Synthesis of Chiral 5-Aryl-2-oxazolidinones via Halohydrin Dehalogenase-Catalyzed Enantio- and Regioselective Ring-Opening of Styrene Oxides

Article abstract of DOI:10.1002/adsc.201901412

An efficient biocatalytic approach for enantio- and regioselective ring-opening of styrene oxides with cyanate was developed by using the halohydrin dehalogenase HheC from Agrobacterium radiobacter AD1, generating the corresponding chiral 5-aryl-2-oxazoli

Full text of DOI:10.1002/adsc.201901412

Title: Synthesis of Chiral 5-Aryl-2-oxazolidinones via Halohydrin
Dehalogenase-Catalyzed Enantio- and Regioselective Ring-
Opening of Styrene Oxides
Authors: Nanwei Wan, Xiaoying Zhou, Ran Ma, Jiawei Tian, Huihui
Wang, Baodong Cui, Wenyong Han, and Yongzheng Chen
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901412
Link to VoR: http://dx.doi.org/10.1002/adsc.201901412

10.1002/adsc.201901412
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Chiral 5-Aryl-2-oxazolidinones via Halohydrin
Dehalogenase-Catalyzed Enantio- and Regioselective Ring-
Opening of Styrene Oxides
Nanwei Wan,ab* Xiaoying Zhou,ab Ran Ma,ab Jiawei Tian,ab Huihui Wang,ab Baodong
Cui,ab Wenyong Han,ab and Yongzheng Chenab*
a
Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Generic Drug Research Center of
Guizhou Province, Green Pharmaceuticals Engineering Research Center of Guizhou Province, School of Pharmacy,
Zunyi Medical University, Zunyi, 563000, China.
Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of
b
Ethnomedicine of Ministry of Education, Zunyi Medical University.
E-mail: nanweiwan@zmu.edu.cn; yzchen@zmu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
catalyze
the
formation
of
epoxides
via
Abstract. An efficient biocatalytic approach for enantio-
and regioselective ring-opening of styrene oxides with dehalogenation of vicinal halohydrins, but also
cyanate was developed by using the halohydrin
involves the reverse reaction of ring-opening
epoxides in the presence of several anionic
dehalogenase HheC from Agrobacterium radiobacter AD1,
nucleophiles.[4]
Synthesis
of
5-substituted
generating
the
corresponding
chiral
5-aryl-2-
oxazolidinones in up to 47% yield and 90% ee.
Additionally, the origin of enantioselectivity and
regioselectivity of the HheC-catalyzed cyanate-mediated
ring-opening process was uncovered by single enantiomer
bioconversions and molecular docking study.
oxazolidinones was achieved for the first time by
Janssen and coworkers using a HHDH from A.
radiobacter AD1 (HheC), which was a milestone for
biocatalytic formation of oxazolidinones. This
approach starts from the readily available epoxides,
in which inorganic cyanate serves as a nucleophile to
be catalyzed by HHDH to generate oxazolidinone
through [3+2] cycloaddition reaction with epoxides.[5]
Although preparation of enantiopure 5-substituted
Keywords: Oxazolidinones; Halohydrin dehalogenase;
Epoxides; Ring-opening; Cyanate
oxazolidinones
via
HHDH-catalyzed
kinetic
resolution or dynamic kinetic resolution of epoxides
have been achieved, the reactions only focus on alky
epoxides, especially for 2,2-disubstituted alkyl
epoxide substrates.[5]
Oxazolidinones are important five-membered
heterocyclic compounds in pharmaceutical chemistry
and organic chemistry, which have received
significant attention in serving as antibiotics, chiral
auxiliaries and synthetic intermediates for a variety of
organic transformations.[1] Therefore lots of synthetic
methods have been developed for preparing
structurally diverse oxazolidinones.[2] Despite
significant advancements in this field, the
construction of the oxazolidinone scaffolds is still a
challenge for organic chemists, due to the
involvement of harsh reaction conditions or the use of
expensive catalysts in many cases. Recently a
growing effort has been devoted to developing
environmentally benign methods for oxazolidinone
synthesis.[3] Biocatalysis is considered as a green
synthetic technology due to its specific selectivity and
mild reaction conditions, while very few enzymes are
reported for oxazolidinones preparation until now.
Halohydrin dehalogenase (HHDH), a catalytically
Enantiopure 5-aryl-2-oxazolidinones as key
building blocks for chiral pharmaceuticals such as
tembamide and aegeline,[6] are usually prepared from
the corresponding enantiopure β-amino alcohols.[7]
Though several efficient methods have been
developed to prepare 5-aryl-2-oxazolidinones via
highly regioselective ring-opening of ayl airidines
using carbon dioxide as
a
C1 source, the
enantioselectivity control in these reactions is still a
challenge.[8] One successful methodology to meet this
goal was reported by Bartoli and coworkers via a
chiral
(salen)CoII-catalyzed
regio-
and
enantioselective ring-opening of epoxides with ethyl
carbamate (Scheme 1).[9] However, this method
requires
a
subsequent cyclization step after
completion of the ring-opening process. In addition,
ethyl carbamate used in this reaction is a known
genotoxic carcinogen. In this study, we describe a
one-step, greener and atom-economic approach for
promiscuous
enzyme
from
short-chain
dehydrogenase superfamily, is not only able to
1
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10.1002/adsc.201901412
Advanced Synthesis & Catalysis
the synthesis of 5-aryl-2-oxazolidinones through the
HHDH-catalyzed enantio- and enantioselective ring-
opening of aryl epoxides with safer inorganic
cyanates (Scheme 1).
Table 1. Screening of HHDHs for enantioselective
synthesis of 2a from 1a.a)
activity
(U/g cdw)b)
0.4
yield 2a
(%)c)
5
2
20
31
20
NR
NR
ee 2a
(%)c)
85(S)
84(R)
96(R)
<5(S)
7(S)
entry HHDH
1
2
3
HheA10
HheA11
HheC
HheE
HheE5
-
0.2
12.0
13.8
7.7
ND
ND
4
5
Scheme 1. Synthesis of chiral 5-aryl-2-oxazolidinones
from aromatic epoxides.
6d)
7e)
ND
ND
-
a) Reaction conditions: 5 mL PB buffer (KH2PO4-Na2HPO4,
50 mM, pH 7.0), 1a (10 mM), NaOCN (15 mM), E. coli
We started our investigation by screening of
HHDH biocatalysts for the reaction of model
substrate styrene oxide (1a) and sodium cyanate.
Preliminary screening reactions were performed on
analytical scale using cell-free extract of HHDHs.
More than twenty recombinant HHDHs from class A
to E were examined, while most of them showed no
or very low catalytic activity (Table S1). Several
HHDHs with relatively good catalytic activity or
enantioselectivity were further tested in whole-cell
biotransformation. As summarized in Table 1, the
HheA10 converted 1a to 5-phenyloxazolidin-2-one
(2a) with the enantioselectivity in favor of the (S)-
enantiomer (Table 1, entry 1), while the HheA11 and
o
b)
(HHDH) cells (10 g cdw/L), 30 C and 6 h. Determined
over the first 1 h. The unit of specific activity was
c)
μmol·min-1·g cdw-1. Determined by chiral HPLC after 6
h. Absolute configurations were judged according to the
literature.[9] d) Reaction was performed in the absence of E.
coli cells. e) Reaction was performed using host cells E. coli
BL21 (DE3) in the absence of HHDH enzyme. ND = not
detected. NR = no reaction.
Condition optimization of the reaction was then
carried out on whole-cell catalysis of recombinant E.
coli (HheC). We first evaluated the reaction in several
buffers, and found the highest yield was obtained in
Tris-H2SO4 buffer, pH 7.0 (Table 2, entry 4).
Subsequent investigation of reaction temperature in a
HheC
exhibited
the
complementary
R
enantioselectivity (Table 1, entries 2-3). The HheA10
and HheA11 showed low activity in this reaction.
Although the HheE and HheE5 exhibited relatively
good activity, the enantioselectivity was too low to
obtain enantioenriched 2a (Table 1, entries 4-5). The
control reactions revealed the spontaneous and host
cell-caused formation of 2a did not take place in the
absence of HHDH (Table 1, entries 6-7). In addition,
trace amounts of the by-product diols were formed in
the enzymatic and nonenzymatic reactions, which
resulted from the spontaneous hydrolysis of epoxides.
Considering catalytic enantioselectivity and activity,
the best candidate HheC was selected as the
biocatalyst for the following investigation on chiral 5-
aryl-2-oxazolidinones synthesis.
o
range from 25 to 50 C revealed that 32% yield was
obtained at the optimal temperature of 45 oC (Table 2,
entry 8). Additionally, increasing equivalence ratio of
cyanate led to increase in yield. The yield was
improved to 40% at the ratio of 3:1 (Table 2, entry
12), while further enhancing cyanate concentration
did not result in apparent increase in yield (Table 2,
entry 13). Examination of cell density indicated that
increasing cell density to a concentration of 15 g
cdw/L generated the highest yield (45%) without the
expense of enantioselectivity (Table 2, entry 15).
Table 2. Screening of reaction conditions for the synthesis of (R)-2a from 1a.a)
cell density
(g cdw/L)
yield
2a (%)
ee
entry
buffer
T (oC)
NaOCN:1a
(R)-2a (%)
1
2
3
4
6.0(PB)
30
30
30
30
1.5:1
1.5:1
1.5:1
1.5:1
10
10
10
10
16
18
12
21
96
7.0(PB)
96
93
96
8.0(PBS)
7.0(Tris-H2SO4)
2
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10.1002/adsc.201901412
Advanced Synthesis & Catalysis
5
8.0(Tris-H2SO4)
30
30
25
35
45
50
45
45
45
45
45
45
45
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
0.5:1
1:1
10
10
10
10
10
10
10
10
10
10
5
11
7
95
95
96
95
93
94
96
95
92
94
93
92
91
6
8.5(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
7.0(Tris-H2SO4)
6
19
25
32
18
18
25
40
41
32
45
44
7
8
9
10
11
12
13
14
15
16
3:1
4:1
3:1
3:1
15
20
3:1
a) The reactions were carried out in 5 mL buffer solution (50 mM) containing 10 mM 1a, E. coli (HheC) cells and NaOCN.
The ee and yields of 2a at each condition were determined by chiral HPLC after reaction for 6 h.
With the optimized reaction conditions in hand
(Table 2, entry 15), substrate concentrations from 5 to
50 mM were investigated. As shown in Figure 1, it
could be found that all reactions were almost finished
in 12 h. Since the maximum theoretical yield for the
kinetic resolution process was 50%, good yields
(>35%) of 2a were obtained at the substrate
concentrations of 5-30 mM. In the case of 30 mM 1a,
the reaction generated 10.8 mM 2a with 36% yield.
Further increasing substrate concentration to 50 mM
led to the formation of 12 mM 2a with a moderate
yield (24% yield, 12 h). Extending reaction time did
not result in noticeable increase in yields, which
might be caused by the inactivation of enzyme after
12 h. Additionally, it was noteworthy that increase of
substrate concentration did not expend the ee of (R)-
2a, which demonstrated the good enantioselectivity
of the HheC in this reaction.
using various styrene oxides as substrates. Reactions
were carried out under the optimized conditions
(Table 2, entry 15) with an epoxide concentration of
30 mM. To gain isolated yields of the desired
products, all the reactions were scaled up to 30 mL.
As shown in Table 3, regardless of the electronic
nature of the substituents, all substrates could be
smoothly transformed into the corresponding chiral
5-aryl-2-oxazolidinones (R)-2a-2i in moderate to
good ee (74-90%), as well as moderate to excellent
yields (32-47%). Noteworthy, enantiopure para-F
substituted 5-aryl-2-oxazolidinones 2f is an important
skeleton structure for the discovery of Δ-5 desaturase
inhibitors.[10] Additionally, the regioselectivities of
the reactions were also determined via analysis of the
ratio of 5-aryl-2-oxazolidinones 2 (Cβ-attack) to 4-
aryl-2-oxazolidinones 3 (Cα-attack) by 1H NMR. The
results revealed that the HheC exhibited a poor to
good Cβ-position regioselectivity toward these
aromatic epoxides (Table 3). In the case of meta-Br
substituted styrene oxide 1d, a good regioselectivity
of 87:13 (Cβ-attack : Cα-attack) was found (Table 3,
entry 4), while the regioselectivity almost lost for the
m-methyl substituted styrene oxide 1e (Table 3, entry
5). It is noteworthy that, despite the fact that the
regioselectivity of ring-opening of these aromatic
epoxides was plagued by conflicting steric and
electronic factors, the yields of the desired products 2
were not severely influenced. Although previous
study indicated that the HheC didn’t catalyze the
reaction between para-nitrostyrene oxide and cyanate
by spectrophotometric assay,[11] low conversion of the
epoxide substrate was actually observed herein. We
speculated that increasing the ratio of nucleophile
cyanate accelerated this reaction.
120
6 h
12 h
50
100
24 h
40
80
30
60
20
40
10
20
0
0
5
15
30
10
20
50
Concentration 1a (mM)
Figure 1. Investigation of substrate concentrations.
Reaction conditions: Tris-H2SO4 buffer (50 mM, pH 7.0, 5
mL); E. coli (HheC) cells (15 g cdw/L), 1a (5-50 mM),
Table 3. Scope of the reaction for synthesis of chiral 5-
aryl-2-oxazolidinones 2 from styrene oxides 1.a)
o
NaOCN (15-150 mM), 45 C. The yield (column) and ee
(scatter) were determined over the formed product at 6, 12
and 24 h by chiral HPLC.
Subsequently, the scope and generality of the
biocatalytic reaction were systematically investigated
ratio yield 2
2:3b) (%)c)
ee (R)-2
entry epoxide
R
(%)d)
3
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10.1002/adsc.201901412
Advanced Synthesis & Catalysis
In an attempt to understand the origin of enantio-
and regioselectivity, the interactions between HheC
and both enantiomers of 1a were then analyzed.
Dijkstra and coworkers have resolved the crystal
structure (PDB ID: 1PWZ) of the HheC complexed
with (R)-1a and chloride in previous study.[13] Here,
molecular docking of (S)-1a to the X-ray structure of
HheC was performed using AutoDock.[14] The
conformations of HheC/(R)-1a (crystal result) and
HheC/(S)-1a (docking result) were then analyzed in
PyMOL to give some insight into the binding of the
substrates in the enzyme active site.[15] As showed in
Figure 2, both enantiomers bind with their aromatic
side chains in a very similar conformation in the
active site, and a slight difference that the oxygen
atom of the epoxide ring was found. Hydrogen bonds
formed between the oxygen atom of the epoxide ring
and Ser132/Tyr145 were similar for the two
enantiomers. The spontaneous formation of 2a was
not observed in the absence of HHDH (Table 1,
entries 6-7), and both enantiomers of 1a could react
with cyanate in the presence of HheC (Scheme 2).
These results demonstrated the formation of (R)-2a
and (S)-2a respectively from (R)-1a and (S)-1a was
contributed by enzymatic conversion. On the basis of
the docking and bioconversion results, we could
conclude that both enantiomers of 1a could be
accepted by HheC to form a productive complex.
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
66:34 39
70:30 36
71:29 37
87:13 32
88
74
81
88
85
90
84
86
90
m-F
m-Cl
m-Br
m-CH3 57:43 38
p-F
p-Cl
p-Br
p-CH3
66:34 36
71:29 39
74:26 34
75:25 47
a) Reaction conditions: Tris-H2SO4 buffer (50 mM, pH 7.0,
30 mL), E. coli (HheC) cells (15 g cdw/L), 1a-1i (30 mM),
o
b)
1
NaOCN (90 mM), 45 C and 12 h. Determined by H
NMR. c) Isolated yield. d) Determined by chiral HPLC.
To gain an understanding of the enantio- and
regioselectivity of the HheC-catalyzed cyanate-
mediated epoxide ring-opening reaction, both
enantiomers of 1a were individually subjected to
bioconversion (Scheme 2). A comparison of the total
yields of 2a and 3a generated from (R)-1a (94%) and
(S)-1a (14%) revealed the HheC showed a higher
catalytic activity toward (R)-1a, which corresponded
to that in the azide-mediated ring-opening reactions
of aromatic epoxides.[12] Interestingly, the ring-
opening regioselectivity toward the two enantiomers
was quite different. In the case of (R)-1a, a
regioselectivity of 79:21 (Cβ-attack : Cα-attack) was
found to give major product (R)-2a in 73% yield
(Scheme 2a); however, the regioselectivity was 29:71
(Cβ-attack : Cα-attack) for (S)-1a, generating major
product (R)-3a in 10% yield (Scheme 2b). These
results indicated the HheC preferred Cβ-position for
ring-opening of (R)-1a while Cα-position for ring-
opening of (S)-1a. Consequently, in the case of (R,S)-
1a, the influence on the ee of (R)-2a caused by the
ring-opening of (S)-1a could be decreased by the high
Cα-attack regioselectivity toward (S)-1a. Additionally,
whether the yield of 2a or 3a generated from (R)-1a
was higher than that obtained from (S)-1a, which
further confirmed the R enantioselectivity of HheC.
Figure 2. Comparation of (R)-1a (pink sticks) and (S)-1a
(cyan sticks) binding to active site of the HheC. The
catalytic triad Ser132-Tyr145-Arg149 was showed as
sticks. Hydrogen bonds (dashed lines) and distances of the
Ser132/Tyr145 toward (R)-1a and (S)-1a were determined
and highlighted in pink and cyan respectively.
In the crystal structure of HheC/(R)-1a, the halide-
binding site was occupied by a chloride which also
served as a nucleophile in the reverse reaction.[13] In
Scheme 2. Investigation of bioconversions of (R)-1a and
(S)-1a catalyzed by HheC. Reaction conditions: Tris-
H2SO4 buffer (pH 7.0, 50 mM, 30 mL), E. coli (HheC)
cells (15 g cdw/L), (R)-1a or (S)-1a (30 mM), NaOCN (90
mM), 45 ˚C and 12 h. The yields of 2a were isolated by
column chromatography; the yields of 3a were calculated
from the yield of 2a by 1H NMR.
-
other ring-opening reactions, nucleophiles (N3 , CN-,
OCN- etc.) would also bound at this region for
epoxides ring-opening attack to produce β-substituted
alcohols. Therefore we could assume the chloride as
the nucleophile cyanate to analyze the possible
interactions between cyanate and (R)-1a/(S)-1a. The
4
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10.1002/adsc.201901412
Advanced Synthesis & Catalysis
distances of the Nu- (blue sphere, represented
cyanate) from Cα atom and Cβ atom of (R)-1a/(S)-1a
were measured and displayed in Figure 3. In the case
of (R)-1a, the Nu- is positioned at approximately 3.46
Å and 3.23 Å from the Cα atom and Cβ of the epoxide
ring, respectively. However, the corresponding
respective distances were 3.51 Å (Cα) and 3.75 Å (Cβ)
in the case of (S)-1a. Accordingly, ring-opening of
(R)-1a would take place in favor of Cβ atom (3.23 <
3.46 Å), while the Cα atom would be easier to be
attacked by Nu- for (S)-1a (3.51 < 3.75 Å).
Additionally, a comparation between the distances of
the Cα atoms to Nu- of the different enantiomers (3.46
< 3.51 Å) would give a reasonable explanation to that
higher yield of (S)-3a obtained from (R)-1a than that
of (R)-3a generated from (S)-1a (Scheme 2). To sum
up from these results, we proposed that the
interrelations between epoxide 1a and nucleophile
cyanate decided the formation rates of (R)-2a, (S)-3a,
(R)-3a and (S)-2a. This might offer a plausible
explanation
for
the
enantioselectivity
and
regioselectivity of the HheC-catalyzed ring-opening
of 1a with cyanate.
Figure 3. Analysis of the complexes of HheC/(R)-1a/Nu- (A) and HheC/(S)-1a/Nu- (B). Catalytic triad Ser132-Tyr145-
Arg149, (R)-1a and (S)-1a were showed as sticks. Nu- represented nucleophile cyanate (OCN-) and was showed as sphere.
The distances (dashed lines) of the Nu- from Cα atom and Cβ atom of (R)-1a/(S)-1a were determined and highlighted in
green and black respectively.
Nitrogen containing compounds are of great
importance because of their interesting and diverse
biological activities. The construction of the C–N
bond is of significant importance as it opens avenues
for the introduction of nitrogen into organic
molecules.[16] Ring-opening of epoxides using
nitrogen-containing nucleophile such as azide and
amines affords a convenient methodology for C-N
bond formation.[17] Chemical ring-opening of
epoxides with these nucleophiles has been widely
studied, while the work on the reaction with inorganic
cyanate is very rare.[18] Herein the synthesis of chiral
aryl-2-oxazolidinones in good yields and ee starting
from styrene oxides, which further expanded
biotechnology applications of HHDH in organic
synthesis. We also tried to uncover the origin of
enantioselectivity and regioselectivity of the
enzymatic
process
by
single
enantiomer
bioconversion and molecular docking experiments.
We expect that findings gained from our present
study will be helpful for preparation and discovery of
chiral oxazolidinone drugs.
5-aryl-2-oxazolidinones
via
enantio-
and
Experimental Section
regioselective ring-opening of styrene oxides was
developed, which showed some greener advantages
than previous method.[9] Recently, we have developed
a biocatalytic route to 4-aryl-2-oxazolidinones via
cyanate-mediated ring-opening of aromatic epoxides
using a highly Cα-position regioselective HHDH.[19]
Hence this study also provided an biocatalytic
approach for regiocomplementary preparation of aryl-
substituted-2-oxazolidinones from aromatic epoxides.
In summary, we have developed an efficient
biocatalytic approach for the synthesis of chiral 5-
General procedure for enantioselective synthesis of
chiral 5-aryl-2-oxazolidinones 2a-2i: To a 30 mL
suspension of 15 g cdw/L E. coli (HheC) cells in Tris-
H2SO4 buffer (50 mM, pH 7.0) was added solid NaOCN to
a final concentration of 90 mM. Epoxide 1a was then
added to a final concentration of 30 mM using 300 μL
DMSO as co-solvent. The reaction mixture was shaken at
250 rpm and 45 oC for 12 h. Then the mixture was
extracted using ethyl acetate (2 × 30 mL). After
centrifugation, the organic phases were separated,
combined, dried over anhydrous Na2SO4, filtered, and
concentrated by rotary evaporation. The residue was
purified by flash column chromatography on silica gel
5
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10.1002/adsc.201901412
Advanced Synthesis & Catalysis
(petroleum ether/ethyl acetate = 1:1) to afford the desired
B. Janssen, ChemBioChem 2008, 9, 1048-1051; c) Z.-Y.
You, Z.-Q. Liu, Y.-G. Zheng, Appl. Microbiol. Biot.
2013, 97, 9-21; d) A. Schallmey, M. Schallmey, Appl.
Microbiol. Biot. 2016, 100, 7827-7839; e) J.
Koopmeiners, C. Diederich, J. Solarczek, H. Voß, J.
Mayer, W. Blankenfeldt, A. Schallmey, ACS Catal.
2017, 7, 6877-6886.
product (R)-5-phenyloxazolidin-2-one 2a.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (No. 21662050 and 31800663),
Guizhou Science and Technology Department (QKHRC-2016-
4029, QKHPTRC-2016-5801, and QKHZC-2019-2579), Program
for Outstanding Youth of Zunyi Medical University (17zy-001),
National First-Rate Construction Discipline of Guizhou Province
(Pharmacy) (YLXKJS-YX-04) and the Fifth Batch of Talent Base
in Guizhou Province (2016).
[5] a) M. M. Elenkov, L. Tang, A. Meetsma, B. Hauer, D.
B. Janssen, Org. Lett. 2008, 10, 2417-2420; b) A.
Mikleušević, Z. Hameršak, B. Salopek-Sondi, L. Tang,
D. B. Janssen, M. M. Elenkov, Adv. Synth. Catal. 2015,
357, 1709-1714.
[6] a) E. Liardo, R. González-Fernández, N. Ríos-
Lombardía, F. Morís, J. García-Álvarez, V. Cadierno, P.
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Advanced Synthesis & Catalysis
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10.1002/adsc.201901412
Advanced Synthesis & Catalysis
UPDATE
Synthesis of Chiral 5-Aryl-2-oxazolidinones via
Halohydrin Dehalogenase-Catalyzed Enantio- and
Regioselective Ring-Opening of Styrene Oxides
Adv. Synth. Catal. Year, Volume, Page – Page
Nanwei Wan,* Xiaoying Zhou, Ran Ma, Jiawei
Tian, Huihui Wang, Baodong Cui, Wenyong Han,
and Yongzheng Chen*
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