Laccase-catalyzed oxidative phenolic coupling of vanillidene derivatives

Article abstract of DOI:10.1039/c2gc35848d

The laccase-catalyzed oxidative phenolic coupling of vanillidene derivatives using aerial oxygen as the oxidant has been developed. Depending on the substitution pattern of the vanillidene double bond of the substrate, either dilactones, dihydrobenzo[b]furans or biphenyls are formed.

Full text of DOI:10.1039/c2gc35848d

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Laccase-catalyzed oxidative phenolic coupling of vanillidene derivatives†
Mihaela-Anca Constantin, Jürgen Conrad and Uwe Beifuss*
Received 31st May 2012, Accepted 26th June 2012
DOI: 10.1039/c2gc35848d
H2O. Laccase-catalyzed transformations have other major
benefits as well: they can be performed in aqueous solvent
systems and under mild reaction conditions. They do not only
meet several of the criteria of green chemistry,10 but also display
a remarkably broad substrate spectrum that can be expanded
even more by using mediators. In addition, many of them exhibit
a surprisingly high level of selectivity, this being the reason why
laccases are highly attractive enzymes for the catalysis of oxi-
dations in organic synthesis.11
Among other applications, laccases have been used success-
fully for the oxidation of several functional groups.12 The
implementation of the laccase-catalyzed oxidation of catechols to
o-benzoquinones and hydroquinones to p-benzoquinones,
respectively, in domino processes for the preparation of carbo-
and heterocycles is also known.13 Another field for laccase-cata-
lyzed oxidations is the oxidative coupling of phenolic sub-
strates.14 As part of our studies related to the development of
selective and efficient oxidations with O2 as the oxidant, we
report on laccase-catalyzed oxidative couplings of compounds
of types (E)-1, 14 and 15, all of which can be regarded as
The laccase-catalyzed oxidative phenolic coupling of vanilli-
dene derivatives using aerial oxygen as the oxidant has been
developed. Depending on the substitution pattern of the
vanillidene double bond of the substrate, either dilactones,
dihydrobenzo[b]furans or biphenyls are formed.
The phenolic coupling is one of the key reactions in the biosyn-
thesis of many plant secondary metabolites. As an example, a
huge number of lignans are formed by oxidative dimerization of
p-hydroxycinnamic alcohols like p-coumaryl alcohol, coniferyl
alcohol and sinapyl alcohol.1 The p-hydroxycinnamic alcohols
are also decisively involved in the formation of the biopolymer
lignin.1b,2 In addition to the p-hydroxycinnamic alcohols, the
oxidative dimerization and trimerization of esters of ferulic acid
also occupy an important role in the biosynthesis of natural
products.3
The phenolic natural products depicted in Fig. 1 impressively
underline the structural diversity of dimeric, trimeric and tetra-
meric coupling products of ferulic acid [(E)-1].4 Many of them
exhibit remarkable biological activities. For example, com-
pounds 3 and 4 show antioxidative properties,5 and the dihydro-
benzo[b]furan 6 is an anticancer agent.6 This is why the
selective and efficient oxidative dimerization of ferulic acid and
its derivatives is of great importance to the preparation of bio-
logically active phenolic compounds.
In contrast to biosynthesis, the oxidative phenolic coupling
still has a minor role in organic synthesis,7 which is mainly due
to the difficulty of controlling both the regio- and stereoselectiv-
ity of such couplings. Another important reason is that phenol
couplings often require the use of expensive and/or toxic
reagents like silver salts. Enzyme-catalyzed phenolic couplings
using O2 as the oxidant provide a valuable alternative as aerial
O2 is one of the cheapest and greenest oxidants available.
In this context, we became interested in laccase-catalyzed oxi-
dations with O2. Laccases belong to the enzyme class of oxi-
dases.8 They catalyze one electron oxidations of electron rich
substrates with O2.9 The resulting radicals can undergo further
reactions like dimerizations and polymerizations. The oxidation
is accompanied by reduction of O2 to completely non-toxic
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim,
Garbenstr. 30, Stuttgart, D-70599, Germany.
E-mail: ubeifuss@uni-hohenheim.de; Fax: (+49) 711 459 22951;
Tel: (+49) 711 459 22171
†Electronic supplementary information (ESI) available: Experimental
data and copies of the 1H NMR and 13C NMR spectra. See DOI:
10.1039/c2gc35848d
Fig. 1 Ferulic acid oligomers of plant origin.
Green Chem., 2012, 14, 2375–2379 | 2375
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Table 1 Optimization of the laccase-catalyzed oxidative dimerization
of (E)-14aa
Fig. 2 Structures of vanillidene derivatives.
Entry
Laccase
Cosolvent (vol%)
t (h)
0.25
1
16
1
1
1
1
1
1
2
1
16
1
Yield 17a (%)b
1
2
3
4
5
6
7
8
Tvc
Tvc
Tvc
Tvc
Tvc
Tvc
Tvc
Tvc
Tvc
Tvc
Abd
Abd
—
DMSO (2)
DMSO (2)
DMSO (2)
DMSO (1)
DMSO (10)
Acetone (2)
Acetone (10)
EtOH (2)
—
11
38
40
37
27
21
31
21
8
26
15
22
—
9
Scheme 1 Laccase-catalyzed oxidation of ferulic acid [(E)-1].
10
11
12
13
—
DMSO (2)
DMSO (2)
DMSO (2)
a 0.4 mmol (E)-14a were reacted. b Yields refer to yields after flash
chromatography. c Commercially available laccase from Trametes
versicolor. d Commercially available laccase from Agaricus bisporus.
Fig. 3 Dihydrobenzo[b]furans 17a,b as products of the oxidative
dimerization of ferulic acid esters (E)-14a,b.
known, but the structures of the products formed have not been
elucidated.22
Our own experiments concerning the laccase-catalyzed reac-
tion of ferulic acid esters (E)-14a–d clearly revealed the for-
mation of dihydrobenzo[b]furans 17a–d as main products in
diastereoselectively pure form. The required esters (E)-14a–d
were obtained in high yields by simple esterification of (E)-1
with the corresponding alcohols according to the procedure of
Ralph et al.21a To start with, the laccase-catalyzed oxidation of
methyl ferulate (E)-14a was performed using different laccases
under different reaction conditions (Table 1). The best yield of
17a was achieved when the coupling of (E)-14a was run with
4 U laccase from T. versicolor as the catalyst in a 98 : 2-mixture
of acetate buffer (0.1 M, pH 5.0) and DMSO (Table 1, entry 3)
for 16 h. These conditions allowed the isolation of the diastereo-
isomerically pure 8,5′-coupling product 17a with 40%
yield. HPLC separation of the enantiomers of 17a using a chiral
phase demonstrated that the product of the laccase-catalyzed oxi-
dation of (E)-14a was racemic. Coupling experiments with
Agaricus bisporus as the catalyst resulted in lower yields
(Table 1, entries 11 and 12) as did the use of other co-solvents
(Table 1, entries 6–8) and other concentrations of DMSO
(Table 1, entries 4 and 5). In a control experiment the oxidative
dimerization of (E)-14a did not occur in the absence of laccase
(Table 1, entry 13).
vanillidene derivatives. Apart from the reactions of ferulic acid
[(E)-1] and other disubstituted vanillidenes 14, we focused on
the transformations of trisubstituted vanillidenes of type 15,
which have remained largely unexplored. This is also the first
report on the influence of the substitution pattern at the vanilli-
dene double bond on the outcome of the oxidative coupling
(Fig. 2).
The oxidation of ferulic acid [(E)-1] has already been studied
with a number of reagents including FeCl3/O2 15 and peroxidase/
H2O2.16 In most cases the dilactone 16 was formed. When, for
example, (E)-1 was reacted with 2 equiv. of FeCl3 in the pres-
ence of aerial O2, 16 was isolated in 56% yield.15b The laccase-
catalyzed oxidative coupling of (E)-1 with aerial O2 as the
oxidant has also been studied.17 But instead of the dilactone
compounds 3 and 6 were formed. When we reacted 2.6 mmol
(E)-1 with 27 U laccase (T. versicolor)‡ and aerial O2 in acetate
buffer (pH 5.0) at rt for 2 h, the dilactone 16 could be isolated in
16% yield (Scheme 1). In addition to 16 we observed the for-
mation of further products whose structures were not elucidated.
Then, the oxidative coupling of the ferulic acid esters (E)-
14a–d was studied. The reactions of (E)-14a,b have already
been performed with a number of oxidants including Ag2O,3b,18
Co(salen)/O2,19 AIBN20 and peroxidase/H2O2.21 In most cases
the main products were dihydrobenzo[b]furans 17a,b (Fig. 3).
As many compounds with a dihydrobenzo[b]furan core exhibit
interesting biological properties, they receive much attention in
medicinal chemistry.16c,18b So far, the best results have been
obtained with Ag2O as the oxidant. This, however, requires the
use of at least one equivalent of the expensive and toxic
oxidant.18 The laccase-catalyzed oxidation of (E)-14a is also
It was also established that 17a is not stable under reaction
conditions but slowly decomposes to yield products of unknown
structure. The laccase-catalyzed dimerization could be extended
to the ethylester (E)-14b, the n-propylester (E)-14c and the
n-butylester (E)-14d (Table 2, entries 1–7). Again, the corre-
sponding dihydrobenzofurans were isolated as the only products
in diastereoisomerically pure form. However, the yields of
17b–d were lower than that of 17a (Table 2, entries 3, 6, and 7).
2376 | Green Chem., 2012, 14, 2375–2379
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Table 2 Laccase-catalyzed oxidative dimerizations of (E)-14b–f
Table 3 Laccase-catalyzed oxidative dimerizations of 15a–da
Yield 17
Laccase U (laccase) t (h) (%)c
Entry (E)-14
R
DMSO
(mL)
Buffer
(mL)
Yield 19
1
2
3
4
5
6
7
8
9
ba
ba
ba
ba
ba
ca
db
ea
fa
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Tvd
Tvd
Tvd
Tvd
Abe
4
4
4
4
4
4
80
4
4
1
5
16
36
16
16
3
23
25
29
23
22
23
22
25
—
Entry 15
R1, R2
t (h)
22
5
(%)b
1
2
a
CO2Et,
CO2Et
COMe,
COMe
CN, CN
CO2Et,
COMe
8
8
72
72
79b
93b
b
CO2n-Pr Tvd
CO2n-Bu Tvd
3
4
c
8
8
72
72
21
3
Quant.d
86b
COMe
CN
Tvd
Tvd
9
10
dc
a 0.4 mmol substrate were reacted. b 2.1 mmol 14d were reacted. c Yields
refer to yields after flash chromatography. d Commercially available
laccase from Trametes versicolor. e Commercially available laccase from
Agaricus bisporus.
a 0.4 mmol 15a–d were reacted. b Yields after flash chromatography.
c 15d was a 4 : 6-mixture of the E- and the Z-isomer (1H NMR). d Yield
after crystallization of the crude product.
Fig. 4 Structures of vanillidene β-dicarbonyls 15a–d.
It is remarkable that the dihydrobenzo[b]furan formation was
not restricted to the unsaturated esters (E)-14a–d but could also
be achieved with the corresponding unsaturated ketone (E)-14e.
Reaction of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one
[(E)-14e]23 under standard conditions delivered the dihydro-
benzo[b]furan 17e in diastereoisomerically pure form with 25%
yield (Table 2, entry 8). Experiments with (E)-3-(4-hydroxy-3-
methoxyphenyl)acrylonitrile [(E)-14f]24 as the substrate were
rather disappointing as an inseparable product mixture was
obtained (Table 2, entry 9). It should be emphasized that the
laccase-catalyzed oxidative dimerization of disubstituted vanilli-
dene derivatives (E)-14a–e occurs with diastereoselective for-
mation of the dihydrobenzo[b]furan skeleton.
Next, the influence of a further substituent at the vanillidene
double bond on the outcome of the oxidation experiments was
studied. The required trisubstituted vanillidene β-dicarbonyls 15
could easily be prepared by Knoevenagel condensation between
vanillin (18) and the corresponding β-dicarbonyls with yields
ranging from 67 to 96% (Fig. 4).25 With the vanillidene β-dicar-
bonyls 15a–d at hand, the laccase-catalyzed oxidations were run
under the conditions that had been optimized for the dimeriza-
tions of 14 (Table 3).
Scheme 2 Proposed reaction mechanism for the oxidative dimerization
of 15.
expected 8,5′-coupling products 17 was formed. Instead, the
exclusive formation of biphenyls 19a–d, which can be regarded
as products of a 5,5′-coupling, was observed with yields between
80 and 100%§ (Table 3, entries 1–4). As demonstrated in control
experiments the dimerization of 15a–d did not proceed in the
absence of laccase.
It is assumed that the formation of 21 proceeds as an oxidative
dimerization of 15 (Scheme 2). In the first step 15 undergoes a
one electron oxidation to the resonance stabilized radical 16.
This is followed by dimerization of 16B, which proceeds with
selective formation of the 5,5′-coupling product 19. As far as we
are aware, a comparable 5,5′-coupling of trisubstituted vanilli-
dene derivatives has only been reported once26 using equimolar
amounts of [(diacetoxy)iodo]benzene (DAIB) as the oxidant.
The structures of all compounds were elucidated unambigu-
ously using MS and NMR methods. The full assignment of all
Again, the exclusive formation of phenolic coupling products
was observed. Using 15a–d as the substrates, not a trace of the
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Acknowledgements
We thank Ms Sabine Mika for recording NMR spectra and Drs
Heiko Leutbecher and Alevtina Baskakova for recording mass
spectra.
Notes and references
‡The activities of the laccases from T. versicolor or A. bisporus were
determined following a modified procedure taken from Danieli et al.14f
using a solution of ABTS [2.2′-azinobis-(-3-ethylbenzothiazolyl-6-sulfo-
nic acid)] as the substrate. The change in absorption was followed via
UV spectroscopy (λ = 414 nm; ε414 = 31 100 L mol−1 cm−1). 1 U is
equivalent to the amount of enzyme that catalyzes the conversion of
1 μmol ABTS per minute at 24 °C and corresponding pH.
§General procedure for the synthesis of biphenyls 19a–d: A solution of
a vanillidene derivative 15 in DMSO (8 mL) was added to NaOAc
buffer (0.1 M, pH 5.0, 72 mL). Laccase from T. versicolor (4 U, 0.4 mg)
was added and the reaction mixture was stirred under air at room temp-
erature for the reaction times given in Table 3. After extraction with
CH2Cl2 (3 × 30 mL) the combined organic phases were dried over
MgSO4, filtered and evaporated in vacuo. The crude product was
purified by flash chromatography over silica gel to afford the biphenyl
19 in analytically pure form.
¶Selected analytical data for 5,5′-di(2,2-diacetylvinyl)-2,2′-dihydroxy-
3,3′-dimethoxybiphenyl (19b): Rf 0.20 (CH2Cl2–MeOH = 40 : 1); 1H
NMR δH(300 MHz; DMSO-d6) 2.23 (6H, s, 4′′-H or 2′′′-H), 2.35 (6H, s,
4′′-H or 2′′′-H), 3.80 (6H, s, OCH3 and OCH3′), 6.90 (2H, s, 6-H and
6′-H), 7.04 (2H, s, 4-H and 4′-H) and 7.60 (s, 2H, 1′′-H); 13C NMR
δC(75 MHz; DMSO-d6) 26.09 (C-4′′ or C-2′′′), 31.40 (C-4′′ or C-2′′′),
55.87 (OCH3 and OCH3′), 112.33 (C-4 and C-4′), 123.03 (C-5 and
C-5′), 125.06 (C-1 and C-1′), 126.16 (C-6 and C-6′), 139.65 (C-2′′),
140.14 (C-1′′), 147.08 (C-2 and C-2′), 147.69 (C-3 and C-3′), 197.20
(C-1′′′ or C-3′′) and 206.37 (C-1′′′ or C-3′′).
Fig. 5 Numbering of 19b and important HMBC correlations.
1H and 13C chemical shifts was achieved by evaluating their
COSY, HSQC and HMBC spectra. As an example, the molecular
formula of compound 19b¶ (C26H26O8) was established by
HRMS (ESI pos.) analysis of its [M + H]+ at m/z 467.1700 (cal-
culated for C26H27O8, 467.1706). This result indicated that 19b
is a dimer originating from oxidative coupling of two substrate
molecules 15b. Furthermore, the 1H NMR spectrum of 19b exhi-
bits two singlets corresponding to two aromatic protons and one
singlet corresponding to a vinylic proton in a 1 : 1 : 1-ratio of
signals suggesting – in accordance with the mass spectrum – that
the product could be symmetrical (Fig. 5). A single set of 13
signals in the 13C NMR spectrum of 19b confirms the symmetri-
4
cal structure of the compound. A J4-H,6-H coupling constant of
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C-4, C-5 and C-1′′ as well as between 4-H and C-2, C-3, C-6
and C-1′′ arrange 4-H and 6-H on the same benzene ring. In
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In summary, we have reported on the laccase-catalyzed oxi-
dative dimerization of di- and trisubstituted vanillidene deriva-
tives with aerial O2 as the oxidant under mild reaction
conditions. Depending on the substitution pattern of the vanilli-
dene double bond, the formation of different products was
observed. While the oxidative coupling of ferulic acid [(E)-1]
resulted in the formation of dilactone 16 as the main product, the
dihydrobenzo[b]furans 17a–e were obtained from the dimeriza-
tion of the disubstituted vanillidenes 14a–e. With trisubstituted
vanillidene β-dicarbonyls 15a–d as substrates, the corresponding
biphenyls 19a–d were formed exclusively and with excellent
yields. The advantages of the laccase-catalyzed oxidative coup-
ling of phenols are obvious: they can be easily run using a com-
mercially available and cheap enzyme as the catalyst which is
non-toxic and environmentally benign. In addition, there is no
need for a cofactor and cofactor regeneration; laccase-catalyzed
processes employ O2, which is the cheapest and most abundant
oxidant, and water is the only by-product formed. The reactions
can be run at room temperature in an aqueous solvent system.
And last but not least the laccase-catalyzed oxidative phenolic
couplings presented here compare well with other oxidants con-
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