Modular Combination of Enzymatic Halogenation of Tryptophan with Suzuki-Miyaura Cross-Coupling Reactions

Article abstract of DOI:10.1002/cctc.201600317

The combination of the biocatalytic halogenation of l-tryptophan with subsequent chemocatalytic Suzuki-Miyaura cross-coupling reactions leads to the modular synthesis of an array of C5, C6, or C7 aryl-substituted tryptophan derivatives. In a three-step one-pot reaction, the bromo substituent is initially incorporated regioselectively by immobilized tryptophan 5-, 6-, or 7-halogenases, respectively, with concomitant cofactor regeneration. The halogenation proceeds in aqueous media at room temperature in the presence of NaBr and O₂. After the separation of the biocatalyst by filtration, a Pd catalyst, base, and boronic acid are added to the aryl halide formed in situ to effect direct Suzuki-Miyaura cross-coupling reactions followed by tert-butoxycarbonyl (Boc) protection. After a single purification step, different Boc-protected aryl tryptophan derivatives are obtained that can, for example, be used for peptide or peptidomimetic synthesis. Putting the pieces together: By combining the enzymatic halogenation of l-tryptophan using flavin adenine dinucleotide dependent halogenases with Pd-catalyzed Suzuki-Miyaura cross-coupling reactions in water, the C5-, C6-, or C7-position of the indole ring can be brominated regioselectively in situ and functionalized chemocatalytically in a stepwise one-pot reaction.

Full text of DOI:10.1002/cctc.201600317

DOI: 10.1002/cctc.201600317
Full Papers
Modular Combination of Enzymatic Halogenation of
Tryptophan with Suzuki–Miyaura Cross-Coupling Reactions
Marcel Frese, Christian Schnepel, Hannah Minges, Hauke Voß, Rebecca Feiner, and
Norbert Sewald*[a]
The combination of the biocatalytic halogenation of l-trypto-
phan with subsequent chemocatalytic Suzuki–Miyaura cross-
coupling reactions leads to the modular synthesis of an array
of C5, C6, or C7 aryl-substituted tryptophan derivatives. In
a three-step one-pot reaction, the bromo substituent is initially
incorporated regioselectively by immobilized tryptophan 5-, 6-,
or 7-halogenases, respectively, with concomitant cofactor re-
generation. The halogenation proceeds in aqueous media at
room temperature in the presence of NaBr and O2. After the
separation of the biocatalyst by filtration, a Pd catalyst, base,
and boronic acid are added to the aryl halide formed in situ to
effect direct Suzuki–Miyaura cross-coupling reactions followed
by tert-butoxycarbonyl (Boc) protection. After a single purifica-
tion step, different Boc-protected aryl tryptophan derivatives
are obtained that can, for example, be used for peptide or
peptidomimetic synthesis.
Introduction
Biocatalysis has emerged as an important research area in or-
ganic synthesis both in academia and industry.[1] The high
stereo- and regioselectivity of enzyme-catalyzed reactions and
their compatibility with many unprotected functional groups
are major advantages. However, there are several important
chemical transformations, such as cross-coupling reactions, for
which no enzymatic processes are known, so the use of bioca-
talysis together with chemocatalysis combines the advantages
of both areas.[2] In particular, multistep one-pot reactions offer
the unique opportunity to circumvent time-consuming, waste-
producing, and solvent-intensive work-up and purification
steps of intermediates, which leads to more sustainable and
economic synthetic routes.[3] A handful of combined chemo-
biocatalytic reactions has been described since the 1980s. The
major bottleneck of these processes is the mandatory compati-
bility of the chemo- and biocatalyst to solvent and reaction
conditions. As few enzymes are stable and active in organic
solvents, the combination of biocatalysis and chemocatalysis in
a multistep one-pot reaction should proceed in aqueous
media, as water provides the potential to combine a huge
toolbox of different enzymes with several chemocatalysts. In
addition, water shows outstanding benefits as a nonflammable,
environmentally friendly, non-toxic, low-cost solvent.
Grçger and co-workers, pioneers in the field of chemoenzy-
matic catalysis, published several reactions that combine both
types of catalysis in an aqueous medium. This includes the
combination of an asymmetric organocatalytic aldol reaction
with the subsequent enzymatic reduction of the ketone to
chiral 1,3-diols.[4,5] The Wacker–Tsuji oxidation of styrene fol-
lowed by enzymatic ketone reduction gives enantiomerically
pure secondary alcohols,[6] and olefin metathesis together with
pig liver esterase hydrolysis provides access to cyclic malonic
acid monoesters in aqueous media.[7]
In this context, the regioselective introduction of halogen
substituents into organic scaffolds using enzymatic approaches
would be a highly beneficial approach to be combined with
further metal-catalyzed modification. Halogenated products
form important intermediates in the synthesis of fine chemicals
as they can be modified easily in established procedures. In
recent years, Pd-catalyzed cross-coupling reactions have
emerged as an outstanding methodology for the formation of
CÀC bonds, especially for large scaffolds. Grçger and co-work-
ers have already shown the combination of Pd-catalyzed cross-
coupling reactions with the enzymatic asymmetric reduction of
ketones.[8,9]
The chemical incorporation of the halide substituent re-
quires corrosive and hazardous chemicals such as Cl2 or Br2
under harsh conditions and often results in product mixtures
because of ambiguous regioselectivity. In contrast to chemical
methods, biocatalytic halogenation using flavin adenine dinu-
cleotide (FAD) dependent halogenases emerged as a promising
and sustainable approach to obtain aryl halides.[10,11] These en-
zymes introduce halogen substituents even at electronically
unfavored positions of the indole ring and only require benign
halide salts such as NaCl or NaBr and oxygen for the regiose-
lective halogenation.[12–16] The first members of this class of en-
zymes that have been characterized in detail are the trypto-
[a] Dr. M. Frese, C. Schnepel, H. Minges, H. Voß, R. Feiner, Prof. Dr. N. Sewald
Organische und Bioorganische Chemie, Fakultät für Chemie
Universität Bielefeld
Universitätsstr. 25
33615 Bielefeld (Germany)
E-mail: norbert.sewald@uni-bielefeld.de
Homepage: http://www.uni-bielefeld.de/chemie/oc3sewald/
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under http://dx.doi.org/10.1002/
cctc.201600317.
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phan 7-halogenase PrnA, which originates from the pyrrolnitrin
biosynthesis in Pseudomonas fluorescens,[10] and RebH from the
bacterium Lechevalieria aerocolonigenes, involved in rebecca-
mycin biosynthesis.[11] By introducing the prnA gene into the
biosynthesis pathway of the uridyl peptide antibiotic pacida-
mycin, the resulting chlorinated indole moiety serves as
a chemical handle for the post-biosynthetic modification to-
wards several new analogs.[17] Likewise, rebH was integrated
into the medicinal plant Catharanthus roseus in the biosynthe-
sis of monoterpene indole alkaloids followed by chemical deri-
vatization of the extracted chlorinated compounds using Pd-
catalyzed Suzuki–Miyaura cross-coupling reactions.[18] As these
secondary metabolites were only formed in minor amounts,
the reactions could not be performed on a preparative scale.
Only recently, Suzuki–Miyaura cross-couplings performed sub-
sequently to the enzymatic halogenation of tryptoline deriva-
tives were communicated.[19]
genase supplemented with flavin reductase PrnF and alcohol
dehydrogenase ADH from Rhodococcus sp. was precipitated by
the addition of ammonium sulfate. After subsequent cross-link-
ing with glutaraldehyde, an active and solid biocatalyst was
obtained for halogenation.
With the optimized cross-linking conditions for combiCLEA
generation, the quantitative halogenation of 150 mg l-trypto-
phan (1 mm, 750 mL) could be obtained in both cases for PyrH
and Thal (Figure S1), which showed conversions similar to
RebH. By using these three Trp-halogenases, the C5-, C6-, or
C7-position can be addressed regioselectively for bromination.
For the subsequent Suzuki–Miyaura cross-coupling, we start-
ed the optimization using purified l-7-bromotryptophan and
phenylboronic acid starting materials. Inspired by the approach
of the Goss group who cross-coupled halotryptophans synthe-
sized from halogenated indoles using tryptophan synthase,[21]
we chose Na2PdCl4 as a Pd source in combination with the
Buchwald ligand SPhos. This system is known to catalyze chal-
lenging substrate combinations with excellent results even at
low temperatures.[18b,19,22,23] Reactions that contained 5 mol%
of Pd and 1.1 equivalents of phenylboronic acid in the pres-
ence of 5 equivalents of K2CO3 resulted in a conversion of only
50% within 3 h at 958C (Table 1, Entry 1). By increasing the
amount of boronic acid to 3 equivalents, the conversion in-
creased to 80% (Table 1, Entry 2). As SPhos is barely soluble in
water, a mixture of water and n-butanol was used.[18b] By re-
placing the solvent system with water/dioxane/toluene, the
aryl halide could be converted completely into the cross-cou-
pling product (Table 1, Entry 3). For the adaptation of these
conditions to the one-pot cross-coupling of in situ formed
l-7-bromotryptophan, the biocatalytic bromination was con-
ducted as described previously using RebH combiCLEAs.[20]
Once halogenation had reached quantitative substrate conver-
sion, the immobilized biocatalyst was removed by filtration.
Phenylboronic acid, base, and Pd catalyst were added to the
solution, which was then heated to 958C for direct Suzuki–
Miyaura cross-coupling without any further purification of in-
termediates. As the enzymatic halogenation was performed in
a phosphate-buffered system, the amount of base needed to
be increased to 25 equivalents to obtain a pH value of nearly
11. Unfortunately, if we used the conditions optimized for the
purified aryl halide, the conversion decreased to 51% for the
Results and Discussion
We established an efficient methodology for the regioselective
enzymatic bromination of l-tryptophan and its derivatives
even on a multigram scale using the immobilized Trp 7-halo-
genase RebH.[20] Precipitation and cross-linking of RebH in the
presence of all auxiliary enzymes necessary for concomitant co-
factor regeneration gives so-called combiCLEAs that brominate
l-tryptophan with full conversion at substrate concentrations
of 200 mgLÀ1. As this biocatalytic halogenation is highly regio-
selective without the formation of any side products, the
crude product is sufficiently pure for further modification
(Figure S1).
Consequently, we embarked on the subsequent modification
of the biocatalytically introduced halogen by in situ Suzuki–
Miyaura cross-coupling reactions without any purification steps
of intermediates in a sequential two-step one-pot process
(Figure 1).
To derivatize different positions of the indole moiety inde-
pendently and selectively, the tryptophan 5-halogenase PyrH
and the 6-halogenase Thal were tested for their ability to bro-
minate tryptophan regioselectively on a preparative scale
using the CLEA methodology as described previously for
RebH.[20] E. coli lysate that contained the overexpressed halo-
Figure 1. Chemoenzymatic synthesis of Boc-protected aryl tryptophan derivatives.
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Table 1. Optimization of the Suzuki–Miyaura cross-coupling of 1 mm l-7-bromotryptophan with phenylboronic acid.
Entry
Pd catalyst
[5 mol %]
Ligand
[15 mol%]
Solvent
Boronic acid
[equiv.]
Base
[equiv.]
T
[8C]
Conversion[d]
[%]
t
[h]
1[a]
Na2PdCl4
Na2PdCl4
Na2PdCl4
Na2PdCl4
Na2PdCl4
Na2PdCl4
Na2PdCl4
Na2PdCl4
SPhos
SPhos
SPhos
SPhos
SPhos
sSPhos
sSPhos
sSPhos
water/nBuOH 3:1
water/nBuOH 3:1
water/dioxane/toluene 10:2:1
water/dioxane/toluene 10:2:1
water/dioxane/toluene 10:2:1
water
R=H (1.1)
R=H (3)
R=H (3)
R=H (3)
R=H (5)
R=H (5)
R=H (5)
R=OCH3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (25)
K3PO4 (25)
K3PO4 (25)
K3PO4 (25)
K3PO4 (25)
95
95
95
95
95
95
95
95
50
80
99
51
53
85
99 (94)[e]
99 (78)[e]
3
3
1
3
3
3
3
3
2[a]
3[a]
4[b]
5[b]
6[b]
7[b,c]
8[b,c]
water
water
General conditions: 5 mmol scale in Eppendorf tubes by using a thermoshaker. [a] Purified product was used. [b] 1 mm l-7-Bromotryptophan that originat-
ed from the CLEA halogenation was used. [c] 0.1 mmol scale, performed under Ar atmosphere. All solutions were degassed using ultrasound with Ar sparg-
ing. The Na2PdCl4 was preactivated together with sSPhos for 10 min at 428C and added to the hot reaction solution. [d] Calculation based on RP-HPLC.
[e] Isolated yield after preparative HPLC.
crude aryl halide that originates from the CLEA halogenation
Table 2. Substrate scope of the three-step one-pot synthesis.
(Table 1, Entry 4). Variation of the base (K2CO3 vs. K3PO4) in ac-
cordance with the phosphate buffer used for RebH halogena-
tion only resulted in a slight increase to 53% conversion
(Table 1, Entry 5). The low water solubility of the SPhos ligand
clearly impeded conversion, which led to lower yields in the
crude CLEA filtrate. Consequently, we changed the ligand to
the sulfonated water-soluble variant sSPhos, and a significantly
higher conversion of 85% could be observed (Table 1, Entry 6).
Further optimization under Ar atmosphere led to a quantitative
conversion of l-7-bromotryptophan with 5 equivalents of phe-
nylboronic acid or 4-methoxyphenylboronic acid, respectively,
on a 0.1 mmol scale in good yields (Table 1, Entries 7–8).
Entry Aryl halide[a] Boronic acid[b] Product[a]
Yield[c] [%]
1
2
3
7-BrÀW
6-BrÀW
5-BrÀW
BocÀ7-PhÀW
BocÀ6-PhÀW
BocÀ5-PhÀW
94
75
32
PhÀR
4
5
6
7-BrÀW
6-BrÀW
5-BrÀW
BocÀ7-(4-CH3OÀPh)ÀW 74
4-CH3OÀPhÀR BocÀ6-(4-CH3OÀPh)ÀW 57
BocÀ5-(4-CH3OÀPh)ÀW 54
7
8
9
7-BrÀW
6-BrÀW
5-BrÀW
BocÀ7-(4-CF3ÀPh)ÀW
BocÀ6-(4-CF3ÀPh)ÀW
BocÀ5-(4-CF3ÀPh)ÀW
66
44
23
4-CF3ÀPhÀR
2-FurylÀR
Remarkably, the unprotected zwitterionic cross-coupling
products can be extracted into the organic phase to facilitate
purification. These findings clearly emphasize the benefits of
the presented one-pot reaction cascade to a prevalent sequen-
tial stepwise reaction in which the bromotryptophans need to
be isolated from the aqueous phase, which contains large
amounts of salts such as NaBr and Na2HPO4 from the biocata-
lytic halogenation.[20] As a result of this modular approach,
each of the C5, C6, or C7 l-bromotryptophan derivatives could
be coupled successfully to six different boronic acids, followed
by Na-tert-butoxycarbonyl (Boc) protection as a third step in
the one-pot reaction (Figure 1). This offers the direct applica-
tion of each synthesized amino acid for further reactions, for
example, in peptide synthesis. For this protection step, the pH
value of the reaction solution after the cross-coupling was re-
adjusted to pH 11, Boc-anhydride (4 equivalents) was added
portionwise, and the mixture was stirred overnight at room
temperature. After acidification, the product was extracted and
purified by using preparative reversed-phase (RP) HPLC. With
l-7-bromotryptophan as the aryl halide, isolated yields up to
10
11
12
7-BrÀW
6-BrÀW
5-BrÀW
BocÀ7-(2’-Furyl)ÀW
BocÀ6-(2’-Furyl)ÀW
BocÀ5-(2’-Furyl)ÀW
69
63
46
13
14
15
7-BrÀW
6-BrÀW
5-BrÀW
BocÀ7-(4-CO2HÀPh)ÀW 87
4-CO2HÀPhÀR BocÀ6-(4-CO2HÀPh)ÀW 28
BocÀ5-(4-CO2HÀPh)ÀW 18
16
17
18
7-BrÀW
6-BrÀW
5-BrÀW
BocÀ7-(3-CH3ÀPh)ÀW
BocÀ6-(3-CH3ÀPh)ÀW
BocÀ5-(3-CH3ÀPh)ÀW
67
56
32
3-CH3ÀPhÀR
[a] W=l-tryptophan [b] R=B(OH)2 [c] Isolated yields over three steps.
94% over three steps could be obtained (Table 2, Entry 1).
Even electron-deficient boronic acids such as 4-carboxyphenyl-
boronic acid or 4-trifluoromethylphenylboronic acid led to sat-
isfactory results (87 and 66% isolated yields, respectively,
Table 2, Entries 13 and 7). Surprisingly, in all cases the C7-bro-
minated aryl halide resulted in the highest yields, even slightly
higher than that of the virtually most reactive, electron-defi-
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cient l-6-bromotryptophan. As expected, l-5-bromotryptophan
showed the lowest conversions and yields, probably because
of the relatively high electron density at the carbonÀhalide
bond.
Molecular cloning of pyrH and thal
PyrH (Uniprot ID: A4D0H5) and thal (Uniprot ID: A1E280) genes
were synthesized codon-optimized for E. coli from GeneArt Tech-
nologies (Invitrogen) and subcloned into the pET28a vector using
NdeI and BamHI restriction sites with standard molecular cloning
procedures.
Conclusions
RP-HPLC
Although the biocatalytic reductions of ketones and hydrolysis
of racemic mixtures are established nowadays as an inherent
part of organic synthesis, halogenation reactions are per-
formed predominantly using chemical approaches. To the best
of our knowledge, our findings represent the first example of
Reactions were monitored by using RP-HPLC by using a Thermo
Scientific Accela 600 equipped with a Thermo Scientific Hypersil
GOLD 3 mm column (C18, 150”2.1 mm, eluent A H2O/CH3CN/tri-
fluoroacetic acid (TFA)=95:5:0.1, eluent B H2O/CH3CN/TFA=
5:95:0.1, flow rate 0.7 mLminÀ1 using a linear gradient from 0–
100% B over 5 min).
a
consecutive biocatalytic halogenation–chemocatalytic
Suzuki–Miyaura cross-coupling combination in a one-pot ap-
proach on a preparative scale. With the modular reaction cas-
cade presented here, a bromine substituent is introduced bio-
catalytically at the C5-, C6-, or C7-position of tryptophan,
which depends on the FAD-dependent halogenase employed.
The CLEA methodology is suitable not only for the Trp-7 halo-
genase RebH but also for the Trp-5 halogenase PyrH and the
Trp-6 halogenase Thal on a preparative scale with comparable
yields. After the separation of the immobilized biocatalyst by
filtration, the bromine substituent can be displaced subse-
quently in Suzuki–Miyaura cross-coupling reactions by the ad-
dition of base, boronic acid, and Pd catalyst to the reaction so-
lution. The resulting cross-coupling product can either be iso-
lated after neutralization in the zwitterionic form or trans-
formed in a third one-pot step to an Na-Boc-protected amino
acid that may be used directly for further (peptide) synthesis.
Depending on the electronic properties of the boronic acid,
this easily scalable reaction gives rise to 18 different trypto-
phan derivatives in good yields over three steps with only one
final purification step. These amino acids form interesting
building blocks for the synthesis of peptides and peptidomi-
metics that are otherwise chemically accessible only through
laborious multistep reactions. The cross-coupling product can
be extracted from the aqueous phase. As a result, only NaBr,
2-propanol, and Boc-anhydride are required in excess, and the
boronic acid can be used in stoichiometric amounts; cofactors
and the Pd catalyst are only used catalytically. In addition, sol-
vent- and time-consuming purification steps are minimized be-
cause of the one-pot approach, which underlines the sustaina-
bility of the presented process towards arylated tryptophan
derivatives. As much effort has been put into the expansion of
the substrate scope of tryptophan halogenases by means of
directed evolution with promising results,[24–26] the one-pot en-
zymatic halogenation–Suzuki–Miyaura cross-coupling method-
ology could also be applied to other non-tryptophan aryl
halides.[19]
For preparative HPLC purification, a LaChrom System (Merck Hita-
chi) equipped with a Phenomenex Jupiter column (10 mm, C18,
300 Š, 250”21.1 mm, eluent A H2O/CH3CN/TFA=95:5:0.1, eluent B
H2O/CH3CN/TFA=5:95:0.1, flow rate 10 mLminÀ1) was used. For
Na-unprotected amino acids, the eluents without TFA were used to
obtain the zwitterionic form after purification.
ESI-MS
ESI/atmospheric-pressure chemical ionization (APCI) mass spectra
were recorded by using an Esquire 3000 ion trap mass spectrome-
ter (Bruker Daltonik GmbH, Bremen, Germany) equipped with
a standard ESI/APCI source. Samples were introduced directly by
using a syringe pump. Nitrogen served both as the nebulizer gas
and the dry gas. Nitrogen was generated by using a Bruker nitro-
gen generator NGM 11. Helium served as cooling gas for the ion
trap and collision gas for MSn experiments.
HRMS was recorded by using a MicroToF mass spectrometer
(Bruker Daltonics, Bremen) with sample-loop injection. Mass cali-
bration was performed immediately before measurement with
sodium formate cluster and quasi-internal calibration.
NMR spectroscopy
NMR spectra were recorded by using a Bruker DRX-500 (1H:
500 MHz, 13C: 126 MHz) spectrometer at 298 K, and chemical shifts
are reported relative to residual solvent peaks ([D6]DMSO: 1H:
2.50 ppm, 13C: 39.52 ppm).
General procedure of the three-step one-pot reaction (enzy-
matic halogenation–Suzuki cross coupling–Boc protection)
The biocatalytic halogenation using combiCLEAs was described in
detail previously.[20] E. coli lysate (30 mL) from 1.5 L of culture that
contained the overexpressed halogenase supplemented with 75 U
flavin reductase PrnF and 50 U alcohol dehydrogenase (ADH) from
Rhodococcus sp. was precipitated by the addition of ammonium
sulfate (95% saturation) for 1 h at 48C. Glutaraldehyde was added
as a cross-linker (final concentration for RebH 0.5%, Thal 1%, PyrH
1.25%) to the solution and incubated for 2 h at 48C. The resulting
combiCLEAs were washed three times with Na2HPO4 (50 mL,
100 mm), stored overnight at 48C, and resuspended the next day
in the reaction solution that contained l-tryptophan (1 mm), NaBr
(30 mm), NAD+ (0.1 mm), FAD (1 mm), 2-propanol (5% v/v), and
Na2HPO4 (15 mm) at pH 7.4 adjusted with H3PO4. The reaction pro-
Experimental Section
Unless otherwise noted, all chemicals were obtained from commer-
cial suppliers as specified for analytical applications (p.a.).
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cess was monitored by RP-HPLC. After full conversion, typically
after 4–6 days, the immobilized biocatalyst was removed by filtra-
tion, and the reaction solution that contained 1 mm brominated
tryptophan was aliquoted and stored at À208C. For the following
Suzuki–Miyaura coupling, 100 mL solution (0.1 mmol scale) was
thawed, boronic acid (5 equiv.) was added, and the solution was
degassed using ultrasound and Ar sparging for 1 h at 608C. The
solution was then heated to reflux under Ar, and K3PO4 (25 equiv.)
and preactivated Pd catalyst (5 mol%) were added. The preactiva-
tion was performed immediately before addition by heating
a 1 mL solution of 5 mm Na2PdCl4 (5 mol%) and 15 mm sSPhos
(15 mol%) for 10 min at 428C by using a thermal shaker. After the
addition of the Pd catalyst, the reaction solution was heated for
additional 4 h at 1008C. After cooling to RT, the cross-coupling
product can either be extracted into ethyl acetate (6”50 mL) at
a pH of 2–4 to obtain the unprotected amino acid after preparative
HPLC, or a Boc protection of the Na-amino functionality can be
performed: The pH was checked and adjusted to ~11 again using
K3PO4. Boc2O (4 equiv.) was added portionwise, and the pH value
was kept constant at ~11. After stirring overnight at RT, the solu-
tion was acidified to pH 2.5, and the cross-coupling product as
well as the boronic acid were extracted into ethyl acetate (6”
50 mL). The solvent was removed under reduced pressure, and
both compounds were separated by using preparative RP-HPLC.
For detailed analytical data of the synthesized compounds, please
refer to the Supporting Information.
Acknowledgements
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We thank Prof. Dr. Karl-Heinz van PØe for donating the plasmid
encoding for the flavin reductase PrnF and Prof. Dr. Werner
Hummel for donating the plasmid encoding for the alcohol dehy-
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Keywords: biocatalysis · enzyme catalysis · cross-coupling ·
multicomponent reactions · palladium
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Received: March 18, 2016
Published online on May 6, 2016
ChemCatChem 2016, 8, 1799 – 1803
www.chemcatchem.org
1803
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim