Asymmetric reduction of prochiral aromatic and hetero aromatic ketones using whole-cell of Lactobacillus senmaizukei biocatalyst

Article abstract of DOI:10.1080/00397911.2021.1931337

Asymmetric bioreduction of aromatic and heteroaromatic ketones is an important process in the production of precursors of biologically active molecules. In this study, the bioreduction of aromatic and hetero aromatic prochiral ketones into optically active alcohols was investigated using Lactobacillus senmaizukei as a whole-cell catalyst, since whole-cells are less expensive than pure enzymes. The study indicates enantioselective bioreduction of various substituted aromatic ketones (1–16) to the corresponding (R)-and (S)-chiral secondary alcohols (1a–16a) in low to excellent enantioselectivity (6–94%) with good yields (58–95%). In addition, heteroaromatic prochiral ketones 1-(pyridin-2-yl)ethanone (17) and 1-(furan-2-yl)ethanone (18) were reduced to (R)-17a and (R)-18a in enantiopure form with excellent conversion (>99%) and yields. These findings show that L. senmaizukei is a very important biocatalyst for asymmetric reduction of both 6-membered and 5-member heteroaromatic methyl ketones. This method promising a green synthesis for the synthesis of biologically important secondary chiral alcohols in an environmentally friendly and inexpensive process.

Full text of DOI:10.1080/00397911.2021.1931337

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Asymmetric reduction of prochiral aromatic
and hetero aromatic ketones using whole-cell of
Lactobacillus senmaizukei biocatalyst
Nida Sezin Çolak, Erbay Kalay & Engin Şahin
To cite this article: Nida Sezin Çolak, Erbay Kalay & Engin Şahin (2021) Asymmetric reduction
of prochiral aromatic and hetero aromatic ketones using whole-cell of Lactobacillusꢀsenmaizukei
biocatalyst, Synthetic Communications, 51:15, 2305-2315, DOI: 10.1080/00397911.2021.1931337
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021, VOL. 51, NO. 15, 2305–2315
2
https://doi.org/10.1080/00397911.2021.1931337
Asymmetric reduction of prochiral aromatic and hetero
aromatic ketones using whole-cell of Lactobacillus
senmaizukei biocatalyst
a
b
c
Nida Sezin C¸ olak , Erbay Kalay , and Engin S¸ ahin
a
b
Faculty of Engineering, Department of Food Engineering, Bayburt University, Bayburt, Turkey; Kars
c
Vocational School, Kafkas University, Kars, Turkey; Faculty of Health Sciences, Department of Nutrition
and Dietetics, Bayburt University, Bayburt, Turkey
ABSTRACT
ARTICLE HISTORY
Asymmetric bioreduction of aromatic and heteroaromatic ketones is
an important process in the production of precursors of biologically
active molecules. In this study, the bioreduction of aromatic and het-
ero aromatic prochiral ketones into optically active alcohols was
investigated using Lactobacillus senmaizukei as a whole-cell catalyst,
since whole-cells are less expensive than pure enzymes. The study
indicates enantioselective bioreduction of various substituted aro-
matic ketones (1–16) to the corresponding (R)-and (S)-chiral second-
ary alcohols (1a–16a) in low to excellent enantioselectivity (6–94%)
with good yields (58–95%). In addition, heteroaromatic prochiral
ketones 1-(pyridin-2-yl)ethanone (17) and 1-(furan-2-yl)ethanone (18)
were reduced to (R)-17a and (R)-18a in enantiopure form with
excellent conversion (>99%) and yields. These findings show that
L. senmaizukei is a very important biocatalyst for asymmetric
reduction of both 6-membered and 5-member heteroaromatic
methyl ketones. This method promising a green synthesis for the
synthesis of biologically important secondary chiral alcohols in an
environmentally friendly and inexpensive process.
Received 19 March 2021
KEYWORDS
Aromatic ketones;
asymmetric synthesis;
bioreduction; hetero
aromatic carbinol;
Lactobacillus senmaizukei
GRAPHICAL ABSTRACT
O
OH
CH3
Lactobacillus senmaizukei
R
CH3
R
pH 5.2, 25 C, 100 rpm, 70 h
°
Conv. 56-99%
ee 6-99%
R=
R= Br, CI, Me, OMe, NO2, Ph
R
N
R=
O
R=
CONTACT Engin S¸ ahin
esahin@bayburt.edu.tr
Faculty of Health Sciences, Department of Nutrition and Dietetics,
Bayburt University, 69000, Bayburt, Turkey.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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N. S. ÇOLAK ET AL.
Introduction
The chemical industry plays an important role in production because it produces a vast
variety of high-value-added goods and is one of the world’s largest economic sectors.
The advantages of biocatalytic processes for organic synthesis have led to an increase in
biocatalytic applications. Organic chemistry relies heavily on biocatalytic reactions for
the manufacture of pharmaceuticals and the investigation of chirality as a means of
[
1]
improving biological reactivity. Chiral alcohol, amines, and amino acids are essential
intermediates in the synthesis of a wide range of agrochemicals and pharmaceuticals.
These compounds, especially chiral alcohols, are very important due to their stable
structure and they can be converted into various functional groups without racemiza-
[
2]
tion. Asymmetric reductions can be used to synthesize these compounds. One of the
most important reactions in organic chemistry is the stereoselective reduction of prochi-
ral ketones to chiral alcohols. Chiral alcohols are useful building blocks in industrial
chemistry. These compounds, for example, are important intermediates in the manufac-
[
3–7]
ture of fine chemicals, natural products, and pharmaceuticals.
Some examples of
[
8]
pharmaceuticals that use chiral alcohols as building blocks are anticholesterol, antiar-
[
9]
[10]
[11]
rhythmic agents, antihypertensive drugs,
and antiviral drugs.
Phenyl ethanol
and its derivatives are other important examples of these compounds, which are useful
[
12]
starting materials for the synthesis of drug precursors.
One of the main nutrients,
carbohydrates, which constitute the basic energy source of the human body, is the most
important nutrient used to obtain energy in our body. Carbohydrates contain a chiral
secondary alcohol functional group in their structure. Carbohydrates are also used in
[
13,14]
enzymatic synthesis reactions.
In the chemical and pharmaceutical industry,
chiral auxiliaries such as (S)-1-phenyl ethanol,2-naphthyl ethanol, and (S)-1-(3-
[
15,16]
methoxyphenyl) ethanol are used.
alcohols are used as drug precursors.
enantiomerically pure (R)-1-(pyridin-2-yl) ethanol (17a) are used as starting materials
On the other hand, chiral heteroaromatic
[
17]
N-heteroaromatic carbinols such as
[
18]
for the synthesis of various biologically active molecules.
furan-2-yl)ethanol (18a) is extensively used in the total production of many pharma-
ceutical and natural products, including Landomycins A, E, (ꢀ)-Angiopterlactone B,
The molecular motif (R)-1-
(
[
19–21]
and (þ)- & (ꢀ)-cis-Osmundalactone.
Chemical and biocatalytic processes can be
used to produce chiral alcohols. Chemical synthesis has a number of disadvantages,
including the use of organic solvents and the need for harsh reaction conditions such as
high or low temperature, high pressure, or the use of an inert atmosphere. In addition,
the enantiomeric excesses (ee) obtained with chemical catalysts are not satisfactory.
High enantiomeric excesses are required for the manufacture of natural products and
especially in drug production. Biocatalytic approaches can be used to accomplish these
aims. Biocatalytic processes are particularly appealing for the organic synthesis of indus-
trial products since (a) biocatalysts are natural catalysts produced by fermentation; (b)
biocatalysts are generally nontoxic catalysts and prevent substantial metal consumption
(unlike many metal and organometallic catalysts); (c) reaction conditions are moderate
and more environmentally friendly than chemical catalysts; (d) biocatalytic reactions are
generally more selective and byproduct formation is low; (e) biocatalytic reactions usu-
ally take place in an aqueous medium and prevent large amounts of organic solvent
consumption. Enzymatic resolution and reduction of ketones with pure enzyme or

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[
22]
whole-cell biocatalysts are biocatalytic methods for producing optically pure alcohols.
Enzymatic resolutions, however, were restricted by a theoretical yield of 50%.
[
23]
In
asymmetric bioreduction reactions, whole-cell biocatalysis is superior to using an iso-
lated enzyme, with the benefit of eliminating the expensive enzyme purification process.
One of the most simple and encouraging routes to the production of enantiomerically
pure secondary alcohols is asymmetric bioreduction of prochiral ketones using biocata-
lysts. There are many reports in the literature involving asymmetric reduction of aceto-
[
24–26]
phenone derivatives with biocatalysts.
While there are numerous studies in the
literature concerning the asymmetric reduction of heteroaromatic substrates with chem-
ical catalysts, there are few studies involving biocatalysts. It has been reported that 20%
of chiral secondary alcohols used in industrial production were obtained by biocatalytic
[
27]
asymmetric reduction.
Therefore, it is very important to develop new biocatalysts
that can be used for asymmetric reduction of both aromatic and heteroaromatic prochi-
ral ketones.
In this research, whole-cell of Lactobacillus senmaizukei was investigated the reduc-
tion activity in asymmetric reduction of aromatic and hetero aromatic ketones. In our
previous study, it was shown that L. senmaizukei can be used in the asymmetric reduc-
tion of acetophenone and the optimum reduction conditions of acetophenone were
[
28]
determined using the response surface methodology (RSM) optimization strategy.
Herein, asymmetric reductions of acetophenone derivatives and hetero aromatic ketones
were carried out under previously optimized conditions using the whole-cell of L. sen-
maizukei. Lactobacillus senmaizukei biocatalyst was used for the first time in asymmetric
reduction of acetophenone derivatives and hetero aromatic substrates, and the effects of
substrates on ee and conversion have been extensively evaluated. The hetero aromatic
carbinols (R)-1-(pyridin-2-yl) ethanol (17a) and (R)-1-(furan-2-yl) ethanol (18a) were
obtained enantiomerically pure form with >99% conversion, high yield, and a
gram scale.
Results and discussion
ꢁ
In our previous study, the asymmetric reduction conditions (pH 5.25, 25 C, 100 rpm
and 70 h) were determined using the model substrate acetophenone 1 using the RSM
[
28]
optimization strategy.
Under these optimized conditions, asymmetric reductions of
acetophenones (2–16), which have ortho-, metha and para electron-withdrawing, and
electron-donating groups, and hetero aromatic substrates (17, 18) were reduced and the
effects of substrates on selectivity and conversion were evaluated. Table 1 shows the
results obtained depending on the location, electronic and steric effects of the groups.
Under these optimized conditions, 1a was obtained by asymmetric reduction of aceto-
phenone 1 in 90% ee, 94% conversion, and 90% yield (Table 1, entry 1). A similar
reactivity to acetophenone was observed in chloroacetophenones, and the corresponding
chiral alcohols were obtained by conversion ranging from 87 to 97% (Table 1, entries
2–4). However, decreasing enantioselectivity was obtained by moving from the 2nd pos-
ition of the chlorine atom in the benzene ring to the 4th position (69, 62, and 49 ee%,
respectively). These results show that the steric effect is important in selectivity. In add-
ition, chlorophenyl ethanols are very important compounds as they are found in drug

2
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N. S. ÇOLAK ET AL.
Table 1. Asymmetric bioreduction of aromatic and heteroaromatic ketons with L. senmaizukei.
Yield
ee
%)
Conv.
(%)
Entry
Substrate
Product
a,b
c
d
(
(
%)
1
2
80 (R)
69 (S)
94
92
90
87
3
62 (S)
87
82
4
5
6
49 (R)
76 (R)
52 (R)
97
56
75
91
51
68
7
8
9
12 (S)
6 (R)
88 (S)
95
67
99
90
58
95
1
0
28 (R)
95
89
1
1
1
2
49 (R)
14 (R)
79
97
69
91
1
3
30 (R)
91
83
(continued)

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14
15
16
94 (R)
72 (S)
88 (R)
99
97
95
92
89
88
1
7
8
>99 (R)
>99 (R)
>99
99
95
92
1
ꢁ
Reaction conditions: substrate 0.5 mmol, pH 5.2, 25 C, 70 h, 100 rpm.
a
b
Determined by HPLC using a chiral column. Determination of absolute configuration was carried out by comparison
of the sign of optical rotation relative to the values in the literature. The conversions were determined by chiral
c
d
HPLC. Isolated yield.
[
29]
structures such as solabegron and chlorprenaline.
For 2-, 3- and 4-bromoacetophe-
nones, as the bromine atom moves away from the carbonyl group, the conversion
increases while the selectivity decreases (Table 1, entries 5–7). Compared to substrates
with bromine atoms, substrates with chlorine atoms, the decrease in selectivity and the
increase in the conversion rate are slightly more. This can be explained by the fact that
the bromine atom is sterically bulkier than the chlorine atom. The best result for the
reduction of nitroacetophenone derivatives was obtained from the reduction of the
meta-nitroacetophenone derivative (88% ee and 99% conversion) (Table 1, entry 9).
While a moderate conversion (67%) and low ee (6%) were obtained in the reduction of
2
-nitroacetophenone, high conversion (95%) and low ee (28%) were obtained in the
reduction of 4-nitroacetophenone (Table 1, entry and 10). The very low selectivity in
-nitroacetophenone can be explained by a steric effect due to the proximity of the nitro
2
group to the carbonyl group (Table 1, entry 8). It has been previously reported that a
similar effect was observed in the reduction of 2-nitroacetophenone with a biocata-
[
30]
lyst.
There are reports in the literature that both the carbonyl group and the nitro
group are reduced in asymmetric reductions with nitro acetophenone derivatives using
[
31]
biocatalysts.
In this study, it was observed that the biocatalyst reduces the carbonyl
group without reducing the nitro group. Enantiomeric excess decreased significantly
when 2-methoxy, 3-methoxy- and 4-methoxyacetophenone were used as the substrates,
compared to the reaction performed with acetophenone (Table 1, entries 11–13).
However, while the conversion rate of 2-methoxyacetophenone is reduced compared to
acetophenone, the conversion values obtained for 3-, and 4-methoxyacetophenone are
very close to that obtained from acetophenone. 3-methylacetophenone was reduced cor-
responding chiral alcohol with excellent conversion (99%) and good ee (94%) compared
to the acetophenone (Table 1, entry 14). Similarly, 4-methylacetophenone has been

2
310
N. S. ÇOLAK ET AL.
converted to the corresponding secondary alcohol with an excellent conversion (97%)
and good ee (72%) (Table 1, entry 15). 4-phenylacetophenone was reduced to corre-
sponding chiral alcohol in high ee (88%) and conversion (95%) (Table 1, entry 16). The
configurations of the obtained chiral secondary alcohols vary as R or S, depending on
the steric and electronic properties of the attached group in the benzene ring as previ-
[
32]
ously reported.
the active site of the enzyme. An excellent enantioselectivity (>99%), conversion
>99%), and yield (95%) in the reduction of 1-(pyridin-2-yl)ethanone (17) were
This can be explained by the different interactions of the groups with
(
obtained with whole-cell of L. senmaizukei (Table 1, entry 17). By asymmetric reduction
of 2-acetylpyridine 17 with costly pure enzyme and cofactor, (S)-17a was obtained in
[
33,34]
high enantiomeric purity in the literature.
In literature, the chiral seconder alcohol
(
>
S)-17a was obtained by asymmetric reduction of the 17 with seed adzuki bean in
[
35]
81% ee and 44% conversion.
Also, the synthesis of (R)-17a was reported to be syn-
[
36]
thesized using Lactobacillus kefiri P2 biocatalyst with 93% ee and 56% conversion,
and using a chemical catalyst (R)-17a was synthesized with high selectivity.
[
37,38]
Compared to the studies in the literature, in this study (R)-17a was obtained in cheap,
higher conversion, higher yield, and in enantiomerically pure form. Enantiomerically
pure form (>99%) and excellent conversion (>%99) were obtained in bioreduction of
1
8 with whole-cell of L. senmaizukei (Table 1, entry 18). In the literature, it was
reported that (S)-18a was obtained with 99% ee and 85% yield as a result of the use of
[
19]
expensive pure enzyme as a biocatalyst.
Also, the synthesis of (R)-18a was reported
to be synthesized using whole-cell of L. kefiri P2 biocatalyst with 95% ee and 99% con-
[
36]
version.
However, in this study, (R)-18a was obtained in high yield, conversion and
enantiomerically pure form by using whole-cell biocatalyst, which is a very cheap
method compared to the pure enzyme.
The last target of this study was to perform the high gram scale manufacture of (R)-
1
7a and (R)-18a using the optimum conditions, since, in the industrial production of
chiral alcohols, high product concentration and high ee are important. In addition, sub-
strate tolerance is one of the important indicators of biocatalyst potential for industrial
[
39,40]
applications.
We investigated the effect of the substrate concentration range of 5
to 25 mmol on the biocatalytic reduction under optimized conditions. When the sub-
strate 17 and 18 concentrations were 15 mmol, the maximum (99%) ee and conversion
(99%) were obtained (Figure 1). When the substrate concentrations passed the 15 mmol,
the ee and conversion of the reactions had an important drop. This reduction can be
explained by the decrease in the enzyme activity of the substrate’s toxicity as previously
[
41]
reported.
In the present study, as a result of biocatalytic reduction of 1.81 g of sub-
strate 17 and 1.65 g of substrate 18, (R)-17a and (R)-18a were obtained as enantiopure
form with 99% conversion and 95%, 92% yield, respectively. In the light of this infor-
mation, these results show that this biocatalyst has the potential to be used in the asym-
metric reduction of hetero aromatic substrates.
Conclusion
In conclusion, we identified a method for producing chiral carbinols using whole-cell of
L. senmaizukei as the biocatalyst, which was very successful in reducing ketones to their

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O
OH
N
Lactobacillus senmaizukei
N
CH3
CH3
17a
°
pH 5.2, 25 C, 100 rpm, 70 h
17
14.25 mmol (1.75 g)
15 mmol (1.81 g)
Conv. >99%
yield 95%
ee>99%
OH
O
Lactobacillus senmaizukei
O
O
CH3
CH3
°
pH 5.2, 25 C, 100 rpm, 70 h
18a
18
15 mmol (1.65 g)
13.8 mmol (1.54 g)
Conv. >99%
yield 92%
ee>99%
Figure 1. Gram scale synthesis of 17a and 18a.
chiral alcohols, some of which are important key intermediates in the synthesis of com-
mercial drugs. (R)-17a and (R)-18a, which can be used as a biologically active com-
pound, was produced in excellent yield, enantiomerically pure form, and gram-scale,
using L. senmaizukei. Compared with past whole-cell biocatalytic methods, (R)-17a and
(R)-18a were obtained in high conversion, yield, gram scale, and enantiopure form.
This study is the first report in which the highest amount of (R)-17a and (R)-18a was
obtained enantiomerically pure form by biocatalytic reduction of 17 and 18 with whole-
cell of L. senmaizukei. The findings obtained here using L. senmaizukei whole-cell as
the biocatalyst could promising method for the reduction of selected prochiral aromatic
and heteroaromatic ketones. Moreover, this process as a green method preventing the
use of expensive metal reducing agents and organic solvents that are widely used in
inorganic synthesis.
Experimental section
General
All solvents, chemicals and culture medium (MRS) were obtained from commercial sup-
pliers in high purity. The progress of the reactions was monitored by TLC using hexane:
ethyl acetate (90:10) as mobile phase. Chiral alcohols (1a–18a) were purified by column
chromatography charged with silica gel using hexane: ethyl acetate (90:10) solvent mix-
ture. Enantiomeric excess was determined from a chiral HPLC analysis on an Agilent
1260 system equipped with UV and chiral detector. Specific optical rotation was meas-
ured by Bellingham þ Stanley, ADP 220, polarimetry. A reference sample of the racemic
alcohol was synthesized by reducing the ketone 1–18 with NaBH in MeOH. The NMR
4
spectra were recorded on a 400 MHz spectrometer in CDCl using TMS as an internal
3
standard (supporting information).
Culture condition and bacterial strain
This study used the L. senmaizukei strain, which was obtained from rye sourdough,
[
42]
previously.

2
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N. S. ÇOLAK ET AL.
General asymmetric bioreduction process
Lactobacillus senmaizukei was inoculated to 10 mL MRS broth and incubated 2 days at
ꢁ
3
7 C followed by the inoculation of grown cells at 10% concentration to 50 mL MRS
broth in 100 mL Erlenmeyer. The pH of the reaction medium was adjusted to 5.2 using
ꢁ
0
.1 M HCl and mixed in a shaker incubator at 25 C and 100 rpm for 2 h. Then sub-
strates (1–18) were added to the mixture and the mixture was stirred under the same
conditions for 70 h. Then, the bacterial cell was separated by centrifugation at 6000 ꢂ g
ꢁ
for 5 min at 4 C and the supernatant was saturated with sodium chloride. The aqueous
phase was extracted with CH Cl (3 ꢂ 100 mL). The extracts were dried over Na SO
2
2
2
4
and then evaporated in a vacuum. The crude product was purified by column chroma-
tography using hexane: ethyl acetate (90:10) solvent mixture and characterized by NMR
analysis. The absolute configuration of the product was determined by a comparison of
their optical rotational values with literature data. Conversion of the substrate was
determined by filtering a small amount of crude product through a small column con-
taining silica gel and the obtained product was analyzed on a chiral column and com-
paring the ketone peak with the alcohol peaks. Enantiomeric excess was calculated by
HPLC analysis using a chiral column. No product or transformation was obtained in
the experiments conducted without using biocatalysts.
Gram-scale synthesis of (R)-17 and (R)-18
In gram-scale biotransformation reaction, 1 L Erlenmeyer flask, containing 500 mL of
MRS broth, was inoculated with 10% concentration L. senmaizukei, and incubated for
ꢁ
2
h at 25 C at 100 rpm in a shaker incubator. The pH of the reaction media was
adjusted at 5.2 by adding 0.1 M HCI and the mixture was stirred for 2 h under the
same conditions. Then, 15 mmol 17 and 18 were added to the reaction mixture and
ꢁ
stirred at 100 rpm, 25 C for 70 h. After completion of the reaction, characterization
and analysis processes of the product were made as stated above.
1
13
Copies of H, C-NMR spectra, spectroscopic data, racemic and chiral HPLC chro-
matograms of 1a–18a related to this article can be found in the supplementary data.
Acknowledgment
We would like to thank Dr. Enes Dertli (Yildiz Technical University) for providing the biocata-
lyst used in this study.
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