Chemoenzymatic Dynamic Kinetic Resolution of Amines in Fully Continuous-Flow Mode

Article abstract of DOI:10.1021/acs.orglett.8b03676

In this study, lipase-mediated dynamic kinetic resolution (DKR) of various benzylic amines (1a-g) is presented which is realized in a so far unprecedented fully continuous-flow system. The DKR process applying sol-gel immobilized lipase B from Candida antarctica as biocatalyst, palladium on 3-aminopropyl-functionalized silica as racemization catalyst, isopropyl 2-ethoxyacetate as acylating agent, ammonium formate as hydrogen and nitrogen sources, and 2-methyl-2-butanol as solvent under regulated pressure provided the desired products in moderate to good yields with excellent enantiomeric excesses.

Full text of DOI:10.1021/acs.orglett.8b03676

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemoenzymatic Dynamic Kinetic Resolution of Amines in Fully
Continuous-Flow Mode
†
†
†
‡
‡
†
§
́
́
́
́
́
́
́
̈
Emese Farkas, Mark Olah, Attila Foldi, Janos Koti, Janos Eles, Jozsef Nagy, Cristian Andrei Gal,
Csaba Paizs, Gabor Hornyanszky,* and Laszlo Poppe*
§
,†,∥
,†,§,∥
́
́
́
́
†
̋
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Muegyetem rkp. 3,
H-1111 Budapest, Hungary
‡Gedeon Richter Plc., P.O. Box 27, H-1475 Budapest, Hungary
§Biocatalysis and Biotransformation Research Centre, Faculty of Chemistry and Chemical Engineering, Babes-
̧
Bolyai University of
́
Cluj-Napoca, Arany Janos str. 11, RO-400028 Cluj-Napoca, Romania
∥SynBiocat LLC., Szilasliget u. 3, H-1172 Budapest, Hungary
S
* Supporting Information
ABSTRACT: In this study, lipase-mediated dynamic kinetic resolution (DKR) of various benzylic amines (1a−g) is presented
which is realized in a so far unprecedented fully continuous-flow system. The DKR process applying sol−gel immobilized lipase
B from Candida antarctica as biocatalyst, palladium on 3-aminopropyl-functionalized silica as racemization catalyst, isopropyl 2-
ethoxyacetate as acylating agent, ammonium formate as hydrogen and nitrogen sources, and 2-methyl-2-butanol as solvent
under regulated pressure provided the desired products in moderate to good yields with excellent enantiomeric excesses.
usually immobilized to enable their recovery and to enhance
their stability.6 The racemization process, in turn, is often
catalyzed by homogeneous catalystssuch as transition
metal−ligand complexes (Ru, Ir)which can be cumbersome
to recover.7
nantiopure amines and their derivatives are important
1
Eingredients of natural and industrial products.
In the
enantiomer or enantiotope selective step of the synthesis of
enantiopure compounds, chiral catalysts2 or enzymes (fore-
most lipases)3 are often used. Catalytic processes avoiding
stoichiometric components result in higher productivity and in
lower level of byproducts related to the chiral component.
When the key step in a catalytic procedure is enantiomer
selectivee.g., the enzymatic step in kinetic resolution
(KR)a major drawback of the process starting from a
racemate is the maximal 50% yield of the desired enantiomeric
product.4
The first chemoenzymatic DKR of an amine utilized a lipase
and Pd on charcoal.8 Although this process has been followed
by numerous further examples,9 improvement of DKR
processes of amines is still a hot field of interest as exemplified
by the efforts toward continuously operated implementa-
tion.7d,10 Generally, racemization of amines is more difficult
than that of alcohols and requires harsher conditions.2b,d,11
Purification of the product from a DKR process could be
simplified by using heterogenized racemization catalyst (e.g.,
Pd, Ni, Co).12 The studies on effectivity of racemization
revealed that acid−base properties of catalyst support
significantly influenced the process, and supports of basic
character were more beneficial than the acidic ones.2c,10,11
Furthermore, heterogeneous catalysts to be used under
A dynamic kinetic resolution (DKR) process combining the
enantiomer selective step with an in situ racemization of the
nonreacting enantiomer overcomes this limitation and enables
a yield from a racemate close to 100%.5 Various solutions such
as changing the enantiopreference of the KR step or
application of enantiodivergent synthetic strategies from the
DKR product to the target compound can be applied if the
opposite enantiomeric form of the target compound is
required.5c The enantiomer selective KR step of a chemo-
enzymatic DKR process is catalyzed by enzymes which are
Received: November 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Substrates Tested for Racemization and DKR in Fully Continuous Mode
continuous-flow conditions in packed-bed systems should have
high mechanical and thermal stability, high surface-to-volume
ratio, and suitable particle size.
reactors were applied.17 Such systems, enabling enzymatic
reactions and racemization at significantly different temper-
atures, however, suffered from unit-number-dependent limi-
tations in conversion.17
Based on these considerations, the key for development of a
fully continuous-flow DKR process of an amine without
conversion limitations is to find an optimal combination of an
enzymatic process (usually requiring relatively mild con-
ditions) and a suitable racemization process (usually needing
elevated temperature).7g,13c A racemization process suitable for
a DKR should be sufficiently active and selective in the
temperature range enabled by the thermal stability of the
enzyme.
Furthermore, due to the homogeneity requirement of a fully
continuous-flow DKR, the limited solubility of the extra
hydrogen and ammonia source in organic solvents should be
remedied. After having found that the solubility of ammonium
formate in 2-methyl-2-butanol (tert-amyl alcohol)being also
compatible with enzymatic reactionwas suitably high,
racemization and further DKR experiments with various
amines were performed in this solvent (Scheme 1).
In addition to the commercially available 10% Pd/C, six
further heterogeneous palladium catalysts were prepared and
studied as racemization catalysts [Pd/BaSO4, Pd/BaCO3,10,18
Pd/Al(O)OH;13c,19 Pd/AMP-D, Pd/AEAP-D, and Pd/AMP-
KG on in-house prepared 3-aminopropyl- and 3-(2-
aminoethylamino)propyl-modified silica20 carriers (for further
details, see SI)]. For the racemization tests in continuous-flow
mode, the above seven heterogeneous Pd catalysts were packed
into stainless steel columns.
Redox racemization of amines proceeds via an imine
intermediate.13 In the metal-catalyzed racemization process,
side reactions besides the reduction of the imine may generate
byproducts such as further imines, secondary amines, hydro-
carbons, and ketones.13 Such undesired side reactions can be
suppressed by additional hydrogen and ammonia sources.11
Ammonium formate has proven to be a suitable, green, and
easy-to-handle hydrogen and ammonia source in reactions
involving imine reduction (DKR, reductive amination).14
However, its poor solubility in solvents commonly used for
DKR of amines enabled only semicontinuously operated DKR
so far, which included a fully continuous-flow enzyme-
catalyzed step combined with a semicontinuous racemization
step requiring filtration.14b
Since amines are stronger nucleophiles than secondary
alcohols,12 minimization of the competition between enzy-
matic and chemical acylation in the KR step is an additional
challenge. Selection of an acylating agent with a proper, slightly
activated acid moiety15,16 could be a solution to avoid
undesired nonselective chemical acylation parallel to the
selective biocatalytic N-acylation. Due to the enhanced rate
of enzymatic reaction and the lowered rate of nonselective
chemical acylation, isopropyl 2-ethoxyacetate was found to be
a suitable acylating agent for KR of amines.3i
To avoid compatibility issues between the different temper-
ature requirements of the enzymatic KR and the racemization
process in fully continuous-flow operated systems, systems
comprising an alternating sequence of serially connected
B
DOI: 10.1021/acs.orglett.8b03676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In the first series of racemization experiments, microreactors
were packed with various Pd catalysts, and a solution of (S)-1-
phenylethylamine (S)-1a containing ammonium formate (1.2
equiv) as hydrogen source was pumped through the micro-
reactor at elevated temperatures (60, 90, and 120 °C). In all
cases, enantiomeric composition of 1a [ee(S)‑1a] and selectivity
(sel(R,S)‑1a) were determined from the effluents. At 120 °C the
AMP-KG is proven to be the most appropriate racemization
catalyst at 60 °C (ee(S)‑1a = 2%) with good selectivity (sel(R,S)‑1a
= 94%; Table 1, entry 7).
Next, the mixture of a robust sol−gel immobilized form of
lipase B from Candida antarctica (CaLB-TDP10)21 and the
most promising Pd/AMP-KG in a mixed-bed reactor (column
B) was tested, in order to test the compatibility of the
racemization with the biocatalyst. In this set of experiments,
the racemization of (S)-1a and two nonbenzylic amines (S)-1h
and (S)-1i were tested. The tests revealed smooth and efficient
racemization of benzylic amine (S)-1a with Pd/AMP-KG even
Pd catalysts converted (S)-1a mostly to byproducts (sel(R,S)‑1
<
5%). At 90 °C appropriate degree of racemization was
achieved (Table S3: ee(S)‑1a < 15%) but only with moderate
selectivity (sel(R,S)‑1a = 2−74%). Because only temperatures
below 70 °C were found to be compatible with the long-term
thermostability of immobilized Candida antarctica (CaLB),21
the most detailed racemization studies were performed at 60
°C (Table 1, entries 1−7).
in the presence of CaLB-TDP10 (ee(S)‑1a = 3% with sel(R,S)‑1a
=
95%: entry 8 in Table 1), while the nonbenzylic amines could
not be racemized at all (ee(S)‑1 ≥ 99%: entries 9 and 10 in
Table 1). Because Pd catalysts could mediate reductive
amination of nonbenzylic amines with the aid of ammonium
formate at even 40 °C,22 hindered oxidation may be the reason
for noneffective racemization of nonbenzylic amines.
Table 1. Racemization Results for (S)-1a, (S)-1h, and (S)-1i
by Supported Pd Catalysts in Packed-Bed Continuous-Flow
Reactor Using Ammonium Formate As the Hydrogen
To address all issues aroused during the preliminary
experiments for continuous-flow DKR of 1-phenylethaneamine
rac-1a (see Section 3.5.6 in SI), the following key elements
were applied in our final DKR system [n = 1 or 2 in Scheme 1,
panel b)]: (i) isopropyl 2-ethoxyacetate 3 was selected as an
efficient amine acylating agent3i in the enzyme-catalyzed step;
(ii) a KR column (column A, filled only with CaLB-TDP-10)
was introduced to minimize the amount of forming 2-
ethoxyacetamide 4; (iii) Pd/AMP-KG was used (as the most
efficient racemization catalyst); (iv) 2-methyl-2-butanol was
replaced with a 2-methyl-2-butanol/toluene 1:1 (v/v) mixture
(to enhance the solubility of the more hydrophilic amines rac-
1c−e in solution A); (v) back pressure was applied at the
outlet of column B; (vi) the Pd/AMP-KG in column B was
preactivated by a flow of ammonium formate solution (30
min).
In this system, the KR column (column A: CaLB-TDP-10)
was fed with solution A of rac-1a and 3, and the outlet stream
containing almost equimolar amounts of the amide (R)-2a and
the unreacted amine (S)-1a was unified with solution B
(ammonium formate in dry 2-methyl-2-butanol) in a three-way
valve and fed to a mixed-bed column (column B: Pd/AMP-KG
+ CaLB-TDP10).
a
Source
b
c
cd
,
entry
amine
catalyst
ee(S)‑1 (%)
sel(R,S)‑1 (%)
1
2
3
4
5
6
7
8
9
10
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1h
(S)-1i
10% Pd/C
>99
57
36
6
1
5
2
3
99
99
13
99
95
66
68
90
94
95
93
90
Pd/AlO(OH)
Pd/AEAP-D
Pd/BaCO3
Pd/BaSO4
Pd/AMP-D
Pd/AMP-KG
Pd/AMP-KG
Pd/AMP-KG
Pd/AMP-KG
e
e
e
a
Entries 1−7: (S)-1a (69 mM), ammonium formate (1.0 equiv, 69
mM) in dry 2-methyl-2-butanol at 60 °C with 20 μL min−1 flow rate.
Entries 8−10: (S)-amine [(S)-1a, (S)-1h, or (S)-1i (69 mM)],
ammonium formate (1.2 equiv, 83 mM) in dry 2-methyl-2-butanol at
b
60 °C with 10 μL min−1 flow rate. See in SI the Sections 3.1 and 3.2
c
for catalysts and Section 3.5.3 on filling weights. Determined by GC
(see SI). sel(R,S)‑1= amount of (R,S)-1/amount of detectable
compounds in reaction mixture × 100 (%). Entries 8−10: see
Section 3.5.4.2 for filling weight of catalyst and experimental details.
d
e
After investigating the effect of imidazolium formate as
hydrogen source (Table S4) and equivalency of ammonium
formate on DKR of rac-1a (Table S5), the most efficient setup
for DKR of rac-1a (temperature: 60 °C; flow rate: 5 μL min−1
in all pumps, 0.6 equiv of ammonium formate) provided amide
At 60 °C, 10% Pd/C converted (S)-1a mostly to byproducts
(sel(R,S)‑1a= 13%) without racemization (ee(S)‑1a > 99%; Table 1,
entry 1), while various degrees of racemization (ee(S)‑1a= 1−
57%) and selectivity (sel(R,S)‑1a = 66−99%) could be achieved
with six other Pd catalysts (Table 1, entries 2−7). Overall, Pd/
a
Table 2. Chemoenzymatic DKR of Seven Benzylic Amines and rac-1a−g in Fully Continuous-Flow Mode
a
b
b
b
entry
amine
n (−)
T (°C)
P (psi)
ee(S)‑1a−f (%)
ee(R)‑2a−f (%)
conv. (%)
yield (%)
c
1
2
3
4
5
6
7
rac-1a
rac-1b
rac-1c
rac-1d
rac-1e
rac-1f
rac-1g
1
1
2
1
2
1
60
60
60
60
60
60
70
30
30
30
30
30
n.d.
99.9
99.5
98.9
99.3
99.2
99.9
>99
61.9
63.5
96.7
65.0
72.0
96
60
60
86
92.0
63.3
8.3
d
74.4
9.7
98(59)
57
30
100
67
n.i.
e
f
g
h
i
0
99.1(99.3)
63(75)
a
Entries 1−6: Solution A: rac-1a−f (138 mM) and 3 (2 equiv, 138 mM) in dry 2-methyl-2-butanol/toluene 1:1 (v/v) at 5 μL min−1. Solution B:
b
c
d
ammonium formate (0.6 equiv) in 2-methyl-2-butanol at 5 μL min−1. Determined by GC (for details, see SI). Not detected. 4-Ethyl-1,1′-
e
byphenyl was isolated as byproduct. Entry 7 (n = 0): no column A, rac-1g (138 mM), 3 (2 equiv, 138 mM), and ammonium formate (0.6 equiv)
f
g
in dry 2-methyl-2-butanol were fed directly to column B at 10 μL min−1. ee(S)‑1g (the value of ee(S)-1a is between parentheses). ee(S)‑2g (the value
h
i
of ee(S)-2a is between parentheses). c(S)‑2g (conversion to (S)-2g + (S)-2a is between parentheses). n.i.: not isolated.
C
DOI: 10.1021/acs.orglett.8b03676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(R)-2a in high isolated yield (96%) with excellent enantio-
meric excess (>99%) (Table 2, entry 1).
Next, in addition to the continuous-flow DKR with rac-1a,
this system was investigated with several further benzylic
amines having different electronic and steric properties to
evaluate the functional group tolerance of the process (Scheme
1).
The most apparent limitation of this type of DKR process
was the presence of functional groups reducible by transfer
hydrogenation with the racemization catalyst. Preliminary
experiments with 4-chloro-, 4-bromo-, and 4-nitro-substituted
phenylethan-1-amines revealed reduction of such groups under
the racemization conditions, rendering such compounds to be
incompatible with this type of DKR process.
Figure 1. Operational stability of the continuously operated Pd/
AMP-KG−CaLB-TDP10 DKR system converting 1-phenylethan-1-
Afterward, the DKR process was studied with a set of six
further valuable benzylic amines rac-1b−g. The KR process
with amines rac-1a−f revealed nearly 50% conversions with a
single CaLB-TDP10-filled column (n = 1 for column A in
Scheme 1), but in the case of bulkier amines rac-1c and rac-1e
the single KR column provided unsatisfactory conversions (n =
1:34% from rac-1c and 25% from rac-1e). Thus, to achieve
near to 50% conversion in the KR part (column A) of the DKR
systems for transformation of rac-1c and rac-1e, a two KR
column system was applied (n = 2, column A in Scheme 1).
The efficiency of racemization could be concluded from the
enantiomeric composition of the residual amine (ee(S)‑1a−g).
Quite efficient racemization happened in the DKR of rac-1a
(no 1a remained, Table 2, entry 1), of rac-1d (ee(S)‑1d = 8.3%,
Table 2, entry 4), and of rac-1f (ee(S)‑1f = 9.7%, Table 2, entry
6). Accordingly, good to excellent conversions and yields could
be achieved by the DKR from these substrates (Table 2,
entries 1, 4, and 5). The slightly enhanced positive inductive
effect of the ethyl group attached to the benzylic position (rac-
1f) did not prevent racemization. The lower conversion of
DKR from rac-1f was due to the decreased rate of the enzymic
KR from this substrate as compared to the KR from rac-1a.
Expectedly, in the case of amines with electron-donating
substituents, such as rac-1c with 3,4-methoxy substituents or
rac-1e with 4-phenyl substituent, the racemization was not
quite efficient (ee(S)‑1c = 63.3% and ee(S)‑1e = 74.4%; Table 2,
entries 3 and 5). Unexpectedly, the 4-fluoro substituent in rac-
●
amine rac-1a [GC conversion ( : dark red) is shown for the DKR
system operated under conditions of Table 2 for 48 h].
In conclusion, a novel system enabling fully continuous-flow
mode DKR of racemic benzylic amines (rac-1a−f) is described
for the first time. The DKR system involving a robust lipase
(CaLB-TDP10) for kinetic resolution and a mild racemization
with palladium on aminopropyl-grafted silica (Pd/AMP-KG)
and ammonium formate fully dissolved in 2-methyl-2-butanol
as hydrogen source could be operated at moderately high
temperature (60−70 °C). Our study revealed that this
racemization process was effective for benzylic amines without
easily reducible functions. The optimized DKR system
comprising a KR unit (1 or 2 packed-bed columns filled
with CaLB-TDP10) and a mixed-bed DKR unit (a column
filled with Pd/AMP-KG + CaLB-TDP10) could be applied
successfully for conversion of six valuable benzylic amines rac-
1a−f to amides (R)-2a−f in medium to high isolated yields
(57−96%) with excellent enantiomeric purity (>98.8%).
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.8b03676.
Catalyst synthesis and characterization, experimental
procedures for racemization, and DKR (PDF)
1b had significant negative impact on racemization (ee(S)‑1b
=
92.0%, Table 2, entry 2). Due to the lowered efficiency of
racemization, only moderate isolated yields (57−60%) but
excellent enantiomeric purities (ee ≥ 98.9%) could be achieved
in the DKRs from rac-1b,c,e.
AUTHOR INFORMATION
Corresponding Authors
■
*Tel.: +36-1-463-3299. Fax: +36-1-463-3697. E-mail: poppe@
mail.bme.hu.
*E-mail: hornyanszky@mail.bme.hu.
ORCID
DKR of rac-1g showed that a fluorine even at aliphatic
position was partially reducible by the racemization catalyst
under the DKR process conditions (0.6 equiv of
+
HCOO−NH4 , 100 psi, 70 °C: Table 2, entry 7). Enantiomeric
́
́
Laszlo Poppe: 0000-0002-8358-1378
Notes
purities of the fluorine-containing product (R)-2g and of the
dehalogenated byproduct (R)-2a were excellent (ee(S)‑1g and
ee(S)‑1g > 99%), but the enantiomeric composition of the
residual halogenated substrate (ee(S)‑1g = 59%) indicated
moderate efficiency of racemization of (S)-1g.
The robustness of a catalytic system under continuous-flow
conditions can be characterized by its operation stability.
Therefore, the DKR system of rac-1a to (R)-2a was operated
and monitored at 60 °C for 48 h, revealing excellent
operational stability (Figure 1). The system was stable for at
least 2 days, producing enantiopure (R)-2a (ee(S)‑1a > 99.8%)
with a space time yield of 103 kg m−3 day−1.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
Thanks to Dr. Diana Balogh-Weiser (BME, Budapest
́
́
́
Hungary) for SEM measurements and Prof. Mihaly Nogradi
(BME, Budapest, Hungary) for helpful discussions. This work
was supported by CELSA (BME-KU Leuven, ConSolid
project), by the National Research, Development and
Innovation Fund of Hungary (FIEK_16-1-2016-0007), by
the Higher Education Excellence Program of the Ministry of
D
DOI: 10.1021/acs.orglett.8b03676
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.8b03676
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