Chemoenzymatic synthesis of (R)- and (S)-1-heteroarylethanols

Article abstract of DOI:10.1016/j.tetasy.2008.08.023

A chemoenzymatic methodology for the synthesis of highly enantiomerically enriched (S)- and (R)-1-heteroarylethanols by enantioselective bioreduction with baker's yeast of the corresponding 1-heteroarylethanones followed by three racemization free chemical steps including a Mitsunobu reaction was developed.

Full text of DOI:10.1016/j.tetasy.2008.08.023

Tetrahedron: Asymmetry 19 (2008) 2068–2071
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chemoenzymatic synthesis of (R)- and (S)-1-heteroarylethanols
*
Monica Ioana Toßsa, Paula Veronica Podea, Csaba Paizs, Florin Dan Irimie
Department of Biochemistry and Biochemical Engineering, Babeßs-Bolyai University, Arany János 11, 400028 Cluj-Napoca, Romania
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2008
Accepted 21 August 2008
A chemoenzymatic methodology for the synthesis of highly enantiomerically enriched (S)- and (R)-1-het-
eroarylethanols by enantioselective bioreduction with baker’s yeast of the corresponding 1-heteroaryl-
ethanones followed by three racemization free chemical steps including a Mitsunobu reaction was
developed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
baker’s yeast reduction of a prochiral ketone. In the absence
of an appropriate DKR system, for converting the (S)-alcohol
There is a considerable interest in efficient routes for obtaining
enantiopure chiral 1-heteroarylalcohols, since they are useful
building blocks in the synthesis of more complex structures. Since
the need for the production of optically active compounds as single
enantiomers is growing rapidly, we have previously studied the li-
pase-catalyzed enantiomerselective kinetic resolutions of the race-
mic 1-heteroarylethanols 2a–d.1,2
The main drawback of the enantiomer selective reactions is that
maximum conversion for the desired enantiomer can only be 50%,
which in turn can be overcome by performing an enantioselective
transformation, with 100% theoretical conversion.
Enantioselective chemical methods for the synthesis of
1-heteroarylethanols 2b–d have already been described. The
enantioselective reduction of the corresponding ketone with
(S)-2-methyl-CBS-oxazaborolidine yielded the optically active
1-(benzo[b]thiophen-2-yl)ethanol ((R)-2b).3 The optically active
1-(benzo[b]thiophen-3-yl)ethanol ((R)-2d) was obtained by the
addition of (CH3)2Zn to the corresponding aldehyde 1d catalyzed
by a commercially available ClCr(Salen).4 The (S)-enantiomer of
1-(benzo[b]-furan-3-yl)ethanol (S)-2c was obtained either by
reducing (S)-benzo[b]furan-3-yl)oxirane with LiAlH4 or by stere-
oselective reduction of 3-acetylbenzofuran with (ꢀ)-DIP-Cl.5
However, no enzymatic methods for enantioselective preparation
of optically active 1-heteroarylethanols 2a–d have been found.
Biotransformations using Saccharomyces cerevisiae are very sim-
ple because of the availability of biomass and the use of water with
or without carbon sources as reaction medium that makes the
work-up procedure easy and reduces costs. There are numerous
examples of using baker’s yeast for asymmetric reductions. Some
of the representative reactions are presented in Nakamura’s re-
view.6 According to Prelog’s rule, the (S)-alcohol is obtained from
into the corresponding (R)-alcohol with high conversion, the
Mitsunobu reaction seems to be an optimal choice for achieving
this inversion.
The Mitsunobu reaction is perhaps the most favored method for
the inversion of secondary alcohols. This transformation was found
to be very efficient for inverting the configuration of chiral second-
ary alcohols since a clean SN2 process is generally observed
(‘Mitsunobu inversion’).7 Chemoenzymatic methods using lipases
have already been described for the preparation of different sec-
ondary alcohols8 or their esters.9 The Mitsunobu reaction allows
the synthesis of different derivatives by the stereoselective incor-
poration of azides, esters, nitriles, phthalimides and sulfonamides
with inversion of configuration. Various protocols including a
Mitsunobu reaction have been developed for obtaining arylbenzo-
ates,10 aryl ethers,11 dialkyl carbonates,12 thiocarbamates13 and
trithiocarbonates.14 Some of these procedures have been modified
for use on solid-phase supports.15
Herein, we report the baker’s yeast-catalyzed preparation of the
highly enantiomerically enriched (S)-1-heteroarylethanols (S)-2a–
d, followed by their racemization free chemical transformation
into the corresponding (R)-heteroarylethanols (R)-2a–d including
a Mitsunobu reaction.
2. Results and discussion
The synthesis of the racemic heteroaryl ethanols was first per-
formed. Racemic 1-(benzo[d]thiazol-2-yl)ethanol rac-2a and 1-
(benzo[b]thiophen-2-yl)ethanol rac-2b were prepared starting
from the corresponding unsubstituted heteroaryl compounds,
which were selectively lithiated at the 2-position with N-butyl lith-
ium in tetrahydrofuran at ꢀ78 °C. The latest compounds were
transformed with acetaldehyde into rac-2a,b.2 For the preparation
of rac-2c,d the corresponding aldehydes served as starting materi-
als, which were transformed with methyl magnesium iodide into
* Corresponding author. Tel.: +40 264 593833; fax: +40 264 590818.
E-mail address: irimie@chem.ubbcluj.ro (F.D. Irimie).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.023

M. I. Toßsa et al. / Tetrahedron: Asymmetry 19 (2008) 2068–2071
2069
OH
OH
O
O
OH
III.
I.
II.
R
H
R
a
R
R
R
R
1c,d
rac-2c,d
2a-d
rac-3a-d
rac-2a,b
O
O
c
b
N
NH2
OH
OH
O
O
IV.
V.
VI.
O
VII.
R
R
R
R
3a-d
R
(S)-2a-d
(R)-4a-d
(R)-2a-d
(R)-5a-d
N
S
R =
S
O
S
a
b
d
c
Scheme 1. (a) Synthesis of the racemic 1-heteroarylethanols and prochiral ethanones; (b) baker’s yeast-mediated bioreduction and (c) chemical reactions for the total
inversion of (S)-1-heteroarylethanols. Reagents and conditions: (I) (1) BuLi, ꢀ78 °C, 1 h; (2) acetaldehyde, ꢀ10 °C, 2 h; (II) CH3I, Mg/EtOEt; (III). PCC/CH2Cl2; (IV) S. cerevisiae;
(V). DIAD, Ph3P, N-hydroxyphtalimide/THF, ꢀ40 °C; (VI) NH2NH2ꢁH2O, rt; (VII) H2, Pd/C/MeOH, rt.
the desired products.2 The prochiral 1-heteroarylethanones 3a–d
were synthesized by the mild oxidation of rac-2a–d with pyridini-
um chlorochromate (PCC) in dichloromethane at room tempera-
ture (Scheme 1a).
tion products was more than 90%, and ee values were the same as
those found for small scale reactions (Table 2).
Table 2
To measure the enantiopurity of both (R)- and (S)-1-heteroaryl-
ethanols obtained by the procedures described below, the
chromatographic enantiomeric separation of rac-2a–d was first
established. For all racemates, the base-line separation of the
enantiomers was found using a GC Astec B-DM column working
in isotherm manner at temperatures described in Section 4.1.
To investigate the baker’s yeast-mediated reduction of ketones
3a–d, the analytical scale reactions were first performed under fer-
menting and non-fermenting conditions (Scheme 1b). Samples
were taken every 12 h over 6 days and analyzed by GC. It was
found that the enantiomeric composition of the optically active
1-(heteroaryl)ethanols remained constant during the reaction
time. In accordance with the majority of the earlier reported re-
sults, the selectivity of the reactions was higher when non-fer-
menting baker’s yeast was used as the biocatalyst (Table 1). Due
to the high ee values for the isolated (S)-1-heteroarylethanols (ee
>98%), further optimization of the bioreduction was not investi-
gated; however, it is known that various additives can significantly
influence the selectivity of the bioreduction with baker’s yeast.
Preparative scale synthesis of (S)-2a–d
Entry
Product
ee (%)
Yield (%)
½
a 2D0
ꢂ
(10 mg ꢃ mLꢀ1
)
1
2
3
4
(S)-2a
(S)-2b
(S)-2c
(S)-2d
98
>99
>99
>99
92
92
94
93
ꢀ18.15, CH3Cl
ꢀ21.2, CH3Cl
ꢀ27.1, CH3Cl
ꢀ18.95, CH3Cl
Furthermore, we tried to transform the previously obtained (S)-
2a–d into the corresponding (R)-heteroarylethanols, (R)-2a–d with
the Mitsunobu reaction, using acetic acid as a nucleophile. The
racemic 1-acetoxy-1-heteroarylethanes were first synthesized by
the chemical acylation of rac-2a–d. The racemic acetates were used
as a chromatographic reference for the detection of the enantio-
meric composition for the products of the Mitsunobu reaction.
The acetylation of (S)-2a–d was performed in several organic sol-
vents, varying the nucleophile–substrate ratio between 1 and 2.
In each case, the reactions were started at ꢀ40 °C, then the reaction
mixture was warmed up to room temperature over 8 h. The unsat-
isfactory yields of the reactions (20–78%) and the low ee values for
the acylated products (46–81%) led us to check the conversion of
the reaction and the enantiopurity of the acylated products using
other nucleophiles, such as propanoic, butyric, chloroacetic and
benzoic acid. Unfortunately, no significant enhancement in the
yield or ee was observed.
Table 1
Baker’s yeast-mediated reduction of ketones 3a–d under fermenting and non-
fermenting conditions
Entry
Substrate
Product
Enantiomeric excess (%)
Fermenting Non-fermenting
Recently, phthalimide and N-hydroxyphthalimide were used
successfully in several types of Mitsunobu reactions.16 Since N-
hydroxyphthalimide is a bulkier and stronger nucleophile than
the above-mentioned carboxylic acids, in our further experiments
we used this compound in order to obtain higher yields and
selectivity.
1
2
3
4
3a
3b
3c
3d
(S)-2a
(S)-2b
(S)-2c
(S)-2d
76
47
>99.5
98
98
>99.5
>99.5
>99.5
First the synthesis of the racemic 2-(1-(heteroaryl)-ethoxy)iso-
indoline-1,3-diones rac-4a–d was performed in several organic sol-
vents. Using 1.1 equiv of N-hydroxyphthalimide was sufficient for
the complete conversion of rac-2a–d in tetrahydrofuran (checked
by TLC). Because the aim of the experiments was the synthesis of
(R)-heteroarylethanols, (R)-2a–d from (S)-2a–d, two extra chemi-
With these results in our hand, the preparative scale synthesis
of (S)-2a–d was attempted. The dilutions and substrate-biocatalyst
ratio were the same as in the case of the analytical scale reactions.
The reactions were stopped when the entire quantity of the sub-
strate was consumed. The yield for the isolated and purified reac-

2070
M. I. Toßsa et al. / Tetrahedron: Asymmetry 19 (2008) 2068–2071
cal steps had to be inserted for the transformation of 2-(1-(hetero-
aryl)-ethoxy)isoindoline-1,3-diones into 1-(heteroaryl)ethanols.
The complete hydrasinolysis of rac-4a–d yielded the
corresponding racemic aminoxy derivatives rac-5a–d. By the
reduction with H2 gas (1atm) in the presence of Pd on charcoal
in methanol at room temperature, the latter compounds were
totally converted into rac-2a–d. Since the global yield for the
three-step transformation of rac-2a–d into itself was around 85%,
this method was further used successfully for the conversion, with
the total inversion of the configuration, of (S)-2a–d into (R)-2a–d
with good yields (Table 3).
parative chromatographic separations were performed using col-
umn chromatography on Merck Kieselgel 60 (63–200 m).
Melting points were determined by hot plate method, and are
l
uncorrected.
4.2. Reagents and solvents
Commercial chemicals and solvents were purchased from Al-
drich or Fluka. All solvents were purified and dried by standard
methods. Racemic 1-heteroarylethanols were prepared from the
corresponding 2-formylheteroaryl derivatives 1c,d with a Grignard
reaction 2c,d or by reaction of the corresponding heteroaryl-2-yl-
lithium derivatives with acetaldehyde, in the case of 1a,b. Hetero-
aryl-ethanones 3a–b as prochiral substrates were prepared by
oxidation of racemic ethanols 2a–d with pyridinium chlorochro-
mate (PCC).
Table 3
Synthesis of (R)-heteroarylethanols by Mitsunobu reaction
Entry
Substrate
Product
ee (%)
Yield (%)
½
a 2D0
ꢂ
(10 mg ꢃ mLꢀ1
)
5
6
7
8
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(R)-2a
(R)-2b
(R)-2c
(R)-2d
98
>99
>99
>99
84
87
80
82
+18.15, CH3Cl
+21.2, CH3Cl
+27.1, CH3Cl
+18.95, CH3Cl
4.3. Synthesis of 1-heteroarylethanones 3a–d
The mixture of one of the rac-1-heteroarylethanols rac-2a–d
(30 mmol) and pyridinium chlorochromate (PCC) (6.5 g) in CH2Cl2
(50 mL) was stirred at room temperature for 10 h. The suspension
formed was filtered and the precipitate was washed with CH2Cl2
(3 ꢃ 10 mL). The solvent was removed by distillation in vacuo
and the crude solid product was purified by preparative vacuum-
chromatography using dichloromethane as eluent, yielding the 1-
heteroarylethanones 3a–d as white solids.
In addition to the high yields and ee, the absolute configurations
of the isolated 1-heteroarylethanols were also confirmed by mea-
suring their optical rotations, which were consistent with the liter-
ature values.2
3. Conclusions
4.3.1. 1-(Benzo[d]thiazol-2-yl)ethanone 3a
The present work describes the usability of a chemoenzymatic
procedure for the preparation of both, highly enantiomerically en-
riched, (R)- and (S)-1-heteroarylethanols. The first enzymatic step
was the baker’s yeast-mediated reduction of the prochiral ketones
which provided the (S)-1-heteroarylethanols with more than 90%
yield and ee >98%. The latter compounds were converted into the
opposite enantiomer by a three-step chemical procedure (approx.
85% yield, ee >98%).
Yield = 74%; mp 112 °C from ethanol (lit. 108–111 °C from
aqueous ethanol17); 1H NMR: (300 MHz, CDCl3): d 2.85 (s, 3H);
7.53–7.61 (m, 2H); 7.99 (d, 1H, J = 8.5 Hz); 8.21 (d, 1H,
J = 8.5 Hz); 13C NMR (75 MHz): d 26.1; 122.4; 125.4; 127.0;
~
127.7; 137.4; 153.5; 166.5; 193.1; IR:(KBr) (cmꢀ1):
m
¼ 3446,
3054, 2364, 1683, 1592, 1548, 1482, 1321, 1268, 1257, 1166,
1079, 1033, 1012, 954, 931, 860, 771, 734, 703, 620, 561, 431;
HRMS: M+ found (M+ calculated for C9H7NOS): 177.02498
(177.02483); MS m/z (%): 178(6), 177(M+, 44), 149(23), 135(53),
108(21), 90(13), 69(24), 63(21), 50(12), 43(100), 39(12).
4. Experimental
4.1. Analytical methods
4.3.2. 1-(Benzo[b]thiophen-2-yl)ethanone 3b
Yield = 78%; mp 88 °C from ethanol (87–88 °C from diethyl
ether, hexane18); 1H NMR: (300 MHz, CDCl3): d 2.67 (s, 3H);
7.39–7.50 (m, 2H); 7.85–7.91 (m, 2H); 7.94 (s, 1H); 13C NMR
(75 MHz): d 26.8; 123.0; 125.0; 125.9; 127.4; 129.7; 139.1;
~
The 1H and 13C NMR spectra were recorded on a Bruker spec-
trometer operating at 300 MHz and 75 MHz, respectively, at
25 °C. Chemical shifts are expressed in ppm values from TMS as
internal standard. Electron impact mass spectra (EI-MS) were ta-
ken on a VG 7070E mass spectrometer operating at 70 eV. IR spec-
tra were recorded in KBr pellets on a Jasco 615 FT-IR spectrometer,
and the wavenumbers are given in cmꢀ1. GC analyses were con-
ducted with a Konik HRGC 4000 B gas chromatograph (carrier
gas N2; head pressure: 60 psi, injector: 250 °C; FID detector:
250 °C) on an Astec chiral column (30 m ꢃ 0.25 mm, dimethylat-
ed-b-cyclodextrin, No. 777023 G0507-30). For all chiral com-
pounds, high resolution enantiomeric separation was performed.
Retention times for (S) and (R)-2a–d are presented in Table 4.
Thin layer chromatography (TLC) was carried out using Merck
Kieselgel 60F254 sheets. Spots were visualized by treatment with
5% ethanolic phosphomolybdic acid solution and by heating. Pre-
142.6; 143.9; 192.3; IR: (KBr) (cmꢀ1):
m
¼ 3448, 3056, 2921,
1660, 1508, 1427, 1355, 1330, 1270, 1243, 1224, 1176, 1074,
1020, 950, 927, 846, 757, 728, 609, 566, 551, 464; HRMS: M+ found
(M+ calculated for C10H8OS): 176.02973 (176.02959); MS m/z (%):
178(M+2, 3), 177(M+1, 5), 176(M+, 45), 163(5), 162(10),
161(100), 147(2), 133(32), 93(8), 90(9), 89(71), 82(7), 74(9),
69(18), 63(35), 62(12), 61(5), 51(10), 50(13), 45(12), 43(57),
39(20), 38(7), 37(4).
4.3.3. 1-(Benzo[b]thiophen-3-yl)ethanone 3c
Yield = 74%; mp 65 °C from ethanol (64–65 °C from aqueous
ethanol19); 1H NMR: (300 MHz, CDCl3): d 2.65 (s, 3H); 7.43–7.53
(m, 2H); 7.88 (d, 1H, J = 8.3 Hz); 8.27 (s, 1H); 8.81 (d, 1H,
J = 8.3 Hz); 13C NMR (75 MHz): d 28.2; 122.2; 125.4; 125.7;
125.8; 135.4; 136.4; 137.4; 139.8.; 193.1; IR: (KBr) (cmꢀ1):
~
Table 4
Retention times for (S) and (R)-2a–d
m
¼ 1656, 1490, 1457, 1421, 1371, 1340, 1259, 1205, 1008, 923,
860, 815, 759, 732, 620, 547, 501, 478; HRMS: M+ found (M+ calcu-
lated for C10H8OS): 176.02973 (176.02959); MS m/z (%): 178(M+2,
3), 177(M+1, 6), 176(M+, 52), 163(5), 162(12), 161(100), 147(2),
133(30), 93(5), 89(53), 82(4), 74(8), 69(10), 63(18), 62(8), 61(4),
51(5), 50(6), 45(8), 43(23), 39(9), 38(4), 37(2).
Racemic ethanols rac-2a–d
tR (min)
tR (min)
t (°C) (GC)
S
R
2a
2b
2c
2d
44.89
12.92
14.60
24.73
51.82
12.48
15.46
23.30
110
140
140
120

M. I. Toßsa et al. / Tetrahedron: Asymmetry 19 (2008) 2068–2071
2071
4.3.4. 1-(Benzofuran-3-yl)ethanone 3d
4.5.2. Hydrolysis of (R)-4a–d
Yield = 76%; mp 39 °C from ethanol (38 °C from CCl420); 1H
NMR: (300 MHz, CDCl3): d 2.56 (s, 3H); 7.35–7.41 (m, 2H); 7.51–
7.55 (m, 1H); 8.22–8.27 (m, 2H); 13C NMR (75 MHz): d 28.1;
111.4; 122.6; 122.8; 124.1; 124.5; 125.6; 151.3; 155.6; 193.0; IR:
~
A mixture of compounds (R)-4a–d (0.4 g), 100% hydrazine hy-
drate (1 equiv) and ethanol (10 mL) was heated at reflux for 4 h.
Aqueous HCl (1 M, 3 mL) was added and the mixture was subse-
quently heated at reflux for 0.5 h. After cooling to room tempera-
ture, the mixture was filtered to remove the precipitated solid.
The filtrate was evaporated under reduced pressure. Aqueous
NaOH (1 M, 5 mL) was added to the residue and the mixture was
then extracted with ether (3 ꢃ 25 mL). The combined ether solu-
tion was dried with magnesium sulfate, filtered and evaporated
in vacuum and the crude product was purified on column chroma-
tography. CH2Cl2 afforded the desired compounds (R)-5a–d.
(KBr) (cmꢀ1):
m
¼ 1671, 1554, 1479, 1450, 1382, 1292, 1130,
1101, 943, 858, 844, 771, 748, 671, 605, 422; HRMS: M+ found
(M+ calculated for C10H8O2): 160.05284 (160.05243); MS m/z (%):
161(M+1, 6), 160(M+, 45), 146(11), 145(100), 117(7), 102(2),
90(5), 89(41), 88(5), 77(5), 63(25), 62(14), 61(4), 51(6), 50(7),
43(21), 39(11), 38(5), 37(2).
4.4. Asymmetric reduction of 1-heteroarylethanones 3a–d by
baker’s yeast
4.5.3. Reduction of (R)-5a–d
A 100-mL three-necked round-bottomed flask equipped with a
magnetic stirrer, nitrogen inlet and hydrogen inlet was charged
with 25 mL methanol and 2.5 g (R)-5a–d. A catalytical quantity
on Pd/C was added into solution. A stream of H2 was passed into
the suspension formed until all the aminoxy compound was re-
duced (checked by TLC). When the reaction was over, the suspen-
sion was filtered and the solvent was distilled off from the forming
solution by rotatory evaporation. The solid crude product was puri-
fied by preparative vacuum-chromatography with dichlorometh-
ane as eluent, yielding the (R)-heteroarylethanols ((R)-2a–d).
4.4.1. Analytical scale reduction of 3a–d
4.4.1.1. Analytical scale non-fermenting reduction of 3a–
d.
Baker’s yeast (1.5 g) was suspended in water (3 mL). After
stirring for 15 min, 1-heteroarylethanones 3a–d (10 mg) dissolved
in methanol (0.2 mL) were added into the resulting cell suspension.
Samples (100
days and extracted with ethyl acetate (300
l
L) were taken periodically for every 12 h over 6
L). The organic layer
l
was dried over anhydrous MgSO4 and used for GC analysis without
further purification.
4.4.1.2. Analytical scale fermenting reduction of 3a–
Acknowledgement
d.
Fresh wet cakes of baker’s yeast (1.5 g) and sucrose
(0.5 g) were added to water (3 mL), and the resulting suspension
was stirred for 30 min. 1-Heteroarylethanones 3a–d (10 mg) dis-
solved in methanol (0.2 mL) were added into the suspension. Fur-
ther experiments were performed as described in the previous
section.
Financial support from the Romanian Ministry of Education and
Research (CEEX Grant No. 1480-6/07.04.2006) is gratefully
acknowledged.
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4.5. Synthesis of (R)-heteroaryl alcohols (R)-2a–d using
Mitsunobu reaction
4.5.1. Mitsunobu reaction
To a solution of (S)-heteroaryl alcohols ((S)-2a–d) (3 mmol) dis-
solved in dry THF (5 mL), PPh3 (1.1 equiv) and N-hydroxy-phthali-
mide (1.1 equiv) were added. The mixture was cooled to 0–5 °C
and DIAD (1.1 equiv) was added. The mixture was stirred at room
temperature for 24 h. Evaporation of solvent and purification by
column chromatography (eluent: dichloromethane) yielded (R)-
4a–d, which were used without further purification in the next
step.
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