Multienzyme One-Pot Cascade for the Stereoselective Hydroxyethyl Functionalization of Substituted Phenols

Article abstract of DOI:10.1021/acs.orglett.8b02058

The operability and substrate scope of a redesigned vinylphenol hydratase as a single biocatalyst or as part of multienzyme cascades using either substituted coumaric acids or phenols as stable, cheap, and readily available substrates are reported.

Full text of DOI:10.1021/acs.orglett.8b02058

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Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Multienzyme One-Pot Cascade for the Stereoselective Hydroxyethyl
Functionalization of Substituted Phenols
†
†
†
†
†
̌
́
Stefan E. Payer, Hannah Pollak, Benjamin Schmidbauer, Florian Hamm, Filip Juricic,
Kurt Faber,*,† and Silvia M. Glueck*,†,‡
†Institute of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28/2, 8010 Graz, Austria
‡Austrian Centre of Industrial Biotechnology (ACIB), Petersgasse 14, 8010 Graz, Austria
S
* Supporting Information
ABSTRACT: The operability and substrate scope of a
redesigned vinylphenol hydratase as a single biocatalyst or as
part of multienzyme cascades using either substituted coumaric
acids or phenols as stable, cheap, and readily available substrates
are reported.
arious strategies are pursued in order to fulfill the
cinnamic acid derivatives from renewable feedstocks15−18 as
Vrequirement for a greener and more sustainable chemical substrates or can be prolonged by two further enzymatic steps,
which have been described in the literature,19 to exploit simple
phenols as starting materials.
production.1 The ability of enzymes to work under ambient
conditions in a highly selective manner evidences biocatalysis
as a powerful concept for eco-friendly synthetic applications of
valuable compounds, which enormously benefit from the rapid
progress in molecular biology and biotechnology. The use of
two or even more enzymes in a cascadewise fashion can
considerably improve the efficiency of a multistage synthesis by
circumventing the isolation of (unstable) intermediates, thus
saving time, resources, and reagents while simultaneously
diminishing the consumption of energy and the production of
waste.2−4 Further aspects such as the overall cascade should
run energetically downhill, and the introduction of an
appropriate (internal) cofactor recycling in the case of
cofactor-dependent enzymes and a preferably irreversible last
step in order to increase the overall yield need to be taken into
account. Limitations faced in one-pot setups, such as
substrate/product/reagent inhibition or the incompatibility
of reaction conditions required by one catalyst to the other(s),
might be circumvented by a sequential (chronological
separation) order.2
Herein, we present a redox-neutral, atom-efficient multi-
enzyme system for the production of valuable (S)-1-(4-
hydroxyphenyl)ethanols as an alternative to biocatalytic redox
processes (Scheme 1).5−9 A promiscuous para-vinylphenol
hydratase activity of ferulic acid decarboxylase from Enter-
obacter sp.,10−12 which was significantly improved by a rational
redesign approach (FDC* mutant),13 was merged with a
prefixed decarboxylation step catalyzed by the wild-type
enzyme (FDC).14 The cascade enables the utilization of
The replacement of a neutral valine by a carboxylate (Glu/
Asp) residue as a catalytic base for the activation of water in
the active site of FDC completely waived the requirement for
bicarbonate as a proton relay cofactor and significantly
enhanced the promiscuous hydration of 4-vinylphenols.13 In
order to evaluate their biocatalytic potential, the substrate
scope of the improved hydratase variants FDC_Es V46E and
V46D was probed with a set of para-vinylphenols (4) bearing
different substituents on the aromatic core or the vinyl side
chain under previously optimized conditions13 (Scheme 2,
Table 1).
A comparison of substrates 4a−e with previously reported
results using wild-type decarboxylase FDC_Es in the presence
of bicarbonate (3 M)10,11 reveals a superior performance of the
redesigned hydratase variants (Table 1). In all cases,
conversion and stereoselectivity could be significantly
increased compared to the wild-type enzyme, except for the
stereoselectivity with 4d, which however was low in general. In
addition to chlorinated vinylphenol (4b), also fluorine (4f)
and bromine (4g) substituents were well tolerated in position
2. A strong electron-withdrawing nitro group in the same
position (4h) was also accepted with high stereoselectivity,
albeit in low conversion. It seems that electronic effects of the
substituents ortho to the phenolic OH group play only a minor
Received: July 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Elements of the Envisioned Multienzyme Decarboxylation/Hydration (A) and Hydroxyethylation (B) Cascade
a
TPL: Tyrosine phenol lyase; TAL: tyrosine ammonia lyase; FDC: ferulic acid decarboxylase; FDC*: FDC − hydratase variant.
in terms of selectivity and reaction rates, with slightly better
results using the glutamate variant (V46E) especially with
halogens in position 3.
Scheme 2. Substrate Scope of FDC_Es V46E and V46D
Hydratase Variants
a
A major limitation for the preparation of chiral benzylic
alcohols via the biocatalytic hydration of 4-vinylphenols is the
preparation and storage of these compounds. A conventional
protocol for the synthesis of hydroxystyrene derivatives
exploits an atom-inefficient Wittig olefination of the corre-
sponding hydroxybenzaldehydes with methyltriphenylphos-
phonium halides under basic conditions.20−22 The obtained
hydroxystyrenes are prone to spontaneous cationic polymer-
ization under neat conditions23,24 and require stabilization in
polar solvents for storage.25 Alternatively, a preceding
decarboxylation step catalyzed by phenolic and ferulic acid
decarboxylases26,27 would allow the design of an enzymatic
cascade that converts stable coumaric acid derivatives into
chiral benzylic alcohols avoiding the isolation of troublesome
vinylphenols (Scheme 1A).
a
For conversion and ee see Table 1.
role, but their influence is mainly of steric nature; i.e., the
results improve in the order of R1 = NO2 < OEt < OMe <
halogen < Me < H. Furthermore, the tolerance toward alkyl
substituents on the styrene double bond was investigated since
the hydration of such substrates would give rise to a quaternary
stereocenter. However, only a methyl group on Cα (4k) was
accepted, yielding the meso tertiary benzylic alcohol with
moderate success, whereas substitution on Cβ (4l−n) was not
tolerated at all. Overall, both variants performed fairly similar
a
Table 1. Substrate Scope of FDC_Es V46E and V46D Hydratase Variants
a
Reaction conditions: purified FDC_Es variant (100 μM), substrates 4a−n (10 mM, as 10% w/w stock in propylene glycol) in potassium
b
phosphate buffer (50 mM, pH 6.0), incubation for 24 h at 25 °C, and 700 rpm shaking (orbital shaker). n.d. = not determined due to low
conversion. Literature results with bicarbonate supplementation.10,11 GC-MS conversion of the olefin 4k to a product with m/z of the alcohol 5k.
c
d
e
f
g
The E-configured olefin was used. The Z-configured olefin was used. The (S)-configured product was formed throughout unless otherwise
h
i
stated. Absolute configuration was not determined. n.i. = not investigated in the literature.
B
DOI: 10.1021/acs.orglett.8b02058
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A time study with 3-chlorocoumaric acid (3b) as a
representative substrate showed rapid reaction progress with
full consumption of the coumaric acid within 17 min and 94%
conversion to the enantiomerically pure benzylic alcohol
product 5b after 2 h (97% ee) (Figure 1a). Continued
Table 2. Results of the Substrate Screening for the
Decarboxylation/Hydration Cascade
a
b
b
substrate product
R
3.5 h conv (ee) [%] 24 h conv (ee) [%]
3a
3b
3c
3e
3f
3g
3i
3j
5a
5b
5c
5e
5f
5g
5i
5j
H
30 (91)
91 (95)
6 (54)
58 (91)
61 (85)
94 (93)
51 (93)
14 (96)
93 (84)
96 (66)
93 (42)
94 (78)
96 (63)
98 (64)
94 (75)
86 (87)
2-Cl
2-OMe
2-Me
2-F
2-Br
3-F
3-Cl
a
Reaction conditions: purified FDC_Es wt (10 μM), purified
FDC_Es V46E variant (100 μM), substrates 3 (10 mM, supplied as
100 mM stock in iPrOH, 10% v/v) in potassium phosphate buffer (50
mM, pH 6.0), incubation for 3.5 and 24 h at 25 °C, and 700 rpm
b
shaking (orbital shaker). The (S)-enantiomer was formed through-
out.
evaluated after 3.5 and 24 h (Table 2, Scheme 3). All products
were initially formed with a moderate to very good ee, which
however decreases upon continued incubation for 24 h and a
correlation between conversion, and rate of ee loss can be
observed. Electron-withdrawing halogen substituents in
position 2 (5b, 5f, 5g) seem to accelerate both the water
addition and decline of ee in the order of Br > Cl > F due to
deactivating polarization, whereas with an electron-donating
group (5c, 5e) or no substitution in this position (5a) this
effect is less pronounced. Halogens in position 3 support the
formation of the quinone-methide form by inductive and
mesomeric effects and hydration, and selectivity decline is
more pronounced with a fluorine (5i) than a chlorine
substituent (5j). Although stereoselectivity slightly suffered in
the two-step setup, conversions comparable to the direct
hydration of 4 were observed, highlighting the viability of this
system.
Figure 1. (a) Time study of the decarboxylation/hydration cascade
with 3-chlorocoumaric acid (3b) as substrate at pH 6.0 (full
conversion within 17 min). (b) Time profile of the four-enzyme
vinylation/hydration cascade at pH 8 with 2-chlorophenol (1b) as
substrate and FDC_Es V46E as hydration catalyst. The amount of
coumaric acid 3b was ≤1% in all samples (not shown).
The most straightforward way to prepare the benzylic
alcohol products would be the direct hydroxyethyl function-
alization of simple substituted phenols. In the present setup we
envision telescoping a recently developed vinylation cascade19
by a fourth biocatalytic hydration step to gain direct access to
chiral benzylic alcohols starting from phenols (Scheme 1B). An
engineered PLP-dependent tyrosine phenol lyase (TPL) from
Citrobacter freundii catalyzes the coupling of phenol with
pyruvate and ammonia in the first step of the cascade to give
the corresponding tyrosine derivative.28 The α-amino group of
the tyrosine is eliminated (and thus formally recycled) by the
action of a tyrosine ammonia lyase (TAL, from Rhodococcus
sphaeroides)29 in the second step of the cascade, arriving at the
substituted coumaric acid as the intermediate. The final
decarboxylation drives the cascade toward complete con-
version into hydroxystyrene derivatives, which in turn serve as
substrates for enzymatic hydration. The redox-neutral net
reaction of this system therefore represents a formal
hydroxyethylation of phenols with pyruvate as cosubstrate
and CO2 as sole side product, which does not require costly
redox cofactors and associated recycling systems (Scheme 4).
A reaction pH of 8.0 was shown to be crucial for the
vinylation cascade to work efficiently,19 but the optimal pH of
the hydration process was found at pH 6.0, above which the
selectivity of the hydratase decreases.13 To address this
compatibility issue, 2-chlorophenol (1b) was used as a
incubation under the reaction conditions is however
accompanied by a linear decrease of the product ee, reaching
66% after 24 h. This phenomenon resembles previous
observations11 and can be explained by a nonselective
background hydration of 4 occurring either spontaneously13
or with FDC_Es wt in the absence of bicarbonate.11,12 Hence,
careful monitoring of the reaction progress and to stop the
biotransformation after an appropriate reaction time are
required for optimal results.
The viability of the envisioned system was validated with
coumaric acid derivatives 3a−j bearing analogous substituents
to vinylphenols 4a−j (except for analogues of poorly accepted
4d and 4h) (Scheme 3, Table 2). To estimate the rate of
racemization observed in the previous time study in the
presence of different substituents, the reaction progress was
a
Scheme 3. Two-Step Decarboxylation/Hydration Cascade
a
For conversion and ee see Table 2.
C
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required for the preceding vinylation step (NH4Cl, pyruvate,
and PLP) and the nonoptimal reaction pH. However,
stereoselectivity was generally improved with this system.
Finally, the one-pot cascade was performed on a 30−40 mg
scale (0.2 mmol) with substrates 1f, 1g, 1i, and 1j (20 mM),
followed by isolation and characterization of the products (for
yields, see Table 3). Comparable results to the analytical scale
reactions without significant erosion of the ee were achieved
(see Table S4, SI).
In conclusion, we evaluated the substrate scope of two
vinylphenol hydratases that were rationally designed from a
ferulic acid decarboxylase and found them to perform the (S)-
selective addition of water with high conversion and stereo-
selectivities although restricted to vinylphenols bearing various
substituents on the aromatic core. These hydratases lack the
dependency on bicarbonate required as the hydration cofactor
by the wild-type decarboxylase, thus facilitating the imple-
mentation of this biotransformation into multienzyme
cascades. Two redox-neutral systems aiming at circumventing
the use of delicate vinylphenol substrates were investigated for
the synthesis of (S)-benzylic alcohols starting from either
substituted coumaric acids or simple phenols as substrates.
Scheme 4. Four-Step Vinylation/Hydration (Redox-Neutral
Hydroxyethylation) Cascade (Net Equation)
a
a
For conversion and ee see Table 3.
model substrate in a time study of the overall vinylation/
hydration cascade at pH 8.0 (Figure 1b).
A steady conversion of phenol 1b to tyrosine 2b and further
conversion of the latter to the corresponding coumaric acid 3b
were observed. Due to its rapid decarboxylation, the amount of
3b was ≤1% over time (not shown in Figure 1b), and only
formation of the hydroxystyrene 4b could be detected after 1
h, reaching a steady state at around 15% after 5 h. The benzylic
alcohol 5b accumulated over time, reaching 75% conversion
after 24 h. As in the two-step decarboxylation/hydration
cascade, the ee of the chiral (S)-alcohol product drops linearly
over time (87% after 24 h), albeit at a lower rate (Figure 1b).
Even though the one-pot cascade was operated at pH 8.0 to
optimize the performance of the vinylation cascade, a good
stereoselectivity for the styrene hydration could be maintained,
and the decline of ee was less pronounced. Attempts to
improve the performance of the cascade by changing to a
sequential mode (providing an option for pH adjustment) did
not lead to significantly better results [see Table S3,
Supporting Information (SI)].
In order to evaluate the biocatalytic scope of the
multienzyme system, a representative set of substituted
phenols (1) were applied as substrates (Table 3). All phenols
were successfully converted into the corresponding benzylic
alcohols (5) via the four-enzyme cascade, except for o-cresol
(1e), whose conversion mainly stalled at the stage of the
corresponding amino acid (2e). Slightly lower conversions to 5
compared to the two-step decarboxylation/hydration cascade
(Table 2) can be explained by the presence of additives
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02058.
Experimental details and supplementary results, prep-
aration of substrates and reference material, and
compound characterization (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kurt.faber@uni-graz.at.
*E-mail: si.glueck@uni-graz.at.
ORCID
Kurt Faber: 0000-0003-0497-5430
Silvia M. Glueck: 0000-0003-2154-7585
Notes
a
Table 3. Results of the Phenol Hydroxyethylation Cascade
b
d
The authors declare no competing financial interest.
substrate
product
R
conv (ee) [%]
yield (ee) [%]
1a
1b
1e
1f
1g
1i
5a
5b
5e
5f
5g
5i
H
73 (92)
85 (83)
12 (95)
91 (81)
84 (87)
80 (87)
36 (95)
−
−
−
ACKNOWLEDGMENTS
2-Cl
2-Me
2-F
2-Br
3-F
■
c
We thank Philipp Neu and Klaus Zangger (Institute of
Chemistry, University of Graz) for the measurement of high-
resolution mass and NMR spectra, respectively. Eduardo Busto
(Department of Organic Chemistry, Complutense University
of Madrid) is cordially thanked for sharing his know-how on
the vinylation cascade. Funding by the Austrian Science Fund
(FWF project P26863-N19) and the Austrian BMWFW,
BMVIT, SFG, Standortagentur Tirol, Government of Lower
Austria, and ZIT through the Austrian FFG-COMET-Funding
Program is gratefully acknowledged.
84 (78)
58 (88)
72 (85)
29 (92)
1j
5j
3-Cl
a
Reaction conditions analytical scale: Lyophilized E. coli whole cells
containing the heterologously expressed TPL_Cf M379 V (10 mg
mL−1, 448 mU), TAL_Rs (40 mg mL−1, 35 mU), FDC_Es wt (2 mg
mL−1, 3.2 U), and purified FDC_Es V46E variant (100 μM, 1 mol %)
in reaction buffer [potassium phosphate buffer (50 mM, pH 8.0),
sodium pyruvate (92 mM), NH4Cl (180 mM), and PLP (80 μM), pH
adjusted to 8.0] with substrate phenol (10 mM, 50 μL of a 200 mM
stock in iPrOH, 5% v/v). Incubation at 30 °C and 850 rpm for 24 h.
HPLC conversion: the corresponding vinylphenol 4 was detected as
the major remaining intermediate. Phenol 1e and tyrosine 2e were
detected as major constituents. Isolated yield after column
chromatography.
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