Asymmetric ring opening of racemic epoxides for enantioselective synthesis of (S)-β-amino alcohols by a cofactor self-sufficient cascade biocatalysis system

Article abstract of DOI:10.1039/c8cy02377h

A novel one-pot epoxide hydrolase/alcohol dehydrogenase/transaminase cascade process for the asymmetric ring opening of racemic epoxides to enantiopure β-amino alcohols is reported. The product (S)-β-amino alcohols were obtained in 97-99% ee and 79-99% conversion from readily available racemic epoxides.

Full text of DOI:10.1039/c8cy02377h

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Asymmetric ring opening of racemic epoxides for
enantioselective synthesis of (S)-β-amino alcohols
by a cofactor self-sufficient cascade biocatalysis
system†
Cite this: Catal. Sci. Technol., 2019,
9, 70
Received 21st November 2018,
Accepted 4th December 2018
a Xiao-Xiao Yang,a Qiao Jia,a Jian-Wei Zhao,a Li-Li Gao,b
*
Jian-Dong Zhang,
DOI: 10.1039/c8cy02377h
When-Chao Gao, a Hong-Hong Chang,a Wen-Long Weia and Jian-He Xuc
rsc.li/catalysis
A novel one-pot epoxide hydrolase/alcohol dehydrogenase/trans-
aminase cascade process for the asymmetric ring opening of race-
mic epoxides to enantiopure β-amino alcohols is reported. The
product (S)-β-amino alcohols were obtained in 97–99% ee and 79–
99% conversion from readily available racemic epoxides.
suffered from one or more disadvantages, such as a limited
scope of substrates, unsatisfactory product ee, moderate
yields and regioselectivities, and the need for extreme condi-
tions. Due to their exquisite chemo-, regio- and stereo-
selectivity, enzymes have been widely used as green catalysts
in organic synthesis. Biocatalytic methods have been devel-
oped for the synthesis of chiral β-amino alcohols using li-
pase,5 transaminase,6 and ketone reductase.7 However, the
high cost or commercial nonavailability of the substrates and
their low yield (50% theoretical yield) of kinetic resolution
has rendered some of these methods inconvenient and un-
economic. Recently, as a green and useful tool, cascade bio-
catalysis reactions catalyzed by multienzymatic systems have
strongly moved into the focus of researchers because of their
unique potential for the environmentally benign synthesis of
chemicals,8 and several types of cascade biocatalysis systems
have been developed for the synthesis of chiral amino alco-
hols,9 for instance in the transformation of glycolaldehyde
Chiral β-amino alcohols are very important chiral molecules
that are used as building block and structural motifs in
pharmaceutically-active molecules and natural products, and
serve as main sources of chirality in asymmetric synthesis.1
For instance, (S)-(+)-2-amino-1-butanol 4a is utilized as an
intermediate for the synthesis of ethambutol (EMB), which is an
important anti-tubercular drug,1a (S)-2-amino-2-phenylethanol
4c is used as a building block for the preparation of indolin-2-
one derivatives as potent p21-activated kinase (PAK4)
inhibitors,1c and (S)-2-amino-2-(4-bromophenyl) ethanol 4f is
used as an intermediate for the synthesis of 4, 4′-bisIJbiphenyl)
substituted bisIJoxazoline) (BOX) ligands, which are among the
most widely studied ligands in asymmetric catalysis.1e
To date, a wealth of methods have been developed for the
synthesis of chiral β-amino alcohols.2 Due to the low cost
and commercial availability of epoxides, the asymmetric ring
opening (ARO) of epoxides provides efficient and straightfor-
ward access to chiral β-amino alcohols.3 In the past few de-
cades, considerable efforts have been devoted to asymmetric
ring opening reactions of epoxides using amines as nucleo-
philes that have shown moderate to good selectivity.4 How-
ever, most of these methodologies, which have to date pre-
dominantly been\ achieved using chemical methods, have
a Department of Biological and Pharmaceutical Engineering, College of Biomedical
Engineering, Taiyuan University of Technology, Taiyuan, Shanxi, China.
E-mail: zhangjiandong@tyut.edu.cn
b College of Environmental Science and Engineering, Taiyuan University of
Technology, Taiyuan, Shanxi, China
c Laboratory of Biocatalysis and Bioprocessing, State Key Laboratory of Bioreactor
Engineering, East China University of Science and Technology, Shanghai, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8cy02377h
Scheme 1 One-pot asymmetric ring opening of racemic epoxides to
enantiopure β-amino alcohols via epoxide hydrolase/alcohol dehydro-
genase/transaminase cascade biocatalysis.
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and β-hydroxypyruvate to 2-amino-1,3,4-butanetriol (ABT),9b
and the conversion of benzaldehyde and pyruvate to
norIJpseudo)ephedrine N(P)E.9c However, to date, no reports
have appeared in the literature detailing the asymmetric ring
opening of racemic epoxides for the enantioselective synthe-
sis of chiral β-amino alcohols via enzymatic catalysis, proba-
bly as a consequence of the difficulties in finding robust en-
zymes with excellent activity and enantioselectivity.10 Besides
that, how to solve the problem of cofactor regeneration in
some cascade biocatalysis reactions is still a challenge.
high activity and excellent enantioselectivity toward vicinal
diol 2a–f, with an activity from 0.133 to 0.791 U mg−1 protein
for BDHA toward (R)-2a–f, and 0.067 to 0.119 U mg−1 protein
for GoSCR toward (S)-2a–f (see the ESI,† Table S3). For the
first hydrolysis step, the epoxide hydrolase (SpEH) from
Sphingomonas sp. HXN-200 was selected as a promising en-
zyme due to its remarkable activity in the enantioselective hy-
drolysis of epoxides.14 The substrate specific and enantio-
selectivity of SpEH was further analyzed with six racemic
epoxides 1a–f, with 20 mM of substrate. After reaction for 2
to 3 h, the substrates were completely converted to vicinal di-
ols 2 (99% conversion), forming the product diol 2 in 3–40%
ee (see the ESI,† Table S4). As the intermediate product 2 was
formed in the first step of the cascade reaction with low ee
values, it was then essential to employ two stereocomple-
mentary alcohol dehydrogenases (2,3-butanediol dehydroge-
nase, BDHA, and polyol dehydrogenase, GoSCR) in the sec-
ond step of the cascade biocatalysis system to ensure the
complete conversion of both enantiomers of the vicinal diol
intermediate.
After SpEH, BDHA, GoSCR and MVTA were selected as the
best candidates for the new cascade biocatalysis system. The
combination of the last two steps into a simultaneous one-
pot in the cascade reaction was first tested with BDHA,
GoSCR and MVTA (Scheme 2). The reaction conditions for
the conversion of diols to chiral β-amino alcohols were opti-
mized using 2c as a model substrate, and the highest conver-
sion of 4c was obtained at pH 7.4 and 30 °C, with 0.5 mM of
NAD+ added (see the ESI,† Tables S5–S7). The adjustment of
the two enzyme concentrations at a ratio of 2 : 1 (20 mg mL−1
of ADH and 10 mg mL−1 of MVTA) resulted in the highest
conversion of 4c (see the ESI,† Table S8). Under the opti-
mized conditions, the enantioselective conversion of racemic
diols 2c (50 mM) with the mixture of BDHA, GoSCR and
MVTA (2 : 2 : 1) reached up to 99% with the product 4c in
>99% ee. The generality of this cascade system (BDHA/
GoSCR/MVTA) was further investigated using five other race-
mic diols (2a–b and 2d–f) and 31–99% conversions were
obtained in 97–99% ee with a mixture of BDHA, GoSCR and
MVTA (2 : 2 : 1) (see the ESI,† Table S9).
In this study, we envisioned a one-pot three-step enzy-
matic cascade reaction for the asymmetric ring opening of ra-
cemic epoxides to enantiopure β-amino alcohols (Scheme 1).
The process includes the complete hydrolysis of a racemic ep-
oxide to a vicinal diol by an epoxide hydrolase (EH), the oxi-
dation of the vicinal diol intermediate to an α-hydroxy ketone
by two stereocomplementary alcohol dehydrogenases (ADH)
and the asymmetric reductive amination of an α-hydroxy ke-
tone intermediate to an enantiopure β-amino alcohol by a
transaminase (TA). ADH/(R)-(+)-1-phenylethylamine (R-MBA)
was also utilized in the cascade system to drive the equilib-
rium towards the product and recycle the NAD+ cofactor.
In order to realize the novel cascade biocatalysis system,
the transaminases for the conversion of α-hydroxy ketones to
enantiopure β-amino alcohols in the third step of the cascade
biocatalysis system were selected. Based on our previously
constructed high-throughput method for the screening of
highly enantioselective amino alcohol specific transami-
nases,11 (R)-ω-transaminase (MVTA) from Mycobacterium
vanbaalenii12 was identified as a robust enzyme with high ac-
tivity and excellent enantioselectivity toward β-amino alco-
hols, and the enzyme was utilized to synthesise chiral
β-amino alcohols from the corresponding α-hydroxy ketones
3a–f for the first time. After 2 to 3 h of reaction time, the con-
version reached 99% with the product in 97–99% ee (see the
ESI,† Table S1). Due to (R)-MBA being used as an efficient
amine donor of MVTA, the co-product acetophenone (AP) was
produced in the asymmetric reductive amination process. In
order to recycle the NAD+ in the second step of the cascade
biocatalysis system, we designed an in situ self-sufficient co-
factor regeneration system (Scheme 1) that involves the alco-
hol dehydrogenase catalyzed oxidation of vicinal diols and
the same alcohol dehydrogenase catalyzed AP reduction.
Then, the alcohol dehydrogenase (ADH)/(R)-MBA in the cas-
cade system can be utilized to recycle the NAD+ cofactor and
simultaneously drive the equilibrium towards the product. In
order to realize this process, sixteen alcohol dehydrogenases
were tested for diol 2c oxidation activity and AP reduction ac-
tivity (see the ESI,† Table S2). BDHA from Bacillus subtilis and
GoSCR from Gluconobacter oxydans13 showed the highest ac-
tivity toward the diols (R)-2c (0.80 U mg−1) and (S)-2c (0.12 U
mg−1) and moderate activity toward AP (0.428 U mg−1 for
BDHA and 1.257 U mg−1 for GoSCR), respectively. Therefore,
BDHA and GoSCR were selected as promising candidates to
catalyze the diol oxidation step of the cascade reaction. Sub-
strate specific analysis revealed that BDHA and GoSCR have
We next sought to combine the SpEH, BDHA, GoSCR and
MVTA biocatalysts in a one-pot cascade to convert 1 to 4. Ra-
cemic 1c was exposed to SpEH followed by BDHA/GoSCR and
MVTA, and the target (S)-4c was obtained in 86.5%–99% con-
version and >99% ee (Table 1, entries 3–4). The generality of
Scheme 2 Enantioselective conversion of racemic vicinal diol 2 to
enantiopure β-amino alcohol 4 using a mixture of BDHA, GoSCR and
MVTA.
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Table 1 Asymmetric ring opening of racemic epoxides 1 to (S)-β-amino alcohol 4 with mixtures of cell-free extracts of E. coli (SpEH), E. coli (BDHA), E.
coli (GoSCR) and E. coli (MVTA)
Sub. conc
[mM]
SpEH
BDHA
GoSCR
MVTA
Time
[h]
Conv. to 4a
[%]
(S)-4 eeb
[%]
Entry
Sub.
[mg mL−1
]
[mg mL−1
]
[mg mL−1
]
[mg mL−1
]
1
2
3
4
5
6
7
1a
1b
1c
1c
1d
1e
1f
20
20
20
30
20
20
20
10
10
10
20
10
10
10
20
20
20
40
20
20
20
20
20
20
40
20
20
20
10
10
10
20
10
10
10
24
24
16
16
24
24
24
47.3
61.2
99.0
86.5
96.9
70.5
34.0
97
98
>99
>99
>99
>99
>99
The reactions were conducted using 25–55 mM of the amine donor (R-MBA) in 100 mM sodium phosphate buffer (pH 7.5) containing 0.1 mM
a
pyridoxal-5′-phosphate (PLP), 0.5 mM NAD+, 20–50 mM substrates, and 10% DMSO at 30 °C. Conversion was determined by GC, error limit:
<2% of the stated values. b ee values were determined by chiral GC.
Table 2 Asymmetric ring opening of racemic epoxides 1 to (S)-β-amino alcohol 4 with resting cells of E. coli (SpEH–BDHA–GoSCR–MVTA) (catalyst 3) in
an aqueous–organic two-phase system
Sub.
Sub. conc. [mM]
RIJ+)-MBA [mM]
Catalyst 3 [g cdw L−1
]
T [h]
Conv. to 4a [%]
(S)-4 eeb [%]
1a
1b
1c
1d
1e
1f
20
20
50
20
20
20
25
25
55
25
25
25
18
18
20
18
18
18
5
5
16
5
5
5
99.0
80.4
92.0
99.0
97.1
79.6
97
98
>99
>99
>99
>99
The reactions were conducted using 25–55 mM of the amine donor (R-MBA) in a two-liquid phase system consisting of sodium phosphate
buffer (100 mM, pH 7.5) and hexadecane (1 : 1). The reactions were carried out using 0.1 mM PLP and 10–50 mM of the substrates at 30 °C.
a
Conversion was determined by GC, error limit: <2% of the stated values. b ee values were determined by chiral GC.
the cascade biocatalysis system was investigated by examin-
ing five other racemic epoxides (1a–b and 1d–f) using SpEH,
BDHA/GoSCR and MVTA (1 : 2 : 2 : 1) in the presence of 0.5
mM of NAD+, and the (S)-β-amino alcohols 4a–b were
obtained in 97–99% ee and 47.3%–61.2% conversion from
the racemic epoxides 1a–b (20 mM) after 24 h of reaction
time (Table 1, entries 1–2). For the halogen para substituted
styrene oxide substrates 1d–f, good to excellent conversions
(34%–96.9%) of the (S)-β-amino alcohols 4d–f were obtained
in >99% ee (Table 1, entries 4–6).
protect the enzyme from rapid deactivation, and the cofactor
NAD+/NADH in cells can be used for targeted reactions with
co-factor recycling. Mixed resting cells of E. coli (SpEH–
MVTA) and E. coli (BDHA–GoSCR) (Fig. S1†) were first exam-
ined for the conversion of epoxides 1a–f to (S)-β-amino alco-
hols 4a–f. Combining E. coli (SpEH–MVTA) cells at 10 g cdw
L−1 and E. coli (BDHA–GoSCR) cells at 16 g cdw L−1 led to the
production of (S)-4a–c in 97–99% ee with 42.5%–68.1% con-
version from 10 mM of 1a and 1b and 20 mM of 1c, respec-
tively. For the conversion of 20 mM of the epoxides 1d–f, rest-
ing cells of E. coli (SpEH–MVTA) and E. coli (BDHA–GoSCR)
were mixed in a 14 : 22 ratio, and after 24 h of reaction time,
the products (S)-4d–f were obtained in >99% ee and 61.8–
77.7% conversion (see the ESI,† Table S10).
Compared to enzymatic catalysis, whole-cell biocatalysts
provide unique properties,15 such as that the intact cells can
A recombinant E. coli strain that co-expresses all of the
necessary enzymes is often used for cascade biocatalysis
since this avoids having to cultivate cells of multiple
strains.16 Resting cells of E. coli (SpEH–BDHA–GoSCR–MVTA)
co-expressing four enzymes were thus used for the one-pot
conversion of the epoxides 1a–f to the (S)-amino alcohols
4a–f. The E. coli (SpEH–BDHA–GoSCR–MVTA) cells showed
specific activities of 14.8–40.6 U g−1 cdw for the conversion of
1c to 4c after growth for 2–16 h (see the ESI,† Fig. S3). The
SDS-PAGE of the cell-free extracts of the E. coli cells harvested
at 4–16 h is shown in Fig. S2.† Reactions of 10–20 mM of the
racemic epoxide 1c with E. coli (SpEH–BDHA–GoSCR–MVTA)
at 10–20 g cdw L−1 afforded (S)-4c in >99% ee and 99% con-
version. When the concentration of the racemic epoxide 1c
Fig. 1 Time course of the conversion of styrene oxide 1c (50 mM) to
(S)-4c with resting cells of E. coli (SpEH–BDHA–GoSCR–MVTA) (20 g
cdw L−1) in a two-liquid phase system. = the concentration of 1c;
= the concentration of 2c;
concentration of (S)-4c.
= the concentration of 3c; and = the
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was increased to 50 mM, only a trace amount of the desired
product (S)-4c was formed (5.6% conversion) (see the ESI,† Ta-
ble S11). We attribute this to the low solubility and high toxic-
ity of the epoxide substrate in aqueous phase. To circumvent
the solubility and toxicity problem of the epoxides, an aque-
ous–organic two-phase system consisting of sodium phos-
phate buffer (100 mM, pH 7.5) and hexadecane at 1 : 1 (v/v)
was used as the reaction medium. Reactions of 20 mM of ep-
oxides 1a and 1b with E. coli (SpEH–BDHA–GoSCR–MVTA) at
18 g cdw L−1 afforded (S)-4a and (S)-4b in 97%–98% ee and
80.4–99% conversion within 5 h of reaction time. The reaction
of epoxide 1c (50 mM) with the same catalysts at 20 g cdw L−1
gave (S)-4c in >99% ee and 92% conversion (Table 2). The
time course of this reaction is shown in Fig. 1. At 2 h, epoxide
1c was totally converted to 1-phenyl-1, 2-ethanediol 2c due to
the high activity of SpEH, 33.5 mM diol 2c remained in the re-
action mixture, and the remainder of diol 2c was converted to
15.5 mM of (S)-2-amino-2-phenylethanol 4c in >99% ee by
BDHA/GoSCR and MVTA. From 2 to 16 h, the concentration
of (S)-4c increased linearly upon a linear decrease in the con-
centration of 2c. At 16 h, 46 mM of (S)-4c was produced in
>99% ee, and a trace amount of 2c remained in the reaction
mixture. In the whole reaction process, almost no
2-hydroxyacetophenone 3c was detected. These results show
that the α-hydroxy ketone produced in the second step was
quickly converted to an β-amino alcohol by MVTA in the third
step of the cascade reaction. Further conversion of epoxides
1d–f (20 mM) with E. coli (SpEH–BDHA–GoSCR–MVTA) at 18 g
cdw L−1 gave (S)-4d–f in >99% ee and 79.6–99% conversion.
The applicability of this new type of cascade biocatalysis
was tested in a 100 mL scale preparative experiment. After 24
h of reaction times, pure (S)-4c was isolated in >99% ee and
80% isolated yield after extraction with ethyl acetate and flash
chromatography (see the ESI,† Fig. S17 and S18). This example
demonstrates the facile and green application of this new type
of cascade biocatalysis for the asymmetric ring opening of ep-
oxides to enantiopure β-amino alcohols in high-yield.
designed cascade process might be generally applicable to ac-
cess a variety of different chiral β-amino alcohols starting
from the corresponding inexpensive racemic epoxides by
combining appropriate enzymes.
This study was supported by the National Natural Science
Foundation of China (Grant No. 21772141), the Shanxi
Province Science Foundation for Youths (grant No.
201701D221042) and the Open Funding Project of the State
Key Laboratory of Bioreactor Engineering.
Conflicts of interest
There are no conflicts to declare.
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was successfully developed for the asymmetric ring opening
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cohols in high ee via epoxide hydrolysis, diol oxidation and
α-hydroxy ketone asymmetric reductive amination. In vitro
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