First green synthesis of (R)-2-methyl-1-phenylpropan-1-ol using whole-cell Lactobacillus paracasei BD101 biotransformation

Article abstract of DOI:10.1080/10242422.2019.1698554

Green chemistry includes a novel process in the production of drugs precursors and biological active molecules using biocatalysts, so reducing the threats for human sanitary and ecological pollutions. Asymmetric bioreduction of prochiral ketones by biocat

Full text of DOI:10.1080/10242422.2019.1698554

Biocatalysis and Biotransformation
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First green synthesis of (R)-2-methyl-1-
phenylpropan-1-ol using whole-cell Lactobacillus
paracasei BD101 biotransformation
Engin Şahin
To cite this article: Engin Şahin (2019): First green synthesis of (R)-2-methyl-1-phenylpropan-1-
ol using whole-cell Lactobacillusꢀparacasei BD101 biotransformation, Biocatalysis and
Biotransformation, DOI: 10.1080/10242422.2019.1698554
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BIOCATALYSIS AND BIOTRANSFORMATION
https://doi.org/10.1080/10242422.2019.1698554
RESEARCH ARTICLE
First green synthesis of (R)-2-methyl-1-phenylpropan-1-ol using whole-cell
Lactobacillus paracasei BD101 biotransformation
Engin S¸ahin
Faculty of Engineering, Department of Food Engineering, Bayburt University, Bayburt, Turkey
ABSTRACT
ARTICLE HISTORY
Received 3 September 2019
Revised 14 October 2019
Accepted 20 November 2019
Green chemistry includes a novel process in the production of drugs precursors and biological
active molecules using biocatalysts, so reducing the threats for human sanitary and ecological
pollutions. Asymmetric bioreduction of prochiral ketones by biocatalysts is one of the best
prevalent used methods in synthetic organic chemistry due to the production of enantiopure
chiral carbinols. This study emphasizes the application biocatalyst L paracasei BD101 for enantio-
selective bioreduction of 2-methyl-1-phenylpropan-1-one ketone, which contain branched alkyl
chain, to (R)-2-methyl-1-phenylpropan-1-ol ((R)-2) in high yields and excellent enantiomeric
excess (>99%). The scale-up production was performed, and 4.61 g of (R)-2 in enantiopure form
was synthesized. L paracasei BD101 was proved to be a substantial biocatalyst in asymmetric
bioreduction of a ketone which contains a branched alkyl chain. There is not any work in the lit-
erature similar to our study. Hence, it is important to work on filling this gap. This study is the
first example for an enantiopure synthesis of (R)-2 by a biocatalyst. The new green method was
developed for bioreduction of bulky ketones, which contains a branched alkyl chain, and it
approves the synthesis of novel chiral carbinols in an easy, cheap, and environmentally friendly
condition using L paracasei BD101.
KEYWORDS
Chirality; biocatalyst; green
synthesis; enantioselective
bioreduction; (R)-2-methyl-
1-phenylpropan-1-ol
GRAPHICAL ABSTRACT
OH
O
ee>99%
yield: 90%
Introduction
prochiral compounds is a significant reaction in
organic chemistry. Enantiopure alcohols are precursors
in the production of valuable molecules used in chem-
ical, medicine, and food industries (Hall et al. 2008;
Winkler et al. 2012; Xiao et al. 2014). For instance, eze-
tibime is a drug that lowers plasma cholesterol levels,
Prozac is used for antidepressant drug, sotalol is used
for rhythm disturbance of the heart (Figure 1)
(Panunzio et al. 2004; Blay et al. 2010; More et al.
2015; Sukhorukov et al. 2016). Chiral alcohols are
beneficial intermediates for the production of compli-
cated molecules (Pollard and Woodley 2007). The
importance of chiral secondary alcohols has led to the
Biological molecules, like enzymes and amino acids in
living organism, exist in enantiomerically pure form,
which demonstrate the significance of chirality in the
living (Brooks et al. 2011). Biologically active chiral
compounds interact in chiral style with receptors and
the receptors behave differently towards each enantio-
mer. As a result, each enantiomer exhibits different
biological properties. Since chirality has an indispens-
able role in the production of drugs, the organic
chemistry industry is interested in the production of
enantiomerically pure compounds (Yang and Huang
2006; LaPlante et al. 2011). Biocatalytic reduction of
CONTACT Engin S¸ahin
esahin@bayburt.edu.tr
Department of Food Engineering, Faculty of Engineering, Bayburt University, Bayburt 69000, Turkey
Supplemental data for this article can be accessed here.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
E. ŞAHIN
(Griffin et al. 1998; Comasseto et al. 2004). In the lit-
erature, (S) or (R)-2-methyl-1-phenylpropan-1-ol was
obtained by asymmetric hydrogenation in the pres-
ence of the chiral ligand or by asymmetric alkylation
of the corresponding aldehyde in high enantiomeric
selectivity (Sato, Saito et al. 2000; Sato, Shibata et al.
2000; Ling et al. 2018). However, biocatalytic asymmet-
ric reduction of 2-methyl-1-phenylpropan-1-one (1),
which contains a branched alkyl chain, was not
reported before in the literature (Alsafadi et al. 2017).
Therefore, it is important to filling this gap. Recently,
we have carried out asymmetric bioreduction of aceto-
phenones, cyclohexyl(phenyl)methanone and piper-
onyl methyl ketone by high ee and bioconversion
using L paracasei BD101 as the biocatalyst (Yılmaz
et al. 2017; Sahin 2018; Sahin et al. 2019).
Based on the strength of this biocatalyst, herein,
we have developed a method where a bulky ketone
which have a branched alkyl chain moiety can be
reduced using an inexpensive and simple process with
L paracasei BD101 as the biocatalyst. Moreover, to the
best of our knowledge, this is the first report for the
asymmetric bioreduction of 2-methyl-1-phenylpropan-
1-one 1 by biocatalyst in the enantiopure form, gram
scale and high yield. The reaction conditions effecting
the conversion and enantiomeric excess were also
optimized.
Figure 1. Drugs examples derived from chiral secondary
alcohols.
need for the development of novel methods to syn-
thesize these compounds more selectively, efficiently
and in high amounts. There are two methods for the
production of these highly important chiral secondary
alcohols. The classic chemical method requires using
metal hydrides, however the obtained alcohol is
racemic. Chiral ligands for the synthesis of enantiopure
chiral secondary alcohols were developed, however
this method demands the use of costly and toxic cata-
lysts and also leaves toxic by-products (Noyori and
Hashiguchi 1997; Corey and Helal 1998; Lawrence
et al. 1999; Mimoun et al. 1999). Biocatalysts have
many benefits over chemical catalysts (Clouthier and
Pelletier 2012). Chemical catalysts produce toxic by-
products and are costly, however biocatalysts provide
simple and environmentally friendly processes and can
be carried out in mild reaction conditions. Therefore,
biocatalysis, especially by whole-cell biocatalyst, is an
appealing process for the production of chiral alcohols
(de Carvalho 2017). Whole-cell biocatalysts are more
favourable than pure enzyme since whole-cells contain
the enzyme and cofactor within their structure,
whereas pure enzymes needs an external cofactor to
be added such as NADH/NADPH which is very costly
(Verho et al. 2003; Lee et al. 2013; Yu et al. 2018).
Biocatalyzed methods are generally used on an indus-
trial scale via the asymmetric bioreduction of cheap
substrates and the resolution of racemates. In reso-
lution of racemate, there is always 50% of the
unwanted product unlike asymmetric bioreduction
which preferably obtained in the formation of only
one enantiomer in high enantimeric excess (ee) and
yields (Ranjan et al. 2017). Alcohols, which have a
chiral centre, are valuable precursors in the production
of biological active molecules and can also be used in
the production of chiral ligands. At the same time, the
alcohol functional group can be readily converted into
the proper functional groups with no racemization
Materials and methods
General
The substrate, bateria growth medium (MRS) and sol-
vents were received from Fluka and Aldrich (purity of
>99%). The growth medium (MRS) of bacteria was
bought from Merck. Progress of the bioreduction reac-
tion was monitored by TLC, using ethyl acetate
(EtOAc): hexane (10:90) as a mobile phase. The
obtained product was purified using column chroma-
tography on silica gel by hexane: EtOAc: (90:10) as a
mobile phase. Reference sample of racemic alcohol 2
was prepared by reducing the ketone 1 using NaBH4
in the MeOH. HPLC analysis for substrate and product
were carried out on an Agilent 1260 system combined
with chiral detector (Ibz Messtechnik Gmbh) and UV
detector. Optical rotation was determined with a
589 nm spectropolarimeter, ADP220, Bellingham þ
Stanley. Absolute configurations were assigned by
comparison of the sign of optical rotations relative to
the values in the literature. The characterization of the
products was performed on a Bruker NMR spectrom-
eter (Ascend TM; Bruker Ltd., Germany). (R)-2-methyl-
1-phenylpropan-1-ol (Yu et al. 2017): Colourless oil,

BIOCATALYSIS AND BIOTRANSFORMATION
3
1
purified yield 90%, H NMR (400 MHz, CDCl3) d ¼ 7.36-
the crude products with a column containing a little
silica gel. Configurations of products were assigned on
the comparison of the rotation sign with litera-
ture data.
7.25 (m, 5 H), 4.36 (dd, J ¼ 6.8, 3.1 Hz, 1 H), 2.00-1.90
(m, 1 H), 1.87 (d, J ¼ 3.1 Hz, 1 H), 1.62 (bs, 1 H, (OH)),
1.00 (d, J ¼ 6.8 Hz, 3 H), 0.80 (d, J ¼ 6.8 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) d ¼ 143.6, 128.2, 127.4, 126.5,
25
80.0, 35.3, 19.0, 18.2; [a]D ¼ 41.6 (c ¼ 1, CHCl3) >99%
Gram scale asymmetric bioreduction of 1
20
ee; Lit. (R)-2-methyl-1-phenylpropan-1-ol, [a]D ¼ 41.6
The gram scale asymmetric reduction of substrate 1
was performed as follows. The 0.5 g dry L paracasei
BD101 was inoculated to 1.5 L sterilized fresh MRS sus-
pension as working volume in 5.0 L and then, incu-
bated on an orbital shaker at 30 ꢀC, 200 rpm for 2 h.
Then, the pH of the medium was adjusted to 6.5 with
1 M HCl, then substrate 1 (33.7 mmol, 5.0 g) was trans-
ferred to the suspension and incubated on an orbital
shaker at 200 rpm, 30 ꢀC for 48 h. The secondary chiral
alcohol was isolated, purified and characterized as
described above.
(c ¼ 1, CHCl3, for 99%ee) (Yu et al. 2017); HPLC condi-
tion, Chiralcel OD-H column, 220 nm, flow rate:
1 mL/min, n-hexane/i-PrOH 98:2, tR (R) 13.9 min. HPLC
condition of substrate is the same as alcohol HPLC
analysis condition and retention time: 5.0 min
(Supplementary matrerial).
Bacterial strain and culture condition
This study used L paracasei BD101 strain was obtained
previously from boza, a fermented beverage (Dertli
et al. 2016). L paracasei BD101 was propagated from
their glycerol stock by inoculation to 10 ml MRS broth
medium (C2H3NaO2.3H2O 5 g/L, Tween 80 1 ml/L,
MnSO4.4H2O 2.8% (w/v)], yeast extract [Difco] 5 g/L,
pepton [Oxoid] 10 g/L, lab lemco [Oxoid] 8 g/L, 2%
glucose, triamonium citrate 2 g/L, K2HPO4 2 g/L, salt
solution [MgSO4.7H2O 11.5% (w/v)) followed by 24 h
growth at 30 ꢀC. Bacterial cells, which were grown in
this mixture, were inoculated to 1 L MRS suspension at
10% concentration and incubated 48 h at 30 ꢀC under
aerobic conditions. After, whole-cell, which is growth,
was dried by freeze-drying (Labconco, TR) and stored
at room temperature without losing activity for three
months.
Results and discussion
Enantiomerically pure (R) or (S) alcohols are precursors
for synthesis of many molecules, and the synthesis of
these alcohols using biocatalyst is very important.
Chiral secondary alcohols could be converted into
beneficial groups which can be used as other pharma-
ceutical precursors without racemization (Pollard and
Woodley 2007). It is very important to optimize the
impacts of some key conditions on the reaction such
as agitation speed, pH, incubation time and tempera-
ture, in order to obtain enantiomerically pure chiral
secondary alcohol in the biocatalytic reactions
(Pereira 1998).
General procedure for microbial bioreduction of 1
Optimizations of bioreaction conditions
50 mg of dry L paracasei BD101 was transferred to a
250 mL Erlenmeyer flask bearing 100 ml MRS broth.
The suspension was stirred on an orbital shaker at
30 ꢀC and 200 rpm for 2 h. Then, the pH of the
medium was adjusted to 6.5 with 1 M HCl and after
2 h, 1 mmol of substrate was added into the suspen-
sion and incubated for 48 h at 30 ꢀC under agitation
speed at 200 rpm. On completion of the reaction, the
cell was removed by centrifugation and the liquid
phase was satiated by sodium chloride, the phases
were extracted thrice with CH2Cl2. The organic phase
was washed with saturated NaCl and then dried with
anhydrous Na2SO4. The solvent was removed; final
product was analyzed using NMR after it was purified
by column chromatography. The conversion of sub-
strates was determined by HPLC analysis comparing
the alcohol peaks with the ketone peak after filtering
The biocatalytic production of (R)-2-methyl-1-phenyl-
propan-1-ol catalyzed by L paracasei BD101 was opti-
mized in terms of several key optimization conditions,
agitation speed, pH, incubation period and tempera-
ture (Table 1).
Effect of pH over ee and conversion
It is well known that pH has an important role in the
process of biocatalytic reduction using whole-cells.
The optimization of pH for the bioreduction of keto
compound 1 to 2 was investigated at pH range from
4.5 to 7.5. The bioreduction reactions were conducted
using 1 mmol of 1 in RT, 24 h and 100 rpm (Table 1).
The pH performs a key role in the biocatalytic reac-
tions when using whole cells due to the fact that it

4
E. ŞAHIN
Table 1. Optimisation of reaction conditions for the asymmetric reduction of 2-methyl-1-phenylpropan-1-one (1).
pH
Temperature
Conv.%a
Incubation period
Conv.%a
Agitation speed
Conv.%a
pH
Conv.%a
ee%b,c
oC
ee%b,c
h
ee%b,c
rpm
ee%b,c
4.5
5
5.5
6
6.5
7
68
74
72
79
87
66
25
54 (R)
61 (R)
53 (R)
80 (R)
89 (R)
17 (R)
12 (R)
25
28
30
32
34
87
81
94
74
57
89 (R)
85 (R)
99 (R)
77 (R)
58 (R)
24
48
72
96
94
97
99
99
99 (R)
99 (R)
83 (R)
64 (R)
100
150
200
250
97
97
99
99
99 (R)
99 (R)
>99 (R)
54 (R)
7.5
Substrate 1 mmol.
aThe conversion was determined by HPLC.
bDetermined by HPLC using Chiralcel OD-H column.
cAbsolute configurations were assigned by comparison of the sign of optical rotations relative to the values in the literature.
affects the activity and enantioselectivity of the
enzymes involved in the reaction, alters the ionic state
of substrates, products and enzymes involved in the
reaction and affects the binding of enzyme’s active
site to substrates, especially for several isoenzymes
with different enantioselectivities (Sahin et al. 2019).
Enantioselectivity of the biocatalyst was markedly
influenced by pH changes. The results indicate that at
pH of 6.5, maximum ee and conversion were obtained.
Therefore, pH 6.5 was used for all further reactions as
an optimal pH. Presumably, as the pH changes, the
structure of the enzyme and, accordingly, the structure
of the active site of the enzyme change. Therefore,
the interaction of the substrate with the active side of
the enzyme is varied and enantioselectivity and con-
version are different and, also, the solubility of the
ketone can have influenced the enantioselectivity of
the L paracasei BD101. The selectivity may have
changed since the interaction of the enzyme with the
active site will change as a result of the ionic state
changes depending on the solubility of the substrate
(Yılmaz et al. 2017; Sahin 2018; Sahin et al. 2019).
Effect of incubation period over ee and
conversion
The catalytic activity of L paracasei BD101 for biore-
duction of substrate 1 was studied in the pH 6.5,
30 ꢀC, 100 rpm and using different incubation period
as the reaction conditions (Table 1). As shown in Table
1, it was observed that as the incubation period
increased, conversion rate of the reaction increased,
however the ee decreased considerably. This could be
owing to the decrease in the enzyme activity, suggest-
ing a reduction in the selectivity of the enzyme
(Zhimin et al. 2018). When the incubation period of
the bioreduction was set to 48 h, maximum conversion
and ee were obtained. Hence, incubation period of
48 h was used for further optimization reaction.
Effect of agitation speed over ee and conversion
The agitation speed can impact the particle transfer
rate of substrates in the biocatalytic process. So, it is
important to investigate the effects of agitation speed
on the bioreduction reaction. The catalytic activity of L
paracasei BD101 for bioreduction of substrate 1 was
studied in the pH 6.5, 30 ꢀC, 48 h and using different
agitation speeds (from 100 to 250 rpm) as the reaction
conditions (Table 1). Increasing the agitation speed
caused a rise in conversion and ee, but a sharp
decrease in ee is observed after 200 rpm. This decrease
can be attributed to the effect of shear stress on the L
paracasei BD101 cells at high agitation speeds, which
changes the cell internal structure (Zilbeyaz et al.
2016). The maximum bioconversion (>99%) and ee
(>99%) was observed at 200 rpm and therefore,
200 rpm was determined as optimum agitation speed.
Effect of the dry biocatalyst amounts on bioconversion
and ee were investigated in the optimum reaction
conditions. The excellent ee (>99%) and bioconversion
(>99%) were carried out when 50 mg dry L paracasei
BD101 was used. When the mass of dry L paracasei
BD101 is less than or over 50 mg, the
Effect of temperature over ee and conversion
Temperature has an important effect on the activity,
selectivity and stability of the biocatalyst and the situ-
ation of dynamic balance of a bioreduction reaction as
well. Hence, the biocatalytic reaction of substrate 1
was carried out at varied temperatures (Table 1). The
bioreductions were accomplished with 1 mmol of 1
using pH 6.5, RT, 100 rpm and varied temperatures
(25–34 ꢀC) as reaction conditions.
A temperature
increase over 30 ꢀC lead to a decrease in the rate of
bioreduction and ee. Probably, there is a decrease in
the biocatalytic activity owing to the partial inactiva-
tion of the enzyme at temperatures above 30 ꢀC, exist-
ing in L paracasei BD101. The conversion and ee were
optimized at 30 ꢀC temperature and hence was recom-
mended for all further reactions.

BIOCATALYSIS AND BIOTRANSFORMATION
5
Biocatalytic effect of L paracasei BD101 was optimised
systematically for production of enantiopure (R)-2 in
gram scale. This study shows the first example of the
efficient production of (R)-2 by the biocatalyst. Also, L
paracasei BD101 was demonstrated to be a significant
biocatalyst in asymmetric bioreduction of ketones con-
taining a branched alkyl chain. Compared with the
past reports, which used chemical catalysis, 2-methyl-
1-phenylpropan-1-one was bioreduced to (R)-2 in
good conversion, yield, and enantiomeric pure form.
Gram scale production of enantiomerically pure chiral
carbinol using green chemistry is important for indus-
trial applications. There is not any study related to bio-
reduction of 1 to 2 using biocatalyst in the literature.
Therefore, it is important to filling this gap.
Asymmetric reduction of substrate 1 using a biocata-
lyst was performed in perfect ee and conversion in
the first time.
Figure 2. Gram-scale synthesis of (R)-2.
enantioselectivity of biocatalyst was decreased. This
can be explained as the change in the activity of the
enzyme with the vary in the amount of NADPH in the
reaction medium as previously reported (Sahin
et al. 2019).
Gram-scale production of (R)-2-methyl-1-
phenylpropan-1-ol (2)
To further increase the scope of the study, with the
optimal conditions in hand (pH 6.5, 30 ꢀC, 48 h and
200 rpm), we carried out the gram scale bioreduction
of 2-methyl-1-phenylpropan-1-one (1). Gram scale syn-
thesis of (R)-2-methyl-1-phenylpropan-1-ol (2) was car-
ried out in a 1.5-L scale in a 5-L Erlenmeyer flask
(Figure 2). Asymmetric reduction in the gram scale
using biocatalysts, the substrate concentration is very
important. In accordance with this information, various
reduction reactions have been made using different
substrate concentrations in the gram scale under opti-
mum reduction conditions. For instance, biocatalysed
reduction of 1 (43 mmol) after 56 h resulted in full bio-
conversion, however the enantiomeric excess of the
product was markedly decreased (71%). This means
that higher concentration of substrate likely causes
the loss of enzyme activity, owing to substrate toxicity
and inhibition as reported formerly (Salvi and
Chattopadhyay 2016). The best results were obtained
when 33.7 mmol (5.0 g) substrate was used.
Bioconversion and ee of 99% were obtained in the
condition of pH 6.5, 30 ꢀC, 200 rpm and 48 h. 2-
methyl-1-phenylpropan-1-one (1) was easily reduced
to the (R)-2 in outstanding yield and ee. This result
indicates that L paracasei BD101 was a strong biocata-
lyst that can be suitable in the synthesis of sterically
bulky carbinols. The configuration of the final product
formed according to the anti-Prelog rule, the pro-S
hydride of NADPH is given to the Si face of the prochi-
ral ketone to produce on R alcohol (Prelog 1964).
Acknowledgements
The author thanks Dr. Enes Dertli (Bayburt University) for
supplying L paracasei BD101 strain used in this study.
Disclosure statement
No potential conflict of interest was reported by the author.
References
Alsafadi D, Alsalman S, Paradisi F. 2017. Extreme halophilic
alcohol dehydrogenase mediated highly efficient synthe-
ses of enantiopure aromatic alcohols. Org Biomol Chem.
15(43):9169–9175.
ꢀ
Blay G, Hernandez-Olmos V, Pedro JR. 2010. Synthesis of (S)-
(þ)-sotalol and (R)-(ꢁ)-isoproterenol via a catalytic enan-
tioselective Henry reaction. Tetrahedron. 21(5):578–581.
Brooks WH, Guida WC, Daniel KG. 2011. The significance of
chirality in drug design and development. Curr Top Med
Chem. 11(7):760–770.
Clouthier CM, Pelletier JN. 2012. Expanding the organic tool-
box: a guide to integrating biocatalysis in synthesis. Chem
Soc Rev. 41(4):1585–1605.
Comasseto JV, Andrade LH, Omori AT, Assis LF, Porto A.
2004. Deracemization of aryl ethanols and reduction of
acetophenones by whole fungal cells of Aspergillus terreus
CCT 4083, A. terreus CCT 3320 and Rhizopus oryzae CCT
4964. J Mol Catal B Enzym. 29(1-6):55–61.
Corey EJ, Helal CJ. 1998. Reduction of carbonyl compounds
with chiral oxazaborolidine catalysts: a new paradigm for
enantioselective catalysis and a powerful new synthetic
method. Angew Chem Int Ed. 37(15):1986–2012.
de Carvalho C. 2017. Whole cell biocatalysts: essential work-
ers from nature to the industry. Microb Biotechnol. 10(2):
250–263.
Conclusion
In summary, asymmetric bioreduction of 2-methyl-1-
phenylpropan-1-one (1) was performed with L paraca-
sei BD101 bacterial strain as whole-cell biocatalyst.
ꢁ
Dertli E, Mercan E, Arıcı M, Yılmaz MT, Sagdıc¸ O. 2016.
Characterisation of lactic acid bacteria from Turkish

6
E. ŞAHIN
sourdough and determination of their exopolysaccharide
(EPS) production characteristics. LWT-Food Sci Technol.
71:116–124.
Sahin E, Serencam H, Dertli E. 2019. Whole cell application
of Lactobacillus paracasei BD101 to produce enantio-
merically pure (S)-cyclohexyl (phenyl) methanol. Chirality.
31:211–218.
Sahin E. 2018. Production of (R)-1-(1,3-benzodioxol-5-yl)etha-
nol in high enantiomeric purity by Lactobacillus paracasei
BD101. Chirality. 30:189–194.
Griffin DR, Yang F, Carta G, Gainer JL. 1998. Asymmetric
reduction of acetophenone with calcium-alginate-
entrapped baker’s yeast in organic solvents. Biotechnol
Prog. 14(4):588–593.
Hall M, Stueckler C, Ehammer H, Pointner E, Oberdorfer G,
Gruber K, Hauer B, Stuermer R, Kroutil W, Macheroux P,
Faber K. 2008. Asymmetric bioreduction of C ¼ C bonds
using enoate reductases OPR1, OPR3 and YqjM: enzyme-
based stereocontrol. Adv Synth Catal. 350(3):411–418.
LaPlante SR, Fader LD, Fandrick KR, Fandrick DR, Hucke O,
Kemper R, Edwards PJ. 2011. Assessing atropisomer axial
chirality in drug discovery and development. J Med Chem.
54:7005–7022.
Salvi NA, Chattopadhyay S. 2016. Laboratory scale-up synthe-
sis of chiral carbinols using Rhizopus arrhizus. Tetrahedron.
27(4-5):188–192.
Sato I, Saito T, Soai K. 2000. Solvent-free catalytic enantiose-
lective addition of diethylzinc to aldehydes. Chem
Commun. 24:2471–2472.
Sato I, Shibata T, Ohtake K, Kodaka R, Hirokawa Y, Shirai N,
Soai K. 2000. Synthesis of chiral dendrimers with a hydro-
carbon backbone and application to the catalytic enantio-
selective addition of dialkylzincs to aldehydes.
Tetrahedron Lett. 41(17):3123–3126.
Sukhorukov AY, Sukhanova AA, Zlotin SG. 2016.
Stereoselective reactions of nitro compounds in the syn-
thesis of natural compound analogs and active pharma-
ceutical ingredients. Tetrahedron. 72(41):6191–6281.
Lawrence
NJ,
Drew
MD,
Bushell
SM.
1999.
Polymethylhydrosiloxane: a versatile reducing agent for
organic syntheses. J Chem Soc Perkin Trans 1. 1(1):
3381–3391.
Lee WH, Kim MD, Jin YS, Seo JH. 2013. Engineering of
NADPH regenerators in Escherichia coli for enhanced bio-
transformation. Appl Microbiol Biotechnol. 97(7):
2761–2772.
Ling F, Nian S, Chen J, Luo W, Wang Z, Lv Y, Zhong W. 2018.
Development of ferrocene-based diamine-phosphine-sul-
fonamide ligands for iridium-catalyzed asymmetric hydro-
genation of ketones. J Org Chem. 83(18):10749–10761.
Mimoun H, de Saint Laumer JY, Giannini L, Scopelliti R,
Floriani C. 1999. Enantioselective reduction of ketones by
polymethylhydrosiloxane in the presence of chiral zinc
catalysts. J Am Chem Soc. 121(26):6158–6166.
More GV, Badgujar KC, Bhanage BM. 2015. Kinetic resolution
of secondary alcohols with Burkholderia cepacia lipase
immobilized on a biodegradable ternary blend polymer
matrix as a highly efficient and heterogeneous recyclable
biocatalyst. RSC Adv. 5(6):4592–4598.
Noyori R, Hashiguchi S. 1997. Asymmetric transfer hydrogen-
ation catalyzed by chiral ruthenium complexes. Acc Chem
Res. 30(2):97–102.
€
Verho R, Londesborough J, Penttila M, Richard P. 2003.
Engineering redox cofactor regeneration for improved
pentose fermentation in Saccharomyces cerevisiae. Appl
Environ Microbiol. 69(10):5892–5897.
ꢀ
Winkler CK, Tasnadi G, Clay D, Hall M, Faber K. 2012.
Asymmetric bioreduction of activated alkenes to industri-
ally relevant optically active compounds. J. Biotechnol.
162(4):381–389.
Xiao M, Li G, Gang X, Jian PW, Li RY. 2014. A new mechan-
ism of enantioselectivity toward chiral primary alcohol by
lipase from Pseudomonas cepacia. J Mol Catal B Enzym.
109:109–115.
Yang GF, Huang X. 2006. Development of quantitative struc-
ture-activity relationships and its application in rational
drug design. Curr Pharm Des. 12(35):4601–4611.
Yılmaz D, S¸ahin E, Dertli E. 2017. Highly enantioselective pro-
duction of chiral secondary alcohols using Lactobacillus
paracasei BD 101 as a new whole cell biocatalyst and
evaluation of their antimicrobial effects. Chem
Biodiversity. 14(11):e1700269.
Yu J, Long J, Yang Y, Wu W, Xue P, Chung LW, Dong X-Q,
Zhang X. 2017. Iridium-catalyzed asymmetric hydrogen-
ation of ketones with accessible and modular ferrocene-
based amino-phosphine acid (f-ampha) ligands. Org Lett.
19(3):690–693.
Yu S, Li H, Lu Y, Zheng G. 2018. A catalyst from Burkholderia
cenocepacia for efficient anti-Prelog’s bioreduction of 3,
5-bis (trifluoromethyl) acetophenone. Appl Biochem
Biotechnol. 184(4):1319–1331.
Panunzio M, Rossi K, Tamanini E, Campana E, Martelli G.
2004. Synthesis of enantiomerically pure (S)-and (R)-fluox-
R
V
etine (Prozac ) via
a
hetero Diels–Alder strategy.
Tetrahedron. 15(22):3489–3493.
Pereira RS. 1998. The use of baker’s yeast in the generation
of asymmetric centers to produce chiral drugs and other
compounds. Crit Rev Biotechnol. 18(1):25–64.
Pollard DJ, Woodley JM. 2007. Biocatalysis for pharmaceut-
ical intermediates: the future is now. Trends Biotechnol.
25(2):66–73.
Prelog V. 1964. Specification of the stereospecificity of some
oxido-reductases by diamond lattice sections. Pure Appl
Chem. 9(1):119–130.
Ranjan P, Pandey A, Binod P. 2017. Resolution of enantio-
pure (S)-1-(1-napthyl) ethanol from racemic mixture by a
novel Bacillus cereus isolate. J Basic Microbiol. 57(9):
762–769.
Zilbeyaz K, Kurbanoglu EB, Kılıc¸ H. 2016. Preperation of
enantiomerically pure (S)-(-)-1-(1-naphthyl)-ethanol by the
fungus Alternaria alternate. Chirality. 28(10):669–673.
Zhimin O, Ma L, Niu Y, Cui J. 2018. Preparation of (R)-
(-)-mandelic acid by two-step biotransformation of ethyl
benzoylformate. Biocatal Biotransformation. 36(6):409–416.