Co-immobilization of metal and enzyme into hydrophobic nanopores for highly improved chemoenzymatic asymmetric synthesis

Article abstract of DOI:10.1039/d0cc06431a

Chemoenzymatic catalysts with hydrophobic nanopores were fabricated by co-immobilizing metal nanoparticles and enzymes into the dendritic organosilica nanoparticles. They demonstrated highly improved catalytic performance in chemoenzymatic asymmetric synthesis of chiral amines and alcohols. The hydrophobic microenvironment proved to be critical to enhanced stability, activity and cascade efficiency. This journal is

Full text of DOI:10.1039/d0cc06431a

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DOI: 10.1039/D0CC06431A
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Co-immobilization of Metal and Enzyme into Hydrophobic
Nanopores for Highly Improved Chemoenzymatic Asymmetric
Synthesis
Received 00th January 20xx,
Accepted 00th January 20xx
Liya Gao,a Zihan Wang,a Yunting Liu,*a Pengbo Liu,a Shiqi Gao,a Jing Gao,a and Yanjun Jiang*a,b
DOI: 10.1039/x0xx00000x
Chemoenzymatic catalysts with hydrophobic nanopores were protective environment, improve their stability and catalytic
fabricated by co-immobilizing metal nanoparticles and enzymes activity.5 For example, Bäckvall co-immobilized Pd
into the dendritic organosilica nanoparticles. They demonstrated nanoparticles (NPs) and Candida antarctica lipase B (CALB) on
highly improved catalytic performance in chemoenzymatic siliceous mesocellular foams, and the obtained catalyst
aysmmetric synthesis of chiral amines and alcohols. The exhibited improved yield and enantioselectivity in DKR of 1-
hydrophobic microenvironment proved to be critical to the phenylethylamine.6 Another factor critical to heterogeneous
enhanced stability, activity and cascade efficiency.
catalytic efficiency is the hydrophilicity/hydrophobicity of
confining environment, which can affect the noncovalent
interactions between the catalytic centres and the guest
substrates. Dong et al explored this effect at a single-molecule
level, disclosing that the hydrophobic nanoconfinement led to
higher catalytic activity and stronger adsorption strength.7 Wu
stepwise loaded Pd NPs and CALB into mesoporous silica
nanoparticles hydrophobized by surface alkylation, achieving
remarkable cascade catalytic performance in organic solvents.8
Although the post-modification of as-synthesized supports is a
very powerful strategy, it usually requires tedious processes and
toxic organic compounds. Dendritic organosilica nanoparticles
(DONs), as a class of mesoporous materials with intrinsic
hydrophobicity, are expected to be excellent supports for direct
co-immobilization of metal and enzymes without extra
hydrophobic modification. The DONs have been explored
extensively in biomedicine, nanofabrication and nanocatalysis,
due to their ordered center-radial mesoporous channels and
high accessible internal surface areas.9 Unfortunately,
compared with their versatile applications, their synthetic
methods are still very limited,10 and to the best of knoeledge,
the assembly of chemo- and bio-catalysts with the DONs matrix
to fabricate chemoenzymatic catalysts has not yet been
reported.
Optically active amines and alcohols are attractive synthetic
targets because they are very important building blocks used in
the pharmaceutical, fragrance, and flavor industry.
Enantioselective reactions catalyzed by chemo- or bio-catalysts,
have proven to be a powerful tool to synthesize these
enantioenriched compounds, arising from their appealing
features of wide reactivity and high selectivity, respectively.1 In
recent years, the combination of chemo- and bio-catalysis in
one-pot reactions to reap the benefits of both catalytic
disciplines is becoming a popular trend in various fields,2 due to
the attractiveness in minimizing purification steps, reducing
waste production, and in situ utilizing unstable or toxic
intermediates. The pioneering works of this concept are the
combination of enzymatic asymmetric transformation with
metal-catalyzed racemization, which achieve the dynamic
kinetic resolution (DKR) of racemic alcohols and amines,3
opening the way for chemoenzymatic asymmetric synthesis of
chiral molecules. More importantly, this approach can even
furnish chiral compounds that cannot be obtained by either
alone. Despite this, the poor stability of the free catalysts and
the incompatibility between them make the concept highly
challenging.4
The co-immobilization of metal catalysts and enzymes into
nanoscale space of mesoporous materials proved to be an
effective way for chemoenzymatic cooperative catalysis. The
porous networks have a significant positive effect on catalytic
performance because they can provide both catalysts a
Herein, chemoenzymatic catalysts with hydrophobic
nanopores were synthesized unprecedentedly by co-
immobilizing metal nanoparticles and enzymes into the DONs.
In this process, the DONs were firstly prepared by a continuous
phase microemulsion method, which were subsequently used
to stepwise immobilize Pd NPs and enzymes, and then grew the
PDA shell on DONs interface by self-polymerization of
dopamine. The novel catalysts demonstrated highly improved
a. School of Chemical Engineering and Technology, Hebei University of Technology,
Tianjin 300130, China.
b. Tianjin Key Laboratory of Chemical Process Safety, Hebei University of Technology, catalytic performance in chemoenzymatic asymmetric
Tianjin, 300130, China.
synthesis of chiral amines and alcohols. The hydrophilic PDA
shell provides a protective barrier for the inner core and
*E-mail: ytliu@hebut.edu.cn; yanjunjiang@hebut.edu.cn.
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000
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enhances the dispersibility in water. The two catalytic species size distribution, respectively (Figure 1c and Figure S2). The
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were co-immobilized in close proximity, reducing the diffusion different loadings of enzyme on DON@PDdO-eI:n1z0y.1m03e9@/DP0DCCA0c6o4u31ldA
distance of intermediates. Preliminary investigation indicated be achieved by adjusting immobilized time. The TEM and high-
that the hydrophobic microenvironment is responsible for angle annular dark-field STEM (HAADF-STEM) images clearly
enhanced stability, activity and cascade efficiency.
revealed the successful encapsulation of PDA shell with a
In previous work, we synthesized a nanocatalyst with a thickness of about 8 nm (Figure 1d-f). Notably, too high the
magnetic Fe3O4 core and a DON shell based on a modified concentration (exceed 25 mM) caused the DONs
continuous
phase
microemulsion
method
using agglomeration, instead of the successful encapsulation (Figure
tetraethylorthosilicate (TEOS) and bis(triethoxysilyl)ethane S3). Moreover, the elemental mappings clearly revealed the
(BTSE) as silicon sources.11 In this study, mesoporous DONs existence of C, N, Si and Pd elements, and further demonstrated
were obtained by further ameliorating the water-oil-surfactant that Pd was uniformly loaded into the channels of DONs and the
ternary systems. In a typical method for synthesizing dendritic PDA was successfully wrapped on DON (Figure 1g-i).
silica nanoparticles (DSNs), the Winsor III system containing
superfluous water and oil is favourable for the formation of
radial wrinkle structures.12 However, we found that the Winsor
II system was preferred for the synthesis of DONs, in which
water was excess while oil was limited. The reason for this
phenomenon might be that the organosilica species had a
higher solubility in organic solvents, thereby hindering their
diffusion from oil to water in the presence of excess oil, which
caused the formation of “premature” DONs and the decrease of
organic content. Moreover, the molar ratio of BTSE and TEOS
had a significant influence on the morphology of DONs. As the
ratio increased from 0/1 to 3/7, a gradually decreasing particle
and pore size was observed (Figure S1). The DONs obtained
under the ratio of 3/7 was selected to fabricate the
nanocatalysts due to their high hydrophobicity and acceptable
pore size.
Figure 1 (a) SEM image of DONs. (b) TEM image of DONs. (c) TEM
image of DON@Pd. (d,e) TEM images, (f) HAADF-STEM image, (g-i)
Elemental mappings of DON@Pd-CALB@PDA.
Scheme 1 Formation mechanism and process of the amphiphilic
chemoenzymatic nanoreactors
As shown in Scheme 1, the immobilization of Pd NPs in the
channels of DONs was achieved by in situ reduction of sodium
tetrachloropalladate (Na2PdCl4) with NaBH4 via physical
adsorption, obtaining DON@Pd. Subsequently, the enzymes
were also immobilized by physical adsorption. Ultimately, the
chemoenzymatic nanocatalyst was created by coating
hydrophilic PDA shell (DON@Pd-enzyme@PDA). Scanning
electron microscope (SEM) image showed that DONs were
uniform nanospheres with obvious wrinkle structures, about 90
nm in diameter (Figure 1a). Transmission electron microscope
(TEM) demonstrated that the DONs consisted of many center-
radial channels on their surface (Figure 1b). The DONs had a
large specific surface area and pore volume, which is conducive
to the subsequent formation of monodisperse, well-separated
Pd NPs. The loading amount of Pd NPs was measured by the
inductively coupled plasma-optical emission spectroscopy (ICP-
AES), and its relationship with the particle size was investigated.
It was found that the larger the loading amount, the bigger the
size of Pd NPs, and severe agglomeration of Pd NPs was
observed when the loading amount exceed 10%. Specifically,
the average particle size of DON@Pd (4.8%), DON@Pd (9.6%)
and DON@Pd (15.1%) was about 1.8, 4.0, 11 nm with a narrow
The elemental compositions and the crystalline structure
of the samples were checked by X-ray diffraction (XRD) and X-
ray photoelectron spectroscopy (XPS). The five diffraction peaks
of XRD patterns located at 2θ = 40.0°, 46.5°, 68.0°, 82.0° and
86.0° corresponding to the (111), (200), (220), (311), (222)
crystalline planes of the face-centered cubic structures of Pd
(JCPDS01-1190), which indicated that the Pd NPs were well
crystallized, and the encapsulation of PDA shell had no effect on
their crystal form (Figure S4). The XPS spectra further verified
the existence of C, N, O, Si and Pd elements (Figure S5a). As
shown in the high-resolution Pd 3d spectrum (Figure S5b), the
two peaks centered at 335.1 and 340.6 eV were attributed to
the Pd0 state, while the peaks at 336.3 and 341.5 eV belong to
the Pd2+ state.
To demonstrate the power of the obtained catalyst and the
effect of hydrophobic microenvironment on catalytic
performance in chemoenzymatic asymmetric synthesis of
chiral molecules, the two-step one-pot DKR of benzylamines in
organic solvent was chosen as a model transformation. In this
cascade reaction, CALB was selected as biocatalyst to mediate
the kinetic resolution (KR), and Pd NPs catalysed the in situ
racemization (Scheme 2). The success of DKRs lies in the
2 | J. Name., 2012, 00, 1-3
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identification of efficient racemization catalysts. To date, S2, Entry 8), while it showed better reusability tVhieawnAkrsticlteoOntlhinee
DOI: 10.1039/D0CC06431A
various immobilized catalysts have been developed for the shell protection. Finally, we expanded the substrate portfolio to
amine DKRs, including Pd/C,13 Pd/BaSO4,14 Pd/AlO(OH),15 Raney different benzylamines, and obtained the corresponding
17
Ni,16 and Pd/AmP-MCF.
However, most of them require enantioenriched amides (Scheme 2, 2b-f) in high yields (85-99%)
elevated temperatures (≥70 °C) to achieve high activity, and and excellent enantioselectivities (93-99% ee). Although no
only very few examples were performed at lower rationale is available for such better results obtained by DON-
temperatures.18 We envisaged that the hydrophobic DON- based catalyst, we speculated that the hydrophobic
based metal-enzyme bifunctional catalyst could provide an nanoconfinement facilitated the adsorption of the substrates,
opportunity to fill this gap.
enhanced the mass transport and catalytic activity, as well as
improved the dispersibility in organic solvent.
O
H2 (0.1 atm)
Na2CO3 (1 equiv)
DON@Pd-CALB (2 mol%)
O
O
NH2
R1 R2
1a-f
HN
The catalytic performance of the DON-based catalyst was
also tested in an aqueous two-step one-pot cascade reaction,
which coupled Pd/Cu-catalyzed Liebeskind-Srogl (L-S) reaction
with asymmetric reduction catalyzed by alcohol dehydrogenase
(ADH) from Rhodococcus ruber for the synthesis of
enantiomerically pure chiral benzyl alcohols (Scheme 3). The
mutual inactivation between the enzyme and copper ions
makes the cascade reactions challenging, especially for the
+
O
O
O
R1 R2
Toluene, 60 o
C
2a-f
3
O
O
O
O
O
HN
HN
HN
MeO
Me
2a
99%, 99% ee
2b
2c
concurrent
ones.19
To
overcome
this
drawback,
92%, 99% ee
93%, 96% ee
compartmentalization20 and biphasic systems21 are usually
required. Schaaf et al effectively conducted the above reaction
sequence in a concurrent mode, where a polydimethylsiloxane
(PDMS) membrane was utilized to compartmentalize the
catalytic system.20c In point of fact, only very few concurrent
cascade reactions have been published.22 The core-shell
structured nanocatalyst (DON@Pd-ADH@PDA) was expected to
realize this transformation, because the copper ions could
bound to the PDA shell, so they did not enter the internal
microenvironment, thereby avoiding the Cu+ inhibition of the
enzyme.
O
O
O
O
O
HN
NH
HN
O
2e
2f
2d
85%, 99% ee
99%, 93% ee
92%, 99% ee
Scheme 2 Chemoenzymatic asymmetric synthesis of chiral amines by
combining Pd-catalyzed racemization and CALB-catalyzed KR.
Initially, the racemization reaction was studied using 1-
phenylethylamine (1a) as a model substrate, Na2CO3 as base at
70 °C in toluene in the presence of a monofunctional catalyst (2
mol% Pd). As expected, the hydrophobic DON@Pd achieved
complete racemization within 4 h, which exhibited better
catalytic performance than the hydrophilic DSN@Pd and
previously reported Pd nanocatalysts (Table S1, Entry 1-6),
demonstrating the enhanced effect of the hydrophobic
microenvironment on catalytic activity and selectivity. Notably,
the smaller the size of Pd NPs, the higher the catalytic activity
(Table S1, Entry 6-8). Delightfully, the DON@Pd enabled the
racemization to be performed at 50 °C, obtaining satisfactory
conversion in 24 h (Table S1, Entry 10). Subsequently, the
chemoenzymatic DKR was investigated by combing the
enzymatic KR at 60 °C. The co-immobilized catalyst (DON@Pd-
CALB, the loadings of Pd and CALB were calculated to be 4.8 and
19.6wt%) achieved a higher yield and selectivity compared to
that of a physical mixture of DON@Pd and DON@CALB (Table
S2, Entry 1 and 2), mainly due to that the former case reduced
diffusion distance of intermediates between the two catalytic
centers. As comparisons, the catalyst with a hydrophilic core
(DSN@Pd-CALB) was examined, resulting in incomplete
conversion under the same conditions, and the comparable
yield could only be obtained after extending reaction time or
increasing reaction temperature (Table S2, Entry 3-5), further
OH
B
OH
CuTC
O
DON@Pd-ADH@PDA
OH
+
buffer, n-heptane, i-PrOH, pH 8.0, 37 o
C
S
R
R
5a-f
4
O
6a-f
Pd/CuTC
ADH
reduction
L-S reaction
R
OH
OH
OH
F
Cl
6a
6b
6c
, 86%, 99% ee
OH
, 72%, 99% ee
OH
, 70%, 99% ee
OH
Br
6d
F3C
6e
Me
6f
, 81%, 98% ee
, 61%, 97% ee
, 82%, 99% ee
Scheme 3 Chemoenzymatic synthesis of chiral alcohols by combining
Pd-catalyzed L-S coupling and ADH-catalyzed asymmetric reduction.
To verify this concept, we selected S-(tert-butyl)
ethanethioate (4) and phenylboronic acid (5a) as model
substrates for the cascade reaction, which was conducted
under modified conditions based on Schaaf’s work (Table S3,
Entry 2), namely 50 mM concentration of 4, 5a (1.1 equiv.),
CuTC (copper(I) thiophene-2-carboxylate, 1.2 equiv.),
DON@Pd-ADH@PDA (50 mg, the loadings of Pd and ADH were
calculated to be 5.2 and 9.8wt%), Tris-HCl buffer (pH 8.0), n-
validating
the
importance
of
the
hydrophobic
o
heptane (20% v/v) and i-PrOH (30% v/v), 37 C, 24 h reaction
microenvironment. In addition, the catalyst with a PDA shell
(DON@Pd-CALB@PDA) was also tested, and it caused a slower
reaction rate due to the increased diffusional restrictions (Table
time. As expected, the desired chiral alcohol 6a was obtained in
86% yield and 99% ee, which showed higher cascade reaction
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3
4
5
O. Verho and J. E. Bäckvall, J Am Chem Soc., 2015, 137, 3996-
efficiency than that using the catalyst with a hydrophilic core
(DSN@Pd-ADH@PDA), mainly due to that the hydrophilic PDA
shell allowed the catalyst dispersing well in water while the
hydrophobic DON core facilitated the absorption of organic
reactants (Table S3, Entry 6). Without the addition of n-
heptane, the yield decreased significantly (Table S3, Entry 1),
probably because the over-enrichment of organic substrates
and products near the reaction sites inhibited the activity of the
catalyst.23 Moreover, the yield significantly reduced to 26%
when used the DON@Pd-ADH as catalyst due to that the
exposed enzyme was severely inactivated by copper ions and
boronic acid, which further confirmed the protection effect of
the PDA shell (Table S3, Entry 5). The substrate portfolio could
be expanded to both electron-deficient and electron-rich
phenylboronic acids, and afforded the corresponding chiral
alcohols (Scheme 3, 6b-f) with good yields (61-86%) and
excellent enantioselectivities (97-99% ee), which demonstrated
the synthetic applicability of this chemoenzymatic nanocatalyst.
In addition, the integrated catalyst could be easily recovered by
centrifugation, and their high catalytic performance was
sustained for four cycles with no significant leaching of Pd NPs
and enzyme (Figure S6).
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In summary, DON-based catalsts with hydrophobic
microenvironment were designed, which were endowed with
outstanding merits, including the hydrophobicity facilitating the
adsorption of the substrates and the mass transfer, core-shell
structure offering a protective barrier for the catalytic species,
and the close proximity between metal and enzyme reducing
the diffusion distance of intermediates. The fabricated catalysts
demonstrated
improved
catalytic
performance
in
chemoenzymatic aysmmetric synthesis of chiral amines and
alcohols. This strategy is universally applicable to various other
enzymes, such as Candida antarctica lipase A, amine
dehydrogenase (Am-DH from Bacillus stearothermophilus), and
3
kinds of old yellow enzymes (TsOYE from Thermus
scotoductus, OYE1 from Saccharomyces pastorianus and YqjM
from Bacillus subtilisn), and the application of thses immobilized
enzymes in asymmetric synthesis is still in progress.
This work supported by the National Natural Science
Foundation of China (21878068, 21901058 and 22078081), the
Science and Technology Research Project of Hebei Higher
Education (ZD2019045), the Natural Science Foundation of
Hebei province (B2017202056 and B2019202216) and the
Program for Top 100 Innovative Talents in Colleges and
Universities of Hebei Province (SLRC2017029).
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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DOI: 10.1039/D0CC06431A
A facile, general strategy to fabricate metal-enzyme catalysts with hydrophobic microenvironment
for highly improved chemoenzymatic asymmetric synthesis.