Stereoselective bioreduction of 1-(5-phenylfuran-2-yl)-ethanones mediated by baker's yeast

Article abstract of DOI:10.3109/10242422.2011.638374

Baker's yeast mediated reduction of various phenylfuran-2-yl-ethanones has been studied. The influence of the reaction conditions, the type and position of the substituents, as well the presence of various additives on the enantiomeric composition of the products and the reaction yield are discussed. The absolute configuration of the reaction products was established using a retrosynthetic procedure.

Full text of DOI:10.3109/10242422.2011.638374

Biocatalysis and Biotransformation, March–April 2012; 30(2): 177–183
ORIGINAL ARTICLE
Stereoselective bioreduction of 1-(5-phenylfuran-2-yl)-ethanones
mediated by baker’s yeast
MARIA TRIF, NOÉMI HAJNALKA KALLÓ, MARA ANA NAGHI
& LÁSZLÓ CSABA BENCZE
Department of Biochemistry and Biochemical Engineering, Babes¸-Bolyai University, Cluj-Napoca,
RO-400028 Cluj-Napoca, Arany János 11, Romania
Abstract
Baker’s yeast mediated reduction of various phenylfuran-2-yl-ethanones has been studied. The influence of the reaction
conditions, the type and position of the substituents, as well the presence of various additives on the enantiomeric com-
position of the products and the reaction yield are discussed. The absolute configuration of the reaction products was
established using a retrosynthetic procedure.
Keywords: phenylfuran-2-yl-ethanols, baker’s yeast, stereoselective, bioreduction, cellular biotransformation
Introduction
enzyme screening kits for the reduction of ketones
Enantiopure heteroaryl secondary alcohols are versa-
tile chiral intermediates and building blocks in the
synthesis of more complex structures (Farina et al.
2006). Phenylfuran derivatives are also important
structural subunits in various biologically active com-
pounds. It was recently found that some phenylfura-
nyl derivatives exhibit cytoprotective effects against
neurotoxin- and lipopolysaccharide-induced cell
death (Nishio et al. 2008), while others proved to be
efficient inhibitors of the methionine aminopeptidase
(MetAP), which is a promising target for the develop-
ment of novel antibacterial, antifungal and antican-
cer agents (Huang et al. 2005). Accordingly, there
is an increasing interest in the synthesis of novel
phenylfuran-based compounds with potential appli-
cations in the pharmaceutical industry.
The bioreduction of ketones is one of the most
important and practical reactions for producing
enantiomerically enriched alcohols (Matsuda et al.
2009, Tos¸a et al. 2002a, 2002b). For this purpose,
numerous efficient biocatalysts have been developed
over the last decades.Among them,38 various types of
oxidoreductase have been commercialised by Daicel
(http://daicelchiral.com/en/contents/chiralscreen/oh/
index.html). Codexis also commercialises various
(http://www.codexis.com/pdf/Product_List.pdf).
However, due to its ready availability and low cost,
baker’s yeast remains widely used for asymmetric
reductions.
Several baker’s yeast mediated enantioselec-
tive syntheses of various heteroarylethanols have
been described. Highly enantiomerically enriched
benzofuranyl-, benzo[b]thiophenyl-, pyridinyl- and
furanyl-ethanols have been synthesised in high yield
by whole cell reduction (Tos¸a et al. 2008, Paizs
et al. 2003, Busto et al. 2006,Takeshita et al. 1987).
Due to its high substrate specificity, only 1-substi-
tuted ethanones are accepted as substrates by yeast
alcohol dehydrogenase (YADH), the main oxi-
doreductase from yeast. However, whole cells of
baker’s yeast are able to stereoselectively reduce a
large variety of ketones, indicating that other oxi-
doreductases are also involved in the cellular
biotransformation. These oxidoreductases, both
(R)- and (S)-specific enzymes, may also display
nearly equal activities towards substrates.Therefore,
a drawback of baker’s yeast bioreduction is that the
isolated products may have low enantiopurity. Sev-
eral procedures can be used to improve the stereo-
selectivity of the reduction, such as modification of
Correspondence: László Csaba Bencze, Department of Biochemistry and Biochemical Engineering, Babes¸-Bolyai University, Arany János 11 RO-400028
Cluj-Napoca, Romania. E-mail: cslbencze@chem.ubbcluj
(Received 15 June 2011; revised 24 July 2011; accepted 2 November 2011)
ISSN 1024-2422 print/ISSN 1029-2446 online © 2012 Informa UK, Ltd.
DOI: 10.3109/10242422.2011.638374

178
M.Trif et al.
the biocatalyst (Nakamura et al. 1995, Kaluzna
et al. 2002) or of the reaction conditions by the
addition of specific enzyme inhibitors (Yang et al.
2004, Meth-Cohn et al. 1994) or modifying the
substrate (Dao et al. 1998).
Merck Kieselgel 60F254 sheets. Spots were visualised
by treatment with 5% ethanolic phosphomolybdic
acid solution and heating. Preparative chromato-
graphic separations were performed using column
chromatographyonMerckKieselgel60(63–200μm).
Melting points were determined by the hot plate
method and are uncorrected. The optical rotatory
powers were determined on a Perkin-Elmer 201
The stereochemical outcome of baker’s yeast
mediated bioreduction of ketones is predictable,
generally following Prelog’s rule (Prelog 1964),
which states that the hydride anion of the cofactor
is delivered from the back face of the ketone, with
the small group positioned on the right, thus gener-
ally producing the (S)-alcohol. Bioreductions that
are not governed by Prelog’s rule have also been
reported, confirming the involvement of various oxi-
doreductases present in the baker’s yeast cells (Ushio
et al. 1993). Recently, an unexpected behaviour of
baker’s yeast cells was noticed concerning the
stereoselective synthesis of various phenylfuran-
2-yl-ethane-1,2-diols by biotransformation of the
correspondingprochiralα-acetoxy-andα-hydroxym-
ethylketones, with substituent effects on the reactiv-
ity and stereochemical outcome of the products
being very diverse (Bencze et al. 2010). Here, we
extend the investigation of baker’s yeast mediated
biotransformation of phenylfuran-2-yl derivatives,
describing the bioreduction of phenylfuran-2-yl-eth-
anones 1a-e into the corresponding (S)-ethanols.
Moreover, using a retrosynthetic procedure, the
absolute configuration of these novel enantiomeri-
cally enriched phenylfuran-2-yl-ethanols was also
determined.
25
polarimeter and [α]D values are given in units of
10–1 deg cm2 g–1.
Reagents and solvents
All organic and inorganic reagents and solvents were
products of Aldrich or Fluka. All solvents were dried
and purified by standard methods as required.
Baker’s yeast, produced as wet cakes by Budafok
Ltd. (Hungary), was from a local store.
Synthesis of 1-(5-phenylfuran-2-yl)-ethanones 1a-e
2-Acetyl-furan (11.6 g, 0.105 mol) and cupric chlo-
ride (0.105 mol) were added at 0–5°C to a solution
of one of the diazonium salts (0.1 mol) in water
(100 mL), and the reaction mixture was stirred at
room temperature for 24 h. The reaction mixture
was extracted with dichloromethane (3 ϫ 100 mL),
the isolated organic layer was dried over anhy-
drous Na2SO4, filtered and the organic solvent was
evaporated in vacuo. The crude product was puri-
fied by column chromatography using dichlo-
romethane as eluent. Further purification of the
products was performed by several recrystallisa-
tions from hexane.
Methods
Analytical methods
The yield of the reaction and the analytical data –
MS, NMR spectra and melting points – were identi-
cal to those reported earlier (Bencze et al. 2010).
1H– and 13C–NMR spectra were recorded on a
Bruker spectrometer operating at 300 and 75 MHz,
respectively. Spectra were recorded at 25°C in
CDCl3. 1H– and 13C–NMR spectra were referenced
internally to the solvent signal. Electron impact mass
spectra (EI-MS) were taken on a VG 7070E mass
spectrometer operating at 70 eV. High performance
liquid chromatography (HPLC) analyses were
conducted with an Agilent 1200 instrument using a
Chiralpak IA column (4.6 ϫ 250 mm) and a mixture
of n-hexane and 2-propanol (90: 10, v/v) as eluent
for the enantiomeric separation of rac-2a and rac-2d,
respectively; a Chiralcel AS-H column and a mixture
of n-hexane and 2-propanol (90:10, v/v) as eluent
for the enantiomeric separation of rac-2b; and a
Chiralpak IC column and a mixture of n-hexane and
2-propanol (90:10, v/v) as eluent for the enantio-
meric separation of rac-2c,e. Retention times for
(R)- and (S)-2a-e are presented in Table IV. Thin
layer chromatography (TLC) was carried out using
Synthesis of racemic 1-(5-phenylfuran-2-yl)
ethanols rac-2a-e
Small portions of sodium borohydride were added to
the stirred mixture of 1-heteroaryl-ethanones 1a-e
(100 mg) in methanol (5 mL), until the entire amount
of ketone was transformed (measured byTLC).Then,
water (1 mL) was added gently to the mixture and
the methanol removed in vacuo. The crude product
was treated with CH2Cl2:water (1:1, v/v) (30 mL).
The organic layer was separated, dried over anhy-
drous Na2SO4 and the solvent was removed in vacuo.
The crude product was purified by column chroma-
tography using n-hexane-ethylacetate:triethylam-
ine (1:2:0.001, v/v) as eluent. The pure racemic
1-heteroarylethanols rac-2a-e were used as reference
for the chiral HPLC separation.

Stereoselective bioreduction of 1-(5-phenylfuran-2-yl)-ethanones 179
1-(5-(2-chlorophenyl)furan-2-yl)ethanol rac-2a:
1-(5-(4-chloro-2-nitrophenyl)furan-2-yl)ethanol
rac-2e: Yield: 93%, yellow semisolid; HRMS: Mϩ
found(Mϩ calculatedforC12H10ClNO4:267.0298):
267.0191; MS: m/z (%) ϭ 269 (Mϩ, 37Cl, 8), 268
(M ϩ 1, 35Cl, 3), 267 (Mϩ, 35Cl, 24), 225 (37Cl, 3),
224 (37Cl, 32), 223 (35Cl, 11), 222 (35Cl, 100), 206
(5), 205 (4), 195 (6), 180 (5), 179 (6), 178 (10), 153
(37Cl, 9), 151 (35Cl, 27), 150 (48), 140 (5), 139 (10),
138 (7), 115 (13), 113 (6), 58 (52), 55 (6), 43 (75);
1H-NMR (CDCl3, 25°C): 1.56 (3H, d, J ϭ 6.6 Hz),
2.33 (1H, s, broad), 4.90 (1H, q, J ϭ 6.5 Hz), 6.35
(1H, d, J ϭ 3.3 Hz), 6.62 (1H, d, J ϭ 3.3 Hz), 7.54
(1H, dd, J ϭ 2.0 Hz, J ϭ 8.4 Hz), 7.64–7.71
(2H, m); 13C-NMR (CDCl3, 25°C): 21.4, 63.6,
67.0, 107.6, 110.8, 122.4, 124.0, 129.6, 132.0,
133.7, 146.5, 159.4.
Yield: 88%, white semisolid; HRMS: Mϩ found
(Mϩ calculated for C12H11ClO2: 222.0448):
222.1007; MS: m/z (%) ϭ 225 (M ϩ 1, 37Cl, 2), 224
(Mϩ, 37Cl, 16), 223 (M ϩ 1, 35Cl, 7), 222 (Mϩ,
35Cl, 50), 210 (37Cl, 3), 209 (37Cl, 30), 208 (35Cl,
12), 207 (35Cl, 100), 179 (5), 151 (5), 149 (9), 144
(10), 141 (5), 139 (9), 116 (10), 115 (21), 114 (5),
113 (4), 111 (6), 83(5), 43 (13); 1H-NMR (CDCl3,
25°C): 1.56 (3H, d, J ϭ 6.7 Hz), 2.00 (1H, s), 4.98
(1H, q, J ϭ 6.6 Hz), 6.35 (1H, d, J ϭ 3.3 Hz), 7.04
(1H, d, J ϭ 3.3 Hz), 7.17–7.40 (2H, m), 7.46,
7.96 (1H, d, J ϭ 7.5); 13C-NMR (CDCl3, 25°C):
19.7, 20.6, 21.3, 63.7, 68.2, 107.3, 108.7, 109.2,
111.5, 126.8, 127.8, 128.0.
1-(5-(4-bromophenyl)furan-2-yl)ethanol rac-2b:
Yield: 91%, yellow semisolid; HRMS: Mϩ found
(Mϩ calculated for C12H11BrO2: 265.9942):
266.0152; MS: m/z (%) ϭ 268 (Mϩ, 81Br, 97), 267
(M–1, 81Br, 12), 266 (Mϩ, 79Br, 100), 265 (M–1,
79Br, 18), 264 (94), 252 (81Br, 19), 251 (81Br, 93),
250 (79Br, 24), 249 (79Br, 96), 195 (81Br, 65), 193
(79Br, 77), 128 (12), 115 (81Br, 11), 114 (42), 113
Cellular biotransformations of
1-(5-phenylfuran-2-yl)-ethanones
1a-e with baker’s yeast
Analytical scale biotransformations
of the prochiral ketones 1a-e
1
(79Br, 15), 88 (16), 74 (17), 63 (12); H-NMR
(CDCl3, 25°C): 1.61 (3H, d, J ϭ 6.6 Hz), 2.21 (1H,
s), 4.95 (1H, q, J ϭ 6.5 Hz), 6.33 (1H, d, J ϭ 3.2
Hz), 6.60 (1H, d, J ϭ 3.2 Hz), 7.47–7.60 (4H, m);
13C-NMR (CDCl3, 25°C): 21.3, 63.7, 106.1, 107.5,
121.1, 125.2, 129.6, 131.7, 152.2, 157.5.
Non-fermenting biotransformations. Baker’s yeast
(2.5 g) was suspended in water (25 mL). After stir-
ring for 15 min, the phenylfuran-2-yl-ethanones
1a-e (10 mg) dissolved in DMSO (0.5 mL) were
added to the resulting cell suspension. Samples (100
μL) were taken every 12 h over 48 h and were
extracted with ethyl acetate. The combined organic
layers were dried over anhydrous Na2SO4, the
solvent was evaporated, the crude solid was redis-
solved in n-hexane-isopropanol (1:1, v/v) and anal-
ysed by HPLC.
1-(5-(2-nitrophenyl)furan-2-yl)ethanol rac-2c:
Yield: 89%, yellow semisolid; HRMS: Mϩ found
(Mϩ calculated for C12H11NO4: 233.0668):
223.0719; MS: m/z (%) ϭ 234 (M ϩ 1, 15), 233
(Mϩ, 40.5), 231 (16), 218 (41), 202 (100), 189
(1.2), 117 (30), 111 (4.3), 109 (35), 97 (59), 83
(5.1), 71 (12), 69 (48), 57 (70), 43 (41); 1H-NMR
(CDCl3, 25°C): 1.46 (3H, d, J ϭ 6.6 Hz), 2.00 (1H,
s, broad), 4.80 (1H, q, J ϭ 6.6 Hz), 6.35 (1H, d,
J ϭ 3.0 Hz), 6.62 (1H, d, J ϭ 3.2 Hz), 7.42 (1H, dd,
J ϭ 7.5 Hz, J ϭ 7.7 Hz), 7.58 (1H, dd, J ϭ 7.3
Hz, J ϭ 7.5 Hz), 7.65 (1H, d, J ϭ 8.1 Hz), 7.72 (1H,
d, J ϭ 7.5 Hz); 13C-NMR (CDCl3, 25°C): 21.8,
64.1, 108.2, 111.0, 122.2, 124.6, 124.8, 129.4,
129.5, 132.9, 148.6, 160.9.
Fermenting biotransformations. A fresh wet cake of
baker’s yeast (2.5 g) and sucrose (1 g) were added
to water (25 mL). The resulting suspension was
stirred for 30 min, followed by the addition of phe-
nylfuran-2-yl-ethanones 1a-e (10 mg) dissolved in
DMSO (0.5 mL). Further experiments were per-
formed as described in the previous section.
1-(5-(4-nitrophenyl)furan-2-yl)ethanol rac-2d:
Yield: 92%, brown semisolid; HRMS: Mϩ found
(Mϩ calculated for C12H11NO4: 233.0668):
233.0691; MS: m/z (%) ϭ 233 (Mϩ, 1.58), 232
(4.8), 231 (13.2), 218 (9.9), 217 (61.8), 216 (100),
203 (5.6), 202 (63), 186 (4.3), 170 (28), 158 (5),
Biotransformationsofketonesunderfermentingconditions
in the presence of additives. Experiments were con-
ducted as previously described. n-Hexane (0.5 mL)
or one of the other additives (15 mg) was introduced
into the suspension together with the sucrose.
1
141 (3.4), 43 (5); H-NMR (CDCl3, 25°C): 1.62
(3H, d, J ϭ 6.7 Hz), 2.34 (1H, s), 4.92 (1H, q,
J ϭ 6.7 Hz), 6.31 (1H, d, J ϭ 3.2 Hz), 6.69 (1H, d,
J ϭ 3.2 Hz), 7.23–7.57 (4H, m); 13C-NMR (CDCl3,
25°C): 21.3, 63.7, 11.2, 112.7, 122.2, 123.8, 123.9,
125.9, 134.9, 149, 154.4, 156.7.
Preparative scale synthesis of (S)-heteroarylethanols
2a,c-e with baker’s yeast
Sucrose (3 g) was added to a suspension of baker’s
yeast (15 g) in water (100 mL) and the mixture was

180
M.Trif et al.
stirred for 30 min. For the biotransformation of 1c,
n-hexane (100 μL) was added to the reaction mix-
ture. Subsequently, the solution of phenylfuran-2-yl-
ethanones 1a-e (100 mg) dissolved in DMSO
(2 mL) was added to the fermenting suspension.The
reaction mixture was stirred at room temperature
until the transformation of the substrate was com-
pleted (checked by TLC: samples of 100 μL were
taken and extracted with ethylacetate, then analysed
with TLC). On completion of the reaction, the mix-
ture was extracted with EtOAc (3 ϫ 200 mL). The
combined organic layer was dried over anhydrous
Na2SO4, the solvent was removed in vacuo and the
crude product was purified by column chromatog-
raphy using n-hexane-ethylacetate-triethylamine
(1:2:0.001, v/v) as eluent.
enzymes (Bencze et al. 2010), probably due to the
high steric demand of 1-(5-(4-bromophenyl)furan-
2-yl)-ethanone preventing the interaction of these
compounds with the catalytic site of cellular oxi-
doreductases.
The high enantiomeric excesses (ee) for (S)-2d
and (S)-2e (Table I, entries 4 and 5) also accord with
the previous good results for the synthesis of the
corresponding 1,2-ethanediols by baker’s yeast medi-
ated biotransformation (Bencze et al. 2010). The
difference between the ee values of the products
obtained by bioreduction of 1c and 1d (Table I,
entries 3 and 4) showed that the baker’s yeast
enzymes preferred the para substituted substrates
over the ortho substituted ones.
Besides position, the electronic effects of the sub-
stituents could also influence the yields and enantio-
meric composition of the obtained compounds. By
selective reduction of 1c-e with SnCl2, the corre-
sponding 1-(amino-5-phenyl-furan-2-yl)-ethanones
were synthesised. Unfortunately, the bioreductions
of these derivatives failed: as in the case of 1b, no
trace of product could be found in the reaction mix-
ture. The absence of the cellular transformation of
the amino ketones suggested a structural incompat-
ibility between these substances and the enzymes in
the baker’s yeast cells, which could be explained by
the different electronic distribution in the amino
ketones compared to that of nitro ketones.
With the exception of the highly stereoselective
bioreduction of 1d,e (Table I, entries 4 and 5), the
biotransformation of the other substrates 1a,c
yielded the corresponding (S)-phenylfuran-2-yl-
ethanols (S)-2a,c with poor ee.These unsatisfactory
results led us to perform the fermenting baker’s
yeast reductions of 1a,c in the presence of various
additives that could enhance the stereoselectivity of
the enzymatic reductions. These compounds could
act as specific inhibitors of (S)- or (R)-selective
oxidoreductases. In most of the cases, their presence
in the reaction mixture caused a variation (increase
or decrease) of ee of the (S)-alcohols produced.The
influence of the additives on the stereoselectivity of
MS and NMR spectra of the optically active
products were indistinguishable from those of their
racemates. Data on yield, the enantiomeric composi-
tion and the optical rotatory power of the products
are presented in Table III.
Results and discussion
The prochiral heteroaryl-ethanones 1a-e used as
substrates were prepared by the Meerwein method
(Meerwein et al. 1939) from the corresponding diaz-
onium salts of various anilines and 2-acetyl-furan.
Further, the racemic phenylfuran-2-yl-ethanols rac-
2a-e were obtained by the chemical reduction of
ketones 1a-e (Scheme 1a). Due to the high instabil-
ity of the phenylfuran-2-yl-ethanols rac-2a-e during
their isolation and purification processes, the use of
even weakly acidic media had to be avoided. The
chromatographic enantiomeric separation of rac-2-
a-e was further developed, which allowed us to
investigate the stereochemical outcome of the baker’s
yeast mediated bioreductions (Table IV).
Initially, the analytical scale baker’s yeast medi-
ated transformation of 1a-e was performed under
fermenting (with sucrose) and non-fermenting (with-
out sucrose) conditions (Table I). In all cases, the
bioreduction in fermentative conditions resulted in
higher stereoselectivity and conversion compared to
the one performed in non-fermentative conditions.
As an example, while the fermenting bioreduc-
tion of 1c occurred with a relatively high yield, the
non-fermenting bioreduction of the same substrate
failed (Table I, entry 3), as well as the biotransforma-
tion of 1b under both conditions, almost quantita-
tively recovering the starting materials. This agrees
with our earlier observation that both (5-(4-bromo-
phenyl)furan-2-yl)-α-hydroxyethanone and (5-(4-
bromophenyl)-furan-2-yl)-α-acetoxy-methyletha-
none are inadequate substrates for the baker’s yeast
Table I. Fermenting and non-fermenting biotransformation
of 1a-e.
Fermenting
system
Non-fermenting
system
Yield
Entry Substrate Product ee (%) (%) ee (%)
Yield
(%)
1
2
3
4
5
1a
1b
1c
1d
1e
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
64
–
41
98
99
70
–
85
80
87
52
–
–
80
27
49
–
–
57
61

Stereoselective bioreduction of 1-(5-phenylfuran-2-yl)-ethanones 181
Table II.The influence of various additives on the stereoselectivity
of bioreduction of ketones 1a,c.
Table III. Baker’s yeast mediated preparative scale synthesis of
(S)-phenylfuran-2-yl-ethanols 2a,c-e.
25
ee (%)
Yield (%)
Entry
Substrate
Product
ee (%)
Yield (%)
[αD ]
Time
(S)-2aa
(S)-2cb
(S)-2da
(S)-2ea
64
58
98
99
65
81
76
80
−6.2
−28
ϩ13
−24
Entry
Additives
(S)-2a (S)-2c (S)-2a (S)-2c (h)
1
2
3
4
1a
1c
1d
1e
1
2
3
4
5
6
Fermenting
Non-fermenting
n-Hexane
L-Cysteine
MgCl2
64
52
46
53
35
41
41
–
58
56
54
49
70
49
40
45
43
51
85
–
79
70
73
81
48
48
48
48
48
48
aFermenting system, 48 h.
bFermenting system with n-hexane 0.1% as additive, 48 h.
MnCl2
known to be an inhibitor of (S)-selective yeast oxi-
doreductases (Dao et al. 1998a, 1998b) impaired
the cellular reduction of 1a,c. Surprisingly, in the
presence of allyl alcohol and ethyl bromoacetate, as
inhibitors of (R)-selective yeast oxidoreductases (Shi
et al. 2009, Cui et al. 1998, Forni et al. 1994, Naka-
mura et al. 1991), the bioreduction of 1a,c failed.
Using the optimal conditions determined for the
analytical scale reactions, preparative scale biore-
the bioreduction of 1a,c differed for each substrate
(Table II). However, none of the additives improved
the ee of the produced (S)-phenylfuran-2-yl-ethanol
(S)-2a, the best result remaining that obtained with-
out additives in fermenting conditions (Table II,
entry 1). The bioreduction of 1c in the presence of
0.1% n-hexane showed the highest selectivity; how-
ever, a slight decrease in yield was observed (Table II,
entry 3). As expected, the use of phenacyl-chloride,
Scheme 1. (a) Chemical synthesis of phenylfuran-2-yl-compounds and baker’s yeast mediated reduction of the ketones. (b) The synthetic
route applied to determine the absolute configuration of the products.

182
M.Trif et al.
Table IV. Retention times of the enantiomers of rac-2a-e.
resolution of racemic 1-(5-phenylfuran-2-yl)ethane-1,2-diols.
Tetrahedron: Asymmetry; 22: 675–683.
Busto E, Gotor-FernandezV, GotorV. 2006. Biocatalytic prepara-
tion of optically active 4-(N,N-dimethylamino)pyridines for
application in chemical asymmetric catalysis. Tetrahedron:
Asymmetry; 17: 1007–1016.
Cui JN, Ema T, Sakai T, Utaka M. 1998. Control of enantiose-
lectivity in the baker’s yeast asymmetric reduction of γ-chloro
β-diketones to γ-chloro (S)-β-hydroxy ketones. Tetrahedron:
Asymmetry; 9: 2681–2692.
Compound
tR (min)
Compound
tR (min)
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
20.8
8.4
14.1
16.8
13.7
(R)-2a
(R)-2b
(R)-2c
(R)-2d
(R)-2e
22.3
9.7
15.9
17.7
17.1
Dao DH, Okamura M, Akasaka T, Kawai Y, Hida K, Ohno A.
1998a. Stereochemical control in microbial reduction. Part 31:
Reduction of alkyl 2-oxo-4-arylbutyrates by baker’s yeast
under selected reaction conditions.Tetrahedron: Asymmetry; 9:
2725–2737.
Dao DH, Kawai Y, Hida K, Hornes S, Nakamura K, Ohno A,
et al. 1998b. Stereochemical control in microbial reduction. 30.
Reduction of alkyl 2-oxo-4-phenylbutyrate as precursors of
angiotensin converting enzyme (ACE) inhibitors. Bull Chem
Soc Jpn; 71: 425–432.
Farina V, Reeves JT, Senanayake CH, Song JJ. 2006. Asymmetric
synthesis of active pharmaceutical ingredients. Chem Rev; 106:
2734–2793.
Forni A, Moretti I, Prati F,Torre G. 1994. Stereochemical control
in yeast reduction of fluorinated β-diketones. Tetrahedron; 50:
11995–12000.
Huang QQ, Huang M, Nan FJ,Ye QZ. 2005. Metalloform-selective
inhibition: synthesis and structure–activity analysis of Mn(II)-
form-selective inhibitors of Escherichia coli methionine ami-
nopeptidase. Bioorg Med Chem Lett; 15: 5386–5391.
Kaluzna I, Andrew AA, Bonilla M, Martzen MR, Stewart JD.
2002. Enantioselective reductions of ethyl 2-oxo-4-phenylbu-
tyrate by Saccharomyces cerevisiae dehydrogenases. J Mol Catal
B: Enzym; 17: 101–105.
ductions of 1a,c-e were performed. In the scale-up
procedure, no significant changes in yield, stereo-
selectivity and reaction time were observed, as
compared to those found for the analytical scale
procedures (Table III).
To determine the absolute configuration of the
novel heteroarylethanols, a known retrosynthetic
pathway was employed (Paizs et al. 2003). Thus,
the known optically active diols (Bencze et al. 2010,
2011) (S)-3a,c-e were selectively mesylated at the
primary hydroxyl group, followed by a reduction of
the mesylated intermediates with LiAlH4, yielding
the corresponding optically active heteroaryletha-
nols (S)-2a,c-e (Scheme 1b). The absolute con-
figuration was established comparing the sign of the
specific rotations and of the retention times of the
heteroarylethanols obtained by the two different
methods.
Matsuda T,Yamanaka R, Nakamura K. 2009. Recent progress in
biocatalysis for asymmetric oxidation and reduction. Tetrahe-
dron: Asymmetry; 20: 513–557.
Conclusions
Meerwein H, Buchner E, Emster K. 1939. Über die einwirkung
aromatischer diazoverbindungen auf α,β-ungesättigte carbon-
ylverbindungen. J Prakt Chem; 152: 237–266.
Meth-Cohn O, Horak RM, Fouche G. 1994. Baker’s yeast-mediated
transformations of α-keto epoxides. J Chem Soc Perkin Trans;
1: 1517–1527.
Nakamura K, KawaiY, Nakajima N, Ohno A. 1991. Stereochem-
ical control of microbial reduction. 17.A method for controlling
the enantioselectivity of reductions with bakers’ yeast. J Org
Chem; 56: 4778–4783.
The baker’s yeast mediated stereoselective synthesis
of novel phenylfuran-2-yl-ethanols was developed.
The procedure yielded the enantiomerically enriched
(S)-alcohols with moderate to high yield and ee.
A strong substituent effect was observed and inves-
tigated in comparison with our previous results
obtained in the baker’s yeast synthesis of novel phe-
nylfuran-2-yl-ethanediols.
Nakamura K, Higaki M, Ushio K, Oka S, Ohno A, 1995. Stere-
ochemical control of microbial reduction. 2. Reduction of
β-keto esters by immobilized bakers’ yeast. Tetrahedron Lett;
26: 4213–4216.
Nishio K, Fukuhara A, Omata Y, Saito Y, Yamaguchi S, Kato H,
et al. 2008. Characterization of novel furan compounds on the
basis of their radical scavenging activity and cytoprotective
effects against glutamate- and lipopolysaccharide-induced
insults. Bioorg Med Chem; 16: 10332–10337.
Paizs C,Tos¸a MI, Majdik C, Moldovan PV, Novák L, Kolonits P,
et al. 2003. Optically active 1-(benzofuran-2-yl)ethanols and
ethane-1,2-diols by enantiotopic selective bioreductions.
Tetrahedron: Asymmetry; 14: 1495–1501.
Declaration of interest: L.C.B. is grateful for the
grant from the Romanian National Council of
Scientific Research of Higher Education (BD, Cod
CNCSIS: 384). The authors report no conflicts of
interest. The authors alone are responsible for the
content and writing of the paper.
References
Prelog V. 1964. Specification of the stereospecificity of some
oxido-reductases by diamond lattice sections. Pure Appl Chem;
9: 119–130.
Shi YG, Fang Y, Ren YP, Guan HL, Zhang JY. 2009. Applying
alpha-phenacyl chloride to the enantioselective reduction of
ethyl 2-oxo-4-phenylbutyrate with baker’s yeast. J Chem
Technol Biotechnol; 84: 681–688.
Bencze LC, Paizs C, Tos¸a MI, Irimie FD. 2010. Substituent
effects on the stereochemical outcome of the baker’s yeast-
mediated biotransformation of α-hydroxy- and α-acetoxyme-
thyl-5-phenylfuran-2-yl-ethanones. Tetrahedron: Asymmetry;
21: 356–364.
Bencze LC, Paizs C, Tos¸a MI, Irimie FD. 2011. Sequential use
of regio- and stereoselective lipases for the efficient kinetic

Stereoselective bioreduction of 1-(5-phenylfuran-2-yl)-ethanones 183
Takeshita M, Terada K, Akutsu N, Yoshida S, Sato T. 1987.
Synthesis of optically active hetero alkylaryl alcohols by baker‘s
yeast. Heterocycles; 26: 3051–3054.
Tos¸a MI, Podea PV, Paizs C, Irimie FD. 2008. Chemoenzymatic
synthesis of (R)- and (S)-1-heteroarylethanols. Tetrahedron:
Asymmetry; 19: 2068–2071.
Tos¸a MI, Paizs C, Majdik C, Novák L, Kolonits P, Irimie FD,
Poppe L. 2002a. Synthesis of optically active 3-substituted-10-
alkyl-10H-phenothiazine-5-oxides by enantioselective biotrans-
formations. Tetrahedron: Asymmetry; 13: 211–221.
Tos¸a MI, Paizs C, Majdik C, Moldovan PV, Novák L, Kolonits
P, et al. 2002b. Baker’s yeast mediated preparation of (10-alkyl-
10H-phenothiazin-3-yl)methanols. J Mol Catal B: Enzym; 17:
241–248.
Ushio K, Hada J, Tanaka Y, Ebara K. 1993. Allyl bromide, a
powerful inhibitor against R-enzyme activities in bakers’ yeast
reduction of ethyl 3-oxoalkanoates. Enzyme Microb Tech; 15:
222–228.
Yang ZH,Yao SJ, Lin DQ. 2004. Improving the stereoselectivity
of asymmetric reduction of 3-oxo ester to 3-hydroxy ester with
pretreatments on baker’s yeast. Ind Eng Chem Res; 43:
4871–4875.