniques. However, there are important conditions for the development of successful bio-hybrid catalysts in the future.
The choice of the biomolecular host is a major challenge in the field. Important considerations are their chemical properties, such as the overall charge, pH and temperature stability and the tolerance to organic solvents. They should be readily available at reasonable costs and in large quantities. The rigidity of the structure is important for the enantioselectivity of the catalyst and they should be amenable to modification. They should have a structure that is large enough to accommodate the desired transition metal complex and the substrates, but the catalytic centre should be in close proximity to the biomolecular scaffold for efficient chirality transfer to take place.
The reactivity of the transition metal catalyst needs to be orthogonal to the biomolecular scaffold, that is, it should be inert to the chemical functionalities of the biomolecule. The structure of the transition metal complex and the chemistry used for its introduction should not adversely affect the stability and tertiary structure of the host protein.
The bio-hybrid catalyst should be straightforward to assemble and easy to handle. The
supramolecular approaches rely on self-assembly and therefore meet that requirement, but strong binding to the host or significant rate accelerations are necessary in order to prevent unbound catalyst from producing a racemic product and consequently lowering ee values.
Further research on the catalytic process is imperative. Currently, there is insufficient knowledge of the exact role that the second coordination sphere plays in introducing enantioselectivity to an achiral metal complex. In most cases, it cannot be elucidated with certainty if the enantioselectivity is the result of direct interactions of the substrates with the second coordination sphere. In some cases, the first coordination sphere, provided by the ligands of the transition metal complex, might as well be affected by the chiral environment of the biomolecular scaffold, thereby blocking one side of the prochiral substrate. Better understanding of the second coordination sphere interactions might allow for the design of catalytic systems capable of conversions that have no equivalent in
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