Production of enantiopure chiral aryl heteroaryl carbinols using whole‐cell Lactobacillus paracasei biotransformation

Article abstract of DOI:10.1080/00397911.2019.1707226

Aryl and heteroaryl chiral carbinols are useful precursors in the synthesis of drugs. Lactobacillus paracasei BD87E6, which is obtained from a cereal based fermented beverage, was investigated as whole cell biocatalyst for the bioreduction of different ketones (including aromatic, hetero-aromatic and fused bicyclic ketone) into chiral carbinols, which can be used as a pharmaceutical intermediate. The study shows that bioreduction of aryl, heteroaryl and fused bicyclic ketone (1–5) to their corresponding chiral carbinols (1a–5a) in excellent enantioselectivity (>99%) with high yields. This study gave the first example for an enantiopure production of (S)-6-chlorochroman-4-ol (3a), which has many antioxidant activity, by a biological method. For asymmetric bioreduction of other prochiral ketones, these results open way to use of L. paracasei BD87E6 as biocatalysts. Also, the present process shows a hopeful and alternative green synthesis for the production of enantiopure carbinols in a mild, inexpensive and environmentally friendly process.

Full text of DOI:10.1080/00397911.2019.1707226

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Production of enantiopure chiral aryl heteroaryl
carbinols using whole‐cell Lactobacillus paracasei
biotransformation
Engin Şahin
To cite this article: Engin Şahin (2020) Production of enantiopure chiral aryl heteroaryl carbinols
using whole‐cell Lactobacillusꢀparacasei biotransformation, Synthetic Communications, 50:4,
549-557, DOI: 10.1080/00397911.2019.1707226
To link to this article: https://doi.org/10.1080/00397911.2019.1707226
View supplementary material
Published online: 27 Dec 2019.
Submit your article to this journal
Article views: 18
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
2020, VOL. 50, NO. 4, 549–557
https://doi.org/10.1080/00397911.2019.1707226
Production of enantiopure chiral aryl heteroaryl carbinols
using whole-cell Lactobacillus paracasei biotransformation
Engin S¸ahin
Department of Food Engineering, Faculty of Engineering, Bayburt University, Bayburt, Turkey
ABSTRACT
ARTICLE HISTORY
Received 19 November 2019
Aryl and heteroaryl chiral carbinols are useful precursors in the syn-
thesis of drugs. Lactobacillus paracasei BD87E6, which is obtained
from a cereal based fermented beverage, was investigated as whole
cell biocatalyst for the bioreduction of different ketones (including
aromatic, hetero-aromatic and fused bicyclic ketone) into chiral carbi-
nols, which can be used as a pharmaceutical intermediate. The study
shows that bioreduction of aryl, heteroaryl and fused bicyclic ketone
(1–5) to their corresponding chiral carbinols (1a–5a) in excellent
enantioselectivity (>99%) with high yields. This study gave the first
example for an enantiopure production of (S)-6-chlorochroman-4-ol
(3a), which has many antioxidant activity, by a biological method.
For asymmetric bioreduction of other prochiral ketones, these results
open way to use of L. paracasei BD87E6 as biocatalysts. Also, the
present process shows a hopeful and alternative green synthesis for
the production of enantiopure carbinols in a mild, inexpensive and
environmentally friendly process.
KEYWORDS
Biotransformation; chiral
heteroaryl carbinol;
enantioselective bioreduc-
tion; (S)-6-chlorochroman-4-
ol; whole-cell biocatalyst
GRAPHICAL ABSTRACT
Introduction
Life and chirality are closely linked to each other in the fulfillment of the metabolic
activity of living organisms, so chirality is very important for living organisms.
Biological molecules, like amino acids in the living, exist in enantiopure form, which
shows the significance of chirality in life. The effects of biological compounds with
chiral molecules result in dissimilar biological impacts and occasionally opposite effects
for the enantiomers. Therefore, it is necessary to use chiral centered drugs as a single
enantiomer if possible.[1–3] Because chirality plays such a vital role in drug synthesis,
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 on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

550
E. ŞAHIN
Figure 1. Drugs examples derived from chiral secondary alcohols.
chemists are highly involved in the production of enantiomers with high enantiomeric
excess. Asymmetric reduction of prochiral ketones to their corresponding chiral
secondary alcohols is one of the most important reactions in organic synthesis. Catalytic
enantioselective reduction especially bioreduction is a significant search area in synthetic
organic chemistry, and biocatalytic technic opens new possibility in the chemistry for
the production of molecules and associates cheap starting substances with environment-
friendly methods.[4–6] Secondary alcohols, which exist enantiomerically pure, are signifi-
cant intermediates for the production of enantiomerically pure molecules such as drugs,
pesticides, flavors, natural products, oligosaccharides[7–10] and synthetic organic chemis-
try.[11–14] For instance, ezetibime 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).[15–18] 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 chiral secondary alcohol functional group in their
structure. Chiral secondary alcohols are useful precursors for the production of compli-
cated molecules since the alcohol functional group can easily be converted with other
functional groups, without racemization.[19] This great importance of chiral secondary
alcohols has led to the need for the development of novel methods to synthesize these
compounds more selectively, efficiently and in high amounts. These highly important
chiral secondary alcohols have been reported in the literature as both biocatalytic and
chemical methods.[20–23] Compared to these two methods, biocatalytic protocols of
chiral secondary alcohols synthesis afford some benefits, like milder reduction condi-
tions (pressure and temperature), no demand to use toxic metal catalysts and expensive
chiral ligands.[24,25] The synthesis of these very important alcohols using biocatalysts has
recently become widespread owing to their mild and environmentally friendly reaction
conditions, high selectivity and high yields. Biocatalyzed methods are generally used on
an industrial scale via the asymmetric bioreduction of cheap prochiral ketones and the
resolution of racemates. In the resolution of racemate, there is always 50% of the
undesired product unlike asymmetric bioreduction which preferably obtained in the for-
mation of solely one enantiomer in high enantiomeric excess and yields.[26] Also, chiral

R
SYNTHETIC COMMUNICATIONSV
551
secondary alcohols can be synthesized by isolated enzyme, but expensive reducing
co-enzymes, such as NADPH, and purification of enzymes are needed for this reac-
tion.[27] These disadvantages limit its use in industrial-scale production.[28–31] When
compared to isolated enzymes, whole-cell biocatalysts are favorable as they are usually
inexpensive and more constant. Furthermore, the use of microbial whole-cells with
metabolic activity as catalysts provides several benefits over pure enzymes, including the
cofactor recycling in situ and better protecting target enzymes against inactivation,
thereby significantly cutting down the process cost.[32,33] Also, it is considered safe, eco-
nomical and environmentally friendly reaction conditions for the synthesis of chiral sec-
ondary alcohols.[34,35] Heterocyclic aromatic compounds are significant buildings blocks
in natural and synthetic products of biological active compound. Chiral heteroaryl alco-
hols are very important precursors in the synthesis of a large number of complex mole-
cules, which have biological activity, and also for the synthesis of chiral ligands, which
are frequently used in asymmetric synthesis. At the same time, the functional group of
alcohol can easily be converted into the desired functional group without any racemiza-
tion.[36,37] In our previous study, we have optimized the asymmetric reduction condi-
tions using the model substrate acetophenone with L. paracasei BD87E6 biocatalyst to
perform asymmetric reductions of acetophenone, and then successfully reduced the ace-
tophenone derivatives with high enantioselectivity.[38]
Herein, we report the asymmetric reduction of prochiral aromatic and heteroaromatic
ketones in gram scale using optimized conditions of L. paracasei BD87E6 as a whole
cell biocatalyst without using any organic solvents and cofactors, and we first reported
the synthesis of fused bicyclic carbinol in the enantiopure form at gram scale using a
biocatalytic method.
Result and discussion
The asymmetric bioreduction of carbonyl moiety to the (R) or (S)-enantiomer of the
secondary alcohols is one of the indispensable research fields of synthetic organic chem-
istry. The fact that the alcohol functional group can be easily transformed into different
functional groups without any racemization further enhances the importance of these
alcohols.[19] Optimizing the reaction conditions such as pH, temperature, incubation
time and agitation speed is very important in obtaining the chiral secondary alcohols.[39]
We have successfully optimized these asymmetric reduction conditions using model
substrate acetophenone with L. paracasei BD87E6 biocatalyst. In this optimization study
using model substrate acetophenone, the optimized conditions of bioreduction were
determined as pH 5.5, 30 ꢀC, 48 h and 150 rpm.[38] With these optimized conditions,
asymmetric reductions of different aromatic and heteroaromatic prochiral ketones
(Figure 2), which can be important for synthetic organic chemistry and the pharmaceut-
ical industry, were carried out on gram scale (Table 1). The (R) and (S) enantiomers of
1-phenylethanol are very important intermediates for the production of various medi-
cines and natural substances.[40–42] (S)-1-phenylethanol 1a was obtained using 1 mmol
of 1 in 30 ꢀC, 48 h and 150 rpm with 94% enantiomeric excess (ee) and 89% yield. The
content of this process was expanded with different prochiral ketones, 2–5 (Figure 2)
for the production of chiral aromatic and heteroaromatic carbinols 2a–5a (Table 1).

552
E. ŞAHIN
Figure 2. Prochiral Ketones 1–5.
Table 1. Asymmetric bioreduction of prochiral ketones using Lactobacillus paracasei BD87E6.
Substrat
Product[a]
ee [%]b
Yield [%]c
1
2
3
4
5
(S)-1-Phenylethanol (1a)
(R)-1-(4-methoxyphenyl)propan-1-ol (2a)
(S)-6-chlorochroman-4-ol (3a)
(S)-phenyl(pyridin-2-yl)methanol (4a)
(R)-1-(naphthalen-2-yl)ethanol (5a)
94
99
99
99
99
89
92
87
91
88
aConfigurations were assigned on the basis of the comparison of the rotation sign with literature data.
c
bDetermined by chiral HPLC. Isolated yield.
These chiral carbinols have the capacity to be used as precursor compounds for the pro-
duction of various important molecules such as drugs, and as can be seen in Table 1,
the chiral secondary alcohols 1a-5a are readily obtained with excellent ee and yield. (S)-
1-(4-methoxyphenyl) propan-1-ol was obtained using whole cell biocatalyst with 95%
conversion and 99% ee in small and large scale.[43,44] In addition, (R)-1-(4-methoxy-
phenyl) propan-1-ol was reported to be obtained in small scale with 99% ee using
expensive enzyme and cofactor.[45] However, the bioreduction of 1-(4-methoxyphenyl)-
propan-1-one (2) using L. paracasei BD87E6 as a whole cell biocatalyst was carried out
in the gram scale with 99% ee and 92% yield using pH 5.5, 30 ꢀC, 150 rpm and 48 h
optimization conditions. Chroman is the building blocks of many natural products such
as flavonoids, tocopherols and neoflavanoids, which have antioxidant activity.[46] 4-
Hydroxy chroman is found in the structure of many natural products with antioxidant
effect. Enantioselective synthesis of chroman-4-amines is very important because these
compounds are indispensable substances in drug discovery programs.[47] The chroman-
4-ol can be obtained by asymmetric reduction of the corresponding ketone, and the
resulting alcohol can be easily converted to chroman-4-amines without racemiza-
tion.[48,49] In the literature, the synthesis of (S)-6-chlorochroman-4-ol was achieved by
50% yield and 80.4% ee in the presence of lipase enzyme and biocatalytic asymmetric
reductions of fused cyclic ketones have been reported to be challenging.[40,50]
Gram scale bioreduction of 3 using L. paracasei BD87E6 was performed and the (S)-6-
chlorochroman-4-ol (3a) was obtained as an enantiopure form in 87% yield in the pH
5.5, 30 ꢀC, 150 rpm and 48 h. This ee and yield is a satisfactory result compared to the
literature. Heterocyclic chiral secondary alcohols are a great attention in pharmaceutical
and agrochemical industries. Important examples of heteroaryl methanols are (R)-
neobenodine, (R)-orphenadrine, (S)-cetrazine, (S)-carbinoxamine, (S)-duloxetine,

R
SYNTHETIC COMMUNICATIONSV
553
(1 R,2S)-mefloquine, HIV reverse-transcriptase inhibitor furo[2,3-c]pyridine thiopyrimi-
dine ether, b-blocker 2-(2-tert-butylamino-1-hydroxyethyl)benzofuran.[51–55] The syn-
thesis of (S)-phenyl(pyridin-2-yl) methanol, which is chiral heterocyclic aromatic
secondary alcohol, is very important due to its analgesic and anti convulsant activ-
ities.[56] Rhizopus arrhizus mediated reduction of phenyl(pyridin-2-yl)methanone gave
(S)-phenyl(pyridin-2-yl)methanol with moderate enantiomeric purity (78.3%) and in
moderate yield (71.3%).[47] The L. paracasei BD87E6 mediated gram scale bioreduction
of substrate 4 was reduced to the (S)-phenyl(pyridin-2-yl)methanol (4a) in 91% yield
and with >99% enantiomeric purity in the optimization conditions. In the literature,
the synthesis of (R) or (S)-1-(naphthalen-2-yl) ethanol using biocatalyst was carried out
by using the method of resolution of racemates and obtained up to 99% ee.[57] In reso-
lution of racemate, there is generally 50% of the unwanted product and low yield. In
this study, substrate 5 was reduced to (R)-1-(naphthalen-2-yl)ethanol (5a) with >99%
ee and 88% yield in the pH 5.5, 30 ꢀC, 150 rpm and 48 h using L. paracasei BD87E6
whole cell biocatalyst. The products were obtained according to anti-Prelog rule as a
result of bioreduction of substrates 2 and 5, while the other products were obtained
according to Prelog rule. The different configurations of the products obtained can be
explained by different interactions of substrates with the active site of the enzyme.
Conclusion
Whole-cell biocatalysts draw attention in many different industries, particularly in the
pharmaceutical industry, because these biocatalysts and useful chiral carbinol com-
pounds are successfully produced. Herein, we have shown that L. paracasei BD87E6
effectively catalyze the enantioselective reduction of arly, heteroarly and fused bicyclic
prochiral ketones with excellent enantiomeric purity and yield to give chiral carbinols.
The results approved the conformity of L. paracasei BD87E6 as a precious whole cell
biocatalyst for the production of chiral carbinols of drug industry. Gram scale produc-
tion of enantiomerically pure chiral carbinol using green chemistry is important for
industrial applications. This study shows the first example of the efficient production of
(S)-6-chlorochroman-4-ol (3a) by the biocatalyst. Therefore, it is important to work
toward filling this gap. Also, L. paracasei BD87B6 was demonstrated to be a significant
biocatalyst in asymmetric bioreduction of ketones contain fused bicyclic ketones. This
efficient and eco-friendly process was found to be a versatile and encouraging applica-
tion for the gram scale green productions of chiral secondary alcohols. A selective and
high-efficient biocatalytic approach for the asymmetric reduction of aryl, heteroarly and
fused bicyclic ketones using L. paracasei BD87E6 has been developed.
Experimental
General
All chemicals were analytically graded and obtained from Fluka. MRS medium (Merck)
was used for the growth of strain BD87E6. Reactions were monitored by TLC analysis
conducted with TLC plates and hexane: ethyl acetate (90:10, v/v) was used as the eluent.
The obtained product was purified using column chromatography on silica gel by

554
E. ŞAHIN
hexane: EtOAc: (90:10, v/v) as a mobile phase. HPLC analysis for substrate and product
was carried out on an Agilent 1260 system combined with chiral detector (Ibz
Messtechnik Gmbh) and UV detector. Substrate 1–5 was reduced with NaBH4 in
methanol to obtain the racemic 1a–5a. A spectropolarimeter (Bellingham þ Stanley) was
1
used to measure the optical rotation at 589 nm. The H and 13C NMR spectra were
obtained with a Bruker 400 MHz spectrometer in CDCl3. The conversion rate of the
product was calculated by comparison of the ketone peak with the alcohol peak after
HPLC analysis of the crude product.
Culture medium and bacterial strain
This study used L. paracasei BD87E6 strain was obtained previously from boza, a fer-
mented beverage.[58] Lactobacillus paracasei BD87E6 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 solu-
tion [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% concentra-
tion 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.
General procedure for microbial bioreduction
50 mg of dry L. paracasei BD87E6 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
150 rpm for 2 h. Then, the pH of the medium was adjusted to 5.5 with 1 M HCl and
after 2 h, 1 mmol of substrate was added into the suspension and incubated for 48 h at
30 ꢀC under agitation speed at 150 rpm. On completion of the reaction, the cell was
removed by centrifugation and the liquid phase was saturated by sodium chloride, the
aqueous phases were extracted with CH2Cl2. The organic phase was washed with satu-
rated 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 substrates was determined by HPLC analysis comparing the alcohol peaks
with the ketone peak after filtering the crude products with a column containing a little
silica gel. Configurations of products were assigned on the comparison of the rotation
sign with literature data (supporting information).
Gram scale production of 1a–5a
The 0.5 g dry strain BD87E6 was inoculated to 1500 mL sterilized fresh MRS broth as
working volume in 5.0 L and incubated on an orbital shaker at 30 ꢀC, 150 rpm for 2 h.
The pH of the reaction was adjusted with 1 M HCl to 5.5 followed by the addition of
substrates 1–5 (1.0 g) to the mixture and incubated on a shaker at 30 ꢀC, 150 rpm for
48 h. The products were obtained and characterized as described above.

R
SYNTHETIC COMMUNICATIONSV
555
1H-NMR and 13C-NMR, chiral and racemic HPLC spectrums of 1a–5a could be
found at Supplementary data.
Acknowledgments
_
The author thanks Dr. Enes DERTLI (Bayburt University) for supplying L. paracasei BD87E6
strain used in this study.
Availability of data
The data that support the findings of this study are openly available in https://doi.org/10.1002/
cbdv.201800028, reference number [38].
References
[1] Patel, R. N. Biomolecules 2013, 3, 741–777. DOI: 10.3390/biom3040741.
€
[2] Wollschlager, J. M.; Simon, K.; Gaedke, M.; Schalley, C. A. Chem. Commun. 2018, 54,
4967–4970. DOI: 10.1039/C8CC01671B.
[3] Liu, X.; Wang, P.; Fu, J.; Yao, K.; Chang, Y.; Xu, K. Chirality 2018, 30, 777–784. DOI: 10.
1002/chir.22848.
[4] Gao, K.; Song, Q.; Wei, D. Appl. Microbiol. Biotechnol. 2006, 71, 819–823. DOI: 10.1007/
s00253-005-0231-3.
[5] Illanes, A.; Cauerhff, A.; Wilson, L.; Castro, G. R. Bioresour. Technol. 2012, 115, 48–57.
DOI: 10.1016/j.biortech.2011.12.050.
[6] Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.;
Wood, A. Nature Chem. 2018, 10, 383–394. DOI: 10.1038/s41557-018-0021-z.
[7] Dey, S.; Wong, C. H. Chem. Sci. 2018, 9, 6685–6691. DOI: 10.1039/C8SC01743C.
[8] Lo, H.-J.; Krasnova, L.; Dey, S.; Cheng, T.; Liu, H.; Tsai, T.-I.; Wu, K. B.; Wu, C.-Y.;
Wong, C.-H. J. Am. Chem. Soc. 2019, 141, 6484–6488. DOI: 10.1021/jacs.9b01991.
[9] Dey, S.; Lo, H. J.; Wong, C. H. J. Am. Chem. Soc. 2019, 141, 10309–10314. DOI: 10.1021/
jacs.9b03266.
[10] Cheng, C. W.; Zhou, Y.; Pan, W. H.; Dey, S.; Wu, C. Y.; Hsu, W. L.; Wong, C. H. Nat.
Commun. 2018, 9, 5202. DOI: 10.1038/s41467-018-07618-8.
[11] Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393–406. DOI: 10.1039/
B513564H.
[12] Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300–1308. DOI: 10.1021/ar700134q.
[13] Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226–236. DOI: 10.1039/B513396C.
€
[14] Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Sturmer, R.; Zelinski, T.
Angew. Chem. Int. Ed. 2004, 43, 788–824. DOI: 10.1002/anie.200300599.
[15] More, G. V.; Badgujar, K. C.; Bhanage, B. M. RSC Adv. 2015, 5, 4592–4598. DOI: 10.
1039/C4RA14478C.
[16] Panunzio, M.; Rossi, K.; Tamanini, E.; Campana, E.; Martelli, G. Tetrahedron: Asymmetry
2004, 15, 3489–3493. DOI: 10.1016/j.tetasy.2004.09.009.
ꢀ
[17] Blay, G.; Hernandez-Olmos, V.; Pedro, J. R. Tetrahedron: Asymmetry 2010, 21, 578–581.
DOI: 10.1016/j.tetasy.2010.02.027.
[18] Sukhorukov, A. Y.; Sukhanova, A. A.; Zlotin, S. G. Tetrahedron 2016, 41, 6191. DOI: 10.
1016/j.tet.2016.07.067.
[19] Pollard, D. J.; Woodley, J. M. Trends Biotechnol. 2007, 25, 66–73. DOI: 10.1016/j.tibtech.
2006.12.005.
[20] Perrone, M. G.; Santandrea, E.; Bleve, L.; Vitale, P.; Colabufo, N. A.; Jockers, R.; Milazzo,
F. M.; Sciarroni, A. F.; Scilimati, A. Bioorg. Med. Chem. 2008, 16, 2473–2488. DOI: 10.
1016/j.bmc.2007.11.060.

556
E. ŞAHIN
[21] Viatcheslav, S.; Melvin, D. J.; Wildeliz, C.; Lorianne, B.; Cindybeth, V.; Irisbel, G.;
Margarita, O. M. Tetrahedron: Asymmetry 2009, 20, 2659. DOI: 10.1016/j.tetasy.2009.11.
009.
[22] Houng, J. Y.; Liau, J. S. Enzyme Microb. Technol. 2006, 38, 879–886. DOI: 10.1016/j.enz-
mictec.2005.02.028.
[23] Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. Engl. 1998, 37, 1986–2012. DOI: 10.1002/
(SICI)1521-3773(19980817)37:15<1986::AID-ANIE1986>3.0.CO;2-Z.
[24] Thomas, S. M.; Dicosimo, R.; Nagarajan, V. Trends Biotechnol. 2002, 20, 238–242. DOI:
10.1016/S0167-7799(02)01935-2.
[25] Sheldon, R. A.; Woodley, J. M. Chem. Rev. 2018, 118, 801–838. DOI: 10.1021/acs.chemrev.
7b00203.
[26] Ranjan, P.; Pandey, A.; Binod, P. J. Basic Microbiol. 2017, 57, 762–769. DOI: 10.1002/
jobm.201700207.
[27] Dey, S.; Bajaj, S. O.; Tsai, T. I.; Lo, H. J.; Wu, K.; Wong, C. H. Tetrahedron 2018, 74,
6003–6011. DOI: 10.1016/j.tet.2018.08.039.
[28] Sahin, E.; Dertli, E. Chem. Biodiversity 2017, 14, e1700121. DOI: 10.1002/cbdv.201700121.
[29] Yılmaz, D.; S¸ahin, E.; Dertli, E. Chem. Biodiversity 2017, 14, e1700269. DOI: 10.1002/cbdv.
201700269.
[30] Hepworth, L. J.; France, S. P.; Hussain, S.; Both, P.; Turner, N. J.; Flitsch, S. L. ACS Catal.
2017, 7, 2920–2925. DOI: 10.1021/acscatal.7b00513.
[31] Vitale, P.; Perna, F. M.; Agrimi, G.; Pisano, I.; Mirizzi, F.; Capobianco, R. V.; Capriati, V.
Catalysts 2018, 8, 55. DOI: 10.3390/catal8020055.
[32] Mandal, D.; Ahmad, A.; Khan, M. I.; Kumar, R. J. Mol. Catal. B Enzym. 2004, 27, 61–63.
DOI: 10.1016/j.molcatb.2003.09.009.
[33] Faber, K. Biotransformations in Organic Chemistry; Springer-Verlag: Berlin, 2000; pp 192.
[34] Silva, V. D.; Stambuk, B. U.; Nascimento, M. D. G. J. Mol. Catal. B Enzym. 2012, 77,
98–104. DOI: 10.1016/j.molcatb.2012.01.012.
[35] Yasohara, Y.; Kizaki, N.; Hasegawa, J.; Takahashi, S.; Wada, M.; Kataoka, M.; Shimizu, S.
Appl. Microbiol. Biotechnol. 1999, 51, 847–851. DOI: 10.1007/s002530051472.
[36] Comasseto, J. V.; Andrade, L. H.; Omori, A. T.; Assis, L. F.; Porto, A. L. M. J. Mol. Catal.
B Enzym. 2004, 29, 55–61. DOI: 10.1016/j.molcatb.2004.01.015.
[37] Griffin, D. R.; Yang, F.; Carta, G.; Gainer, J. L. Biotechnol. Prog. 1998, 14, 588–593. DOI:
10.1021/bp9800586.
[38] Oksuz, S.; Sahin, E.; Dertli, E. Chem. Biodiversity 2018, 15, e1800028. DOI: 10.1002/cbdv.
201800028.
[39] Pereira, R. S. Crit. Rev. Biotechnol. 1998, 18, 25–64. DOI: 10.1080/0738-859891224211.
[40] Bui, V.; Hansen, T. V.; Stenstrom, Y.; Ribbons, D. W.; Hudlicky, T. J. Chem. Soc, Perkin
Trans. 1 2000, 11, 1669. DOI: 10.1039/b002143l.
[41] Persson, B. A.; Larsson, A. L. E.; Le Ray, M.; Backvall, J. E. J. Am. Chem. Soc. 1999, 121,
1645–1650. DOI: 10.1021/ja983819þ.
[42] Inoue, K.; Makino, Y.; Itoh, N. Tetrahedron: Asymmetry 2005, 16, 2539–2549. DOI: 10.
1016/j.tetasy.2005.06.036.
[43] Raminelli, C.; Kagohara, E.; Pellizari, V. H.; Comasseto, J. V.; Andrade, L. H.; Porto, A. L.
Enzyme Microb. Technol. 2007, 40, 362–369. DOI: 10.1016/j.enzmictec.2006.06.002.
[44] Tozlu, C.; S¸ahin, E.; Serencam, H.; Dertli, E. Biocatal. Biotransformation 2019, 37,
388–398. DOI: 10.1080/10242422.2019.1568416.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
[45] Rıos-Lombardıa, N.; Vidal, C.; Liardo, E.; Morıs, F.; Garcıa-Alvarez, J.; Gonzalez-Sabın, J.
Angew. Chem. 2016, 128, 8833. DOI: 10.1002/anie.201601840.
[46] Pietta, P. G. J. Nat. Prod. 2000, 63, 1035–1042. DOI: 10.1021/np9904509.
[47] Salvi, N. A.; Chattopadhyay, S. Tetrahedron: Asymmetry 2016, 27, 188–192. DOI: 10.1016/
j.tetasy.2016.01.008.
[48] Nijveldt, R. J.; van Nood, E.; van Hoorn, D. E. C.; Boelens, P. G.; van Norren, K.; van
Leeuwen, P. A. M. Am. J. Clin. Nutr. 2001, 74, 418–425. DOI: 10.1093/ajcn/74.4.418.

R
SYNTHETIC COMMUNICATIONSV
557
[49] Lloyd, J.; Atwal, K. S.; Finlay, H. J.; Nyman, M.; Huynh, T.; Bhandaru, R.; Kover, A.;
Schmidt, J.; Vaccaro, W.; Conder, M. L.; et al. Bioorg. Med. Chem. Lett. 2007, 17,
3271–3275. DOI: 10.1016/j.bmcl.2007.04.020.
[50] Alsafadi, D.; Alsalman, S.; Paradisi, F. Org. Biomol. Chem. 2017, 15, 9169–9175. DOI: 10.
1039/C7OB02299A.
[51] Salvi, L.; Kim, J. G.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 12483–12493. DOI: 10.
1021/ja9046747.
[52] Kamal, A.; Malik, M. S.; Shaik, A. A.; Azeeza, S. J. Mol. Catal. B Enzym. 2009, 58,
132–137. DOI: 10.1016/j.molcatb.2008.12.003.
[53] Knight, J. D.; Sauer, S. J.; Coltart, D. M. Org. Lett. 2011, 13, 3118–3121. DOI: 10.1021/
ol2010193.
[54] Wishka, D. G.; Graber, D. R.; Seest, E. P.; Dolak, L. A.; Han, F.; Watt, W.; Morris, J. J.
Org. Chem. 1998, 63, 7851–7859. DOI: 10.1021/jo9810359.
[55] Machin, P. J.; Hurst, D. N.; Osbond, J. M. J. Med. Chem. 1985, 28, 1648–1651. DOI: 10.
1021/jm00149a018.
[56] Frank, E.; Gearien, J.; Megahy, M.; Pokorny, C. J. Med. Chem. 1971, 14, 551. DOI: 10.
1021/jm00288a025.
[57] Li, Y. L.; Xu, J. H.; Xu, Y. J. Mol Catal. B Enzym. 2010, 64, 48–52. DOI: 10.1016/j.mol-
catb.2010.01.031.
ꢁ
[58] Dertli, E.; Mercan, E.; Arıcı, M.; Yılmaz, M. T.; Sagdıc¸, O. LWT-Food Sci. Technol. 2016,
71, 116–124. DOI: 10.1016/j.lwt.2016.03.030.