PQQ-dependent Dehydrogenase Enables One-pot Bi-enzymatic Enantio-convergent Biocatalytic Amination of Racemic sec-Allylic Alcohols

Article abstract of DOI:10.1002/cctc.202001707

The asymmetric amination of secondary racemic allylic alcohols bears several challenges like the reactivity of the bi-functional substrate/product as well as of the α,β-unsaturated ketone intermediate in an oxidation-reductive amination sequence. Heading for a biocatalytic amination cascade with a minimal number of enzymes, an oxidation step was implemented relying on a single PQQ-dependent dehydrogenase with low enantioselectivity. This enzyme allowed the oxidation of both enantiomers at the expense of iron(III) as oxidant. The stereoselective amination of the α,β-unsaturated ketone intermediate was achieved with transaminases using 1-phenylethylamine as formal reducing agent as well as nitrogen source. Choosing an appropriate transaminase, either the (R)- or (S)-enantiomer was obtained in optically pure form (>98 % ee). The enantio-convergent amination of the racemic allylic alcohols to one single allylic amine enantiomer was achieved in one pot in a sequential cascade.

Full text of DOI:10.1002/cctc.202001707

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: PQQ-dependent dehydrogenase enables one-pot bi-enzymatic
enantio-convergent biocatalytic amination of racemic sec-allylic
alcohols
Authors: Somayyeh Gandomkar, Raquel Rocha, Frieda Sorgenfrei, Lía
Martínez Montero, Michael Fuchs, and Wolfgang Kroutil
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.202001707
Link to VoR: https://doi.org/10.1002/cctc.202001707
01/2020

10.1002/cctc.202001707
ChemCatChem
COMMUNICATION
PQQ-dependent dehydrogenase enables one-pot bi-enzymatic
enantio-convergent biocatalytic amination of racemic sec-allylic
alcohols
Somayyeh Gandomkar,[a] Raquel Rocha,[a] Frieda A. Sorgenfrei,[a,b] Lía Martínez Montero,[a] Michael
Fuchs,[a] Wolfgang Kroutil*[a,c,d]
Abstract: The asymmetric amination of secondary racemic allylic
alcohols bears several challenges like the reactivity of the bi-
functional substrate/product as well as of the α,β-unsaturated ketone
intermediate in an oxidation-reductive amination sequence. Heading
for a biocatalytic amination cascade with a minimal number of
enzymes, an oxidation step was implemented relying on a single
PQQ-dependent dehydrogenase with low enantioselectivity. This
enzyme allowed the oxidation of both enantiomers at the expense of
iron(III) as oxidant. The stereoselective amination of the α,β-
unsaturated ketone intermediate was achieved with transaminases
using 1-phenylethylamine as formal reducing agent as well as
nitrogen source. Choosing an appropriate transaminase, either the
(R)- or (S)-enantiomer was obtained in optically pure form (>98% e.e.).
The enantio-convergent amination of the racemic allylic alcohols to
one single allylic amine enantiomer was achieved in one pot in a
sequential cascade.
Allylic alcohols have only been investigated recently in a
sequential two-step chemoenzymatic approach[8] by oxidizing the
racemic alcohols using TEMPO in combination with a laccase
followed by the reductive amination using transaminases yielding
the chiral amines in moderate to good yields (29–75%). Although
here the non-enantioselective chemical oxidation allows to
transform both enantiomers, it requires a non-natural and non-
chemoselective reagent (TEMPO) in combination with an
oxidizing enzyme.
previous work
(R)-selective ADH
+ (S)-selective ADH
OH
O
O
NH2
*
amination
amination
R
R
R
cofactor recycling
racemate
OH
NH2
*
TEMPO + laccase
O2
R
R
R
racemate
this study
OH
OH
NH2
Chiral allylic amines are versatile building blocks in organic
chemistry and have been widely used in the synthesis e.g. of
pharmaceuticals.[1] Although various methods for their preparation
have been published,[2] the direct metal catalyzed stereoselective
amination of non-activated allylic alcohols to unprotected primary
allylic amines has not been reported, yet. One possible reason
might be isomerization of the allylic alcohols in the presence of
R'
R'
single
1c 4c
(R)-
-
O
stereoselective
amination
PQQ-dependent
dehydrogenase
K3[Fe(CN)6]
e.e. >98%
+
R'
or
transaminase
NH2
1b 4b
-
amine donor
R'
R'
1c 4c
(S)-
-
rac-1a-4a
racemate
e.e. >98%
selected metal catalysts.[3] Therefore,
a concept for the
stereoselective amination of allylic alcohols would expand the
toolbox for their synthesis, ideally when racemic alcohols are used
as starting material.
R':
amine donors:
NH2
NH2
Cl
Ph
Biocatalytic methods have emerged as mild, sustainable
alternatives for the synthesis of chiral amines using various
classes of enzyme.[4] For the amination of (racemic) sec-alcohols
(not allylic) artificial biocatalytic cascades[5] have been reported by
combining an alcohol-dehydrogenase or oxidase catalyzed
oxidation with asymmetric amination using transaminases[6] or
amine dehydrogenases (Scheme 1, top).[7]
5c
6c
1
2
3
4
Scheme 1. Stereoselective amination of racemic allylic sec-alcohols. Previous
amination cascades employed alcohol dehydrogenase (ADHs), mostly two to
transform both enantiomers or used TEMPO as oxidant.
[a]
Dr. Somayyeh Gandomkar, Raquel Rocha, Frieda A. Sorgenfrei, Dr.
Lía Martínez Montero, Dr. Michael Fuchs, Prof. Dr. Wolfgang Kroutil
Institute of Chemistry
The ideal sequence would encompass a non-enantioselective
oxidation using a single (bio)catalyst followed by amination of the
intermediate α,β-unsaturated ketone employing also a single
enzyme, thus requiring in total just two enzymes (Scheme 1,
bottom). The bio-amination of racemic sec-alcohols in previous
studies required at least two enzymes just for the oxidation step,
namely for each enantiomer one,[7g-i] or in case where only one
enzyme was used the conversion did not reach values >90%.[7h,9]
Thus, a high yielding alcohol amination cascade with a single
suitable active oxidative enzyme with low enantioselectivity
applicable for a racemic substrate remains elusive.
University of Graz, NAWI Graz
Heinrichstr. 28, 8010 Graz, Austria
E-mail: wolfgang.kroutil@uni-graz.at
Austrian Centre of Industrial Biotechnology c/o University of Graz
Heinrichstr. 28, 8010 Graz, Austria
Field of Excellence BioHealth - University of Graz
Graz, Austria
[b]
[c]
[d]
BioTechMed Graz
Graz, Austria
Supporting information for this article is given via a link at the end of the
document
Searching for a single enzyme capable of oxidizing both
enantiomers of a racemate, we have previously reported on
1
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10.1002/cctc.202001707
ChemCatChem
COMMUNICATION
alcohol dehydrogenases (ADH)[10] applicable for aliphatic sec-
alcohols and on oxidases for sec-allylic alcohols.[11] Also variants
of an ADH from Thermoanaerobacter ethanolicus have been
reported to display low enantioselectivity.[12] Since ADHs require
in general another enzyme for cofactor recycling, they were not
considered here (the coupled substrate approach leads to
chemoselectivity issues with the subsequent amination step). The
O2-dependent oxidases mentioned above showed low
enantioselectivity, however the activity was not sufficient to
enable also the oxidation of the slower reacting enantiomer within
reasonable time and at a reasonable concentration of the enzyme.
Since neither flavin-dependent oxidases nor NAD(P)+-dependent
ADHs were available with satisfying properties, we turned our
attention to a group of enzymes less investigated in biocatalysis,
The organic solvent tolerance of the PQQ-DH was rather
encouraging, since for instance the enzyme was active in DMSO
up to 30% v/v (Table S6). Applying an aqueous two-phase system,
isooctane and n-heptane can be used at up to 50% v/v.
Turning to the amination step, the biocatalytic asymmetric
synthesis of allylic amines from the corresponding α,β-
unsaturated ketones has only been reported using commercial
enzymes with undisclosed amino acid sequence whereby e.g.
optically active (3E)-4-phenylbut-3-en-2-amine was obtained with
low conversion (<30%)[15] or with conversion up to 70%.[8]
Table 1. Oxidation of racemic sec-allylic alcohols using the PQQ-dependent
dehydrogenase from Devosia mutans.
Substr.
Conv.pure
App.
Activity
[U/mg][b]
E[c]
Stereopref.[d]
Conv.E.
namely
pyrroloquinoline
quinone
(PQQ)
dependent
[a]
[e]
enzyme
coli/PQQ-DH
dehydrogenases (PQQ-DH). These enzymes have until now
mainly been investigated from a structural or biochemical point of
view.[13] PQQ-DHs can be used for instance with Fe(III) as the
oxidant [e.g. in the form of Fe(CN)63-], which additionally reduces
the challenges of a gas-liquid phase as present in the case of
oxidases requiring molecular oxygen. Thus, for the PQQ-DH
dependent enzyme using Fe(III) as the oxidant, the oxidant as
well as the enzyme are present in the same phase.
[%]
>99
>99
>99
>99
[%]
rac-1a
rac-2a
rac-3a
rac-4a
1.6
0.9
1.4
1.8
19
22
16
41
(S)
(S)
(S)
(S)
90
98
95
98
[a] Reaction conditions: 1 mL volume, substrate (10 mM), purified PQQ-DH (16
µM), Tris-HCl buffer (100 mM, pH 7.5), PQQ (100 µM), potassium ferricyanide
(20 mM), 0.5 hour, 170 rpm, 21 °C. The reaction was analyzed by GC-FID. [b]
Activity was deduced from the time course transforming the racemic substrate
using 0.1 mg/mL of purified enzyme (see Table S4). [c] The enantioselectivity E
was calculated from conv. and e.e. of the remaining substrate at a conv. ~50%
(see Table S5) using the online tool http://biocatalysis.uni-graz.at/biocatalysis-
tools/enantio. [d] Enantiomer which was oxidized faster. [e] Reaction conditions
as in [a] but lyophilized E. coli/PQQ-DH cells (20 mg/mL), 24 h.
A PQQ-dependent dehydrogenase identified in a detoxification
sequence of deoxynivalenol (DON) at a substrate concentration
of just 100 µM in the bacterial strain Devosia mutans (PQQ-
DH_Dm)[14] attracted our attention. We investigated this enzyme
for the oxidation of sec-allylic alcohols 1a-4a as model
compounds and its potential for incorporation in a cascade for
amination. Initially, the oxidation and amination step were tested
separately, to check whether compatible conditions are feasible
for the PQQ-DH and a transaminase. A transaminase was
considered as the enzyme of choice for the second step, since in
contrast to other options (amine dehydrogenase) a single enzyme
would be sufficient.
At an enzyme concentration of 16 µM, the purified PQQ-DH_Dm
enabled the quantitative oxidation of racemic substrate rac-1a-4a
at a substrate concentration of 10 mM in Tris-HCl buffer (100 mM,
pH 7.5) within only 0.5 hour at 21 °C (Table 1); thus, both
enantiomers were readily oxidized to the corresponding ketone.
This indicated that the PQQ-DH_Dm may be indeed suitable for
the desired purpose.
Especially the amination of an unsaturated ketone may be prone
to undesired side products considering that the amination reagent
such as e.g. 2-propylamine or 1-phenylethylamine may also
undergo a Michael-addition with the α,β-unsaturated ketones.
This side reaction may occur additionally to the expected
hemiaminal and Schiff base formation between amines and
ketones present in the reaction mixture.
Testing various (R)-selective enzymes for the stereoselective
amination of 1b-4b, ArRmut11 ω-TA[16] was identified as the best
suitable candidate (Table 2, see also Supporting Information
section 2.2).
Measuring the activity, the apparent value for the racemate varied
between 0.9 and 1.8 U/mg depending on the substrate, whereby
rac-4a was oxidized fastest (1.8 U/mg). Since for applications the
use of crude enzyme preparations or even permeabilized E. coli
cells containing the overexpressed enzyme is preferred over
purified enzyme, the oxidation was re-investigated using
lyophilized E. coli/PQQ-DH_Dm cells. Luckily, it turned out, that
also this crude preparation can be used, whereby conversion
between 90-98% were reached within 24 hours at a substrate
concentration of 10 mM. To get an idea of the enantioselectivity
E of the enzyme for the two enantiomers, thus, what is the ratio
of the rate constants of the oxidation for the two enantiomers
(kS/kR), the E-value was determined from the e.e. of the remaining
alcohol and the conversion. As expected, the E-value was low,
varying between 16 and 41. For all substrates investigated
preferentially the (S)-enantiomer was oxidized. Thus, the here
investigated PQQ-DH_Dm displayed the same stereopreference
as O2-dependent oxidases previously reported (e.g. HMFO).[11]
Out of three amine donors tested [2-propylamine (5c), (R)-1-
phenylethylamine (R)-6c and all-rac-1,2-diaminocyclohexane],
(R)-1-phenylethylamine (R)-6c led to the highest conversion at
1.25 M compared to the other amine donors investigated (Table
2, Figures S3-S6). In all cases, optically pure (R)-allylic amines
(R)-1c-4c were obtained (>98% e.e.).
To access the (S)-enantiomer, the transaminase originating from
Silicibacter pomeroyi[17] was identified best (Tables S10-S14)
using ketone 1b as the model substrate. Ketone 1b was aminated
with 97% conversion leading to optically pure (S)-1c (>98% e.e.)
(Table 2). This transaminase was subsequently also used for the
asymmetric amination of the other α,β-unsaturated ketones
providing in all cases optically pure (S)-amine (S)-2c-4c. Thus,
depending on the TA chosen, the (R)- as well as the (S)-allylic
amines 1c-4c were accessible in optically pure form.
2
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10.1002/cctc.202001707
ChemCatChem
COMMUNICATION
Table 2. Stereoselective amination of α,β-unsaturated ketones 1b-4b.[a]
For rac-β-ionol (rac-4a) 57% of amine were obtained. In the case
of asymmetric (S)-amination, the amount of amine for the racemic
alcohols rac-1a-3a was always above 90% (91-98%). For all
cascade reactions, the conversion of the oxidation step was
analyzed separately, and it turned out, that the oxidation has gone
to completion prior the addition of the amination agents.
For the three best converted racemic alcohols rac-1a-3a, the bi-
enzymatic (R)-amination cascade was also performed on a 0.2
mmol scale to get sufficient amounts (30%, 25% and 41% isolated
yields for 1c, 2c and 3c, respectively) to measure the optical
rotation and confirm and support the absolute configuration
(Table S18). Due to the still rather high price of PQQ, larger scale
experiments were not performed.
Substr.
Transaminase
Amine
Donor
Donor
conc. [M]
Conv.
[%]
e.e.
[%][b]
1b
1b
2b
2b
3b
3b
4b
4b
ArRmut11
S. pomeroyi
ArRmut11
S. pomeroyi
ArRmut11
S. pomeroyi
ArRmut11
S. pomeroyi
(R)-6c
(S)-6c
(R)-6c
(S)-6c
(R)-6c
(S)-6c
(R)-6c
(S)-6c
1.25
0.3
93[c]
97[d]
96[c]
96[d]
78[c]
76[d]
55[c]
24[d]
>98 (R)
>98 (S)
>98 (R)
>98 (S)
>98 (R)
>98 (S)
>98 (R)
>98 (S)
1.25
0.3
1.25
0.3
1.25
0.3
In conclusion, the enantioconvergent biocatalytic sequential
cascade enables the transformation of racemic allylic alcohols to
one single enantiomer of the corresponding primary amine
requiring just two enzymes in an oxidation-reduction sequence.
Although allylic alcohols and also the intermediate α,β-
unsaturated ketone are bi-functionalized compounds prone to
side reactions, this cascade run with high chemoselectivity
without detecting any side products under the conditions
employed. The oxidation was achieved by a PQQ-dependent
dehydrogenase displaying low enantioselectivity at the expense
of iron(III) as the oxidant thereby circumventing the need for
cofactor recycling as well as challenges to handle a gas such as
molecular oxygen. For the formal reductive amination of the
carbonyl functionality of the α,β-unsaturated ketone defined
enzymes were reported for the first time leading to the optically
pure (R)- or (S)-amine enantiomer. The results show, that PQQ-
dependent dehydrogenases relying on Fe(III) are highly
interesting and useful enzymes for the oxidation of secondary
allylic alcohols and can be incorporated in challenging sequential
cascade reactions e.g. to prepare optically pure allylic amines
paving the way to a new chapter for synthetic applications.
[a] For a complete overview of all transaminases and conditions tested see
Supporting Information. [b] The e.e. was measured by HPLC on a chiral phase
after acetylation. [c] Reaction condition: 1 mL reaction volume, KPi (200 mM,
pH 8.0), substrate (50 mM), 10% v/v DMSO, amine donor, PLP (1 mM),
lyophilized cells (40 mg/mL) in 2 mL tubes, 16 h, 450 rpm, 40 ºC. Conv. was
measured by GC-FID. [d] Reaction conditions as in [c] but 1.5 mL volume,
substrate (10 mM), 4 mL glass vials, 24 h, 350 rpm, 30 ºC. The conversion
reported is based on calibration.
Turning now to the cascade to transform the racemic sec-allylic
alcohols to optically pure amines, the oxidation and amination
steps were started simultaneously in one pot; however, this led
only to low amounts of amine formation (2-6%), which was mainly
attributed to an incompatibility of the PQQ-DH with the amine
donor of the second step. Consequently, the cascade was
performed in one pot in a sequential fashion using the optimal
conditions for each step; thus, after the oxidation at pH 7.0, the
transaminase, PLP and the amine donor were added and the pH
was adjusted to pH 8.0 and the amination was run for 24 hours.
Performing the first step at the same pH as the amination (pH 8.0)
led to less amine formation.
The results of the cascade showed that the asymmetric (R)-
amination of racemic alcohols rac-1a-3a went to completion
giving optically pure amines (R)-1c-3c (>98% e.e.) (Table 3).
Acknowledgements
Table 3. Bi-enzymatic (R)- and (S)-stereoselective amination of racemic allylic
alcohols rac-1a-4a using a PQQ-DH and a (R)- or (S)-transaminase (TA)
SG and WK acknowledge the Austrian Science Fund FWF for
funding (Lise Meitner program M 2271). RR acknowledges
CAPES/OeAD for funding (Science without Borders program).
Substr.
rac-1a
rac-1a
rac-2a
rac-2a
rac-3a
rac-3a
rac-4a
rac-4a
Transaminase
ArRmut11
Amine Donor
(R)-6c
Conv.[b] [%]
e.e. [%][c]
>98 (R)
>98 (S)
>98 (R)
>98 (S)
>98 (R)
>98 (S)
>98 (R)
>98 (S)
>99
99
S. pomeroyi
ArRmut11
(S)-6c
Keywords: Amination of alcohols • PQQ dependent
dehydrogenase • sec-allylic alcohols • biocatalytic cascade •
allylic amines • transaminases
(R)-6c
>99
96
S. pomeroyi
ArRmut11
(S)-6c
(R)-6c
>99
92
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(S)-6c
(R)-6c
57
S. pomeroyi
(S)-6c
66
[a] Reaction condition: substrate (10 mM), KPi (200 mM, pH 7.0 for oxidation
step, 8.0 for amination step) DMSO (2% v/v), PQQ-DH (20 mg/mL), PQQ (100
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10.1002/cctc.202001707
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Enantioconvergent amination: Combining the chemoselective oxidation of racemic allylic secondary alcohols to the corresponding
unsaturated ketone at the expense of Fe(III) as oxidant in the presence of a PQQ-dependent enzyme with the formal reductive bio-
amination of the intermediate ketone opened a route to optically pure/enriched allylic amines.
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