Lipase-catalyzed synthesis of both enantiomers of 3-chloro-1-arylpropan-1- ols

Article abstract of DOI:10.1055/s-0030-1260149

The lipase-catalyzed synthesis of both enantiomers of 3-chloro-1-(4- fluorophenyl)propan-1-ol, 3-chloro-1-(4-iodophenyl)propan-1-ol, and 3-chloro-1-phenylpropan-1-ol is described. The procedure is based on the enantiomer-selective acylation of the racemic alcohols in presence of lipase from Pseudomonas fluorescens (LAK) followed by the lipase from Candida rugosa (CRL) mediated hydrolysis of previously obtained enantiomerically enriched 1-aryl-3-chloropropyl esters. For the production of enantiopure (S)-1-aryl-3-chloropropan-1-ols (99% ee, 34-42% yield) the reactions were stopped at higher conversions than the theoretical optimum of 50%, while for enantiopure (R)-1-aryl-3-chloropropyl acetates (99% ee) the reactions were stopped at lower conversions. The latter compounds were enzymatically hydrolyzed into the corresponding (R)-1-aryl-3-chloropropan-1-ols (97-99% ee, 18-24% yield). The absolute configuration of the resolution products was determined by VCD measurements combined with quantum chemical calculations. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260149

PAPER
2921
Lipase-Catalyzed Synthesis of Both Enantiomers of
3-Chloro-1-arylpropan-1-ols
Laura Ancuţa Pop,a Andrea Czompa,b Csaba Paizs,a Monica Ioana Toşa,a Elemér Vass,c Péter Mátyus,b
Florin-Dan Irimie*a
a
Babes-Bolyai University, Faculty of Chemistry and Chemical Engineering, Arany János street, Nr. 11, 400028 Cluj Napoca, Romania
Fax +40(264)590818; E-mail: irimie@chem.ubbcluj.ro
b
c
Semmelweis University, Department of Organic Chemistry, Hőgyes Endre u. 7., 1092 Budapest, Hungary
Eötvös Loránd University, Laboratory for Chiroptical Structure Analysis, Institute of Chemistry, PO Box 32, 1518 Budapest 112,
Hungary
Received 4 March 2011; revised 17 June 2011
Hydrolases and especially lipases, have proved to be
versatile biocatalysts for synthetic biotransformations.
Lipases can retain their high chemo-, regio-, and stereose-
lectivity and catalytic activity also in organic media and
Abstract: The lipase-catalyzed synthesis of both enantiomers of 3-
chloro-1-(4-fluorophenyl)propan-1-ol,
3-chloro-1-(4-iodophe-
nyl)propan-1-ol, and 3-chloro-1-phenylpropan-1-ol is described.
The procedure is based on the enantiomer-selective acylation of the
racemic alcohols in presence of lipase from Pseudomonas fluore- are versatile biocatalysts for kinetic resolutions,6,7 derace-
mizations, and dynamic kinetic resolutions8 of a broad
range of substrates.
scens (LAK) followed by the lipase from Candida rugosa (CRL)
mediated hydrolysis of previously obtained enantiomerically en-
riched 1-aryl-3-chloropropyl esters. For the production of enan-
The low cost of many lipases makes them very useful cat-
alysts for the kinetic resolution of variously substituted
secondary aryl alcohols including 1-aryl-2-chloro-
ethanols9 and 1-aryl-3-chloropropan-1-ols.10–15
tiopure (S)-1-aryl-3-chloropropan-1-ols (99% ee, 34–42% yield)
the reactions were stopped at higher conversions than the theoretical
optimum of 50%, while for enantiopure (R)-1-aryl-3-chloropropyl
acetates (99% ee) the reactions were stopped at lower conversions.
The latter compounds were enzymatically hydrolyzed into the cor-
responding (R)-1-aryl-3-chloropropan-1-ols (97–99% ee, 18–24%
yield). The absolute configuration of the resolution products was
determined by VCD measurements combined with quantum chem-
ical calculations.
1-Aryl-3-chloropropan-1-ols are important racemic build-
ing blocks for the synthesis of pharmaceuticals, e.g. anti-
fungal agents that act against different species of Candida
and exhibit low cytotoxicity.16 A number of derivatives
Key words: enzymes, kinetic resolution, enantioselectivity, chiral obtained from the above-mentioned chiral building blocks
resolution, alcohols, halide
have turned out to be potent inhibitors of Candida albi-
cans strains resistant to Fluconazole, with minimal inhib-
itory concentrations (MICs) <10 mg mL–1. Against
dermatophyte strains (MICs £ 5 mg mL–1), they have been
The need for the production of optically active com-
found to be equipotent with Ketoconazole, Econazole,
and Miconazole.17 (R)- or (S)-1-Aryl-3-chloropropan-1-
ols have served as starting materials for the synthesis of
(S)- or (R)-oxetanes in enantiopure form.18 Both enantio-
mers of 3-chloro-1-phenylpropan-1-ol are commercially
available from Pharmacon Technology Co. Ltd., China.
Several biocatalytic procedures are known for their prep-
aration. Most of them are based on the enantiomer-selec-
tive enzymatic acylation of racemic 3-chloro-1-
phenylpropan-1-ol10 or on the stereoselective hydrolysis
of their acylated counterparts.11 For the Novozyme 435
catalyzed dynamic kinetic resolution, ruthenium com-
plexes were used for the in situ racemization of 3-chloro-
1-phenylpropan-1-ol.12 Microbial biotransformations
have also been developed for this purpose. Oxidoreduc-
tase from baker’s yeast13 and Merulius tremellosus14 ste-
reoselectively reduce 3-chloro-1-phenylpropan-1-one to
give the desired product, but the occurrence of secondary
undesired reactions involving the elimination of HCl, fol-
lowed by the reduction of the in situ formed 1-phenyl-
prop-2-en-1-one, leads to a low overall yield of the target
compound. An interesting procedure for deracemization
of the racemic substrate through the use of Sphingomonas
paucimobilis, involving enzymatic redox reactions, fur-
pounds as single enantiomers is growing rapidly. Classi-
cal resolution via diastereomeric salts of chiral
compounds is still used widely, but in recent decades
many catalytic enantioselective procedures have been de-
veloped for the synthesis of enantiopure compounds.
By virtue of their chiral nature, biocatalysts are predomi-
nantly preferred for the production of enantiopure stereoi-
somers. Thus, biocatalysis is widely used for the synthesis
of pharmaceuticals and fine chemicals.1–3 Biotransforma-
tions are already applied in industry for the manufacture
of various products, such as drugs, agricultural chemicals,
fine chemicals, and plastics.4,5
Biocatalytic methodologies based on enantiomer-selec-
tive kinetic resolutions of racemates and enantiotope-
selective transformations of prochiral substrates have
been devised for the efficient, economical, and environ-
mentally friendly synthesis of optically active com-
pounds.
SYNTHESIS 2011, No. 18, pp 2921–2928
x
x.
x
x
.
2
0
1
1
Advanced online publication: 02.08.2011
DOI: 10.1055/s-0030-1260149; Art ID: T49711SS
© Georg Thieme Verlag Stuttgart · New York

2922
L. A. Pop et al.
PAPER
nished (R)-3-chloro-1-phenylpropan-1-ol15 in 79% yield in the presence of several enzymes. For rac-2a–c most of
and with excellent stereoselectivity.
the tested enzymes such as lipase A, G, M, N, and P, lipase
from Pseudomonas cepacia (LPS), lipase B from Candida
antarctica (CaLB), and Lipozym TLIM were mostly cat-
alytically inactive or displayed low reactivity and moder-
ate selectivity. For the enzymatic kinetic resolution of
rac-2a, only lipase from Pseudomonas fluorescence
(LAK) and lipase from Candida rugosa (CRL) exhibited
high selectivity, though their activity in neat vinyl acetate
was low (E = 64–168, 5–9% conversion). LAK was also
the best biocatalyst for the enantioselective transforma-
tion of rac-2b,c in neat vinyl acetate (for rac-2b E = 45,
13% conversion, and for rac-2c E = 47, 17% conversion).
The present paper describes the biocatalytic synthesis of
(R)- and (S)-3-chloro-1-(4-fluoro- and 4-iodophenyl)pro-
pan-1-ols and reports a comparison with the results ob-
tained for the unsubstituted phenyl counterpart.
Ketones 1a and 1c are commercially available. The reduc-
tion of 3-chloro-1-(4-fluorophenyl)propan-1-one (1a)
was achieved according to a literature procedure.19
A
modified reduction of 1c was performed in order to obtain
rac-2c. The Friedel–Crafts reaction of 3-chloropropionyl
chloride with iodobenzene to obtain ketone 1b was carried
out as described in the literature,20 while the reduction was
performed as in the case of the unsubstituted ketone deriv-
atives (Scheme 1).
It is known that the nature of the solvent and the acylating
agent can significantly influence the selectivity and activ-
ity of the enantiomer-selective acylation of rac-2a–c. The
acylation of rac-2a with vinyl acetate was first tested in
the presence of LAK and CRL in several solvents, such as
aliphatic and aromatic hydrocarbons, cyclic saturated
ethers, and acetonitrile. The selectivity and the activity of
CRL in all the tested solvents were strongly decreased rel-
ative to those in neat vinyl acetate (E <25). N-Hexane
proved to be the most appropriate solvent for the LAK-
mediated acylation (E = 65 and 35% conversion after 20
h; Table 1, entry 2), but the enantiomer-selective acyla-
tion of rac-2a in toluene, cyclohexane, or n-octane was
also satisfactory (entries 1, 3, and 4).
For the acylation of rac-2a–c all the classical methods
(acid anhydride or acid chloride in the presence of a base)
failed. The yields were poor and several byproducts were
formed. Lipase A from Candida antarctica (CaLA) is
known to be an appropriate catalyst for the nonselective
acylation of small racemic secondary alcohols. Thus, with
vinyl esters as acyl donors, alcohols rac-2a–c were quan-
titatively transformed with CaLA into the corresponding
racemic esters rac-3a–c in n-hexane, as shown in
Scheme 1 (a).
To investigate the stereoselectivity of the enzymatic acy-
lation of racemic 1-aryl-3-chloropropan-1-ols rac-2a–c,
they and their acylated counterparts rac-3a–c were first
chromatographically separated (Table 5).
The same solvents were tested for the enzymatic acylation
of rac-2b,c. Appropriate catalytic activity and selectivity
of the previously selected enzyme were observed in only
a few solvents. For both substrates, n-hexane proved to be
a suitable acylation solvent, with E >200 and 20–28%
conversion after 12 hours.
An approach to the synthesis of the enantiomerically en-
riched (R)-3a–c and (S)-2a–c is based on enantiomeric
acylation of rac-2a–c, as depicted in Scheme 1 (b). For
this, the analytical-scale enantiomer selective enzyme-
catalyzed acylations in neat vinyl acetate were first tested
In view of the unsatisfactory result for the LAK-mediated
acylation of rac-2a (E <200), the enzymatic acylation of
O
O
OH
R
O
i
ii
iii
a
b
Ar
H
Ar
Cl
Ar
Cl
Ar
Cl
a–c
1a–c
rac-2a–c
rac-3a–c
O
O
OH
OH
R
iv
+
Ar
Cl
Ar
Cl
Ar
Cl
(S)-2a–c
(R)-3a–c
rac-2a–c
c
v
Ar =
OH
F
I
a
b
c
Ar
Cl
R = Me, n-Pr
(R)-2a–c
Scheme 1 (a) Synthesis of racemic 1-aryl-3-chloropropyl alkanoates; (b) enzymatic enantioselective acylation of rac-2a–c; (c) enzymatic
enantioselective hydrolysis of (R)-3a–c. Reagents and conditions: (i) Cl(CH2)2COCl, AlCl3, CH2Cl2; (ii) NaBH4, EtOH, –15 °C; (iii) CaLA,
vinyl acetate or vinyl butanoate, n-hexane; (iv) LAK, n-hexane, vinyl acetate or vinyl butanoate; (v) CRL in phosphate buffer, pH 8.
Synthesis 2011, No. 18, 2921–2928 © Thieme Stuttgart · New York

PAPER
Synthesis of Both Enantiomers of 3-Chloro-1-arylpropan-1-ols
2923
With regard to their low water solubility, the enzymatic
alcoholysis of rac-3a–c was first tested. The same wide
selection of commercial hydrolases as used for the enzy-
matic acylation was screened for the analytical-scale alco-
holysis of the racemic esters rac-3a–c. Experiments were
first carried out in neat anhydrous methanol, ethanol, pro-
panol, or butanol, followed by experiments using the same
enzymes in all of the tested solvents checked for enzymat-
ic esterification; five equivalents of alcohol were added to
the reaction mixture. Since the enzymatic alcoholysis
proved to be totally inefficient in all cases (yields <5% af-
ter 5 d, substrate/enzyme ratio 1:1), the enzymatic hydrol-
ysis of rac-3a–c was studied. When the same enzymes
were tested (substrate/enzyme ratio 1:1), it was found that
only CRL and pig liver esterase (PLE) exhibited high en-
zymatic activity toward all rac-3a–c. Experiments were
conducted in sonicated double distilled water, in phos-
phate or Tris buffer (pH 6.5, 7, 7.5, or 8, all 20 mM). Sam-
ples were taken every 30 minutes and analyzed via HPLC
and GC. In all cases, the complete and nonstereoselective
hydrolysis of rac-3a–c occurs in 2–5 hours.
Table 1 Influence of the Solvents upon the Selectivity of the LAK-
Mediated Acylation of rac-2a with Vinyl Acetatea
Entry
Solvent
Conv. (%) ees (%)
eep (%)
96
E
1
2
3
4
n-octane
n-hexane
cyclohexane
toluene
23
35
24
26
29
51
29
34
65
65
43
54
95
94
95
a Substrate (10 mg), enzyme (10 mg), vinyl acetate (10 mL), solvent (1
mL), 20 h.
rac-2a–c was tested with vinyl butanoate in the previously
selected solvents. While the selectivity for the enzymatic
transformation of rac-2a was enhanced (E >200, 28%
conversion after 19 h) the enantiomeric purity for the res-
olution products of rac-2b,c was lower as compared with
that observed with vinyl acetate as acyl donor (data not
given).
As all the enzymatic reactions gave good, but not excel-
lent enantioselectivities, two additional experiments were
performed for the synthesis of the highly enantiomerically
enriched reaction products (S)-2a–c and (R)-3a–c.
In order to obtain (R)-2a–c, (R)-3a–c obtained from the
enantioselective enzymatic acylation of rac-2a–c was
subjected to enzymatic hydrolysis [Scheme 1 (c)] under
the same conditions as described in the previous para-
graph. In the cases of the fluoro and iodo derivatives, par-
tial racemization of the produced alcohols was observed.
The level of racemization was strongly dependent on the
reaction time, the type of enzyme used, the buffer, and the
pH. The highest extent of racemization was observed
when water was used as reaction medium. This can be ex-
plained by the strong decrease in pH during the reaction,
determined by the accumulation of acetic or butanoic acid
as a product of the enzymatic hydrolysis. To avoid a long
contact of the alcohols formed with the water from the re-
action medium, the reaction time was shortened with a
higher enzyme/substrate ratio (2:1).
While the reactions were stopped at lower conversions for
enantiopure (R)-3a–c (Table 2, entries 1–3), for enan-
tiopure (S)-2a–c the reactions were stopped at higher con-
versions than the theoretical optimum of 50% (Table 2,
entries 4–6).
Table 2 Optimal Conditions for the Resolution of the Racemic Al-
cohols rac-2a–ca
Entry Substrate Acyl donor
Time Conv. ees
eep
(h)
(%)
28
20
28
55
59
54
(%)
39
25
39
99
99
99
(%)
1
2
3
4
5
6
rac-2a
rac-2b
rac-2c
rac-2a
rac-2b
rac-2c
vinyl butanoate
vinyl acetate
vinyl acetate
vinyl butanoate
vinyl acetate
vinyl acetate
19
99
99
99
80
70
83
22
21
Table 3 The Optimal Conditions for the Enzymatic Hydrolysis of
(R)-3a–ca
70
Entry Substrate
ees (%)
99
Time (h) Product
eep (%)
98
100
82
1
2
3
(R)-3a
(R)-3b
(R)-3c
1.5
5
(R)-2a
(R)-2b
(R)-2c
99
97
a Substrate (10 mg), enzyme (10 mg), vinyl ester (10 mL), n-hexane (1
mL).
99
5
99
a Substrate (10 mg), CRL (20 mg), phosphate buffer (1 mL), pH 8.
Lipases usually retain their enantiomer preference in hy-
drolysis or alcoholysis.1–3,6 Consequently, such reactions
should result in opposite enantiomeric forms of the enan-
tiomerically enriched 1-aryl-3-chloropropan-1-ols 2a–c
and 1-aryl-3-chloropropyl acetates or 1-aryl-3-chloropro-
pyl butanoates 3a–c as compared with those found in the
kinetic resolution by acylation. The hydrolysis and alco-
holysis of the corresponding racemic 1-aryl-3-chloropro-
pyl acetates and 1-aryl-3-chloropropyl butanoates rac-
3a–c were also considered.
The optimal conditions for the enzymatic hydrolysis of
(R)-3a–c are presented in Table 3. When CRL was used as
biocatalyst and phosphate buffer (pH 8, 20 mM) as reac-
tion medium for the complete hydrolysis of (R)-3a–c
(Table 3), the lowest loss of enantiomeric excess was ob-
served for the produced (R)-2c. Following the sequence
depicted in Scheme 1 (b) and (c), the preparative-scale
synthesis of both (S)- and (R)-2a–c was next performed
(Table 4). The dilutions, substrate/biocatalyst ratio and re-
action conditions were the same as in the case of the ana-
Synthesis 2011, No. 18, 2921–2928 © Thieme Stuttgart · New York

2924
L. A. Pop et al.
PAPER
Table 4 Yield, Enantiomeric Excess and Optical Rotation
Compound (R)-3a–c
(R)-2a–c
(S)-2a–c
25
25
25
Yield (%)
ee (%)
99
[a]D
Yield (%)
ee (%)
98
[a]D
+20
+ 9
+21
Yield (%)
ee (%)
99
[a]D
a
b
c
26
20
25
+58.7
+52.1
+59.5
24
18
23
38
34
42
–22
–10
–24
99
97
99
99
99
99
lytical-scale reactions. In order to obtain enantiopure (R)- defined as the differential absorption of left- and right cir-
3a–c, the enzymatic reactions were stopped at low con- cular polarized infrared radiation during vibrational exci-
versions (30–45%). For enantiopure (S)-2a–c, the reac- tation of chiral molecules is today considered a well-
tions were stopped at high conversions (60–75%) by established and extremely reliable technique for the deter-
filtering off the enzyme. In both cases, the enantiomeric mination of the absolute configuration and conformation
composition of the reaction counterparts was monitored of small to medium-sized molecules in solution.21,22
via GC and HPLC to stop the reaction at conversions and
enantiomeric excess levels of (R)-3a–c and (S)-2a–c close
to those found in the analytical-scale procedures. After the
enzyme had been filtered off from the reaction mixture,
VCD spectra in CDCl3 of (–)- and (+)-2a–c, with un-
known absolute configuration, are shown in Figure 1 (top)
in comparison with the simulated VCD spectra of their R-
enantiomers (bottom). The VCD bands of aromatic ring
the solvents were removed in vacuo at room temperature.
vibrations at ~1600 cm–1 were the most intense in the case
It was important to avoid heating of the solution during of the fluorinated derivatives (+)- and (–)-2a, while only a
the distillation because (S)- and (R)-2a–b displayed ther- very weak band was observed for (+)- and (–)-2c, bearing
mal instability, which leads to racemization. Moreover, no substituent on the phenyl group. This shows that in this
the same effect was observed in the presence of polar and case even substituents situated far from the stereogenic
protic solvents such as methanol, ethanol, organic acids, center have influence on the spectrum, and coupling of the
or amines in the solution containing the enantiopure prod- aromatic ring vibrations with the vibrations of bonds
ucts, or a longer contact time with silica gel. For this rea- placed around the stereogenic center cannot be neglected.
son, the preparative-scale separation of the reaction As the VCD spectra of such chiral molecules may strong-
counterparts was performed with vacuum chromatogra- ly depend on the relative orientation of the aromatic ring,
phy, using the minimal amount of silica gel. After (R)-3a– a very careful conformational analysis was needed and no
c had been eluted with dichloromethane, the chromato- structural simplifications could be done for molecular
graphic column was washed with acetone in order to re- modeling.
cover (S)-2a–c rapidly.
Since the investigated compounds are conformationally
The preparative-scale enzymatic hydrolysis of (R)-3a–c very flexible molecules, the calculation of their theoretical
was also performed under the same conditions as used for VCD spectra was preceded by a systematic conformation-
the analytical-scale reactions. After the complete hydrol- al analysis, the R-enantiomers of 2a–c were chosen for the
ysis of the esters, the reaction mixture was extracted with quantum chemical calculations. A total of 25–27 con-
dichloromethane. The organic layer was dried over anhy- formers were found for each compound, of which ~9 had
drous sodium sulfate, followed by evaporation of the sol- an estimated population of more than 1%. The simulated
vent at room temperature. Compounds (R)-2a–c were VCD spectra of (R)-2a–c in Figure 1 were obtained as the
purified using the procedure described above.
population-weighted sums of the calculated VCD spectra
of their individual conformers with populations of more
than 1%, the contributions of other, higher-energy con-
formers being neglected (for the computational details,
see the VCD spectroscopic measurements and quantum
chemical calculations).
The residual enantiomers formed in the low-conversion
and in the high-conversion enzymatic acylations, were
used to recover the racemic starting materials rac-2a–c.
First, (R)-3a–c from the high-conversion reaction was en-
zymatically hydrolyzed to (R)-2a–c. These compounds
were mixed with the (S)-2a–c formed in the low-conver- The VCD spectra of enantiomers are opposite in sign and
sion enzymatic acylation. In consequence of their thermal in general there is very good agreement between the mea-
enantiostability, on refluxing mixtures in toluene, the sured spectra of the (+)-enantiomers and the calculated
complete racemization occurred in 3–4 hours for 2a,b and spectra of the R-enantiomers of the same compounds, in
48 hours for 2c. The recovery rate for all compounds was terms of both the positions, and the signs of the VCD
around 90%.
bands, the matching pairs of vibrational bands being la-
beled with corresponding numbers (Figure 1).
The absolute configuration of the synthesized enantio-
merically enriched 1-aryl-3-chloropropanol derivatives The common spectral feature of (+)-2a–c showing up as a
(+)-2a–c and (–)-2a–c was assigned by vibrational circu- +/–/+ band pattern around 1300 cm–1 and a positive band
lar dichroism (VCD) measurements combined with quan- at ~1200 cm–1, very well reproduced by the calculations
tum chemical calculations at DFT level of theory. VCD,
Synthesis 2011, No. 18, 2921–2928 © Thieme Stuttgart · New York

PAPER
Synthesis of Both Enantiomers of 3-Chloro-1-arylpropan-1-ols
2925
Figure 1 VCD spectra of compounds (–)-2a and (+)-2a, (–)-2b and (+)-2b, and (–)-2c and (+)-2c measured in CDCl3 (top) in comparison
with the simulated VCD spectrum of (R)-2a, (R)-2b, and (R)-2c (bottom), obtained as a population-weighted sum of the calculated spectra of
individual conformers. Corresponding bands are labeled with identical numbers.
a ChiralPak IB column and n-hexane–i-PrOH (98:2) were used. GC
for (R)-2a–c, suggests that these compounds belong in the
analyses were carried out with an Agilent 7890 A GC system. Enan-
same stereochemical series.
tiomeric separations of rac-2a–c and rac-3a–c were run on an
The comparison of the measured and calculated VCD
spectra and the considerations presented above allow the
unequivocal assignment of the absolute configurations of
(+)-2a–c as R and of (–)-2a–c as S.
Astec-Chiral column (30 m × 0.25 mm, B-DM) at a flow rate of 1
mL min–1, with a split ratio of 80 in isothermic mode at 180 °C (car-
rier gas N2; head pressure: 0.276 bar; injector: 250 °C; FID detector:
250 °C; Table 5).
Table 5 Retention Time (tR) of Compounds rac-2a–c and rac-3a–c
All air- or moisture-sensitive reactions were conducted under an at-
mosphere of dry argon. All starting materials and reagents were pur-
chased from Aldrich, Alfa-Aesar, Fluka, or Merck Company. All
solvents were of reagent grade, but anhyd solvents were freshly dis-
tilled before use (CH2Cl2 was distilled from CaH2). CDCl3 (99.96%
D) used as solvent for VCD spectroscopy was purchased from
Aldrich.
Compound
HPLC analysis
GC analysis
S
R
S
R
2a
2b
2c
3a
3b
3c
22.8
32.3
14.4
13.1
11.7
6.0
24.8
36.4
16.5
11.1
10.0
5.7
11.9
50.9
11.0
12.9
32.6
8.7
12.6
50.4
11.3
13.1
33.3
8.9
Lipases A, G, M, N, P and lipases from Pseudomonas fluorescens
(LAK) and Pseudomonas cepacia (LPS) were acquired from
Amano, England. Lipase from Candida rugosa (CRL) and pig liver
esterase (PLE) were purchased from Fluka. Immobilized lipase B
from Candida antarctica (CaLB, Novozym 435), lipase A from
Candida antarctica (CaLA), and lipase from Thermomyces lanugi-
nosus (Lipozyme TLIM) were purchased from Novozyms, Den-
mark.
1H NMR spectra were recorded on a Varian Mercury Plus 400 MHz
TLC was carried out using Merck Kieselgel 60F254 sheets. Spots
were visualized using a UV lamp and by treatment with 5% ethan-
olic phosphomolybdic acid soln and heating. Preparative chromato-
graphic separations were performed using column chromatography
on Merck Kieselgel 60 (63–200 mm). Yields refer to chromato-
graphically and spectroscopically pure compounds. IR spectra were
recorded in KBr pellets on a Perking-Elmer FT-IR 1650 spectrom-
eter. Optical rotations were determined on a Bellingham-Stanley
ADP 220 polarimeter and [a]D values are given in units of 10–1 deg
cm2 g–1. Electron impact mass spectra (EI-MS) were taken on a
LCQ Advantage spectrometer by Thermo Fisher operating at 70 eV.
spectrometer; except rac-3a and rac-3b (300 MHz, CDCl3) and 13
C
NMR spectra were recorded on a Bruker Advance spectrometer op-
erating at 75 MHz; 1H spectra were referenced internally to the sol-
vent signal (CHCl3, d = 7.26) and 13C spectra to the solvent signal
(CDCl3, d = 77.7).
Melting points were determined on a Büchi B-540 apparatus and are
uncorrected. Elemental analysis was collected on Carlo Erba Ele-
mental Analyzer, Model 1012. HPLC analyses for the enzymatic re-
actions and for the racemic and enantiopure forms of 2a–c and 3a–
c were made with an Agilent 1200 instrument. Enantiomeric sepa-
ration of rac-2a,b and rac-3a,b was performed with a tandem of
ChiralPak-IA and -OJ columns (4.6 × 250 mm) using n-hexane–i-
PrOH (95:5). For the enantiomeric separation of rac-2c and rac-3c,
The determination of E was based on the equations: E = ln[(1 – c)(1
– eeS)]/ln[(1 – c)(1 + eeS)]; c = ees/(eeS + eeP) using linear regression
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L. A. Pop et al.
PAPER
{E as the slope of the line ln[(1 – c)(1 – eeS)] vs ln[(1 – c)(1 +
NaBH4 (1.29 g, 34 mmol) with stirring at –15 °C for 2 h. Workup
used ice-cold H2O (50 mL) and the pH was adjusted to 4–5 with
10% HCl; extraction with CH2Cl2 (3 × 50 mL) and washing with
H2O (2 × 15 mL) gave an oil residue that was purified by column
chromatography (silica gel, CHCl3) to give rac-2b (3.17 g, 10.69
mmol, 63%) as a colorless oil; (Lit.24 bp 151–152 °C/0.13 mbar);
Rf = 0.4 (CHCl3).
eeS)]}.23
The prochiral ketones 1a and 1c were commercially available and
only the prochiral ketone 1b was chemically synthesized.
3-Chloro-1-(4-iodophenyl)propan-1-one (1b)
To a suspension of AlCl3 (6.00 g, 45 mmol) and CH2Cl2 (10 mL)
was added, under argon, 3-chloropropionyl chloride (5 mL, 53.64
mmol) over 15 min and the mixture was stirred at r.t. for a further
15 min. To the cooled soln (0–5 °C), iodobenzene (5 mL, 44.70
mmol) was added dropwise over 30 min and the soln was stirred at
r.t. for 3 h. Ice-cold H2O (30 mL) was then added and the organic
layer was washed with H2O (3 × 30 mL), Na2S2O3 soln (15%, 2 ×
20 mL), sat. Na2CO3 (2 × 30 mL), and finally H2O (2 × 10 mL). Af-
ter drying (anhyd MgSO4) and evaporation in vacuo, the crude
product was crystallized [CH2Cl2 (10 mL) and hexane (40 mL]20 to
give 1b (6.71 g, 22.78 mmol, 51%); mp 83–85 °C (Lit.20 83–84 °C);
Rf = 0.6 (toluene).
IR (KBr): 661, 715, 818, 927, 1004, 1059, 1195, 1259, 1357, 1399,
1482, 1587, 1718, 1764, 2958, 3410 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01–2.08 (m, 2 H, H2x, OH),
2.14–2.25 (m, 1 H, H2y), 3.51–3.57 (m, 1 H, H3x), 3.70–3.76 (m, 1
H, H3y), 4.91 (dd, J = 8.6, 4.5 Hz, 1 H, H1), 7.07–7.13 (m, 2 H,
HAr), 7.66–7.70 (m, 2 H, HAr).
13C NMR (75 MHz, CDCl3): d = 41.16, 41.45, 70.56, 93.21, 127.65,
137.59, 143.22.
MS (EI, 70 eV): m/z (%) = 298 (37Cl, 3, M+), 296 (35Cl, 6, M+), 233
(95), 78 (100), 49 (44).
1H NMR (400 MHz, CDCl3): d = 3.41 (t, J = 6.7 Hz, 2 H, H2 or
H3), 3.91 (t, J = 6.7 Hz, 2 H, H3 or H2), 7.65–7.67 (m, 2 H, HAr),
7.84–7.86 (m, 2 H, HAr).
Anal. Calcd for C9H10ClIO (296.53): C, 36.45; H, 3.40; Found: C,
36.53; H, 3.71.
13C NMR (75 MHz, CDCl3): d = 39.13, 41.82, 102.44, 130.13,
3-Chloro-1-phenylpropan-1-ol (rac-2c)
Following the general procedure using commercially available 3-
chloro-1-phenylpropan-1-one (25.28 g, 0.15 mol), 96% EtOH (500
mL), and 98% NaBH4 (19.90 g, 0.52 mol); workup used ice-cold
H2O (250 mL) and the pH was adjusted to 5–6 with concd HCl; ex-
traction with CHCl3 (3 × 150 mL) and washing with H2O (2 × 50
mL) gave a residue that was purified by vacuum distillation to give
rac-2c (18.30 g, 0.11 mol, 72%) as a colorless oil; bp 115–116 °C/
4–5.33 mbar (Lit.25 125–130 °C/8–10.6 mbar), Rf = 0.3 (toluene).
136.31, 138.82, 196.73.
Anal. Calcd for C9H8OClI: C, 36.67; H, 2.72. Found: C, 36.25; H,
2.57.
Racemic Alcohols; General Procedure
A soln of commercially available or chemically synthesized
prochiral ketone 1a–c in 96% EtOH was cooled to –20 °C and
NaBH4 (98%) was added in small portions. The suspension was
stirred at –15 °C for 3 h. Ice-cold H2O was then added and the mix-
ture was stirred for 15 min and concentrated under reduced pres-
sure. The inorganic salt was filtered off and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were washed
with H2O, dried (anhyd MgSO4), and concentrated under reduced
pressure. The residue was purified by vacuum distillation to give the
desired product.21
IR (KBr): 656, 699, 767, 914, 968, 1019, 1061, 1143, 1201, 1285,
1338, 1452, 1492, 2957, 2985, 3030, 3250 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.03–2.11 (m, 1 H, H2x), 2.17–
2.26 (m, 2 H, H2y, OH), 3.51–3.57 (m, 1 H, H3x), 3.69–3.75 (m, 1
H, H3y), 4.91 (dd, J = 8.4, 4.7 Hz, 1 H, H1), 7.25–7.37 (m, 5 H,
HAr).
13C NMR (75 MHz, CDCl3): d = 41.31, 41.66, 71.18, 125.70,
127.82, 128.57, 143.59.
MS (EI, 70 eV): m/z (%) = 172 (37Cl, 14, M+), 170 (35Cl, 44, M+),
107 (100), 79 (87), 51 (33).
3-Chloro-1-(4-fluorophenyl)propan-1-ol (rac-2a)
Following the general procedure using a soln of commercially
available 3-chloro-1-(4-fluorophenyl)propan-1-one (25.53 g, 0.14
mol) in 96% EtOH (250 mL), 98% NaBH4 (7.80 g, 0.21 mol); work-
up with ice-cold H2O (100 mL) and extraction CH2Cl2 (3 × 50 mL)
and washing H2O (2 × 30 mL) gave a residue that was purified by
vacuum distillation to give rac-2a (19.80 g, 0.10 mol, 77%) as a col-
orless oil; bp 116–118 °C/4 mbar (Lit.20 101–102 °C/0.13 mbar);
Rf = 0.3 (toluene).
Anal. Calcd for C9H11ClO (170.64): C, 63.35; H, 6.50; Found: C,
62.98; H, 6.54.
Acylation Reaction; General Procedure
The chemical acylation of rac-2a–c was performed, but it was ob-
served that other compounds appeared and we could not observe
rac-3a–c by HPLC analysis. Then enzymatic acylation of rac-2a–c
was performed and the compounds rac-3a–c were observed by
HPLC analysis.
IR (KBr): 656, 726, 836, 926, 1013, 1054, 1158, 1225, 1293, 1510,
1603, 2950, 3200 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.99–2.07 (m, 1 H, H2x), 2.14–
2.23 (m, 1 H, H2y), 2.35 (s, 1 H, OH), 3.49–3.54 (m, 1 H, H3x),
3.67–3.74 (m, 1 H, H3y), 4.91 (dd, J = 8.4, 4.9 Hz, 1 H, H1), 6.99–
7.06 (m, 2 H, HAr), 7.28–7.33 (m, 2 H, HAr).
13C NMR (75 MHz, CDCl3): d = 41.39, 41.56, 70.61, 115.30 (d,
JC-F = 21.4 Hz), 127.35 (d, JC-F = 8.2 Hz), 139.36 (d, JC-F = 3.3 Hz),
160.65 (d, JC-F = 245.9 Hz).
Enzymatic acylation reaction: To a mixture of rac-2a–c (200 mg)
in n-hexane (10 mL), CaLA (100 mg) and vinyl acetate (10 mL) or
vinyl butanoate (10 mL) were added and the mixture was shaken for
24 h at 250 rpm at r.t. After the reaction was complete (TLC), rac-
3a–c was separated from the enzyme, the solvent was removed in
vacuo affording the pure product.
MS (EI, 70 eV): m/z (%) = 190 (37Cl, 4, M+), 188 (35Cl, 27, M+), 125
(100), 97 (61), 77 (31).
3-Chloro-1-(4-fluorophenyl)propyl Butyrate (rac-3a)
Following the general procedure gave, after column chromatogra-
phy (CH2Cl2), rac-3a a colorless liquid, (273.2 mg, 1.06 mmol,
99.5%); Rf = 0.9 (CH2Cl2).
Anal. Calcd for C9H10ClFO (188.63): C, 57.31; H, 5.34; Found: C,
57.48; H, 5.35.
IR (KBr): 739, 836, 939, 966, 1152, 1223, 1267, 1356, 1510, 1605,
1708, 2956, 2988 cm–1.
3-Chloro-1-(4-iodophenyl)propan-1-ol (rac-2b)
Following the general procedure using 3-chloro-1-(4-iodophe-
nyl)propan-1-one (1b, 5.00 g, 17 mmol), 96% EtOH (100 mL), 98%
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PAPER
Synthesis of Both Enantiomers of 3-Chloro-1-arylpropan-1-ols
2927
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.2 Hz, 3 H, H4¢x, H4¢y,
H4¢z), 1.61 (m, 2 H, H3¢x, H3¢y), 2.15 (t, J = 6.8 Hz, 2 H, H2¢x, H2¢y),
2.29–2.43 (m, 2 H, H2x, H2y), 3.40–3.59 (m, 2 H, H3x, H3y), 5.90
(dd, J = 8.3, 5.3 Hz, 1 H, H1), 7.04–7.00 (m, 2 H, HAr), 7.33–7.29
(m, 2 H, HAr).
13C NMR (75 MHz, CDCl3): d = 13.54, 18.34, 36.20, 38.94, 40.51,
72.16, 115.64 (d, JC-F = 21.9 Hz), 128.1 (d, JC-F = 8.8 Hz), 135.44
(d, JC-F = 3.3 Hz), 172.55.
Samples from the mixture (10 mL) were diluted with n-hexane (400
mL) and analyzed with HPLC/GC. For enantiomerically pure (R)-3-
chloro-1-arylpropanoates (R)-3a–c, the reactions were stopped by
filtering the enzyme at approx 23–40% conversion, while for enan-
tiopure (S)-3-chloro-1-arylpropanols (S)-2a–c at 55–65% conver-
sion. Solvents were removed in vacuo and the crude product was
purified by vacuum chromatography (CH2Cl2) resulting in both op-
tically active (R)-3a–c and (S)-2a–c as semisolids. The whole
amount of the previously isolated (R)-3a–c, CRL, and the phosphate
buffer (20 mL) was shaken at 1000 rpm for several hours (2 h for
1a, 3 h for 1b,c). The dilution and substrate/enzyme ratio was the
same as previously described. The mixture was extracted with
CH2Cl2 (3 × 30 mL), the organic layers were dried (anhyd Na2SO4),
and the solvent removed in vacuo. The crude product was purified
by preparative vacuum-chromatography (CH2Cl2). The solvent was
removed in vacuo affording the enantiomerically enriched product
(R)-2a–c.
MS (EI, 70 eV): m/z (%) = 258.1 (35Cl, 0.04, M+), 188.1 (3.75),
125.1 (100), 97.1 (51.97), 77.1 (24.52), 43 (10.44).
3-Chloro-1-(4-iodophenyl)propyl Acetate (rac-3b)
Following the general procedure gave, after column chromatogra-
phy (CH2Cl2), rac-3b (227.2 mg, 0.67 mmol, 99.5%) as a colorless
liquid; Rf = 0.6 (CH2Cl2).
IR (KBr): 700, 736, 819, 965, 1005, 1238, 1370, 1484, 1524, 1734,
2957, 2989 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.98 (s, 3 H, H2¢x, H2¢y, H2¢z),
2.04–2.30 (m, 2 H, H2x, H2y), 3.31–3.49 (m, 2 H, H3x, H3y), 5.79
(dd, J = 8.3, 5.3 Hz, 1 H, H1), 6.99 (d, J = 8.3 Hz, 2 H, HAr), 7.58
(d, J = 8.3 Hz, 2 H, HAr).
13C NMR (75 MHz, CDCl3): d = 20.94, 38.60, 40.34, 72.40, 93.76,
128.18, 128.49, 137.59, 169.74.
MS (EI, 70 eV): m/z (%) = 339.9 (37Cl, 8.1, M+), 337.9 (35Cl, 21.59,
M+), 275 (40.98), 232.9 (74.73), 217 (17.90), 203 (13.71), 172.1
(37Cl, 31.05), 170.1 (35Cl, 82.26), 117.1 (100), 107.1 (74.34), 91.1
(41.69), 77.1 (32.51), 43 (43.94).
VCD Spectroscopic Measurements and Quantum Chemical
Calculations
VCD spectra of (+)-2a–c and (–)-2a–c at a resolution of 4 cm–1 were
recorded in CDCl3 soln with a Bruker PMA 37 VCD/PM-IRRAS
module connected to an Equinox 55 FTIR spectrometer.
The ZnSe photoelastic modulator of the instrument was set to 1300
cm–1 and an optical filter with a transmission range of 1800–800
cm–1 was used in order to optimize the sensitivity in the fingerprint
region of the spectrum. The instrument was calibrated for VCD in-
tensity with a CdS multiple-wave plate. A BaF2 cell with a path
length of 50 mm and sample concentrations of 100 mg/mL [for (+)-
and (–)-2a] and 200 mg/mL [for (+)- and (–)-2b,c] were used. In
order to increase the signal/noise ratio of the low-intensity VCD
signals, measurement times of 7 h (corresponding to ~24,000 accu-
mulated interferograms) were applied. Since both enantiomers of
the investigated compounds were available at comparable enantio-
meric purity, the instrumental baseline was calculated as the aver-
age of the raw VCD spectra of the opposite enantiomer samples and
this average was used for baseline correction (being subtracted from
the original VCD spectra). This way all eventual dichroic artifacts
caused by the BaF2 windows of the measurement cell or arising
from detector nonlinearity at the absorption band positions could be
cancelled.
3-Chloro-1-phenylpropyl Acetate (rac-3c)
Following the general procedure gave, after column chromatogra-
phy (CH2Cl2), rac-3c (248.3 mg, 1.2 mmol, 99.5%) as a colorless
liquid; Rf = 0.6 (CH2Cl2).
IR (KBr): 660, 699, 760, 971, 1023, 1225, 1284, 1370, 1452, 1495,
1734, 3033 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.07 (s, 3 H, H2¢x, H2¢y, H2¢z),
2.15–2.43 (m, 2 H, H2x, H2y), 3.40–3.60 (m, 2 H, H3x, H3y), 5.90
(dd, J = 8.3, 5.3 Hz, 1 H, H1), 7.30–7.36 (m, 5 H, HAr).
13C NMR (75 MHz, CDCl3): d = 20.91, 38.84, 40.49, 72.94, 126.19,
128.07, 128.46, 139.34, 169.80.
MS (EI, 70 eV): m/z (%) = 214.1 (37Cl, 0.89, M+), 212.1 (35Cl, 4.35,
M+), 172.1 (37Cl, 4.36), 170.1 (35Cl, 14.79), 117.1 (30.68), 105.1
(30.60), 91.1 (37.82), 77.1 (35.62), 43.0 (100).
Geometry optimizations and the computation of vibrational fre-
quencies and VCD rotatory strengths were performed for (R)-2a–c
with the Gaussian 03 quantum chemical software package.26 For
(R)-2a and (R)-2c at the B3LYP/6-31G(d) DFT level of theory was
used, while in the case of (R)-2b the B3LYP functional was applied
in combined with the LANL2DZ basis set for the iodine atom (for
which the 6-31G(d) basis set is not defined) and the 6-31G(d) basis
set for other atoms (C, H, O, Cl). The vibrational frequencies were
scaled by a factor of 0.963. VCD curves were simulated from the
calculated wave number and rotatory strength data by using Lorent-
zian band shape and a half-width at half-height value of 6 cm–1.
Analytic-Scale Enzymatic Acylation of rac-2a–c; General Pro-
cedure
A mixture of enzyme (10 mg), rac-2a–c (10 mg) and vinyl acetate
or vinyl butanoate (10 mL) in hexane (1 mL) was shaken at 1000
rpm and r.t. Samples (10 mL) were taken after 24 h and diluted with
n-hexane (400 mL). Samples (10 mL) were analyzed with HPLC,
GC, and TLC.
Acknowledgment
Analytic-Scale Enzymatic Hydrolysis of (R)-3a–c; General Pro-
cedure
Laura Ancuţa Pop wishes to thank for the financial support provi-
ded from programs co-financed by The Sectoral Operational Pro-
gramme Human Resources Development, Contract POSDRU 6/1.5/
S/3 – ‘Doctoral studies: through science towards society’. VCD
spectroscopic investigations were supported by the Hungarian Re-
search Fund OTKA (grant K81175 to Miklós Hollósi and K73389
to Péter Mátyus) and TÁMOP-4.2.1/B-09/1/KMR-2010-0001
(Péter Mátyus).
A mixture of enzyme (10 mg) and rac-3a–c (10 mg) in phosphate
buffer (20 mM, pH 8) was shaken at 1000 rpm and r.t. Samples (2
mL) were taken at every 30 min, diluted with n-hexane (400 mL),
dried (anhydrous Na2SO4), filtered, and analyzed with HPLC, GC,
and TLC.
Preparative-Scale Enzymatic Synthesis of (S)- and (R)-2a–c
A mixture of rac-2a–c (400 mg), vinyl butyrate/vinyl acetate (5
equiv), and LAK (300 mg) in n-hexane (10 mL) was shaken at r.t.
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(14) Hage, A.; Petra, D. G. I.; Field, J. A.; Schipper, D.;
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