Biocatalytic One-Pot Synthesis of l-Tyrosine Derivatives from Monosubstituted Benzenes, Pyruvate, and Ammonia

Article abstract of DOI:10.1021/acscatal.5b02129

l-Tyrosine derivatives were obtained in >97% ee via a biocatalytic one-pot two-step cascade using substituted benzenes, pyruvate, and NH₃ as starting materials. In the first step, monosubstituted arenes were regioselectively hydroxylated in the o-position by monooxygenase P450 BM3 (using O₂ as oxidant with NADPH-recycling) to yield the corresponding phenols, which subsequently underwent C-C coupling and simultaneous asymmetric amination with pyruvate and NH₃ using tyrosine phenol lyase to furnish l-DOPA surrogates in up to 5.2 g L^-1. Instead of analytically pure arenes, crude aromatic gasoline blends containing toluene were used to yield 3-methyl-l-tyrosine in excellent yield (2 g L^-1) and >97% ee.

Full text of DOI:10.1021/acscatal.5b02129

Letter
pubs.acs.org/acscatalysis
Biocatalytic One-Pot Synthesis of L‑Tyrosine Derivatives from
Monosubstituted Benzenes, Pyruvate, and Ammonia
Alexander Dennig, Eduardo Busto,† Wolfgang Kroutil,* and Kurt Faber*
Department of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria
S
* Supporting Information
ABSTRACT: L-Tyrosine derivatives were obtained in >97% ee
via a biocatalytic one-pot two-step cascade using substituted
benzenes, pyruvate, and NH3 as starting materials. In the first
step, monosubstituted arenes were regioselectively hydroxy-
lated in the o-position by monooxygenase P450 BM3 (using O2
as oxidant with NADPH-recycling) to yield the corresponding phenols, which subsequently underwent C−C coupling and
simultaneous asymmetric amination with pyruvate and NH3 using tyrosine phenol lyase to furnish L-DOPA surrogates in up to
5.2 g L−1. Instead of analytically pure arenes, crude aromatic gasoline blends containing toluene were used to yield 3-methyl-L-
tyrosine in excellent yield (2 g L−1) and >97% ee.
KEYWORDS: tyrosine, lyase, phenol, monooxygenase, hydroxylation
In the first step, the regio- and chemoselective o-
roteinogenic (canonical) and nonproteinogenic α-amino
Pacids are among the top-five families of natural compounds hydroxylation of an arene (1a−f) is catalyzed by a mutant of
P450 BM3 (variant M2: R47S, Y51W, I401M)11,12 with high o-
used for the synthesis of materials, pharmaceuticals, and
nutrients.1 Enantiomerically pure L-tyrosine derivatives repre-
sent key precursors for anticancer drugs (e.g., saframycin A),
biochemical markers, and are important noncanonical amino
acids for synthetic biology.2 In particular, 3-methoxy-L-tyrosine
(L-4c) is a pro-drug of L-DOPA, as it is significantly more stable
and shows beneficial properties in the treatment of Parkinson’s
disease.3 In addition, it constitutes an important biochemical
marker for human L-amino-acid decarboxylase deficiency.2c,4
Chemical de novo synthesis of tyrosine derivatives proceeds
through several steps and leads to racemic material,5 which
requires late-stage racemate resolution. Direct functionalization
of L-Tyr is based on protective group chemistry2e or needs
harsh reagents, such as F2 or HNO3.6 In order to shortcut
chemical synthesis, a biocatalytic C−C coupling was developed
employing tyrosine phenol lyase mutant M379V (TPL) from
Citrobacter freundii.7 Despite the good yields and excellent
stereoselectivity (conversions 27−99%, ee’s >97%), this
method depends on o-substituted phenols (3a−f) as indis-
pensable starting materials. The latter are industrially produced
by air-oxidation of substituted benzenes through the Hock-
process with low efficiency (∼5% yield).8 Due to the harsh
reaction conditions (∼20 bar, > 100 °C, strong acids),8,9 isomer
purification is necessary to obtain o-substituted phenols in high
purity. Alternatively, phenol can be synthesized from benzene
using a fungal peroxidase and H2O2 as oxidant.10 However, due
to overoxidation issues and the use of H2O2, this method is
unsuitable for a multienzyme cascade. Aiming at a more
efficient process for synthesis of L-tyrosine derivatives, we
designed a synthetic one-pot biocascade that utilizes the
combined activity of a monooxygenase and a C−C lyase
(Scheme 1).
selectivity (3a−f vs 2a−f > 95/5). The use of atmospheric O2
as oxidant allowed us to combine it in situ with the TPL-
catalyzed C−C coupling of the o-phenolic intermediate (3a−f)
to pyruvate under consumption of NH3 to afford L-4a-f.7 The
feasibility of this cascade was evaluated using 1c as model
substrate.7a,12a P450 BM3 and TPL were both employed as cell-
free lyophilized lysate providing an “off-the-shelf” catalyst that
can be stored over several months. Initial conversions of 1c
using reported reaction conditions for TPL7a yielded ∼5% of L-
4c, proving that both enzymatic steps can be performed
simultaneously in a one-pot fashion (see Supporting
Information (SI); Figure S1). However, the majority of
intermediate 3c (83%) remained unconverted, thus identifying
the C−C coupling (step 2) as bottleneck.
In order to avoid inhibition of TPL, the concentration of
reaction components was varied to elucidate their effect on the
cascade productivity and (chemo)selectivity (defined as % of L-
4a-f in the product mixture). A substantial effect on the
selectivity for L-4c was identified when varying concentrations
of NADP+ and P450 BM3, whereas the presence of gluconic
acid (<100 mM, derived from nicotinamide-recycling) or
intermediate 2c had no influence on TPL activity (see SI).
However, the most critical parameter for the insufficient
coupling between steps 1 and 2 turned out to be the drop in
pH due to release of gluconic acid during NADPH-
regeneration,13 which shifts the equilibrium of the TPL-reaction
unfavorably toward C−C cleavage (pH ≤ 7).7a,c In order to
maintain a slightly alkaline pH to support C−C coupling, the
Received: September 23, 2015
Revised: November 5, 2015
© XXXX American Chemical Society
7503
DOI: 10.1021/acscatal.5b02129
ACS Catal. 2015, 5, 7503−7506

ACS Catalysis
Letter
Scheme 1. One-Pot Two-Step Biocascade Employing P450 Monooxygenase BM3 Variant M2 (R47S, Y51W, I401M)11 and
a
Tyrosine Phenol Lyase Mutant M379V (TPL)7a To Form L-Tyrosine Derivatives (L-4a-f) from Substituted Benzenes (1a−f)
a
Minor side products/reactions are highlighted in brackets. PLP = pyridoxal phosphate; GDH = glucose dehydrogenase.
KPi-buffer (pKa 7.2; 48% conversion of 1c; 18% L-4c) was
exchanged by a Tris-system (pKa 8.2; 21% conversion of 1c;
71% L-4c), which improved the formation of L-4c by a factor of
1.7 (Figure S2, SI). As alternative to the GDH/NADPH/
glucose-recycling system, the use of formate dehydrogenase/
NADH/formate14 was less efficient (14% conversion of 1c,
9.7% L-4c, SI; Figure S5), most likely due to the lower coupling
efficiency of P450 BM3 with NADH as cofactor. Similarly,
disappointing results were obtained with a NADH-dependent
P450 BM3-variant15 in combination with the FDH-system
(55% of the GDH system; 24% conversion of 1c; 19% L-4c).
The isomeric p-phenolic side product (2c) was detected in
trace amounts (<5%)12a together with p-hydroquinone 5c as a
consequence of secondary hydroxylation of 3c by the P450
catalyst.16 In order to monitor the reaction in more detail, a
time study was performed (Figure 1). Substrate 1c was oxidized
rapidly (57 μM min−1 of 3c formed) by the P450 catalyst and L-
4c was already detectable after 10 min (20 μM min−1 of L-4c
formed), indicating efficient coupling of both steps. 2c was
produced only in traces (<5%) and 5c started to accumulate at
detectable amounts (>5%) after 2 h. After 6 h, 75% of 1c was
converted by P450 BM3 and L-4c peaked at 42% (0.88 g L−1).
To explore the substrate scope of the cascade, six arenes (1a−f)
were converted at three different substrate concentrations
(Table 1; see SI for 10 mM values). All substrates were
converted to the respective L-amino acids with large variation in
conversion of 1a−f (7−87%) and selectivity (26−82% of L-4a-
f) (Table 1). The best substrate with regard to productivity was
1c (20 mM), generating 5.5 mM of L-4c (1.16 g L−1; 72% of 1c
converted), whereas significant amounts (5.47 mM, 27%) of
intermediate 3c remained unconverted by TPL. The highest
selectivity in amino acid formation (82%, Table 1) was
obtained for 1a, albeit at low conversion (7−18%). The
successful transformation of 1a was unexpected, because P450
BM3 was reported to depend on a perfluorinated fatty acid
(PFA) as a decoy molecule to catalyze phenol formation.17 p-
Hydroquinone formation was particularly high for halogenated
substrates, because 3e is a good substrate for second oxidation
by P450 BM316a due to the lower pKa of 3e (pKa 8.5)
compared to 3a (pKa 10),18 which enhances the solubility and
accessibility in the aqueous phase. To demonstrate the practical
utility of the cascade, all substrates were converted at 30 mL
scale and 40 mM 1a−f (Table 2, entries 1−6). As Tris base
impedes the purification of L-4a-f, we switched to a KPi-system
for prep-scale reactions and pH-stat control to maintain the pH
at 8.0. With this reaction setup, the product concentration for L-
4a-f was improved significantly (3.9 to 22.7 mM L-4a-f;
conversion of 1a-f ranged between 10 to 68%). In addition to
the enhanced productivity, the cascade displayed also a better
selectivity for L-4b-f (53−99%; L-4a was slightly decreased) due
to an equilibrium shift toward carboligation by TPL at slightly
alkaline pH. The enhanced performance of step 2 efficiently
removes phenols 3a−f and thereby decreases the formation of
p-hydroquinones via overoxidation, which was very successul in
particular for conversion of 1b and 1c. Best conversions in
scale-up reactions were obtained for 1b (53%) and 1c (68%),
yielding 3.51 g L−1 (18 mM) of L-4b and 5.2 g L−1 (22.7 mM)
of L-4c. The product titer for L-4c (Table 2, entry 3)
corresponds to a space time yield (STY) of 0.11 g L−1 h−1,
which is exceptionally high for a P450-supported reaction
(0.01% catalyst loading).19 Although 1a and 1d−f displayed
improved product formation for the target amino acids (3.9 to
5.8 mM); Table 2), product titers did not exceed 1.3 g L−1
(max. 28 % conversion of arene to amino acid). Overoxidation
prevailed for 1e and 1f yielding 43 and 28% of 5e and 5f,
respectively (Table 2, entries 5 and 6). In contrast, this could be
Figure 1. Time-dependent conversion of 1c (10 mM) by the P450-
monooxygenase-TPL-lyase cascade employing 2 μM P450 BM3
variant M2 (R47S, Y51W, I401M), 400 μM NADP+, 3 mg TPL
mutant M379V, 40 mM pyruvate, 1200 U catalase (supplemented for
removal of traces of H2O2 formed by uncoupling of P450 BM3), 40
μM PLP, 12 U GDH, 100 mM D-glucose, 1% (v/v) DMSO and 180
+
mM NH4 in Tris-HCl buffer (pH 8.0, 0.1 M) in a final reaction
volume of 1 mL.
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DOI: 10.1021/acscatal.5b02129
ACS Catal. 2015, 5, 7503−7506

ACS Catalysis
Letter
a
Table 1. Substrate Scope of the P450-TPL Cascade
b
c
entry
substrate
concn [mM]
3a−f [mM]
L-4a−f [mM]
5a−f [mM]
conv. [%]
selectivity L-4a−f [%]
1
2
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
20
5
0.05
0.06
1.89
0.24
5.47
0.38
1.44
1.01
0.41
0.16
0.56
0.28
1.09
0.74
2.85
1.45
5.49
3.01
0.98
0.7
0.23
0.1
7
80
82
29
33
41
74
40
41
31
33
27
26
18
49
87
72
82
12
34
27
72
19
60
3
20
5
4.97
2.65
1.52
0.25
n.d.
4
5
20
5
6
7
20
5
8
n.d.
9
20
5
1.67
1.19
1.02
0.77
3.33
2.25
2.24
1.94
10
11
12
20
1f
5
a
Reaction conditions: Tris buffer (0.1 M; pH 8.0), 12 U mL−1 GDH, 400 μM NADP+, 2 μM P450 BM3 variant M2 (5.43 mg mL−1 freeze-dried
lysate), 40 μM PLP, 180 mM NH4 , substrate (1a−f), 1% (v/v) DMSO (cosolvent), 100 mM D-glucose, 40 mM pyruvate, 1200 U ml−1 catalase, and
3 mg of TPL. Experiments were done in triplicate in a final volume of 1 mL with 170 rpm shaking at RT and 6 h reaction time. Calculated from the
sum of products formed from 1a−f. Selectivity = % L-4a−f in the final product mixture. n.d. = not determined.
+
b
c
Table 2. Preparative-Scale Reactions with the P450-TPL Cascade under Continuous pH Control
b
c
entry
substrate
1a
3a−f [mM]
L-4a−f [mM]
5a−f [mM]
conv. [%]
selectivity [% L-4a−f]
isol. yield [%]
ee L-4a−f [%]
1
2
0.3
3.9
1.2
14
53
68
10
28
21
31
52
17
40
72
85
84
>99
53
65
0
7.6
34
>97
>97
>97
>97
>97
>97
---
1b
1.4
18.0
22.7
4.0
1.9
3
1c
2.6
<0.5*
n.d.
4.8
49
4
1d
<0.25*
0.4
6.2
7.8
6.0
---
5
1e
5.8
6
1f
0.6
5.3
2.3
7
1c (no TPL)
7.2
0
4.5
d
8
1c (90 mL)
0.8
18.4
6.4
<0.5*
0.3
89
43
>97
n.d.
>97
e
f
9
TN10050%
<0.25*
0.5
95
n.d.
26
e
f
10
TN10065%
15.5
0.1
96
a
b
All experiments were done in duplicate or triplicate, and reaction conditions are described in the experimental section (see SI). Sum of products
c
d
e
obtained from 1a−f. Selectivity is defined as % of L-4a−f in the final product mixture. 20 h of reaction time with external O2 supply. Substrate
addition led to a final concentration of 40 mM of 1b; TN100 is a crude technical grade fraction of a commercial gasoline blending (see SI)
containing 50−65% 1b. Selectivity calculation based on conversion of 1b in TN100 blend (28−39% HPLC area (280 nm) derived from
unquantified side products; for details, see Figures S26−S29 in SI); n.d. = not determined. Limit of detectability.
f
*
efficiently suppressed for 5b and was completely abolished in
the case of 5c. Lower conversions for 1a and 1d (14 and 10%)
can be attributed to the high volatility substrates and a low
coupling efficiency of P450 BM3.12a,17,20 In the absence of TPL,
the oxidation of 1c decreased by 54%, and formation of the
overoxidation product 5c increased by 3.8-fold (Table 2, entry
7). From this, we conclude that TPL enhances the productivity
of P450 BM3 by avoiding the accumulation of inhibiting
phenolic intermediates (3a−f) and overoxidation products
(5a−f). FMN-/FAD-containing multicomponent-enzymes, like
P450 BM3,20 are easily inhibited by electron-rich phenols/p-
hydroquinones through formation of charge-transfer complexes
with electron-deficient flavin species,21 which impede the
binding of NAD(P)H.22 Products L-4a-f produced at 30 mL
scale were purified yielding 14.9 to 124 mg (6 to 49% isolated
yield) all in >97% ee. Reduced KOH consumption (pH stat)
was observed upon scale-up of 1c (40 mM, 90 mL, Table 2,
entry 8), indicating limitation in the P450 monooxygenase
activity (H+ release from cofactor recycling; Scheme 1). We
assumed limited availability of O2,19b which was circumvented
by external O2 supply resulting in a ∼3-fold increased KOH
consumption rate.13a Under these reaction conditions (90 mL
scale, pH stat, O2 supply), 3.88 g L−1 of L-4c (330 mg, 18.4
mM, 89% selectivity) were produced within 20 h (30 mL scale
reaction done for 48 h)which corresponds to a STY of 0.19 g
L−1 h−1 and a conversion of 52% of 1c (Table 2, entry 8). To
challenge the system further, a technical-grade aromatic
gasoline blend TN100 obtained from petroleum steam-cracking
(containing 50 to 65% of 1b and other benzenes23) was used as
starting material. Although all ingredients of the latter are
potential substrates of P450 BM3 oxidation,11,12b,20,24 against
all expectations, the conversion of gasoline blend TN100 gave
L-4b in 95−96% selectivity (based on conversion of 1b) and in
good quantity (6.4−15.5 mM; 1.3 to 3 g L−1, 17 to 40%
conversion of 1b, Table 2, entries 9 and 10, see SI). Minor
products and residual intermediates 2a or 2b (28−39% HPLC
area, see SI) were simply removed by extraction. After
purification, 60 mg of isolated L-4b (a precursor for antitumor
agents, such as saframycin A or renieramycin H2c,f) were
obtained in >97% purity and ee > 97%.
In summary, a one-pot artificial biocascade employing a P450
monooxygenase and a C−C lyase allowed the preparative scale
synthesis of L-tyrosine derivatives with product titers up to 5.2 g
L−1, a STY of up to 0.19 g L−1 h−1 and close to perfect ee
(>97%). The key to success was the in situ removal of
inhibiting phenolic reaction intermediates during the course of
the cascade.
7505
DOI: 10.1021/acscatal.5b02129
ACS Catal. 2015, 5, 7503−7506

ACS Catalysis
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b02129.
■
S
Catalyst preparation, cascade optimization, and analytical
data (HPLC traces, LC-MS, 1H-, 13C-, and 19F-NMR) for
isolated and purified compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: Wolfgang.Kroutil@Uni-Graz.at.
*E-mail: Kurt.Faber@Uni-Graz.at.
■
(11) Dennig, A.; Marienhagen, J.; Ruff, A. J.; Guddat, L.;
Schwaneberg, U. ChemCatChem 2012, 4, 771−773.
Present Address
†Department of Organic Chemistry I, Universidad Complu-
tense de Madrid, 28040 Madrid (Spain).
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Chem., Int. Ed. 2013, 52, 8459−8462. (b) Whitehouse, C. J.; Yang, W.;
Yorke, J. A.; Rowlatt, B. C.; Strong, A. J.; Blanford, C. F.; Bell, S. G.;
Bartlam, M.; Wong, L. L.; Rao, Z. ChemBioChem 2010, 11, 2549−
2556.
Notes
The authors declare no competing financial interest.
General reaction conditions: KPi buffer (0.1 M; pH 8.0), 12 U
mL−1 GDH, 400 μM NADP+, 4 μM P450 BM3 variant M2
(R47S, Y51W, I401M; cell-free lysate), 40 μM PLP, 180 mM
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Green Chem. 2013, 15, 2408−2421. (b) Muller, C. A.; Dennig, A.;
̈
Welters, T.; Winkler, T.; Ruff, A. J.; Hummel, W.; Groger, H.;
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+
NH4 , 40 mM substrate 1a−f, 1% (v/v) DMSO (cosolvent),
Schwaneberg, U. J. Biotechnol. 2014, 191, 196−204. (c) Muller, C. A.;
Akkapurathu, B.; Winkler, T.; Staudt, S.; Hummel, W.; Groger, H.;
Schwaneberg, U. Adv. Synth. Catal. 2013, 355, 1787−1798. (d) Pennec,
A.; Hollmann, F.; Smit, M. S.; Opperman, D. J. ChemCatChem 2015,
̈
1.18 g of D-glucose, 660 mg of pyruvate, 1200 U ml−1 catalase,
and 90 mg of TPL mutant M379V;22 (cell-free lysate).
Conversions were done at 30 mL scale with 400 rpm stirring
at RT and with pH stat control using 0.5 M KOH for 48 h.
̈
7, 236−239. (e) Staudt, S.; Burda, E.; Giese, C.; Muller, C. A.;
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ACKNOWLEDGMENTS
■
Bernhard Hauer and co-workers (University of Stuttgart) are
acknowledged for providing the plasmid containing the gene of
P450 BM3. E.B. received funding from the European
Commission by a Marie Curie Actions-Intra-European Fellow-
ship (IEF) in the project “BIOCASCADE” (FP7-PEOPLE-
2011-IEF, PIEF-GA-2011−298030).
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D.; Urlacher, V. B. Adv. Synth. Catal. 2005, 347, 1090−1098.
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DOI: 10.1021/acscatal.5b02129
ACS Catal. 2015, 5, 7503−7506