A One-Pot Cascade Reaction Combining an Encapsulated Decarboxylase with a Metathesis Catalyst for the Synthesis of Bio-Based Antioxidants

Article abstract of DOI:10.1002/anie.201607777

The combination of enzymes with traditional chemical catalysts unifies the high selectivity of the former with the versatility of the latter. A major challenge of this approach is the difference in the optimal reaction conditions for each catalyst type. In this work, we combined a cofactor-free decarboxylase with a ruthenium metathesis catalyst to produce high-value antioxidants from bio-based precursors. As suitable ruthenium catalysts did not show satisfactory activity under aqueous conditions, the reaction required the use of an organic solvent, which in turn significantly reduced enzyme activity. Upon encapsulation of the decarboxylase in a cryogel, the decarboxylation could be conducted in an organic solvent, and the recovery of the enzyme after the reaction was facilitated. After an intermediate drying step, the subsequent metathesis in pure organic solvent proved to be straightforward. The synthetic utility of the cascade was demonstrated by the synthesis of the antioxidant 4,4′-dihydroxystilbene in an overall yield of 90 %.

Full text of DOI:10.1002/anie.201607777

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International Edition: DOI: 10.1002/anie.201607777
German Edition: DOI: 10.1002/ange.201607777
Catalytic Cascades
A One-Pot Cascade Reaction Combining an Encapsulated
Decarboxylase with a Metathesis Catalyst for the Synthesis of Bio-
Based Antioxidants
ꢀlvaro Gꢁmez Baraibar+, Dennis Reichert+, Carolin Mꢂgge, Svenja Seger, Harald Grçger, and
Robert Kourist*
Abstract: The combination of enzymes with traditional
chemical catalysts unifies the high selectivity of the former
with the versatility of the latter. A major challenge of this
approach is the difference in the optimal reaction conditions
for each catalyst type. In this work, we combined a cofactor-
free decarboxylase with a ruthenium metathesis catalyst to
produce high-value antioxidants from bio-based precursors.
As suitable ruthenium catalysts did not show satisfactory
activity under aqueous conditions, the reaction required the use
of an organic solvent, which in turn significantly reduced
enzyme activity. Upon encapsulation of the decarboxylase in
a cryogel, the decarboxylation could be conducted in an
organic solvent, and the recovery of the enzyme after the
reaction was facilitated. After an intermediate drying step, the
subsequent metathesis in pure organic solvent proved to be
straightforward. The synthetic utility of the cascade was
demonstrated by the synthesis of the antioxidant 4,4’-dihy-
droxystilbene in an overall yield of 90%.
excludes a large number of synthetically useful metathesis
catalysts from their application in chemoenzymatic processes.
On the other hand, conducting the cascade reaction in organic
media requires enzymes that are active under non-aqueous
conditions. As only very few enzyme classes tolerate organic
media, this approach is not generally applicable. A pragmatic
compromise is a sequential reaction form with an extraction
of the intermediary product. Whereas this strategy is often the
easiest, it poses problems with intermediates of low stability
and typically requires time-consuming extraction and other
work-up steps as well as significant solvent consumption.
Enzyme encapsulation is a strategy to provide an aqueous
microenvironment while keeping the conditions hydrophobic
for the metal catalyst, thus broadening the compatibility
window. Compartmentalization allows to use both catalysts
under their optimal conditions, which makes it an easy,
generally applicable approach.[7]
Resveratrol and its analogues have received considerable
attention owing to their diverse biological effects, which
include chemoprotection, anti-oxidant, anti-inflammatory,
antidiabetic, antithrombotic, cancer prevention, and antiag-
ing properties.[8,9] Their natural synthesis requires CoA
derivatives, which makes this reaction too expensive for
in vitro processes.[8] As resveratrol synthase is highly specific
for the production of 3,4’,5-trihydroxystilbene, analogous
antioxidants such as 4,4’-dihydroxy-trans-stilbene (3a) are not
available with this system. The antioxidant 3a has been
reported to prevent cancer invasion and metastasis.[9,10]
Moreover, the antioxidant activity of 3a is four times higher
than that of resveratrol.[10] Known synthetic routes for the
production of 4,4’-disubstituted stilbene derivatives such as
the Wittig and McMurry coupling reactions are complicated
multistep approaches.[11] Olefin metathesis, on the other hand,
has proven to be a suitable reaction for the chemoselective
Chemoenzymatic cascade reactions are quite recent, excit-
ing reaction concepts as they are able to combine the benefits
of two catalysis fields.[1] Chemoenzymatic cascades have been
applied for the synthesis of amino acids,[2] the dynamic kinetic
resolution of secondary alcohols,[3] or for the generation of
polymers, for example.[4] The combination of enzymatic
reactions with water-tolerant metathesis catalysts has been
demonstrated for P450 monooxygenases and hydrolases.[5,6]
However, the mutual compatibility of all involved catalysts
and their reaction conditions, especially the solvent, is
a decisive factor that requires the existence of a compatibility
window that is often difficult to meet. On the one hand,
cascades in aqueous media or biphasic systems are limited to
catalysts with a pronounced tolerance towards water. This
[*] Dr. ꢀ. Gꢁmez Baraibar,[+] D. Reichert,[+] Dr. C. Mꢂgge, S. Seger,
Prof. Dr. R. Kourist
=
formation of C C bonds, enabling the synthesis of complex
biomolecules.[12]
Nachwuchsgruppe fꢂr Mikrobielle Biotechnologie
Ruhr-Universitꢃt Bochum
Universitꢃtsstrasse 150, 44780 Bochum (Germany)
E-mail: Robert.Kourist@rub.de
Thus we reasoned that a chemoenzymatic approach can
give rise to symmetric stilbene derivatives in a two-step one-
pot reaction (Scheme 1). This could be achieved by combining
the enzymatic decarboxylation of para-coumaric acid (1a)
with a phenolic acid decarboxylase from Bacillus subtilis
(bsPAD), yielding 4-vinylphenol (2a), with metathesis of two
4-vinylpenol molecules to produce 3a. Owing to the abun-
dance of hydroxycinnamic acid derivatives in lignocellulosic
biomass, such as wheat and rice brans, but also in waste
residues from sugar production, they are very attractive
resources for bio-based polymers and other materials.[13] The
Prof. Dr. H. Grçger
Lehrstuhl fꢂr Organische Chemie I
Fakultꢃt fꢂr Chemie, Universitꢃt Bielefeld
Universitꢃtsstrasse 25, 33615 Bielefeld (Germany)
[+] These authors contributed equally to this work.
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/anie.201607777.
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Scheme 1. Chemoenzymatic reaction concepts for the synthesis of 4,4’-dihydroxystilbene derivatives by combining the enzymatic decarboxylation
of different hydroxycinnamic acids with [Ru]-catalyzed metathesis.
subsequent olefin metathesis does not occur in nature and
thus requires a chemical catalyst. Coupling the enzymatic
decarboxylation with the metathesis step in a one-pot
reaction avoids the need to purify the vinylphenol intermedi-
ates. As these are prone to undergo polymerization,[14] a one-
pot cascade approach significantly facilitates this route.
Furthermore, this concept avoids time-consuming protect-
ing-group chemistry and purification of intermediate 2a.
Herein, we achieve the combination of enzymatic decarbox-
ylation and metathesis in organic solvents in a two-step one-
pot fashion by entrapment of the biocatalysts.
The cofactor-free phenolic acid decarboxylase (bsPAD)
from B. subtilis has already been shown to be a robust and
suitable biocatalyst for the conversion of hydroxycinnamic
acids 1a–c.[15] After cloning from genomic DNA, soluble
expression and purification yielded 40 mg semi-purified
bsPAD from 1 g cell pellet. The hydroxycinnamic acids 1a–c
were efficiently converted by the purified enzyme in potas-
sium phosphate buffer (KPi, 50 mm, pH 6.0, 308C) with
specific activities of 312 Æ 40 (1a), 188 Æ 2 (1b), and 129 Æ
4 UmgÀ1 (1c), respectively. Although the enzyme showed an
observable activity of 1.0 Æ 0.3 UmgÀ1 towards sinapinic acid
(1d), this was judged to be too low for the envisioned cascade
process. Sinapinic acid was therefore excluded from further
studies.
To find suitable catalysts for this cascade reaction, differ-
ent ruthenium complexes C1–C7 were evaluated for the
metathesis of 2a into 3a, as well as that of styrene (2e) to give
stilbene (3e) as a robust model substrate (see the Supporting
Information, Table S1). The catalysts were selected based on
reports of the preparation of polyhydroxystilbene deriva-
tives,[16] and their reported tolerance towards air and appreci-
able reactivity in non-degassed and non-dried solvents such as
ethyl acetate and isopropanol.[17] Aside from dichlorome-
thane (DCM) and tetrahydrofuran (THF) as standard meta-
thesis solvents, reactions were additionally conducted in
2-methyltetrahydrofuran (2-MeTHF), as an environmentally
friendly alternative solvent derived from renewable resour-
ces,[18] and in methyl tert-butyl ether (MTBE), which was also
chosen for extraction. Notably, the specific activity of the [Ru]
catalysts towards the two substrates 2a and 2e differed
remarkably (Table S1, entries 2–8): Catalysts with high activ-
ity towards 2e, such as C5, showed poor conversion of 2a and
vice versa. With Grubbsꢀ second-generation catalyst (C1), the
metathesis reaction could be conducted in anhydrous solvents
and under anaerobic conditions. Catalyst C2, however,
converted 2a with satisfactory performance in several sol-
vents, with yields ranging from 40% in 2-MeTHF to 67% in
MTBE under aerobic conditions (Table S1, entry 3). Based on
these results, catalysts C1 and C2 were chosen for establishing
the chemoenzymatic cascade reaction. Owing to low con-
versions, DCM was excluded as a metathesis solvent from
further studies. At this point, it should also be noted that the
direct coupling of para-coumaric acid was not possible under
the screened reaction conditions (data not shown), emphasiz-
ing the need for a decarboxylation step prior to metathesis. A
possible reason might be a less favorable reaction equilibrium
owing to the formation of non-volatile fumaric acid as
opposed to volatile ethylene.
Once both the enzymatic and the metathesis reaction had
been reliably established, the combination of both steps in
a chemoenzymatic cascade was pursued. Three different
procedures were considered (Scheme 1): a sequential two-pot
reaction with intermediate work-up (I), the combination of
both steps in a biphasic one-pot system (II), and a sequential
one-pot reaction with encapsulated bsPAD in pure organic
solvent, an intermediary drying step, and subsequent meta-
thesis (III).
The straightforward two-pot cascade with free enzyme in
aqueous buffer (I) bears the advantage that the enzymatic
step as well as the metathesis reaction can be conducted under
their individually optimized conditions. Hence, as a first step,
the decarboxylation reaction was performed in buffered
solutions using 100 mg of substrate 1a–c, which resulted in
full conversion within 18 h–24 h. Compounds 2 were obtained
in high yields of 80% to 95% after extraction with MTBE
(Table 1, entries 1–4). The tendency of intermediates 2 to
undergo spontaneous polymerization reduces their storage
stability considerably and requires immediate further proc-
essing. As 1H NMR spectra of the extracted fractions showed
no unreacted 1a–c, the subsequent metathesis could be
performed by simply re-dissolving the vinyl derivatives 2 in
2
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Table 1: Product yields for two-pot (top) and one-pot (bottom) cascade reactions for the synthesis of polysubstituted stilbene derivatives.
Entry
1
Conversion[a]
[%]
Yield 2[b]
[%]
Metathesis
solvent
[Ru]
Conversion[c]
[%]
Yield 3[d]
[%]
Total yield
[%]
[mg]
[mg]
1
2
3
4
5
6
a
b
c
a
a
a
>99
>99
>99
>99
>99
>99
95
80
93
87
95
91
70
62
70
64
70
67
THF
THF
THF
2-MeTHF
MTBE
MTBE
C1
C1
C1
C1
C1
C2
59
68
0
95
44
85
49
27
0
67
33
78
30
15
0
38
20
46
46
21
0
58
31
71
7
8
9
a
a
b
c
>99
>99
>99
>99
–
–
–
–
–
–
–
–
MTBE
MTBE
MTBE
MTBE
C1
C2
C2
C2
73
95
–
–
–
–
39
58
60
90
76
25
36
10
n.d.[e]
25[e]
ca. 37[e]
[a] Conversion of 1 into 2 determined by TLC. [b] Yield of isolated product for the transformation of 100 mg 1a–c with 20 mg crude cell-free extract in
potassium phosphate buffer (50 mm, pH 6.0, 308C) after extraction with MTBE. [c] Conversion of 2 into 3 determined by 1H NMR spectroscopy.
[d] Yield of isolated product after metathesis of the vinyl derivatives 2a–c with 5 mol% [Ru] catalyst. For the one-pot process (entries 7–10), the
solution was predried with anhydrous MgSO4 prior to addition of the [Ru] catalyst. [e] The conversion could not be determined owing to signal overlap;
the product was obtained with about 68% purity as judged by HPLC.
the respective solvent without intermediate purification. The
[Ru] catalyst was added as a solid, and the second reaction
was run under the optimized conditions. However, a first
attempt with C1 as the catalyst produced 3a in only 10% yield
after isolation despite good conversion of 2a (79%, data not
shown).
decarboxylation proceeded smoothly in the biphasic buffer/
isooctane system with full conversion of a 5 mm solution of 1a
after 20 minutes, the lability of the investigated metathesis
catalysts towards water and air made it difficult to achieve full
conversion. In fact, even the quite stable metathesis catalyst
C2 did not exceed 20% conversion.
By treating the reaction solution with 20 mol% di(eth-
yleneglycol)–monovinyl ether as a scavenger[19] prior to
purification, the yield of 3a could be increased to 46% in
THF (entry 1) and 58% (at 95% conversion of 2a) in
2-MeTHF (entry 4). Furthermore, although good enzymatic
conversion of methoxy derivative 1b into 2b (67%) was
achieved, the corresponding stilbene 3b was isolated in only
27% yield after the second step (entry 2). The synthesis of 3c
proved to be challenging under all studied conditions as 2c
did not undergo measureable conversion with C1 (entry 3).
Despite the promising total conversions that were ach-
ieved for 3a and 3b, the cascade process required careful
handling of the reaction intermediates 2a–c. Thus we
reasoned that a direct one-pot cascade would alleviate this
limitation and facilitate the upscaling of the reaction. There-
fore, we first investigated the possibility of using a biphasic
system (Scheme 1, II) comprising buffer and 2,2,4-trimethyl-
pentane (isooctane).[5] However, whereas the enzymatic
As it became clear that the metathesis of vinylphenol
intermediate 2 required conditions with low water activity,
and bsPAD did not show activity in the hydrophobic solvents
tested, we assumed that a chemoenzymatic one-pot cascade
could only be achieved by increasing the enzyme stability in
a non-aqueous environment. Thus the overall reaction was
run as a one-pot, two-step cascade (Scheme 1, III) using
MTBE as the solvent for both reactions. Recently, Ansorge-
Schuhmacher et al. developed poly(vinyl alcohol)/poly(ethy-
lene glycol) (PVA/PEG) cryogels[20] that entrap an enzyme in
an aqueous environment. This enabled the decarboxylation of
1a–c to be conducted in water with pure organic solvent
outside the capsules (Figure 1). Entrapment of a cell-free
extract of bsPAD retained 39% of the enzymatic activity
compared to an equivalent amount of crude extract.
The recyclability of encapsulated bsPAD was confirmed
by running the decarboxylation of 1a for several cycles, with
62% of the original enzymatic activity retained after the fifth
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tion was proven to be a successful strategy to facilitate the
sequential application of an enzyme with low stability in
organic media and metathesis catalysts with low water
tolerance. Overcoming the mutual incompatibility of differ-
ent catalysts and their reaction conditions is an essential task
for the development of robust one-pot cascade concepts that
avoid problems such as unstable intermediates and reduce
intermediate extraction steps. In this context, the use of
enzyme PVA/PEG cryogels proved to be a simple, practical
approach for the application of the decarboxylase in organic
media. A major advantage lies in the facile removal of the
particles by filtration, which simplifies downstream process-
ing. Owing to its applicability with cell-free extracts contain-
ing enzymes with low tolerance towards organic solvents, we
expect that this elegant approach will be applicable to a large
number of cascade reactions. Despite the intrinsic challenges
posed by the metathesis reaction, the high conversions
obtained at a substrate concentration of 3 gLÀ1 on 100 mg
scale are an excellent proof of concept for the possibility to
combine encapsulated enzymes and traditional chemical
catalysts in one-pot reactions.
Figure 1. Encapsulation of bsPAD in PVA/PEG cryogels enables the
combination of the enzymatic decarboxylation with subsequent meta-
thesis in MTBE. The enzyme is entrapped in an aqueous environment
while the substrates (1a–c) and products (2a–c) can freely diffuse
through the gel.
usage of the same capsules (Figure S1). The performance of
the encapsulated bsPAD enzymes was then tested in different
organic solvents (Table S2). Non-polar solvents such as
MTBE or isooctane gave better results than the partially
water-miscible solvents THF and 2-MeTHF. As isooctane had
been determined not to be an effective medium for the
metathesis of 2a, MTBE was chosen as a good compromise
for both reactions.
Acknowledgments
The Federal Ministry for Innovation, Science and Research of
North Rhine-Westphalia (PtJ-TRI/1411ng006) is gratefully
acknowledged for financial support.
The decarboxylation of 100 mg 1a in a biphasic system
with bsPAD encapsulated in PVA/PEG cryogels achieved
> 99% conversion after 24 h using 1 g of the gel beads in
30 mL MTBE. Owing to the large size of the beads (ca. 3 mm
diameter), the capsules can be easily removed from the
reaction medium, leaving only the substrate for the meta-
thesis. Afterwards, the solvent was dried with anhydrous
MgSO4, producing a sufficiently “dry” reaction medium for
the metathesis reaction. Finally, catalyst C1 was added and
after 4 hours of reaction, 73% conversion of 2a was achieved
with a final overall yield of 60% for 3a (Table 1, entry 7). In
an analogous two-pot cascade process using MTBE for
extraction and direct addition of catalyst C1, significantly
lower conversion (44%, entry 5) of 2a after 4 h was achieved,
which underlines the advantages of a one-pot cascade using
PVE/PEG cryogels for compartmentalization. According to
the catalyst screen, [Ru] complex C2 showed considerable
activity towards 2a. Hence, the one-pot cascade was repeated
using 5 mol% of C2 for the homodimerization of the vinyl
derivatives 2a–c. Notably, the conversion of 2a was increased
to 95% after 4 h (entry 8), resulting in a total yield of 90% for
3a. Furthermore, the use of C2 improved the formation of 3b
(76%). Although it could not be isolated in pure form (68%
purity after flash chromatography), this catalyst system also
gave access to 3c, which was not possible with C1.
Keywords: bio-based antioxidants · biocatalysis ·
compartmentalization · decarboxylation · metathesis
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Received: August 10, 2016
Published online: && &&, &&&&
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Communications
Catalytic Cascades
ꢁ. Gꢂmez Baraibar, D. Reichert,
C. Mꢃgge, S. Seger, H. Grçger,
R. Kourist*
&&&& — &&&&
A One-Pot Cascade Reaction Combining
an Encapsulated Decarboxylase with
a Metathesis Catalyst for the Synthesis of
Bio-Based Antioxidants
The mutual incompatibility of catalysts
and their reaction conditions is a frequent
challenge for chemoenzymatic one-pot
reactions. The encapsulation of a decar-
boxylase in PVA/PEG gel capsules ena-
bled its combination with a ruthenium
metathesis catalyst in organic solvents
for the synthesis of antioxidants from
inexpensive, bio-based hydroxycinnamic
acids in up to 90% yield.
6
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