Kinetic resolution of primary alcohols having remote stereogenic centers: lipase mediated kinetic resolution of (±)-3-chloro-3-arylpropanols

Article abstract of DOI:10.1016/j.tetasy.2006.06.001

Kinetic resolutions of (±)-3-chloro-3-arylpropanols by lipase mediated acetylation are described for the first time. Acetylation with CCL provided the best enantioselectivity amongst the enzymes used. Enantiomerically enriched products were obtained with up to 78% ee after two successive lipase-catalyzed acetylations. Different substituents on the aromatic ring and bromide, instead of chloride, on the substrates were found to have no drastic influence on the enantioselectivity of the reaction.

Full text of DOI:10.1016/j.tetasy.2006.06.001

Tetrahedron: Asymmetry 17 (2006± 1561–1567
Kinetic resolution of primary alcohols having remote
stereogenic centers: lipase mediated kinetic resolution of
(± ±)-)chloro)-)arylpropanols
*
¨
*
Alper Isleyen, Cihangir Tanyeli and Ozdemir Dogan
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 2 May 2006; accepted 5 June 2006
Abstract—Kinetic resolutions of (± ±)-)chloro)-)arylpropanols by lipase mediated acetylation are described for the first time. Acetylation
with CCL provided the best enantioselectivity amongst the enzymes used. Enantiomerically enriched products were obtained with up to
7
8% ee after two successive lipase)catalyzed acetylations. Different substituents on the aromatic ring and bromide, instead of chloride, on
the substrates were found to have no drastic influence on the enantioselectivity of the reaction.
2006 Elsevier Ltd. All rights reserved.
ꢀ
1
. Introduction
reacting carbonyl or alcohol group. Very limited examples
have been reported in which the chiral/prochiral center is
three or more bonds away from the reacting carbonyl/
Benzanilide derivatives are dual)acting agents, which have
both a)1)adrenoceptor antagonistic action and steroid 5a
reductase inhibitory activity. These properties make them
7
alcohol center. In one of these examples, Cambou and
1
7b
Klibanov used pig liver esterase to esterify alcohols
potent therapeutic agents for urethral obstruction caused
by benign prostatic hyperplasia, which is a common disease
in aging men. -)Chloro)-)arylpropanols are key inter)
having three bonds between the alcohol and the stereogenic
center with ees generally above 90%. However, the method
suffers from poor reproducibility and a low operational
2
8
mediates in the synthesis of biologically active benzanilide
stability of the enzyme. In order to overcome these prob)
1
derivatives. Recently, a new methodology was developed
lems, Ruppert and Gais colyophilized pig liver esterase
with methoxypolyethylene glycol to obtain a catalyst (PLE/
MPEG±, which showed an enhanced activity in organic
solvents but ees did not exceed -8% for the resolution of
in our group for the one)pot synthesis of racemic -)
-
chloro)-)arylpropanols. The synthesis of enantiopure -)
chloro)-)arylpropanols is a challenge for the synthesis of
the corresponding enantiopure benzanilide derivatives,
which might possibly display better biological activities.
9
-)methoxy butanol. Goj et al. studied the kinetic resolutions
of (± ±)1)acetoxy)2)fluoro)2)phenylalkanes by enzymatic
hydrolysis and of (± ±)1)hydroxy)2)fluoro)2)phenylalkanes
1
0
The chemo)enzymatic approach for asymmetric synthesis is
becoming increasingly accepted in synthetic strategies,
while the use of biocatalysts as routine chiral catalysts
has already found widespread application in preparative
by lipase)catalyzed acetylation. Although the reactive
center was two bonds away from the tertiary chiral center,
hydrolysis of 1)acetoxy)2)fluoro)2)stereogenic using CCL
gave 2)fluoro)2)phenylpropanol in -7% ee and 1)acetoxy)
2)fluoro)2)phenylpropane in 27% ee with 46% conversion.
When Amano PS was used in the hydrolysis of the same
substrate, an improved selectivity (79% ee for the alcohol
and 88% ee for the acetate with 42% conversion± was ob)
tained with an opposite specific rotation relative to the
CCL catalyzed hydrolysis. It was also reported that enzy)
matic esterification of 2)fluoro)2)phenylpropanol yielded
1)acetoxy)2)fluoro)2)phenylpropane in 95% ee with 46%
conversion.
4
organic chemistry over the last decade. Lipases are able
5
6
to catalyze asymmetric hydrolysis and esterification in a
wide range of substrates. However, in most cases, the sub)
strates undergoing the enzymatic reaction have the chiral/
prochiral center only one or two bonds away from the
*
Corresponding authors. Tel.: +90 -12 210 -2 22; fax: +90 -12 210 -2 00
¨
(
C.T.±; tel.: +90 -12 210 51 -4; fax: +90 -12 210 -2 00 (O.D.±; e)mail
addresses: tanyeli@metu.edu.tr; dogano@metu.edu.tr
0957)4166/$ ) see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.001

1562
A. Isleyen et al. / Tetrahedron: Asymmetry 17 (2006) 1561–1567
From these limited examples, it is difficult to make a gener)
alization that the enzymes studied are suitable for the
transformations of substrates with remote stereogenic cen)
The results of these studies are summarized in Table 2.
As can be seen in Table 2, stoichiometric amounts of
CCL and 0.6 equiv of vinyl acetate with respect to sub)
strate 1a gave the best results. Among the solvents tested,
cyclohexane and toluene gave good results. Although the
yields are very similar, the reaction in toluene requires a
longer time and the ee of alcohol 1a is lower compared
to cyclohexane (Table 2, entries 4 and 5±. When tert)butyl
vinyl ether was used as solvent, comparable ees relative to
cyclohexane were obtained, although the chemical yields
were too low (Table 2, entry 6±. In the case of tetrahydro)
furan the reaction was sluggish. Six days were required for
49% conversion even with the addition of fivefold excess of
vinyl acetate. Although the reaction in THF proceeded
slowly, there was no improvement in the enantioselectivity
(Table 2, entry 7±. We also tried the reaction at 14 ꢁC in
cyclohexane, which slowed down the reaction, -0% conver)
sion obtained after 22 h, but had no effect on the
enantioselectivity.
7
b,10
ters. The promising results obtained in the literature
triggered us to study the enzymatic resolution of (± ±)1)
hydroxy)-)chloro)-)arylpropanes and (± ±)1)acetoxy)-)
chloro)-)arylpropanes. Herein, we report the details of
our study.
2
. Results and discussion
For the synthesis of starting materials 1a–f, we have
-
already reported a one)pot procedure. When the styrenes
were reacted with methylene diacetate in the presence of
BF and tetra)n)butylammonium chloride, (± ±)-)chloro)
-
-
)arylpropanols 1a–f were obtained in 45–84% yield along
with minor amounts (<5%± of (± ±)1)acetoxy)-)chloro)-)
arylpropanes 2a–f (Scheme 1±.
Due to the relatively lower enantioselectivities of the enzym)
atic acetylation of (± ±)1, we tried a multiple resolution
strategy. When substrate (± ±)1a was subjected to CCL
mediated double enzymatic resolution, alcohol (+±)1a
was obtained in 78% ee (Scheme -±. However, the same
strategy with HLE gave (ꢀ±)1a in 42% ee. In the second
kinetic resolution step, for both CCL and HLE, a reversal
of enantioselectivity for the acetylated product 2a relative
to the first kinetic resolution step was observed. This result
can be attributed to the increased rate of the acyl transfer
to a less reactive enantiomeric form of alcohol due to the
increase in its concentration relative to the first kinetic res)
olution step. We also tried a third acetylation run with
CCL (not shown in Scheme -±, which diminished the ee
of alcohol (+±)1a from 78% to 68% after a -0% conversion.
Ester (+±)2a was isolated in 42% ee in the third run.
O
O
Cl
OH
Cl
OAc
Me
Bu
BF
O
O
Me
+
4
NCl, CH
o
2 2
Cl
X
3
(g), -78 C to rt
X
X
(
±)1a-f
(±)ꢀa-f
X= H(1a), o-Br(1b), o-F(1c), p-Br(1d), p-Cl(1e), p-F(1f)
Scheme 1.
Over the course of our studies on the biotransformations of
± ±)-)chloro)-)phenylpropanol 1a, screening reactions
were first examined with CCL, PPL, PLE, HLE, Amano
PS, and Amano PSC)II (Scheme 2±. Among the enzymes
studied, CCL mediated esterification of substrate (± ±)1a
gave the highest enantioselectivity by giving (+±)alcohol
(
1
a in 45% yield with 25% ee and (ꢀ±)ester 2a in -5% yield
with 28% ee (Table 1, entry 1±. HLE mediated esterification
of the same substrate, on the other hand, gave the products
in slightly lower yields and ees with an opposite configura)
tion (Table 1, entry 4±. We also planned to study the
enzymatic hydrolysis of (± ±)1)acetoxy)-)chloro)-)phenyl)
propane 2a, but (± ±)2a was found to decompose almost
completely in both phosphate and tris buffer conditions
in the absence of enzymes. This was presumably due to
the side reactions of the benzylic chloride group, which
might undergo elimination and displacement reactions
under aqueous conditions. Due to these uncontrolled side
reactions, we continued our studies with enantioselective
esterification in the organic medium.
In the study of Goj et al., they observed that the isobutyl
group on the aromatic ring of (± ±)1)acetoxy)2)fluoro)2)
(
p)isobutylphenyl±propane decreased the ee value
10
dramatically in enzymatic hydrolysis. This result clearly
demonstrates the importance of the substituents on the
aromatic ring in chiral recognition of such compounds.
In the light of this observation, we thought that it would
be interesting to find out the substituent effect on the
enzymatic acetylation of our substrates. For this reason,
various racemic -)chloro)-)arylpropanols 1a–f and -)bro)
mo)-)phenylpropanol - were subjected to single enzymatic
acetylation by CCL (Scheme 4±. The results of these studies
are summarized in Table -. Enantiomeric excesses for the
unreacted alcohols ranged between 21% and 4-%, while
those of acetylated products were between 24% and -8%.
Based on these results, it can be concluded that different
substituents at different position of the aromatic ring have
no real effect on the lipase CCL selectivity. A slight increase
in ees was observed in case of bromide at the ortho position
Cl
OH
Cl
OAc Cl
+
OH
enzyme
vinyl acetate
2
0-25 o
C
cyclohexane
(
±)-1a
(-)-ꢀa
(+)-1a
(
Table -, entry 6±. This result can be explained with the bet)
Scheme 2.
ter fit into the enzyme’s pocket due to fixed conformation
of substrate 1f caused by restricted rotation of the aromatic
ring because of proximal halides in the molecule. In order
to determine whether a different halide at the benzylic
position of substrate 1 had any effect on the selectivity,
After finding out that CCL is the best enzyme for the acet)
ylation of racemic 1a, we studied the effect of amount of
the enzyme and acetylating reagent as well as the solvent.

A. Isleyen et al. / Tetrahedron: Asymmetry 17 (2006) 1561–1567
Table 1. Enzymatic acetylation studies of (± ±)1a with various enzymes
156-
a
b
Entry
Enzyme
Time
Conv. (%±
Alcohol 1a
Ester 2a
c
d
c
d
Yield (%±
ee (%±
Yield (%±
ee (%±
1
2
-
4
5
6
CCL
PPL
PLE
HLE
Amano PS
Amano PSC)II
- h
1 d
1 d
1 d
2 h
1 d
44
4-
-0
52
-7
64
47
-5
-4
-1
57
20
25
4
2
--
20
16
29
--
-0
28
6
5
ꢀ21
ꢀ20
5
8
4
1
a
b
c
1
75.0 mg of enzyme/mmol (± ±)1a and same equivalent of vinyl acetate as that of (± ±)1a was used in reactions.
1
Determined by H NMR analysis.
Yields are isolated yields.
Determined by HPLC using Chiralcel ODH column.
d
Table 2. Effect of the amount of CCL and vinyl acetate on enzymatic acetylation of (± ±)1a
b
Entry
Amount
of CCL
Equiv of
vinyl acetate
Solvent
Time
Conversion (%±
Alcohol 1a
Ester 2a
a
c
d
c
d
Yield (%±
ee (%±
Yield (%±
ee (%±
1
2
-
4
5
6
17.5
175.0
175.0
175.0
175.0
175.0
175.0
-8
-8
—
—
- d
49
5-
61
44
50
46
49
29
44
27
45
41
5
21
24
-5
29
24
27
14
-1
46
54
--
-9
6
22
21
2-
--
24
-0
26
-5 min
165 min
225 min
455 min
22 h
1.2
0.6
0.6
0.6
0.6
Cyclohexane
Cyclohexane
Toluene
TBVE
e
7
THF
6 d
28
22
a
b
c
In mg CCL/mmol (± ±)1a.
Determined by H NMR analysis.
Yields (%± are given as isolated yields.
Enantiomeric excess values were determined by HPLC using Chiralcel ODH column.
Total of fivefold excess of vinyl acetate was added in portions during 6 days.
1
d
e
Cl
OAc Cl
+
OH
Cl
OH
Cl
OH
+
Cl
OAc
HLE
CCL
vinyl acetate
vinyl acetate
5 hr.
5
0 hr.
(+)-ꢀa
(-)-1a
28% ee
(±)-1a
(+)-1a
29% ee
(-)-ꢀa
31% ee
5
7% conversion
46% conversion
2
0% ee
vinyl acetate
26 hr.
2% conversion
vinyl acetate
8 hr.
64% conversion
HLE
CCL
OH
4
Cl
(
OAc
Cl
OH
Cl
Cl
OAc
+
+
-)-ꢀa
2% ee
(-)-1a
16% ee
(+)-1a
78% ee
(+)-ꢀa
8% ee
4
Scheme -.
we synthesized compound -. When this substrate was
subjected to CCL mediated acetylation under the same
reaction conditions as previous substrates, similar results
were obtained in terms of yield and enantioselectivity
(Table -, entry 7±. This experiment showed that the
bromide has a larger size than chloride and had no effect
on the enzyme selectivity. Interestingly, enantiomerically
enriched compound - racemized completely within a few
days upon standing in solution (n)hexane/2)propanol,
10:1, v/v± at +4 ꢁC. This can be attributed to the better
Y
OH
Y
X
OAc
+
Y
OH
CCLa
b
vinyl acetate
c
7
h
2
0-25 oC
cyclohexane
X
X
(
-)-ꢀa-f, 4
(+)-1a-f, 3
(±)-1a-f, 3
Scheme 4. Reagents and conditions: (a± 175.0 mg CCL/mmol (± ±)1 or
± ±)- was used in reactions; (b± 0.6 equiv vinyl acetate was used relative to
substrate (± ±)1 or (± ±)-; (c± except substrate 1a, for which reaction time
(
was 225 min.

1564
A. Isleyen et al. / Tetrahedron: Asymmetry 17 (2006) 1561–1567
Table -. Enzymatic acetylation of (± ±)-)halo)-)aryl)propanols 1a–f and - with CCL
a
Entry
Substrate
X, Y
Conversion (%±
Alcohol 1, -
Ester 2, 4
b
c
d
25
b
c
d
p
25
Yield (%±
ee (%±
E
s
½aꢁD
Yield (%±
ee (%±
E
½aꢁD
1
2
-
4
5
6
7
1a
1b
1c
1d
1e
1f
-
H, Cl
44
40
-9
-8
52
52
-8
45
60
51
--
45
24
27
29
21
21
2-
25
4-
21
2.8
2.-
2.4
2.7
2.0
-.4
2.5
+12.1
+15.4
+10.0
+8.4
+6.7
+6.0
--
-6
29
17
44
28
19
--
-2
-7
-0
24
-6
-8
2.5
2.4
2.7
2.2
2.1
-.0
2.8
ꢀ1-.8
ꢀ16.-
ꢀ19.7
ꢀ11.2
ꢀ18.0
ꢀ11.8
ꢀ28.7
p)F, Cl
p)Cl, Cl
p)Br, Cl
o)F, Cl
o)Br, Cl
H, Br
+14.2
a
b
c
1
Determined by H NMR analysis.
Yields (%± are given as isolated yields.
Enantiomeric excess values were determined by HPLC using Chiralcel ODH column.
d
11
Calculated using Sih et al.’s method.
leaving ability of bromide than chloride. Under the same
conditions, racemization of compound 4 (acetylated form
of -± was not observed. This may indicate that hydroxyl
group plays a role in the racemization process.
chromatography was performed on silica gel (60 mesh,
Merck±. Analytical thin layer chromatography (TLC± was
performed on precoated silica gel (60 F254, Merck±. Com)
mercially available reagents and solvents were used, unless
otherwise stated, without further purification. CCL (lipase,
Type VII, from Candida rugosa±, PPL (Lipase Type II,
from Porcine pancreas±, Amano PS, Amano PSC)II and
HLE (Horse Liver Esterase)acetone powder± were
purchased from Aldrich. PLE (Pig Liver Esterase± was
purchased from Sigma as powder.
-. Conclusion
We have studied enzymatic resolutions of (± ±)-)halo)-)
arylpropanols for the first time. Among the enzymes used
under the esterification conditions, CCL showed the best
enantioselectivity. Even though these substrates have a ste)
reogenic center three bonds away from the reaction site,
they showed enantioselectivities up to 4-% for the alcohols
and -8% for the esters. We have also showed that the enan)
tiopurity of alcohol 1a can be raised to 78% by double
enzymatic acetylation. It was also found that CCL and
HLE show opposite stereoselectivity in the products. Sub)
stituents on the aromatic ring or benzylic bromide instead
of chloride were found to have no drastic influence on the
enantioselectivity of the reaction.
4.1. Preparation of methylene diacetate stock solution
Bu NOAc (11.4 g, -7.8 mmol± and dry benzene (60 mL±
4
were placed in a round)bottomed flask equipped with a
Dean–Stark apparatus. This solution was refluxed under
an argon atmosphere with continuous removal of the azeo)
trope over a period of 1 h. Then the flask was connected to
a vacuum line to remove the rest of the benzene. Finally,
dry CH Cl (-7 mL± was added to the flask containing
2
2
NBu OAc (11.2 g, -7.1 mmol± under an argon atmosphere.
4
This stock solution was allowed to stand at rt for - days
before use and then was kept at 4 ꢁC.
4. Experimental
4.2. General procedure for the synthesis of -)chloro)-)
arylpropanols
1
1-
The H and C NMR spectra were recorded in CCl4/
CDCl (2:-, v/v± solvent system on a Bruker Spectrospin
-
1
Avance DPX 400 spectrometer. H NMR spectra were
Methylene diacetate stock solution (5.0 mL± and alkene
1a–f (0.78 mmol± were added to a 10 mL flask under an
argon atmosphere. The flask was then cooled to ꢀ78 ꢁC
reported in parts per million using TMS as an internal stan)
dard (TMS at 0.00 ppm±. C NMR spectra were reported
in parts per million using solvent as an internal standard
1
-
and BF gas slowly bubbled through the solution for
-
(
CDCl at 76.9 ppm±. Infrared spectra were recorded on
20 min to give a cloudy solution. At this point, the BF-
flow was stopped and the reaction flask allowed to warm
up to rt and left stirring overnight at this temperature. In
the morning, water was added (10 mL± to the reaction
flask, followed by extraction with CH Cl (- · 10 mL±.
-
a Bruker IFS 66V/S series FT)IR spectrometer using
CHCl as the solvent. GC–MS spectra were obtained with
-
a Thermo)Quest (TSP± TraceGC)2000 Series instrument
equipped with a Phenomenex Zebron ZB)5 capillary
column (5% phenylmethylsiloxane, -0 m, 250 lm±, MS:
Thermo Quest Finnigan multi Mass (EI, 70 eV±. High
resolution mass spectra (HRMS± were recorded on a Kra)
tos MS25RFA mass spectrometer using electron impact
2
2
The combined organic layer was dried over MgSO and
4
concentrated. Final purification was carried out by flash
column chromatography on silica gel using 5:1 hexanes/
ethyl acetate as the eluent.
(
EI± method. Optical rotations were measured in CHCl-
solutions in a 1 dm cell using a Rudolph Autopol III polar)
imeter at 25 ꢁC. HPLC measurements were performed with
Dionex System instrument. Separations were carried out
on Chiralcel OD)H analytical column (250 · 4.60 mm±
with hexane/2)propyl alcohol as eluent. Flash column
Compounds (± ±)1a–f were synthesized and all were in
accordance with our previous report.
-
4.2.1. Synthesis of (± ±)-)bromo)-)phenylpropan)1)ol (-±.
Methylene diacetate (MDA± was isolated from MDA stock

A. Isleyen et al. / Tetrahedron: Asymmetry 17 (2006) 1561–1567
1565
solution as follows: MDA stock solution was concentrated
under reduced pressure and then n)hexane was added to the
at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow 1.0 mL
ꢀ
1
min , 20 ꢁC, R for (+±)1a: -6.- min; (ꢀ±)1a: 5-.2 min.
f
residue. Solid particles (NBu Cl± were separated by filtra)
All spectroscopic data are in agreement with those pub)
4
-
tion and the liquid part was concentrated under reduced
pressure to give MDA.
lished for racemic 1a.
4
.-.-. (ꢀ±)-)Chloro)-)(4)fluorophenyl±propyl acetate (2b±.
2
D
5
MDA (155 mg, 1.17 mmol±, NBu Br (754 mg, 2.-4 mmol±,
and styrene 1a (81 mg, 0.78 mmol± were added to a 10 mL
flask under an argon atmosphere. The flask was then
4
Colorless oil (14.2 mg, -6% yield±, ½aꢁ ¼ ꢀ16:- (c 1.4,
CHCl ± for -2% ee; HPLC: Chiralcel OD)H column, UV
-
detection at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow
ꢀ
1
cooled to ꢀ78 ꢁC and BF gas was slowly bubbled through
-
1.0 mL min , 20 ꢁC, Rf for (ꢀ±)2b: 8.- min; (+±)2b:
the solution for 20 min to give a cloudy solution. At this
9.- min. IR (CHCl ±: m = 2925, 1742, 1607, 1505, 1464,
-
ꢀ
1
1
point, the BF flow was stopped and the reaction flask
-
1-69, 1250, 1195, 1157, 1029, 724, 548 cm ; H NMR
CDCl –CCl ±: d 2.0- (s, -H, COCH ±, 2.26–2.4- (m, 2H,
was allowed to warm up to rt and left stirring overnight
at this temperature. In the morning, water was added
(
-
4
-
CH , H)2±, 4.12 (m, 1H, CH , H)1±, 4.21 (m, 1H, CH ,
H)1±, 4.94 (dd, J = 5.9, 8.7 Hz, 1H, CH, H)-±, 7.0- (m,
2H, CH, Ar±, 7.-5 (m, 2H, CH, Ar±; C NMR (CDCl-–
CCl4±: 20.71, -8.99, 58.84, 61.-0, 115.68 (d,
J = 21.6 Hz±, 128.64 (d, J = 7.7 Hz±, 1-6.90, 162.55 (d,
2
2
2
(
10 mL± to the reaction flask, followed by extraction with
1
-
CH Cl (- · 10 mL±. The combined organic layer was dried
2
2
over MgSO and concentrated. Final purification was done
4
d
by flash column chromatography on silica gel using 5:1
hexanes/ethyl acetate as the eluent to give product -
J = 247.1 Hz± 170.18 (C@O±; MS (EI± m/z (%±: 171 (40±
+
(
1-8 mg, 82% yield± as a colorless oil. R (EtOAc/hexane
f
[M ꢀOAc], 169 (100±, 142 (90±, 1-5 (90±, 1-4 (100±, 121
2
1
:1±: 0.61; IR (CHCl ±: m = -444, 2926, 1456, 125-, 109-,
-
1 1
(90±, 108 (40±, 101 (40±, 95 (-5±, 75 (-0±, 4- (100±.
ꢀ
005, 889, 806, 721, 626, 5-7 cm ; H NMR (CDCl –
-
CCl ±: d 1.60 (br s, 1H, OH±, 2.-0 (m, 1H, CH , H)2±,
4
2
4
.-.4. (+±)-)Chloro)-)(4)fluorophenyl±propan)1)ol (1b±.
2
.46 (m, 1H, CH , H)2±, -.72 (m, 1H, CH , H)1±, -.81
25
2
2
Colorless oil (19.4 mg, 60% yield±, ½aꢁ ¼ þ15:4 (c 1.9,
D
(
m, 1H, CH , H)1±, 5.17 (dd, J = 5.7, 9.1 Hz, 1H, CH,
2
CHCl ± for 21% ee; HPLC: Chiralcel OD)H column, UV
-
H)-±, 7.26 (d, J = 7.- Hz, 1H, CH, Ph±, 7.-1 (t,
J = 7.- Hz, 2H, CH, Ph±, 7.-8 (d, J = 7.- Hz, 2H, CH,
detection at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow
1.0 mL min , 20 ꢁC, R
2
ꢀ1
1
-
f
for (ꢀ±)1b: 2-.9 min; (+±)1b:
Ph±. C NMR (CDCl –CCl ±: d 42.-1, 51.65, 60.49,
-
4
6.7 min. All spectroscopic data are in agreement with
1
27.--, 128.--, 128.66, 141.88.
-
those published for racemic 1b.
4.-. General procedure for enzymatic acetylation of 1a–f
and -
4
.-.5. (ꢀ±)-)Chloro)-)(4)chlorophenyl±propyl acetate (2c±.
2
D
5
Colorless oil (12.- mg, 29% yield±, ½aꢁ ¼ ꢀ19:7 (c 1.2,
CHCl ± for -7% ee; HPLC: Chiralcel OD)H column, UV
To a solution of racemic alcohol 1a–f/- (0.171 mmol± and
vinyl acetate (9.5 lL, 0.10- mmol± in cyclohexane (1 mL±,
-
detection at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow
ꢀ
1
1
1
1
.0 mL min , 20 ꢁC, Rf for (ꢀ±)2c: 9.6 min; (+±)2c:
-
0 mg CCL (or lipase± was added and the reaction mixture
0.8 min. IR (CHCl ±: m = 2925, 1741, 1492, 1458, 1-6-,
shaken at 20–25 ꢁC (TLC monitoring±. The reaction
mixture was filtered and the filtrate concentrated under
reduced pressure. The products, ester 2a–f/4 and alcohol
-
ꢀ1
1
257, 1201, 1095, 1008, 806, 721, 620, 5-0 cm
;
H
NMR (CDCl –CCl ±: d 2.0- (s, -H, COCH ±, 2.24–2.41
-
4
-
(m, 2H, CH , H)2±, 4.11 (m, 1H, CH , H)1±, 4.21 (m,
1
a–f/-, were separated and purified by flash column chro)
2
2
1
7
2
1
1
1
H, CH , H)1±, 4.92 (dd, J = 5.9, 8.7 Hz, 1H, CH, H)-±,
matography (EtOAc/hexanes, 1:5±.
2
1
-
.-1 (br s, 4H, CH, Ar±; C NMR (CDCl –CCl ±: d
-
4
0.71, -8.86, 58.75, 61.22, 128.24, 128.94, 1-4.4-, 1-9.49,
4
.-.1. (ꢀ±)-)Chloro)-)phenylpropyl acetate (2a±. Light
+
2
D
5
70.16 (C@O±; MS (EI± m/z (%±: 171 (40± [M ꢀOAc],
yellow oil (12.0 mg, --% yield±, ½aꢁ ¼ ꢀ19:9 (c 1.2,
86 (15±, 185 (20±, 158 (10±, 150 (45±, 1-7 (10±, 115 (-0±,
0- (20±, 89 (10±, 77 (15±, 75 (10±, 4- (100±.
CHCl ± for --% ee; HPLC: Chiralcel OD)H column, UV
-
detection at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow
ꢀ
1
1
1
1
.0 mL min , 20 ꢁC, R for (ꢀ±)2a: 9.1 min; (+±)2a:
f
2.- min. IR (CHCl ±: m = 2921, 17-8, 1490, 1457, 1-6-,
248, 1199, 10--, 785, 54- cm
4.-.6. (+±)-)Chloro)-)(4)chlorophenyl±propan)1)ol (1c±.
-
ꢀ1
1
25
D
;
H NMR (CDCl-–
Colorless oil (17.9 mg, 51% yield±, ½aꢁ ¼ þ10:0 (c 1.8± for
CCl ±: d 2.02 (s, -H, COCH ±, 2.29–2.4- (m, 2H, CH ,
21% ee; HPLC: Chiralcel OD)H column, UV detection at
2-0 nm, eluent: hexane/2)propanol = 98:2 flow 1.0 mL
4
-
2
H)2±, 4.12 (m, 1H, CH , H)1±, 4.21 (m, 1H, CH , H)1±,
2
2
ꢀ
1
4
5
5
.95 (dd, J = 5.9, 8.6 Hz, 1H, CH, H)-±, 7.29–7.-7 (m,
min , 20 ꢁC, R
All spectroscopic data are in agreement with those pub)
lished for racemic 1c.
f
for (+±)1c: 28.7 min; (ꢀ±)1c: -0.1 min.
1
-
H, CH, Ph±; C NMR (CDCl –CCl ±: d 20.61, -8.78,
-
4
-
9.58, 61.-1, 126.78, 128.-4, 128.59, 140.89, 170.10
+
(
C@O±; MS (EI± m/z (%±: 15- (55± [M ꢀOAc], 151 (100±,
1
6
24 (90±, 118 (100±, 117 (100±, 10- (100±, 91 (90±, 77 (90±,
- (-0±, 51 (55±, 4- (100±.
4.-.7. (ꢀ±)-)Chloro)-)(4)bromorophenyl±propyl acetate (2d±.
25
Light yellow wax (8.5 mg, 17% yield±, ½aꢁ ¼ ꢀ11:2
D
(c 0.85, CHCl ± for -0% ee; HPLC: Chiralcel OD)H column,
-
4
.-.2. (+±)-)Chloro)-)phenylpropan)1)ol (1a±. Colorless oil
UV detection at 2-0 nm, eluent: hexane/2)propanol = 98:2
25
ꢀ1
(
1-.1 mg, 45% yield±, ½aꢁ ¼ þ12:1 (c 1.-, CHCl ± for 29%
flow 1.0 mL min , 20 ꢁC, R
f
for (ꢀ±)2d: 10.0 min;
±: m = 29-2, 17-8, 1589,
-
D
-
25
ee; ½aꢁ ¼ þ-2:- (c 1.0, CHCl ± for 78% ee after double
(+±)2d: 11.8 min. IR (CHCl
1490, 1-6-, 1242, 1028, 816, 716, 6-2, 5-2 cm ; H NMR
D
-
ꢀ1 1
resolution; HPLC: Chiralcel OD)H column, UV detection

1566
A. Isleyen et al. / Tetrahedron: Asymmetry 17 (2006) 1561–1567
(
CDCl –CCl ±: d 2.02 (s, -H, COCH ±, 2.24–2.40 (m, 2H,
(20±, 196 (-0±, 194 (-0±, 181 (10±, 150 (20±, 116 (90±, 115
(100±, 10- (80±, 102 (80±, 89 (40±, 77 (70±, 6- (20±, 51 (-0±,
4- (100±.
-
4
-
CH , H)2±, 4.11 (m, 1H, CH , H)1±, 4.20 (m, 1H, CH , H)
1
2
2
2
±, 4.90 (dd, J = 6.0, 8.5 Hz, 1H, CH, H)-±, 7.24 (d,
J = 8.- Hz, 2H, CH, Ar±, 7.47 (d, J = 8.- Hz, 2H, CH,
1
-
Ar±; C NMR (CDCl –CCl ±: d 20.71, -8.81, 58.78,
4.-.12. (+±)-)Chloro)-)(2)bromorophenyl±propan)1)ol (1f±.
-
4
25
6
(
1.21, 122.51, 128.56, 1-4.4-, 1-1.91, 140.01, 170.18
Colorless oil (10.2 mg, 24% yield±, ½aꢁ ¼ þ4:4 (c 1.00,
D
+
C@O±; MS (EI± m/z (%±: 2-1 (-0± [M ꢀOAc], 2-0 (40±,
CHCl ± for 4-% ee; HPLC: Chiralcel OD)H column, UV
-
2
1
28 (-0±, 20- (10±, 194 (10±, 181 (10±, 150 (40±, 116 (80±,
15 (100±, 10- (-5±, 89 (-0±, 77 (40±, 6- (20±, 51 (20±, 4- (100±.
detection at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow
ꢀ
1
1.0 mL min , 20 ꢁC, Rf for (+±)1f: 41.- min; (ꢀ±)1f:
4
8.- min. All spectroscopic data are in agreement with
-
those published for racemic 1f.
4
.-.8. (+±)-)Chloro)-)(4)bromorophenyl±propan)1)ol (1d±.
25
Colorless oil (14.1 mg, --% yield±, ½aꢁ ¼ þ7:6
D
4
.-.1-. (ꢀ±)-)Bromo)-)phenylpropyl acetate (4±. Colorless
(
c 1.4, CHCl ± for 2-% ee; HPLC: Chiralcel OD)H column,
-
2
D
5
oil (8.4 mg, 19% yield±, ½aꢁ ¼ ꢀ28:7 (c 0.84± for -8% ee;
UV detection at 2-0 nm, eluent: hexane/2)propanol = 98:2
ꢀ
1
HPLC: Chiralcel OD)H column, UV detection at 2-0 nm,
flow 1.0 mL min , 20 ꢁC, R for (ꢀ±)1d: --.1 min; (+±)1d:
f
ꢀ1
eluent: hexane/2)propanol = 98:2 flow 1.0 mL min
,
-
4.5 min. All spectroscopic data are in agreement with
-
20 ꢁC, R for (ꢀ±)4: 10.1 min; (+±)4: 16.5 min. IR (CHCl ±:
those published for racemic 1d.
f
-
m = 2926, 174-, 1451, 1-6-, 1258, 1196, 1088, 1027, 801,
ꢀ
1
1
7
27, 626, 5-1 cm ; H NMR (CDCl –CCl ±: d 2.07 (s,
- 4
4
.-.9. (ꢀ±)-)Chloro)-)(2)fluorophenyl±propyl acetate (2e±.
25
-H, COCH ±, 2.46 (m, 1H, CH , H)2±, 2.59 (m, 1H, CH ,
- 2 2
Colorless oil (17.4 mg, 44% yield±, ½aꢁ ¼ ꢀ18:0 (c 1.7,
D
H)2±, 4.19 (m, 2H, CH , H)1±, 5.06 (t, J = 7.5 Hz, 1H,
2
CHCl ± for 24% ee; HPLC: Chiralcel OD)H column, UV
1-
-
CH, H)-±, 7.28–7.42 (m, 5H, CH, Ph±;
(CDCl –CCl ±: d 20.70, -8.89, 50.62, 62.2-, 127.2-,
28.50, 128.74, 141.-7, 170.08 (C@O±; HRMS (EI±:
C NMR
detection at 2-0 nm, eluent: hexane/2)propanol = 98:2 flow
ꢀ1
-
4
1
9
1
.0 mL min , 20 ꢁC, R for (ꢀ±)2e: 7.7 min; (+±)2e:
f
1
.2 min. IR (CHCl ±: m = 29-7, 1726, 1620, 1587, 1495,
+
-
ꢀ
1
1
M ꢀBr, found 177.0916, C11
H O requires 177.0916.
1- 2
-68, 125-, 1185, 1157, 10-2, 818, 721, 626, 5-6 cm ; H
NMR (CDCl –CCl ±: d 2.02 (s, -H, COCH ±, 2.29–2.45
m, 2H, CH , H)2±, 4.19 (m, 2H, CH , H)1±, 5.-1 (dd,
J = 5.9, 8.6 Hz, 1H, CH, H)-±, 7.0- (t, J = 7.6 Hz, 1H,
CH, Ar±, 7.15 (t, J = 7.6 Hz, 1H, CH, Ar±, 7.25–7.-0 (m,
H, CH, Ar±, 7.47 (td, J = 7.6, 1.4 Hz, 1H, CH, Ar±;
NMR (CDCl –CCl ±: d 20.68, -7.89, 52.22 (d, J =
.7 Hz±, 61.20, 115.67 (d, J = 22.0±, 124.51 (d, J =
.9 Hz±, 128.07 (d, J = 12.7 Hz±, 128.45 (d, J = -.0 Hz±,
-
4
-
4
.-.14. (+±)-)Bromo)-)phenylpropan)1)ol (-±. Yellow wax
(
25
2
2
(
9.9 mg, 27% yield±, ½aꢁ ¼ þ8:8 (c 0.99± for 21% ee;
D
HPLC: Chiralcel OD)H column, UV detection at 2-0 nm,
ꢀ1
1
-
eluent: hexane/2)propanol = 98:2 flow 1.0 mL min
,
1
C
2
0 ꢁC, R for (+±)-: -6.- min; (ꢀ±)-: 5-.2 min. All spectro)
f
-
4
scopic data agree with racemic -. Complete racemization of
compound - within a few days upon standing in n)hexane/
-
2
1
2)propanol solution (10:1, v/v± at +4 ꢁC was observed.
29.96 (d, J = 8.9 Hz±, 159.75 (d, J = 250.0±, 170.25
+
(
C@O±; MS (EI± m/z (%±: 171 (60± [M ꢀOAc], 169 (100±,
1
9
42 (80±, 1-5 (75±, 1-4 (100±, 121 (90±, 108 (40±, 101 (50±,
6 (40±, 95 (-5±, 75 (-0±, 4- (100±.
Acknowledgments
We thank the Scientific and Technical Research Council of
Turkey (TUBITAK, Grant No. TBAG)104T501± and the
Middle East Technical University Research Foundation
for the financial support.
4
.-.10. (+±)-)Chloro)-)(2)fluorophenyl±propan)1)ol (1e±.
25
Colorless oil (14.5 mg, 45% yield±, ½aꢁ ¼ þ6:7 (c
D
1
.4, CHCl ± for 25% ee; HPLC: Chiralcel OD)H column,
-
UV detection at 2-0 nm, eluent: hexane/2)propanol = 98:2
ꢀ
1
flow 1.0 mL min , 20 ꢁC, R for (+±)1e: 24.5 min; (ꢀ±)1e:
f
2
9.8 min. All spectroscopic data are in agreement with
-
References
those published for racemic 1e.
1
. Yoshida, K.; Horikoshi, Y.; Eta, M.; Chikazawa, M. O.;
Fukuda, Y.; Sato, H. Bioorg. Med. Chem. Lett. 1998, 8,
2967.
4
.-.11. (ꢀ±)-)Chloro)-)(2)bromorophenyl±propyl acetate
2
D
5
(
(
2f±. Colorless oil (14.0 mg, 28% yield±, ½aꢁ ¼ ꢀ11:8
c 1.4, CHCl ± for -6% ee; HPLC: Chiralcel OD)H column,
-
2. Geller, J. J. Am. Geriat. Soc. 1991, 39, 1208.
-. Isleyen, A.; Dogan, O¨ . Synthesis 2006, 1427.
4. Faber, K. Biotransformations in Organic Chemistry, -rd ed.;
UV detection at 2-0 nm, eluent: hexane/2)propanol = 98:2
ꢀ
1
flow 1.0 mL min , 20 ꢁC, R for (ꢀ±)2f: 9.0 min; (+±)2f:
f
9
1
.6 min. IR (CHCl ±: m = 2925, 17-2, 1471, 1-64, 1251,
Springer: Heidelberg, 1997.
-
ꢀ1 1
5
6
. Ladner, W. E.; Whitesides, G. M. J. Am. Chem. Soc. 1984,
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. (a± Zaks, A.; Klibanov, A. M. Science 1984, 224, 1249; (b±
Zaks, A.; Klibanov, A. M. Proc. Natl. Acad. Sci. U.S.A.
0-6, 809, 702, 62-, 54- cm ; H NMR (CDCl –CCl ±:
-
4
1
d 2.0- (s, -H, COCH ±, 2.2-–2.-2 (m, 2H, CH , H)2±,
4
CH, H)-±, 7.12 (td, J = 7.9, 1.4 Hz, 1H, CH, Ar±, 7.-4 (t,
J = 7.9 Hz, 1H, CH, Ar±, 7.5- (d, J = 7.9 Hz, 1H, CH,
Ar±, 7.59 (dd, J = 7.9, 1.4 Hz, 1H, CH, Ar± ; C NMR
-
2
.22 (m, 2H, CH , H)1±, 5.48 (dd, J = 5.2, 8.9 Hz, 1H,
2
1
985, 82, -192; (c± Sweers, H. M.; Wong, C.)H. J. Am. Chem.
Soc. 1986, 108, 6421; (d± Wang, Y.)F.; Wong, C.)H. J. Org.
Chem. 1988, 53, -127.
1
-
(
CDCl –CCl ±: d 20.75, -8.27, 57.99, 61.1-, 122.72,
- 4
7. (a± Hughes, D. L.; Bergan, J. J.; Amato, J. S.; Bhupaty, M.;
Leazer, J. L.; McNamara, J. M.; Sidler, D. R.; Reider, P. J.;
Grabowski, E. J. J. Org. Chem. 1990, 55, 6252, and references
1
28.01, 128.66, 129.64, 1-2.92, 140.1-, 170.2- (C@O±; MS
+
(
EI± m/z (%±: 2-1 (40± [M ꢀOAc], 2-0 (80±, 228 (60±, 20-

A. Isleyen et al. / Tetrahedron: Asymmetry 17 (2006) 1561–1567
1567
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