Substituent effects on the stereochemical outcome of the baker's yeast-mediated biotransformation of α-hydroxy- and α-acetoxymethyl-5-phenylfuran-2-yl-ethanones

Article abstract of DOI:10.1016/j.tetasy.2010.02.004

In this Letter the baker's yeast-mediated biotransformation of variously substituted α-hydroxy- and α-acetoxymethyl-5-phenylfuran-2-yl-ethanones is described. The stereochemical outcome of the reactions was strongly influenced by the nature of the substituents on the phenyl ring.

Full text of DOI:10.1016/j.tetasy.2010.02.004

Tetrahedron: Asymmetry 21 (2010) 356–364
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Substituent effects on the stereochemical outcome of the baker’s
yeast-mediated biotransformation of
5-phenylfuran-2-yl-ethanones
a-hydroxy- and a-acetoxymethyl-
*
László Csaba Bencze, Csaba Paizs, Monica Ioana Tosßa, Florin Dan Irimie
Department of Biochemistry and Biochemical Engineering, Babeßs-Bolyai University, Cluj-Napoca, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter the baker’s yeast-mediated biotransformation of variously substituted
a-hydroxy- and a-
Received 5 January 2010
Accepted 5 February 2010
Available online 1 March 2010
acetoxymethyl-5-phenylfuran-2-yl-ethanones is described. The stereochemical outcome of the reactions
was strongly influenced by the nature of the substituents on the phenyl ring.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Valer Färcäsßan on the
occasion of his 90th birthday.
1. Introduction
2-yl)ethane-1,2-diols. Moreover, the unexpected stereochemical
outcome of the biotransformation of a-acetoxymethyl ketones gives
Optically active 1,2-ethanediols are important chiral building
blocks in organic synthesis, with numerous applications as chiral
auxiliaries for asymmetric synthesis.1 Phenylfuran-based struc-
tures are also important structural subunits in various biologically
active compounds. It was recently found that some phenylfuranyl
derivatives exhibit cytoprotective effects against neurotoxin- and
LPS-induced cell death,2 while others have proven to be efficient
inhibitors of the methionine aminopeptidase (MetAP), which is a
promising target for the development of novel antibacterial, anti-
fungal, and anticancer agents.3 Accordingly there is an increasing
interest for the synthesis of novel phenylfuran-based compounds
with potential applications in the pharmaceutical industry. There-
fore in this work devoted to the stereoselective synthesis of hetero-
cyclic molecules with potential biological activity, our aim was to
produce optically active phenylfuranyl-1,2-ethane diols.
novel information concerning the baker’s yeast-mediated reactions
of the aforementioned compounds.
2. Results and discussion
The synthesis of the substrates was performed in accordance
with the chemoenzymatic method previously developed by us.6
The heteroaryl-ethanones 1a–e used as starting materials were
prepared by the Meerwein method7 from the corresponding diazo-
nium salts of various anilines and 2-acetyl-furan. The ketones 1a–e
obtained were further
mation into -acetoxymethylketones 3a–e using sodium acetate
as the reactant, dioxane as the solvent, and 18-C-6 crown ether
as the phase transfer catalyst. The -acetoxymethylketones 3f–h
were prepared from the -acetoxymethylketones 3c–e by the
selective reduction of the nitro group with SnCl2 in ethanol. Enzy-
matic ethanolysis of 3a–h allowed us to obtain the -hydroxym-
a-brominated, followed by their transfor-
a
a
a
For the synthesis of 1,2-diols, the baker’s yeast-mediated
biotransformation of
a-hydroxymethyl- and a-acetoxy-methyl
a
ketones proved to be an environmentally friendly and efficient
method.4–6 Thus, ketones with a relatively small and hydrophilic
hydroxymethyl group were all reduced from the same face, whereas
ethylketones 4a–h in excellent yields. Finally the latest
compounds were reduced with sodium borohydride to yield the
rac-heteroaryl-1,2-ethanediols rac-5a–h (Scheme 1).
Next, the chromatographic separation of the enantiomers of
rac-5a–h was developed, which allowed us to investigate the ste-
reochemical outcome of the baker’s yeast-mediated biotransfor-
mations (Scheme 2).
In our first approach, the baker’s yeast-mediated transformation
of 3,4a–e under fermenting and non-fermenting conditions was per-
formed (Table 1). In order to increase the enantiopurity of the prod-
ucts, the reactions were performed under conditions of higher
stereoselectivity (fermenting or non-fermenting system) using var-
ious additives (Table 2), which can influence the stereoselectivity of
the cellular transformation as described in previous reports.8,9
the a-acetoxymethyl ketones were reduced with the opposite enan-
tiotopic preference. This behavior of the enzymatic equipment of the
baker’s yeast cells allowed us to synthesize with high enantiomeric
purity (ee 84–93%) both enantiomeric forms of various benzofura-
nyl-, benzo[b]thiophenyl-, and benzthiazolyl-1,2-ethanediols.4,5
Encouraged by these results, in our attempts to synthesize novel
heterocyclic 1,2-ethanediols we herein report the baker’s yeast-
mediated synthesis of various, optically active 1-(5-phenylfuran-
* Corresponding author. Tel.: +40 740312855; fax: +40 264590818?
E-mail address: irimie@chem.ubbcluj.ro (F.D. Irimie).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.004

L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
357
O
O
O
Br
III.
OAc
O
O
O
+Cl-
N]
N
II.
I.
O
X
X
X
+
X
O
3a-e
1a-e
3f-h
2a-e
X
1-5
IV.
3c-e
2-Cl
4-Br
a
b
c
d
e
O
O
HO
2-NO2
4-NO2
2-NO2, 4-Cl
OAc
OH
OH
O
O
O
V.
VI.
2-NH2
4-NH2
f
g
X
X
X
h
3a-h
4a-h
rac-5a-h
2-NH2, 4-Cl
Scheme 1. Synthesis of prochiral ketones 3,4a–h and racemic 1,2-heteroaryl-ethane diols 5a–h. Reagents and conditions: (I) CuCl2/H2O, acetone; (II) pyridinium tribromide/
CH3COOH, 80 °C; (III) CH3COOꢀNa+, 18-C-6/1,4-dioxane, reflux; (IV) SnCl2/EtOH, ultrasound; (V) Novozyme 435/EtOH; (VI) NaBH4/MeOH.
HO
HO
O
a
OAc
S. cerevisiae
OH
OAc
S. cerevisiae
YADHs
O
O
O
X
hydrolases
X
X
3a,f,h
(R)-5a,f,h
O
HO
O
b
OH
OH
OAc
O
O
O
S. cerevisiae
S.
cerevisiae
X
X
X
YADHs
hydrolases
4b-e
3b-e
(S)-5b-e
O
HO
c
OH
OH
O
O
S. cerevisiae
X
X
YADHs
4a-f,h
(S)-5a-f,h
Scheme 2. Baker’s yeast-mediated stereoselective biotransformation of ketones 3,4a–f,h.
Table 1
Fermenting and non-fermenting biotransformations of 3,4a–e
Table 2
The influence of various additives on the stereoselectivity of bioreduction of ketones
Entry
Substrate
Product
Fermenting
ee (%)
Yielda (%)
Non-fermenting
3a and 4e
ee (%)
Yielda (%)
Entry Additives
ee (%)
Yield (%)
Time (h)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
(R)-5a
(S)-5b
(S)-5c
(S)-5d
(S)-5e
(S)-5a
(S)-5b
(S)-5c
(S)-5d
(S)-5e
67
58
80
87
39
90
41
83
60
75
81
58
85
90
80
89
65
70
75
61
60
46
73
69
37
97
36
79
52
52
85
49
79
60
75
90
61
59
72
60
(S)-5e (R)-5a (S)-5e (R)-5a
1
2
3
4
5
Fermentinga
Non-fermentinga
Allyl alcoholb
n-hexaneb
75
52
40
71
77
67
60
89
51
58
52
91
49
58
85
81
93
87
85
48
48
48
48
48
L
-Cysteineb
66.7
6
7
Ethyl bromoacetateb 20
93
71.9
47
55
91
89
48
48
b
MgCl2
87
10
a
Without additives.
Fermenting system.
a
b
After 3 days.

358
L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
Table 3
The influence of various additives on the stereoselectivity of the
Baker’s yeast-mediated preparative scale biotransformation of heteroaryl-ketones
3a–f,h and 4a,f,h
reactions differs for each substrate. While the bioreduction of 3a
showed the highest selectivity in the presence of allyl alcohol
and ethyl-bromoacetate (Table 2, entries 3 and 6), in the case of
4e these additives decreased the selectivity of the bioreduction
(Table 2, entries 3 and 6) and the highest selectivity appeared in
the presence of Mg2+ ions (Table 2, entry 7). For the biotransforma-
tions of 3c,d, the best results were obtained when using MgCl2 and
dimethyl-sulfoxide (DMSO), respectively, as additives (Table 3, en-
tries 4 and 5). In case of 3b,e and 4a, the use of different additives
did not increase the selectivity of the processes, for 4a the non-fer-
menting system (Table 1, entry 6), while in case of 3b,e the fer-
menting system (Table 1, entries 2 and 5) showed the highest
selectivity.
½ ꢂ
a 2D5
Entry
Substrate
Product
ee (%)
Reaction
time (days)
Yield (%)
1
2
3
4
5
6
7
8
9
3a
4a
3b
3c
3d
4e
3f
4f
3h
4h
(R)-5aa
(S)-5ab
(S)-5bc
(S)-5cd
(S)-5de
(S)-5ed
(R)-5fc
(S)-5fc
(R)-5hc
(S)-5hc
94
97
50
91
88
87
9
80
29
41
2
2
2
2
3
3
2
2
2
2
88
90
60
75
79
82
65
72
56
78
+45
ꢀ48.1
ꢀ17.1
ꢀ61
ꢀ41.7
ꢀ49
+4.1
ꢀ28.1
+9.8
10
ꢀ16.1
a
b
c
Fermenting system with ethyl-bromoacetate as an additive.
Non-fermenting system.
Generally, the cellular transformation of the a-acetoxymethylk-
etones involves two concurring processes: the reduction of the car-
bonyl group catalyzed by yeast alcohol dehydrogenases (YADHs)
and the enzymatic hydrolysis of the a-acetoxy group, respectively
Fermenting system.
d
e
Fermenting system with Mg2+ as an additive.
Fermenting system with dimethyl-sulfoxide as an additive.
(Scheme 2a.). In previous work it was demonstrated that the
reduction is faster than the hydrolysis.4–6
2.1. The absolute configuration of the diols synthesized
As we expected, the biotransformation of
a-acetoxymethyl ke-
tones 3a and the respective -hydroxyethanones 4a took place
with opposite enantiopreference and with good selectivity (Table 1,
a
Since the absolute configuration of the produced (+)- and
(ꢀ)-diols was unknown, the both enantiomers of 5a–b were pre-
pared from the corresponding (R)- and (S)-cyanohydrins,17 as shown
in Scheme 3. The absolute configuration of the products was estab-
lishedcomparing thechromatographic retention times and thesigns
of the specific rotation of the diols obtained by the two different
methods. The same signs of the specific rotations of (R)-5a,f,h and
other (R)-1-(5-phenylfuran-2-yl)ethane-1,2-diols18,19 were also in
accordance with the assignment of the absolute configuration for
the (+)-enantiomers described herein.
entries 1 and 6). However, in contrast to most reported re-
sults4,5,10–16, the biotransformation of
a
-acetoxymethyl ketones
3b–e (Table 1, entries 2–5) and the corresponding -hydroxyetha-
a
nones 4b–e (Table 1, entries 7–10) showed the same stereochem-
ical outcome while the selectivities of the processes were also
lower than those obtained in the cellular transformation of 3,4a.
The same stereochemical preference for the transformation of 3b
and 4b (Table 1, entries 2 and 7) and the lower enantioselectivity for
thereductionof 3,4b couldbe explainedbythefactthatbaker’syeast
possesses several alcohol dehydrogenases, both (R)- and (S)-specific
enzymes, which could display nearly equal activities toward this
substrate, or due to the high steric demand of the bromine group
only one enzyme acts, but with low stereoselectivity. It is important
to note that during the biotransformation of 3b, the presence of 4b
could not be detected, proving that the rate of reduction is consider-
ably higher than that of hydrolysis of the ester group.
3. Conclusions
The baker’s yeast-mediated reduction of a-hydroxy-5-phenylfu-
ran-2yl-ethanones occurred from the same prochiral face of the ke-
tones providing in all cases (S)-5-phenylfuran-2-yl-1,2-ethanediols.
The biotransformation of the a-acetoxymethyl-5-phenylfuran-2yl-
ethanones involved two enzymatic steps. When the reduction was
faster than the enzymatic hydrolysis, the opposite enantiomeric
form of the 5-phenylfuran-2-yl-1,2-ethanediols was obtained. Due
to the strong electron-withdrawing effect of the nitro group, the
The same stereochemical outcome for the biotransformation of
a-acetoxymethyl ketones 3c–e (Table 1, entries 3–5) and a-
hydroxymethyl ketones 4c–e (Table 1, entries 8–10), respectively,
could be explained by the higher activity of the hydrolases than
those of the YADHs present in baker’s yeast cells, toward
a-acet-
a-acetoxymethyl-(5-(nitrophenyl)furan-2yl)ethanones hydrolysis
oxymethyl ketones 3c–e. By monitoring in time the biotransforma-
tion of 3c–e, the appearance of hydroxyethanones 4c–e was
observed, proving that in these cases hydrolysis is faster than
reduction (Scheme 2b).
was favored, thus the in situ formed -hydroxy-(5-(nitrophenyl)-
a
furan-2-yl)ethanones were further enzymatically reduced into the
corresponding (S)-5-(nitrophenyl)furan-2-yl-1,2-ethane-diols.
We supposed that the strong electron-withdrawing effect of the
nitro group would reduce the electron density on the ester carbon,
enhancing its reactivity, thus favoring the enzymatic hydrolytic
process being favored.
4. Experimental part
4.1. Analytical methods
To prove our supposition, prochiral ketones 3c–e were trans-
formed into 3f–h, by selective chemical reduction of the nitro
group (Scheme 1, step IV) followed by their enzymatic alcoholysis
into 4f–h. As it was expected, the baker’s yeast-mediated biotrans-
The 1H and 13C NMR spectra were recorded on a Bruker spec-
trometer operating at 300 MHz and 75 MHz, respectively. Spectra
were recorded at 25 °C in CDCl3 or acetone-d6. 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 spec-
trometer operating at 70 eV. High performance liquid chromatog-
raphy (HPLC) analyses were conducted with an Agilent 1200
instrument using a Chiralpak IC column (4.6 ꢁ 250 mm) and a mix-
ture of n-hexane and 2-propanol 90:10 (v/v) and 55:45 (v/v) as elu-
ent for the enantiomeric separation of rac-5a and rac-5e,
respectively, a Chiralcel AS-H column and a mixture of n-hexane
and 2-propanol 85:15, 80:20, and 60:40 (v/v) as eluent for the
enantiomeric separation of rac-5b, rac-5c, and rac-5g, a Chiralpak
formations of
all of which bear an amino group as the substituent, took place
with opposite enantiopreference and no trace of -hydroxyetha-
a-acetoxyketones 3f,h and a-hydroxyketones 4f,h,
a
nones 4f,h could be detected during the biotransformations of 3f,h.
However, in both the fermenting and non-fermenting systems,
the enantiopurity of the products was low (Table 3, entries 7–10)
and it could not be considerably enhanced using additives.
Moreover, the (R)- and (S)-1-(5-aminophenyl-furan-2-yl)ethane-
1,2-diols produced were very sensitive, unstable compounds. The
5gdiol produceddecomposedcompletelyinsituduringthereaction.

L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
359
O
I.
OH
OH
II.
OH
O
IV.
+
OH
R
O
R
CN
7a,b
R
R
CN
R
CN
6a,b
(S)-7a,b
(S)-5a,b
(R)-8a,b
III.
O
X
OH
OH
R
IV.
OH
X:
R
CN
2-Cl, 4-Br
(R)-5a,b
(R)-7a,b
Scheme 3. Retrosynthetic scheme for determination of the absolute configuration. Reagents: (I) (a) TMSCN, ZnI2/CH2Cl2; (b) HCl/MeOH; (II) CaL-B, vinyl-acetate/toluene; (III)
CaL-A, MeOH/DIPE; (IV) (a) 1 N HCl/1,4-dioxane; (b) LiAlH4/THF.
IB column and a mixture of n-hexane and 2-propanol 80:20 (v/v) as
eluent for the enantiomeric separation of rac-5d, and a Chiralpak IA
column and a mixture of n-hexane and 2-propanol 90:10 (v/v) as
eluent for the enantiomeric separation of rac-5f and rac-5h. Reten-
tion times for (R)- and (S)-2,3a–h are presented in Table 4. Thin
layer chromatography (TLC) was carried out using Merck Kieselgel
60F254 sheets. Spots were visualized by treatment with 5% etha-
nolic phosphomolybdic acid solution and heating. Preparative
chromatographic separations were performed using column chro-
Further purification of the products obtained was performed by
several recrystallizations from hexane.
4.3.1.1. 1-(5-(2-Chlorophenyl)furan-2-yl)ethanone 1a. Yield: 45%,
white solid; mp: 64–65 °C; HRMS: M+ found (M+ calcd for C12H9ClO2:
220.0291): 220.3964; MS: m/z (%) = 222 (M+, 37Cl, 23.8), 221 (M+1,
35Cl, 8.8), 220 (M+, 35Cl, 75.3), 207 (37Cl, 30.4), 205 (35Cl, 100.0),
151 (37Cl, 13.9) 149 (35Cl, 45.4), 114 (10.9), 43 (8.6); 1H NMR (CDCl3,
25 °C): 2.55 (3H, s), 7.22–7.42 (4H, m), 7.49 (1H, d, J = 7.5 Hz), 7.97
(1H, d, J = 7.4 Hz); 13C NMR (CDCl3, 25 °C): 26.1, 113, 118.9, 127.1,
127.9, 128.9, 129.8, 130.9, 131.3, 151.5, 153.7, 186.5.
matography on Merck Kieselgel 60 (63–200 lm). Melting points
were determined by the hot plate method and are uncorrected.
Optical rotations were determined on a Perkin–Elmer 201 polarim-
eter and ½a 2D5
ꢂ
the values are given in units of 10ꢀ1 deg cm2 gꢀ1
.
4.3.1.2. 1-(5-(4-Bromophenyl)furan-2-yl)ethanone 1b. Yield: 39%,
white solid; mp: 91 °C; HRMS: M+ found (M+ calcd for C12H9BrO2:
263.9786): 264.0174; MS: m/z (%) = 267 (M+1, 81Br, 12.3), 266 (M+,
81Br, 84.7), 265 (M+1, 79Br, 18.9), 264 (M+, 79Br, 100.0), 195 (81Br,
67.4), 193 (79Br, 53.4), 114 (33.4); 1H NMR (CDCl3, 25 °C): 2.53 (3H,
s), 6.79 (1H, d, J = 3.7 Hz), 7.25 (1H, d, J = 3.7 Hz), 7.56 (2H, d,
J = 8.6 Hz), 7.65 (2H, d, J = 8.6 Hz); 13C NMR (CDCl3, 25 °C): 26,
107.9, 119.5, 123.4, 126.4, 128.2, 132.1, 152, 156, 186.4.
4.2. Reagents and solvents
Pyridinium tribromide, sodium acetate, phase transfer catalyst
18-C-6, and all inorganic and organic reagents and solvents were
products of Aldrich or Fluka. All solvents were dried and purified
by standard methods as required. Novozyme 435 (lipase B from
Candida antarctica) and CLEA (lipase A from Candida antarctica
reticulated with glutaraldehyde) were purchased from Novozymes,
Denmark and Fluka, respectively. Baker’s yeast produced as wet
cakes by Budafok Ltd, Hungary, was from a local store.
4.3.1.3. 1-(5-(2-Nitrophenyl)furan-2-yl)ethanone 1c. Yield: 44%,
yellow solid, mp: 97 °C; HRMS: M+ found (M+ calcd for C12H9NO4:
231.0532): 231.1019; MS: m/z (%) = 232 (M+1, 1.1), 231 (M+,
47.5), 188 (10.1), 116 (4.5), 114 (2.8), 90 (1.6), 89 (2.4), 77 (2.1),
58 (39.5), 43 (100.0), 39 (3.2); 1H NMR (CDCl3, 25 °C): 2.52 (3H, s),
6.76 (1H, d, J = 3.7 Hz), 7.29 (1H, d, J = 3.7 Hz), 7.51 (1H, dd,
J = 7.9 Hz, J = 7.4 Hz), 7.62 (1H, dd, J = 7.4 Hz, J = 7.9 Hz), 7.69–7.75
(2H, m); 13C NMR (CDCl3, 25 °C): 26.1, 111.5, 118.9, 122.5, 124.2,
129.1, 130.2, 132.2, 147.3, 150.4, 152.2, 182.7.
4.3. Chemoenzymatic synthesis of the prochiral ketones
4.3.1. Synthesis of 5-phenylfuran-2-ethanones 1a–e
Into a solution of one of the diazonium salts (0.1 mol) in water
(100 mL), 2-acetyl-furan (11.6 g, 0.105 mol) and cuprous chloride
(0.105 mol) were added at 0–5 °C and the reaction mixture was
stirred at room temperature for 24 h. The reaction mixture was ex-
tracted with dichloromethane (3 ꢁ 100 mL). The isolated organic
layer was dried over anhydrous Na2SO4, filtered, and the organic
solvent was evaporated in vacuo. The crude product was purified
by column chromatography using dichloromethane as an eluent.
4.3.1.4. 1-(5-(4-Nitrophenyl)furan-2-yl)ethanone 1d. Yield: 45%,
orange solid, mp: 161 °C; HRMS: M+ found (M+ calcd for
C12H9NO4: 231.0532): 231.1129; MS: m/z (%) = 232 (M+1, 10.4),
231 (M+, 86.4), 216 (82.6), 170 (18.6), 114 (29.5), 58 (15.7), 43
(100.0); 1H NMR (CDCl3, 25 °C): 2.55, 6.98 (1H, d, J = 3.7 Hz), 7.35
(1H, d, J = 3.7 Hz), 7.97 (2H, d, J = 8.4 Hz), 8.29 (2H, d, J = 8.4 Hz);
13C NMR (CDCl3, 25 °C): 26.2, 110.5, 119.7, 124.5, 125.5, 134.5,
150.1, 155.3, 181.2.
Table 4
Retention times of the enantiomers of rac-5a–h
Compound
tR (min)
Compound
tR (min)
4.3.1.5. 1-(5-(4-Chloro-2-nitrophenyl)furan-2-yl)ethanone
1e. Yield: 41%, yellow solid, mp: 102 °C; HRMS: M+ found (M+
calcd for C12H18ClNO4: 265.0142): 265.0852; MS: m/z (%) = 267
(M+,37Cl, 10.9), 266 (M+1, 35Cl, 6.1), 265 (M+, 35Cl, 33.4), 224
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(R)-5e
(R)-5f
(R)-5g
(R)-5h
14.1
14.1
16.1
11.0
6.9
11.8
21.6
36.4
(S)-5a
(S)-5b
(S)-5c
(S)-5d
(S)-5e
(S)-5f
(S)-5h
(S)-5h
11.8
17.3
19.4
11.4
12.6
24.7
24.3
37.7
(
37Cl, 31.5), 222 (35Cl, 100.0), 152 (37Cl, 15.0), 150 (35Cl, 43.8),
113 (21.8), 43 (84.7); 1H NMR (CDCl3, 25 °C): 2.51 (3H, s), 6.78
(1H, d), J = 3.7 Hz), 7.26 (1H, d, J = 3.7 Hz), 7.61–7.65 (1H, dd,
J = 2.1 Hz, J = 7.8 Hz), 7.78 (1H, d, J = 7.8), 7.80 (1H, d, J = 2.1 Hz);

360
L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
13C NMR (CDCl3, 25 °C): 26.1, 112.1, 118.2, 121.4, 124.4, 130.6,
132.4, 135.7, 150.4, 153.2, 186.8.
4.3.5. Synthesis of 2-(heteroaryl)-2-oxo-ethyl-acetates 3a–h
4.3.5.1. Synthesis of 2-(heteroaryl)-2-oxo-ethyl-acetates 3a–
e. Into a solution of the heteroaryl-bormoethanones (10 mmol)
in 1,4-dioxane (25 mL), anhydrous sodium acetate (2.46 g,
30 mmol) and 18-C-6 crown ether (50 mg) as phase catalyst were
added. The resulting mixture was refluxed until the reaction was
completed (controlled by TLC, approx. 4–6 h). After cooling, the
deposited solid was filtered off and washed with dioxane
(3 ꢁ 10 mL). The solvent was removed by distillation in vacuo
and the crude product was purified by column chromatography
using dichloromethane as an eluent.
4.3.2. Synthesis of heteroaryl-2-bromoethanones 2a–e
Into a solution of heteroaryl-ketones 1a–e (10 mmol) in acetic
acid (20 mL) pyridinium tribromide (4.4 g, 15 mmol) was added
in small portions. After the mixture was refluxed for 2 h, the sol-
vent was removed in vacuo. The crude product was resuspended
in dichloromethane and sonicated for 5 min. The suspension
formed was filtered and the solvent from the filtrate was removed
in vacuo. The product was purified by column chromatography
using dichloromethane as an eluent.
4.3.5.2. Synthesis of 2-(heteroaryl)-2-oxo-ethyl-acetates 3f–
h. Into
a solution of 3c,d,e (1 mmol) in ethanol (10 mL),
4.3.2.1. 2-Bromo-1-(5-(2-clorophenyl)furan-2-yl)ethanone
2a. Yield: 62%, brown solid, mp: 69.5 °C; HRMS: M+ found (M+
calcd for C12H8BrClO2: 297.9396): 298.0037; MS: m/z (%) = 302
(M+, 81Br, 37Cl, 14.1), 301 (M+1, 81Br, 35Cl and 79Br, 37Cl, 7.7), 300
(M+, 81Br, 35Cl and 79Br, 37Cl, 59.2), 299 (M+1, 79Br, 35Cl, 5.9), 298
(M+, 79Br, 35Cl, 44.3), 207 (31.3), 205 (100.0), 43 (18.3); 1H NMR
(CDCl3, 25 °C): 4.38 (2H, s), 7.29 (1H, d, J = 3.9 Hz), 7.38 (2H, d),
7.45 (1H, d, J = 3.9 Hz), 7.51 (1H, d, J = 7.7 Hz), 7.98 (1H, d,
J = 7.7 Hz); 13C NMR (CDCl3, 25 °C): 29.9, 113.4, 120.9, 127.2,
127.6, 129, 130.2, 131, 131.5, 149, 154, 180.
SnCl2 ꢁ 2H2O (2.25 g, 10.0 mmol) was added. The mixture was
sonicated for 2 h at 30 °C until the reaction was complete (checked
by TLC). The solvent was removed under reduced pressure and the
crude residue was partitioned between ethyl acetate and 2 M KOH.
The aqueous layer was extracted with ethyl acetate (3 ꢁ 25 mL)
and the combined organic layer was washed with brine
(2 ꢁ 25 mL) and water (3 ꢁ 50 mL), dried over anhydrous MgSO4,
and concentrated under reduced pressure. The crude residue was
purified by column chromatography using hexane–ethyl acetate
1:2 (v/v) as an eluent.
4.3.2.2. 2-Bromo-1-(5-(4-bromophenyl)furan-2-yl)ethanone
2b. Yield: 57%, brown solid, mp 87–88 °C; HRMS: M+ found (M+
calcd for C12H8Br2O2: 341.8891): 341.9518; MS: m/z (%) = 346
(M+, 2 81Br, 33.5), 344 (M+, 79Br, 81Br, 75.4), 342 (M+, 79Br, 79Br,
37.9), 253 (2 81Br, 18.7), 251 (79Br, 81Br, 73.8), 249 (79Br, 79Br,
100.0), 195 (81Br, 24.6), 193 (79Br, 31.4), 114 (7.8), 58 (9.7), 43
(8.5); 1H NMR (CDCl3, 25 °C): 4.37 (2H, s), 6.85 (1H, d, J = 3.8 Hz),
7.42 (1H, d, J = 3.8 Hz), 7.61 (2H, d, J = 8.6 Hz), 7.69 (2H, d,
J = 8.6 Hz); 13C NMR (CDCl3, 25 °C): 29.8, 108.4, 121.5, 123.9,
126.6, 127.8, 132.3, 157.6, 179.9.
4.3.5.3. 2-(5-(2-Chlorophenyl)furan-2-yl)-2-oxoethyl acetate
3a. Yield: 79%; light brown solid, mp: 99–100 °C; HRMS: M+ found
(M+ calcd for C14H11ClO4: 278.0346): 278.0789; MS: m/z (%) = 280
(M+, 37Cl, 8.7), 279 (M+1, 35Cl, 4.1), 278 (M+, 35Cl, 27.1), 207
(
37Cl, 24.4), 205 (37Cl, 85.6), 151 (37Cl, 6.8), 149 (35Cl, 22.5), 114
(5.9), 58 (35.2), 43 (100.0); 1H NMR (CDCl3, 25 °C): 2.2 (3H, s),
5.27 (2H, s), 7.28 (1H, d, J = 3.7 Hz), 7.3–7.4 (3H, m), 7.49 (1H, d,
J = 7.6 Hz), 7.93 (1H, d, J = 7.5 Hz); 13C NMR (CDCl3, 25 °C): 20.5,
65.4, 113, 119.5, 127.2, 128.9, 130.1, 131.1, 131.5, 149.2, 154.3,
170.4, 181.2.
4.3.2.3. 2-Bromo-1-(5-(2-nitrophenyl)furan-2-yl)ethanone
2c. Yield: 65%, brown solid, mp: 67–68 °C; HRMS: M+ found (M+
calcd for C12H8BrNO4: 308.9637): 309.1199; MS: m/z (%) = 311
(M+, 81Br, 2.9), 309 (M+, 79Br, 2.9), 188 (100.0), 116 (23.3), 114
(12.2), 43 (19.9); 1H NMR (CDCl3, 25 °C): 4.37 (2H, s), 6.81 (1H, d,
J = 3.78 Hz), 7.39 (1H, d, J = 3.78 Hz), 7.56 (1H, dd, J = 8 Hz,
J = 7.5 Hz), 7.67 (1H, dd, J = 8 Hz, J = 7.5 Hz) 7.77–7.82 (m, 2H);
13C NMR (CDCl3, 25 °C): 30, 112.1, 120.2, 122.7, 124.2, 129.8,
130.3, 132.4, 150,4, 152.6, 180.1.
4.3.5.4. 2-(5-(4-Bromophenyl)furan-2-yl)-2-oxoethyl acetate
3b. Yield: 87%, brown solid, mp: 138–139 °C; HRMS: M+ found
(M+ calcd for C14H11BrO4: 321.9841): 322.0211; MS: m/z
(%) = 325 (M+1, 81Br, 7.1), 324 (M+, 81Br, 49.7), 323 (M+1, 79Br,
7.5), 322 (M+, 79Br, 50.5), 251 (99.1, 81Br), 249 (100.0, 79Br), 195
(39.5, 81Br), 193 (40.3, 79Br), 114 (31.2), 113 (11.3), 88 (7.6), 63
(3.8), 43 (44.8); 1H NMR (CDCl3, 25 °C): 2.25 (3H, s), 5.24 (2H, s),
6.82 (1H, d, J = 3.7 Hz), 7.35 (1H, d, J = 3.7 Hz), 7.58 (2H, d,
J = 8.9 Hz) 7.65 (2H, d, J = 8.9 Hz); 13C NMR (CDCl3, 25 °C): 20.6,
65.3, 108, 120.1, 123.7, 126.5, 127.9, 132.2, 149.7, 157, 170.4,
181.2.
4.3.3. 2-Bromo-1-(5-(4-nitrophenyl)furan-2-yl)ethanone 2d
Yield: 67%, orange solid, mp: 161.5–162 °C; HRMS: M+ found
(M+ calcd for C12H8BrNO4: 308.9637): 308.9893; MS: m/z
(%) = 311 (M+,81Br, 33.4), 309 (M+, 79Br, 34.70), 216 (100), 170
(22.6), 114 (18.6); 1H NMR (CDCl3, 25 °C): 4.39 (2H, s), 7.06 (1H,
d, J = 3.7 Hz), 7.48 (1H, d, J = 3.7 Hz), 7.91 (2H, d, J = 8.5 Hz), 8.29
(2H, d, J = 8.5 Hz); 13C NMR (CDCl3, 25 °C): 29.7, 111, 121.2,
124.5, 125.6, 134.5, 147.9, 150.5, 155.6, 180.2.
4.3.5.5. 2-(5-(2-Nitrophenyl)furan-2-yl)-2-oxoethyl
acetate
3c. Yield: 91%, yellow solid, mp: 95–96 °C; HRMS: M+ found (M+
calcd for C14H11NO6: 289.0586): 289.2064; MS: m/z (%) = 289
(M+, 1.1), 216 (12.3), 189 (4.1), 188 (29.6), 116 (10.5), 89 (4.8),
58 (31.6), 43 (100.0); 1H NMR (CDCl3, 25 °C): 2.19 (3H, s), 5.14
(2H, s), 6.78 (1H, d, J = 3.7 Hz), 7.31 (1H, d, J = 3.7 Hz), 7.53 (1H,
dd, J = 7.5 Hz, J = 7.1 Hz), 7.64 (1H, dd, J = 7.2 Hz, J = 7.5 Hz), 7.73–
7.78 (2H, m); 13C NMR (CDCl3, 25 °C): 20.4, 65.3, 111.7, 118.9,
122.6, 124.2, 129.7, 130.2, 132.3, 147.8, 150.6, 152.2, 170.2, 181.5.
4.3.4. 2-Bromo-1-(5-(4-cloro-2-nitrophenyl)furan-2-yl)ethan-
one 2e
Yield: 64%, brown solid, mp: 77.5–78 °C; HRMS: M+ found (M+
calcd for C12H7BrClNO4: 342.9247): 343.0017; MS: m/z (%) = 345
(M+, 81Br, 35Cl and 79Br, 37Cl, 7.2), 343 (M+, 79Br, 35Cl, 5.2), 224
(32.6), 222 (100), 152 (17.8), 150 (57.6), 113 (26.2), 43 (23.4); 1H
NMR (CDCl3, 25 °C): 4.31 (2H, s), 6.83 (1H, d, J = 3.8 Hz), 7.41
(1H, d, J = 3.8 Hz), 7.67 (1H, dd, J = 8.4 Hz, J = 2.1 Hz), 7.78 (1H,d,
J = 8.4 Hz), 7.82 (1H, d, J = 2.1 Hz); 13C NMR (CDCl3, 25 °C): 29.9,
112.5, 120.3, 124.6, 130.8, 132.6, 136.2, 150.6, 151.4, 180.2.
4.3.5.6. 2-(5-(4-Nitrophenyl)furan-2-yl)-2-oxoethyl acetate
3d. Yield: 87%, yellow solid, mp: 140.5–141 °C; HRMS: M+ found
(M+ calcd for C14H11NO6: 289.0586): 289.0617; MS: m/z (%) = 290
(M+1, 9.2), 289 (M+, 64.2), 217 (24.4), 216 (100.0), 170 (49.8),
160 (10.8), 114 (40.1), 43 (88.9); 1H NMR (CDCl3, 25 °C): 2.26
(3H, s), 5.27 (2H, s), 7.04 (1H, d, J = 3.8 Hz), 7.41 (1H, d,
J = 3.8 Hz), 7.95 (2H, d, J = 9.1 Hz), 8.33 (2H, d, J = 9.1 Hz); 13C

L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
361
NMR (CDCl3, 25 °C): 20.5, 65.4, 110.7, 119.8, 124.5, 125.5, 134.5,
150.7, 155.2, 170.4, 181.5.
4.3.6.2. 1-(5-(4-Bromophenyl)furan-2-yl)-2-hydroxyethanone
4b. Yield: 99%, yellow solid, mp: 103–104 °C; HRMS: M+ found
(M+ calcd for C12H9BrO3: 279.9735): 280.0156; MS: m/z (%) = 283
(M+1, 81Br, 11.3), 282 (M+, 81Br, 78.9), 280 (M+, 79Br, 100.0), 251
4.3.5.7. 2-(5-(4-Chloro-2-nitrophenyl)furan-2-yl)-2-oxoethyl
acetate 3e. Yield: 86%, yellow solid, mp: 142 °C, HRMS: M+ found
(M+ calcd for C14H10ClNO6: 323.0197): 323.1062; MS: m/z (%) = 325
(M+, 37Cl, 2.1), 323 (M+, 35Cl, 6.1), 252 (37Cl,12.8), 250 (35Cl, 40.6),
224 (37Cl, 21.6), 222 (35Cl, 66.7), 152 (37Cl, 10.1), 150 (35Cl, 38.1),
113 (19.8), 73 (28.5), 43 (100.0); 1H NMR (CDCl3, 25 °C): 2.23
(3H, s), 5.16 (2H, s), 6.81 (1H, d, J = 3.8 Hz), 7.35 (1H, d,
J = 3.8 Hz), 7.64 (1H, dd, J = 8.5 Hz, J = 1.9 Hz), 7.75 (1H, d,
J = 8.5 Hz), 7.8 (1H, d, J = 1.9 Hz); 13C NMR (CDCl3, 25 °C): 20.5,
65.3, 112.2, 119, 121.1, 124.5, 130.6, 132.5, 136.1, 150.8, 170.3,
181.6.
(
81Br, 78.1), 249 (79Br, 83.6), 195 (81Br, 96.1), 193 (79Br, 60.9),
114 (7.7), 113 (11.9); 1H NMR (CDCl3, 25 °C): 3.46–3.66 (1H, s,
broad), 4.78 (2H, s), 6.80 (1H, d, J = 3.7 Hz), 7.34 (1H, d,
J = 3.7 Hz), 7.64 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J = 8.6 Hz); 13C
NMR (CDCl3, 25 °C): 64.8, 107.9, 120.2, 123.7, 126.4, 127.7, 132.1,
149, 157.2, 186.9.
4.3.6.3. 1-(5-(2-Nitrophenyl)furan-2-yl)-2-hydroxyethanone
4c. Yield: 98%, yellow solid, mp: 87–88 °C; HRMS: M+ found (M+
calcd for C12H9NO5: 247.0481): 247.2173; MS: m/z (%) = 247 (M+,
1.2), 216 (3.1), 188 (5.5), 114 (2.6), 58 (42.1), 43 (100.0); 1H NMR
(CDCl3, 25 °C): 3.2–3.4 (1H, s, broad), 4.71 (2H, s), 6.79 (1H, d,
J = 3.8 Hz), 7.35 (1H, d, J = 3.8 Hz) 7.55 (1H, dd, J = 7.9 Hz,
J = 7.5 Hz), 7.65 (1H, dd, J = 7.4 Hz, J = 7.9 Hz), 7.72–7.79 (2H, m);
13C NMR (CDCl3, 25 °C): 65, 111.7, 119, 122.6, 124.2, 129.7,
130.3, 132.3, 147.8, 150.1, 152.5, 187.5.
4.3.5.8. 2-(5-(2-Aminophenyl)furan-2-yl)-2-oxoethyl
acetate
3f. Yield: 64%, yellow solid, mp: 101.5–102 °C; HRMS: M+ found
(M+ calcd for C14H13NO4: 259.0845): 259.1323; MS: m/z (%) = 260
(M+1, 13.6), 259 (M+, 100.0), 217 (7.7), 201 (10.9), 186 (53.8),
130 (64.6), 43 (30.3); 1H NMR (acetone-d6, 25 °C): 2.13 (3H, s),
2.9–3.1 (2H, s, broad), 5.25 (2H, s), 6.71 (1H, ddd, J = 7.2 Hz,
J = 7 Hz, J = 1.1 Hz) 6.89 (1H, d, J = 7.8 Hz), 6.96 (1H, d, J = 3.8 Hz),
7.15 (1H, ddd, J = 7.2 Hz, J = 7 Hz, J = 2 Hz), 7.55 (1H, d, J = 3.8 Hz),
7.59 (1H, dd, J = 7.8 Hz, J = 1.5 Hz); 13C NMR (acetone-d6, 25 °C):
21.4, 67, 110, 114.7, 118.8, 121.9, 128.4, 129.8, 132.3, 147.5,
150.2, 157.7, 171.6, 182.4.
4.3.6.4. 1-(5-(4-Nitrophenyl)furan-2-yl)-2-hydroxyethanone
4d. Yield: 98%, yellow solid, mp: 98 °C; HRMS: M+ found (M+ calcd
for C12H9NO5: 247.0481): 247.0652; MS: m/z (%) = 248 (M+1, 4.40),
247 (M+, 33.9), 217 (12.3), 216 (100.0), 170 (25.1), 160 (5.7), 114
(18.3), 88 (3.8), 43 (1.8); 1H NMR (CDCl3, 25 °C): 2.93 (1H, s),
5.34 (2H, s), 7.41 (1H, d, J = 3.8 Hz), 7.57 (1H, d, J = 3.8 Hz), 8.14
(2H, d, J = 8.6 Hz), 8.34 (2H,d, J = 8.6 Hz); 13C NMR (CDCl3, 25 °C):
65.3, 111.2, 119.8, 124.3, 125.7, 148.9, 150.6, 169.7, 181.4.
4.3.5.9. 2-(5-(4-Aminophenyl)furan-2-yl)-2-oxoethyl
acetate
3g. Yield: 59%, brown solid, mp: 108.5–109 °C; HRMS: M+ found
(M+ calcd for C14H13NO4: 259.0845): 259.1194; MS: m/z (%) = 260
(M+1, 21.7), 259 (M+, 84.4), 186 (42.3), 186 (67.7), 130 (93.3), 58
(41.6), 43 (100.0); 1H NMR (acetone-d6, 25 °C): 2.12 (3H, s), 5.22
(2H, s), 6.74–6.79 (3H, m), 7.45 (1H, d, J = 3.8 Hz), 7.59 (2H, m);
13C NMR (acetone-d6, 25 °C): 21.4, 66.9, 106.3, 116.1, 119.5,
122.5, 128.3, 150, 151.9, 161.4, 171.5, 181.9.
4.3.6.5. 1-(5-(4-Chloro-2-nitrophenyl)furan-2-yl)-2-hydroxy-
ethanone 4e. Yield: 97%, yellow solid, mp: 87–88 °C; HRMS: M+
found (M+ calcd for C12H8ClNO5: 281.0091): 281.1021; MS: m/z
(%) = 283 (M+, 37Cl, 7.2), 282 (M+1, 35Cl, 11.4), 281 (M+, 35Cl,
21.5), 252 (37Cl, 26.8), 250 (35Cl, 78.9), 224 (37Cl, 25.5), 222 (35Cl,
82.9), 152 (37Cl, 22.1), 150 (37Cl, 35Cl, 84.8), 148 (35Cl, 100.0), 114
(31.3), 113 (72.6), 43 (30.3); 1H NMR (CDCl3, 25 °C): 3.23–3.37
(1H, s, broad), 5.12 (2H, s), 6.82 (1H, d, J = 3.8 Hz), 7.37 (1H, d,
J = 3.8 Hz), 7.68 (1H, dd, J = 8.5 Hz, J = 1.9 Hz), 7.74 (1H, d,
J = 8.5 Hz) 7.81 (1H, d, J = 1.9 Hz); 13C NMR (CDCl3, 25 °C): 65.4,
112.4, 119.8, 121.7, 124.5, 130.8, 132.5, 136.3, 150.8, 152.1, 183.2.
4.3.5.10. 2-(5-(4-Chloro-2-aminophenyl)furan-2-yl)-2-oxoethyl
acetate 3h. Yield: 53%, brown solid, mp: 159–160 °C; MS: M+
found (M+ calcd for C14H12ClNO4: 293.0455): 293.0784; MS: m/z
(%) = 295 (M+, 37Cl, 39.9), 294 (M+1, 35Cl, 19.2), 293 (M+, 35Cl,
99.1), 253 (37Cl, 8.3), 251 (35Cl, 22.2), 222 (37Cl, 22.5), 220 (35Cl,
58.1), 164 (100.0), 58 (13.1); 1H NMR (acetone-d6, 25 °C): 2.13
(3H, s), 5.26 (2H, s), 5.63 (2H, s, broad), 6.72 (1H, dd, J = 8.5 Hz,
J = 2.1 Hz), 6.96 (1H, d, J = 2.1 Hz), 6.99 (1H, d, J = 3.8 Hz), 7.55
(1H, d, J = 3.9 Hz), 7.59 (1H, d, J = 8.5 Hz); 13C NMR (acetone-d6,
25 °C): 21.4, 67, 110.5, 113.7, 117.9, 118.8, 121.7, 131.5, 137.4,
148.8, 150.6, 159.2, 171.5, 182.5.
4.3.6.6. 1-(5-(2-Aminophenyl)furan-2-yl)-2-hydroxyethanone
4f. Yield: 91%, brown semisolid; HRMS: M+ found (M+ calcd for
C12H11NO3: 217.0739): 217.1713; MS: m/z (%) = 218 (M+1, 13.1),
217 (M+, 100.0), 186 (69.6), 159 (5.9), 130 (84.6), 77 (9.2), 43
(2.6); 1H NMR (acetone-d6, 25 °C): 3.25–3.5 (1H, s, broad), 4.71
(2H, s), 6.71 (1H, ddd, J = 8.6 Hz, J = 7.5 Hz, J = 1.2 Hz), 6.88 (1H,
dd, J = 8.3 Hz, J = 1.2 Hz), 6.93 (1H, d, J = 3.8 Hz), 7.14 (1H, ddd,
J = 8.6 Hz, J = 8.3 Hz, J = 1.5 Hz), 7.53 (1H, d, J = 3.8 Hz), 7.57 (1H,
dd, J = 7.5 Hz, J = 1.5 Hz); 13C NMR (acetone-d6, 25 °C): 66.6,
109.9, 118.9, 121.8, 129.8, 132.2, 147.4, 150.4, 160.2, 188.6.
4.3.6. Synthesis of 1-(heteroaryl)-2-hydroxy-ethanones 4a–h
A mixture of heteroaryl-oxoethyl-acetate 3a–h (200 mg) and
Novozyme 435 (CaL-B) (200 mg) in ethanol (15 mL) was shaken
at 300 rpm at room temperature until the reaction was complete
(controlled by TLC, approx. 48 h). Then the enzyme was filtered
and washed with ethanol (3 ꢁ 10 mL). The solvent was removed
in vacuo and the crude product was purified by column chroma-
tography using hexane–ethylacetate 1:1 (v/v) as an eluent.
4.3.6.7. 1-(5-(4-Aminophenyl)furan-2-yl)-2-hydroxyethanone
4g. Yield: 93%, brown semisolid; HRMS: M+ found (M+ calcd for
C12H11NO3: 217.0739): 217.2099; MS: m/z (%) = 218 (M+1, 8.2),
217 (63.8, M+), 186 (46.2), 167 (29.1), 149 (63.9), 130 (54.1), 97
(22.1), 83 (20.6), 71 (22.1), 58 (37.2), 43 (100.0); 1H NMR (ace-
tone-d6, 25 °C): 3.5–3.6 (1H, s, broad), 4.7 (2H, s), 6.74–6.78 (3H,
m), 7.44 (1H, d, J = 3.8 Hz), 7.59 (2H, m); 13C NMR (acetone-d6,
25 °C): 66.6, 106.4, 116.3, 119.7, 122.8, 128.5, 150.3, 152.3, 161.6,
188.4.
4.3.6.1. 1-(5-(2-Chlorophenyl)furan-2-yl)-2-hydroxyethanone
4a. Yield: 98%, white solid, mp: 97 °C; HRMS: M+ found (M+ calcd
for C12H9ClO3: 236.0240): 236.1025; MS: m/z (%) = 238 (M+, 37Cl,
16.1), 237 (M+1, 35Cl, 6.1), 236 (M+, 35Cl, 60.7), 207 (37Cl, 47.6),
205 (35Cl, 100.0), 151 (37Cl, 16.1), 149 (35Cl, 60.9), 114 (11.9), 43
(4.5); 1H NMR (CDCl3, 25 °C): 3.25–3.35 (1H, s, broad), 4.82 (1H,
s), 7.25 (1H, d, J = 3.8 Hz), 7.32–7.42 (3H, m), 7.49 (1H, d,
J = 7.6 Hz), 7.93 (1H, d, J = 7.6 Hz); 13C NMR (CDCl3, 25 °C): 65.1,
113.1, 119.6, 127.2, 128.9, 130.2, 131, 131.5, 148.7, 154.6, 187.3.
4.3.6.8. 1-(5-(2-Amino-4-chlorophenyl)furan-2-yl)-2-hydroxy-
ethanone 4h. Yield: 98%, yellow semisolid; HRMS: M+ found (M+
calcd for C12H10ClNO3: 251.0349): 251.1225; MS: m/z (%) = 253

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L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
(M+, 37Cl, 19.2), 252 (M+1, 35Cl, 6.8), 251 (M+, 35Cl, 70.6), 222 (37Cl,
16.4), 220 (37Cl, 43.5), 166 (37Cl, 28.1), 164 (35Cl, 100.0), 43 (80.9);
1H NMR (acetone-d6, 25 °C): 3.25–3.35 (1H, s, broad), 4.71 (2H, s),
5.62 (2H, s, broad), 6.71 (1H, dd, J = 8.5 Hz, J = 2.1 Hz), 6.97 (2H, m),
7.53 (1H, d, J = 3.8 Hz), 7.58 (1H, d, J = 8.2 Hz); 13C NMR (acetone-
d6, 25 °C): 65.1, 110.9, 113.8, 118.1, 118.9, 121.8, 131.4, 137.7,
149.5, 152, 159.1, 181.9.
NMR (acetone-d6, 25 °C): 66.3, 70, 110.9, 111.9, 125.4, 125.8,
138.2, 147.8, 159.7, 174.6
4.3.7.5. 1-(5-(4-Chloro-2-nitrophenyl)furan-2-yl)ethane-1,2-
diol rac-5e. Yield: 95%, orange solid, mp: 86–87 °C; HRMS: M+
found (M+ calcd for C12H10ClNO5: 283.0248): 283.07118; MS: m/z
(%) = 285 (M+, 37Cl, 5.1), 283 (M+, 35Cl, 15.2), 254 (37Cl, 32.7), 252
(
35Cl, 100.0), 151 (37Cl, 11.2), 149 (37Cl, 23.5), 115 (11.5), 100
(18.6), 74 (27.2), 55 (27.4), 43 (25.7); 1H NMR (acetone-d6,
25 °C): 2.5 (2H, s), 3.77 (2H, ddd, J = 6.8 Hz, J = 4.5 Hz, J = 10.9 Hz),
4.72 (1H, dd, J = 4.5 Hz, J = 6.8 Hz), 6.48 (1H, d, J = 3.4 Hz), 6.78
(1H, d, J = 3.4 Hz), 7.68 (1H, dd, J = 8.4 Hz, J = 1.9 Hz), 7.73 (1H, d,
J = 8.4 Hz), 7.88 (1H, d, J = 1.9 Hz); 13C NMR (acetone-d6, 25 °C):
66.8, 70, 110.4, 112.5, 123.6, 125.2, 131.2, 133.6, 134.6, 147.8,
159.5, 174.6.
4.3.7. Synthesis of rac-1-(heteroaryl)-ethane-1,2-diols rac-5a–h
Sodium borohydride was added in small portions into a stirred
mixture of 1-(heteroaryl)-2-hydroxyethanones 4a–h (100 mg) in
methanol (5 mL), until all of the ketone was transformed (con-
trolled by TLC). Then water (1 mL) was added gently into the mix-
ture and the methanol was removed in vacuo. The crude product
was treated with CH2Cl2–water 1:1 (v/v) (30 mL). The organic layer
was isolated, dried over anhydrous Na2SO4, and the solvent was re-
moved in vacuo. The crude product was purified by column chro-
matography using hexane–ethylacetate 1:2 (v/v) as an eluent.
The pure racemic 1,2-diols were used as reference for the chiral
HPLC separation.
4.3.7.6. 1-(5-(2-Aminophenyl)furan-2-yl)ethane-1,2-diol
rac-
5f. Yield: 78%, yellow semisolid; HRMS: M+ found (M+ calcd for
C12H13NO3: 219.0895): 219.122; MS: m/z (%) = 219 (M+, 28.4),
169 (38.9), 149 (18.7), 131 (7.9), 130 (100.0), 103 (12.4), 77
(16.1), 43 (14.6); 1H NMR (acetone-d6, 25 °C): 3.98 (2H, dd,
J = 4.5 Hz, J = 6.8 Hz, J = 10.9 Hz), 4.94 (1H, dd, J = 6.8 Hz,
J = 4.5 Hz), 5.23–5.31 (2H, s, broad), 6.74 (1H, ddd, J = 7.6 Hz,
J = 7.2 Hz, J = 1.2 Hz), 6.91 (1H, dd, J = 7.2 Hz, J = 1.5 Hz), 6.97 (1H,
d, J = 3.8 Hz), 7.17 (1H, ddd, J = 7.5 Hz, J = 7.6 Hz, J = 1.5 Hz), 7.55
(1H, d, J = 3.8 Hz), 7.61 (1H, dd, J = 7.5 Hz, J =1.2 Hz); 13C NMR (ace-
tone-d6, 25 °C): 66.2, 69.3, 109.9, 118.7, 121.9, 128.7, 129.8, 132.1,
147.3, 150.5, 160.4.
4.3.7.1. 1-(5-(2-Chlorophenyl)furan-2-yl)ethane-1,2-diol
rac-
5a. Yield: 92%, white semisolid; HRMS: M+ found (M+ calcd for
C12H11ClO3: 238.0397): 238.1011; MS: m/z (%) = 240 (M+, 37Cl,
8.3), 238 (M+, 35Cl, 26.1), 209 (37Cl, 60.1), 207 (35Cl, 100.0), 151
(
37Cl, 5.1), 149 (37Cl, 9.3), 115 (38.3), 114 (6.5), 43 (7.3); 1H NMR
(acetone-d6, 25 °C): 3.2 (2H, s, broad), 3.87 (2H, ddd, J = 6.8 Hz,
J = 5.3 Hz, J = 11.3 Hz), 4.72 (1H, dd, J = 5.3 Hz, J = 6.8 Hz), 6.50
(1H, d, J = 3.4 Hz), 7.10 (1H, d, J = 3.4 Hz), 7.28 (1H, dd, J = 7.9 Hz,
J=7.8 Hz), 7.40 (1H, dd, J = 7.8 Hz, J = 7.9 Hz), 7.48 (1H, d,
J = 7.8 Hz), 7.88 (1H, d, J = 7.9 Hz); 13C NMR (acetone-d6, 25 °C):
66.6, 70.1, 110, 113.3, 128.8, 129.6, 129.8, 130.6, 130.8, 132.2,
150.4, 157.5.
4.3.7.7. 1-(5-(4-Aminophenyl)furan-2-yl)ethane-1,2-diol
rac-
5g. Yield: 50%, brown semisolid; HRMS: M+ found (M+ calcd for
C12H13NO3: 219.0895): 219.1224; MS: m/z (%) = 219 (M+, 20.2),
169 (30.8), 149 (22.6), 131 (21.5), 97 (40.5), 83 (39.1), 71 (34.8),
69 (100.0), 57 (46.1), 55 (36.6), 43 (82.6); 1H NMR (acetone-d6,
25 °C): 2.57 (2H, s, broad), 3.66 (2H, ddd, J = 6.8 Hz, J = 5.3 Hz,
J = 10.9 Hz), 4.52 (1H, dd, J = 5.3 Hz, J = 6.8 Hz), 5.43 (1H, dd,
J = 5.3 Hz, J = 5.9 Hz), 6.81–6.85 (3H, m), 7.39 (2H, d, J = 3.7 Hz),
7.56 (2H, m); 13C NMR (acetone-d6, 25 °C): 67.3, 69.7, 110.5,
116.2, 124.4, 124.8, 126.9, 131.7, 151.3, 154.4.
4.3.7.2. 1-(5-(4-Bromophenyl)furan-2-yl)ethane-1,2-diol
rac-
5b. Yield: 94%, white semisolid; HRMS: M+ found (M+ calcd for
C12H11BrO3: 281.9892): 282.0298; MS: m/z (%) = 284 (M+, 81Br,
1.1), 282 (M+, 79Br, 1.2), 195 (81Br, 32.9), 193 (79Br, 35.7), 118
(39.7), 114 (82.1), 74 (100.0), 73 (36.9), 45 (84.8), 43 (22.2); 1H
NMR (acetone-d6, 25 °C): 3.04–3.24 (2H, s, broad), 3.83 (2H, ddd,
J = 6.8 Hz, J = 5.3 Hz, J = 11.3 Hz), 4.75 (1H, dd, J = 5.3 Hz,
J = 6.8 Hz), 6.43 (1H, d, J = 3.4 Hz), 6.82 (1H, d, J = 3.4 Hz), 7.57
(2H, d, J = 8.7 Hz), 7.63 (2H, d, J = 8.7 Hz); 13C NMR (acetone-d6,
25 °C): 66.7, 70.3, 108.6, 110.5, 122.4, 127, 131.9, 133.6, 153.4, 158.
4.3.7.8. 1-(5-(2-Amino-4-chlorophenyl)furan-2-yl)ethane-1,2-
diol rac-5h. Yield: 67%, yellow semisolid; HRMS: M+ found (M+
calcd for C12H12ClNO3: 253.0506): 253.1009; MS: m/z (%) = 255
(M+, 37Cl, 11.2), 253 (M+, 35Cl, 30.1), 222 (37Cl, 14.1), 220 (35Cl,
57.6), 166 (37Cl, 33.4), 164 (35Cl, 91.4), 153 (37Cl, 11.1), 149 (35Cl,
25.6), 43 (100.0); 1H NMR (acetone-d6, 25 °C): 2.47–2.51 (2H, s),
3.78 (2H, ddd, J = 6.8 Hz, J = 4.5 Hz, J = 10.9 Hz), 4.54 (2H, dd,
J = 4.5 Hz, J = 6.8 Hz), 5.49–5.6 (2H, s, broad), 6.74 (1H, dd,
J = 8.4 Hz, J = 2 Hz), 7.04 (1H, d, J = 2 Hz), 7.13 (1H, d, J = 3.8 Hz),
7.57 (1H, d, J = 3.8 Hz), 7.61 (1H, d, J = 8.4 Hz); 13C NMR (acetone-
d6, 25 °C): 66.5, 69.7, 110.7, 113.5, 118, 118.9, 121.5, 131.4,
137.3, 149.1, 150.9, 159.7.
4.3.7.3. 1-(5-(2-Nitrophenyl)furan-2-yl)ethane-1,2-diol
rac-
5c. Yield: 89%, yellow semisolid HRMS: M+ found (M+ calcd for
C12H11NO5: 249.0637): 249.1796; MS: m/z (%) = 249 (M+, 11.2),
218 (72.3), 188 (36.8), 172 (16.4), 116 (17.5), 115 (20.8), 83 (5.3),
71 (7.5), 58 (39.9), 43 (100.0); 1H NMR (acetone-d6, 25 °C): 3.77
(2H, ddd, J = 6.8 Hz, J = 4.9 Hz, J = 11.3 Hz), 4.71 (1H, dd, J = 4.9 Hz,
J = 6.8 Hz), 6.47 (1H, d, J = 3.4), 6.73 (1H, d, J = 3.4 Hz), 7.54 (1H,
dd, J = 7.9 Hz, J =7.6 Hz), 7.60 (1H, dd, J = 7.6 Hz, J = 8 Hz), 7.77
(1H, d, J = 8 Hz), 7.84 (1H, d, J = 7.9 Hz); 13C NMR (acetone-d6,
25 °C): 66.8, 70.3, 110.5, 112, 125.5, 129.9, 130.2, 130.4, 131.5,
133.8, 149.1, 159.4.
4.4. Cellular biotransformations of 2-(heteroaryl)-2-oxo-
ethylacetates 3a–h and 1-(heteroaryl)-2-hydroxy-ethanones
4a–h with baker’s yeast
4.4.1. Analytical scale biotransformations of the prochiral
ketones 3,4a–h
4.4.1.1. Non-fermenting biotransformations. Baker’s yeast (2.5)
was suspended in 25 mL water. After stirring for 15 min., the 2-
(heteroaryl)-2-oxo-ethylacetates 3a–h or 1-(heteroaryl)-2-hydro-
xy-ethanones 4a–h (10 mg) dissolved in EtOH (0.5 mL) was added
into the resulting cell suspension. Samples (100 lL) were taken
every 12 h over 48 h and extracted with ethyl acetate. The
combined organic layers were dried over anhydrous Na2SO4, the
4.3.7.4. 1-(5-(4-Nitrophenyl)furan-2-yl)ethane-1,2-diol
rac-
5d. Yield: 91%, yellow semisolid, mp: 98–99 °C; HRMS: M+ found
(M+ calcd for C12H11NO5: 249.0637): 249.1796; MS: m/z (%) = 250
(M+1, 11.7), 249 (M+, 67.8), 219 (23.7), 218 (100.0), 171 (31.7),
160 (17.8), 114 (39.8), 43 (61.7); 1H NMR (acetone-d6, 25 °C):
2.54 (2H, s), 3.87 (2H, ddd, J = 6.8 Hz, J = 5.7 Hz, J = 11.3 Hz), 4.83
(1H, dd, J = 5.7 Hz, J = 6.8 Hz), 6.52 (1H, d, J = 3.6 Hz), 7.11 (1H, d,
J = 3.6 Hz), 7.93 (2H, d, J = 9.2 Hz), 8.25 (2H, d, J = 9.1 Hz); 13C

L. C. Bencze et al. / Tetrahedron: Asymmetry 21 (2010) 356–364
363
solvent was evaporated, and the crude solid was redissolved in
hexane–isopropanol 1:1 (v/v) and analyzed by HPLC.
reactions were stopped at approximately 50% conversions by filter-
ing off the enzyme. The solvent was removed in vacuo and the
crude product was purified by column chromatography using
dichloromethane/acetic acid (99:1 v/v) as an eluent, to give the
optically active heteroaryl-2-hydroxyacetonitrile (S)-7a,b and het-
eroaryl(cyano)-methyl acetate (R)-8a,b.17
4.4.1.2. Fermenting biotransformations. A fresh wet cake of ba-
ker’s yeast (2.5 g) and sucrose (1 g) was added in water (25 mL).
The resulting suspension was stirred for 30 min., followed by the
addition of 2-(heteroaryl)-2-oxo-ethylacetates 3a–h or 1-(hetero-
aryl)-2-hydroxy-ethanones 4a–h (10 mg) dissolved in EtOH
(2 mL). Further experiments were performed as described in the
previous section.
4.5.3. Enzymatic alcoholysis of optically active cyanohydrin
esters (R)-8a,b
The optically active cyanohydrin esters (R)-8a,b (100 mg),
methanol (300
shaken at 300 rpm at room temperature. Samples from the reac-
tion mixture (5 L) were diluted with n-hexane/2-propanol (9:1,
100 L) and analyzed with HPLC. When the reaction was com-
pleted (approx. 24 h), the enzyme was filtered off, and the solvent
was removed in vacuo and the crude product was purified by col-
umn chromatography using dichloromethane: acetic acid (99:1, v/
v), resulting in the optically active heteroaryl-2-hydroxyacetonitri-
le (R)-7a,b.
lL), and CLEA (100 mg) in diisopropyl–ether were
4.4.1.3. Biotransformations of ketones in fermenting condi-
tions in the presence of additives. Experiments were conducted
as previously described. Hexane (0.5 mL) or one of the other addi-
tives (15 mg) was introduced into the suspension together with
the sucrose.
l
l
4.4.2. Preparative scale synthesis of (R)- and (S)-heteroaryl-
ethanediols 5a–f,h with baker’s yeast
Into a suspension of baker’s yeast (15 g) in water (100 mL)
sucrose was added (3 g) and the mixture was stirred for 30 min.
For the biotransformation of 3a, 3c, and 3d, ethyl–bromoacetate
4.5.4. Chemical hydrolysis and subsequent reduction of
enantiomerically pure cyanohydrins into the corresponding
diols
(20 lL), MgCl2 (20 mg), and DMSO (0.5 mL), respectively, were
added into the reaction mixture. After this the solution of 2-
(heteroaryl)-2-oxo-ethylacetates 3a–h or 1-(heteroaryl)-2-hydro-
xy-ethanones 4a–h (100 mg) in EtOH (3 mL) was added into the
fermenting suspension. The reaction mixture was stirred at room
temperature until the transformation of the substrate was
Into the solution of one of the cyanohydrins (S)- or (R)-7a,b
(1 mmol) in 1,4-dioxane (10 mL) concd aqueous HCl (800 lL,
8 mmol) was added and heated at reflux for 24 h. After the comple-
tion of the reaction, the solution was concentrated under reduced
pressure. The crude mixture was diluted with water (15 mL) and
extracted with EtOAc (3 ꢁ 10 mL). The organic layer was washed
with saturated NaHCO3 solution (15 mL), then the pH was adjusted
to 2 and the mixture was extracted with EtOAc (3 ꢁ 5 mL). The
combined organic layer was washed with brine (15 mL), dried over
MgSO4, and evaporated under reduced pressure to give the corre-
completed (checked by TLC: samples of 100 lL were taken and
extracted with ethylacetate, then analyzed with TLC). After the
completion of reaction, the mixture was extracted with EtOAc
(3 ꢁ 200 mL). The combined organic layer was dried over anhy-
drous Na2SO4, the solvent was removed in vacuo and the crude
product obtained was purified by column chromatography using
hexane–ethylacetate 1:2 (v/v) as an eluent.
sponding
a-hydroxy acid which was transformed without any
other purification into the optically active heteroaryl-1,2-ethane-
MS and NMR spectra of the optically active products were indis-
tinguishable from those of their racemates. Data on yield, enantio-
meric composition, and specific rotation of the products are shown
in Table 3.
diol 5a,b.
Into a suspension of LiAlH4 (230 mg, 6 mmol) in THF (10 mL) a
solution of optically active a-hydroxy acid (1 mmol) in THF (3 mL)
was added gently at 0 °C under inert (Ar) atmosphere, maintaining
the temperature bellow 5 °C. After the completion of the reaction
(6–8 h), 5% NaOH solution (2 mL) and H2O (5 mL) were added into
the reaction mixture under cooling, followed by the filtration of the
deposited white precipitate. The resulted solution was extracted
with Et2O (3 ꢁ 10 mL), the combined organic layers were dried
over anhydrous Na2SO4, and the solvent was evaporated in vacuo.
The crude product was purified by column chromatography using
dichloromethane/ethanol (9:1) as an eluent.
4.5. Determination of the absolute configuration of the
obtained diols
4.5.1. Synthesis of racemic cyanohydrins rac-7a,b
Using a known method,20 a catalytic amount of ZnI2 (3.2 mg,
10 lmol) and trimethylsilyl cyanide (119 mg, 1.2 mmol) was
added into a stirred solution of one of the aldehydes 6a,b (previ-
ously prepared21 by the Meerwein method) (1 mmol) in dry
dichloromethane (10 mL) and the resulting mixture was stirred
at room temperature until all of the aldehyde was transformed.
The solvent was evaporated and the crude product was redis-
solved in methanol (10 mL). The trimethylsilyl cyanohydrin
decomposed when HCl (3 M, 5 mL) was added. The reaction mass
was evaporated to the final volume of 5 mL; water (5 mL) and
dichloromethane (10 mL) were added. After the separation of
the two layers, the aqueous layer was extracted with dichloro-
methane (2 ꢁ 10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and the solvent was evaporated in vacuo.
The resulted crude cyanohydrins were purified by recrystalliza-
tion from n-hexane.
Acknowledgments
L.C.B. is grateful for grant from the Romanian National Council
of Scientific Research of Higher Education (BD, Cod CNCSIS: 384)
and for the Domus Hungarica fellowship. The financial support to
C.P. from the Romanian Ministry of Education and Research (CNC-
SIS No. 527/2461) is gratefully acknowledged.
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