Laccase/TEMPO-mediated system for the thermodynamically disfavored oxidation of 2,2-dihalo-1-phenylethanol derivatives

Article abstract of DOI:10.1039/c4gc00066h

An efficient methodology to oxidize β,β-dihalogenated secondary alcohols employing oxygen was achieved in a biphasic medium using the laccase from Trametes versicolor/TEMPO pair, providing the corresponding ketones in a clean fashion under very mild conditions. Moreover, a chemoenzymatic protocol has been applied successfully to deracemize 2,2-dichloro-1-phenylethanol combining this oxidation with an alcohol dehydrogenase-catalyzed bioreduction. the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00066h

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Laccase/TEMPO-mediated system for the
thermodynamically disfavored oxidation of
2,2-dihalo-1-phenylethanol derivatives†
Cite this: Green Chem., 2014, 16,
2448
Received 14th January 2014,
Accepted 19th February 2014
Kinga Kędziora, Alba Díaz-Rodríguez, Iván Lavandera, Vicente Gotor-Fernández and
Vicente Gotor*
DOI: 10.1039/c4gc00066h
www.rsc.org/greenchem
An efficient methodology to oxidize β,β-dihalogenated secondary desirable when dealing with hydrophobic derivatives. Phenolic
alcohols employing oxygen was achieved in a biphasic medium compounds are their natural substrates, but laccases have shown
using the laccase from Trametes versicolor/TEMPO pair, providing to be also effective towards primary alcohols or amines making
the corresponding ketones in a clean fashion under very mild con- use of, e.g. ABTS, benzotriazole, or syringaldehyde, among
ditions. Moreover, a chemoenzymatic protocol has been applied others.6 One of the most employed is (2,2,6,6-tetramethylpiperi-
successfully to deracemize 2,2-dichloro-1-phenylethanol combin- din-1-yl)oxy (TEMPO) due to its accessibility and high compatibil-
ing this oxidation with an alcohol dehydrogenase-catalyzed ity with this class of enzyme. Recently, the laccase/TEMPO
bioreduction.
catalytic system has been reported as a potent alternative to
oxidize chemoselectively benzylic and primary alcohols over sec-
ondary ones.7
Oxidation of alcohols into the corresponding carbonylic com-
pounds is one of the fundamental reactions in organic chem-
istry. Traditionally these transformations comprised the use of
hazardous metal-based reagents in stoichiometric amounts,
however catalytic methodologies employing oxygen (or air) as a
mild oxidant in aqueous media are being recognized for large
scale applications, and therefore they are currently emerging
as potent competitors.1 From an economic and environmental
point of view, these strategies are highly appealing since they
produce water as the only by-product.
In this context, biological catalysts are gaining more
relevance applied to oxidative processes, especially due to the
mild conditions and high selectivities displayed in these transfor-
mations.2 Among the different types of enzymes implicated
in these reactions, oxidases have appeared as an interesting
class since they use molecular oxygen as the electron acceptor.3
In particular laccases are multicopper biocatalysts present in
many fungi, plants and bacteria, and are responsible for the
reduction of O2 into H2O at the expense of the substrate oxida-
tion.3a,4 Additionally, they are accessible and cheap compared
to other reported metal complexes. Apart from that, laccases
work efficiently in water as the natural medium, although they
can also accept organic co-solvents,5 which can be highly
Especially challenging is the oxidation of alcohols substi-
tuted at the β-position with electron-withdrawing groups
(EWG), e.g. halohydrins. To date, Dess–Martin periodinane,8
ruthenium9 and iridium-based10 catalysts, Swern,11 tetrapropyl-
ammonium perruthenate (TPAP),11,12 and Jones’ reagent13
have been reported for the oxidation of this type of substrates.
Owing to their high reactivity, α,α-dihalogenated ketones are
versatile building blocks for the synthesis of, among
others, mandelic acid,14 oxazines,15 triazines,16 α,β-unsatu-
rated ketones,17 and triazole derivatives.18 In the course of our
investigations on biocatalyzed redox processes, it was observed
that the oxidation of halohydrins was hardly feasible under
alcohol dehydrogenase (ADH)-catalyzed hydrogen transfer
conditions.19 Following this study and based on our previous
experience with the selective oxidation of alcohols using
Trametes versicolor laccase and TEMPO,7a we have explored
this catalytic system in the disfavored oxidation of secondary
alcohols 1a–i.
Since the laccase/mediator system is able to oxidize primary
and secondary benzylic alcohols,7b,d,20 we reasoned that
laccase/TEMPO could also lead to carbonylic compounds
bearing electron-withdrawing groups at the α-position
under aerobic conditions. Therefore, several 2,2-dihalogenated
1-phenylethanol derivatives (1a–h) and 2-chloro-1-phenyletha-
nol 1i (Scheme 1) were synthesized, and these compounds
were tested as possible substrates.
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de
Biotecnología de Asturias, Universidad de Oviedo, C/Julián Clavería 8, 33006
Oviedo, Spain. E-mail: vgs@uniovi.es
In a first set of experiments, the influence of the oxygen-
ation was investigated.21 Thus, the oxidation of 2,2-dichloro-
1-phenylethanol (1a, 0.1 mmol, 50 mM) as a model substrate
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, ab initio and E-factor calculations, substrate characterization, and
analytical data are described. See DOI: 10.1039/c4gc00066h
2448 | Green Chem., 2014, 16, 2448–2453
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Scheme 1 General methodology to synthesize α,α-dihalogenated aceto-
phenone derivatives 2a–h and 2-chloroacetophenone (2i) through oxi-
dation reactions with the laccase/TEMPO system.
Fig. 1 Effect of the organic co-solvent concentration in the T. versico-
lor laccase/TEMPO (20 mol%) system to oxidize alcohol 1a (50 mM) into
2a, bubbling oxygen in a 50 mM NaOAc buffer pH 4.5 at 20 °C (toluene
and MTBE) or 30 °C (MeCN) after 24 h.
was performed in a 50 mM sodium acetate (NaOAc) buffer
pH 4.5 at 30 °C and 20 mol% of TEMPO under two different
conditions: (a) opening the reaction mixture to ambient air;
and (b) bubbling oxygen in the vessel with a balloon. Remark-
ably, while for the first case a conversion of 33% was attained
after 24 h, the second protocol led to 53% of ketone 2a. The
reactions were carried out using 10% v/v of acetonitrile
(MeCN) as a result of the low solubility of 1a. Although the
conversions still were not quantitative, we observed that this
method was able to afford smoothly the final compound,
avoiding the formation of undesired by-products. Therefore,
the reaction conditions of bubbling oxygen were chosen for
further optimization. Other parameters such as temperature
(20–40 °C), TEMPO equivalents (20–40 mol%), or pH (3.5–6.0)
were also examined, without finding significant improvements
(see ESI†).
Next, we decided to study the effect of the organic co-
solvent by adding water miscible and non-miscible co-solvents,
giving rise to mono- or biphasic systems. The addition of
organic co-solvents can improve the solubility of hydrophobic
substrates and the stability of this catalytic method, as
observed for similar transformations.5,22 To minimize mass
transfer issues, a gentle magnetic stirring was performed in
all cases. Thus, dimethylsulfoxide (DMSO) and MeCN were
studied as additives in monophasic mixtures while dichloro-
methane, toluene and methyl tert-butyl ether (MTBE) were
added to form biphasic systems (see ESI†). Among them,
MeCN, toluene and MTBE afforded the best oxidation conver-
sions (56–70%), so further studies were developed with these
organic solvents.
Fig. 2 Reaction course of the T. versicolor laccase/TEMPO (20 mol%)
system to oxidize alcohol 1a (50 mM) into 2a, bubbling oxygen in a
50 mM NaOAc buffer pH 4.5 at 20 °C in the presence of MTBE (66% v/v).
After 2–3 h, the disappearance of the organic solvent was observed. For
comparison, the reaction in plain buffer was also studied.
ence on the oxidation of 1a. In addition, following the guide-
lines of greener alternatives for chlorinated or diethyl ether
solvents, MTBE appeared as one of the best options for an
immiscible organic co-solvent.23 We also studied the use of a
lower amount of TEMPO equivalents (5–10 mol%), but conver-
sions were incomplete (51–85%).
The continuous oxygen bubbling process evaporated the
organic solvent after a short period of time (2–3 h). Overall, it
can be considered that this oxidation was accomplished at the
end in an aqueous medium. To investigate the possible effect of
MTBE in the reaction, we followed the oxidation of 1a with time
(Fig. 2), with and without the presence of MTBE. While a con-
version of nearly 50% into 2a was achieved in the first 3 h for
the biphasic system, less than 10% conversion was detected for
the solely aqueous system.24 The positive effect of MTBE seems
to be more related to an improvement of the substrate solubility
than to the TEMPO stability, as conversions in plain buffer were
continuously increasing at comparable rates after 4 h. Similar
positive properties have already been described for other water–
organic media employing a laccase with a chemical mediator.22
Hence, the effect of the concentration of these organic co-
solvents was studied with respect to the NaOAc buffer (2–66%
v/v, Fig. 1). Due to the low boiling point of MTBE, the reactions
with this solvent were carried out at 20 °C, and therefore, this
was also the temperature of choice for the other non-miscible
solvent (toluene), while the oxidations with water-miscible
MeCN were performed at 30 °C. In this case, it remained clear
that percentages higher than 20% v/v inhibited the laccase/
TEMPO system while non-miscible solvents could be employed
in larger amounts. Especially with MTBE, excellent conver-
sions were achieved after 24 h (95%), showing that the
addition of this organic co-solvent displayed a positive influ-
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Table 1 Oxidation of secondary alcohols 1a–j using the laccase/
TEMPO systema
Entry
Alcohol
R
X
Y
2a–jb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
F
95 2.8
o-Cl
m-Cl
p-Cl
m-OMe
m-NO2
H
H
H
H
4
1.4
78 3.5
91 2.1
82 4.2
95 4.2
89 5.7
75 2.1
62 3.2
78 3.5
Fig. 3 Oxidation of alcohol 1a into 2a employing different reaction
conditions. In some cases, benzaldehyde (3a), benzoic acid (4a), and/or
mandelic acid (5a) were obtained as by-products.
H
H
10
1j
a Reaction conditions: alcohol 1a–j (0.1 mmol), T. versicolor laccase
(31 U) and TEMPO (20 mol%) in a 50 mM NaOAc buffer pH 4.5 and
MTBE (66% v/v) bubbling oxygen at 20 °C for 24 h. b Conversion values
measured by GC.
To emphasize the ability of the laccase/TEMPO system to
oxidize secondary alcohols with varying redox strength, we
evaluated the relative thermodynamic stability of the halo-
genated alcohol/ketone pairs 1a, i, j/2a, i, j with respect to the
acetone/2-propanol pair by computing the Gibbs free energy
change in aqueous solution (ΔrG, see ESI† for more details).19a
The computed ΔrG energies in kcal mol−1 were +7.33 (1a),
+4.86 (1i), and +0.61 (1j), showing clearly that the dichlori-
nated alcohol 1a was a weaker reducing agent compared to the
mono- (1i, by 2.5 kcal mol−1) or unsubstituted (1j, by 6.7 kcal
mol−1) derivatives. Since 1a showed the largest conversion
value, it turned out that the differences in the intrinsic redox
strength of 1a, i, j did not affect their oxidation, which is in
agreement with the accepted ionic mechanism of oxidation
mediated by TEMPO.27 These results highlight the flexibility of
our laccase/TEMPO system.
To demonstrate the mildness and selectivity of this system
to oxidize these substrates, different chemical oxidative
methods were assessed for the oxidation of 1a (Fig. 3).
Thus, the laccase was combined with 4-hydroxy-TEMPO
(4-OH-TEMPO), but in this case just 5% conversion was
achieved after 24 h. Several mixtures of oxidant(s) and TEMPO
were tried in aqueous media such as NaOCl (9 equiv.),28
NaOCl (1 equiv.)/KBr (0.2 equiv.),28 NaOCl2 (1.5 equiv.)/NaOCl
(0.2 equiv.),29 CuCl (0.2 equiv.),30 CuBr2 (0.2 equiv.),31 or
iodine (1.5 equiv.),32 but negligible or very low conversions
were attained. Just when using a stoichiometric amount or an
excess of NaOCl, a complex mixture of products formed by
benzaldehyde (3a), benzoic acid (4a) and mandelic acid (5a)
was detected. This observation correlates with previous reports
describing the synthesis of mandelic acid from dihalogenated
ketones in an aqueous basic medium.33
Having found appropriate conditions to oxidize alcohol 1a
(Table 1, entry 1), the scope of this transformation was
expanded to other dihalogenated derivatives 1b–h. The system
efficiency depended on the position of the phenyl ring substi-
tution, observing high to excellent conversions for meta- or
para-substituted compounds, while a very low formation of
ketone 2b was found for the ortho-derived alcohol 1b (compare
entries 2 to 4). On the other side, alcohols with differing elec-
tronic properties such as chlorine, methoxy or nitro were oxi-
dized (entries 3–6). Additionally, substrates with other halogen
atoms at the α-position such as bromine (entry 7) or fluorine
(entry 8) also afforded the halogenated ketones with conver-
sions higher than 75%. It is remarkable that the desired car-
bonylic compounds were formed as the sole products, without
the detection of other derivatives in any case. When using the
alcohol 1a, the substrate concentration could be increased up
to 200 mM obtaining a conversion of 93% after 24 h. This is in
line with other reports that have demonstrated the perfor-
mance of laccases at high substrate concentrations.7b,25 Satisfy-
ingly, some of these oxidative transformations could be easily
performed at the 100 mg scale, isolating the corresponding
ketones in very high yields (76–81%, see ESI† for more details).
Then, chlorohydrin 1i was also tested as plausible substrate
(entry 9). In this case, we observed a 62% conversion to
α-chloro ketone 2i after 24 h under these oxidative conditions.
This result is very important due to the difficulty to achieve
this oxidation by other chemical methods, and also because of
the versatility of these compounds as intermediates of several
high added-value derivatives. Furthermore, when a non-
halogenated alcohol such as 1-phenylethanol (1j) was used, a
similar conversion compared to the dihalogenated counter-
parts was achieved (78%, entry 10), showing that this methodo-
logy can work with different types of secondary alcohols.26
The application of NaOCl or NaOCl/KBr led again to a
mixture of compounds 3–5a, while NaOCl2 or Dess–Martin
periodinane in water did not afford any conversion, recovering
the starting material. Only the employment of Dess–Martin
periodinane in dichloromethane,8 allowed the synthesis of
ketone 2a at 54% as the sole product at room temperature
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Scheme 2 One-pot two-step protocol to deracemize alcohol 1a via oxidation with the laccase/TEMPO system plus reduction with an alcohol
dehydrogenase and 2-propanol.
after 1.5 h. To show the environmental benefits of this system enriched alcohol (R)-1a was obtained in total conversion with
compared to the others, we have performed a simplified 97% ee. This first example opens the door to sustainable
environmental impact analysis making use of the E-factor chemoenzymatic deracemization protocols applied to other
concept.34 Although it provides a rough estimation of the β-substituted alcohols that under other chemical conditions
environmental impact, this value assesses the sustainability of cannot be obtained easily.
a process.35 Thus, we compared36 our laccase/TEMPO system
with the other three (laccase/4-OH-TEMPO, NaOCl/KBr/TEMPO
and Dess–Martin in dichloromethane) which afforded a mea-
surable amount of ketone 2a, obtaining an E-factor of 3.5 for
Conclusions
the laccase/TEMPO process (excluding solvents) and values In summary, we have shown here an efficient and green
higher than 21 for the others (see ESI† for details). Also, the method for the selective oxidation of secondary (di)halo-
solvent demand in our method (330 mL g−1 product) was hydrins into the corresponding halogenated ketones using the
much lower in comparison with the other strategies. As a laccase from Trametes versicolor and TEMPO pair. Although
result, these data demonstrate the favorable ecological impact this process is thermodynamically impeded, the use of this
of the laccase/TEMPO pair.
system under aerobic conditions in a biphasic media could
Taken together, we have shown that this methodology, provide exclusively the corresponding carbonylic compounds
making use of a laccase/TEMPO system in a biphasic medium with very high conversions in a clean fashion. This practical
with oxygen as final electron acceptor, is a practical method to method represents a potent alternative to other known oxi-
get access to α- or α,α-dihalogenated ketones via oxidation of dative methods, which were not able to oxidize these substrates
the corresponding (di)halohydrins, which in other reaction or afforded undesired by-products. Moreover, coupled with a
conditions cannot be obtained selectively.
second enzymatic bioreduction, deracemization of a secondary
Encouraged by these results and as an interesting appli- dihalogenated alcohol in a one-pot two-step protocol was feasi-
cation of this methodology, we envisaged the deracemization ble, obtaining the enantioenriched (R)-alcohol in a very mild
of alcohol 1a through a one-pot two-step chemoenzymatic pro- and elegant fashion.
cedure. To date, the only example for the deracemization of
chlorohydrins has been reported by Kroutil and co-workers,10a
combining an alcohol dehydrogenase (for the reduction) with
an iridium catalyst (for the oxidation) in a one-pot concurrent
Acknowledgements
system. Unfortunately, the ee values did not exceed 40% due to Financial support from the Spanish Ministerio de Ciencia e
undesired interference of both processes. Herein, we propose Innovación (MICINN-12-CTQ2011-24237), the Principado de
an alternative strategy starting from the racemic alcohol 1a. In Asturias (SV-PA-13-ECOEMP-42 and SV-PA-13-ECOEMP-43)
a first step we achieve the complete oxidation into ketone 2a and the Universidad de Oviedo (UNOV-13-EMERG-01 and
with the laccase/TEMPO pair. Subsequently, the addition of a UNOV-13-EMERG-07) is gratefully acknowledged. I. L. acknowl-
selective ADH leads to enantioenriched alcohol 1a (Scheme 2).
edges MICINN for his research contract under the Ramón y
Hence, this system was successfully applied to deracemize Cajal Program. We thank Professor Dimas Suárez (University
40 mg of racemic alcohol 2a. After oxidation mediated by of Oviedo) for ab initio calculations and helpful discussions.
T. versicolor laccase and TEMPO under the previously opti-
mized conditions, the buffer pH was adjusted to 7.5 by adding
tris(hydroxymethyl)aminomethane (Tris) and a few drops of
HCl (thus inactivating the laccase). Then, alcohol dehydroge-
Notes and references
nase from Rhodococcus ruber overexpressed in Escherichia coli
(E. coli/ADH-A)37 and 2-propanol as hydrogen donor (10% v/v)
were successively added. After 48 h at 30 °C, the enantio-
1 (a) A. Baiker and T. Mallat, Catal. Sci. Technol., 2013, 3, 267;
(b) C. Parmeggiani and F. Cardona, Green Chem., 2012, 14,
547–564; (c) I. W. C. E. Arends and R. A. Sheldon, Modern
This journal is © The Royal Society of Chemistry 2014
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View Article Online
Communication
Green Chemistry
Oxidation Methods, ed. J.-E. Bäckvall, Wiley-VCH, Wein-
heim, 2nd edn, 2010, pp. 147–185.
2 Modern Biooxidation: Enzymes, Reactions and Applications,
ed. R. D. Schmid and V. B. Urlacher, Wiley-VCH, Weinheim,
2007.
9 (a) A. Träff, K. Bogár, M. Warner and J.-E. Bäckvall, Org.
Lett., 2008, 10, 4807–4810; (b) B. Martín-Matute, M. Edin,
K. Bogár, F. B. Kaynak and J.-E. Bäckvall, J. Am. Chem. Soc.,
2005, 127, 8817–8825; (c) J. H. Choi, Y. K. Choi, Y. H. Kim,
E. S. Park, E. J. Kim, M.-J. Kim and J. Park, J. Org. Chem.,
2004, 69, 1972–1977; (d) O. Pàmies and J.-E. Bäckvall,
J. Org. Chem., 2002, 67, 9006–9010.
3 (a) Redox Biocatalysis: Fundamentals and Applications, ed.
D. Gamenara, G. A. Seoane, P. Saenz-Méndez and
P. Domínguez de María, John Wiley & Sons, Hoboken, 10 (a) F. G. Mutti, A. Orthaber, J. H. Schrittwieser, J. G. de
2013; (b) F. Hollmann, K. Bühler and B. Bühler, in
Enzyme Catalysis in Organic Synthesis, ed. K. Drauz,
H. Gröger and O. May, Wiley-VCH, Weinheim, 2012, pp.
1325–1438.
4 (a) A. Piscitelli, A. Amore and V. Faraco, Curr. Org. Chem.,
2012, 16, 2508–2524; (b) P. Giardina, V. Faraco, C. Pezzella,
A. Piscitelli, S. Vanhulle and G. Sannia, Cell. Mol. Life Sci.,
2009, 67, 369–385; (c) S. Witayakran and A. J. Ragauskas,
Adv. Synth. Catal., 2009, 351, 1187–1209; (d) S. Riva, Trends
Vries, R. Pietschnig and W. Kroutil, Chem. Commun., 2010,
46, 8046–8048; (b) T. Jerphagnon, A. J. A. Gayet, F. Berthiol,
V. Ritleng, N. Mršić, A. Meetsma, M. Pfeffer,
A. J. Minnaard, B. L. Feringa and J. G. de Vries, Chem. –
Eur. J., 2009, 15, 12780–12790; (c) R. M. Haak, F. Berthiol,
T. Jerphagnon, A. J. A. Gayet, C. Tarabiono, C. P. Postema,
V. Ritleng, M. Pfeffer, D. B. Janssen, A. J. Minnaard,
B. L. Feringa and J. G. de Vries, J. Am. Chem. Soc., 2008,
130, 13508–13509.
Biotechnol., 2006, 24, 219–226; (e) S. G. Burton, Curr. Org. 11 T. M. Poessl, B. Kosjek, U. Ellmer, C. C. Gruber,
Chem., 2003, 7, 1317–1331; (f) H. Claus, Arch. Microbiol.,
2003, 179, 145–150; (g) E. I. Solomon, U. M. Sundaram and
T. E. Machonkin, Chem. Rev., 1996, 96, 2563–2605.
K. Edegger, K. Faber, P. Hildebrandt, U. T. Bornscheuer
and W. Kroutil, Adv. Synth. Catal., 2005, 347, 1827–1834.
12 B. Seisser, I. Lavandera, K. Faber, J. H. Lutje Spelberg and
W. Kroutil, Adv. Synth. Catal., 2007, 349, 1399–1404.
5 (a) N. A. Mohidem and H. B. Mat, Bioresour. Technol., 2012,
114, 472–477; (b) I. Matijosyte, I. W. C. E. Arends, S. de 13 F. R. Bisogno, A. Cuetos, A. A. Orden, M. Kurina-Sanz,
Vries and R. A. Sheldon, J. Mol. Catal. B: Enzym., 2010, 62,
142–148; (c) S. Ncanana, L. Baratto, L. Roncaglia, S. Riva
I. Lavandera and V. Gotor, Adv. Synth. Catal., 2010, 352,
1657–1661.
and S. G. Burton, Adv. Synth. Catal., 2007, 349, 1507–1513; 14 E. B. Ayres and C. R. Hauser, J. Am. Chem. Soc., 1943, 65,
(d) M. Zumárraga, T. Bulter, S. Shleev, J. Polaina, 1095–1096.
A. Martínez-Arias, F. J. Plou, A. Ballesteros and M. Alcalde, 15 (a) S. Asghari and A. K. Habibi, Tetrahedron, 2012, 68,
Chem. Biol., 2007, 14, 1052–1064; (e) A. Intra, S. Nicotra,
S. Riva and B. Danieli, Adv. Synth. Catal., 2005, 347, 973–
977; (f) F. d’Acunzo, A. M. Barreca and C. Galli, J. Mol.
Catal. B: Enzym., 2004, 31, 25–30; (g) J. Rodakiewicz-Nowak,
8890–8898; (b) R. Zimmer, J. Angermann, U. Hain, F. Hiller
and H. U. Reissig, Synthesis, 1997, 1467–1474; (c) A. Le
Rouzic, M. Duclos and H. Patin, Bull. Soc. Chim. Fr., 1991,
952–961.
S. M. Kasture, B. Dudek and J. Haber, J. Mol. Catal. B: 16 J. Limanto, R. A. Desmond, D. R. Gauthier, Jr.,
Enzym., 2000, 11, 1–11.
6 See, for instance: (a) P. Könst, S. Kara, S. Kochius,
P. N. Devine, R. A. Reamer and R. P. Volante, Org. Lett.,
2003, 5, 2271–2274.
D. Holtmann, I. W. C. E. Arends, R. Ludwig and 17 (a) C. Peppe and R. P. das Chagas, J. Organomet. Chem.,
F. Hollmann, ChemCatChem, 2013, 5, 3027–3032;
(b) T. Kudanga, G. S. Nyanhongo, G. M. Guebitz and
2006, 691, 5856–5860; (b) J. M. Concellón, H. Rodríguez-
Solla, C. Concellón and P. Díaz, Synlett, 2006, 837–840.
S. Burton, Enzyme Microb. Technol., 2011, 48, 195–208; 18 (a) S. S. van Berkel, S. Brauch, L. Gabriel, M. Henze,
(c) O. V. Morozova, G. P. Shumakovich, S. V. Shleev and
Y. I. Yaropolov, Appl. Biochem. Microbiol., 2007, 43, 523–
535; (d) A. Wells, M. Teria and T. Eve, Biochem. Soc. Trans.,
2006, 34, 304–308; (e) M. Fabbrini, C. Galli and P. Gentili,
J. Mol. Catal. B: Enzym., 2002, 16, 231–240.
S. Stark, D. Vasilev, L. A. Wessjohann, M. Abbas and
B. Westermann, Angew. Chem., Int. Ed., 2012, 51, 5343–
5346; (b) M. S. Raghavendra and Y. Lam, Tetrahedron Lett.,
2004, 45, 6129–6132; (c) K. Sakai, N. Hida and K. Kondo,
Bull. Chem. Soc. Jpn., 1986, 59, 179–183.
7 (a) A. Díaz-Rodríguez, I. Lavandera, S. Kanbak-Aksu, 19 (a) F. R. Bisogno, E. García-Urdiales, H. Valdés,
R. A. Sheldon, V. Gotor and V. Gotor-Fernández, Adv. Synth.
Catal., 2012, 354, 3405–3408; (b) I. W. C. E. Arends, Y.-X. Li,
R. Ausan and R. A. Sheldon, Tetrahedron, 2006, 62, 6659–
6665; (c) M. Marzorati, B. Danieli, D. Haltrich and S. Riva,
I. Lavandera, W. Kroutil, D. Suárez and V. Gotor, Chem. –
Eur. J., 2010, 16, 11012–11019; (b) I. Lavandera, A. Kern,
V. Resch, B. Ferreira-Silva, A. Glieder, W. M. F. Fabian, S. de
Wildeman and W. Kroutil, Org. Lett., 2008, 10, 2155–2158.
Green Chem., 2005, 7, 310–315; (d) M. Fabbrini, C. Galli, 20 (a) A. M. Barreca, M. Fabbrini, C. Galli, P. Gentilli and
P. Gentili and D. Macchitella, Tetrahedron Lett., 2001, 42,
7551–7553.
8 (a) V. Pace and W. Holzer, Tetrahedron Lett., 2012, 53, 5106–
5109; (b) V. Pace, A. Cortés Cabrera, M. Fernández,
S. Ljunggren, J. Mol. Catal. B: Enzym., 2003, 26, 105–110;
(b) E. Srebotnik and K. E. Hammel, J. Biotechnol., 2000, 81,
179–188; (c) H. Xu, Y.-Z. Lai, D. Slomczynski, J. P. Nakas
and S. W. Tanenbaum, Biotechnol. Lett., 1997, 19, 957–960.
J. V. Sinisterra and A. R. Alcántara, Synthesis, 2010, 3545– 21 The blank experiments using just the laccase or TEMPO
3555.
(20 mol%), did not afford any conversion.
2452 | Green Chem., 2014, 16, 2448–2453
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22 (a) G. Cantarella, F. d’Acunzo and C. Galli, Biotechnol. 28 P. L. Anelli, S. Banfi, F. Montanari and S. Quici, J. Org.
Bioeng., 2003, 82, 395–398; (b) F. d’Acunzo, C. Galli and Chem., 1989, 54, 2970–2972.
B. Masci, Eur. J. Biochem., 2002, 269, 5330–5335; 29 M. Zhao, J. Li, E. Mano, Z. Song, D. M. Tschaen,
(c) J. Rodakiewicz-Nowak, Top. Catal., 2000, 11/12, 419–434.
23 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings,
E. J. J. Grabowski and P. J. Reider, J. Org. Chem., 1999, 64,
2564–2566.
T. A. Johnson, H. P. Kleine, C. Knight, M. A. Nagy, 30 M. F. Semmelhack, C. R. Schmid, D. A. Cortés and
D. A. Perry and M. Stefaniak, Green Chem., 2008, 10, 31–36. C. S. Chou, J. Am. Chem. Soc., 1984, 106, 3374–3376.
24 Another indication that substrate solubilization played an 31 T. Miyazawa and T. Endo, J. Mol. Catal., 1985, 32, 357–
important role in this oxidative reaction was the fact that 360.
when alcohol 1a (a crystal solid) was crushed into very tiny 32 R. A. Miller and R. S. Hoerrner, Org. Lett., 2003, 5, 285–287.
pieces, the conversion in plain NaOAc buffer (50 mM, 33 J. G. Aston, J. D. Newkirk, J. Dorsky and D. M. Jenkins,
pH 4.5) increased from less than 10% to 47% after 24 h
at 20 °C.
25 I. W. C. E. Ardens, Y. Li and R. A. Sheldon, Biocatal. Bio-
transform., 2006, 24, 443–448.
26 Further experiments oxidizing mixtures of dichlorinated
alcohol 1a with monohalogenated derivative 1i or unsubsti-
J. Am. Chem. Soc., 1942, 64, 1413–1416.
34 (a) R. A. Sheldon, Chem. Ind., 1992, 903–906;
(b) R. A. Sheldon, Green Chem., 2007, 9, 1273–1283.
35 A recent example can be found in: J. H. Schrittwieser,
F. Coccia, S. Kara, B. Grischek, W. Kroutil, N. d’Alessandro
and F. Hollmann, Green Chem., 2013, 15, 3318–3331.
tuted compound 1j afforded, as expected, mixtures of the 36 (a) M. Eissen and J. O. Metzger, Chem. – Eur. J., 2002, 8,
corresponding ketones in similar ratios (see ESI† for more
details).
27 (a) S. A. Tromp, I. Matijošytė, R. A. Sheldon, I. W. C.
3580–3585; (b) EATOS: Environmental Assessment Tool
for Organic Syntheses, http://www.metzger.chemie.uni-
oldenburg.de/eatos/english.htm, accessed: 05.02.2014.
E. Arends, G. Mul, M. T. Kreutzer, J. A. Moulijn and S. de 37 K. Edegger, C. C. Gruber, T. M. Poessl, S. R. Wallner,
Vries, ChemCatChem, 2010, 2, 827–833; (b) F. D’Acunzo,
P. Baiocco, M. Fabbrini, C. Galli and P. Gentili, Eur. J. Org.
Chem., 2002, 4195–4201.
I. Lavandera, K. Faber, F. Niehaus, J. Eck, R. Oehrlein,
A. Hafner and W. Kroutil, Chem. Commun., 2006, 2402–
2404.
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