Asymmetric reduction of aromatic heterocyclic ketones with bio-based catalyst Lactobacillus kefiri P2

Article abstract of DOI:10.1007/s11696-020-01364-2

Abstract: Chiral heterocyclic secondary alcohols have received much attention due to their widespread use in pharmaceutical intermediates. In this study, Lactobacillus kefiri P2 biocatalysts isolated from traditional dairy products, were used to catalyze the asymmetric reduction of prochiral ketones to chiral secondary alcohols. Secondary chiral carbinols were obtained by asymmetric bioreduction of different prochiral substrates with results up to > 99% enantiomeric excess (ee). (R)-1-(benzofuran-2-yl)ethanol 5a, which can be used in the synthesis of pharmaceuticals such as bufuralols potent nonselective β-blockers antagonists, Amiodarone (cardiac anti-arrhythmic), and Benziodarone (coronary vasodilator), was produced in gram-scale, high yield and enantiomerically pure form using L. kefiri P2 biocatalysts. The gram-scale production was carried out, and 9.70?g of (R)-5a in enantiomerically pure form was obtained in 96% yield. Also, production of (R)-5a in terms of yield and gram scale through catalytic asymmetric reduction using the biocatalyst was the highest report so far. This is a cost-effective, clean and eco-friendly process for the preparation of chiral secondary alcohols compared to chemical processes. From an environmental and economic perspective, this biocatalytic method has great application potential, making it a green and sustainable way of synthesis. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11696-020-01364-2

Chemical Papers
https://doi.org/10.1007/s11696-020-01364-2
ORIGINAL PAPER
Asymmetric reduction of aromatic heterocyclic ketones
with bio‑based catalyst Lactobacillus kefri P2
Yasemin Baydaş1 · Erbay Kalay2 · Engin Şahin3
Received: 9 July 2020 / Accepted: 15 September 2020
© Institute of Chemistry, Slovak Academy of Sciences 2020
Abstract
Chiral heterocyclic secondary alcohols have received much attention due to their widespread use in pharmaceutical interme-
diates. In this study, Lactobacillus kefri P2 biocatalysts isolated from traditional dairy products, were used to catalyze the
asymmetric reduction of prochiral ketones to chiral secondary alcohols. Secondary chiral carbinols were obtained by asym-
metric bioreduction of diferent prochiral substrates with results up to>99% enantiomeric excess (ee). (R)-1-(benzofuran-
2-yl)ethanol 5a, which can be used in the synthesis of pharmaceuticals such as bufuralols potent nonselective β-blockers
antagonists, Amiodarone (cardiac anti-arrhythmic), and Benziodarone (coronary vasodilator), was produced in gram-scale,
high yield and enantiomerically pure form using L. kefri P2 biocatalysts. The gram-scale production was carried out, and
9.70 g of (R)-5a in enantiomerically pure form was obtained in 96% yield. Also, production of (R)-5a in terms of yield and
gram scale through catalytic asymmetric reduction using the biocatalyst was the highest report so far. This is a cost-efective,
clean and eco-friendly process for the preparation of chiral secondary alcohols compared to chemical processes. From an
environmental and economic perspective, this biocatalytic method has great application potential, making it a green and
sustainable way of synthesis.
Graphical Abstract
Keywords Asymmetric reduction · Lactobacillus kefri · Chiral alcohol · Biocatalytic transformation · (R)-1-(benzofuran-
2-yl)ethanol
Introduction
Chirality has become important in various industries such
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-020-01364-2) contains
supplementary material, which is available to authorized users.
as, pharmaceutical, agrochemical and fne chemical. Chi-
ral aromatic and hetero aromatic alcohols are widely used
for synthetic procedures in the pharmaceutical and fne-
chemical industries, owing to their stable structure (Qua-
glia et al. 2013). The functional groups of chiral secondary
alcohols can be easily transformed into other functional
* Engin Şahin
esahin@bayburt.edu.tr
Extended author information available on the last page of the article
Vol.:(0123456789)
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Chemical Papers
groups without racemation (Şahin and Dertli 2019). Enan-
tiopure 1-phenylethanol and its derivatives are useful chiral
building blocks or intermediates for synthesis of various
complex molecules used in a spectrum of industries. For
instance, (S)-1-phenyl ethanol, 2-naphthyl ethanol and (S)-
1-(3-methoxyphenyl) ethanol are used as chiral auxiliaries
in chemical and pharmaceutical industries (Lou et al. 2009;
Mangas-Sánchez et al. 2009). On the other hand, impor-
tant examples of heteroarylmethanols are (R)-neobenodine,
(R)-orphenadrine, (S)-cetrazine, (S)-carbinoxamine, (S)-
duloxetine, (1R,2S)-mefoquine, HIV reverse-transcriptase
inhibitor furo[2,3-c]pyridine thiopyrimidine ether, β-blocker
2-(2-tert-butylamino-1-hydroxyethyl)benzofuran and analge-
tic (S)-phenyl(pyridin-2-yl)methanol (Şahin et al. 2019a, b).
Enantiopure N-heteroaryl methanols, such as (R)-1-(pyridin-
2-yl)ethanol (1a), are widely used in synthetic organic and
medicinal chemistry as key intermediates for the synthesis
of various pharmaceutical products (Nian et al. 2019). The
(R)-1-(furan-2-yl)ethanol (2a) is valuable structural motif,
widely used in the total synthesis of numerous pharmaceuti-
cal and natural product such as Landomycins A, E (Zhou and
O’Doherty 2008), (−)-Angiopterlactone B (Thomson et al.
2017), and (+)- and (−)-cis-Osmundalactone (Blume et al.
2016). Enantioenriched chiral aryl heteroaryl alcohols (R)-
phenyl(thiophen-2-yl)methanol (3a) and (S)-phenyl(pyridin-
2-yl)methanol (4a) are signifcant precursors in the synthesis
of numerous pharmaceuticals, and agrochemicals, such as
bepotastine besilate (Ohnmacht et al. 1971), carbinoxam-
ine (Salvi et al. 2009), and (R,S)-mefoquine (Corey and
Helal 1996; Nian et al. 2019). Benzofuran-based structures,
such as (R)-1-(benzofuran-2-yl)ethanol (5a), are signifcant
synthetic building blocks in the manufacturing of pharma-
ceuticals such as bufuralols potent nonselective β-blockers
antagonists, Amiodarone (cardiac anti-arrhythmic), and
Benziodarone (coronary vasodilator) (Goudarshivannana-
var et al. 2009). Antifungal and antibacterial properties of
various benzofuran carbinol derivatives were investigated.
At the same time, such compounds have found wide applica-
tion area in the cosmetic industry and chemical pesticides
(Ryu et al. 2010). Molecules contained piperonyl ring, such
as (S)-1-(benzo[d][1,3]dioxol-5-yl)ethanol (6a), are found
in the skeleton of natural products such as podophylltoxin
and diphyllin, which have been reported to exhibit biologi-
cal activity such as anticancer (Oliveira et al. 2010), anti-
convulsant (Prasanthi et al. 2013; Aboul-Enein et al. 2012),
antiamoebic (Wani et al. 2012), antiproliferactive (Alizadeh
et al. 2010), antiviral (Yeo et al. 2005), antitumor properties
(Feng et al. 2009).
such as Rh-complexes with diferent nitrogen containing
compounds, metal–ligand complexes, chiral Lewis acid
and oxazaborolidine (Yadav and Devendran 2012a, b;
Touchard et al. 1999; Mikhailine and Morris 2010; He et al.
2014). However, there are several drawbacks associated
with chemical processes such as requirement of expensive
chiral ligands and hazardous metals, harsh conditions, low
conversion and low enantioselectivity, and formation of by-
products (Şahin and Dertli 2017; Shrivas and Pratap 2019).
Various biocatalytic approaches for synthesis of enantiose-
lective chiral secondary alcohols have been introduced as
alternatives to chemical approaches (Matsunami et al. 2018).
Biocatalytic processes can ofer highly selective, environ-
mentally benign and energy efective solution for production
of optically active compounds. They have advantages such
as mild reaction conditions, no need of tedious protection/
de-protection steps, less or absence of by-product formation
and they can exhibit high chemo-, regio- and stereo-selectiv-
ity (Ni and Xu 2012; Muñoz Solano et al. 2012; Şahin 2020).
These biocatalysts have two procedures, such as direct asym-
metric reduction of ketones or resolution of racemic alco-
hols. However, enzymatic resolution was limited by 50%
theoretical yield. Therefore, a suitable biocatalyst that can be
used to production of chiral alcohol is more advantageous.
Enantioselective bioreduction can be carried out using either
isolated enzymes or whole cells. Whole-cell biocatalysts are
advantageous as they are generally inexpensive and more
stable. They contain multiple dehydrogenases that are able
to accept a broad range of unnatural substrates. All enzymes
and co-factors are well protected within their natural cellular
environment. Moreover, the use of whole-cell biocatalysts
avoids enzyme purifcation and cofactor addition (Yu et al.
2018). Chemical chiral reductants are used limited in the
commercial production because of low chiral selectivity and
costly (Yılmaz et al. 2017). Therefore, diferent biocatalytic
approaches for production of enantioselective chiral second-
ary alcohols have been introduced as alternatives to chemical
approaches like whole-cell or purifed enzymes (Yadav and
Devendran 2012a, b; Wu et al. 2007; Schmidt et al. 2017;
Şahin et al. 2019a, b). Biocatalytic reduction seems to be
the most potential and competitive industrialization pro-
cess, which is refected in the application of some important
products. It has been reported that the chiral compounds
produced by biocatalytic reduction accounted for 20% of
the total chiral alcoholic intermediates in industrial products
(Honda et al. 2017). Asymmetric bioreduction of prochi-
ral ketones via biocatalysts is one of the most encouraging
and simple routes to production of enantiomerically pure
secondary alcohols. Although there are many studies in the
literature involving asymmetric reduction of heteroaromatic
substrates with chemical catalysts, there are limited stud-
ies on the reduction of these substrates with biocatalysts.
Therefore, it is very important to develop new biocatalysts
Diferent chemical processes are used to prepare sec-
ondary alcohols such as enantioselective crystallization,
electrode reduction, chromatography separation and asym-
metric reduction of prochiral ketone using diferent chiral
specifc catalysts that are derived from transition metals
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Chemical Papers
that can be reduced heteroaromatic substrates as an asym-
metric. In the literature, pure alcohol dehydrogenase enzyme
(ADH) isolated from L. kefri was used catalysts for asym-
metric reduction of aromatic ketones and diferent prochiral
ketones to corresponding chiral secondary alcohols with
high ee and conversion (Weckbecker and Hummel 2006).
Ethyl (S)-4-chloro-3-hydroxybutanoate was obtained with
high ee and yield using L. kefri (Amidjojo and Weuster-Botz
2005). (2,5)-hexanedione was reduced to (5R)-hydroxyhex-
ane-2-one with>99% ee using with whole-cell immobilized
L. kefri (Tan et al 2006). These studies show that L. kefri
is an important biocatalyst. However, to our knowledge, the
use of L. kefri for asymmetric reduction in the hetero aro-
matic ketones has not been investigated yet.
comparison of the ketone peak with the alcohol peak after
HPLC analysis of the crude product.
Culture medium and bacterial strain
Lactobacillus kefri P2 strain used in this study was previ-
ously isolated from kefr and stored at − 80 °C in glycerol
and this strain was grown in MRS broth as described previ-
ously (Baydaş et al. 2020).
General procedure for asymmetric bioreduction
Lactobacillus kefri P2 was added from its glycerol stock by
inoculation to 10 mL MRS mixture (MgSO4·7H2O 11.5%
(w/v), K2HPO4 2 g/L, pepton [Oxoid] 10 g/L, yeast extract
2% glucose, [Difco] 5 g/L, C2H3NaO2·3H2O 5 g/L, salt solu-
tion [MgSO4·7H2O 11.5% (w/v), triamonium citrate 2 g/L],
Tween 80 1 mL/L) followed by 48 h growth at 37 °C. From
this mixture, 1 mL bacterial cell was inoculated to 100 mL
sterilized MRS mixture in 250 mL Erlenmeyer fask and
then pH was adjusted to 4.5 by 1 M HCl (approximately
1 mL). Following the 2 h of incubation, 1 mmol of 1–6
were added directly to the reaction medium and the reaction
was stirred at 25 °C for 64 h under agitation at 150 rpm.
After the catalytic reaction was complete, the supernatant
was separated with centrifuged. The aqueous phase was
saturated with solid NaCl and extracted with dichlorometh-
ane (2 × 100 mL). The organic phase back-extracted with
brine (50 mL). After the organic phase was combined, they
were dried over anhydrous Na2SO4 and fltered to remove
the salt. The organic solvent was removed in a vacuum and
the crude product was characterized by NMR analysis. The
crude product was purifed using column chromatography
with mixture of hexane: ethyl acetate (90:10, v/v) solvent.
The aim of this study is to investigate the catalytic activity
of L. kefri P2 in asymmetric reduction of hetero aromatic
ketones. In our previous work, L. kefri P2 was demonstrated
efective biocatalysts for the asymmetric reduction of aro-
matic ketones (Baydaş et al. 2020). Herein, we report on the
application of L. kefri P2 for the synthesis of heterocyclic
aromatic secondary alcohols. Moreover, to the best of our
knowledge, it is the frst report that (R)-5a was synthesized
as enantiopure form using biocatalyst in the highest yield
and highest gram. The present study provides a practical
approach for producing (R)-5a, which can meet the demand
for industrial green production of this heterocyclic chiral
alcohol. The efect of the steric properties of the hetero aro-
matic ketones on the bioreaction catalyzed by L. kefri P2 is
also discussed.
Experimental
Materials
Gram scale production of (R)‑5a
Chemicals
The gram scale asymmetric bioreduction of ketone 5 was
performed as follows. L. kefri P2 was added from its glyc-
erol stock by inoculation to 10 mL MRS mixture followed
by 48 h growth at 37 °C. Then this 10 mL starting culture
was inoculated to 1 L sterilized MRS mixture in 5 L Erlen-
meyer fask and incubation for 2 h under optimization con-
ditions. Then the pH of the mixture was adjusted to 4.5 by
1 M HCl (approximately 2 mL). Following the 2 h of incu-
bation, substrate 5 (10 g) was added directly as the solid to
the mixture and incubated on an orbital shaker at 25 °C,
150 rpm for 64 h. At the end of the incubation period, the
cell was separated by centrifugation at 6000×g for 5 min at
4 °C. The aqueous phase was saturated with solid NaCl and
extracted with dichloromethane (2×600 mL). The organic
phase back-extracted with brine (100 mL). After the organic
phases were combined, they were dried over anhydrous
MRS, which is growth medium of bacteria, solvents and
substrate were purchased from Fluka and Aldrich. Purifca-
tion of 1a–6a were carried out by column chromatography
and the alcohols were obtained using ethyl acetate/hexane:
(10:90, v/v) solvent mixture. TLC was used for checked the
progress of reaction, using ethyl acetate/hexane (10:90, v/v)
as a mobile phase. Racemic alcohols 1a–6a as a reference
sample was obtained by reducing the substrate with NaBH4
in the CH3OH at room temperature. Agilent 1260 HPLC
system, which have UV and chiral detector, was used for the
HPLC analysis of substrate and product. The product char-
acterization was determined by Bruker NMR spectrometer
(Bruker Ltd., Germany). Bellingham+ Stanley (ADP220,
589 nm) spectropolarimeter was used for the optical rota-
tion of the product. The conversion rate was calculated by
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Chemical Papers
Na2SO4 and fltered to remove the salt. The organic solvent
was removed in a vacuum and the crude product was charac-
terized by NMR analysis. After removal of the solvent under
reduced pressure, the crude product was purifed on a 40 cm
column containing 50 g silica gel and eluted using hexane:
ethyl acetate (90:10, v/v) to aford the product. As a result
of purifcation, 9.7 g of (R)-5a was obtained in 96% yield.
CHCl3, %70 ee for S enantiomer) (Maerten and Agbossou-
Niedercorn 2008); HPLC condition of product, Chiralcel
AD column, 254 nm, fow rate: 0.8 mL/min, i-PrOH/n-hex-
ane 10:90, tR (R) 15.9, (S) 19.8 min. HPLC analysis condi-
tion of ketone 4 is the same as alcohol (S)-4a and retention
time of substrate was determined as 9.3 min.
(R)‑1‑(benzofuran‑2‑yl)ethanol (5a) (Sokeirik et al.
1
(R)‑1‑(pyridin‑2‑yl)ethanol (1a) (Wu et al. 2016) Colorless
oil, 1H-NMR (400 MHz, CDCl3) δ=8.49 (d, J=4.8 Hz, 1H),
7.67 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.17–7.14
(m, 1H), 1.86 (q, J=6.5, 6.4 Hz, 1H), 1.47 (d, J=6.5 Hz,
3H);13C-NMR (100 MHz, CDCl3) δ=163.2, 148.1, 136.8,
122.2, 119.8, 68.9, 24.2; [α]D25 = 19.5 (c 0.52, CH2Cl2),
93% ee; Lit.[α]D25 = 20.8 (c 0.52, CH2Cl2, 99% ee for R
enantiomer) (Wu et al. 2016); HPLC condition of product,
Chiralcel OD-H column, 230 nm, fow rate: 0.6 mL/min,
i-PrOH/n-hexane 3:97, tR (R) 20.8, (S) 24.2 min. HPLC
analysis condition of ketone 1 is the same as alcohol (R)-1a
and retention time of substrate was determined as 9.4 min.
2007) Light yellow oil, H-NMR (400 MHz, CDCl3))
δ = 7.55–7.52 (m, 1H), 7.48–7.44 (m, 1H), 7.29–7.19 (m,
1H), 7.24–7.20 (m, 1H), 6.61 (s, 1H), 5.02 (q, J=6.5, Hz,
1H), 2.19 (bs, 1H (OH)), 1.64 (d, J = 6.5, Hz, 3H); 13C-
NMR (100 MHz, CDCl3) δ = 160.2, 154.7, 128.1, 124.2,
122.8, 121.1, 111.2, 101.8, 64.2, 21.4; [α]D25 =23.5 (c 0.53,
CHCl3),>99% ee; Lit.[α]D25 =19.8 (c 0.53, CHCl3, %84 ee
for R enantiomer) (Sokeirik et al. 2007); HPLC condition of
product, Chiralcel OD-H column, 254 nm, fow rate: 0.5 mL/
min, i-PrOH/n-hexane 1:99, tR (R) 72.8, (S) 68.8 min. HPLC
analysis condition of ketone 5 is the same as alcohol (R)-5a
and retention time of substrate was determined as 19.4 min.
(R)‑1‑(furan‑2‑yl)ethanol (2a) (Kang and Shin 2017) Pale yel-
low oil, 1H-NMR (400 MHz, CDCl3) δ=7.36 (dd, J=1.8,
0.7 Hz 1H), 6.31 (dd, J=3.2, 1.8 Hz 1H), 6.21 (d, J=3.2 Hz
1H), 4.86 (q, J= 6.4 Hz 1H), 1.20 (s, 1H, (OH)), 1.52 (d,
J = 6.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ = 157.6,
141.9, 110.1, 105.1, 63.6, 21.2; [α]D25 = 7.69 (c 0.9,
CH2Cl2), 95% ee; Lit.[α]D25 =7.86 (c 0.9, CHCl3, % 97 ee
for R enantiomer) (Kang and Shin 2017); HPLC condition of
product, Chiralcel AS-H column, 220 nm, fow rate: 1.0 mL/
min, i-PrOH/n-hexane 1:99, tR (R) 46.4, (S) 40.6 min. HPLC
analysis condition of ketone 2 is the same as alcohol (R)-2a
and retention time of substrate was determined as 18.1 min.
(S)‑1‑(benzo[d][1,3]dioxol‑5‑yl)ethanol (6a) (Şahin
2018) Colorless oil, 1H-NMR (400 MHz, CDCl3 δ=6.89–
6.75 (m, 3H), 5.94 (s, 2H), 4.81 (q, J = 6.4, Hz, 1H),
1.82 (bs, 1H, (OH)), 1.45 (d, J = 6.4 Hz, 3H); 13C-NMR
(100 MHz, CDCl3) δ = 148.0, 147,1, 140.2, 118.9, 108.3,
106.3, 101.1, 70.5, 25.4; [α]D20 =-33.9 (c 1.0, CHCl3), 73%
ee; Lit.[α]D20 =46.5 (c 1.0, CHCl3) for 99% ee for R enanti-
omer) (Şahin 2018), HPLC condition of product, Chiralcel
OD column, 210 nm, fow rate: 1.0 mL/min, i-PrOH/n-hex-
ane 5:95, tR (R) 18.7, (S) 16.8 min. HPLC analysis condition
of ketone 6 is the same as alcohol (S)-6a and retention time
of substrate was determined as 10.0 min.
Phenyl(thiophen‑2‑yl)methanol (3a) (Wang et al.
1
2017) White solid, M.p: 51–53 °C H-NMR (400 MHz,
Results and discussion
CDCl3) δ=7.47–7.26 (m, 6H), 6.96–6.88 (m, 2H), 6.06 (d,
J = 3.9 Hz, 1H), 2.42 (d, J= 3.9 Hz, 1H (OH)); 13C-NMR
(100 MHz, CDCl3) δ = 148.1, 143.1, 128.5, 128.0, 126.4,
126.3, 125.4, 124.9, 72.4; [α]D25 = 0 (c 1.0, CHCl3), 0%
ee; HPLC condition of product, Chiralcel OD-H column,
220 nm, fow rate: 0.8 mL/min, i-PrOH/n-hexane 8:92, tR
(R) 18.1, (S) 16.6 min. HPLC analysis condition of ketone
3 is the same as alcohol 3a and retention time of substrate
was determined as 9.6 min.
In this study, the biocatalytic reactions were carried out
using 1 mmol substrates (1–6) under optimized conditions
which is obtained in the previous study (Table 1). In our
previous study, asymmetric reduction reaction conditions
were optimized using the model substrate acetophenone
with L. kefri P2 and optimization conditions were obtained
as pH 4.5, time 64 h, temperature 25 °C, agitation speed
150 rpm (Baydaş et al.2020). The catalytic activity of L.
kefri P2 on heteroaromatic ketones (1–6) was investigated
and compared to the literature (Table 1). L. kefri P2 efec-
tively catalyzed the reduction of 1 to (R)-1a with 93% ee
and satisfactory conversion (56%) (Table 1, entry 1). In the
literature, (S)-1a was reported to be synthesized in small
scale in high enantiomeric purity by asymmetric reduction
of 2-acetylpyridine 1 using expensive pure enzyme and
cofactor (Yanga et al. 2008; Ni et al. 2011). However, to our
(S)‑phenyl(pyridin‑2‑yl)methanol (4a) (Maerten and Agbos‑
1
sou‑Niedercorn 2008) White solid, M.p: 72–74 °C; H-
NMR (400 MHz, CDCl3) δ=8.56–8.54 (m, 1H), 7.63–7.59
(m, 1H), 7.40–7.27 (m, 5H), 7.20–7.15 (m, 1H), 5.76 (s, 1H),
5.38 (bs, 1H (OH)); 13C-NMR (100 MHz, CDCl3) δ=160.9,
147.8, 143.2, 136.8, 128.6, 127.8, 127.1, 122.4, 121.3, 75.0;
[α]D25 =21.5 (c 1.0, CHCl3), 43% ee; Lit.[α]D25 =35.0 (c 1.0,
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Chemical Papers
Table 1 Asymmetric reduction
of prochiral ketones (1–6) with
novel L. kefri P2 biocatalyst
Entry
1
Substrate
Product
ee (%)a,b
Conversion(%)c
56
Yield (%)d
52
93 (R)
2
3
95 (R)
99
27
95
24
Racemic
4
43 (S)
8
6
5
6
>99 (R)
73 (S)
>99
98
96
95
aDetermined by HPLC using a chiral column
bDetermination of absolute confguration was carried out by comparison of the sign of optical rotation rela-
tive to the values in the literature
cThe conversions were determined by chiral HPLC
dIsolated yield
knowledge, the synthesis of (R)-1a with biocatalyst has not
been known yet. The asymmetric reduction of the 1 with
seed adzuki bean was carried out to corresponding chiral
seconder alcohol (S)-1a in>81% ee with 44% conversion
and small scale (Xie et al. 2009). In the literature, synthesis
of (R)-1a at high ee was carried out using chemical catalyst
(Utepova et al. 2018; Zhou et al. 2012). High conversion
(99%) and ee (95%) were obtained in asymmetric reduc-
tion of 2 with whole-cell L. kefri P2 (Table 1, entry 2). The
enantioselective reduction of 2 with alcohol dehydrogenase
enzyme was carried out to (S)-2a in 99% ee with 85% yield
(Blume et al. 2016). Asymmetric reduction of aryl heter-
oaryl ketones are generally carried out using toxic metals,
such as Ru, Rh, Ir, and Pd, as efcient catalysts (Ling et al.
2019). The L. kefri P2 mediated bioreduction of substrate
3 was reduced to racemic 3a with 27% conversion and 24%
yield (Table 1, entry 3). The asymmetric reduction of 3 to
the (S)-3a with L. paracasei BD101 as biocatalyst had been
previously reported for the frst time by Sahin and co-work-
ers in the enantiopurepure form, high yield, and gram-scale
(Şahin and Dertli 2019). Substrate 4 was reduced to (S)-4a
with L. kefri P2 in 43% ee and 8% conversion (Table 1,
entry 4). In the literature, in the presence of biocatalysts
such as, carbonyl reductase enzyme, isolated fungal strains,
Camellia sinensis cell culture, and cell cultures of Nicotiana
tabacum, 4a was obtained with 99%, 91%, 86%, 48% ee
respectively, in good yields and small scale (Li et al. 2009;
Pal et al. 2012; Takemoto and Tanaka 2001; Takemoto et al.
1995). Additionally, substrate 4 was reduced to (R)-4a with
19% ee and 92% yield using Catharanthus Roseus (Take-
moto and Achiwa 1995). Compared with the literature, low
conversion and ee was achieved in the asymmetric reduction
of substrates 3 and 4 in the presence of L. kefri P2 biocata-
lyst (Table 1, entries 3, 4). The reason for the low conver-
sion of substrates 3 and 4 may be due to the low solubility
of these substrates in water. Therefore, it was observed that
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Chemical Papers
there were no changes in the conversion and ee using organic
solvents such as 5% ethyl alcohol, isopropyl alcohol and
DMSO in the reaction medium. The low ee and conversion
for substrates 3 and 4 could be explained by the bulky groups
on both sides of the carbonyl group in this substrates. Since
it is difcult for substrates to interact with the active site of
the enzyme due to the bulky groups, conversion and ee may
be reduced. This indicated that the bulky groups on the both
side of carbonyl group adversely afected the conversion rate
of the enzymatic reaction. Similarly, ketone 1 was converted
faster than 4 with L. kefri P2. Clearly, for ketone 3 and 4, the
steric efect is infuence the conversion. In this study, excel-
lent enentiomeric excess (>99%) and conversion (>99%)
was achieved in the asymmetric bioreduction of substrate
5 to (R)-5a using L. kefri P2 (Table 1, entry 5). Baker’s
yeast reduction of 5 gave (S)-5a with moderate enantiomeric
purity (55%) and in moderate yield (60%) (Toşa et al. 2008).
Rhizopus arrhizus mediated bioreduction of 5 furnished (S)-
5a in 99% yield with 92% enantiomeric purity (Salvi and
Chattopadhyay 2016). The enzymatic reduction of prochi-
ral heterocyclic ketone 5 by carrot root (Daucus carota) in
water aforded the corresponding (S)-5a with 47% yield and
95% ee (Aldabalde et al. 2007). In our previous study, we
reported that (S)-5a had reached 92% yield with ee of higher
than 99% using L. paracasei BD87E6 (Şahin 2019). Under
the optimized conditions, piperonyl methyl ketone 6 was
reduced to the corresponding chiral alcohol (S)-6a by L.
kefri P2 with good ee (73%) and high conversion (98%)
(Table 1, entry 6). The (R)-6a has been obtained in the high
enantioselectivity by reducing piperonyl methyl ketone 6
with the expensive chiral reagent and toxic chemical cat-
alysts (Ling et al. 2018; Chen and Lu 2016). The limited
study is available on obtaining this chiral secondary alcohol
6a with biocatalysts. In one of these studies, production of
(R)-6a was performed in 89% yield and 99% enantiomeric
purity L. paracasei BD101 (Şahin 2018).
indicated that the cause of the conversion in the reactions
was the L. kefri P2.
The last aim of the study was to attempt gram scale syn-
thesis of (R)-5a using the determined optimum bioreduction
conditions, since highly gram scale synthesis of enantiopure
chiral alcohol using green method is extremely signifcant
for industrial applications. The asymmetric reduction of 5
for the high gram scale synthesis of (R)-5a with L. kefri P2
is seen in Fig. 1.
It has been shown that a change in substrate concentra-
tion has an efect on ee of product and the conversion of
substrate, higher concentrations decrease the biotransforma-
tion, which has been reported to cell toxicity and product/
substrate inhibition (Roy et al. 2003). In line by this infor-
mation, the concentration of substrate from 5 to 15 g was
gradually varied and examined. Higher than concentrations
of 10 g decreased the ee and yield of product. The best ee
(>99%) of product and complete conversion were achieved
with 10 g/2L concentration of substrate 5. Under optimized
conditions, substrate 5 (62.4 mmol) was converted to (R)-5a
in 96% yield with>99% ee and conversion with the L. kefri
P2. There is only one study in the literature involving the
biocatalytic gram-scale synthesis of (R)-5a (Şahin 2019).
Şahin (2019) reported the gram scale production of (R)-5a
(6.26 g, ee>99%, 99% conversion, 92% yield) from 6.73 g
5 whole cells of L. paracasei BD87E6. This study in the
literature gave relatively lower yield and low substrate toler-
ance. The present study gave advantages of higher substrate
tolerance (10 g/2L) and yield (96%). This is the frst report
on production of (R)-5a with L. kefri P2 as a whole-cell bio-
catalyst in highest gram and yield. These results indicate that
L. kefri P2 can be used on a gram scale in the production
of substantial drug precursors. In light of this information,
these results may reveal useful information for further inves-
tigation of purifed enzyme systems from these bacteria.
Substrates 5 and 6, which are similar in sterically, are
reduced to the corresponding alcohol with almost the same
conversion ratio. However, (R)-5a was obtained with higher
ee. Thus, benzofuran structure of substrate 5 might be better
stabilized in the enzyme active site in such a way to increase
the ee of the product. This shows that the heteroatoms in the
substrate structure are very important in selectivity.
Conclusions
In conclusion, L. kefri P2 was proved an efective biocata-
lyst for asymmetric bioreduction of prochiral hetero aromatic
ketones with high conversion (8–99%) and ee (0–99%).
(R)-5a, which can be used in the synthesis of pharmaceu-
ticals such as bufuralols potent nonselective β-blockers
antagonists, Amiodarone (cardiac anti-arrhythmic), and
The confgurations of obtained alcohols in this study var-
ied according to the structure of substrates. The probable
reason for this can be explained by the fact that diferent
confgurations might occur due to the diferent interaction
of substrates with the active center of the enzyme. Based
on these results, it can be concluded that this biocatalyst
might work as substrate selective as previously stated in
the literature (Baydaş et al. 2020). When the bioreduction
reactions were performed in the absence of the L. kefri P2
in the medium, practically no conversion occurred, which
Fig. 1 Gram scale synthesis of (R)-1-(benzofuran-2-yl)ethanol (5a)
1 3

Chemical Papers
synthesized from the N,N,N-trimethylammonium derivative of
ARC-111,5H–2,3-dimethoxy-8,9-methylenedioxy-5-[(2-N, N,
N-trimethylammonium)-ethyl]di-benzo[c, h][1,6]naphthyri-
din-6-one iodide. Eur J Med Chem 44:3433–3438. https://doi.
org/10.1016/j.ejmech.2009.02.004
Benziodarone (coronary vasodilator), was synthesized
in gram scale, high yield and enantiomerically pure form
using L. kefri P2. Compared with the past report, which
used biocatalyst, 5 was bioreduced to (R)-5a in higher yield
and gram scale. To the best of our knowledge, we are the
frst to successfully synthesis highest amount of enantio-
pure (R)-5a from 5 using a whole-cell biocatalytic reduc-
tion method. These results showed that current process has
signifcant potential for the green synthesis of (R)-5a at an
industrial scale. The biocatalytic reduction should have great
importance for the synthesis of optically pure chiral alco-
hols owing to the alluring biocatalysts and environmentally
friendly reaction condition. L. kefri P2 catalyzed asymmet-
ric bioreduction of prochiral hetero aromatic ketones is a
cost-efective, environmentally benign and easily scalable
processes compared to chemical processes. To expand the
catalytic reduction activity of this biocatalyst, studies are
continuing on new substrates, in particular, which could be
drug precursors.
Goudarshivannanavar BC, Jayadevappa H, Mahadevan KM (2009)
A convenient synthesis of 2(2-benzo[b]furo)indoles and benzo-
furopyrazoles. Indian J Chem 48:1419–1423
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of ketones catalyzed by a chiral oxazaborolidinium ion. Org
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Acknowledgements The authors thank Dr. Enes DERTLİ (Yildiz
Technical University) for providing the bacteria strain used in this
study.
Ling F, Hou H, Chen J, Nian S, Yi X, Wang Z, Song D, Zhong
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Afliations
Yasemin Baydaş1 · Erbay Kalay2 · Engin Şahin3
1
3
Department of Food Engineering, Faculty of Engineering,
Department of Nutrition and Dietetics, Faculty of Health
Bayburt University, 6900 Bayburt, Turkey
Sciences, Bayburt University, 69000 Bayburt, Turkey
2
Kars Vocational School, Kafkas University, 36100 Kars,
Turkey
1 3