Aqueous chemoenzymatic one-pot enantioselective synthesis of tertiary α-aryl cycloketonesviaPd-catalyzed C-C formation and enzymatic C=C asymmetric hydrogenation

Article abstract of DOI:10.1039/d1gc00372k

An aqueous chemoenzymatic cascade reaction combining Pd-catalyzed C-C formation and enzymatic C=C asymmetric hydrogenation (AH) was developed for enantioselective synthesis of tertiary α-aryl cycloketones in good yields and excellent enantioselectivities. The stereopreference of the enzyme in AH of α-aryl cyclohexenones was studied. An enantiocomplementary enzyme was obtained by site-directed mutation.

Full text of DOI:10.1039/d1gc00372k

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Aqueous chemoenzymatic one-pot
enantioselective synthesis of tertiary α-aryl
cycloketones via Pd-catalyzed C–C formation and
enzymatic CvC asymmetric hydrogenation†
Cite this: Green Chem., 2021, 23,
1960
Received 1st February 2021,
Accepted 22nd February 2021
Pengqian Luan,a Yunting Liu,*a,b Yongxing Li,a Ran Chen,a Chen Huang,a Jing Gao,a
DOI: 10.1039/d1gc00372k
a
rsc.li/greenchem
Frank Hollmann c and Yanjun Jiang
*
An aqueous chemoenzymatic cascade reaction combining ment of stable and compatible systems to realize aqueous che-
Pd-catalyzed C–C formation and enzymatic CvC asymmetric moenzymatic processes.
hydrogenation (AH) was developed for enantioselective synthesis
Chiral tertiary α-aryl cycloketones are prevalent structural
of tertiary α-aryl cycloketones in good yields and excellent motifs in pharmaceuticals, bioactive molecules and natural
enantioselectivities. The stereopreference of the enzyme in AH of products.7 The enantioselective synthesis of such acidic α-H-
α-aryl cyclohexenones was studied. An enantiocomplementary containing compounds has always been a challenging task due
enzyme was obtained by site-directed mutation.
to their prone-to-racemization nature under basic conditions.8
Metal-catalyzed asymmetric α-arylation of preformed soft eno-
lates with low basicity carbonyls,9 and enantioselective proto-
nation of achiral enolate complexes using Lewis-acid assisted
chiral Brønsted acid catalysts,10 have proven to be a powerful
tool to deliver tertiary α-aryl cyclohexanones (Scheme 1a and
b). Shi et al. achieved the asymmetric synthesis of more chal-
lenging tertiary α-aryl cyclopentanones by enantioselective
Biocatalysts have become one of the fundamental pillars in the
toolbox of synthetic chemistry due to their high stereo-
selectivity. More importantly, biocatalysis can produce enantio-
enriched molecules in a green way based on the mild reaction
conditions and the use of water as the preferred solvent, which
meets the requirements of environmentally friendly catalytic
processes and sustainable development strategy.1 Although the
catalytic repertoire of enzymes is striking, many valuable trans-
formations catalyzed by artificial catalysts until now have no
known enzyme-catalysed counterparts,2 and the catalytic capa-
bilities of enzyme towards non-natural substrates are limited.3
The chemoenzymatic catalysis has proven to be effective to
tackle these limitations, where the wide catalytic capabilities
of chemocatalysts and the exquisite selective properties of bio-
catalysts are usually merged in a one-pot aqueous system.4 The
pioneering work on combining Pd-catalyzed C–C bond for-
mation with the enzymatic carbonyl reduction developed by
Gröger,5a provides a paradigm for aqueous chemoenzymatic
cascade catalysis, which is becoming a popular trend in asym-
metric synthesis.5 However, this strategy often suffers from the
poor stability of the free enzymes and the incompatibilities
between the two catalytic disciplines,6 motivating the develop-
aSchool of Chemical Engineering and Technology, Hebei University of Technology,
Tianjin 300130, China. E-mail: ytliu@hebut.edu.cn, yanjunjiang@hebut.edu.cn
bTianjin Key Laboratory of Brine Chemical Engineering and Resource Eco-utilization
(Tianjin University of Science and Technology), Tianjin 300457, China
cDepartment of Biotechnology, Delft University of Technology, 2629 HZ Delft, The
Netherlands
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc00372k
Scheme 1 Strategies for asymmetric synthesis of chiral tertiary
α-substituted cycloketones.
1960 | Green Chem., 2021, 23, 1960–1964
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Table 1 Optimization
studies
of
OYEs-catalyzed
AH
of
epoxidation of benzylidene cyclobutane and subsequent
epoxide rearrangement (Scheme 1c).11 Albeit effective, none of
these approaches enable the direct use of ketone substrates.
The asymmetric hydrogenation (AH) of readily available pro-
chiral enones catalyzed by transition metals or organocatalysts,
is one of the straightforward and simple strategies for access
to chiral ketones.12 Although great progress has been made in
AH of acyclic and exocyclic enones,13,14 only few method-
ologies have been developed for endocyclic enones,15 and no
reports on AH of α-aryl endocyclic enones. In addition, for
most of the above strategies, toxic organic solvents and expen-
sive chiral ligands are inevitably used, deviating from the prin-
ciples of Green Chemistry. Therefore, it is still highly urgent to
develop a facile, general and green method for enantioselective
synthesis of chiral tertiary α-aryl cycloketones.
Old yellow enzymes (OYEs) are an important class of ene-
reductases (ERs), which possess the ability to generate up to
two chiral centers via the stereospecific trans-hydrogenation
(hydride addition/protonation) of conjugated CvC bonds.16
OYEs-catalyzed AH has emerged as a valuable synthetic
approach, which enabled various chiral compounds to be
reduced in mild reaction conditions with high enantioselectivi-
ties, such as α-alkyl endocyclic enones.17 However, the ability
of OYEs in AH of α-aryl endocyclic enones and the integration
of OYEs with other catalytic disciplines have been rarely inves-
tigated.18 Herein, we developed an aqueous chemoenzymatic
two-step one-pot cascade reaction for the direct synthesis of
enantioenriched tertiary α-aryl cycloketones from readily avail-
able 2-iodocycloenones. In this process, the aryl groups were
installed through Suzuki–Miyaura coupling (SMC) catalyzed by
2-phenylcyclohexenonea
Entry Cosolvents
Enzymes
Yieldb (%) eeb (%)
1c
2
DMF (10%)
DMF (10%)
DMF (10%)
DMF (10%)
DMF (10%)
DME (10%)
OYE1
TsOYE
YqjM
YqjM
YqjM
YqjM
YqjM
YqjM
YqjM
YqjM
YqjM
YqjM
n.d.
n.d.
9
26
42
n.d.
n.d.
42
39
43
58
64
70
76
32
54
43
79
—
—
85
85
87
—
—
60
59
92
94
95
95
95
67
90
82
97
99
99
3
4c
5d
6
7
8
9
Acetone (10%)
DMSO (10%)
THF (10%)
10
11
12
13
14
15
16e
17
18
19
20f
n-Hexane (10%)
Isooctane (10%)
[BMIm][PF6] (10%)
[BMIm][NTf2] (10%) YqjM
[BMIm][NTf2] (20%) YqjM
[BMIm][NTf2] (50%) YqjM
[BMIm][NTf2] (20%) YqjM
[BMIm][NTf2] (20%) YqjM + FDH
[BMIm][NTf2] (20%) YqjM + GDH
[BMIm][NTf2] (20%) YqjM-RBS-GDH 89
[BMIm][NTf2] (20%) YqjM-RBS-GDH 86
a Reactions were carried out at 30 °C in Tris-HCl buffer (pH 7.5) using
1a (5 mM), OYEs whole-cell lyophilizates (0.2 g), NADPH as hydrogen
source. b The yields and the values of ee were determined by HPLC.
c Using 1a (2 mM). d Using 1a (1 mM). e NADH as hydrogen source.
f Using 1a (25 mM). n.d. = not determined.
an immobilized Pd catalyst (DON@Pd), and subsequently, the and 9). Water-immiscible isooctane and ionic liquids (ILs) sig-
acidic α-H-containing stereocenters were constructed by OYE- nificantly improved the yield and enantioselectivity of the reac-
catalyzed AH of α-aryl endocyclic enones (Scheme 1d).
tion (Table 1, entries 11–13). The best result was obtained with
To test the feasibility of this strategy, 2-phenylcyclohexe- [BMIm][NTf2] (20% v/v) as cosolvent (Table 1, entry 14), which
none (1a) synthesized by SMC reaction of 2-iodocyclohexenone was attributed to its better biocompatibility and extraction
and phenylboronic acid,19 was selected as a model substrate. ability.21 In this biphasic system, the substrate was partitioned
For the AH reaction, we evaluated three different OYEs (TsOYE into the IL phase, which served as substrate reservoir and
from Thermus scotoductus, OYE1 from Saccharomyces pastoria- product sink,22 thereby preventing the interaction between the
nus and YqjM from Bacillus subtilisin) in form of freeze-dried substrate/cosolvent and the YqjM. However, a further increase
Escherichia coli cells overexpressing these enzymes. All reac- to 1 : 1 (v/v) [BMIm][NTf2] proved to be harmful to YqjM
tions were carried out under the following conditions: sub- (Table 1, entry 15). The effect of cosolvents on relative enzyme
strates (5 mM), NADPH (15 mM), in a Tris-HCl buffer solution activity was also evaluated, and the results were summarized
(10 mL, pH 7.5) at 30 °C, using DMF (v/v 10%) as cosolvent to as shown in Fig. S1.† The water-miscible solvents (DMF, DME,
overcome the poor substrate solubility in water. Unfortunately, DMSO, THF and acetone) had a severely deleterious effect on
1a was not transformed by TsOYE and OYE1, only YqjM could enzyme activity, while the water-immiscible solvents (n-hexane,
produce (R)-2-phenylcyclohexanone (2a) in extremely low yield isooctane and ILs) were more biocompatible, especially
(9%), albeit with high stereoselectivity (Table 1, entries 1–3). [BMIm][NTf2], which was consistent with the reaction results.
The R configuration of 2a was determined by optical rotation
According to literature,17a the type of cofactor and recycling
compared with the literature data.20 Although the yield and system can cause remarkable variation of yields and stereose-
the ee value were further increased when the reaction was con- lectivities. This effect was also examined in our reactions
ducted under diluted conditions, it was still far from satisfac- (Table 1, entries 16–18). Using NADPH gave better results than
tory (Table 1, entries 4 and 5). Subsequent experiments using NADH. With catalytic amounts of NADPH, the recycling
revealed a significant cosolvent effect on the catalytic perform- system of glucose dehydrogenase (GDH)/glucose (Glu) pair
ance of YqjM. Water-miscible DME and acetone led to no con- achieved 79% yield and 97% ee (Table 1, entry 18).
version (Table 1, entries 6 and 7), DMSO and THF caused Furthermore, recombinant cells co-expressing the enzymes of
decreases in the enantioselectivity of the AH (Table 1, entries 8 YqjM and GDH (YqjM-RBS-GDH) were constructed to avoid
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adding extra GDH (Fig. S2†), and they produced 2a in a higher
yield and stereoselectivity (Table 1, entry 19). This result was
mainly ascribed to that the two enzymatic transformations
occurred within the cell, which enhanced the cofactor regener-
ation efficiency.23 Under the optimal solvent system, the sub-
strate concentration could increase to 25 mM with only a
slight decrease in yield (Table 1, entry 20).
The integration of SMC and enzymatic hydrogenation in the
same reaction medium was explored to realize the two-step one-
pot chemoenzymatic cascade synthesis of enantioenriched ter-
tiary α-aryl cycloketones. Preliminary experiments revealed that
the direct combination of the two steps caused incomplete bior-
eduction (only 41% overall yield), which was ascribed to the
inhibition of enzyme by the residual boronic acid.5a Because
the heterogeneous Pd/C could not convert boronic acid comple-
tely, especially in the case of using recycled catalyst. While the
homogeneous catalysts, such as Pd(PPh3)4 and Pd(OAc)2/PPh3,
could make the coupling reaction proceed more thoroughly, the
metal cation and phosphine ligand were also inhibitors of the
enzyme.24 To solve this problem, an immobilized-Pd catalyst
was fabricated using our previously reported dendritic organosi-
lica nanoparticles as carrier (DON@Pd, the particle size and the
loading amount of Pd were calculated to be 1.8 nm and 5 wt%,
respectively) (Fig. S3–S5†).25 The wrinkle structure with high
specific surface area is conductive to the formation of ultra-
small and high dispersed Pd nanoparticles. After a simple
optimization of the reaction conditions (Table S1†), the
obtained DON@Pd produced 1a in almost quantitative yield.
Fortunately, its combination with YqjM in a biphasic system
Scheme 2 (a) Chemoenzymatic asymmetric synthesis of tertiary α-aryl
cycloanones and (b) enzymatic asymmetric hydrogenation of α-alkyl
enones.
where Pd-catalyzed C–C formation was performed in the IL the reduction of α-phenyl and α-methyl cyclohexenones (2a and
phase, and enzymatic CvC AH was performed in the buffer 3a). In order to rationalize this phenomenon, induced docking
phase, could produce the final product 2a in 81% yield and experiments were performed based on the crystal structure of
99% ee. It should be mentioned that the yield of cascade syn- YqjM. In the process of YqjM-catalyzed hydrogenation,
thesis was higher than that of stepwise synthesis (63%).
H-bonding formed between His167 and CvO bond of the sub-
After the optimized reaction protocol for the chemoenzymatic strate is essential for the activation of CvC bond (Fig. S6–S8†).28
asymmetric synthesis of tertiary α-aryl cyclohexanones was estab- Ala-60 and Ile-69 build up the entrance of the active site cavity
lished, the substrate scope of the reaction was surveyed. As indi- forming a deep and small pocket on the bottom, which can
cated in Scheme 2a, substrates containing electron-donating and accommodate the methyl group of 3a, but cannot accept the steri-
electron-withdrawing substituents were converted into the cally hindered phenyl ring of 2a (Fig. S6 and S7†), thus forcing 2a
corresponding target products (2a–k) in moderate to high yields to turn around and to bind in the opposite orientation. In
(40–81%) and excellent enantioselectivities (91–99% ee). The addition, the reorientation by 180° of 2a in the active site resulted
ortho-substituents of the aryl groups caused much slower reac- in a strong π–π interaction between the phenyl ring of 2a and the
tion rates and lower yields due to the increased steric bulk imidazole ring of His167 (Fig. S7†), in which the distance
(2b, 2g and 2i). In addition, the five- and seven-membered ring between the two planes is about 3.3–3.7 Å (Fig. S9†). The effective
substrates were also investigated. The tertiary α-aryl cyclopenta- H-bond and π–π interactions bring the substrate closer to the
nones (2l–o) were also obtained in good yield (71–78%) and active center of the enzyme, which is responsible for the high
excellent enantioselectivities (96–99% ee). However, α-phenyl level of enantio-induction.
cycloheptenone (2p) could not be converted, which may be due
The access to enantiocomplementary products is highly
to that the substrate specificity of YqjM is generally limited to valuable for manufacturing drugs since the two mirror-image
small molecules.26 The enzymatic AH of α-alkyl enones in this forms of a chiral molecule usually exhibit different pharmaco-
biphasic system was also evaluated (3a–d), achieving improved logical activities. Site-directed mutation was performed to
yields and increased substrate concentrations compared to the develop an enantiocomplementary variant of YqjM for obtain-
previous reported results (Scheme 2b and Table S2†).
ing the opposite enantiomer products. We envisioned that
As shown in previous reports,27 the stereoselectivity of the widening the active pocket to accommodate the sterically hin-
YqjM strongly depends on the substrate and is hardly predict- dered phenyl group might be a viable solution. After careful
able. We also observed a striking switch of stereopreference in screening of the amino acids around the active pocket, a
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nols bearing two contiguous stereocenters by combining ADH-
catalyzed AH of CvO bond. An enantiocomplementary variant
of the YqjM was also obtained by site-directed mutation. This
concept, which integrates the versatile reactivity of chemocataly-
sis and the exquisite selectivity of biocatalysis, is a green,
reliable alternative and supplement to the existing approaches
for the asymmetric synthesis of chiral molecules.
Scheme 3 (a) Chemoenzymatic asymmetric synthesis of (S)-2a and (b)
three-step one-pot chemoenzymatic asymmetric synthesis of chiral Conflicts of interest
α-aryl cycloalkanol.
There are no conflicts to declare.
double amino acid mutation (Gly-60 and Gly-69 were installed in
place of Ala-60 and Ile-69, respectively) was found to induce com-
plete reversal of the enantioselectivity of YqjM (Fig. S8†). After a
Acknowledgements
This work supported by the National Natural Science Foundation
slight optimization of the reaction conditions, (S)-2a was pro-
duced by the mutant YqjM through the above developed chemo-
enzymatic process with 42% yield and 99% ee (Scheme 3a).
To expand the applicability of the chemoenzymatic proto-
col, a three-step one-pot cascade reaction was developed for
asymmetric synthesis of chiral α-aryl cycloalkanols via the
combination of this process with AH of CvO bond catalyzed
by alcohol dehydrogenase from Rhodococcus ruber (ADH-A).29
Without any purification of intermediates, enantioenriched
(1S,2R)-2-phenylcyclohexan-1-ol (4) was directly produced from
2-iodocyclohexenone in 62% yield and 98% ee (Scheme 3b).
Finally, the recyclability of the both types of catalysts was
investigated by the model reaction of chemoenzymatic pro-
duction of (R)-2a under the optimal conditions. The DON@Pd
could be recovered by centrifugal separation before enzymatic
AH, and its high catalytic performance was completely sustained
for 5 cycles with no significant leaching and aggregation of
Pd NPs (Fig. S10 and S11†). However, the recovery of the catalyti-
cally active cells was difficult due to significant cell lysis observed
under these reaction conditions. To solve this problem, the two
enzymes (YqjM and GDH) were purified and co-immobilized on
DONs (for details see ESI†). Under optimized immobilization
of China (21901058, 21878068 and 22078081), the Science and
Technology Research Project of Hebei Higher Education
(ZD2019045), the Natural Science Foundation of Hebei Province
(B2017202056 and B2019202216), the Natural Science
Foundation of Tianjin City (20JCYBJC00530) and the Foundation
of Tianjin Key Laboratory of Brine Chemical Engineering and
Resource Eco-utilization (Tianjin University of Science and
Technology), People’s Republic of China (BCERE202001).
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