Synthesis of optically active α-bromohydrins via reduction of α-bromoacetophenone analogues catalyzed by an isolated carbonyl reductase

Article abstract of DOI:10.1016/j.tetasy.2012.03.015

Enantiomerically pure (S)-α-bromohydrins were prepared by the reduction of α-bromoacetophenone analogues catalyzed by an isolated carbonyl reductase from Candida magnolia with high yield and excellent enantiomeric excess when methyl tert-butyl ether was employed as the co-solvent, while avoiding the formation of by-products. This provides a new approach to access these chiral α-bromohydrins which are of pharmaceutical importance.

Full text of DOI:10.1016/j.tetasy.2012.03.015

Tetrahedron: Asymmetry 23 (2012) 497–500
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Tetrahedron: Asymmetry
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Synthesis of optically active
a-bromohydrins via reduction of
a-bromoacetophenone analogues catalyzed by an isolated carbonyl reductase
⇑
Jie Ren, Wenyue Dong, Benqing Yu, Qiaqing Wu, Dunming Zhu
National Engineering Laboratory for Industrial Enzymes, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 Xi Qi Dao,
Tianjin Airport Economic Area, 300308 Tianjin, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 March 2012
Accepted 28 March 2012
Enantiomerically pure (S)-a-bromohydrins were prepared by the reduction of a-bromoacetophenone
analogues catalyzed by an isolated carbonyl reductase from Candida magnolia with high yield and excel-
lent enantiomeric excess when methyl tert-butyl ether was employed as the co-solvent, while avoiding
the formation of by-products. This provides a new approach to access these chiral
are of pharmaceutical importance.
a-bromohydrins which
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
the efficiency of the microbial reduction of some a-bromoacetoph-
enones, and thus enhance the yield and enantiomeric purity of the
products.28 However, the enantiomeric excess of the product alco-
hol still needs to be improved and the reduction must be conducted
under an inert atmosphere. As a result, an efficient asymmetric
Enantiomerically pure halohydrins are widely employed as
synthetic building blocks for optically active molecules in pharma-
ceutical industries,1 such as adrenergic receptor agonists, bron-
chodilators, anti-depressants, and HIV-1 protease inhibitors.2–8
Both chemical and biocatalytic methodologies have been developed
in order to obtain enantiomerically pure halohydrins.9–11 Among
reduction of
a-bromoacetophenones still presents a worthwhile
challenge in organic synthesis.
Since the use of isolated enzymes can simplify the components
of the reaction mixtures, we envisioned that it might be a promising
way to prevent the formation of by-products. Therefore, we
screened several carbonyl reductases available in our laboratory
them, the asymmetric reduction of a-haloacetophenones provides
a straightforward approach to access these compounds.12,13 In the
synthesis of most adrenergic receptor agonists and other structur-
ally-related compounds, bromohydrins should be a better choice
than chlorohydrins, because the bromo group can be more readily
substituted by an amino group or other nucleophiles, and cyclized
to a five or six membered ring or epoxide.14–16 Although the
using
carbonyl reductase from Candida magnolia (CMCR) catalyzed the
reduction of -bromoacetophenone to (S)-2-bromo-1-phenyletha-
nol with high yield. We thus examined the capability of this enzyme
toward the reduction of other -bromoacetophenone analogues,
a-bromoacetophenone 1 as the substrate and found that a
a
asymmetric reduction of
transition metal-based catalysis and biocatalysis have been greatly
explored, studies have been mainly focused on -chloroacetophe-
nones.17–19 There have been a few reports on the asymmetric
reduction of -bromoacetophenone and its analogues with moder-
a-haloacetophenones by organocatalysis,
a
and the results are presented herein.
a
2. Results and discussion
a
ate enantiomeric excess and low yield via whole cell catalysis
The reduction of
reductase CMCR was studied using a NADPH regeneration system
consisting of -glucose dehydrogenase (GDH) and -glucose
(Scheme 2). The conversion and enantioselectivity were deter-
mined by chiral HPLC analysis. Due to the poor solubility of
a-bromoacetophenones by the carbonyl
reduction.20–27 It has been reported that the whole cell reduction
of
a-bromoacetophenones was usually contaminated by the forma-
D
D
tion of by-products such as an
a-chlorohydrin, phenylethandiol,
acetophenone, and phenylethanol (Scheme 1),20,22 because the
bromo group could be substituted by a hydroxyl or chloride ion
in the culture medium, or lost via electron transfer to give an aceto-
phenone, which in turn could be reduced.20,22 In this context, an
anionic surfactant was used in an argon atmosphere to improve
a-bromoacetophenones in a potassium phosphate buffer, the
reduction conditions were optimized by employing 2-bromo-1-
(4-methylphenyl)ethanone 2 and 2-bromo-1-(4-fluorophenyl)eth-
anone 9 as substrates in the potassium phosphate buffer with both
hydrophilic and hydrophobic organic solvents. The results are
shown in Table 1. The enzyme could tolerate both hydrophilic
and hydrophobic organic solvents to some extent. For 2-bromo-1-
⇑
Corresponding author. Tel.: +86 22 84861962; fax: +86 22 84861996.
E-mail address: zhu_dm@tib.cas.cn (D. Zhu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.015

498
J. Ren et al. / Tetrahedron: Asymmetry 23 (2012) 497–500
OH
OH
OH
O
O
Cl
OH
Br
Whole cell
+
+
+
Scheme 1. Biotransformation of a-bromoacetophenone with whole cells of Aspergillus. sydowii Ce19.
O
OH
phenyl)ethanone to (S)-2-bromo-1-(4-methylphenyl)ethanol. The
conversion of 2-bromo-1-(4-fluorophenyl)ethanone in a potassium
phosphate buffer without organic solvents was low, with only 50%
conversion being observed after 16 h. This might be due to the poor
solubility of 2-bromo-1-(4-fluorophenyl)ethanone in the buffer. In
addition to water-miscible solvents, such as dimethylsulfoxide,
methanol and iso-propanol, the water-immiscible solvents, such
as methyl tert-butyl ether and iso-propyl ether, also benefited the
reduction of 2-bromo-1-(4-fluorophenyl)ethanone to some extent.
The activity of the carbonyl reductase from Candida magnoliae
Br
CMCR
Br
R
R
NADP+
NADPH
D-gluconic Acid
D-glucose
GDH
Scheme 2. Reduction of
cofactor recycle system of GDH and D-glucose.
a-bromoacetophenones catalyzed by CMCR with a
toward the reduction of
a-bromoacetophenone analogues was
determined by spectrophotometrically measuring the rate for the
oxidation of NADPH as described in the Experimental, and the re-
sults are shown in Table 2. From these results it can be seen that
the substituents on the a-bromoacetophenone derivatives greatly
Table 1
CMCR-catalyzed reduction of 2-bromo-1-(4-methylphenyl)ethanone 2 and 2-bromo-
1-(4-fluorophenyl)-ethanone 9 in reaction media with different co-solvents
affected the enzyme catalytic activity. Electron-withdrawing sub-
stituents enhanced the enzyme activity, while substrates with
electron-donating substituents were less active. The same trend
was also observed for the reduction of acetophenone analogues
to the corresponding alcohols catalyzed by CMCR.29
Since the bioreduction of 2-bromo-1-(4-methylphenyl)etha-
none catalyzed by CMCR proceeded cleanly with high conversion
when methyl tert-butyl ether was used as a co-solvent in the reac-
Solvent in buffera
Conversionb (%)
Ketone 2c
Ketone 9d
No organic solvent
DMSO
MeOH
91
95
92
94
70
—
46
44
37
61
67
60
72
65
15
17
iso-PrOH
Methyl tert-butyl ether
iso-Propyl ether
Ethyl acetate
Butyl acetate
tion medium, the reductions of several
a-bromoacetophenones
e
were studied under the same reaction conditions, and the results
are summarized in Table 2. The products were isolated by extraction
with methyl tert-butyl ether in good to excellent yields. Chiral HPLC
a
Potassium phosphate buffer (100 mM, pH 7.0) containing 10% (v/v) of organic
solvent.
analysis indicated that the enantiomeric excesses of all the a-bro-
mohydrins were greater than 99%. Itoh et al. have reported that a
NADH-dependent phenylacetaldehyde reductase (PAR) from Cory-
nebacterium strain ST-10 and a Leifsonia alcohol dehydrogenase
(LSADH) catalyzed the reduction of 4-bromo-3-oxo-butanoate to
give 4-bromo-3-hydroxybutanoate in the (R)- and (S)-form,30,31
respectively. In the case of PAR, the reaction was carried out on a
1 mL scale without reporting a yield.30 For LSADH, (S)-4-bromo-3-
hydroxybutanoate was obtained in only 35% yield, although the
conversion was 100%.31 Herein, CMCR catalyzed a cleaner reduction
b
Determined by HPLC analysis.
c
d
e
Reaction time was 16 h.
Reaction time was 3 h.
Not determined.
(4-methylphenyl)ethanone, the addition of water-miscible solvents
such as dimethylsulfoxide, methanol, or iso-propanol had
a
minimal effect on enzyme activity, while water-immiscible sol-
vents decreased the conversion of 2-bromo-1-(4-methyl-
of
a-bromoacetophenones in the bi-phasic medium than the
Table 2
Bioreduction of various
a-bromoacetophenone analogues catalyzed by CMCR
Ketonea
Specific activityb
Isolated yield (%)
Eec (%)
2-Bromo-1-phenylethanone 1
203
278
95
92
81
84
85
91
79
82
84
89
>99
>99
>99
>99
>99
>99
>99
>99
>99
2-Bromo-1-(4-methylphenyl)ethanone 2
2-Bromo-1-(3-methoxyphenyl)ethanone 3
2-Bromo-1-(4-methoxyphenyl)ethanone 4
2-Bromo-1-(3-nitrophenyl)ethanone 5
2-Bromo-1-(4-nitrophenyl)ethanone 6
2-Bromo-1-(4-chlorophenyl)ethanone 7
2-Bromo-1-(3,4-dichlorophenyl)ethanone 8
2-Bromo-1-(4-fluorophenyl)ethanone 9
21
847
329
1438
1279
597
a
b
c
The reaction was carried out in a potassium phosphate buffer (100 mM, pH 7.0) containing 10% (v/v) of methyl tert-butyl ether.
The unit of specific activity is nmol mgꢀ1 minꢀ1
Determined by chiral HPLC analysis.
.

J. Ren et al. / Tetrahedron: Asymmetry 23 (2012) 497–500
499
previously reported whole-cell reaction.20 In spite of this improve-
ment, it should also be noted that, from the point view of an indus-
trially practical production, this method is not yet efficient enough
in terms of substrate concentration, enzyme efficiency and so on.
subjected to HPLC analysis to measure the conversion and enantio-
meric excess.
4.4. Synthesis of chiral -bromohydrins
The synthesis of various
a
-bromohydrins was carried out as fol-
3. Conclusion
lows: -glucose (540 mg),
D
D
-glucose dehydrogenase (15 mg),
NADPH (5 mg), and ketoreductase (CMCR, 60 mg) were mixed in
a potassium phosphate buffer (27 mL, 100 mM, pH 6.5). The mix-
ture was added to a ketone solution (100 mg in 3 mL of MTBE).
The mixture was stirred at 30 °C for 12–16 h until the conversion
was complete. The mixture was then extracted with methyl tert-
butyl ether. The organic extract was dried over anhydrous sodium
sulfate and removal of the solvent gave the product alcohol, which
was identified by 1H NMR and comparison of the retention time by
chiral HPLC analysis with authentic samples. (S)-2-Bromo-1-phen-
ylethanol 10.33 1H NMR (CDCl3), d: 2.58 (s, 1H), 3.58 (t, 1H,
The use of an isolated carbonyl reductase from Candida magno-
lia and a
system in a bi-phasic reaction medium effectively prevents the
side-reactions previously observed for the reduction of -bromo-
acetophenones, leading to enantiomerically pure (S)- -bromohy-
D-glucose dehydrogenase/D-glucose cofactor regeneration
a
a
drins in high yields. This offers a new method to access this type
of pharmaceutically interesting chiral alcohol, although the effi-
ciency needs to be further improved upon.
4. Experimental
4.1. General
2
3
2JH–H = 9 Hz), 3.68 (dd, 1H, JH–H = 10.2 Hz, JH–H = 3.0 Hz), 4.96
(dd, 1H, JH–H = 6.6 Hz, JH–H = 2.4 Hz), 7.39 (m, 5H). ½a D20
ꢂ
¼ þ13:1
3
3
(c 0.62, methanol). (S)-2-Bromo-1-(4-methylphenyl)ethanol 11.34
1H NMR (CDCl3), d: 2.25 (s, 3H), 2.58 (br s, 1H), 3.54 (dd, 1H,
Carbonyl reductase from Candida magnolia and D-glucose dehy-
3
2
2JH–H = 10.2 Hz, JH–H = 9.0 Hz), 3.62 (dd, 1H, JH–H = 10.8 Hz,
drogenase was prepared as described previously.29,30,32 All the ke-
tones were purchased from Sigma–Aldrich and the cofactors were
obtained from Codexis. The racemic alcohol standards were pre-
pared by reduction of the corresponding ketones with sodium
borohydride. Chiral HPLC analysis was performed on an Agilent
1200 series high-performance liquid chromatography system with
AD column (25 cm ꢁ 4.6 mm, Dacel Inc.). The enzyme activities to-
ward the reduction of ketones were assayed using a SpectraMax
M2 microplate reader (Molecular Devices). The 1H NMR was mea-
sured by Brucker Avance 600 using CDCl3 as the solvent. The opti-
cal rotation was recorded on an Anton paar MCP 200.
3
3
3JH–H = 3.6 Hz), 4.89 (dd, 1H, JH–H = 9.0 Hz, JH–H = 3.0 Hz), 7.19
(d, 2H, JH–H = 7.8 Hz), 7.27 (d, 2H, JH–H = 7.8 Hz). ½a D20
ꢂ
¼ þ20:0 (c
3
3
1.92, methanol). (S)-2-Bromo-1-(3-methoxyphenyl)ethanol 12.35
1H NMR (CDCl3), d: 2.60 (br s, 1H), 3.54 (dd, 1H, JH–H = 10.2 Hz,
2
2
3
3JH–H = 9.0 Hz), 3.63 (dd, 1H, JH–H = 10.2 Hz, JH–H = 3.6 Hz), 3.82
3
(s, 3H), 4.89 (d, 1H, JH–H = 9.0 Hz), 6.87 (t, 1H), 6.95 (d, 2H,) 7.28
(t, 1H, JH–H = 8.4 Hz). ½a D20
ꢂ
¼ þ19:7 (c 2.0, methanol). (S)-2-Bro-
3
mo-1-(4-methoxyphenyl)ethanol 13.34 1H NMR (CDCl3), d: 2.66
2
3
(s, 1H), 3.54 (dd, 1H, JH–H = 10.2 Hz, JH–H = 9.0 Hz), 3.63 (dd, 1H,
3
2JH–H = 10.2 Hz, JH–H = 3.6 Hz), 3.82 (s, 3H), 4.89 (d, 1H,
3JH–H = 9.0 Hz), 6.87 (t, 1H), 6.95 (d, 2H,) 7.28 (t, 1H,
3JH–H = 8.4 Hz). ½a D20
¼ þ29:0 (c 1.88, methanol). (S)-2-Bromo-1-
ꢂ
(3-nitrophenyl)ethanol 14.36 1H NMR (CDCl3), d: 2.81 (s, 1H),
4.2. Activity assay for the reduction of
catalyzed by CMCR
a-bromoacetophenones
2
3
3.56 (dd, 1H, JH–H = 10.8 Hz, JH–H = 8.4 Hz), 3.69 (dd, 1H,
3
3
2JH–H = 10.8 Hz, JH–H = 3.6 Hz),5.04 (d, 1H, JH–H = 8.4 Hz), 7.57 (t,
3
3
The activity of carbonyl reductase from Candida magnoliae to-
ward the reduction of -bromoacetophenones was determined
by spectrophotometrically measuring the oxidation of NADPH at
340 nm (
= 6.22 mMꢀ1 cmꢀ1) in the presence of an excess amount
1H, JH–H = 8.4 Hz), 7.74 (d,1H, JH–H = 7.8 Hz), 8.18 (d, 1H,
3JH–H = 8.4 Hz). 8.29 (s, 1H). ½a 2D0
ꢂ
¼ þ18:5 (c 1.36, methanol).
a
(S)-2-Bromo-1-(4-nitrophenyl)ethanol 15.27,33,34 1H NMR (CDCl3),
2
3
ꢀ
d: 2.76 (br s, 1H), 3.53 (dd, 1H, JH–H = 10.2 Hz, JH–H = 8.4 Hz),
2
3
of ketones. The activity was measured at room temperature in a
96-well plate, in which each well contained ketone (4.0 mM) and
NADPH (0.6 mM) in potassium phosphate buffer (100 mM, pH
3.67 (dd, 1H, JH–H = 10.8 Hz, JH–H = 3.6 Hz), 5.04 (d, 1H,
3JH–H = 5.4 Hz), 7.58 (d, 2H, 3JH–H = 8.4 Hz), 8.24 (d, 2H,
3JH–H = 8.4 Hz). ½a D20
¼ þ20:4 (c 1.6, methanol). (S)-2-Bromo-1-(4-
ꢂ
chlorophenyl)ethanol 16.33 1H NMR (CDCl3), d: 2.68 (br s, 1H),
6.5, 180
lL). The reaction was initiated by the addition of the car-
2
2
bonyl reductase (20
l
L solution containing 4–40 g of enzyme).
l
3.51 (t 1H, JH–H = 10.2 Hz), 3.61 (dd, 1H, JH–H = 10.2 Hz,
3JH–H = 3.0 Hz), 4.91 (d, 1H, 3JH–H = 8.4 Hz), 7.34 (q, 4H,
The specific activity was defined as the number of nanomoles of
NADPH converted in 1 min by 1 mg of enzyme (nmol minꢀ1 mgꢀ1).
3JH–H = 15.6 Hz, JH–H = 8.4 Hz). ½a 2D0
ꢂ
¼ þ21:9 (c 1.28, methanol).
3
(S)-2-Bromo-1-(3,4-dichloro-phenyl)ethanol 17.37 1H NMR
2
4.3. CMCR-catalyzed reduction of 2-bromo-1-(4-methylphenyl)
ethanone 2 and 2-bromo-1-(4-fluorophenyl)ethanone 9 in
reaction media with different co-solvents
(CDCl3), d: 2.70 (br s, 1H), 3.51 (t 1H, JH–H = 9.0 Hz), 3.61 (dd,
2
3
3
1H, JH–H = 9.6 Hz, JH–H = 2.4 Hz), 4.89 (dd, 1H, JH–H = 8.4 Hz,
3JH–H = 3.0 Hz), 7.21 (d, 1H, 3JH–H = 8.4 Hz), 7.44 (d,1H,
3JH–H = 8.4 Hz), 7.51 (s, 1H). ½a 2D0
¼ þ16:1 (c 0.82, methanol).
ꢂ
2-Bromo-1-(4-methylphenyl)ethanone
fluorophenyl)-ethanone were chosen as substrates for the
reduction in reaction media with different co-solvents as listed in
Table 1. The reaction procedure was as follows: -glucose
(36 mg), -glucose dehydrogenase (4 mg), NADP (2 mg), ketore-
2
and 2-bromo-1-(4-
(S)-2-Bromo-1-(4-fluorophenyl)ethanol 18.38 1H NMR (CDCl3), d:
2
3
9
2.65 (s, 1H), 3.51 (dd, 1H, JH–H = 10.2 Hz, JH–H = 9 Hz), 3.61 (dd,
2
3
3
1H, JH–H = 10.8 Hz, JH–H = 3.6 Hz), 4.91 (d, 1H, JH–H = 8.4 Hz),
D
7.06 (t, 2H, 3JH–H = 9 Hz), 7.58 (q, 2H, 3JH–H = 8.4 Hz,
D
3JH–H = 5.4 Hz).
½
a 2D0
ꢂ
¼ þ16:1 (c 1.4, methanol). The absolute
ductase (CMCR, 2 mg) and 2-bromo-1-(4-methylphenyl)ethanone
(0.04 mmol, dissolved in 0.1 mL of organic solvent) were mixed
with 0.9 mL of potassium phosphate buffer (100 mM, pH 6.5).
The mixture was shaken for 16 h (or 3 h) at 30 °C for 2-bromo-1-
(4-methylphenyl)ethanone (or 2-bromo-1-(4-fluorophenyl)etha-
none), and then extracted with methyl tert-butyl ether (0.8 mL).
The organic extract was dried over anhydrous sodium sulfate and
configurations of the product alcohols 10,33 11,34 12,34 15,27,33,34
and 1633 were determined by comparison of the sign of the specific
rotation with those in the literature. For 13,35 14,36 1737 and 18,38
they were considered to have the same absolute configuration as
those listed before because they exhibited the same sign of specific
rotation. The enantiomeric excess was determined by chiral HPLC
analysis.

500
J. Ren et al. / Tetrahedron: Asymmetry 23 (2012) 497–500
17. Zhu, D.; Mukherjee, C.; Hua, L. Tetrahedron: Asymmetry 2005, 16, 3275–3278.
Acknowledgements
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Biotechnol. Lett. 2001, 23, 1603–1606.
This work was financially supported by the National Basic Re-
search Program of China (973 Program, No. 2011CB710801), Na-
tional Natural Science Foundation of China (No. 21072151),
Chinese Academy of Sciences (No. KGCX2-YW-203) and Tianjin
Municipal Science & Technology Project (No. 10ZCZDSY06600).
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