Chemoenzymatic Dynamic Kinetic Resolution of Primary Benzylic Amines using Pd0-CalB CLEA as a Biohybrid Catalyst

Article abstract of DOI:10.1002/chem.201901418

Herein, we report on the use a biohybrid catalyst consisting of palladium nanoparticles immobilized on cross-linked enzyme aggregates of lipase B of Candida antarctica (CalB CLEA) for the dynamic kinetic resolution (DKR) of benzylic amines. A set of amines were demonstrated to undergo an efficient DKR and the recyclability of the catalysts was studied. Extensive efforts to further elucidate the structure of the catalyst are presented.

Full text of DOI:10.1002/chem.201901418

A Journal of
Accepted Article
Title: Chemoenzymatic Dynamic Kinetic Resolution of Primary Benzylic
Amines using Pd(0)-CalB CLEA as a Biohybrid Catalyst
Authors: Jan-E. Bäckvall, Karl Gustafson, Tamás Görbe, Gonzalo de
Gonzalo, Ning Yang, Cynthia Schreiber, Andrey Shchukarev,
Cheuk-Wai Tai, Ingmar Persson, and Xiaodong Zou
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
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201901418
Link to VoR: http://dx.doi.org/10.1002/chem.201901418
Supported by

Chemistry - A European Journal
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COMMUNICATION
Chemoenzymatic Dynamic Kinetic Resolution of Primary Benzylic
Amines using Pd(0)-CalB CLEA as a Biohybrid Catalyst
Karl P. J. Gustafson,[†,a,b] Tamás Görbe,[†,a] Gonzalo de Gonzalo, Ning Yuan, Cynthia Schreiber,[a]
[a]
[b,c]
[
d]
[b]
[c]
[b]
[a]
Andrey Shchukarev, Cheuk-Wai Tai, Ingmar Persson, Xiaodong Zou, and Jan-E. Bäckvall*
[†]These author contributed equally to this work
Abstract: Herein, we report on the use a biohybrid catalyst consisting
of palladium nanoparticles immobilized on cross-linked enzyme
aggregates of lipase B of Candida antarctica (CalB CLEA) for the
dynamic kinetic resolution (DKR) of benzylic amines. A set of amines
were demonstrated to undergo an efficient DKR and the recyclability
of the catalysts was studied. Extensive efforts to further elucidate the
structure of the catalyst are presented.
Palomo[9] groups have studied a promising design of bifunctional
catalysts, where enzyme solutions are converted to
heterogeneous catalysts. Inspired by their research we have
applied a more rationally designed system, where an aggregate
of the CalB enzyme is formed by cross-linking with glutaraldehyde,
which creates
a well-established spherical heterogeneous
material. The application of such cross-linked enzyme aggregates
(
CLEAs) in process chemistry has been well illustrated in many
examples.[
10]
Moreover, as the CLEA itself constitutes the
Recent developments in materials science and nanotechnology
have greatly accelerated the field of heterogeneous catalysis.
Today, a large number of catalysts, ranging from organometallic
complexes to enzymes, can be efficiently immobilized onto
heterogeneous supports.[1] Most heterogeneous catalysts used in
different organic transformations rely on the concept of having a
support onto which the catalyst can be immobilized.[2] The co-
immobilization of different catalysts can in certain cases improve
the efficiency of the reaction even further.[3] To make use of these
co-immobilized species, the reaction design requires the
orchestration of coupling reactions which exploits the reactivity of
all the immobilized catalytically active species.[4] Previously our
group reported on the co-immobilization of Pd nanoparticles[5] and
the enzyme Candida antarctica lipase B (CalB) into the cavities of
a siliceous mesocellular foam (MCF) and demonstrated the use
heterogeneous phase, it can also be considered to be
biodegradable and to exhibit rather low toxicity. The use of CLEA
as a support for metal nanoparticles to generate bifunctional
biohybrid catalysts may therefore be a possible alternative to
improve the applicability and scalability of metal-enzyme
composites.
Recently, our group reported the synthesis of a Pd(0)-CalB CLEA
catalyst. This catalyst was successfully used in a cascade
reaction, where 4-pentynoic acid was cycloisomerized by Pd to
an exo-cyclic vinyl lactone which was used in situ as acyl donor
11]
in
a
CalB-catalyzed kinetic resolution of sec-alcohols.[
Unfortunately, the Pd(0) catalyst was not able to racemize the
sec-alcohols as required for a DKR and therefore the cascade
enzyme acylation of the alcohol was limited to a kinetic resolution.
During this work, we became interested in using this biohybrid
catalyst for DKR of amines,[ since the Pd(0) of the composite is
expected to racemize amines. A few years after the first report by
Reetz, the group of Bäckvall reported the use of Shvo’s catalysts
as the first homogeneous catalyst employed in the DKR of
12]
of this nanohybrid catalyst in dynamic kinetic resolution (DKR) of
amines.[6] An intrinsic drawback with this immobilization is that the
amount of the catalytically active species is still quite low
compared to the total mass of the solid material.
The performance of heterogeneous biocomposite catalysts has
emerged during the past few years.[7] Both the Zare[8] and the
amines. To date this Ru protocol is still the most versatile protocol,
applicable to both benzylic and aliphatic amines.[
14,15]
At the same
time as Bäckvall’s publication, the group of De Vos and Jacobs
independently described the use of palladium nanoparticles
immobilized on alkaline salts as racemization catalyst in the
chemoenzymatic DKR of benzylic amines.[ In subsequent work
several other similar heterogeneous systems were reported for
16]
[
a]
Dr. K. P. J. Gustafson, Dr. T. Görbe, Dr. G. de Gonzalo-Calvo, C.
Schreiber, Prof. Dr. J.-E. Bäckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University
[6,17,18,19,20,21,22,23]
[6]
DKR of amines
including a nanohybrid catalyst.
One intrinsic drawback with all these heterogeneous protocols is
that the catalysts employed consist of an excess inert material as
support. With this in mind we wanted to explore the use of the
previously described Pd(0)-CalB CLEA bifunctional biohybrid
catalyst for DKR of amines.
The Pd(0)-CalB CLEA biohybrid catalyst was previously
characterized using different microscopic techniques. To
complement the results from the previous studies other
techniques such as X-ray Photoelectron Spectroscopy (XPS), X-
ray Absoprtion Spectroscopy (XAS) and annular dark-field
SE-106 91, Stockholm (Sweden)
E-mail: jeb@organ.su.se
[
[
[
b]
c]
d]
Dr. C.-W. Tai, N. Yuan, Prof. Dr. X. Zou
Department of Materials and Environmental Chemistry
Stockholm University
SE-106 91, Stockholm (Sweden)
Prof. Dr. I. Persson
Department of Molecular Sciences
Swedish University of Agricultural Sciences
SE-106 91, Uppsala, Sweden
Dr. A. Shchukarev
Department of Chemistry
Umeå University
SE-750 07, Umeå, Sweden
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Figure 1. XPS spectrum of Pd 3d5/2 of catalyst reduced with a) NaBH
3
3
4
CN and b) NaBH . Fourier transformed k -weighed EXAFS spectra of catalysts reduced with
c) NaBH
3
CN and d) NaBH
4
. The spectra are not phase corrected. e) Normalized Pd K-edge XANES spectra of the pre-catalyst, the reduced catalyst and Pd foil
CN and g) NaBH
reference. HAADF-STEM images of catalyst reduced with f) NaBH
3
4
.
scanning transmission electron microscopy (HAADF-STEM)
studies were carried out on the Pd(0)-CalB CLEA catalyst (Figure
lies at a slightly lower energy than the catalyst reduced by
NaBH CN, and their edge shape profile features are not identical.
These details support our conclusion that there are more Pd
nanoparticles in the catalyst reduced by NaBH , and hint as well
that the Pd(II) species in these two catalysts could be different.
However, the HAADF-STEM of the two catalysts did not show
enough significant differences that allowed to draw any
conclusions concerning the relative amount of Pd(0) and Pd(II)
(Figure 1f and g).
3
1
). Also, the effect of two different reducing agents (NaBH
NaBH CN) for the generation of the palladium nanoparticles were
studied. When comparing the Pd 3d
spectrum of the two catalysts from the two reductions it was clear
that the catalyst reduced by NaBH contained more reduced Pd
Pd(0)) relative to the catalyst reduced by NaBH CN (Figure 1a
and b, Pd(0) signal at 335.1 eV relative to overall: 1:1,5
NaBH CN) and 1:1 (NaBH ). The two catalysts showed an
4
vs.
3
4
5
/2
signals in the XPS
4
(
3
(
3
4
After previously demonstrating that the Pd-CLEA biocomposite is
capable of catalyzing kinetic resolutions, the focus now was on
optimizing the racemization of amines. Initial attempts to racemize
-methyl benzylamine (R)-1a, using the previously prepared
3
intriguing composition of different Pd(II)-species, the species
were present in different ratios in the two catalysts (signal at 336.1
relative to the one at 338.0 eV). The catalysts were further
compared by extended X-ray absorption fine structure (EXAFS),
and their Fourier transformed spectra are presented in Figure 1c-
d. Similarities were observed in both the mononuclear region (Pd–
catalyst (where NaBH CN was employed as reducing agent for
generating Pd-nanoparticles) yielded poor racemization.
A
change of the reducing agent from the mild NaBH CN to the more
3
N/O, ~1.5
Å
without phase correction) and the region
strongly reducing NaBH , gave a catalyst with an enhanced rate
4
corresponding to the Pd nanoparticle (Pd–Pd, ~2.4 Å without
phase correction) (Figure 1c-d). Interestingly, the relative
magnitude of the Pd–Pd peak in Figure 1d appears slightly higher
than that in Figure 1c, which corresponds to a minor difference in
the average coordination number of Pd–Pd derived from
refinement of the spectra (Table S5). This can be attributed to a
larger fraction of Pd nanoparticles in the catalyst reduced by
of racemization. Initial attempts to use the latter catalyst (with 4.4
mol% Pd) in toluene at 90 C under 1 atm of hydrogen gas led to
racemization, where enantiomerically pure amines (R)-1a
afforded the semi-racemized amine in 31% ee after 6 h. However,
the by-product ethylbenzene 4a was also formed in substantial
amounts (Table 1, entry 1).[ By the use of other solvents such
as 1,4-dioxane and THF, the side-product 4a was formed in
smaller amounts, however, at the same time the rate of
racemization went down (entries 2-3). Attempts to reduce the side
product formation further by lowering the temperature (entries 4-
5), changing other ethereal solvents, or lowering the
concentration were unsuccessful (See supporting information,
Table S1).
24]
4 3
NaBH than that reduced by NaBH CN. The X-ray absorption near
edge structure (XANES) spectra (Figure 1e) show that the edge
positions of Pd in the reduced catalysts are between the positions
of Pd(II) pre-catalyst and metallic palladium. This means that the
Pd(II) and Pd(0) species coexist in the catalysts, which agrees
well with the observations from XPS and EXAFS. With a closer
look, the edge position of Pd in the catalyst reduced by NaBH
4
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COMMUNICATION
5
6
7
THF
THF
THF
K
2
CO
3
60
60
60
45
53
66
99
99
91
<1
<1
<1
Table 1. Optimization table for the racemization of (R)-1a.[a]
NaOAc
TEA
[
4
a] Reaction conditions: 1a (0.25 mmol, 0.166 M), Pd(0)-CalB CLEA (22 mg,
.4 mol% Pd) under 1 atm of hydrogen gas at 90 °C. [b] Determined using
NMR yield with 1,3,5-trimethoxybenzene as internal standard. [c] GC-FID
with chiral column.
Entry[a]
Solvent
Toluene
1,4-Dioxane
THF
T [ºC]
90
t [h]
6
ee [%][b]
31
4a [%][c]
1
2
3
4
5
29
9
90
6
62
In an attempt to increase the yield of the DKR, different
concentrations were tried, and with an increase of the
concentration to 0.25 M the yields were improved in 1,4-dioxane
and THF, to 87% and 82% yield, respectively (Table 3, entries 1-
90
6
58
3
THF
60
6
94
<1
<1
2
). The ee was slightly higher in THF than in 1,4-dioxane. In
1,4-Dioxane
60
6
96
toluene on the other hand, the results were not affected or got
slightly worse (entry 3) on increasing the concentration. An
additional increase of the concentration in THF and 1,4-dioxane
improved the yield, however, the ee became lower and no overall
improvement was obtained (entries 4-5). When increasing or
decreasing the catalyst loading, no improvement of the reaction
was observed (entries 6-7).
[
4
a] Reaction conditions: 1a (0.25 mmol, 0.166 M), Pd(0)-CalB CLEA (22 mg,
.4 mol% Pd) under 1 atm of hydrogen gas at 90 °C. [b] GC-FID with chiral
b
column. [c] Determined using NMR yield with 1,3,5-trimethoxybenzene as
internal standard.
After establishing the limits of the Pd-catalyzed racemization, the
focus was directed to find the optimal reaction conditions for DKR
Table 3. Optimization of concentration and catalyst loading in the DKR of
1a.[
a]
of 1a. From previous successful studies in our group and by
others,[
23,25]
2 equiv. of ethyl methoxyaceate was employed as
CO as drying agent/acid scavenger
acyl donor at 90 ºC using Na
2
3
in toluene at a concentration of 0.166 M (Table 2, entry 1).
Gratifyingly, amide 3a was obtained in 81% yield with an ee of
95%. Changing the solvent to 1,4-dioxane marginally improved
the yield and ee of amide 3a, however, the main improvement was
seen in that the conversion to the by-product ethyl benzene 4a
was reduced from 19% to 5% (entry 2). Changing the solvent to
THF improved the ee and further reduced the amount of ethyl
benzene 4a, however, the yield was slightly reduced to 65% (entry
Entry
Solvent
1a [M]
Pd
mol%]
3a
ee
[%]
4a
[%]
[%][
b]
[c]
[b]
[
1
2
3
4
5
6
7
1,4-Dioxane
THF
0.25
0.25
0.25
0.5
4.4
4.4
4.4
4.4
4.4
2.2
8.8
87
82
77
83
90
82
83
94
98
93
95
92
93
93
5
3). Other ethereal solvents were screened, but they did not
5
improve the results (see Supporting Information, Table S2). When
the base was changed to other organic or inorganic bases, no
further improvement of the reaction was observed (entries 5-7).
Toluene
18
6
THF
Table 2. Optimization of the DKR of 1a with regards to additives,
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0.5
10
3
temperature and solvent.[
a]
0.25
0.25
17
[
a] Reaction condtions: 1a (0.25 mmol), Pd(0)-CalB CLEA (22 mg, 4.4 mol%
Pd) under 1 atm of hydrogen gas at 90 °C. [b] Determined using NMR yield
with 1,3,5-trimethoxybenzene as internal standard. [c] GC-FID with chiral
column.
Entry
Solvent
Base
T
3a
[%][
ee
[%]
4a
[%]
b]
[c]
[b]
[ºC]
1
2
3
4
Toluene
1,4-Dioxane
THF
Na
2
Na
2
Na
2
Na
2
CO
CO
CO
CO
3
3
3
3
90
90
90
60
81
82
65
60
95
96
99
99
19
5
After the optimized reaction conditions had been established for
the DKR of the amines (using 4.4 mol% of catalyst) in either 1,4-
dioxane or THF (0.25 M) at 90 ºC and Na CO as base under 1
2 3
atm of hydrogen, differently substituted benzylic amines were
studied in the reaction (Scheme 1). All the chiral amides 2a-g
<1
<1
THF
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COMMUNICATION
Scheme 1. Substrate scope of the DKR of amines catalyzed by Pd(0)-CalB CLEA. [a] Reaction conditions: 1a (0.25 mmol), 2 (0.5 mmol), Pd(0)-CalB CLEA (22 mg,
.4 mol% Pd), dry Na CO (28 mg, 0.26 mmol) in THF (0.25 M) under 1 atm of hydrogen gas at 90 °C. [b] Reaction was performed in 1,4-dioxane (0.25 M). [c]
Product ee was determined by using chiral column on GC or HPLC. [d] Isolated yield. [e] NMR-yield of product 3 or the equivalent debenzylated structure.
4
2
3
were obtained in good yields and in good to high ee. In general, it
was established that the use of 1,4-dioxane led to higher
conversions but resulted in an increased amount of side product
ee dropped from 95% to 86%. After the first two cycles the yield
and ee was reduced even further. Recycling in toluene (Figure
1b), was more successful and after the first three cycles the yield
only dropped slightly from 78% to 72% and the ee changed from
95% to 92%. In the following cycles the yield and ee were reduced
further.
4a-g (around 10%), while the use of THF afforded higher
selectivities and lower amounts of side product compared to 1,4-
dioxane.
To demonstrate the recyclability of the biohybrid catalyst Pd(0)-
CalB CLEA, the DKR of (rac)-1-phenylethylamine 1a in 1,4-
dioxane and toluene at 90 ºC was performed over four and five
cycles, as shown in Figure 2a and 2b. After each cycle, the
reaction mixture was separated by centrifugation, in order to
recover the solid catalyst. The recovered solid catalyst was
successively washed with 2 mL of phosphate buffer (0.1 M, pH
Because of the significant deactivation of the catalyst used in
1,4-dioxane, the HAADF-STEM, XAS and XPS were carried out
on the recovered catalyst to gain information concerning the
deactivation. The leaching was first tested but in neither 1,4-
dioxane nor toluene any significant leaching could be detected
(Pd <0.5 ppm), showing that deactivation was not due to leaching.
The XPS spectrum of Pd in the reused catalyst did not change
significantly and was comparable to the spectrum of the starting
catalyst.
7.2), 2 mL of acetone and 2 mL of diethyl ether. As shown in
Figure 2a, the catalyst activity and enantioselectivity decreased
when 1,4-dioxane was used as solvent. Already in the second the
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COMMUNICATION
a)
00
% Amide
% Side product
ee (%)
b)
% Amide
% Side product
ee (%)
1
00
80
60
40
1
80
60
40
20
0
20
0
1
2
3
4
1
2
3
4
5
CYCLE
CYCLE
Figure 2. Recycling of Pd(0)-CalB CLEA in the DKR of 1-phenylehtylamine 1a at 90 ºC: a) in 1,4-dioxane and b) in toluene.
Figure 3. a) XPS spectrum of Pd 3d5/2 of the reused catalyst in 1,4-dioxane. b) Fourier transformed k3-weighted EXAFS spectrum of the reused catalyst in 1,4-
dioxane. The spectrum is not phase corrected. c) HAADF-STEM of the reused catalyst in 1,4-dioxane.
When examining the EXAFS spectrum of the reused catalyst
Figure 3b) the same peaks as in fresh catalyst (Pd–N/O and Pd–
metalloenzyme.26 This type of cross-linked enzymes with
immobilized nanometal particles is promising and should open up
new opportunities in the area of dynamic kinetic resolution.
Interesting structural changes were observed in the catalyst
recycled in 1,4-dioxane, and the appearance of a Pd–Cl or Pd–S
bond or similar bond was observed in the Fourier transformed
EXAFS, that most likely arise from impurities after destabilization
of the Pd nanoparticles in 1,4-dioxane. Continued efforts in the
research group will be focused on improving the synthesis of
CLEA biohybrids, and to explore new reactivities of the reported
catalyst, as well as to make new biocomposite materials for
catalysis.
(
Pd) could be observed. Unlike in the spectrum of the unused
catalyst a second peak had appeared at 1.9 Å (not phase
corrected), suggesting that a new bond previously not present had
been formed. The bond distances according to the best fit was
determined to be 2.29 Å (Table S6). This distance is in the range
of a Pd–Cl or Pd–S (XPS spectrum of S 2p did not indicate a
significant change in the sulphur, which suggest another element
than S (Figure S4). This new bond can arise from contamination
of chloride ions in the reagents and solvents. In an attempt to get
a visual support of the deactivation, the catalyst was examined by
electron microscopy (HAADF-STEM). It is obvious from the
HAADF-STEM images that Pd had agglomerated and in certain
regions of the material Pd had been washed out (Figure 3c).
Herein we have reported the continued structure elucidation of
the Pd(0)-CalB CLEA using different techniques such as TEM,
XPS and XAS. Gratifyingly, the Pd biocomposite was successfully
implemented in the DKR of primary amines using a set of benzylic
amines and the results compare very well with previously
developed DKRs of amines. The strength of this approach is that
a new type of hybrid catalyst is used in the DKR as an artificial
Experimental Section
General procedure for the dynamic kinetic resolution (DKR) of 1. Into
a flame-dried Schlenk flask were added dry Na CO (0.28 mmol, 30 mg),
2 3
Pd(0)-CalB CLEA (22 mg) and 1,3,5-trimethoxybenzene (16.8 mg, 0.1
mmol). The reaction vessel was evacuated and refilled with hydrogen gas
three times. Then, dry solvent (1.0 mL), the corresponding racemic amine
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Chemistry - A European Journal
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COMMUNICATION
1
a-g (0.25 mmol), and ethyl methoxyacetate (0.5 mmol, 59 휇L) were added
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and the system was evacuated and followed by refilling with hydrogen gas.
The mixture was heated to the indicated temperatures and stirred for the
times established. After reaching completion, reactions were filtered with
ethyl acetate through Celite® plug. The NMR yield of the final amides (R)-
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a-g and the amount of the ethyl benzene 4a obtained as by-product were
determined by 1H-NMR using 1,3,5-trimethoxybenzene as internal
standard or isolated using silica gel chromatography (gradient 0-40%
EtOAc in pentane) while the optical purity of the amides (R)-3a-f was
determined by GC. Enantiomeric excess of compound (R)-3g was
determined by HPLC.
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Acknowledgements
Financial support from The Swedish Research Council (2016-
03897, 2015-04099), the Berzelii Center EXSELENT, and the
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Knut and Alice Wallenberg Foundation (KAW 2016.0072) is
gratefully acknowledged. Gonzalo de Gonzalo thanks MINECO
[
(
Ramón y Cajal Program) for personal funding.
2954–2975.
Keywords: heterogeneous catalysis • key cross-linked enzyme
aggregates • dynamic kinetic resolution • amide • biohybrid
catalyst
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